Infectious Disease Special Edition - Fall 2021 by McMahon Group

Volume 25 • Fall 2021

cordant s i D s d d A nt Delta Varia ID-19 Pandemic V Note to CO

Difference Between ID and Gastro C. diff Guides Is it Safe to Stop ABx for Neutropenia? Pan-Resistant C. auris Makes U.S. Appearance Cutting-Edge Issues in HIV

RUKOBIA: for heavily treatment-experienced (HTE) patients with multidrug-resistant HIV-1

INDICATION RUKOBIA, in combination with other antiretrovirals (ARVs), is indicated to treat HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current ARV regimen due to resistance, intolerance, or safety considerations. IMPORTANT SAFETY INFORMATION Contraindications • Do not use in patients with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA. • Do not use RUKOBIA in patients receiving strong cytochrome P450 (CYP)3A inducers, including but not limited to enzalutamide, carbamazepine, phenytoin, rifampin, mitotane, and St John’s wort (Hypericum perforatum). Warnings and precautions Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported with the use of RUKOBIA.

QTc Prolongation with Higher than Recommended Dosages: RUKOBIA at 2,400 mg twice daily has been shown to significantly prolong the QTc interval of the electrocardiogram. Use RUKOBIA with caution in patients with a history of QTc interval prolongation or in patients with relevant pre-existing cardiac disease or who are taking drugs with a known risk of Torsade de Pointes. Elderly patients may be more susceptible to drug-induced QT interval prolongation. Elevations in Hepatic Transaminases in Patients with Hepatitis B or C Virus Co-infection: • Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection. • Diligence should be applied in initiating or maintaining effective hepatitis B therapy when starting RUKOBIA in patients co-infected with hepatitis B. Adverse Reactions or Loss of Virologic Response Due to Drug Interactions with concomitant use of RUKOBIA and other drugs may occur (see Contraindications and Drug Interactions).

A first-in-class treatment with a novel mechanism of action1,2

Sustained rates of virologic suppression in patients who were previously unable to construct a viable regimen1 Robust CD4+ T-cell recovery, even in the most immunocompromised patients1 BRIGHTE is a Phase 3, partially randomized trial in HTE patients with confirmed HIV-1 RNA ≥400 copies/mL. The randomized cohort (double-blind, placebo-controlled through Day 8, then open-label) enrolled 272 patients who had 1 or 2 ARV classes remaining due to resistance, intolerability, or contraindications. At baseline, 73% had CD4+ T-cell counts of <200 cells/mm3 and 89% had HIV-1 RNA ≥1000 copies/mL. The primary endpoint was the adjusted mean decline in HIV-1 RNA at Day 8: 0.79 log10 copies/mL (RUKOBIA 600-mg BID + failing regimen, n=201) vs 0.17 log10 copies/mL (placebo + failing regimen, n=69); difference: -0.625 (95% CI: -0.810, -0.441); P<0.0001. At Week 96, 60% of patients were virologically suppressed, an increase from 53% at Week 24. The mean increase in CD4+ T-cell counts from baseline at Week 96 was 205 cells/mm3. In a subgroup summary analysis, those with a baseline CD4+ T-cell count <20 cells/mm3 had a mean increase of 240 cells/mm3. The most common adverse reaction (all grades) observed in ≥5% of patients was nausea (10%).1

Visit RUKOBIAhcp.com to learn more

Adverse reactions

Use in speciﬁc populations

• The most common adverse reaction (all grades, randomized cohort) observed in ≥5% of subjects was nausea (10%).

• Pregnancy: There are insufficient human data on the use of RUKOBIA during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. An Antiretroviral Pregnancy Registry has been established.

• 81% of adverse reactions reported with RUKOBIA were mild or moderate in severity. Drug interactions • See the full Prescribing Information for RUKOBIA for a complete list of significant drug interactions. • Temsavir may increase plasma concentrations of grazoprevir and voxilaprevir. Use an alternative hepatitis C virus regimen if possible. • Use the lowest possible starting dose for statins and monitor for statin-associated adverse events. • Patients receiving RUKOBIA should not take doses of estrogen-based therapies, including oral contraceptives, that contain more than 30 mcg/day of ethinyl estradiol. Caution is advised particularly in patients with additional risk factors for thromboembolic events.

• Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission, developing viral resistance, and adverse reactions in a breastfed infant. Please see Brief Summary of Prescribing Information for RUKOBIA on the following pages. ARV=antiretroviral; BID=twice daily; CI=confidence interval; HIV-1=human immunodeficiency virus type 1. References: 1. Data on file, ViiV Healthcare. 2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. https://clinicalinfo. hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf. Updated December 18, 2019. Accessed September 18, 2020.

BRIEF SUMMARY

RUKOBIA (fostemsavir) extended-release tablets, for oral use The following is a brief summary only; see full prescribing information for complete product information. CONTRAINDICATIONS RUKOBIA is contraindicated in patients: with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA; coadministered strong F\WRFKURPH 3 &<3 $ LQGXFHUV DV VLJQL¿FDQW GHFUHDVHV LQ WHPVDYLU (the active moiety of fostemsavir) plasma concentrations may occur which may result in loss of virologic response. These drugs include, but are not limited to: Androgen receptor inhibitor: Enzalutamide; Anticonvulsants: Carbamazepine, phenytoin; Antimycobacterial: Rifampin; Antineoplastic: Mitotane; Herbal product: St John’s wort (Hypericum perforatum). WARNINGS AND PRECAUTIONS Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including RUKOBIA. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may GHYHORS DQ LQÀDPPDWRU\ UHVSRQVH WR LQGROHQW RU UHVLGXDO RSSRUWXQLVWLF infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, Guillain-Barré syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment. QTc Prolongation with Higher than Recommended Dosages: RUKOBIA at 2,400 mg twice daily, WLPHV WKH UHFRPPHQGHG GDLO\ GRVH KDV EHHQ VKRZQ WR VLJQL¿FDQWO\ prolong the QTc interval of the electrocardiogram. RUKOBIA should be used with caution in patients with a history of QTc interval prolongation, when coadministered with a drug with a known risk of Torsade de Pointes, or in patients with relevant pre-existing cardiac disease. Elderly patients may be more susceptible to drug-induced QT interval prolongation. Elevations in Hepatic Transaminases in Patients with Hepatitis B or C Virus Co-infection: Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection. Elevations in hepatic transaminases were observed in a greater proportion of subjects with HBV and/or HCV co-infection compared with those with HIV mono-infection. Some of these elevations in transaminases were consistent with hepatitis B reactivation, particularly in the setting where anti-hepatitis therapy was withdrawn. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting RUKOBIA in patients co-infected with hepatitis B. Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The concomitant use of RUKOBIA and certain other drugs PD\ UHVXOW LQ NQRZQ RU SRWHQWLDOO\ VLJQL¿FDQW GUXJ LQWHUDFWLRQV VRPH RI which may lead to: Loss of therapeutic effect of RUKOBIA and possible development of resistance due to reduced exposure of temsavir; possible prolongation of QTc interval from increased exposure to temsavir. See Drug Interactions for steps to prevent or manage these possible and known VLJQL¿FDQW GUXJ LQWHUDFWLRQV LQFOXGLQJ GRVLQJ UHFRPPHQGDWLRQV &RQVLGHU the potential for drug interactions prior to and during therapy with RUKOBIA, review concomitant medications during therapy with RUKOBIA, and monitor for the adverse reactions associated with the concomitant drugs. ADVERSE REACTIONS Clinical Trials Experience: A total of 620 subjects with HIV-1 infection received at least one dose of RUKOBIA as part of a controlled clinical trial. The primary safety assessment of RUKOBIA is based on 96 weeks of data from a Phase 3 partially randomized, international, multicenter, double-blind, placebo-controlled trial (BRIGHTE) conducted in 371 heavily treatmentexperienced adult subjects. A total of 370 subjects (271 randomized and 99 nonrandomized) received at least 1 dose of RUKOBIA 600 mg twice daily in the BRIGHTE trial. Overall, most (81%) of the adverse reactions reported with RUKOBIA were mild or moderate in severity. The proportion of subjects who discontinued treatment with RUKOBIA due to an adverse event was 7% at Week 96 (randomized: 5% and nonrandomized: 12%). The most common adverse events leading to discontinuation were related to infections (3% of subjects receiving RUKOBIA). Serious drug reactions occurred in 3% of VXEMHFWV DQG LQFOXGHG FDVHV RI VHYHUH LPPXQH UHFRQVWLWXWLRQ LQÀDPPDWRU\ syndrome. Data from the randomized cohort form the basis of the safety DVVHVVPHQW RI 58.2%,$ EHFDXVH WKH SUHVHQFH RI VLJQL¿FDQW FRPRUELG illness in the nonrandomized cohort (associated with advanced HIV infection) may confound the assessment of causality. Adverse reactions (all JUDGHV UHSRUWHG LQ RI VXEMHFWV LQ WKH UDQGRPL]HG FRKRUW LQ WKH :HHN 96 analysis are listed in Table 1.

Table 1. Adverse Reactionsa *UDGHV WR 5HSRUWHG LQ RI 6XEMHFWV Receiving RUKOBIA plus OBT in the BRIGHTE Trial, Randomized Cohort (Week 96 Analysis) Adverse Reaction Nausea Diarrhea Headache Abdominal painc Dyspepsia Fatigued Rashe Sleep disturbancef Immune Reconstitution ,QÀDPPDWRU\ 6\QGURPH Somnolence Vomiting

RUKOBIA plus OBT Q b 10% 4% 4% 3% 3% 3% 3% 3% 2% 2% 2%

Frequencies of adverse reactions are based on all treatment-emergent adverse events attributed to study drug by the investigator. b Of the 272 subjects enrolled in the randomized cohort, 1 subject who received placebo withdrew from the trial prior to receiving RUKOBIA in the open-label phase of the trial. c Includes pooled terms: abdominal discomfort, abdominal pain, and abdominal pain upper. d Includes pooled terms: fatigue and asthenia. e Includes pooled terms: rash, rash generalized, rash maculo-papular, rash pruritic, and dermatitis allergic. f ,QFOXGHV SRROHG WHUPV LQVRPQLD VOHHS GH¿FLW VOHHS GLVRUGHU DEQRUPDO GUHDPV a

Adverse reactions in the nonrandomized cohort were similar to those observed in the randomized cohort. The most common adverse reactions reported in nonrandomized subjects were fatigue (7%), nausea (6%), and diarrhea (6%). Less Common Adverse Reactions: The following adverse reactions occurred in <2% of subjects receiving RUKOBIA in the randomized cohort of the BRIGHTE trial. These events have been included based on the assessment of potential causal relationship and were also reported in the nonrandomized cohort. – Cardiac Disorders: Electrocardiogram QT prolonged. All reports were asymptomatic. – Musculoskeletal Disorders: Myalgia. – Nervous System Disorders: Dizziness, dysgeusia, neuropathy peripheral (includes pooled terms: neuropathy peripheral and peripheral sensory neuropathy). – Skin and Subcutaneous Tissue Disorders: Pruritus. Laboratory Abnormalities: Selected laboratory abnormalities (Grades 3 to 4) with a worsening grade from baseline and representing the worst-grade WR[LFLW\ LQ RI VXEMHFWV LQ WKH UDQGRPL]HG FRKRUW RI WKH %5,*+7( WULDO DUH presented in Table 2. 7DEOH 6HOHFWHG /DERUDWRU\ $EQRUPDOLWLHV *UDGHV WR 5HSRUWHG LQ RI 6XEMHFWV LQ WKH 5DQGRPL]HG &RKRUW 5HFHLYLQJ 58.2%,$ SOXV OBT in the BRIGHTE Trial (Week 96 Analysis) Laboratory Parameter Preferred Term ALT (>5.0 x ULN) AST (>5.0 x ULN) Direct bilirubin (>ULN)b %LOLUXELQ [ 8/1

&KROHVWHURO PJ G/ b Creatinine (>1.8 x ULN or 1.5 x baseline) &UHDWLQH NLQDVH [ 8/1

Hemoglobin (<9.0 g/dL) Hyperglycemia (>250 mg/dL) Lipase (>3.0 x ULN) /'/ &KROHVWHURO PJ G/

1HXWURSKLOV FHOOV PP3) Triglycerides (>500 mg/dL) Urate (>12 mg/dL)

RUKOBIA plus OBT Q a) 5% 4% 7% 3% 5% 19% 2% 6% 4% 5% 4% 4% 5% 3%

ULN = Upper limit of normal. a Percentages were calculated based on the number of subjects with post-baseline toxicity grades for each laboratory parameter (n = 221 for cholesterol and triglycerides, n = 216 for LDL cholesterol, and n = 268 for all other parameters). b Grade 3 only (no Grade 4 values reported).

The incidence of selected laboratory abnormalities (Grades 3 to 4) in the nonrandomized cohort were overall consistent with those of the randomized cohort, with the exception of direct bilirubin (14% versus 7%), bilirubin (6% (cont’d on next page)

BRIEF SUMMARY

RUKOBIA (fostemsavir) extended-release tablets, for oral use (cont’d) versus 3%), lipase (10% versus 5%), triglycerides (10% versus 5%), neutrophils (7% versus 4%), and leukocytes (6% versus 1%), respectively. Changes in Serum Creatinine: Clinically relevant increases in serum FUHDWLQLQH KDYH SULPDULO\ RFFXUUHG LQ SDWLHQWV ZLWK LGHQWL¿DEOH ULVN IDFWRUV for reduced renal function, including pre-existing medical history of renal disease and/or concomitant medications known to cause increases in creatinine. A causal association between RUKOBIA and elevation in serum creatinine has not been established. Changes in Direct Bilirubin: Increases in direct (conjugated) bilirubin have been observed following treatment with 58.2%,$ 7DEOH &DVHV RI FOLQLFDO VLJQL¿FDQFH ZHUH XQFRPPRQ DQG were confounded by the presence of intercurrent serious comorbid events (e.g., sepsis, cholangiocarcinoma, or other complications of viral hepatitis co-infection). In the remaining cases, elevations in direct bilirubin (without clinical jaundice) were typically transient, occurred without increases in liver transaminases, and resolved on continued RUKOBIA. Changes in ALT and AST in Subjects with Hepatitis B and/or Hepatitis C Virus Co-infection: A total of 29 subjects with Hepatitis B and/or Hepatitis C co-infection were enrolled in the BRIGHTE trial (randomized and nonrandomized cohorts combined). Grade 3 and 4 elevations in ALT and AST occurred in 14% of these subjects compared with 3% (ALT) and 2% (AST) of subjects without viral hepatitis co-infection. Some of these elevations in transaminases were consistent with hepatitis B reactivation particularly in the setting where antihepatitis therapy was withdrawn. DRUG INTERACTIONS Potential for RUKOBIA to Affect Other Drugs: Temsavir may increase plasma concentrations of grazoprevir or voxilaprevir to a clinically relevant extent due to organic anion transporting polypeptide (OATP)1B1/3 inhibition. When RUKOBIA was coadministered with oral contraceptives, temsavir increased concentrations of ethinyl estradiol. Potential for Other Drugs to Affect RUKOBIA: Coadministration of RUKOBIA with rifampin, a strong &<3 $ LQGXFHU VLJQL¿FDQWO\ GHFUHDVHV WHPVDYLU SODVPD FRQFHQWUDWLRQV The use of RUKOBIA with drugs that are strong inducers of CYP3A4 can VLJQL¿FDQWO\ GHFUHDVH WHPVDYLU SODVPD FRQFHQWUDWLRQV ZKLFK PD\ OHDG WR loss of virologic response. (VWDEOLVKHG DQG 2WKHU 3RWHQWLDOO\ 6LJQLÀFDQW Drug Interactions: Information regarding potential drug interactions with RUKOBIA is provided below. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss RI HI¿FDF\ • Androgen receptor inhibitor: Enzalutamide—Coadministration is contraindicated due to potential for loss of therapeutic effect to RUKOBIA. • Anticonvulsants: Carbamazepine, Phenytoin—Coadministration is contraindicated due to potential for loss of therapeutic effect to RUKOBIA. • Antimycobacterial: Rifampin—Coadministration is contraindicated due to potential for loss of therapeutic effect to RUKOBIA. • Antineoplastic: Mitotane—Coadministration is contraindicated due to potential for loss of therapeutic effect to RUKOBIA. • Herbal product: St John’s wort (Hypericum perforatum)— Coadministration is contraindicated due to potential for loss of therapeutic effect to RUKOBIA. • Hepatitis C virus direct-acting antivirals: Grazoprevir, Voxilaprevir— Coadministration may increase exposures of grazoprevir or voxilaprevir; however, the magnitude of increase in exposure is unknown. Increased exposures of grazoprevir may increase the risk of ALT elevations. Use an alternative HCV regimen if possible. • Oral contraceptive: Ethinyl estradiol—Ethinyl estradiol daily dose VKRXOG QRW H[FHHG PFJ Caution is advised particularly in patients with additional risk factors for thromboembolic events. • Statins: Rosuvastatin, Atorvastatin, Fluvastatin, Pitavastatin, Simvastatin—Use the lowest possible starting dose for statins and monitor for statin-associated adverse events. Consult the full Prescribing Information for potential drug interactions; this list is not all-inclusive. Drugs that Prolong QT Interval: Coadministration of RUKOBIA with a drug with a known risk of Torsade de Pointes may increase the risk of Torsade de Pointes. Use RUKOBIA with caution when coadministered with drugs with a known risk of Torsade de Pointes. Drugs without Clinically 6LJQLÀFDQW ,QWHUDFWLRQV ZLWK 58.2%,$ Based on drug interaction study results, the following drugs can be coadministered with RUKOBIA without a dose adjustment: atazanavir/ritonavir, buprenorphine/naloxone, cobicistat, darunavir/cobicistat, darunavir/ritonavir with and without etravirine, etravirine,

famotidine, maraviroc, methadone, norethindrone, raltegravir, ritonavir, rifabutin with and without ritonavir, tenofovir disoproxil fumarate. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to RUKOBIA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary: 7KHUH DUH LQVXI¿FLHQW KXPDQ GDWD RQ WKH use of RUKOBIA during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. In animal reproduction studies, oral administration of fostemsavir to pregnant rats and rabbits during organogenesis resulted in no adverse developmental effects at clinically relevant temsavir exposures (see Data). Lactation: Risk Summary: The Centers for Disease Control and Prevention recommends that HIV-1– infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. It is not known whether RUKOBIA is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, fostemsavir-related drug was present in rat milk. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving RUKOBIA. Pediatric Use: The safety and effectiveness of RUKOBIA have not been established in pediatric patients. Geriatric Use: &OLQLFDO WULDOV RI 58.2%,$ GLG QRW LQFOXGH VXI¿FLHQW QXPEHUV RI VXEMHFWV aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in administration RI 58.2%,$ LQ HOGHUO\ SDWLHQWV UHÀHFWLQJ JUHDWHU IUHTXHQF\ RI GHFUHDVHG hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients may be more susceptible to drug-induced QT interval prolongation. Renal Impairment: No dosage adjustment is required for patients with renal impairment or those on hemodialysis. Hepatic Impairment: No dosage adjustment is required in patients with mild to severe hepatic impairment (Child-Pugh Score A, B, or C). OVERDOSAGE 7KHUH LV QR NQRZQ VSHFL¿F WUHDWPHQW IRU RYHUGRVH ZLWK 58.2%,$ ,I overdose occurs, the patient should be monitored and standard supportive treatment applied as required, including monitoring of vital signs and ECG (QT interval), as well as observation of the clinical status of the patient. As fostemsavir is highly bound to plasma proteins, it is unlikely that it will be VLJQL¿FDQWO\ UHPRYHG E\ GLDO\VLV

ViiV Healthcare Research Triangle Park, NC 27709

GlaxoSmithKline Research Triangle Park, NC 27709

Fall 2021 8 10 18 25 26 28

Editorial: Why Are We Still Talking About This?

32 34 35 36 38 42

When Is it Safe to Stop ABx for Febrile Neutropenia?

From

Delta Blues: Delta Variant Adds Discordant Note to COVID-19 HIV News Antibiotic Use Highly Tied to C. diff in Hospitals What's the Difference Between ID and Gastro C. difﬁcile Recommendations? Is it Really a Penicillin Allergy? PharmD Intervention Improves Antibiotic Use, Decreases Costs

2-Dose Hepatitis B Vaccine More Seroprotective, Cost-Effective WHO's European Region Making Progress Toward HBV Control Neonatal HBV: Where Are We in Preventing Chronic Infection? Pan-Resistant C. auris Spreading in Texas and Washington, D.C. Pulmonary Infections Due to Endemic Fungi: Misdiagnosis Often the Norm

Parasite Develops Multidrug Resistance to Treatment; Y U Dog Should We Worry About Endangered Parasites?

46 ACIP Aligns Pediatric and Adult Rabies PrEP Schedule

IDSE Reviews

49 The Importance of Rapid Diagnostic Testing and Stewardship For Infectious Disease Management By Karen Fong, PharmD, BCIDP

The Persistence of PrEP: Essential For Ending HIV By Milena Murray, PharmD, MSc, BCIDP, AAHIVP

69 Antibiotic Use in the Emergency Department: A 2-Door Opportunity for Stewardship By Karen Fong, PharmD, BCIDP

81 Cutting Edge Issues in HIV Clinical Management: No End to the Dynamism of HIV Medicine By Rajesh T. Gandhi, MD

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IDSE EDITORIAL ADVISORY BOARD John A. Bosso, PharmD, FCCP, FIDSA

Debra A. Goff, PharmD

Medical University of South Carolina Charleston, South Carolina

The Ohio State University Wexner Medical Center Columbus, Ohio

Philip A. Brunell, MD

Nancy D. Hanson, PhD

Emeritus, National Institutes of Health Bethesda, Maryland

Creighton University School of Medicine Omaha, Nebraska

Paul P. Cook, MD, FACP, FIDSA James S. Lewis II, PharmD, FIDSA Brody School of Medicine

Oregon Health & Science University Portland, Oregon

East Carolina University Greenville, North Carolina

Jonathan Z. Li, MD

Brian Currie, MD, MPH

Emeritus, Albert Einstein College of Medicine Harvard Medical School Brigham and Women’s Hospital Monteﬁore Medical Center Boston, Massachusetts New York, New York Stuart Campbell Ray, MD, FIDSA

Thomas M. File Jr, MD, MSc, MACP, FIDSA, FCCP

Johns Hopkins University School of Medicine Baltimore, Maryland

Summa Health Akron, Ohio Northeast Ohio Medical University Rootstown, Ohio

Michael J. Rybak, PharmD, MPH, PhD, FCCP, FIDSA, FIDP

Rajesh T. Gandhi, MD, FIDSA

Wayne State University Detroit, Michigan

Harvard University Center for AIDS Research Massachusetts General Hospital Boston, Mass.

Shmuel Shoham, MD, FIDSA,

Julia Garcia-Diaz, MD

Mark H. Wilcox, MD, FRCPath

Ochsner Health System New Orleans, Louisiana

Leeds Teaching Hospitals NHS Trust University of Leeds Leeds, United Kingdom

Johns Hopkins University Medical School, Baltimore, Maryland

EDITORIAL

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Marie Rosenthal, MS

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EDITOR’S BLOG:

Why Are We Still Talking About This? Every week when I take my Weim, Lizzie, to agility training, I pass this lawn sign that really irks me: “Maskism = Marxism.” And it’s not because I suspect the person, who I do not know, did not read “The Communist Manifesto.” It’s because this symbolizes all that is wrong with the public health effort to fight the COVID-19 pandemic. Here we are some 19 months into the pandemic, and there is still resistance to practicing measures to reduce transmission and—if not end the circulation of SARS-CoV-2 strains—at least end the pandemic spread of the virus and its variants. Where did the message go so wrong and change from a sense of public responsibility and a “we-are-all-in-this-together” fight to a political “youcan’t-tell-me-what-to-do because-I-have rights” response? Yes, everyone has rights, but my rights end where yours begin. We don’t have the right to act in a way that endangers others. Since we began with “maskism,” let’s talk about masks. For me, who is still pretty much sequestering at home because I am fortunate to work from home, it’s no big deal to wear a mask when I go somewhere, even though I am fully vaccinated. But I might feel differently if I were a grocery store clerk and had to wear it for eight hours. Is there a way to make mask wearing more comfortable for people who have to wear them for long periods, such as more frequent breaks where they can take them off? Would that be out of order for management to schedule? If masks are going to be required, I think companies need to find ways to make the adjustment easier for workers. But I still think that wearing a mask in public is better than getting or passing COVID-19 to others. But what about masking in schools? Again, I am fortunate because my children are grown, and I feel for teachers and parents trying to enforce mask wearing and social distancing among any group of kids. Just as in restaurants, how can that possibly help in the cafeteria? And if they are spreading germs in the cafeteria, does the rest of the day matter? I honestly don’t know. But I do think wearing a mask sometimes is better than not wearing one at all, and data seem to support masking in schools. In one study that looked at schools in two Arizona counties, those that adopted mask wearing early suffered fewer outbreaks than those who waited to enact mask requirements or never enacted them. From July 15 to Aug. 31, there were 191 outbreaks among the schools: 113 in schools that never required a mask; 62 in schools that decided to implement masks later; and 16 in schools with early mask requirements (MMWR Morb Mortal Wkly Rep 2021 Sep 24. http://dx.doi.org/10.15585/mmwr.mm7039e1external icon). Public health messages have to cross all barriers. COVID-19 is the leading cause of death in this country, and this virus has killed more 650,000 Americans. So, why are we still arguing about masks? We must find ways to make them more bearable for people who have to wear them for hours, but next to vaccination—and I am not going to even go there—masking and social distancing are the best measures we have. And your right to not wear a mask ends at my right not to get COVID-19. —Marie Rosenthal, MS The views expressed here belong to the author and do not necessarily reflect those of the publisher.

Continuous COVID-19 news for ID specialists at www.idse.net/Section/Covid-19/664

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IDSE.NET

ROSENTH

e had finally figured out the rhythm of COVID-19. There were ways to detect SARS-CoV-2, treat SARS-CoV-2 infection and prevent COVID-19. Cases had plateaued and were starting to decline, and people began going about their business, going back to work, visiting friends and family, taking vacations and enjoying dinner in restaurants. However, some people had their own take on the pandemic and resisted the mitigation actions that were still in place, particularly mask wearing and vaccination, and as the United States headed into those hot, steamy summer days, there was yet another surge. In late June, the seven-day moving average of reported cases was around 12,000. On July 27, it was more than 60,000, which was similar to the case rate seen before COVID-19 vaccines became available, according to the CDC. By Sept. 7, the United States passed a landmark: 40 million positive cases of COVID-19 since the start of the pandemic, with more than 4 million occurring in just a couple of weeks in August. Along with that increase in cases, the country saw an increase in hospitalizations and deaths, mostly among the unvaccinated. By Sept. 8, a total of 652,480 people had died from COVID19 in the United States—one in every 500 people. On Sept. 21, the nation hit the saddest milestone: U.S. deaths from COVID-19 totaled 676,200, more than the estimated 675,000 Americans who died in the 1918-1919 influenza pandemic, making COVID-19 the worst pandemic in U.S. history. More than 9,000 people were hospitalized, and more than 1,500 were dying each day.

Striking a Dominant Chord The delta variant quickly surpassed the wild-type strain and other variants to become the dominant strain circulating in the United States. Of sequenced specimens, 99% have been identified as delta by the CDC’s surveillance laboratories as of Sept. 24. In fact, the wild-type SARS-CoV-2 strain can no longer be detected, and “variants of the virus that causes COVID-19 are now responsible for all cases in the United States,” the CDC said. “This variant [delta] is certainly a concern because of the evidence that it is more transmissible,” said Jay C. Butler, MD, FIDSA, the deputy director for infectious diseases at the CDC during a press briefing in July. “More transmissible” might have been an understatement, because the delta variant’s basic reproduction number (R0) is twice the original SARS-CoV-2 strain (R0, 5 vs. 2.5). Mutations are always a concern because there is a chance they can develop resistance to therapeutics or reduce vaccine efficacy, according to Dr. Butler. All of the variants have been a concern, but none more so than B.1.617.2, commonly called delta, because of its transmissibility and some data that point to it causing more severe disease, according to CDC Director Rochelle P. Walensky, MD.

July 7

Daily new COVID-19 cases in the United States. By July 7, 2021, the delta variant was the dominant strain of the coronavirus. Source: CDC “It is one of the most infectious respiratory viruses we know of and that I have seen in my 20-year career,” she said at a briefing this summer. Emergency departments (EDs) and hospitals started filling up, which increased the unease. One ED at the UC Davis Medical Center, in San Diego, saw a 33% increase in COVID-19 patients during the first week of August. The proportion of ED patients diagnosed with COVID-19 had tripled between June 21, when it was 0.6%, and Sept. 5, when it was 1.8%, according to the CDC. Most of the cases occurred in people who had not received COVID-19 vaccination, and states with low vaccination rates, mostly in the South and West, saw the worst of the surge, but delta affected every state in the country. Several states declared crisis standards of care. Rationing of care in Alaska, Idaho, Kentucky, Montana, New Mexico, Ohio and Wisconsin began in September due to a shortage of beds and hospital staff. Physicians were triaging patients based on their prognosis (Crisis Standards of Care: Summary of a Workshop Series. https://www.ncbi.nlm.nih.gov/books/ NBK32753/). “Our health care professionals are accustomed to providing the best care they possibly can for their patients, but resources are now stretched to a point that most of us never expected to see in our careers. Difficult decisions will need to be made over whose care should be prioritized, and we’re here to support our providers to provide the best care for as many patients as possible during these challenging times,” said Alaska’s Chief Medical Officer Anne Zink, MD, FACEP-ASTHO. The CDC formed COVID-19 rapid response teams to help states, but by press time we had not heard from the agency about how many teams were dispatched.

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Some data indicate the delta variant might cause more severe illness than previous variants in unvaccinated people. In two different studies from Canada and Scotland, patients infected with the delta variant were more likely to be hospitalized than patients infected with the alpha variant (B.1.1.17) or wild-type SARS-CoV-2. The Canadian study, which looked at variants of concern (VOC) that were circulating in Canada from February to June found that the adjusted increase in risk associated with delta was 108% (80%-138%) for hospitalization, 234% (164%-331%) for ICU admission and 132% (47%-230%) for death (MedRxiv 2021 Aug 4. doi:10.1101/2021.07.05.21260050 https://bit.ly/3ueZmm1-IDSE). “The progressive increase in transmissibility and virulence of SARS-CoV-2 VOCs will result in a significantly larger, and more deadly, pandemic than would have occurred in the absence of VOC emergence,” the authors concluded. The Scottish study looked at surveillance data between April 1 and June 6. There were 19,543 confirmed cases of COVID-19, of whom 377 were hospitalized. Although they saw more younger people hospitalized than earlier in the pandemic, most of the hospitalizations were among older people and people with multiple comorbidities. “Risk of COVID-19 hospital admission was approximately doubled in those with the Delta VOC when compared to the Alpha VOC, with risk of admission particularly increased in those with five or more relevant comorbidities,” they wrote (Lancet 2021;397[10293]:2461-2462 https://bit.ly/3i8zofi-IDSE). In the United States, the vast majority of hospitalizations and death caused by COVID-19 during the surge were among unvaccinated people. Low vaccine uptake is what drove the most recent surge, according to Dr. Butler. When delta began to assert dominance, only 49% of people in the United States were fully vaccinated, and the experts who worried that low vaccination rates and disregard of mitigation efforts would allow the virus more opportunities to mutate were proved correct.

“CDC data continue to show the power of vaccination, with recent reports showing a fivefold reduction in the risk for infection, 10-fold reduction in the risk for hospitalization, and 11-fold reduction in the risk for death after vaccination,” said Dr. Walensky on Sept. 24. An analysis by Public Health England found that the PfizerBioNTech messenger RNA (mRNA) vaccine (Comirnaty) was 96% effective against hospitalization, which is comparable to the effectiveness against the alpha variant (https://bit. ly/3m1mT6m-IDSE), but reports from Israel claim the vaccine is only 64% effective against delta in preventing infection and symptomatic illness. “Nevertheless, the vaccine maintains an effectiveness rate of about 93% in preventing serious illness and hospitalizations, they said (https://www.gov.il/en/ departments/news/05072021-03). Recent data published by the CDC examined vaccine efficacy across nine states based on 32,867 medical encounters, including 14,636 hospitalizations between June and August 2021, during the time when the delta variant became predominant in the United States. In the analysis, the Moderna COVID-19 vaccine efficacy against COVID-19 urgent care or ED visit was 92% (95% CI, 89%-93%) and against hospitalization was 95% (95% CI, 92%-97%) at a median of 96 and 106 days, respectively, after vaccination. Across all age groups, efficacy was reported to be significantly higher for the Moderna vaccine than other COVID-19 vaccines (MMWR Morb Mortal Wky Rep 2021;70[37]:1291-1293). A study from Canada found that both mRNA vaccines were highly effective at preventing hospitalizations, but less effective in preventing symptomatic infection (Pfizer, 87%; Moderna, 72%) (medRxiv 2021 Jul 3. https://doi.org/10.1101 /2021.06.28.21259420; https://bit. ly/3o7ZfYt-IDSE). The Johnson & Johnson singledose adenovirus vaccine has an efficacy of about 85% in protecting against severe disease, hospitalization and death, according to one trial (N Engl J Med 2021;384:2187-2201). Breakthrough infections have been reported in people who are fully vaccinated. A May 28 report said there were 10,262 breakthrough infections in 46 states as of April 30, out of 101 million people who were fully vaccinated (MMWR Morb Mortal Wkly Rep 2021;70[21]:792-793).

On Sept. 21, U.S. deaths from COVID-19 surpassed those who died in the 1918-1919 influenza pandemic.

Blue Note Data continue to come in about whether the COVID-19 vaccines are effective against the infection. Early data point to high efficacy for hospitalizations and death, but lower efficacy against infection.

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Please contact your AbbVie representative for more information. LEARN MORE AT DALVANCE.COM

Delta Blues continued from page 12

Even if the rate is low, there is concern about continued transmission, according to Dr. Walensky. “Some vaccinated people infected with the delta variant after vaccination may be contagious and spread the virus to others,” she said. “The science is worrisome.” Vaccination has arguably been the most contentious COVID19 issue, with many people still hesitant to receive their shots. Many states, health systems and long-term care facilities, and companies have made COVID-19 vaccination a condition of employment. In fact, tired of cajoling and begging people to be vaccinated, President Joe Biden announced a similar policy for federal workers and federal vendors in September. In addition, he expanded his requirement that all nursing home employees who treat Medicare and Medicaid patients be vaccinated to include all health care workers who work in hospitals, home health care or other medical facilities that accept Medicare and Medicaid patients. “If you are seeking care at a health facility, you should be able to know that the people treating you are vaccinated. Simple. Straightforward. Period,” he said. But it isn’t quite so simple. Several states, including California and New York, have also said state workers must be vaccinated as a condition of employment, even though they faced staff shortages. But many people are complying. As Infectious Disease Special Edition went to press, most of New York's health care workers were lining up for the shot by the Sept. 27 deadline: 87% of hospital workers and 92% of longterm care staff had received at least one vaccine. California is seeing similar success. On Sept. 22, the FDA approved a booster dose of the PfizerBioNTech vaccine for people ages 65 years and older and individuals at high risk for severe COVID-19, as well as those whose work puts them at risk for COVID-19 infection, such as health care workers and teachers. Among the data considered for the approval, the FDA looked at data presented from Israel that included an analysis of about 1.1 million people, 60 years and older, who were eligible for a booster dose of the vaccine between July 30 and Aug. 31. The booster dose restored very high levels of protection against COVID-19 infection and severe disease against the delta strain. People who received a booster dose were less likely, by a factor of 11.3 (95% CI, 10.412.3), to develop a confirmed infection and less likely by a factor of 19.5 (95% CI, 21.9-29.5) to develop severe disease than those who were fully vaccinated but did not receive a booster dose (N Engl J Med 2021 Sep 15. doi:10.1056/NEJMoa2114255 https://bit.ly/3uh1J7U-idse). With news of waning immunity came recommendations for boosters and third doses. The FDA expanded its emergency

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use authorization (EUA) and the CDC recommended a third dose for anyone with a weakened immune system, such as those with cancer, in early September. Then the FDA expanded the EUA for the Pfizer-BioNTech mRNA vaccine to allow boosters six months after the primary series for a wide group of people, including those with an occupational exposure such as health care workers, and the CDC endorsed that recommendation. Not everyone agrees that those with an occupational exposure should receive boosters. In fact, the Advisory Committee on Immunization Practices, which advises the CDC, did not recommend it. In a highly unusual move, Dr. Walensky decided not to accept that recommendation and instead aligned with the FDA’s EUA. “As CDC Director, it is my job to recognize where our actions can have the greatest impact. At CDC, we are tasked with analyzing complex, often imperfect data to make concrete recommendations that optimize health. In a pandemic, even with uncertainty, we must take actions that we anticipate will do the greatest good,” Dr. Walensky said in a statement, released after that recommendation was made. “I believe we can best serve the nation’s public health needs by providing booster doses for the elderly, those in long-term care facilities, people with underlying medical conditions, and for adults at high risk of disease from occupational and institutional exposures to COVID-19. This aligns with the FDA’s booster authorization and makes these groups eligible for a booster shot,” she added. As of Sept. 29, only 55.5% of Americans were fully vaccinated, but 64.5% have had at least one dose. If one just looks at adults, 66.8% are fully vaccinated and 77.2% have had at least one dose, and 2.4 million people have received a third dose. What is clear is there is no coda for COVID-19 more than 19 months into the pandemic, and although America is not recommending that everyone sequester at home, mitigation actions, such as masking and social distancing, have been reinstituted in many places, even for those who are vaccinated. So, the rhythm of COVID-19 has adapted once again. The way out of the pandemic, according to public health officials, remains vaccination, and the goal is to vaccinate the unvaccinated, and give boosters to those who need it to increase their immune response against infection. “Vaccinating the unvaccinated remains a high priority, and we must not lose sight of this goal with all the discussion around booster shots. That is why we will continue our efforts to reach those who are not yet vaccinated, using a combination of increased access and community-based information campaigns to help people get accurate scientific information from sources they trust,” said Vice Adm. Vivek J. Murthy, MD, MBA, the surgeon general. “Getting our nation vaccinated remains our most important ■ path out of this pandemic,” he said.

Supported by

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

National Guidance, Local Implementation: Considerations for Local Blood Culture Identification Guideline Development Using the BioFire® Blood Culture Identification 2 (BCID2) Panel Introduction Locally developed testing and treatment guidelines may complement implementation of the BioFire® Blood Culture Identification 2 (BCID2) Panel for bloodstream infections. The BioFire BCID2 Panel may be incorporated by either updating existing local guidelines or the adoption of national guidelines to create local syndromic testing guidelines. Together, local guidelines

and the BioFire BCID2 Panel help to facilitate clinician decision making in routine patient care activities. Many aspects should be considered when approaching the development of these clinical documents including interdisciplinary stakeholder involvement, approaches for adapting national guidelines for local implementation, ensuring accurate local antibiograms for assisting in document development,

Table. Example Local Treatment Guidancea BioFire BCID2 Panel Result

Preferred Therapy

Special Notes/Comments

Staphylococcus aureus MREJ+mecA detected

Vancomycin

ID consult recommended for all SA-BSIb

Klebsiella pneumoniae BlaNDM detected

Aztreonam + ceftazidime/ avibactam OR cefiderocol OR polymyxin

ID consult recommended for all carbapenemase resultsb

Escherichia coli No resistance detected

Ceftriaxone

Ceftriaxone 91% susceptible overall (99% in absence of resistance detection)c

Sample and local guideline considerations of therapy do not supersede clinical judgment based on clinical status, patient history, and local epidemiology of resistance. b Where available. c

Values as example only.

BCID2, BioFire® Blood Culture Identification 2 Panel; ID, infectious disease; SA-BSI, Staphylococcus aureus bloodstream infection Courtesy of BioFire Diagnostics.

potential for genotypic antibiograms in select syndromes, clinical value of an infectious disease (ID) consult for select syndromes and organisms, and synergy of antimicrobial stewardship programs (ASPs) in both the development and follow-up of guideline and rapid diagnostic test (RDT) implementation.

Team Work Makes the Dream Work Interdisciplinary collaboration with key stakeholder involvement is essential for the development and success of local syndromic testing-based guidelines. When approached from the perspective of adopting a new diagnostic assay, the formation of a laboratory test utilization committee, akin to a pharmacy and therapeutics committee, can greatly facilitate optimal implementation of the testing.1 These committees will generally include microbiology, antimicrobial stewardship, infectious diseases, and relevant front-line clinical stakeholders where the test will be commonly employed (eg, emergency medicine, internal medicine, critical care). These committees can help to mitigate barriers to optimal implementation such as pre-analytical processing issues (eg, transport delays of specimens),2 develop education for clinicians on adoption of new testing, and develop clinical pathways for use with testing results to facilitate optimal clinical decision making on patient management and treatment changes.

INFECTIOUS DISEASE SPECIAL EDITION • FALL 2021

THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES

Laboratory test committee development

Genotypic antibiograma

ID consult criteriaa

Lab testing algorithms

Adapt national guidelines

Incorporation of antibiogram for therapies

Post implementation ASP rolea BCID2-based guideline

Figure. Local BioFire BCID2 Panel guideline development. a

Optimally when possible.

ASP, antimicrobial stewardship program; BCID2, BioFire® Blood Culture Identification 2 Panel; ID, infectious disease Courtesy of BioFire Diagnostics.

Adapting National Guidance For Local Implementation The local adaptation of national and/ or international evidence-based practice guidelines (eg, CDC, Infectious Diseases Society of America [IDSA]) is often challenging as local patient populations, organism epidemiology, available therapies, clinical practices, and practice culture may not align to recommendations. Resource toolkits exist to facilitate the adaptation of guidelines.3,4 These resources review important local guideline development processes including overall preparation, defining scope and purpose, searching and

screening guidelines, assessment of guidelines (ie, quality, content, consistency), decision and selection, external reviews and acknowledgments by non-committee stakeholders, and post-process planning for follow-up evaluations of implementation.

Antibiogram Development Accurate local susceptibility epidemiology is a key component to improving patient care through pathogen-directed therapy based on the BioFire BCID2 Panel. This information is provided through the use of local antibiogram data. The development of accurate antibiograms generally relies on the expertise of laboratory specialists through their application of Clinical Laboratory and Standards Institute guidelines on analysis and presentation of cumulative antimicrobial susceptibility test (AST) data (M39).5 Among its various procedures, this document guides the avoidance of bias through its sampling procedures and minimum reporting sample sizes. Routine updating (generally annually) of the antibiogram will ensure trends in resistance are captured such that these data may be used in drafting and updating of local guidelines for use in general therapy selection recommendations in the setting of the BioFire BCID2 Panel results.

Genotypic Antibiogram In addition to the use of organism identification from RDT along with antibiogram susceptibilities to drive pathogen-directed therapy, genotypic antibiograms have recently been proposed to facilitate clinical decision making with genotypic resistance testing in bloodstream infections.6 While gram-positive resistance markers (ie, vanA/B for vancomycin resistance in Enterococcus spp. and MREJ+mecA for methicillin resistance in Staphylococcus aureus [MRSA]) approach near complete overall concordance with AST, gram-negative resistance

INFECTIOUS DISEASE SPECIAL EDITION • FALL 2021

markers (eg, extended-spectrum beta-lactamase, carbapenem-resistant Enterobacterales), can strongly change the overall probabilities of presence or absence of resistance in an individual patient. The performance of these detections may be combined at the population level for an institution to determine pathogen-directed therapies for guideline adaptation based on the BioFire BCID2 Panel results. National guidelines have reported clinical thresholds for selection of empiric therapies with not more than 10% to 20% resistance potential for serious infections.7 Combined with the genotypic antibiogram, such thresholds could be evaluated by the local committee for syndromic guideline incorporation. Precedence exists for this approach as analogous to the use of non-AST testing (ie, MRSA nasal polymerase chain reaction assay) to change probabilities of a resistant organism in directing therapy. This approach has been supported by the recent IDSA communityacquired pneumonia guidelines and CDC Core Elements of Stewardship Programs.8,9

ID Consult In drafting of local guidelines, the benefit of an ID consult for select difficult-to-treat infections should be considered. ID consults have been associated with decreased relapse and mortality in Staphylococcus aureus bacteremia and decreased mortality in multidrug-resistant (MDR) infections.10,11 Therefore, where applicable, clinical guidelines may benefit in encouraging ID consults, if locally available, for complicated infections when identified by the BioFire BCID2 Panel.

Stewardship Synergy In addition to playing a role as a key stakeholder during guideline development, ASP teams can help to increase the effectiveness of the BioFire BCID2 Panel and guideline adoption. For instance, improved outcomes

Supported by

with use of rapid diagnostics in bloodstream infections have been established as heavily influenced by ASP involvement, particularly in cost-effectiveness analyses reflecting an 80% chance of effectiveness with ASP versus only 41% chance without.12,13 ASPs can monitor guideline adherence, where applicable, and perform interventions when needed. Common ASP interventions such as IV-to-PO switch can streamline patient care, often decreasing length of stay.

Example Treatment Guidance And Additional Resources Clear, locally preferred therapies based on the BioFire BCID2 Panel results in local treatment guidelines may benefit frontline clinicians. Comprehensive examples of RDT-based clinical pathways may be found elsewhere.14-15

References 1. Messacar K, Parker SK, Todd JK, et al. Implementation of rapid molecular infectious disease diagnostics: the role of diagnostic and antimicrobial stewardship. J Clin Microbiol. 2017;55(3):715-723.

4. Guidelines International Network. Guideline adaptation: a resource toolkit. Accessed August 30, 2021. https://g-i-n.net/wp-content/ uploads/2021/03/ADAPTE-Resource-toolkitMarch-2010.pdf 5. CLSI. Analysis and Presentation of Cumulative Antimicrobial Susceptibility Test Data; Approved Guideline—Fourth Edition. CLSI document M39A4. Clinical and Laboratory Standards Institute; 2014. 6. Pogue JM, Heil EL, Lephart P, et al. An antibiotic stewardship program blueprint for optimizing Verigene BC-GN within an institution: a tale of two cities. Antimicrob Agents Chemother. 2018;62(5):e02538-17. 7. Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61-e111. 8. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with communityacquired pneumonia. An official clinical practice guideline of the American Thoracic Society and Infectious Diseases Society of America. Am J Respir Crit Care Med. 2019;200(7):e45-e67. 9. CDC. Core Elements of Hospital Antibiotic Stewardship Programs. Accessed August 30,

2021. https://www.cdc.gov/antibiotic-use/ healthcare/pdfs/hospital-core-elements-H.pdf 10. Burnham JP, Olsen MA, Stwalley D, et al. Infectious diseases consultation reduces 30-day and 1-year all-cause mortality for multidrug-resistant organism infections. Open Forum Infect Dis. 2018;5(3):ofy026. 11. Vogel M, Schmitz RP, Hagel S, et al. Infectious disease consultation for Staphylococcus aureus bacteremia–a systematic review and metaanalysis. J Infect. 2016;72(1):19-28. 12. Timbrook TT, Morton JB, McConeghy KW, et al. The effect of molecular rapid diagnostic testing on clinical outcomes in bloodstream infections: a systematic review and meta-analysis. Clin Infect Dis. 2017;64(1):15-23. 13. Pliakos EE, Andreatos N, Shehadeh F, et al. The cost-effectiveness of rapid diagnostic testing for the diagnosis of bloodstream infections with or without antimicrobial stewardship. Clin Microbiol Rev. 2018;31(3):e00095-17. 14. Rödel J, Karrasch M, Edel B, et al. Antibiotic treatment algorithm development based on a microarray nucleic acid assay for rapid bacterial identification and resistance determination from positive blood cultures. Diagn Microbiol Infect Dis. 2016;84(3):252-257. 15. Southern TR, VanSchooneveld TC, Bannister DL, et al. Implementation and performance of the BioFire FilmArray® Blood Culture Identification Panel with antimicrobial treatment recommendations for bloodstream infections at a midwestern academic tertiary hospital. Diagn Microbiol Infect Dis. 2015;81(2):96-101.

Disclaimer: This article is designed to be a summary of information. While it is detailed, it is not an exhaustive review. McMahon Publishing and BioFire Diagnostics neither affirm nor deny the accuracy of the information contained herein. No liability will be assumed for the use of the article, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature. Copyright © 2021 McMahon Publishing, 545 West 45th Street, New York, NY 10036. Printed in the USA. All rights reserved, including the right of reproduction, in whole or in part, in any form.

INFECTIOUS DISEASE SPECIAL EDITION • FALL 2021

BB2115

BFR0001-5488-01

2. Banerjee R, Özenci V, Patel R. Individualized approaches are needed for optimized blood cultures. Clin Infect Dis. 2016;63(10):1332-1339.

3. Fervers B, Burgers JS, Voellinger R, et al; ADAPTE Collaboration. Guideline adaptation: an approach to enhance efficiency in guideline development and improve utilisation. BMJ Qual Saf. 2011;20(3):228-236.

HI News HIV Linked With Increased reased Risk for Su Sudden Cardiac Death

eople living with HIV have a higher risk for or sudot have den cardiac death than people who do not led or if HIV, especially if the virus is not well controlled D) risk they have other cardiovascular disease (CVD) /doi. factors (J Am Heart Assoc 2021 Sep 8. https://doi. org/10.1161/JAHA.121.021268). 0 A previous single-center study of 2,800 speople at an HIV clinic in San Francisco disas covered the rate of sudden cardiac death was four times higher in people with HIV. n to “People living with HIV are already known have a higher risk of heart attack, stroke, heart pheral failure, blood clots in the lungs and peripheral artery disease,” said Matthew S. Freiberg, MD, MSc, the Dorothy and Laurence Grossman Chair in Cardiology and a professor of medicine at Vanderbilt University School of Medicine, in Nashville, Tenn. However, he said it was unclear if it was actually the compromised immune system or another reason they were at risk. The new study examined the rate of sudden cardiac death on a national scale, along with the influence of HIV viral loads and other heart disease risk factors on the risk for sudden cardiac death. Researchers evaluated participants from a national study of people with HIV that has a matched participant group without HIV: VACS (Veterans Aging Cohort Study), which is an ongoing long-term national study that follows veterans with and without HIV, and matched by age, sex, race/ethnicity and the Veterans Affairs site where they receive care. The study explores the role of HIV and HIV disease status, along with other health conditions. Among the more than 144,000 veterans in VACS, 30% were diagnosed with HIV and evaluated at VA hospitals across the country. Overall, 97% of the participants were men, 47% were Black, and the average age was 50 years at enrollment. Each

particip participant entered the study at an initial medical appoin appointment on or after April 2003, and were followed through Dec. 31, 2014, for the occurrence of sudd sudden cardiac death. During the median followup o of nine years, sudden cardiac death was cited as th the cause of death for 3,035 of the veterans, 26% (777) of whom had HIV. Afte After adjusting for numerous factors, including age, sex sex, race/ethnicity, the presence of cardiovascular or ren renal disease, cocaine or alcohol dependence or abuse, an and various CVD risk factors, the analysis found the risk fo for sudden cardiac death was: • not high higher in people with HIV who had healthy CD T cells or among those with low viral levels of CD4 loads; • progressively higher with each risk factor for sudden cardiac death that was present, including existing CVD, hypertension, smoking, hepatitis C infection, anemia, alcohol dependence or abuse, and chronic obstructive pulmonary disease—regardless of HIV disease status; • 14% higher in people with HIV; • 57% higher in people with HIV with low CD4 counts over time, an indicator that HIV was progressing and the immune system was compromised; and • 70% higher in people with HIV with high viral loads. “Addressing risk factors related to both cardiovascular disease and HIV is essential to prevent the higher rates of sudden cardiac death in people with HIV,” said Zian H. Tseng, MD, MAS, a professor of medicine in residence and the Murray Davis Endowed Professor at the University of California, San Francisco. “Clinicians should consider screening for specific warning signs of sudden cardiac death, such as fainting or heart palpitations. And, if indicated, clinicians should request additional testing, such as echocardiograms or continuous rhythm monitoring.”

CRISPR for HIV? Maybe Closer

or the last seven years, researchers at the Lewis Katz School of Medicine at Temple University have been developing and refining CRISPRbased gene-editing technology for the treatment of HIV. A potential therapy known as EBT-101 has emerged, which thanks to recent acceptance as an

IDSE.NET

Investigational New Drug (IND) by the FDA, could become the first functional cure for chronic HIV infection. The new IND acceptance for EBT101 opens the way to the first phase 1/2 clinical trial of a CRISPR-based therapy for HIV. The clinical trial will be initiated and managed by Excision

BioTherapeutics, which has been a major collaborator with Temple on the development of the CRISPR-based systems. In preclinical studies, Kamel Khalili, PhD, the director of the Center for Neurovirology and Gene Editing at the Lewis Katz School of Medicine,

England Making Strides in Diagnosing People With HIV

ngland is on track to diagnose 95% of people living with HIV by 2025, putting it in a strong position to eliminate HIV transmission by 2030, according to researchers at the Medical Research Council (MRC) Biostatistics Unit, University of Cambridge, and Public Health England. In 2019, there were an estimated 105,200 people living with HIV in the United Kingdom, of whom 94% were aware of their HIV status. In addition, 98% of those living with diagnosed HIV were receiving antiretroviral treatment, and 97% of these were virally suppressed. The researchers analyzed multiple surveillance, demographic and survey data sets relevant to HIV in England to estimate trends over time rather than a single year. According to their analysis, the estimated number of people from 15 to 74 years of age living in England who were unaware of their infection halved from 11,600 in 2013 to 5,900 in 2019, with a corresponding fall in prevalence from 0.29 to 0.14 per 1,000 people (Lancet Public Health 2021 Sep 23. doi:10.1016/ S2468-2667[21]0042-0). At the same time, the increase in the number of diagnosed HIV cases resulted in the total number of people living with HIV rising from 83,500 to 92,800 over the same period. Therefore, the percentage of people living with HIV whose infection was diagnosed steadily increased from 86% in 2013 to 94% in 2019. “Overall, we see a positive picture forr the HIV epidemic in England, with a dra-vmatic fall in the number of people living with undiagnosed HIV,” said Danielaa cs De Angelis, PhD, from the MRC Biostatistics Unit. he “However, examined more closely, the ne. situation is not as positive for everyone. de We estimate that areas of England outside

in Philadelphia, and his colleagues at Temple showed that EBT-101 can effectively excise HIV proviral DNA from the genomes of different cells and tissues, including HIV-infected human cells and cells and tissues of humanized mice. In collaboration with Tricia H. Burdo, PhD, an associate professor and the associate chair of education in the Department of Microbiology,

London have not seen as steep a decrease in undiagnosed HIV prevalence as in London, and there is evidence of missed opportunities to diagnose HIV infections among some population subgroups,” said Anne Presanis, PhD, also from the MRC Biostatistics Unit. In England, men who have sex with men (MSM) and Black African heterosexuals remain disproportionately affected by HIV, with considerably higher undiagnosed HIV prevalence per population in 2019 than heterosexual people in other ethnic groups. However, undiagnosed HIV prevalence rates within these communities have seen dramatic falls: For MSM, prevalence fell from 13.9 to 5.4 per 1,000, and for Black African heterosexuals, prevalence fell from 3.3 to 1.7 per 1,000 population. London saw more dramatic falls in the prevalence of undiagnosed HIV during the study period than other regions of England, down from 0.74 to 0.31 per 1,000, compared with a decrease from 0.20 to 0.11 per 1,000 outside London. Although sexual health clinics provide free and confidential HIV testing to all clinic patients, the researchers estimated that among heterosexual people in an ethnic group other than Black African, undiagnosed pr prevalence in clinic patients in 2019 was more than 30 times gre greater than in those who had not attended in the past year. This implies that sexual health clinics are missing oppo opportunities for testing attendees, th they said. The researchers said their es estimates have important implica cations for efforts to eliminate H HIV transmission in the United K Kingdom. T research was funded by the The Medical Research Council and M Public Health England. P

Immunology and Inflammation at Lewis Katz, the Temple team further showed that the gene-editing technology can eliminate simian immunodeficiency virus from the genomes of nonhuman primates. “Temple-based preclinical studies, in both small animal and primate models, have successfully shown that CRISPRbased therapies are safe and effective,”

Dr. Burdo said. “These studies have paved the way for Excision to advance this technology with a primary focus of bringing this therapy to the HIV community to improve long-term out■ comes.” Dr. Burdo serves on the scientific advisory board of Excision BioTherapeutics. Dr. Khalili is a co-founder of Excision BioTherapeutics.

I N F E C T I O U S D I S E A S E S P E C I A L E D I T I O N • FA L L 2 0 2 1

ONCE-DAILY ISENTRESS HD 1200 mg (2 x 600 mg)

INDICATION ISENTRESS HD is indicated in combination with other antiretroviral (ARV) agents for the treatment of HIV-1 infection in adult patients. For treatment-naïve adult patients with HIV-1 infection, or adult patients who are virologically suppressed on an initial regimen of ISENTRESS 400 mg twice daily, the dosage of ISENTRESS HD is 1200 mg taken as two 600 mg film-coated tablets, swallowed whole, once daily with or without food.

SELECTED SAFETY INFORMATION • Severe, potentially life-threatening and fatal skin reactions have been reported. This includes cases of Stevens-Johnson syndrome, hypersensitivity reaction and toxic epidermal necrolysis. Immediately discontinue treatment with ISENTRESS HD and other suspect agents if severe hypersensitivity, severe rash, or rash with systemic symptoms or liver aminotransferase elevations develops and monitor clinical status, including liver aminotransferases closely.

• Immune reconstitution syndrome can occur, including the occurrence of autoimmune disorders with variable time to onset, which may necessitate further evaluation and treatment. • Coadministration of ISENTRESS HD with drugs that are strong inducers of uridine diphosphate glucuronosyltransferase (UGT) 1A1 may result in reduced plasma concentrations of raltegravir. Coadministration of ISENTRESS HD with drugs that inhibit UGT1A1 may increase plasma levels of raltegravir. • Coadministration of ISENTRESS HD and other drugs may alter the plasma concentration of raltegravir. The potential for drug-drug interactions must be considered prior to and during therapy. Coadministration or staggered administration of aluminum and/or magnesium-containing antacids and ISENTRESS HD is not recommended. Coadministration of ISENTRESS HD with calcium carbonate antacids, tipranavir/ritonavir, or etravirine is also not recommended. • Rifampin, a strong inducer of UGT1A1, reduces plasma concentrations of ISENTRESS HD. Coadministration with rifampin is not recommended with ISENTRESS HD.

GOING STRONG In a 96-week analysis of treatment-naïve adults with HIV-1, ISENTRESS HD + FTC/TDF showed:

PROVEN EFFICACY • 82% (433/531) of patients attained <40 copies/mL of HIV-1 RNA (vs 80% [213/266] of patients taking ISENTRESS + FTC/TDF). • At 48 weeks ISENTRESS HD + FTC/TDF and ISENTRESS + FTC/TDF showed attainment of HIV-1 RNA <40 copies/mL (NC=F approach) of 89% and 88%, respectively.

DEMONSTRATED TOLERABILITY • The rate of discontinuation of therapy due to adverse events was 1% (vs 2% in patients taking ISENTRESS + FTC/TDF). • There were no clinical adverse reactions of moderate to severe intensity occurring in ≥2% of patients in either treatment group.

FEW DRUG INTERACTIONS • Can be used with a wide range of ARVs and non-ARVs. Coadministration of ISENTRESS HD with aluminum and/or magnesium-containing antacids, calcium carbonate antacids, rifampin, tipranavir/ritonavir, etravirine, and other strong inducers of drug-metabolizing enzymes (eg, carbamazepine, phenobarbital, and phenytoin) is not recommended.

AND THE CONVENIENCE OF ONCE-DAILY DOSING SELECTED SAFETY INFORMATION (continued) • The impact of other strong inducers of drug metabolizing enzymes on raltegravir is unknown (e.g., Carbamazepine, Phenobarbital, and Phenytoin). Coadministration of ISENTRESS HD with other strong inducers is not recommended. • The most commonly reported (≥2%) clinical adverse reactions of all intensities (Mild, Moderate, and Severe) in treatment-naïve adult patients receiving ISENTRESS HD or ISENTRESS were abdominal pain, diarrhea, vomiting, and decreased appetite. Intensities were defined as follows: Mild (awareness of sign or symptom, but easily tolerated); Moderate (discomfort enough to cause interference with usual activity); or Severe (incapacitating with inability to work or do usual activity). • Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS HD. Myopathy and rhabdomyolysis have been reported. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions and patients with a history of rhabdomyolysis, myopathy or increased serum creatine kinase.

• There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ISENTRESS HD during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. • Women infected with HIV-1 should be instructed not to breastfeed if they are receiving ISENTRESS HD due to the potential for HIV transmission. • No hepatic impairment study has been conducted with ISENTRESS HD and therefore administration in patients with hepatic impairment is not recommended. The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied.

Please see the adjacent Brief Summary of the Prescribing Information. For more information, please visit isentressHD.com. CYP450, cytochrome P450 enzyme; FTC, emtricitabine; HIV-1, human immunodeficiency virus type 1; RNA, ribonucleic acid; TDF, tenofovir disoproxil fumarate.

ISENTRESS® (raltegravir) film-coated tablets, for oral use ISENTRESS® HD (raltegravir) film-coated tablets, for oral use ISENTRESS® (raltegravir) chewable tablets, for oral use ISENTRESS® (raltegravir) for oral suspension INDICATIONS AND USAGE Adult Patients: ISENTRESS® and ISENTRESS® HD are indicated in combination with other antiretroviral agents for the treatment of human immunodeficiency virus (HIV-1) infection in adult patients. Pediatric Patients: ISENTRESS is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients weighing at least 2 kg. ISENTRESS HD is indicated in combination with other antiretroviral agents for the treatment of HIV-1 infection in pediatric patients weighing at least 40 kg. DOSAGE AND ADMINISTRATION General Dosing Recommendations Because the formulations have different pharmacokinetic profiles, do not substitute ISENTRESS chewable tablets or ISENTRESS for oral suspension for the ISENTRESS 400 mg film-coated tablet or the ISENTRESS HD 600 mg filmcoated tablet. See specific dosing guidance for chewable tablets and the formulation for oral suspension. Because the extent to which ISENTRESS may be dialyzable is unknown, dosing before a dialysis session should be avoided. ISENTRESS film-coated tablets must be swallowed whole. The recommended adult dosage of ISENTRESS film-coated tablets is displayed in Table 1. ISENTRESS and ISENTRESS HD should be taken by mouth and may be taken with or without food. Table 1: Dosing Recommendations for ISENTRESS and ISENTRESS HD in Adult Patients Population Treatment-naïve patients or patients who are virologically suppressed on an initial regimen of ISENTRESS 400 mg twice daily

Recommended Dose 1,200 mg (2 x 600 mg) once daily or 400 mg twice daily

Treatment-experienced

400 mg twice daily

Treatment-naïve or treatment-experienced when coadministered with rifampin (see Drug Interactions)

800 mg (2 x 400 mg) twice daily

For the recommended pediatric dosage, please read the Prescribing Information. CONTRAINDICATIONS None WARNINGS AND PRECAUTIONS Severe Skin and Hypersensitivity Reactions Severe, potentially life-threatening, and fatal skin reactions have been reported. These include cases of Stevens-Johnson syndrome and toxic epidermal necrolysis. Hypersensitivity reactions have also been reported and were characterized by rash, constitutional findings, and sometimes, organ dysfunction, including hepatic failure. Discontinue ISENTRESS or ISENTRESS HD and other suspect agents immediately if signs or symptoms of severe skin reactions or hypersensitivity reactions develop (including, but not limited to, severe rash or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema). Clinical status including liver aminotransferases should be monitored and appropriate therapy initiated. Delay in stopping ISENTRESS or ISENTRESS HD treatment or other suspect agents after the onset of severe rash may result in a life-threatening reaction. Immune Reconstitution Syndrome Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including ISENTRESS. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jiroveci pneumonia, tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable, and can occur many months after initiation of treatment. Phenylketonurics ISENTRESS Chewable Tablets contain phenylalanine, a component of aspartame. Each 25 mg ISENTRESS Chewable Tablet contains approximately 0.05 mg phenylalanine. Each 100 mg ISENTRESS Chewable Tablet contains approximately 0.10 mg phenylalanine. Phenylalanine can be harmful to patients with phenylketonuria. ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Clinical Trials Experience Treatment-Naïve Adults The safety of ISENTRESS was evaluated in HIV-infected treatment-naïve subjects in 2 Phase III studies: STARTMRK evaluated ISENTRESS 400 mg twice daily versus efavirenz, both in combination with emtricitabine (+) tenofovir disoproxil fumarate (TDF), and ONCEMRK evaluated ISENTRESS HD 1200 mg (2 x 600 mg) once daily versus ISENTRESS 400 mg twice daily, both in combination with emtricitabine (+) tenofovir disoproxil fumarate. Safety data from these two studies are presented side-by-side in Tables 6 and 7 to simplify presentation; direct comparisons across trials should not be made due to differing duration of follow-up and study design. STARTMRK (ISENTRESS 400 mg twice daily) In STARTMRK, subjects received ISENTRESS 400 mg twice daily (N=281) or efavirenz (EFV) 600 mg at bedtime (N=282) both in combination with emtricitabine (+) tenofovir disoproxil fumarate, (N=282). During double-blind treatment, the total follow-up for subjects receiving ISENTRESS 400 mg twice daily + emtricitabine (+) tenofovir disoproxil fumarate was 1104 patient-years and 1036 patient-years for subjects receiving efavirenz 600 mg at bedtime + emtricitabine (+) tenofovir disoproxil fumarate. In STARTMRK, the rate of discontinuation of therapy due to adverse events through Week 240 was 5% in subjects receiving ISENTRESS + emtricitabine (+) tenofovir disoproxil fumarate and 10% in subjects receiving efavirenz + emtricitabine (+) tenofovir disoproxil fumarate. ONCEMRK (ISENTRESS HD 1200 mg [2 x 600 mg] once daily) In ONCEMRK, subjects received ISENTRESS HD 1200 mg once daily (N=531) or ISENTRESS 400 mg twice daily (N=266) both in combination with emtricitabine (+) tenofovir disoproxil fumarate. During double-blind treatment, the total follow-up for subjects with ISENTRESS HD 1200 mg once daily was 913 patient-years and for ISENTRESS 400 mg twice daily was 450 patient-years. In ONCEMRK, the rate of discontinuation of therapy due to adverse events through Week 96 was 1% in subjects receiving ISENTRESS HD 1200 mg (2 x 600 mg) once daily and 2% in subjects receiving ISENTRESS 400 mg twice daily. Clinical adverse reactions of moderate to severe intensity occurring in ≥2% of treatment-naïve subjects treated with ISENTRESS 400 mg twice daily or efavirenz in STARTMRK through Week 240 or ISENTRESS HD 1200 mg once daily or ISENTRESS 400 mg twice daily in ONCEMRK through Week 96 are presented in Table 6. In STARTMRK, clinical adverse reactions of all intensities (mild, moderate and severe) occurring in ≥2% of subjects on ISENTRESS 400 mg twice daily through Week 240 also include diarrhea, flatulence, asthenia, decreased appetite, abnormal dreams, depression and nightmare. In ONCEMRK, clinical adverse reactions of all intensities (mild, moderate and severe) occurring in ≥2% of subjects on ISENTRESS HD or ISENTRESS 400 mg twice daily through Week 96 also include abdominal pain, diarrhea, vomiting, and decreased appetite.

Table 6: Adverse Reactions* of Moderate to Severe Intensity† Occurring in ≥2% of Treatment-Naïve Adult Subjects Receiving ISENTRESS and ISENTRESS HD STARTMRK Week 240 System Organ Class, Preferred Term Headache Insomnia Nausea Dizziness Fatigue

ONCEMRK Week 96

ISENTRESS 400 mg Twice Daily (N=281)

Efavirenz 600 mg At Bedtime (N=282)

ISENTRESS HD 1200 mg Once Daily (N=531)

ISENTRESS 400 mg Twice Daily (N=266)

4% 4% 3% 2% 2%

5% 4% 4% 6% 3%

1% <1% 1% <1% 0%

<1% <1% 0% 0% 0%

Note: ISENTRESS BID, ISENTRESS HD and efavirenz were administered with emtricitabine (+) tenofovir disoproxil fumarate. *Includes adverse experiences considered by investigators to be at least possibly, probably, or definitely related to the drug. † Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity). N = total number of subjects per treatment group Laboratory Abnormalities The percentages of adult subjects with selected Grade 2 to 4 laboratory abnormalities (that represent a worsening Grade from baseline) who were treated with ISENTRESS 400 mg twice daily or efavirenz in STARTMRK or ISENTRESS HD 1200 mg once daily or ISENTRESS 400 mg twice daily in ONCEMRK are presented in Table 7. Table 7: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Naïve Subjects STARTMRK Week 240 Laboratory Parameter Preferred Term (Unit)

Limit

ISENTRESS 400 mg Twice Daily (N=281)

Efavirenz 600 mg At Bedtime (N=282)

ONCEMRK Week 96 ISENTRESS HD 1200 mg Once Daily (N=531)

ISENTRESS 400 mg Twice Daily (N=266)

Hematology Absolute neutrophil count (103/μL) Grade 2 0.75 - 0.999 3% 5% 2% 1% Grade 3 0.50 - 0.749 3% 1% 1% 1% Grade 4 <0.50 1% 1% <1% 0% Hemoglobin (gm/dL) Grade 2 7.5 - 8.4 1% 1% 0% 0% Grade 3 6.5 - 7.4 1% 1% 0% 0% Grade 4 <6.5 <1% 0% 0% 0% 3 Platelet count (10 /μL) Grade 2 50 - 99.999 1% 0% 1% <1% Grade 3 25 - 49.999 <1% <1% 0% 0% Grade 4 <25 0% 0% 0% <1% Blood chemistry Fasting (non-random) serum glucose test (mg/dL)† Grade 2 126 - 250 7% 6% Grade 3 251 - 500 2% 1% Grade 4 >500 0% 0% Total serum bilirubin Grade 2 1.6 - 2.5 x ULN 5% <1% 3% 2% Grade 3 2.6 - 5.0 x ULN 1% 0% 1% <1% Grade 4 >5.0 x ULN <1% 0% <1% 0% Creatinine Grade 2 1.4 - 1.8 x ULN 1% 1% 0% <1% Grade 3 1.9 - 3.4 x ULN 0% <1% 0% 0% Grade 4 ≥3.5 x ULN 0% 0% 0% 0% Serum aspartate aminotransferase Grade 2 2.6 - 5.0 x ULN 8% 10% 5% 3% Grade 3 5.1 - 10.0 x ULN 5% 3% 2% <1% Grade 4 >10.0 x ULN 1% <1% 1% <1% Serum alanine aminotransferase Grade 2 2.6 - 5.0 x ULN 11% 12% 4% 2% Grade 3 5.1 - 10.0 x ULN 2% 2% 1% <1% Grade 4 >10.0 x ULN 2% 1% 1% <1% Serum alkaline phosphatase Grade 2 2.6 - 5.0 x ULN 1% 3% 1% 0% Grade 3 5.1 - 10.0 x ULN 0% 1% <1% 0% Grade 4 >10.0 x ULN <1% <1% 0% 0% Lipase* Grade 2 1.6 - 3.0 x ULN 7% 5% Grade 3 3.1 - 5.0 x ULN 2% 1% Grade 4 >5.0 x ULN 2% 1% Creatine kinase* Grade 2 6.0 - 9.9 x ULN 4% 5% Grade 3 10.0 - 19.9 x ULN 3% 3% Grade 4 ≥20.0 x ULN 3% 2% ULN = Upper limit of normal range Notes: ISENTRESS BID, ISENTRESS HD and Efavirenz were administered with emtricitabine (+) tenofovir disoproxil fumarate *Test not done in STARTMRK † Test not done in ONCEMRK

Lipids, Change from Baseline Changes from baseline in fasting lipids are shown in Table 8.

Table 10: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Experienced Subjects (96 Week Analysis) (continued)

Table 8: Lipid Values, Mean Change from Baseline, STARTMRK Study Laboratory Parameter Preferred Term

ISENTRESS® (raltegravir) 400 mg Twice Daily + Emtricitabine (+) Tenofovir Disoproxil Fumarate (N=207)

Efavirenz 600 mg At Bedtime + Emtricitabine (+) Tenofovir Disoproxil Fumarate (N=187)

Change from Baseline at Week 240

LDL-Cholesterol* HDL-Cholesterol* Total Cholesterol* Triglyceride*

Change from Baseline at Week 240

Baseline Mean (mg/dL)

Week 240 Mean (mg/dL)

Mean Change (mg/dL)

Baseline Mean (mg/dL)

Week 240 Mean (mg/dL)

Mean Change (mg/dL)

96 38 159 128

106 44 175 130

10 6 16 2

93 38 157 141

118 51 201 178

25 13 44 37

*Fasting (non-random) laboratory tests at Week 240. Notes: N = total number of subjects per treatment group with at least one lipid test result available. The analysis is based on all available data. If subjects initiated or increased serum lipid-reducing agents, the last available lipid values prior to the change in therapy were used in the analysis. If the missing data was due to other reasons, subjects were censored thereafter for the analysis. At baseline, serum lipid-reducing agents were used in 5% of subjects in the group receiving ISENTRESS and 3% in the efavirenz group. Through Week 240, serum lipid-reducing agents were used in 9% of subjects in the group receiving ISENTRESS and 15% in the efavirenz group. Treatment-Experienced Adults The safety assessment of ISENTRESS in treatment-experienced subjects is based on the pooled safety data from the randomized, double-blind, placebo-controlled trials, BENCHMRK 1 and BENCHMRK 2 in antiretroviral treatmentexperienced HIV-1 infected adult subjects. A total of 462 subjects received the recommended dose of ISENTRESS 400 mg twice daily in combination with optimized background therapy (OBT) compared to 237 subjects taking placebo in combination with OBT. The median duration of therapy in these trials was 96 weeks for subjects receiving ISENTRESS and 38 weeks for subjects receiving placebo. The total exposure to ISENTRESS was 708 patient-years versus 244 patient-years on placebo. The rates of discontinuation due to adverse events were 4% in subjects receiving ISENTRESS and 5% in subjects receiving placebo. Clinical ADRs were considered by investigators to be causally related to ISENTRESS + OBT or placebo + OBT. Clinical ADRs of moderate to severe intensity occurring in ≥2% of subjects treated with ISENTRESS and occurring at a higher rate compared to placebo are presented in Table 9. Table 9: Adverse Drug Reactions* of Moderate to Severe Intensity† Occurring in ≥2% of Treatment-Experienced Adult Subjects Receiving ISENTRESS and at a Higher Rate Compared to Placebo (96 Week Analysis) Randomized Studies BENCHMRK 1 and BENCHMRK 2

System Organ Class, Adverse Reactions

ISENTRESS 400 mg Twice Daily + OBT (N=462)

Placebo + OBT (N=237)

Nervous System Disorders Headache

<1%

*Includes adverse reactions at least possibly, probably, or definitely related to the drug. † Intensities are defined as follows: Moderate (discomfort enough to cause interference with usual activity); Severe (incapacitating with inability to work or do usual activity). N = total number of subjects per treatment group. Laboratory Abnormalities The percentages of adult subjects treated with ISENTRESS 400 mg twice daily or placebo in Studies BENCHMRK 1 and BENCHMRK 2 with selected Grade 2 to 4 laboratory abnormalities representing a worsening Grade from baseline are presented in Table 10. Table 10: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Experienced Subjects (96 Week Analysis) Laboratory Parameter Preferred Term (Unit)

Randomized Studies BENCHMRK 1 and BENCHMRK 2 Limit

ISENTRESS 400 mg Twice Daily + OBT (N=462)

Hematology Absolute neutrophil count (103/μL) Grade 2 0.75 - 0.999 Grade 3 0.50 - 0.749 Grade 4 <0.50 Hemoglobin (gm/dL) Grade 2 7.5 - 8.4 Grade 3 6.5 - 7.4 Grade 4 <6.5 Platelet count (103/μL) Grade 2 50 - 99.999 Grade 3 25 - 49.999 Grade 4 <25 Blood chemistry Fasting (non-random) serum glucose test (mg/dL) Grade 2 126 - 250 Grade 3 251 - 500 Grade 4 >500 Total serum bilirubin Grade 2 1.6 - 2.5 x ULN Grade 3 2.6 - 5.0 x ULN Grade 4 >5.0 x ULN

Placebo + OBT (N=237)

4% 3% 1%

5% 3% <1%

1% 1% <1%

3% 1% 0%

3% 1% 1%

5% <1% <1%

10% 3% 0%

7% 1% 0%

6% 3% 1%

3% 3% 0%

Table 10: Selected Grade 2 to 4 Laboratory Abnormalities Reported in Treatment-Experienced Subjects (96 Week Analysis) (continues on next column)

Laboratory Parameter Preferred Term (Unit)

Randomized Studies BENCHMRK 1 and BENCHMRK 2 Limit

ISENTRESS 400 mg Twice Daily + OBT (N=462)

Placebo + OBT (N=237)

Serum aspartate aminotransferase Grade 2 2.6 - 5.0 x ULN 9% 7% Grade 3 5.1 - 10.0 x ULN 4% 3% Grade 4 >10.0 x ULN 1% 1% Serum alanine aminotransferase Grade 2 2.6 - 5.0 x ULN 9% 9% Grade 3 5.1 - 10.0 x ULN 4% 2% Grade 4 >10.0 x ULN 1% 2% Serum alkaline phosphatase Grade 2 2.6 - 5.0 x ULN 2% <1% Grade 3 5.1 - 10.0 x ULN <1% 1% Grade 4 >10.0 x ULN 1% <1% Serum pancreatic amylase test Grade 2 1.6 - 2.0 x ULN 2% 1% Grade 3 2.1 - 5.0 x ULN 4% 3% Grade 4 >5.0 x ULN <1% <1% Serum lipase test Grade 2 1.6 - 3.0 x ULN 5% 4% Grade 3 3.1 - 5.0 x ULN 2% 1% Grade 4 >5.0 x ULN 0% 0% Serum creatine kinase Grade 2 6.0 - 9.9 x ULN 2% 2% Grade 3 10.0 - 19.9 x ULN 4% 3% Grade 4 ≥20.0 x ULN 3% 1% ULN = Upper limit of normal range Less Common Adverse Reactions Observed in Treatment-Naïve and Treatment-Experienced Studies The following ADRs occurred in <2% of treatment-naïve or treatment-experienced subjects receiving ISENTRESS or ISENTRESS HD in a combination regimen. These events have been included because of their seriousness, increased frequency compared with efavirenz or placebo, or investigator’s assessment of potential causal relationship. Gastrointestinal Disorders: abdominal pain, gastritis, dyspepsia, vomiting General Disorders and Administration Site Conditions: asthenia Hepatobiliary Disorders: hepatitis Immune System Disorders: hypersensitivity Infections and Infestations: genital herpes, herpes zoster Psychiatric Disorders: depression (particularly in subjects with a pre-existing history of psychiatric illness), including suicidal ideation and behaviors Renal and Urinary Disorders: nephrolithiasis, renal failure Selected Adverse Events - Adults In studies of ISENTRESS 400 mg twice daily, cancers were reported in treatment-experienced subjects who initiated ISENTRESS or placebo, both with OBT, and in treatment-naïve subjects who initiated ISENTRESS or efavirenz, both with emtricitabine (+) tenofovir disoproxil fumarate; several were recurrent. The types and rates of specific cancers were those expected in a highly immunodeficient population (many had CD4+ counts below 50 cells/mm3 and most had prior AIDS diagnoses). The risk of developing cancer in these studies was similar in the group receiving ISENTRESS and the group receiving the comparator. Grade 2-4 creatine kinase laboratory abnormalities were observed in subjects treated with ISENTRESS and ISENTRESS HD (see Tables 6 and 8). Myopathy and rhabdomyolysis have been reported with ISENTRESS. Use with caution in patients at increased risk of myopathy or rhabdomyolysis, such as patients receiving concomitant medications known to cause these conditions and patients with a history of rhabdomyolysis, myopathy or increased serum creatine kinase. Rash occurred more commonly in treatment-experienced subjects receiving regimens containing ISENTRESS + darunavir/ritonavir compared to subjects receiving ISENTRESS without darunavir/ritonavir or darunavir/ritonavir without ISENTRESS. However, rash that was considered drug related occurred at similar rates for all three groups. These rashes were mild to moderate in severity and did not limit therapy; there were no discontinuations due to rash. Patients with Co-existing Conditions - Adults Patients Co-infected with Hepatitis B and/or Hepatitis C Virus In Phase III studies of ISENTRESS, patients with chronic (but not acute) active hepatitis B and/or hepatitis C virus coinfection were permitted to enroll provided that baseline liver function tests did not exceed 5 times the upper limit of normal (ULN). In the treatment-experienced studies, BENCHMRK 1 and BENCHMRK 2, 16% of all patients (114/699) were co-infected; in the treatment-naïve studies, STARTMRK and ONCEMRK, 6% (34/563) and 3% (23/797), respectively, were co-infected. In general the safety profile of ISENTRESS in subjects with hepatitis B and/or hepatitis C virus co-infection was similar to that in subjects without hepatitis B and/or hepatitis C virus co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or hepatitis C virus coinfection for all treatment groups. At 96 weeks, in treatment-experienced subjects receiving ISENTRESS 400 mg twice daily, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 29%, 34% and 13%, respectively, of co-infected subjects treated with ISENTRESS as compared to 11%, 10% and 9% of all other subjects treated with ISENTRESS. At 240 weeks, in treatment-naïve subjects receiving ISENTRESS 400 mg twice daily, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 22%, 44% and 17%, respectively, of co-infected subjects treated with ISENTRESS as compared to 13%, 13% and 5% of all other subjects treated with ISENTRESS. At 96 weeks, in treatment-naïve subjects receiving ISENTRESS HD 1200 mg (2 x 600 mg) once daily, Grade 2 or higher laboratory abnormalities that represent a worsening Grade from baseline of AST, ALT or total bilirubin occurred in 27%, 40% and 13%, respectively, of co-infected subjects treated with ISENTRESS HD 1200 mg once daily as compared to 7%, 5% and 3% of all other subjects treated with ISENTRESS HD 1200 mg once daily. Pediatrics 2 to 18 Years of Age ISENTRESS has been studied in 126 antiretroviral treatment-experienced HIV-1 infected children and adolescents 2 to 18 years of age, in combination with other antiretroviral agents in IMPAACT P1066. Of the 126 patients, 96 received the recommended dose of ISENTRESS. In these 96 children and adolescents, frequency, type and severity of drug related adverse reactions through Week 24 were comparable to those observed in adults. One patient experienced drug related clinical adverse reactions of Grade 3 psychomotor hyperactivity, abnormal behavior and insomnia; one patient experienced a Grade 2 serious drug related allergic rash. One patient experienced drug related laboratory abnormalities, Grade 4 AST and Grade 3 ALT, which were considered serious. 4 Weeks to Less than 2 Years of Age ISENTRESS has also been studied in 26 HIV-1 infected infants and toddlers 4 weeks to less than 2 years of age, in combination with other antiretroviral agents in IMPAACT P1066. In these 26 infants and toddlers, the frequency, type and severity of drug related adverse reactions through Week 48 were comparable to those observed in adults. One patient experienced a Grade 3 serious drug related allergic rash that resulted in treatment discontinuation.

HIV-1 Exposed Neonates Forty-two neonates were treated with ISENTRESS for up to 6 weeks from birth, and followed for a total of 24 weeks in IMPAACT P1110 [see Use in Specific Populations]. There were no drug related clinical adverse reactions and three drug-related laboratory adverse reactions (one case of transient Grade 4 neutropenia in a subject receiving zidovudine-containing regimen for prevention of mother to child transmission (PMTCT), and two bilirubin elevations (one each, Grade 1 and Grade 2) considered non-serious and not requiring specific therapy). The safety profile in neonates was generally similar to that observed in older patients treated with ISENTRESS. No clinically meaningful differences in the adverse event profile of neonates were observed when compared to adults. Postmarketing Experience The following adverse reactions have been identified during postapproval use of ISENTRESS. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: thrombocytopenia Gastrointestinal Disorders: diarrhea Hepatobiliary Disorders: hepatic failure (with and without associated hypersensitivity) in patients with underlying liver disease and/or concomitant medications Musculoskeletal and Connective Tissue Disorders: rhabdomyolysis Nervous System Disorders: cerebellar ataxia Psychiatric Disorders: anxiety, paranoia DRUG INTERACTIONS Effect of Other Agents on the Pharmacokinetics of Raltegravir Raltegravir is not a substrate of cytochrome P450 (CYP) enzymes. Based on in vivo and in vitro studies, raltegravir is eliminated mainly by metabolism via a UGT1A1-mediated glucuronidation pathway. Coadministration of ISENTRESS with drugs that inhibit UGT1A1 may increase plasma levels of raltegravir and coadministration of ISENTRESS with drugs that induce UGT1A1, such as rifampin, may reduce plasma levels of raltegravir (see Table 11). Selected drug interactions are presented in Table 11. In some cases, recommendations differ for ISENTRESS versus ISENTRESS HD. Table 11: Selected Drug Interactions in Adults Concomitant Drug Class: Drug Name

Effect on Concentration of Raltegravir

Clinical Comment for ISENTRESS

Clinical Comment for ISENTRESS HD

Metal-Containing Antacids Aluminum and/or magnesium-containing antacids

Coadministration or staggered administration is not recommended.

Calcium carbonate antacid

No dose adjustment

Co-administration is not recommended

Rifampin

The recommended dosage is 800 mg twice daily during coadministration with rifampin. There are no data to guide co-administration of ISENTRESS with rifampin in patients below 18 years of age.

Coadministration is not recommended.

Tipranavir/ritonavir

No dose adjustment

Coadministration is not recommended

Etravirine

No dose adjustment

Coadministration is not recommended

Strong inducers of drug metabolizing enzymes not mentioned above e.g., Carbamazepine Phenobarbital Phenytoin

The impact of other strong inducers of drug metabolizing enzymes on raltegravir is unknown. Coadministration is not recommended.

Other Agents

Drugs without Clinically Significant Interactions with ISENTRESS or ISENTRESS HD ISENTRESS In drug interaction studies performed using ISENTRESS film-coated tablets 400 mg twice daily dose, raltegravir did not have a clinically meaningful effect on the pharmacokinetics of the following: ethinyl estradiol/ norgestimate, methadone, midazolam, lamivudine, tenofovir disoproxil fumarate, etravirine, darunavir/ritonavir, or boceprevir. Moreover, atazanavir, atazanavir/ritonavir, boceprevir, calcium carbonate antacids, darunavir/ ritonavir, efavirenz, etravirine, omeprazole, or tipranavir/ritonavir did not have a clinically meaningful effect on the pharmacokinetics of 400 mg twice daily raltegravir. No dose adjustment is required when ISENTRESS 400 mg twice daily is coadministered with these drugs. There is no predicted pharmacokinetic drug interaction between ISENTRESS and tenofovir alafenamide. ISENTRESS HD In drug interaction studies, efavirenz did not have a clinically meaningful effect on the pharmacokinetics of ISENTRESS HD 1200 mg (2 x 600 mg) once daily. No dose adjustment is recommended when ISENTRESS HD 1200 mg once daily is coadministered with atazanavir, atazanavir/ritonavir, hormonal contraceptives, methadone, lamivudine, tenofovir disoproxil fumarate, darunavir/ritonavir, boceprevir, efavirenz and omeprazole. There is no predicted pharmacokinetic drug interaction between ISENTRESS HD and tenofovir alafenamide. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary Available data from the APR show no difference in the rate of overall birth defects for raltegravir compared to the background rate for major birth defects of 2.7% in the U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP). The rate of miscarriage is not reported in the APR. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15-20%. The background risk for major birth defects and miscarriage for the indicated population is unknown. Methodological limitations of the APR include the use of MACDP as the external comparator group. The MACDP population is not disease-specific, evaluates women and infants from a limited geographic area, and does not include outcomes for births that occurred at <20 weeks gestation.

In animal reproduction studies in rats and rabbits, no evidence of adverse developmental outcomes was observed with oral administration of raltegravir during organogenesis at doses that produced exposures up to approximately 4 times the maximum recommended human dose (MRHD) of 1200 mg. Data Human Data Based on prospective reports from the APR of over 850 exposures to raltegravir during pregnancy resulting in live births (including over 450 exposures in the first trimester), there was no difference between the overall risk of birth defects for raltegravir compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. The prevalence of defects in live births was 3.1% (95% CI: 1.7% to 5.1%) following first trimester exposure to raltegravir-containing regimens and 3.7% (95% CI: 2.1% to 6.0%) following second and third trimester exposure to raltegravir-containing regimens. There are limited data on the use of ISENTRESS 1200 mg (2 x 600 mg) once daily in pregnant women. Animal Data In a combined embryo/fetal and pre/postnatal development study, raltegravir was administered orally to rats at doses of 100, 300, 600 mg/kg/day on gestation day 6 to 20 or from gestation day 6 to lactation day 20. No effects on pre/postnatal development were observed up to the highest dose tested. Embryo-fetal findings were limited to an increase in the incidence of supernumerary ribs in the 600 mg/kg/day group. Systemic exposure (AUC) at 600 mg/kg/day was approximately 3 times higher than exposure at the MRHD of 1200 mg. In pregnant rabbits, raltegravir was administered orally at doses of 100, 500, or 1000 mg/kg/day during the gestation days 7 to 20. No embryo/fetal effects were noted up to the highest dose of 1000 mg/kg/day. Systemic exposure (AUC) at 1000 mg/kg/day was approximately 4 times higher than exposures at the MRHD of 1200 mg. In both species, raltegravir has been shown to cross the placenta, with fetal plasma concentrations observed in rats approximately 1.5 to 2.5 times greater than in maternal plasma and fetal plasma concentrations in rabbits approximately 2% that of maternal concentrations on gestation day 20. Lactation Risk Summary The Centers for Disease Control and Prevention recommend that HIV-1 infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. There are no data on the presence of raltegravir in human milk, the effects on the breastfed infant, or the effects on milk production. When administered to lactating rats, raltegravir was present in milk (see Data). Because of the potential for: 1) HIV transmission (in HIV-negative infants), 2) developing viral resistance (in HIV-positive infants), and 3) adverse reactions in a breastfed infant, instruct mothers not to breastfeed if they are receiving ISENTRESS/ISENTRESS HD. Data Raltegravir was excreted into the milk of lactating rats following oral administration (600 mg/kg/day) from gestation day 6 to lactation day 14, with milk concentrations approximately 3 times that of maternal plasma concentrations observed 2 hours postdose on lactation day 14. Pediatric Use ISENTRESS HIV-1 Infected Children The safety, tolerability, pharmacokinetic profile, and efficacy of twice-daily ISENTRESS were evaluated in HIV-1 infected infants, children and adolescents 4 weeks to 18 years of age in an open-label, multicenter clinical trial, IMPAACT P1066. The safety profile was comparable to that observed in adults. HIV-1 Exposed Neonates The safety and pharmacokinetics of ISENTRESS for oral suspension were evaluated in 42 full-term HIV-1 exposed neonates at high risk of acquiring HIV-1 infection in a Phase 1, open-label, multicenter clinical study, IMPAACT P1110. Cohort 1 neonates received 2 single doses of ISENTRESS for oral suspension: the first within 48 hours of birth and the second at 7 to 10 days of age. Cohort 2 neonates received daily dosing of ISENTRESS for oral suspension for 6 weeks: 1.5 mg/kg once daily starting within 48 hours of birth through day 7 (week 1); 3 mg/kg twice daily on days 8 to 28 of age (weeks 2 to 4); and 6 mg/kg twice daily on days 29 to 42 of age (weeks 5 and 6). Sixteen neonates were enrolled in Cohort 1 (10 were exposed and 6 were unexposed to raltegravir in utero) and 26 in Cohort 2 (all unexposed to raltegravir in utero); all infants received a standard of care antiretroviral drug regimen for prevention of mother to child transmission. All enrolled neonates were followed for safety for a duration of 24 weeks. The 42 infants were 52% male, 69% Black and 12% Caucasian. HIV-1 status was assessed by nucleic acid test at birth, week 6 and week 24; all patients were HIV-1 negative at completion of the study. The safety profile was comparable to that observed in adults [see Adverse Reactions]. ISENTRESS is not recommended in pre-term neonates or in pediatric patients weighing less than 2 kg. ISENTRESS HD ISENTRESS HD once daily has not been studied in pediatric patients. However population PK modeling and simulation support the use of 1,200 mg (2 x 600 mg) once daily in pediatric patients weighing at least 40 kg. Geriatric Use Clinical studies of ISENTRESS/ISENTRESS HD did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger subjects. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Use in Patients with Hepatic Impairment No dosage adjustment of ISENTRESS is necessary for patients with mild to moderate (Child-Pugh A and B) hepatic impairment. No hepatic impairment study has been conducted with ISENTRESS HD and therefore administration in subjects with hepatic impairment is not recommended. The effect of severe hepatic impairment on the pharmacokinetics of raltegravir has not been studied. Use in Patients with Renal Impairment No dosage adjustment of ISENTRESS or ISENTRESS HD is necessary in patients with any degree of renal impairment. The extent to which ISENTRESS may be dialyzable is unknown; therefore, dosing before a dialysis session should be avoided. OVERDOSAGE In the event of an overdose, it is reasonable to employ the standard supportive measures, e.g., remove unabsorbed material from the gastrointestinal tract, employ clinical monitoring (including obtaining an electrocardiogram), and institute supportive therapy if required. The extent to which ISENTRESS may be dialyzable is unknown. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies of raltegravir in mice did not show any carcinogenic potential. At the highest dose levels, 400 mg/kg/day in females and 250 mg/kg/day in males, systemic exposure was 1.8-fold (females) or 1.2-fold (males) greater than the AUC (54 μM•hr) at the 400-mg twice daily human dose. Treatment-related squamous cell carcinoma of nose/nasopharynx was observed in female rats dosed with 600 mg/kg/day raltegravir for 104 weeks. These tumors were possibly the result of local irritation and inflammation due to local deposition and/or aspiration of drug in the mucosa of the nose/nasopharynx during dosing. No tumors of the nose/nasopharynx were observed in rats dosed with 150 mg/kg/day (males) and 50 mg/kg/day (females) and the systemic exposure in rats was 1.7-fold (males) to 1.4-fold (females) greater than the AUC (54 μM•hr) at the 400-mg twice daily human dose.

for oral suspension 100 mg

For more detailed information, please read the Prescribing Information. uspi-mk0518-mf-2108r037 Revised: 08/2021

Antibiotic Use Highly Tied to C. diff in Hospitals BY ETHAN COVEY

ntibiotic use is significantly associated with hospitalonset Clostridioides difficile infection (HO-CDI), according to data taken from a large cohort of U.S.-based acute care hospitals (ACHs). The findings build upon previous research that reported on antibiotic usage and HO-CDI rates from 2006 to 2012 (Infect Control Hosp Epidemiol 2021 May 7. doi:10.1017/ice.2021.151 https://bit.ly/3ojGVfc-IDSE). “This study is important because it confirms and extends previous research on the association of broad-spectrum antibiotics and CDI,” said Sophia Kazakova, MD, PhD, a health scientist with the CDC’s Division of Healthcare Quality Promotion. “These findings should encourage clinicians, infection control and antibiotic stewardship programs to strengthen antibiotic use monitoring and continue to focus on reducing use across all classes of antibiotics to reduce CDI.” The researchers reviewed data on adult discharge and inpatient charge records for antibiotic use, CDI testing and CDI treatment for 921 ACHs from Jan. 1, 2012, to Dec. 31, 2018, HO-CDI rates were calculated and compared with days of therapy (DOT) for seven antibiotic classes. The results showed a clear association between higher levels of antibiotic use and rates of HO-CDI. For every 50 DOT per 1,000 patient days (PD) increase in antibiotic use, HO-CDI rates increased by 2.8%. When looking at specific classes of antibiotics, 10 DOT per 1,000 PD increases in the use of carbapenems, cephalosporins and piperacillin-tazobactam were associated with 1.3%, 0.6%, and 1.1% increases in the rate of HO-CDI, respectively. New to this batch of data was information regarding the use of nucleic acid amplification testing (NAAT) for diagnosis.

Upon examining temporal trends in hospital use of NAAT testing, the authors found that hospitals using only NAAT diagnostic tests for CDI had a 16% higher HO-CDI rate. “Even when controlling for NAAT use and other known patient and hospital confounders, we found strong positive cross-sectional and temporal associations between CDI and total and class specific antibiotic use,” Dr. Kazakova noted. “This indicates that future studies should include this factor in CDI models.” Among the four hospitals that decreased total antibiotic use during the study period by 30% or more, HO-CDI rates decreased by 40%. Decreases in fluoroquinolone and carbapenem use corresponded with annual decreases in HO-CDI rates of 4% to 7% and 4% to 8%, and decreases in cephalosporins, fluoroquinolones, and carbapenems corresponded with annual decreases in the HO-CDI rate of 4% to 16%. Mohamed H Yassin, MD, PhD, an associate professor of medicine, University of Pittsburgh School of Medicine, told Infectious Disease Special Edition that the paper showed that hospitals need to focus efforts on traditional infection prevention efforts as well as antibiotic stewardship programs to reduce unnecessary antibiotic use. “This paper sends a clear message to hospitals to increase their efforts further to reduce antibiotic use,” he said. And Dr. Kazakova added that additional study may help clarify appropriate antibiotic usage. “Since higher antibiotic use is associated with higher rates of CDI, more research into defining and quantifying inappropriate and unnecessary use ■ would be valuable,” she said. The sources reported no relevent financial disclosures.

I N F E C T I O U S D I S E A S E S P E C I A L E D I T I O N • FA L L 2 0 2 1

What's the Difference Between ID and Gastro C. difficile Recommendations? BY DAVID WILD

linicians have two updated sets of recommendations for managing patients with Clostridioides difficile infection (CDI), and there are some notable differences to consider. The Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA), recently released a focused update of their 2017 CDI recommendations, homing in on the advantages of fidaxomicin (Dificid, Cubist) over vancomycin for certain patients, and on the benefit of adjunctive bezlotoxumab (Zinplava, Merck) for achieving sustained response (Clin Infect Dis 2021 Jun 24. doi:10.1093/cid/ciab549). Earlier this year, the American College of Gastroenterology (ACG) issued wider ranging recommendations that were more equivocal regarding the superiority of fidaxomicin over vancomycin and emphasized the value of fecal microbiota transplantation (FMT) for managing recurrent CDI (Am J Gastroenterol 2021;116[6]:1124-1147). “The question of how physicians should choose between the different recommendations is a personal one and should not be specific to gastroenterology or infectious disease,” said CDI expert Paul Feuerstadt, MD. “As physicians, we are trained to review the literature and be critical ourselves, and I would suggest doing the same for the guidelines and determining which recommendation might

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fit your practice best,” added Dr. Feuerstadt, an assistant clinical professor of medicine in the Division of Digestive Disease at Yale New Haven Hospital, in Connecticut, who was not involved in developing either set of recommendations.

Treatment: Fidaxomicin The focused IDSA/SHEA update includes three new recommendations, all of which are “conditional,” reflecting low to moderate certainty based on the existing evidence. The first two recommendations specify that fidaxomicin is preferred over vancomycin for patients with an initial CDI episode or a first recurrence. For those with a first CDI episode, vancomycin is now a recommended alternative to fidaxomicin, whereas metronidazole is suggested only for patients with an initial nonsevere CDI episode and only when fidaxomicin and vancomycin are unavailable. The fidaxomicin recommendations are based on pooled analyses conducted by the authors, in which they found the likelihood of sustained CDI response four weeks after treatment for a first episode was 16% higher with fidaxomicin than with vancomycin. They also found that for patients with recurrent CDI, fidaxomicin increased sustained CDI response one month after the end of therapy by 27% compared with vancomycin.

Although fidaxomicin has a clinical advantage over vancomycin, “a big barrier that keeps the recommendation for fidaxomicin conditional is its high cost,” said Stuart Johnson, MD, the lead author of the IDSA/ SHEA recommendations. Dr. Johnson, a professor of medicine at Loyola University Stritch School of Medicine, in Maywood, Ill., cited an average sales price of $4,871 per 20-tablet package as a prohibitive factor for some. In contrast to the IDSA/SHEA guidelines, the ACG guidelines place vancomycin and fidaxomicin on the same footing for the management of a first episode of nonfulminant CDI, leaving metronidazole as a suggested treatment for initial nonsevere CDI in very low-risk patients. Berkeley Limketkai, MD, PhD, a co-author of the ACG guidelines, said the evidence that the IDSA/ SHEA group used to develop their recommendation “was not compelling enough to ignore the potential role and benefit of vancomycin for treatment of CDI.” Dr. Limketkai, the director of clinical research at the Center for Inflammatory Bowel Diseases at the University of California, Los Angeles David Geffen School of Medicine, said, “There are design flaws to the studies; there is no significant difference in initial cure, adverse events or mortality; and the difference in sustained clinical response favoring fidaxomicin was modest.” So, he added. “a more holistic view of the data would warrant recommending both fidaxomicin and vancomycin as viable treatment options.”

Prevention: Bezlotoxumab, FMT

However, in cases in which “logistics is not an issue, patients with a primary CDI episode and other risk factors for CDI recurrence may particularly benefit from receiving bezlotoxumab,” he added. In contrast to the IDSA/SHEA recommendation, the ACG issued a conditional recommendation suggesting that bezlotoxumab be considered for the prevention of CDI recurrence in patients at high risk for repeat episodes. The ACG was more emphatic about the use of FMT for preventing recurrence, issuing a strong recommendation that FMT be used after a second or later CDI recurrence and that it be administered in patients with severe and fulminant CDI refractory to antibiotic therapy. The focused IDSA/SHEA update does not include a revised statement on FMT use, instead sticking to the 2017 guidelines that urge clinicians to consider FMT only after patients have failed appropriate antibiotic treatment for at least two CDI recurrences. From Dr. Johnson’s perspective, the ACG “pulls the trigger on FMT a bit earlier,” but concerns about safety and access leave FMT farther back in the clinical algorithm in the IDSA/ SHEA recommendations. “Although there are good centers that perform rigorous screening of donors and selection of patients for FMT, screening donors in the real world can be poor, and there’s the possibility of transmitting infectious agents,” he said, pointing to FDA safety alerts published since 2019 documenting the transmission of pathogenic organisms (https://bit.ly/3gKXZED-IDSE). He added that the long-term safety of FMT is not fully understood and that the availability of thoroughly screened specimens from stool banks has been limited, especially during the COVID19 pandemic. Dr. Limketkai acknowledged that there is a paucity of data on which to create clear recommendations for some aspects of FMT use, and there are no data to indicate precisely how many antibiotic treatments should be attempted before referral to FMT. “The ACG guidelines are designed to be practical for the clinical gastroenterologist,” he said, “and so we’ve made some of these guidelines based largely on expert opinion, with caveats regarding the strength of the recommendations and the ■ assessments of the evidence.”

The ACG guidelines are wider ranging than the IDSA guidelines.

IDSA/SHEA also recommend bezlotoxumab for use as an adjunct to standard-ofcare (SOC) antibiotics for patients with recurrent CDI. The conditional recommendation is based on data showing that bezlotoxumab with SOC antibiotics reduced CDI recurrence at three months by 38% after initial clinical cure of primary or recurrent CDI. It also decreased CDI-associated hospital readmissions at one month by 54% compared with SOC antibiotics alone (N Engl J Med 2017;376:305-317). For patients with a primary episode and risk factors, including age older than 65 years, immunocompromised state and severe CDI presentation, IDSA/SHEA consider bezlotoximab to be an option. Noting that the drug seems to have clear benefits, Dr. Johnson said, “exclusion of the drug from most hospital inpatient formularies and the need to arrange an appointment at an infusion center present barriers to universal use.”

Dr. Feuerstadt reported financial relationships with Ferring, Merck and Seres. Dr. Johnson reported relationships with Acurx, Bio-K+, Cutis, Ferring, Pfizer, Summit Therapeutics and Synthetic Biologics. Dr. Limketkai reported no relevant financial disclosures.

I N F E C T I O U S D I S E A S E S P E C I A L E D I T I O N • FA L L 2 0 2 1

Is It Really a Penicillin Allergy? PharmD Intervention Improves Antibiotic Use, Reduces Costs BY GINA SHAW

bout 10% of all U.S. patients have a penicillin allergy noted in their medical records. But in more than 90% of patients, that label is incorrect (JAMA 2017;318[1]:82-83). Patients labeled with penicillin allergies often receive broad-spectrum antibiotics, which can lead to multidrugresistance. At the 2021 annual MAD-ID (Making a Difference in Infectious Diseases) virtual meeting, researchers from the Moses H. Cone Memorial Hospital, in Greensboro, N.C., and Lee Health, in Fort Myers, Fla., demonstrated the effectiveness of penicillin allergy assessment interventions in improving antibiotic use among these patients. In the first study, pharmacists at Moses Cone prospectively evaluated 48 patients admitted to the hospital with an infection between September 2020 and February 2021 for penicillin allergy, using one of three strategies for the assessment: • an amoxicillin challenge under direct observation for lowrisk patients; • penicillin skin testing followed by an amoxicillin challenge if skin testing was negative for moderate-risk patients; or • allergy/immunology referral or desensitization for patients with a positive penicillin skin test or a high-risk history, such as anaphylaxis, recurrent penicillin reactions or hypersensitivities to multiple beta-lactams. The investigators compared these patients with a retrospective cohort of 50 patients admitted from January 2019 to January 2020 who had a documented penicillin allergy. Of the 48 patients enrolled in the study, the allergy label was changed in 98% and the antibiotic therapy was optimized in 56%. Only one patient developed a delayed rash reaction and was relabeled as penicillin-allergic. Hospital readmission rates due to infection and total cost of therapy were significantly lower in the prospective arm. In the retrospective group, 19 patients (38%) were rehospitalized within 30 days; 11 of these cases were attributed to recurrent or worsening infection. In the prospective group, only seven patients (15%) met the criteria for 30-day readmission, just three of whom were determined to be due to recurrent or worsening infection (P<0.001). “By utilizing preferred antibiotics, we estimated that average drug cost savings was $192 per patient in the prospective group,” said Tyler Baumeister, PharmD, a PGY-2 infectious diseases pharmacy resident at Moses Cone. Although the prospective group had a longer overall antibiotic duration than the retrospective arm (9.9±12.1 vs. 6.3±3.6 days), the prospective group could use preferred antibiotics 77% of

IDSE.NET

the time, which the retrospective group had been unable to use.

The Lee Health Approach At Lee Health, a pharmacist-led penicillin allergy assessment was implemented beginning in July 2019, including pharmacist education and a standardized interview note template in the electronic health record (EHR). The interview template included questions such as: • What was the name of the agent which caused the event? • When did the reaction occur? • What was the course of the reaction? • How was the reaction treated? • Can you name other antibiotics you remember having taken and tolerated? After a chart review for allergy history and the patient/caregiver allergy interview, pharmacists documented their findings and updated the EHR, then discussed notable findings and deescalation recommendations, if any, with the patient’s provider. In a retrospective chart review of 100 patients with documented penicillin allergies who underwent the allergy assessment after admission to one of Lee Health’s four adult acute care hospitals between March 2019 and October 2020, more than one-fourth of the cohort (28%) was successfully transitioned to a preferred beta-lactam antibiotic after the interview. In total, 46% of patients’ regimens were deescalated. “While not all patients could be transitioned to a preferred beta-lactam due to a true allergy, the average cost savings was $76 per allergy interview, largely attributable to aztreonam avoidance,” said presenting author Elisabeth Chandler, PharmD, BCIDP, a pharmacy clinical specialist in infectious diseases. The cost savings in the entire patient cohort was ■ more than $7,000. The sources reported no relevant financial disclosures.

Adding an adjuvant makes a difference1

FLUAD® QUADRIVALENT is an MF59®-adjuvanted seasonal inﬂuenza vaccine approved for adults 65+2 Design ned to strengtthen, broaden, and len ngthen the du uration n of the 1,3,,4 immun ne respo onse

Learn more at ﬂuad.com For more information, please see Important Safety Information below and the Brief Summary on adjacent page.

INDICATION and IMPORTANT SAFETY INFORMATION INDICATION AND USAGE FLUAD® QUADRIVALENT is an inactivated influenza vaccine indicated for active immunization against influenza disease caused by influenza virus subtypes A and types B contained in the vaccine. FLUAD QUADRIVALENT is approved for use in persons 65 years of age and older. This indication is approved under accelerated approval based on the immune response elicited by FLUAD QUADRIVALENT.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Do not administer FLUAD QUADRIVALENT to anyone with a history of severe allergic reaction (e.g. anaphylaxis) to any component of the vaccine, including egg protein, or to a previous inﬂuenza vaccine.

WARNINGS AND PRECAUTIONS If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of receipt of prior inﬂuenza vaccine, the decision to give FLUAD QUADRIVALENT should be based on careful consideration of the potential beneﬁts and risks. Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine.

The immune response to FLUAD QUADRIVALENT in immunocompromised persons, including individuals receiving immunosuppressive therapy, may be lower than in immunocompetent individuals. Syncope (fainting) may occur in association with administration of injectable vaccines including FLUAD QUADRIVALENT. Ensure procedures are in place to avoid injury from falling associated with syncope. Vaccination with FLUAD QUADRIVALENT may not protect all vaccine recipients against inﬂuenza disease.

ADVERSE REACTIONS The most common ( 10%) local and systemic reactions in elderly subjects 65 years of age and older were injection site pain (16.3%), headache (10.8%) and fatigue (10.5%). To report SUSPECTED ADVERSE REACTIONS, contact Seqirus USA Inc. at 1-855-358-8966 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov. Before administration, please see the full US Prescribing Information for FLUAD QUADRIVALENT. FLUAD® QUADRIVALENT is a registered trademark of Seqirus UK Limited or its affiliates.

REFERENCES: 1. O’Hagan DT, Ott GS, De Gregorio E, Seubert A. The mechanism of action of MF59—an innately attractive adjuvant formulation. Vaccine. 2012;30(29):4341-4348. doi:10.1016/j.vaccine.2011.09.061 2. FLUAD QUADRIVALENT. Package insert. Seqirus Inc; 2020. 3. O’Hagan DT, Ott GS, Nest GV, Rappuoli R, Del Giudice G. The history of MF59® adjuvant: a phoenix that arose from the ashes. Expert Rev Vaccines. 2013;12(1):13-30. doi:10.1586/erv.12.140 4. Banzhoff A, Pellegrini M, Del Giudice G, Fragapane E, Groth N, Podda A. MF59-adjuvanted vaccines for seasonal and pandemic inﬂuenza prophylaxis. Inﬂuenza Other Respir Viruses. 2008;2(6):243-249. doi:10.1111/j.1750-2659.2008.00059.x FLUAD QUADRIVALENT and MF59 are registered trademarks of Seqirus UK Limited or its affiliates. Manufactured by: Seqirus Inc., 475 Green Oaks Parkway, Holly Springs, NC 27540, USA Distributed by: Seqirus USA Inc., 25 Deforest Avenue, Summit, NJ 07901, USA ©2021 Seqirus USA Inc. May 2021 USA-aQIV-21-0012

FLUAD® QUADRIVALENT (Influenza Vaccine, Adjuvanted) Injectable Emulsion for Intramuscular Use 2020-2021 Formula

BRIEF SUMMARY OF PRESCRIBING INFORMATION Consult the full US Prescribing Information for complete product information.

Table 1b. Percentages of Subjects Reporting Solicited Systemic Adverse Reactionsa in the Solicited Safety Populationb within 7 Days of Vaccination (Study 1)

INDICATIONS AND USAGE FLUAD QUADRIVALENT is an inactivated influenza vaccine indicated for active immunization against influenza disease caused by influenza virus subtypes A and types B contained in the vaccine. FLUAD QUADRIVALENT is approved for use in persons 65 years of age and older. This indication is approved under accelerated approval based on the immune response elicited by FLUAD QUADRIVALENT. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial. For intramuscular injection only. CONTRAINDICATIONS Do not administer FLUAD QUADRIVALENT to anyone with a history of severe allergic reaction (e.g. anaphylaxis) to any component of the vaccine, including egg protein, or to a previous influenza vaccine. WARNINGS AND PRECAUTIONS Guillain-Barré Syndrome: If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of receipt of prior influenza vaccine, the decision to give FLUAD QUADRIVALENT should be based on careful consideration of the potential benefits and risks. The 1976 swine influenza vaccine was associated with an elevated risk of GBS. [see Reference (1)] Evidence for a causal relationship of GBS with other influenza vaccines is inconclusive; if an excess risk exists, it is probably slightly more than 1 additional case per 1 million persons vaccinated. Preventing and Managing Allergic Reactions: Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine. Altered Immunocompetence: The immune response to FLUAD QUADRIVALENT in immunocompromised persons, including individuals receiving immunosuppressive therapy, may be lower than in immunocompetent individuals. Syncope: Syncope (fainting) may occur in association with administration of injectable vaccines including FLUAD QUADRIVALENT. Ensure procedures are in place to avoid injury from falling associated with syncope. Limitations of Vaccine Effectiveness: Vaccination with FLUAD QUADRIVALENT may not protect all vaccine recipients against influenza disease. ADVERSE REACTIONS The most common (≥10%) local and systemic reactions in elderly subjects 65 years of age and older were injection site pain (16.3%), headache (10.8%) and fatigue (10.5%). Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a vaccine cannot be directly compared to rates in the clinical trials of another vaccine and may not reflect rates observed in clinical practice. The safety of FLUAD QUADRIVALENT was evaluated in two clinical studies in 4269 elderly subjects 65 years of age and older. Study 1 (NCT02587221) was a multi-center, randomized, observer-blind, non-influenza comparator-controlled efficacy and safety study conducted in 12 countries during the 2016-2017 Northern Hemisphere and 2017 Southern Hemisphere seasons. In this study, 3381 subjects received FLUAD QUADRIVALENT and 3380 subjects received a US-licensed non-influenza comparator vaccine (Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Boostrix® [GlaxoSmithKline Biologicals]). The mean age of subjects at enrollment was 72 years, 62% were female, 48% White, 34% Asian, 16% Other, 2% American Indian/Alaska Native, and 18% of Hispanic/Latino ethnicity. Solicited local and systemic adverse reactions were collected for 7 days after vaccination in a subset of 665 subjects who received FLUAD QUADRIVALENT and 667 subjects who received the comparator vaccine. The percentages of subjects reporting solicited local adverse reactions are presented in Table 1a and systemic adverse reactions are presented in Table 1b. Onset usually occurred within the first 2 days after vaccination. The majority of solicited reactions resolved within 3 days. a

Table 1a. Percentages of Subjects Reporting Solicited Local Adverse Reactions in the Solicited Safety Populationb within 7 Days of Vaccination (Study 1) Local (Injection site) Reactionsc Injection site pain Erythema ≥25mm Induration ≥25mm Ecchymosis ≥25mm

FLUAD QUADRIVALENT N=595-659 16.3 3.8 4.0 0.5

Solicited Safety Population: all subjects in the exposed population who received a study vaccine and provided post-vaccination solicited safety data Severe reactions of each type were reported in 1.1% or fewer subjects receiving FLUAD QUADRIVALENT; severe reactions of each type were also reported in the comparator group at similar percentages. Severe deﬁnitions: Erythema, Induration and Ecchymosis = >100 mm diameter; Injection site pain = prevents daily activity.

Non-Influenza Comparator Vaccine N=607-664 11.2 1.8 2.6 0.7

Systemic Reactionsc Headache Fatigue Myalgia Arthralgia Chills Diarrhea Nausea Loss of appetite Fever ≥100.4°F (38°C) Vomiting

FLUAD QUADRIVALENT N=595-659 10.8 10.5 7.7 7.3 5.0 4.1 3.8 3.6 1.7 0.8

Non-Influenza Comparator Vaccine N=607-664 8.3 8.8 6.1 6.6 3.9 3.0 2.3 3.6 1.2 1.1

Study 1: NCT02587221 Abbreviation: N=number of subjects with solicited safety data Non-Inﬂuenza Comparator Vaccine = combined Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Boostrix® (GlaxoSmithKline Biologicals) a All solicited systemic adverse events reported within 7 days of vaccination are included b Solicited Safety Population: all subjects in the exposed population who received a study vaccine and provided post-vaccination solicited safety data c Severe reactions of each type were reported in 1.1% or fewer subjects receiving FLUAD QUADRIVALENT; severe reactions of each type were also reported in the comparator group at similar percentages. Severe deﬁnitions: Nausea, Fatigue, Myalgia, Arthralgia, Headache, and Chills = prevents daily activity; Loss of appetite = not eating at all; Vomiting = 6 or more times in 24 hours or requires intravenous hydration; Diarrhea = 6 or more loose stools in 24 hours or requires intravenous hydration; Fever = ≥102.2°F (39°C).

Unsolicited adverse events (AEs) were collected for all subjects for 21 days after vaccination. Related unsolicited AEs were reported by 303 (9.0%) and by 261 (7.7%) of the subjects for FLUAD QUADRIVALENT and Boostrix, respectively. For FLUAD QUADRIVALENT, injection site pain and influenza-like illness were the only unsolicited adverse reactions reported in ≥ 1% of subjects (1.7% and 1.5%, respectively). Serious adverse events (SAEs) and potentially immune-mediated adverse events of special interest (AESIs) were collected up to 366 days after vaccination. SAEs were reported by 238 (7.0%) FLUAD QUADRIVALENT recipients and 234 (6.9%) comparator recipients. There were no SAEs, AESIs or deaths in this study that were related to FLUAD QUADRIVALENT. Study 2 (NCT03314662) was a multicenter, randomized, double-blind, comparator-controlled study conducted during the 2017-18 Northern Hemisphere influenza season. In this study, 888 subjects received FLUAD QUADRIVALENT, 444 subjects received the licensed adjuvanted trivalent vaccine (aTIV-1 - FLUAD® (trivalent formulation)) and 444 subjects received an adjuvanted trivalent influenza vaccine with an alternate B strain (aTIV-2). The mean age of subjects at enrollment who received FLUAD QUADRIVALENT was 72.5 years. Female subjects represented 56.6% of the study population and the racial distribution of subjects was 91.6% Caucasian, 7.0% Black or African American, and ≤ 1% each for Asian, Native Hawaiian or Pacific Islander, American Indian or Alaska Native or Other. Solicited local and systemic adverse reactions reported within 7 days after vaccination were similar to those reported for Study 1. Unsolicited AEs were collected for 21 days after vaccination. Related unsolicited AEs were reported by 39 (4.4%) and by 17-19 (3.8%-4.3%) of subjects administered FLUAD QUADRIVALENT or aTIV, respectively. For FLUAD QUADRIVALENT, injection site bruising (1.0%) was the only unsolicited adverse reaction reported in ≥ 1% of subjects. Serious AEs and AESIs were collected up to 181 days after vaccination. Within 6 months after vaccination, 37 (4.2%) FLUAD QUADRIVALENT recipients and 18-28 (4.1%-6.3%) aTIV recipients experienced an SAE. There were no SAEs, AESIs or deaths in this study that were related to the study vaccine. There were no AEs leading to withdrawal from the study. Postmarketing Experience: There are no postmarketing data available for FLUAD QUADRIVALENT. However, the postmarketing experience with FLUAD (trivalent formulation) is relevant to FLUAD QUADRIVALENT because both vaccines are manufactured using the same process and have overlapping compositions. Because these events are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to the vaccine. Blood and lymphatic system disorders: Thrombocytopenia (some cases were severe with platelet counts less than 5,000 per mm3), lymphadenopathy General disorders and administration site conditions: Extensive swelling of injected limb lasting more than one week, injection site cellulitis-like reactions (some cases of swelling, pain, and redness extending more than 10 cm and lasting more than 1 week) Immune system disorders: Allergic reactions including anaphylactic shock, anaphylaxis, and angioedema

Musculoskeletal and connective tissue disorders: Muscular weakness

Pediatric Use

Nervous systems disorders: Encephalomyelitis, Guillain-Barré Syndrome, convulsions, neuritis, neuralgia, parasthesia, syncope, presyncope

Safety and effectiveness of FLUAD and FLUAD QUADRIVALENT (same manufacturing process and overlapping composition with FLUAD) were evaluated in clinical trials conducted in children 6 months to <72 months of age. Data from these trials are inconclusive to demonstrate the safety and effectiveness of FLUAD in children 6 months to <72 months of age. The safety and effectiveness of FLUAD in infants less than 6 months of age and in children older than 72 months of age have not been evaluated.

Skin and subcutaneous tissue disorders: Generalized skin reactions including erythema multiforme, urticaria, pruritus or nonspeciﬁc rash Vascular disorders: Vasculitis, renal vasculitis DRUG INTERACTIONS Concomitant Use With Other Vaccines: No clinical data on concomitant administration of FLUAD QUADRIVALENT with other vaccines is available. If FLUAD QUADRIVALENT is given at the same time as other injectable vaccine(s), the vaccine(s) should be administered at different injection sites. Do not mix FLUAD QUADRIVALENT with any other vaccine in the same syringe. Concurrent Use With Immunosuppressive Therapies: Immunosuppressive or corticosteroid therapies may reduce the immune response to FLUAD QUADRIVALENT.

Geriatric Use Safety and immunogenicity of FLUAD QUADRIVALENT have been evaluated in adults 65 years of age and older. REFERENCE 1. Lasky T, Terracciano GJ, Magder L, et al. The Guillain-Barré syndrome and the 1992-1993 and 19931994 inﬂuenza vaccines. N Engl J Med 1998; 339(25):1797-1802. To report SUSPECTED ADVERSE REACTIONS, contact Seqirus at 1-855-358-8966 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary FLUAD QUADRIVALENT is not approved for use in persons < 65 years of age. There are insufﬁcient human data to establish whether there is a vaccine-associated risk with use of FLUAD QUADRIVALENT in pregnancy. There were no developmental toxicity studies of FLUAD QUADRIVALENT performed in animals. A developmental toxicity study has been performed in female rabbits administered FLUAD (trivalent formulation) prior to mating and during gestation. A 0.5 mL dose was injected on each occasion (a single human dose is 0.5 mL). Lactation Risk Summary FLUAD QUADRIVALENT is not approved for use in persons < 65 years of age. No human or animal data are available to assess the effects of FLUAD QUADRIVALENT on the breastfed infant or on milk production/excretion.

FLUAD QUADRIVALENT is a registered trademark of Seqirus UK Limited or its afﬁliates. Manufactured by: Seqirus Inc., 475 Green Oaks Parkway, Holly Springs, NC 27540, USA Distributed by: Seqirus USA Inc., 25 Deforest Avenue, Summit, NJ 07901, USA US License No. 2049 ©2021 Seqirus USA Inc. April 2021 USA-aQIV-21-0010

When Is It Safe to Stop ABx for Febrile Neutropenia? BY KAREN BLUM

t may be safe to discontinue or deescalate antibiotics in some cancer patients who develop febrile neutropenia (FN) before the condition resolves, but guidelines and studies are not yet fully conclusive, a panel of speakers said during the Hematology/Oncology Pharmacy Association’s 2021 virtual annual conference. Presenters offered evidence for and against early discontinuation of antibiotics. Marked by fever and absolute neutrophil count (ANC) of less than 500 cells/mm3, FN occurs in 5% to 80% of patients with solid tumors and hematologic malignancies, said Devon Greer, PharmD, BCOP, a clinical pharmacy specialist at BarnesJewish Hospital, in St. Louis. Risk factors include myelosuppressive chemotherapy regimens, older age and advanced disease. Although some patients are given granulocyte colonystimulating factor or fluoroquinolones as prophylaxis, the complication still can occur, she said. If so, patients generally are given broad-spectrum antibiotics, either intravenously or orally, until ANC recovers. Whether or not to stop antibiotics sooner has been a topic of interest, Dr. Greer said. Guidelines from groups such as the Infectious Diseases Society of America and the National Comprehensive Cancer Center recommend continuing antibiotics until ANC reaches at least 500 cells/mm3, said Jessie Signorelli, PharmD, BCOP, an attending clinical pharmacist at Massachusetts General Hospital, in Boston. Both organizations suggest considering deescalation to prophylactic antibiotics if patients are afebrile and hemodynamically stable. However, neither group mentions what patient population this action would be appropriate for, or

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provides any clinical criteria to guide decision making, she said. Some studies used for these guidelines date back decades, Dr. Signorelli noted. A 1966 study (Ann Intern Med 1966;64[2]:328-340) of patients with leukemia found that once ANC dropped below 500 cells/mm3, the rate of infection increased. A study (Am J Med 1979;67[2]:194-200) of pediatric patients with fever and neutropenia showed that when antibiotics were discontinued, some patients had recurrent fevers or documented infection, or died. However, the study was small, with only 17 patients in the group for whom antibiotics were halted, she noted. “For the first time, this showed us we really should be continuing treatment until count recovery,” Dr. Signorelli said. “The trial showed that discontinuing antibiotics can have devastating outcomes, and the benefit of continuing really outweighed the risk of increasing multidrug-resistant organisms.” A more recent study, from 2014 (Clin Microbiol Infect 2014;20[7]:O453-0455), also supports continuing antibiotics in FN. In this study of 38 patients with 59 episodes of neutropenia, only seven patients met the criteria to discontinue antibiotics. The average number of days of antibiotics saved was four; however, three patients had recurrent fever, of which two had gram-negative bacterial infections and one had septic shock. The trial was stopped early because two-thirds of patients with fever recurrence developed bacteremia, leading the authors to conclude that high-risk neutropenic patients are not appropriate candidates for antibiotic discontinuation, Dr. Signorelli said.

Better Stewardship May Be the Answer On the flip side, arguments can be made for better antibiotic stewardship for patients with FN. Society guidelines now contain “hedging language” noting that clinicians can consider deescalation or prophylactic antibiotics in the right patient population, said Jared Matya, PharmD, BCOP, a focused population pharmacist at Nebraska Medicine, in Omaha. Still to be determined is which patients are most appropriate for this option, he cautioned. There are more effective antibiotics available today than when the 1979 study was conducted, Dr. Matya said, and diagnostic and imaging tests also have come a long way. “Just because we deescalate does not mean you cannot reintroduce antibiotics and still have favorable outcomes,” he said, and while fevers are important, they can cause other issues not always related to infection, he reminded.. The ANTIBIOSTOP study (Infect Dis 2018;50[7]:539-549) of early discontinuation of antibiotics in 238 neutropenia patients either after 48 hours of being afebrile or after five days even if febrile provides some support for discontinuing antibiotics, Dr. Matya said. The study had a fairly high percentage of patients receiving induction chemotherapy for leukemia, who may be at higher risk for FN, he said, and some patients undergoing allogeneic stem cell transplant. The overall ven duration of antibiotic use was five to seven days—shorter than waiting for patientss to defervesce—and patients continued to have fever at the same rate regardless of when antibiotics were discontinued, he said, indicating antibiotics might be safely discontinued after 48 hours. The How Long trial (Lancet Haematol 2017;4[12]:e573-e583) randomized 157 FN patients to continue antibiotics until ANC rose above 500 cells/mm3 or discontinue them after 72 hours if patients were afebrile, had normal vital signs and no evidence of infection. The number of antibiotic free days was higher in the discontinued group, but other outcomes such as all-cause mortality and recurrent fever did not differ by much. There also was an increase in secondary infections such as candidiasis in the continued therapy group.

leading to worse outcomes such as increased medical costs and mortality (Int J Antimicrob Agents 2012;40[2]:123-126). An antibiotic use duration of more than seven days confers the greatest risk, he said. A recurrent theme in some studies is that patients continuing on empiric therapy often receive two to three weeks of antibiotics, which is a longer course than is given for known infections, Dr. Matya said. “It’s another potential argument for using good stewardship.” Continuing antibiotics until neutrophil counts recover is the safest option and an approach supported by treatment guidelines, Dr. Signorelli said. However, the strategy has limitations. “We are seeing an increase in the development of multidrug-resistant organisms in people with cancer,” she said, and continuing IV antibiotics requires patients to stay in the hospital, increasing length of stay and decreasing quality of life. Conversely, deescalating antibiotics is not yet fully endorsed by national guidelines and could increase resistance to fluoroquinolones. Another uncertainty is how long broad-spectrum antibiotics should be used before deescalation, Dr. Signorelli said. Some studies suggest five to seven days, while others recommend doing so after 48 to 72 hours. Also, what clinical criteria should be used? Should clinicians deescalate to fluoroquinolones or discontinue antibiotics altogether? Furthermore, should patients remain in the hospital for monitoring versus being discharged home? If patients are discharged, how soon should follow-up occur? Criteria for deescalation derived from studies (Ann Hematol 2020;99[8]:1917-1924, and others) indicate patients should be afebrile and hemodynamically stable for at least 72 hours, have no signs or symptoms of infection or documented microbiological or clinical infection, and have not taken antibiotics prior to becoming febrile, Dr. Signorelli said. The studies also suggest that to ensure success, patients should remain hospitalized for 48 hours of surveillance following antibiotic discontinuation if ANC is 500 cells/mm3 or lower. They should not be discharged if they reside more than 30 minutes from the nearest hospital and should have a caregiver who can drive them to the hospital if necessary. If fever recurs, patients should stay on broad-spectrum antibiotics until the neutrophil count rises to at least 500 cells/mm3, Dr. ■ Signorelli said.

Fe Febrile ne neutropenia oc occurs in 5% to 80% of cancers.

Drug Resistance Another Issue Antibiotic resistance is a documented problem in both the general population and patients with cancer, Dr. Matya said. Prior antibiotic therapy is a risk factor for infection with multidrug-resistant organisms, rendering patients more likely to require ICU admission or mechanical ventilation and

The sources reported no relevant financial disclosures.

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2-Dose Hepatitis B Vaccine More Seroprotective, Cost-Effective BY LEAH LAWRENCE

dministration of the two-dose adjuvanted hepatitis B virus vaccine (Heplisav-B, Dynavax Technologies) may be cost-effective in many of the adults recommended for HBV vaccination by the CDC and may result in cost savings in some high-risk groups (Vaccine 2021;39[33]:4733-4741). However, uptake of the two-dose vaccine may not be as high as it could be, according to Catherine Freeland, MPH, the public health program director of the Hepatitis B Foundation. “I don’t think it has gotten a lot of attention, although it is fairly new,” said Ms. Freeland, who admits her involvement in the hepatitis B arena may bias her opinion. “There could be a lot more awareness among the adult general practitioner community and a lot more outreach done to increase uptake.”

HBV Trends, Vaccinations In 2018, 3,322 cases of acute HBV were reported to the CDC, but with adjustment for under-ascertainment and underreporting, the estimated number is about 21,600. Between 850,000 to 2.4 million people in the United States are chronically infected with HBV (Hepatology 2021 Mar 3. doi:10.1002/ hep.31782). The CDC currently recommends HBV vaccination in all people from ages 0 to 18 years, all adults in risk groups for HBV infection, and any adults who want to be protected against HBV (MMWR Morb Mortal Wkly Rep 2018;67[1]:1-31).

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Unfortunately, recent numbers from the CDC estimated that as of 2018, a little less than one-third of U.S. adults had received a series of HBV vaccine (MMWR Morb Mortal Wkly Rep 2021 May 14. doi:10.15585/mmwr.ss7003a1). Two HBV vaccines are approved by the FDA. GlaxoSmithKline’s three-dose HBV vaccine Engerix-B was originally approved as a serum vaccine in 1989 and later as a recombinant vaccine. Dynavax Technologies’ two-dose Heplisav-B for adult vaccination was approved in late 2017. “The standard of care for many years was a three-dose adjuvant vaccine,” said Randall Hyer, MD, PhD, the senior vice president of global medical affairs at Moderna, and a former employee of Dynavax Technologies. “We know that if you get vaccinated, you want the antibody titer to exceed 10 million IU/mL. The problem with the three-dose adjuvant vaccine was not everybody got to 10, and you had to get three doses.” For the three-dose vaccine, doses are given at baseline, one month and six months. A 2011 study using data from the National Health Interview Survey found that about half of high-risk individuals and 40% of those without risk factors got one or more doses, but only 42% and 34%, respectively, completed the three-dose series (Vaccine 2011;29[40]:7049-7057). “The third dose is really a challenge, and that leaves people not fully immunized,” Ms. Freeland said. “In the public health space it is hard to get people to follow-up, so a two-dose

vaccine makes it less of a burden on the final results from a large an interim individual.” analysis of a post-marketing study conThe two-dose vaccine combines hepducted at Kaiser Permanente Southern atitis B surface antigen (HBsAg) with a California showed no evidence of an proprietary toll-like receptor 9 agonist increase in acute MI in patients receivadjuvant CpG 1018; it is given over ing Heplisav-B (Pharmacoepidemiol Drug the course of one month. When the Saf 2021;1-6). Advisory Committee on Immunization “There were no data to show an Practices Hepatitis Vaccines Work increase in autoimmune disease either,” Group conducted a systematic review Dr. Hyer said. of evidence, it found seroprotective Source: Hepatology 2021 Mar 3. doi:10. More recently, final data from a antibody levels to HBsAg were achieved 1002/hep.31782 study at Kaiser Permanente Southern in 90% to 100% of patients given the California showed that of more than two-dose vaccine compared with 70.5% to 90.2% of patients 10,000 adults who initiated the HBV vaccine series, 62.7% given the three-dose vaccine (MMWR Morb Mortal Wkly Rep completed the two-dose vaccine at 360 days compared with 2018;67[15]:455-458). 34.9% who completed the three-dose vaccine (JAMA Network According to Dr. Hyer, studies suggested some differences Open 2020;3[11]:e2027577). in adverse events between the two vaccines. For example, in Dr. Hyer was a co-author on the study looking at comone clinical study of the two-dose vaccine there was an imbal- parative cost-effectiveness of the two- versus three-dose ance of acute myocardial infarction (MI) among patients who HBV vaccines. This study was a follow-up to a previous continued on page 37 received the two- versus three-dose vaccine. However, the

WHO’s European Region Making Progress Toward HBV Control By Leah Lawrence The CDC recently updated its progress toward hepatitis B virus (HBV) control in the World Health Organization’s European Region (EUR) (MMWR Morb Mortal Wkly Rep 2021;70[30]:1029-1035). In 2019, an estimated 14 million people in Europe were chronically infected with HBV. During the period of 2016 to 2019, the EUR made substantial progress toward control of HBV. Specifically, of 53 countries in this region, 35 (73%) met the coverage targets of 90% or more for three doses of HBV vaccine, 19 (83%) met coverage of 90% or more for the birth dose, and 17 (57%) met coverage of 90% or more for HBV screening of pregnant women. “Most countries in the WHO European Region began childhood vaccination programs for hepatitis B 15 to 20 years ago,” said Nino Khetsuriani, MD, PhD, of the CDC’s Global Immunization Division, Center for Global Health. “As the report shows, most countries have achieved high coverage with hepatitis B vaccine doses given at birth and later in infancy. This vaccination progress has

allowed many countries in the European Region to maintain low levels of hepatitis B transmission and to reduce infections in countries with previously high levels of hepatitis B.” In January 2020, Italy and the Netherlands became the first two countries in this region to have achieved the regional HBV control by improving coverage with the HBV vaccine and intervention to prevent mother-to-child transfer, and documenting achievement of the HBV surface antigen seroprevalence target. “The key to achieving hepatitis B control is to vaccinate babies within 24 hours of birth, followed by two to three doses within months,” n six months, Dr. Khetsuriani said. “This This would prevent hepatitis B virus chronic hronic infections, which are the leading g cause of liver cancer globally.” According to Dr. Khetsuriani, hetsuriani, the EUR is ahead off some other regions in reducing ucing HBV burden, largely due ue to the early introduction of HPV vaccine and high vaccine

coverage. However, more work is needed. Several other countries in the EUR also may have achieved regional HBV control targets, but further documentation is required to verify those achievements. “Countries can further improve hepatitis B vaccination coverage by strengthening their immunization programs, including identifying and addressing the causes of vaccine hesitancy,” Dr. Khetsuriani said. “Countries that do not have enough data on the occurrence of hepatitis B virus in their populations should consider conducting special surveys or utilizing information from their pregnant women screening programs to document the low levels of hepatitis B infections.”

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Neonatal HBV: Where Are We in Preventing Chronic Infection? BY BOB KRONEMYER

ithout postexposure immunoprophylaxis, roughly 40% of infants born to hepatitis B virus (HBV)-infected mothers in the United States will develop chronic HBV infection, according to the CDC. Fortunately, since the implementation of universal childhood HBV vaccination in the early 1990s, “we have made tremendous inroads in decreasing new cases of neonatal HBV, on the order of about 90%,” said Ravi Jhaveri, MD, FIDSA, a professor of pediatrics at Northwestern University Feinberg School of Medicine, in Chicago. Ideally, the infants should receive both the hepatitis B vaccine and hepatitis B immune globulin (HBIG) within the first 12 hours after birth, according to Dr. Jhaveri. “The combination of these two injections will prevent about 90% of neonatal HBV cases,” he said. “HBIG basically serves to neutralize the virus that might be passed from mother to child, whereas the vaccine stimulates the infant’s own immunity so the infant is protected on an ongoing basis.” There is a window of 72 hours where the two injections can be administered, “but the sooner, the better,” Dr. Jhaveri said. Over the past decade, additional measures have decreased the rates of HBV breakthrough cases in mothers and infants. “We

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know that pregnant women have higher levels of hepatitis B infection and that the DNA levels in their bloodstream are very high: above the 200,000-IU/mL threshold,” he said. “If we start treating these mothers during pregnancy with an antiviral medicine in the 28-week range, we can reduce the amount of virus, and we can then prevent the transmission to babies. Mothers might also continue taking the medicine a bit after they deliver.” Current therapy for both mother and infant is well tolerated without any reported adverse events. “The babies do well and obviously they grow and thrive,” Dr. Jhaveri said. With no therapy, about 30% of all babies born to HBVpositive mothers will develop the virus, according to Dr. Jhaveri. “Some of these babies may have no symptoms for many years,” he said. “But in the old days, before we had any of these interventions, there was a significant percentage of infants who developed severe forms of hepatitis that manifested within the first few weeks of birth.” To eliminate all cases of neonatal HBV, Dr. Jhaveri said providers need to become better at identifying pregnant women who are at a higher risk level of HBV and increasing use of antivirals in preventing breakthrough cases. John W. Ward, MD, a professor of public health at Emory

An infant infected with HBV at birth has a:

90% chance of developing a chronic infection

25% risk for premature death from hepatitis B–related liver disease, including liver cancer. University, in Atlanta, and the director of the Coalition for Global Hepatitis Elimination, said an infant infected with HBV at birth has a 90% chance of developing a chronic infection, along with a 25% risk for premature death from hepatitis B–related liver disease, including liver cancer. “For many, this is a shortening of several decades of their life expectancy,” he said. More than 90% of pregnant women in the United States are screened for HBV infection, according to Dr. Ward. “We know that the virus is transmitted to the infant typically during birth, not earlier in the development process,” he said. “So, by giving a vaccine to the infant immediately after birth, the vaccine can interrupt transmission.” For mothers who test positive for HBV infection during pregnancy and have a high viral load, “there is an increased chance that the infection will overwhelm the vaccine protection because there are simply too many viruses to contend with,” Dr. Ward said. “Hence, to assure protection of these infants, there is value in giving the expectant mother hepatitis B therapy to lower her viral load and increase the protection of her infant provided by the vaccine.” There is compelling clinical evidence for mothers to receive appropriate HBV treatment, including for their own health, in the form of either tenofovir or a different version of tenofovir known as tenofovir alafenamide, he added. Entecavir also can be given as treatment; however, the drug cannot be given during pregnancy. For infants, the hepatitis B vaccine alone provides about 75% protection and up to 95% when combined with a dose of HBIG, according to Dr. Ward. “Presently, 76% of all infants receive the vaccine,” he said. Because of the different stages of HBV and how it interacts with the body, the vaccine and HBIG are the only two acceptable therapies for infants immediately after birth. “That is why prevention is so important,” Dr. Ward said. “Children and adolescents normally are not treated until later in life, ■ and there is no cure for chronic HBV infection. Dr. Jhaveri is a consultant to Dynavax Technologies. Dr. Ward reported no relevant financial disclosures.

HBV Vaccination continued from page 35

cost-effectiveness study that showed favorable cost-effectiveness for the two-dose vaccine in multiple at-risk populations (Vaccine 2013;31:4024-4032). The updated study with 2020 costs showed that despite higher per-dose cost of the two-dose vaccine, it still was cost-effective or led to cost savings compared with other available HBV vaccines. “This is essentially an update supporting use of Heplisav-B in the adult population,” Dr. Hyer said. A cost–utility analysis assessing the two-dose vaccine found that it led to cost savings compared with the threedose vaccine in adults with diabetes, obesity, chronic kidney disease, HIV, and in older adults and people who inject drugs (Vaccine 2020;38[51]:8206-8215).

Of >10,000 adults who initiated the HBV vaccine series: 62.7% completed the 2-dose vaccine at 360 days compared with 34.9% who completed the 3-dose vaccine. Source: JAMA Network Open 2020;3(11):e2027577

Ms. Freeland said she thinks the availability of a two-dose vaccine should be beneficial in ensuring that adults are fully protected against HBV. Anecdotally, however, she has heard both pros and cons to the pricing of the two-dose vaccine, and about challenges related to availability of the two-dose vaccine. “There is definitely a lack of awareness about hepatitis B in general, and even less awareness that this new vaccine even exists,” Ms. Freeland said. “Viral hepatitis just does not get a ton of attention and remains an not discussed issue in the community.” Dr. Hyer also admitted that uptake of the two-dose vaccine, which has been on the market for more than three years, is not what people expected. He said this may partly be due to incentivizing use of the three-dose vaccine over the two-dose vaccine by packaging it with other types of vaccines at a lower price point. “One thing we can say right now is that the word vaccine is front and center; it is on the front page almost every day,” Dr. Hyer said. “It generates a background in the scientific community that vaccines work and work well. How that will translate into the public health setting for other diseases is a ■ bigger question.” Dr. Hyer is a former employee of Dynavax Technologies. Ms. Freeland reported no relevant financial disclosures.

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Pan-Resistant C. auris Spreading in Texas and Washington, D.C. BY ETHAN COVEY

recent CDC report describes instances of the spread of pan- and echinocandin-resistant strains of Candida auris in Texas and Washington, D.C., shining light on the evolving threat posed by drug-resistant fungal infections in the United States. “This report is the first evidence suggesting spread of echinocandin- and pan-resistant strains of C. auris among patients, rather than cases in which patients develop resistance independently during their own antifungal treatment,” said Meghan Lyman, MD, a medical officer with the CDC’s Division of Foodborne, Waterborne, and Environmental Diseases, National Center for Emerging and Zoonotic Infectious Diseases (MMWR Morb Mortal Wkly Rep 2021;70[29]:1022-1023). It is estimated that 85% of U.S. C. auris isolates are resistant to azoles, 33% to amphotericin B and 1% to echinocandins. Due to their high level of effectiveness against C. auris, echinocandins are recommended as first-line therapy. However, reports of resistance to echinocandins have begun to appear. “Resistance to echinocandins is a concerning public health threat that health care professionals should be aware of,” Brian Katzowitz, MS, a health communications specialist with the CDC, told Infectious Disease Special Edition. “With only three classes of antifungals available, treatment options for C. auris infections are limited, and very few options exist for treatment of cases that are pan-resistant or echinocandin-resistant.” om the Antibiotic The MMWR report focuses on data from tarting in Resistance Laboratory Network, which, starting n Texas January 2021, detected clusters of C. auris in vels and Washington, D.C., that exhibited high levels of drug resistance. In Washington, D.C., of 101 total C. auriss cases identified between January and April 2021, three isolates that were identified at a single long-term care facility were found to be pan-resistant. And in Texas, among 22 cases identified during the same period, two were pan-resistant, and five additionall hicases were found to be resistant to both echinocandins and fluconazole. covered In the Texas cluster, the cases were discovered at two facilities in the same city that share patients; ute care two of the patients were at a long-term acute hospital, three at a short-term acute care hospital and two at both facilities. orces the According to Dr. Lyman, such spread reinforces edures. importance of proper infection control procedures.

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“Infection control involves proper and consistent adherence to recommended practices for hand hygiene, personal protective equipment use, and cleaning and disinfection of medical equipment and the health care environment,” she said. “C. auris can persist on patients and in the environment for weeks and can spread among patients through contact with contaminated surfaces. For this reason, it is important to quickly identify C. auris in a hospitalized patient so that health care facilities can take special precautions to stop its spread.” Dr. Lyman added that clinicians should conduct resistance testing on samples from patients with C. auris infection, especially those with treatment failure. And prompt, well-coordinated efforts are key to preventing further spread.

Antifungal Susceptibility Testing “Antifungal susceptibility testing plays a critical role in early identification of antifungal resistance and guiding treatment decisions,” she said. “Early and accurate identification of C. auris, rigorous infection control practices and streamlined communication between facilities are key to reducing the spread of C. auris.” Epidemiologists believe that the Texas and Washington, D.C., clusters were not linked. Yet, the fact that they occurred at the same time, independently of one another, likely means that further transmission may be occurring in U.S. health care facilities. With such clu clusters occurring, Dr. Lyman emphasized the im importance of further research into effective ttreatment options for these drugresistant infections. “Dat “Data about treatment and health outcomes of patients with echinocandinresista resistant and pan-resistant infections are lim limited,” she told Infectious Disease Special Edition. “More research is needed to ident identify the appropriate treatment for pan-resis pan-resistant infections.” “Ultima “Ultimately, it’s critical that we can continue to identify sources and possible amplifying fac factors of C. auris,” she continued. “Improving our understanding in these areas can help us preven prevent future introductions of C. auris and new fungal fung pathogens into human populations.” ■ Dr. Lyman reported re no relevant financial disclosures.

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Now available in a new formulation produced using a caprylate chromatography process

HyperHEP B is the only hepatitis B immune globulin also offered in a pre-filled syringe specifically for neonatal administration. www.HyperHEPB.com

HyperHEP B is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent that can cause disease. There is also the possibility that unknown infectious agents may be present in such products.

HyperHEP B is available through all major distributors. References: 1. Centers for Disease Control and Prevention. Hepatitis B. In: Hamborsky J, Kroger A, Wolfe S, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. 13th ed. Washington, DC: Public Health Foundation; 2015:149-174. http://cdc.gov/vaccines/pubs/pinkbook/downloads/hepb.pdf. Accessed December 23, 2020. 2. Centers for Disease Control and Prevention. Hepatitis B questions and answers for health professionals. https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm#overview. Accessed December 23, 2020. 3. Schillie S, Murphy TV, Fenlon N, et al. Update: Shortened interval for postvaccination serologic testing of infants born to Hepatitis B-infected mothers. MMWR Morb Mortal Wkly Rep. 2015;64(39):1118-1120.

Please see Important Safety Information and brief summary of Prescribing Information for HyperHEP B® on adjacent pages, or visit www.HyperHEPB.com for full Prescribing Information. © 2021 Grifols All rights reserved August 2021 US-HH-2100019

Important Safety Information HyperHEP B® (hepatitis B immune globulin [human]) is indicated for postexposure prophylaxis in the following situations: acute exposure to blood containing HBsAg, perinatal exposure of infants born to HBsAg-positive mothers, sexual exposure to an HBsAg-positive person, and household exposure to persons with acute HBV infection. HyperHEP B should be given with caution to patients with a history of prior systemic allergic reactions following the administration of human immunoglobulin preparations. Epinephrine should be available. In patients who have severe thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections, hepatitis B immune globulin (human) should be given only if the expected benefits outweigh the risks. Local pain and tenderness at the injection site, urticaria, and angioedema may occur; anaphylactic reactions, although rare, have been reported following the injection of human immunoglobulin preparations. Administration of live virus vaccines (eg, MMR) should be deferred for approximately 3 months after hepatitis B immune globulin (human) administration. HyperHEP B is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, and, theoretically, the Creutzfeldt-Jakob disease (CJD) agent that can cause disease. There is also the possibility that unknown infectious agents may be present in such products. Please see brief summary of Prescribing Information for HyperHEP B® on adjacent page, or visit www.HyperHEPB.com for full Prescribing Information.

HyperHEP B

Immune Globulin ( Human) BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION INDICATIONS AND USAGE Recommendations on postexposure prophylaxis are based on available efficacy data and on the likelihood of future HBV exposure for the person requiring treatment. In all exposures, a regimen combining Hepatitis B Immune Globulin (Human) with hepatitis B vaccine will provide both short- and long-term protection, will be less costly than the two-dose Hepatitis B Immune Globulin (Human) treatment alone, and is the treatment of choice. HyperHEP B is indicated for postexposure prophylaxis in the following situations: Acute Exposure to Blood Containing HBsAg After either parenteral exposure, e.g., by accidental “needlestick” or direct mucous membrane contact (accidental splash), or oral ingestion (pipetting accident) involving HBsAg-positive materials such as blood, plasma or serum. For inadvertent percutaneous exposure, a regimen of two doses of Hepatitis B Immune Globulin (Human), one given after exposure and one a month later, is about 75% effective in preventing hepatitis B in this setting. Perinatal Exposure of Infants Born to HBsAg-positive Mothers Infants born to HBsAg-positive mothers are at risk of being infected with hepatitis B virus and becoming chronic carriers. This risk is especially great if the mother is HBeAg-positive. For an infant with perinatal exposure to an HBsAg-positive and HBeAg-positive mother, a regimen combining one dose of Hepatitis B Immune Globulin (Human) at birth with the hepatitis B vaccine series started soon after birth is 85%–95% effective in preventing development of the HBV carrier state. Regimens involving either multiple doses of Hepatitis B Immune Globulin (Human) alone or the vaccine series alone have 70%–90% efficacy, while a single dose of Hepatitis B Immune Globulin (Human) alone has only 50% efficacy. Sexual Exposure to an HBsAg-positive Person Sex partners of HBsAg-positive persons are at increased risk of acquiring HBV infection. For sexual exposure to a person with acute hepatitis B, a single dose of Hepatitis B Immune Globulin (Human) is 75% effective if administered within 2 weeks of last sexual exposure. Household Exposure to Persons with Acute HBV Infection Since infants have close contact with primary care-givers and they have a higher risk of becoming HBV carriers after acute HBV infection, prophylaxis of an infant less than 12 months of age with Hepatitis B Immune Globulin (Human) and hepatitis B vaccine is indicated if the mother or primary care-giver has acute HBV infection. Administration of Hepatitis B Immune Globulin (Human) either preceding or concomitant with the commencement of active immunization with Hepatitis B Vaccine provides for more rapid achievement of protective levels of hepatitis B antibody, than when the vaccine alone is administered. Rapid achievement of protective levels of antibody to hepatitis B virus may be desirable in certain clinical situations, as in cases of accidental inoculations with contaminated medical instruments. Administration of Hepatitis B Immune Globulin (Human) either 1 month preceding or at the time of commencement of a program of active vaccination with Hepatitis B Vaccine has been shown not to interfere with the active immune response to the vaccine. CONTRAINDICATIONS None known.

WARNINGS HyperHEP B is made from human plasma. Products made from human plasma may contain infectious agents, such as viruses, and, theoretically, the Creutzfeldt-Jakob Disease (CJD) agent that can cause disease. The risk that such products will transmit an infectious agent has been reduced by screening plasma donors for prior exposure to certain viruses, by testing for the presence of certain current virus infections, and by inactivating and/or removing certain viruses. Despite these measures, such products can still potentially transmit disease. There is also the possibility that unknown infectious agents may be present in such products. Individuals who receive infusions of blood or plasma products may develop signs and/or symptoms of some viral infections, particularly hepatitis C. ALL infections thought by a physician possibly to have been transmitted by this product should be reported by the physician or other healthcare provider to Grifols Therapeutics LLC [1-800-520-2807]. The physician should discuss the risks and beneﬁts of this product with the patient, before prescribing or administering it to the patient. HyperHEP B should be given with caution to patients with a history of prior systemic allergic reactions following the administration of human immune globulin preparations. Epinephrine should be available. In patients who have severe thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injections, Hepatitis B Immune Globulin (Human) should be given only if the expected beneﬁts outweigh the risks. PRECAUTIONS General HyperHEP B should not be administered intravenously because of the potential for serious reactions. Injections should be made intramuscularly, and care should be taken to draw back on the plunger of the syringe before injection in order to be certain that the needle is not in a blood vessel. Intramuscular injections are preferably administered in the deltoid muscle of the upper arm or lateral thigh muscle. The gluteal region should not be used as an injection site because of the risk of injury to the sciatic nerve. An individual decision as to which muscle is injected must be made for each patient based on the volume of material to be administered. Laboratory Tests None required. Drug Interactions Although administration of Hepatitis B Immune Globulin (Human) did not interfere with measles vaccination, it is not known whether Hepatitis B Immune Globulin (Human) may interfere with other live virus vaccines. Therefore, use of such vaccines should be deferred until approximately 3 months after Hepatitis B Immune Globulin (Human) administration. Hepatitis B Vaccine may be administered at the same time, but at a different injection site, without interfering with the immune response. No interactions with other products are known. Pregnancy Animal reproduction studies have not been conducted with HyperHEP B. It is also not known whether HyperHEP B can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. HyperHEP B should be given to a pregnant woman only if clearly needed. Pediatric Use Safety and effectiveness in the pediatric population have not been established. ADVERSE REACTIONS Local pain and tenderness at the injection site, urticaria and angioedema may occur; anaphylactic reactions, although rare, have been reported following the injection of human immune globulin preparations.

Grifols Therapeutics LLC Research Triangle Park, NC 27709 USA U.S. License No. 1871

3059642 Revised: 12/2020

Pulmonary Infections Due to Endemic Fungi: Misdiagnosis Is Often the Norm BY BOB KRONEMYER

ases of pulmonary infections due to endemic fungi in the United States frequently are misdiagnosed, often because they are not considered in the differential. They are relatively rare and can mimic other pulmonary diseases. Histoplasmosis, for instance, can be mistaken for lung cancer, so some patients get extensive oncology workups instead of antifungal treatment, explained Mitsuru Toda, PhD, an epidemiologist in the Mycotic Diseases Branch at the CDC. In addition to histoplasmosis, the most common form of endemic mycoses in the United States is coccidioidomycosis. Coccidioidomycosis is found in western states, mostly in Arizona and California, “but we are seeing locally acquired cases in the Pacific Northwest, including the state of Washington,” Dr. Toda said. Histoplasmosis, in contrast, is concentrated in the central and eastern regions of the country. “It is estimated that 60% to 90% of the people who live around the Ohio and Mississippi River Valleys can be exposed to histoplasmosis in their lifetime,” Dr. Toda said. Although coccidioidomycosis is a nationally notifiable disease, only half of the states report it to the CDC. “We receive about 15,000 new infection reports a year,” Dr. Toda said. “In 2019, the number of cases was 18,407.” Roughly 6,700 cases of coccidioidomycosis annually require

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hospitalization, and about 1% of patients die. For histoplasmosis, roughly 4,600 cases require hospitalization, with a 5% mortality rate. Coccidioidomycosis likely induces symptomatic disease in about 40% of infected people versus about 1% for histoplasmosis. When you spread these diseases over the entire United States, they can appear quite rare, according to Dr. Toda. “But when you examine hot spot areas, they are actually quite prevalent,” she said. “For instance, in Phoenix, it is believed that up to one-third of pneumonias is caused by coccidioidomycosis.” Nathan Bahr, MD, an associate professor of infectious diseases at the University of Kansas Medical Center, in Kansas City, said there have always been infections due to endemic fungi around the United States and the world. “But we are seeing more, due to increased use of immune-suppressive medications and the ongoing HIV pandemic,” he said. The exact reasons these fungi thrive vary by the fungus. “The environment is a big part, and that is why climate change is important,” Dr. Bahr said. Dr. Toda said it is important for physicians to be more familiar with these diseases, because she expects their numbers to increase. “With changes in temperature and climate, we know that the geographic distribution of these fungal diseases is going to expand,” she said.

The reality, though, is that “so little research is being done in endemic mycoses right now that we do not truly know what the epidemiology is,” said Andrej Spec, MD, an assistant professor of medicine at Washington University in St. Louis. “In fact, we have not updated our epidemiology maps in a thorough and consistent way since the 1960s, due to expense. Back then, the only entity able to create epidemiology maps was the U.S. Navy.” The big challenge with endemic fungi is that as the climate changes, their locations change and to unexpected places, according to Dr. Spec. “If you don’t know to look for endemics, you do not diagnose them,” he said. “Even in endemic areas, people are misdiagnosed at very high rates or have a late diagnosis.” The fungi have shifted from almost exclusively in the Midwest to now the East Coast. “Anyone who lives in an endemic area is inhaling the fungus basically every day,” Dr. Spec said. “Manifesting a clinical disease is the result of perhaps a weakened immune system or a larger inoculum.” Because these fungi cause highly pleomorphic diseases, “you should always maintain a high level of suspicion for them,” Dr. Spec said. “Rarely will you make a diagnosis by accident. You literally have to look for it to help the patient.” Most patients present with a mild fever or chills that last for a long period, along with some weight loss. “Efficient diagnoses are usually serologic or antigen-based,” said Dr. Spec, the director of the invasive mycoses clinic at Washington University. Recognition of the potential for infection is really important, the experts said, because travel can mean that an infection seen in New Jersey might have come from a trip to Arizona, and immigrants might bring back unusual fungal diseases from their native countries. A clinician in the United States, for instance, might not recognize that talaromycosis is a concern for someone immigrating from Vietnam, according to Dr. Bahr. Likewise, a clinician in Florida might not think of his patient as being at risk for histoplasmosis, but he or she could be. “As with any infection, a delay in diagnosis can lead to bad outcomes,” said Dr. Bahr, who believes these fungi should be considered in the differential diagnoses. “Every situation is different, but particularly in a patient that had recurrent pulmonary infections, or has immune suppression, these infections should be considered and tested for,” he said. Dr. Bahr is senior author of a newly published review of diagnosis of pulmonary infections due to endemic fungi in the journal Diagnostics (2021;11[5]:856), which found that a high level of suspicion is required, “especially in those with recurrent pneumonia, which may really be a progression of an endemic fungal infection, and/or immune suppression,” he said. “Clinicians should familiarize themselves with the endemic fungal infections in their regions and the general distributions of all endemic fungal infections.”

Dr. Bahr also urged clinicians to closely monitor the literature and be aware of resources, such as the CDC and its mycoses study group, to keep up-to-date with any changes in the distribution of these infections. There is also a need for medications for severe disease that are more effective, tolerable and less toxic. Treatment has remained the same for decades: up-front therapy with amphotericin for extremely ill patients or up-front therapy with one of the azoles if the patient is doing well.

The current estimates of where the fungus that causes histoplasmosis (above) and Coccidioidomycosis (below) live in the environment in the United States. Source: CDC

Such therapy reduces mortality rates, according to Dr. Spec, but there are longer term consequences, such as cognitive decline with brain infections or a weaker and more fatigued state overall. “Unfortunately, we have not tested many of the newer drugs that are less toxic and easier to use,” Dr. Spec said. “We also need additional younger investigators in the field.” Dr. Toda noted that ibrexafungerp (Brexafemme, Scynexis) is a new class of antifungal drug that was approved by the FDA in June to treat vaginal yeasts. But there is hope that someday it might prove successful in treating endemic mycoses. She is also excited about a potential coccidioidomycosis ■ vaccine, which is currently being tested in dogs. The sources reported no relevant financial disclosures.

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Dog Parasite Develops Multidrug Resistance to Treatment BY MARIE ROSENTHAL

.S. veterinarians rely on three types of drugs to kill hookworms, but the parasites are apparently becoming resistant to all of them. Canine hookworms can infect humans. Hookworms (Ancylostoma caninum, Ancylostoma braziliense, Uncinaria stenocephala) are common parasites that latch onto an ey feed on tissue fluids and blood. animal’s intestines, where they ence dramatic weight loss, bloody Infected animals can experience mong other issues. stool, anemia and lethargy, among arch from the University of According to new research Georgia (UGA), they have become rasitol multidrug resistant (Int J Parasitol p 2. Drugs Drug Resist 2021 Sep 05). doi:10.1016/j.ijpddr.2021.08.005). wed The researchers followed reycurrent and former racing greyarhounds. Dog racetracks are pardticularly conducive to spreadhe ing the parasite due to the isandy ground of the facilid ties, an ideal breeding ground

for hookworms. Because of the conditions, all the dogs are dewormed about every three to four weeks. After analyzing fecal samples from greyhound adoption kennels, three veterinary practices that work with adoption groups and an active racing kennel, the researchers found the parasites were highly prevalent in the breed. Four out of every five greyhounds tested were positive for hookworms, said Ray Kaplan, DA DVM, PhD, DACVM, DEVPC, a professor in the Department of In Infectious Diseases in the College of Veterinary M Medicine at UGA, in Athens, Ga. But perhaps more alarming, the team saw that th dogs still had high levels of infection with the hookw hookworms after treatment. “There’s a very committed greyhound adoption industry because they are lovely dogs,” Dr. Kaplan said. “But as those dogs are adop adopted, the drug-resistant hookworms are going to show up in other oth pet dogs.” One possible breeding ground for potential resistance is also the place many dog owners use to exercise their animals: dog parks. “Until new ty types of drugs are available, taking your dog to a dog park has to be cconsidered a risky activity,” Dr. Kaplan said.

Should We Worry About Endangered Parasites?

alf of the world’s roughly 500 pri- given all the efforts to deworm and mate species are at risk for extinc- delouse ourselves and our pets. But some tion. But the demise of the world’s parasites can have some surprising benthreatened primates could also trigger efits to the microbiome of the gut. extinctions for the parasites they carry, To gauge the potential loss of biodiveraccording to a Duke University–led study. sity if primates go extinct, the research“That’s a whole realm of biodiversity ers used network analysis techniques to that could be going measure the potential extinct without us ripple effects on the even noticing,” said parasites in or on priJames Herrera, PhD, mates (Philos Trans R of the Duke Lemur Soc Lond B Biol Sci 2021 Center, in Durham, Sep 20. doi:10.1098/ N.C. “There’s so little rstb.2020.0355). that we know about In their model, spewhat they do in the cies are connected in body, that we don’t complex webs of intereven know what we’re actions involving 213 losing.” primates—monkeys, One previous study Courtesy of Marie-Claire Chelini and TriCEM apes, lemurs and galasuggests that 85% to go—and 763 worms, 95% of the parasitic worms of animals mites, protists and other parasites. When aren’t even known to science. one primate host disappears, the parasites Dr. Herrera admitted this may seem no longer have a host. Sever enough of like an odd thing to get worked up about, these connections, and their loss sets off

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a deadly cascade where one extinction begets another, they said. Currently, 108 of the 213 primate species in their data set are considered threatened by the International Union for Conservation of Nature. The team found that if all those species became extinct, an additional 250 parasites could be doomed, and 176 of these parasite species have no other suitable hosts. The extinction cascade would likely be worse in isolated places like the island of Madagascar. There, shrinking forests, illegal hunting and collection for the pet trade are pushing 95% of lemur species ever closer to the brink, and more than 60% of lemur parasites inhabit a single host. Although the researchers could not predict how many parasites could potentially avert extinction by adapting to new hosts that are more abundant, many human diseases occurred because a parasite was able to adapt to another host. “It’s not that hard to imagine,” Dr. ■ Herrera said.

ACIP Aligns Pediatric and Adult PrEP Rabies Vaccine Schedule BY MARIE ROSENTHAL, MS

he Advisory Committee on Immunization Practices (ACIP) recently harmonized the schedule for pre-exposure prophylaxis (PrEP) of rabies vaccination to provide the same schedule for children as adults. In February, the ACIP recommended a two-dose intramuscular (IM) rabies vaccine series—given on days 0 and 7—in immunocompetent people 18 years of age and older for whom rabies PrEP is indicated. The ACIP also recommended an IM booster dose of rabies vaccine—as an alternative to a titer check—for immunocompetent adults who have a sustained elevated risk for recognized rabies exposures beyond three years, such as laboratory workers, veterinary staff and others who work with animals. The booster should be administered no sooner than day 21 but no later than three years after the two-dose PrEP series. The previous 2008 recommendations required three doses of PrEP over the course of 21 to 28 days. Extending the timing of the third booster dose can be a cost-effective option, especially for some traveling to a rabies endemic country, because people can wait until they return for the booster dose, experts said. On June 24, the ACIP voted unanimously to make these same recommendations for children younger than 18 years of age. PrEP should be administered to children who are at elevated risk for rabies exposure, such as those who travel to a canine rabies endemic country, explained Sharon Frey, MD, FACP, FIDSA, the chair of the ACIP Rabies Work Group. Dr. Frey is a professor and the clinical director for the Center for

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Vaccine Development, Division of Infectious Diseases, Allergy and Immunology at Saint Louis University School of Medicine. Although bats are the most common source of rabies exposure in the United States, dogs are the most common source of rabies in many other countries, and children are at a particularly high risk for dog bites, said Agam K. Rao, MD, a medical officer at the CDC’s National Center for Emerging and Zoonotic Infectious Diseases. In addition, they are more likely to receive multiple and severe bites, particularly to the head and neck. Rabies immune globulin (RIG), which is used for postexposure prophylaxis (PEP) is not always available in developing countries, and rabies vaccines may not be readily available, especially in rural areas, she explained. There was no reason to maintain separate recommendations, Dr. Rao told the ACIP because children mount a good immune response to the primary series, and titers may even stay higher longer in children. “Since boost-ability is not a concern for adults, it should not be a concern for children,” she told the committee. There could be problems if the schedules are not harmonized, she added. When people were following the 2008 recommendations, if the three-dose series could not be completed within 28 days before leaving the United States, people did not receive any PrEP before traveling, so there could be cases where parents would be vaccinated but not children, who are at greater risk, she explained. And the schedules were the same in 2008. About 170,000 doses of PrEP are given in the United States

each year, mostly to travelers, but also to veterinary staff, animal control officers, laboratory personnel, wildlife biologists and others, according to Dr. Rao. Although there was no vote about PEP, the committee heard a presentation on PEP and new formulations of RIG, which provides passive immunity before vaccine-induced humoral immunity occurs. RIG is given as part of PEP to people who did not receive PrEP or have never had PEP, according to Dr. Rao. The ACIP has been recommending 20 IU/kg of RIG within the first seven days of initiation of a rabies vaccine. RIG should be given around the wound and the remaining administered intramuscularly in a different location than the vaccine. RIG could be diluted for large or multiple wounds. In 2018, the World Health Organization modified its recommendations, saying RIG should only be given around the wound and the remaining should not be given in an IM injection. There are several reasons for this change, Dr. Rao explained. The supply of RIG in some countries is limited and expensive, and less than 2% of people with serious wounds receive RIG. Because dog bites are the most common cause of rabies in many of these countries, wounds are large and the maximum infiltration of RIG around a wound is sufficient, and the benefits of IM RIG administration are limited. The WHO recommended that RIG be prioritized to high-risk exposures, people with multiple bites, deep wounds and bites to highly innervated body parts. In addition, severely immunocompromised people and those with confirmed or probable rabies or who had a bat exposure should also be prioritized. The ACIP Rabies Work Group reviewed the 2018 position statement to see whether the United States should consider similar changes. The group found that the data cited by the WHO were limited, and the issues in the United States were different. There was no difficulty obtaining RIG in the United States, so there was no need to limit its use. In addition, the most common rabies exposure in the United States is from ry bats, and those bites tend to be very small or barely visible, so little RIG would be administered at the wound site. Therefore, an IM injection of the remaining product could be of benefit: Data suggest that IM RIG is detected in sera 24 hours later, Dr. Rao explained. he Dr. Rao also gave an update on the ailnewly licensed RIG products availRab able in the United States: HyperRab on by Grifols and Kedrab by Kedrion Biopharma.

Both RIG products are prepared from plasma of donors who were hyperimmunized with rabies vaccine. HyperRab was licensed in 2018 and is indicated for PEP along with rabies vaccine. HyperRab is a higher concentration formulation of what used to be HyperRab S/D, which is no longer distributed by the manufacturer. HyperRab has a greater concentration of anti-rabies virus antibodies within each milliliter of volume, so less volume is needed when administering PEP. “A more concentrated product could be preferable for small bites, such as bat bites,” Dr. Rao said. “Given differences in potency between products, oversight is needed to ensure that the correct volume is administered for a particular product,” she added. Under certain circumstances, if a larger volume is needed, HyperRab can be diluted with dextrose 5% in water, rather than normal saline, and clinicians should be made aware of this. Kedrab was licensed in 2017 and is similar to other RIG products, licensed as part of PEP. “Kedrab and HyperRab actually make up most of the market share for rabies immune globulin,” Dr. Rao said. She said production and manufacturing processes have improved for RIG products, and their safety and efficacy are similar; therefore, the work group does not recommend one over the other. “As far as selection of a RIG product goes, the indications are the same for all of them. A more concentrated product could potentially be preferable for small wounds, like what is involved with those from a bat bite,” Dr. Rao said. “Given the differences in potency between the products, oversight is obviously needed to ensure that the correct volume is administered for a particular product. There could be errors made and twice the volume inadvertently administered if care is not taken to recognize th the fact that one is more co concentrated. “It’s really up to individ vidual facilities to decide wh which product they want to stock,” she said. “We’ve lea learned that facilities typ typically just stock one pr product.” The ACIP is expected to discuss RIG at the regu ularly scheduled October mee ■ meeting.

Although bats are the most common source of rabies exposure in the United States, dogs are the most common source of rabies in many other countries, and children are at a particularly high risk for dog bites.

The sources sourc reported no relevant financial financia disclosures.

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Don’t chance it. Improve treatment decisions with results from the BioFire® FilmArray® Gastrointestinal (GI) Panel. Making patient management decisions while you’re waiting on traditional methods to return results can feel like a game of chance. The BioFire GI Panel uses the syndromic approach, simultaneously testing for 22 of the most common GI pathogens in about an hour. Fast, comprehensive, and easy to interpret results can help you prescribe targeted therapy sooner—making you and your patients feel like a million bucks.

The BioFire GI Panel vs Traditional Testing Decreased turnaround time. 84% reduction in time-to-results.1 Increased diagnostic yield. 25%-36% more potential pathogens detected.1-4 Improved treatment decisions. 41% increase in targeted therapy.2 Decreased antibiotics. Patients were 11% less likely to be prescribed antibiotics.3 Decreased downstream procedures. Reduced X-rays, ultrasounds, CT scans, and endoscopies.1,3

1. Beal S, et al. A gastrointestinal PCR panel improves clinical management and lowers healthcare costs. J Clin Microbiol. 2018 Jan. 56:1 e01457-17. 2. Cybulski R, et al. Clinical impact of a multiplex gastrointestinal PCR panel in patients with acute gastroenteritis. 2018. Clin Infect Dis. 2018 Nov.13; 67(11):1688-1696. 3. Axelrad JE, et al. Impact of gastrointestinal panel implementation on health care utilization and outcomes. J Clin Microbiol. 2019 Feb, 57(3)e01775-18. 4. Spina A, et al. Spectrum of enteropathogens detected by the FilmArray GI Panel in a multicentre study of community-acquired gastroenteritis. Clin Microbiol Infect. 2015 Aug. 21(8):719-28.

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The Importance of Rapid Diagnostic Testing and Stewardship for Infectious Disease Management KAREN FONG, PHARMD, BCIDP

apid diagnostic tests (RDTs) have fundamentally transformed infectious disease management by providing rapid and robust microbiological diagnoses. In the modern-day expansion of molecular technology, direct-specimen rapid amplification and detection platforms and next-generation sequencing (NGS) are techniques that provide laboratory diagnoses at a speed, sensitivity, and breadth never before possible with conventional microbiology.1 Newer technologies have expanded rapidly to detect genotypic markers of resistance, but rapid phenotypic antimicrobial susceptibility testing has been available only recently. Thus, these commercial advances add data to the clinical presentation and assist empiric antimicrobial selection by enabling the prediction of susceptibility patterns based on local antibiograms, but are not yet a replacement for cultures. Moreover, there may be drawbacks associated with RDTs, including cost and overuse, highlighting the potential beneficial role of stewardship in making clinical decisions.1 The general advantages and disadvantages of RDTs, specific to bloodstream infections (BSIs), are outlined by Briggs et al in Table 1.2

Due to the complexity of intervention with RDTs, RDT development and implementation must be coupled with education to facilitate informed decision making about implementation.2 Before implementation, an assessment of the clinical utility of these tests should be conducted, considering patient population and local epidemiology, along with antimicrobial stewardship programs (ASPs)

to justify the acquisition of new equipment testing methodologies.3 Along with rapid turnaround time for pathogen identification and accurate interpretation of susceptibility results, great pragmatism is required to ensure results are actionable and promptly addressed to improve clinical outcomes and reduce unnecessary antimicrobial use.3 ASPs may facilitate the correct

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IDSE Review

interpretation and rapid communication of results, directing clinicians to appropriate adjustment of antimicrobial therapy.4 RDTs combined with ASP intervention, particularly for BSIs and rapid testing for broad panels of respiratory viruses, have been deemed important interventions to optimize antimicrobial use and patient outcomes.5-7 Although RDTs may provide a promising level of diagnostic accuracy, combination with routine ASP efforts has been found to be imperative, to improve clinical outcomes for BSIs.6,8-10 We should be mindful that evaluations of the clinical efficacy of RDTs beyond BSI are still evolving as we discuss novel RDTs, including advances in blood culture testing, syndromic panels of direct-specimen molecular testing for respiratory infections, gastrointestinal (GI) infections, and meningitis/encephalitis, as well as prospects of outpatient point of care, and their performance with current diagnostic stewardship practices.11

Blood The management of BSIs and blood culture contaminants (eg, coagulase-negative Staphylococcus) has been fundamentally changed by molecular RDT by providing actionable information much earlier in the course of treatment. Matrix-assisted laser desorption/ionization time of flight, or MALDI-TOF (eg, bioMérieux, BD Bruker), polymerase chain reaction (PCR)-based technologies (eg, BioFire FilmArray BCID, GenMark ePlex BCID), and nanoparticle probe technology (eg, Verigene BC-GP & BC-GN) have been associated with decreases in time to effective therapy, hospital length of stay (LOS), and mortality when paired with ASP interventions.6 Table 2 shows available blood RDTs with respect to detection method, sample type required, turnaround time, pathogen identification, resistance gene detection, and susceptibility testing. In a cost-effectiveness analysis, the benefits of molecular RDTs in BSIs have been observed.8 Interestingly, there is a strong synergism between stewardship and RDT being highlighted by these data—RDT has an 80% chance of cost-effectiveness with ASP but only 41.1% in its absence. Recently, RDT platforms have been compared on potential desirability of antimicrobial therapy decisions using the Desirability of Outcome Ranking Management of Antimicrobial Therapy (DOOR-MAT) as a framework. When compared in an observational study at a single center, both Verigene BC and ePlex BCID had high positive predictive value (PPV) for on-panel targets, but ePlex BCID was able to identify more organisms than Verigene BC, resulting in higher mean DOOR-MAT scores (91.9 [SD ±23.1] vs 86.8 [SD ±28.5], P=0.01), respectively.12 Similarly, Verigene BC-GN was compared with BioFire BCID and BCID2. The mean DOOR-MAT score was higher for BioFire BCID2, 89.7 (SD ±24.7), than both BioFire BCID, 59.9 (SD ±33.7)

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(P<0.0001) and Verigene BC-GN, 83.8 (SD ±25.7) (P=0.07).13 Higher mean DOOR-MAT score for BioFire BCID2 can be largely attributed to the expanded detection of panel organisms and resistance determinants. These findings highlight the importance of considerations of local infection epidemiology with RDT implementation. The introduction of the Accelerate Pheno system from Accelerate Diagnostics, an automated rapid phenotypic testing system, has developed further potential changes in the management of BSIs. This system can yield organism identification, minimum inhibitory concentration (MIC), and susceptibility interpretation with a turnaround time of approximately 7 hours after positive blood culture. Compared with routine methods, overall sensitivity and specificity for the identification of organisms and essential agreement and categorical agreement for antimicrobial susceptibility were 95.6%, 99.5%, 95.1%, and 95.5%, respectively.14 Recently, several studies explored the Accelerate Pheno system coupled with ASP intervention. A randomized controlled trial of patients with gramnegative BSIs combined with prospective audit and feedback demonstrated significantly faster antibiotic changes (median decrease of about 25 hours for gramnegative antibiotics, P<0.0001) and antibiotic deescalation (median decrease of about 43 hours; P=0.01) with Accelerate Pheno, but no differences in clinical outcomes were seen compared with culture-based methods.15 Five quasi-experimental before-and-after observational studies that analyzed the integration of Accelerate Pheno with ASP intervention had variable results in patient outcomes. Although median time to optimal or targeted therapy and step-down antimicrobial therapy were significantly shorter with the use of Accelerate Pheno, LOS and duration of therapy (DOT) were not consistently shorter despite ASP intervention.16-20 Future studies on a larger scale with ASP intervention are needed to assess its impact on clinical outcomes.

The management of BSIs has been fundamentally changed by molecular rapid diagnostic tests.

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Table 1. Advantages and Disadvantages of Rapid Blood Culture Assessment Advantages

Disadvantages

• Major pathogens identified ~24 h sooner than conventional methods

• Limited panel sizes

• High-impact resistance markers or phenotypic antimicrobial susceptibility testing detected ~48 h sooner than conventional methods

• All systems require concurrent conventional identification and antimicrobial susceptibility testing

• Reduced overall cost of hospital stay • Improved patient outcomes in observational studies

• Reduced diagnostic quality identifying polymicrobial cultures

• Platforms expensive to implement; no additional direct Medicare reimbursement • Sparse high-quality outcome studies (eg, randomized controlled trials) • Co-implementation of ASP may be required to appreciate full benefit

The Accelerate Pheno system lacks resistance gene testing. Bhalodi et al evaluated 40 Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis isolates to understand the correlation between ceftriaxone nonsusceptibility of Accelerate Pheno and extendedspectrum beta-lactamase (ESBL) production. Ceftriaxone categorical agreement of the Accelerate Pheno and broth microdilution was 97.5%.21 The ESBL confirmatory disk test was positive in 84.6% (22/26) of ESBL-producing isolates and negative in 92.9% (13/14) of non–ESBL- and/or AmpC-producing isolates, resulting in 4 false negatives and 1 false positive.21 ESBL production is well correlated with ceftriaxone nonsusceptibility, allowing expedited phenotypic detection for potential optimization of antimicrobial regimens and improved clinical outcomes. In critically ill patients, the ability to optimize therapeutic dosing to maximize pharmacokinetic and pharmacodynamic (PK/PD) parameters in the setting of a known MIC has been associated with improved outcomes.22 Moreover, prospective evaluations of critically ill patients have reflected frequent underdosing for PK/PD targets.23 Despite variable susceptibility interpretation due to MIC testing, the introduction of rapid phenotypic testing may be of particular importance to ASPs as it relates to PK/PD optimization.24 The use of Accelerate Pheno with therapeutic drug monitoring in this patient population may have the potential to significantly improve future patient outcomes. In the United States, candidemia is one of the most common hospital-acquired BSIs, associated with up to 47% attributable mortality, which is even higher among patients who develop septic shock. As much as a 50% reduction in mortality has been associated with prompt initiation of appropriate antifungal therapy and source control. However, this is often delayed due to blood culture insensitivity, prolonged turnaround time (median time to positivity of 2-3 days, ranging from 1 to ≥7 days) needed to yield growth, and possibility of negative growth with invasive abdominal candidiasis.25 Considering these limitations, overuse of empiric antifungal therapy for suspected invasive candidiasis has been propagated.26 The Fungitell Beta-Dglucan (BDG) detection assay (Associates of Cape

Cod) and the T2Candida Panel (T2 Biosystems) are nonculture diagnostic tests with a much shorter turnaround time (3-5 hours), and have entered clinical practice as adjunctive RDTs to cultures.25,27,28 BDG is a component of the cell wall in Candida species, Aspergillus species, and Pneumocystis jiroveci. Due to cross-reactivity with other organisms, true-positive results have limited specificity for candidemia, and false positivity may be caused by physiologic changes, selected antimicrobials, hemodialysis, albumin or immunoglobulin therapy, or use of surgical material containing glucan.25 A few studies explored the use of BDG in suspected candidemia and showed deescalation of antifungal therapy through avoidance and reduction, but they were limited by small sample size and did not incorporate active ASP intervention.29,30 In 2 small, single-center cohort studies, BDG combined with ASP intervention showed mixed results in antifungal use and clinical outcomes of patients with suspected or proven invasive candidiasis. Overall antifungal use was not consistently decreased, and improvements in clinical failure rate and mortality were likely not related to BDG but rather more likely influenced by choice of antifungal, dosage adjustments, source removal, and further workup of invasive candidiasis, as recommended by the respective ASP interventions.31,32 Furthermore, the findings from a recent retrospective study challenge the test’s frequent use in the early discontinuation of empiric antifungal therapy. In a small cohort of adult patients with proven candidemia, 17.6% of patients had persistently negative BDG tests probably due to lower systemic fungal burden, signaling a concern for false-negative BDG results.33 Molecular Candida platforms, such as the T2Candida Panel by T2 Biosystems and Karius Test by Karius that detect Candida species DNA from whole blood, have emerged. While sensitivity and specificity seem to be much more promising compared with blood cultures—91% and 99%, respectively—the role of the T2Candida Panel in the early diagnosis and management of candidemia remains unclear.25,28 In 3 retrospective, single-center cohort studies, the T2Candida Panel was evaluated with the combination of active ASP intervention in adult patients with suspected

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mPCR, gold nanoparticle technology

Fluorescencelabeled nucleic acid probe, morphokinetic cellular analysis

mPCR, magnetic resonance

Verigene Blood Culture Test (Luminex)

Accelerate Pheno (Accelerate Diagnostics)

T2Bacteria Panel (T2 Biosystems)

T2Candida Panel (T2 Biosystems)

3-5 h

Identification: 2 h Susceptibility: 7 h

2.5 h

1.5 h

Turnaround Time

Pathogens: E. faecalis, E. faecium, Listeria, Micrococcus, Staphylococcus, S. aureus, S. epidermidis, S. lugdunensis, Streptococcus, S. agalactiae, S. anginosus, S. pneumoniae, Streptococcus pyogenes, Acinetobacter, Citrobacter, Escherichia coli, Enterobacter, Klebsiella oxytoca, K. pneumoniae, Proteus, P. aeruginosa, S. marcescens Resistance markers: mecA, vanA, vanA/B, CTX-M, IMP, KPC, NDM, OXA, VIM

Pathogens: C. albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis

Pathogens: E. faecium, S. aureus, E. coli, K. pneumoniae, P. aeruginosa

Yes

Pathogens: Bacillus cereus group, Bacillus subtilis group, Corynebacterium, Cutibacterium acnes, Enterococcus, E. faecalis, E. faecium, Lactobacillus, Listeria, Listeria monocytogenes, Micrococcus, Staphylococcus, S. aureus, S. epidermidis, S. lugdunensis, Streptococcus, S. agalactiae, Streptococcus anginosus, S. pneumoniae, S. pyogenes, A. baumannii, B. fragilis, Citrobacter, Cronobacter sakazakii, E. coli, E. cloacae complex, Enterobacter (non-cloacae complex), Fusobacterium necrophorum, Fusobacterium nucleatum, H. influenzae, K. oxytoca, K. pneumoniae, Morganella morganii, N. meningitidis, Proteus, Proteus mirabilis, P. aeruginosa, Salmonella, Serratia, S. marcescens, Stenotrophomonas maltophilia, Candida albicans, Candida auris, Candida dubliniensis, Candida famata, Candida glabrata, Candida guilliermondii, Candida kefyr, Candida krusei, Candida lusitaniae, Candida parapsilosis, Candida tropicalis, Cryptococcus gattii, C. neoformans, Fusarium, Rhodotorula Resistance markers: mecA, mecC, vanA, vanA/B, CTX-M, IMP, KPC, NDM, OXA, VIM

Pathogens: E. faecalis, E. faecium, Staphylococcus, S. aureus, S. lugdunensis, Streptococcus, A. baumannii, Citrobacter, E. coli, Enterobacter, Klebsiella, Proteus, P. aeruginosa, S. marcescens, C. albicans, C. glabrata

Susceptibility Testing

Pathogens: Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Staphylococcus, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus lugdunensis, Streptococcus, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Acinetobacter baumannii, Bacteroides fragilis, Escherichia coli, Enterobacter cloacae complex, Haemophilus influenzae, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Neisseria meningitidis, Proteus, Pseudomonas aeruginosa, Salmonella, Serratia marcescens, Stenotrophomonas maltophilia, Candida albicans, Candida auris, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans Resistance markers: mecA, mecC, vanA, vanA/B, CTX-M, IMP, KPC, mcr-1, NDM, OXA-48-like, OXA

Pathogens/Resistance Markers

BSI, bloodstream infection; mPCR, multiplex polymerase chain reaction; NAAT, nucleic acid ampliﬁcation test

Yes

NAAT

ePlex Blood Culture Identification (GenMark)

Direct From Whole Blood

mPCR

Detection Method

FilmArray Blood Culture Identification (BioFire)

Blood

Table 2. Selected RDTs for BSIs: Detection Method, Sample Type, Turnaround Time, Pathogen identification, Resistance Markers, and Susceptibility

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any organism was 43% (95% CI, 32%-54%) and 89% (95% CI, 87%-91%).40 Time from initiation of testing to detection and identification of pathogens was shorter for the T2Bacteria Panel (mean, 7.70 [SD, 1.38] hours) than for blood cultures (71.7 [39.3] hours). A 10% false-positive rate was observed for its targeted organisms.40 A small prospective, noninterventional T2Bacteria Panel clinical study in the emergency department (ED) demonstrated that the T2Bacteria Panel, relative to blood culture, showed a 100% percent agreement and 98.4% negative agreement.41 Compared with blood culture, the T2Bacteria assay identified bacteria, on average, 56.6 hours faster with the potential to de-escalate therapy, reduce time to species-directed therapy, and reduce time to effective therapy.41 Although the T2Bacteria assay appeared to have detected 25% more positives than blood culture, which is thought to be associated with evidence of infection, true positivity remains unclear.41 In an interventional study, Drevinek et al evaluated 53 patients and observed high sensitivity and specificity—94% and 100%, respectively—with 36.4% (8/22) causes of BSI detected only by the T2Bacteria Panel.42 On average, the results were provided 55 hours faster than blood culture. Early targeted antibiotic therapy and/ or modifications of antimicrobial treatment occurred in 9 of 15 patients with positive results.42 A recent substudy of a larger prospective, multicenter clinical trial evaluated the significance of positive T2Bacteria cases when blood culture was negative to gain a better understanding of whether these results were false positives or potentially associated with an infection. In 233 participants, 20 patients were identified with 21 (9%) discordant results. Eleven (52.5%) cases had probable BSI, 4 (19%) had possible BSI, and 6 (28.5%) were presumptive false positives.43 Among the probable and possible BSIs, discrepancies appeared to be associated with closed space and localized infections (mostly, pyelonephritis and abscess) and recent use of active antimicrobial agents.43 A recent systematic review by Giannella et al, of 14 controlled studies (most were observational), comparing T2MR with blood culture for the detection of bacterial and fungal BSI found that patients testing positive received targeted antimicrobial therapy faster (about 42 hours; P<0.001) and patients testing negative were deescalated from empiric therapy faster (about 7 hours; P<0.02).44 LOS in the ICU (mean difference, –5.0 days; P=0.03) and hospital stay (mean difference, –4.8 days; P=0.03) were shorter with T2MR, but mortality rates were comparable (28.9% vs 29.9%; relative risk, 1.02; P=0.86).44 Further prospective, ideally interventional, studies are needed to validate the role of T2MR along with ASPs in patient care.45 The Karius Test offered a new potential tool in the

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or proven candidemia. Time to appropriate therapy decreased in patients with proven candidemia while shorter micafungin DOT and cost savings were observed in patients without microbiological evidence of invasive candidiasis. However, antifungal discontinuation with negative tests was inconsistent, despite antimicrobial stewardship intervention such as prospective audit and feedback being performed on negative results.34-36 Bomkamp et al found that overall antifungal DOT improved after implementation of the T2Candida Panel, but the use of micafungin continued to decline after the panel was removed, likely due to the concomitant increased stewardship resources, including physician-directed prospective audit and feedback around implementation. Conversely, Steuber et al observed antifungal discontinuation with negative tests to be unexpectedly low even with pharmacist-driven prospective audit and feedback. In the regression model, LOS in the ICU was predictive of failure to discontinue antifungal therapy within 48 hours of negative results (odds ratio [OR], 0.96; 95% CI, 0.94-0.99; P=0.002).35 The stewardship potential of the T2Candida Panel may be heavily contingent on the effectiveness of the ASP intervention because clinicians are particularly apprehensive about deescalation in patients already at substantially high risk for fungal infections. The performance of the T2Candida Panel on whole blood specimens for detection of intra-abdominal candidiasis (IAC) was assessed recently. IAC is another indication with high mortality rates if antifungal treatment is delayed, but limited by low sensitivity and slow turnaround of intra-abdominal cultures and deficiencies in the BDG.37,38 Blood cultures remain the gold standard for invasive candidiasis but are typically sterile in more than 80% of patients with IAC.37,38 In 48 highrisk patients for IAC, the sensitivity, specificity, positive predictive value, and negative predictive value (NPV) of the T2Candida Panel relative to blood cultures were 33%, 93%, 71%, and 74%, respectively.39 IAC was present, diagnosed by intra-abdominal culture, in 100% of cases with concordant positive T2Candida/BDG, but absent in 90% of concordant negative results.39 Further study is needed to determine whether the T2Candida Panel has a role in the diagnosis of IAC and other types of invasive candidiasis. By detecting bacterial DNA with T2 magnetic resonance (T2MR) in whole blood, the T2Bacteria Panel by T2 Biosystems recently made its debut to improve early initiation of appropriate antibiotic therapy in BSIs. The T2Bacteria Panel’s sensitivity and specificity, paired with a single set of blood cultures, in diagnosing BSIs caused by Enterococcus faecium, Staphylococcus aureus, K. pneumoniae, Pseudomonas aeruginosa, and E. coli were 90% (95% CI, 76%-96%) and 90% (95% CI, 88%-91%), respectively.40 NPV was 99.7%. Limited to only 5 bacteria, sensitivity and specificity for

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antimicrobial stewardship armamentarium of microbiologists. This novel metagenomic microbiological diagnostic test uses NGS of microbial cell-free DNA in plasma, which can identify 1,250 bacteria, fungi, parasites, and viruses.46,47 While clinical data are currently limited, this new technology has shown promise in diagnosing and identifying etiologies for pneumonia, bacteremia, infective endocarditis, and general sepsis despite pretreatment with antibiotics. Its role may be useful in immunocompromised hosts with febrile neutropenia to curb delay in targeted treatment and prolonged broad-spectrum antimicrobial use where a broader range of pathogens may be associated with illness. Given its noninvasive nature, NGS has been given the term “liquid biopsy” for the diagnosis of invasive mold infections (IMI). The performance of NGS for specifically IMI in immunocompromised patients, mostly hematopoietic cell transplant recipients and leukemia/lymphoma patients, was evaluated in 3 studies. NGS was able to detect both biopsy-proven/probable Aspergillus and non-Aspergillus IMI with a sensitivity of 51%.48-50 The specificity and PPV were estimated to be 100% based on no findings of false positives in 19 controls.48 The NPV was estimated to be 81% to 99%.48 NGS combined with serum galactomannan yielded an improved sensitivity of 84% for patients with proven/probable IMI.48 Future larger studies are needed to validate the sensitivity and specificity of this approach. NGS was explored recently for periprosthetic joint infections where standard-of-care cultures fail to detect organisms in 10% to 20% of cases.51 In a prospective observational study, NGS was performed on peripheral blood of 53 adults with hip or knee periprosthetic joint infections along with standard-of-care intraoperative tissue and synovial fluid cultures. An organism was identified by cultures in 46 (87%) of patients while NGS identified the joint pathogen in 35 cases, including 4 of 7 culture-negative cases.51 As an adjunct to cultures, NGS increased detection from 87% to 94%.51 Additional organisms were detected in 14 cases not grown in cultures by NGS.51 This test may offer a novel resource for identification with promise as an adjunct to tissue cultures to increase cases with identified pathogens.

Respiratory Respiratory Viral Panels In the United States, pneumonia has been a major contributor to morbidity and mortality, with an estimated 63,000 annual deaths and 1.2 million annual hospitalizations.52,53 The American Thoracic Society (ATS) and Infectious Diseases Society of America (IDSA) recommendations for empiric antimicrobial therapy in community-acquired pneumonia (CAP) are based on selecting agents targeted against the major treatable respiratory bacterial pathogens.54 However, systematic surveillance studies indicate that patients

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hospitalized for suspected CAP are more than twice as likely to harbor respiratory viruses than bacteria, and influenza accounts for only a minority of respiratory viruses that could cause pneumonia.55-57 There is difficulty in distinguishing between bacterial and viral etiologies in lower respiratory tract infections (LRTIs) due to similar manifestations, commonly resulting in the overuse of antibiotics.58 In patients with isolated viral pneumonia, antibiotic therapy may be safely withheld if these infections can be easily differentiated from those with concomitant bacterial etiology.59 Procalcitonin (PCT) is a component of the innate proinflammatory response to bacterial challenge, discriminating between viral and bacterial infections.60 A Cochrane review demonstrated a 2.4-day reduction in antibiotic exposure (5.7 vs 8.1 days; 95% CI, –2.71 to –2.15 days; P<0.001), a lower risk for antibiotic-related adverse effects (16.3% vs 22.1%; adjusted OR, 0.68; 95% CI, 0.57-0.82; P<0.001), and significantly lower mortality (8.6% vs 10.0%; adjusted OR, 0.83; 95% CI, 0.70-0.99; P=0.037) with a PCT-guided antibiotic stewardship algorithm in adults with acute respiratory infections (ARIs) compared with usual care, respectively.61 Still, clinicians cannot rely solely on PCT to guide antibiotic treatment decisions according to findings from a multicenter, prospective surveillance study of adults hospitalized with CAP. A PCT threshold allowing perfect discrimination between viral and bacterial detection could not be identified.62 Results were further supported by a meta-analysis of CAP patients, demonstrating that the PCT sensitivity and specificity are too low and variable to provide reliable evidence to enable clinicians to confidently address whether the infection is bacterial and antibiotics need to be administered or whether it is viral and antibiotics may be withheld.63 The ATS/IDSA guidelines for the diagnosis and treatment of adults with CAP recommend empiric antibiotic therapy to be initiated in adults with clinically suspected and radiographically confirmed CAP regardless of initial serum PCT level.54 Furthermore, PCT use does not consistently reduce antibiotic days in patients with LRTI compared with usual care, likely a consequence of subpar adherence to the PCT antibiotic prescribing guideline and lack of real-time prospective audit and feedback.58 Respiratory viral PCR assays, such as FilmArray Respiratory Panel 1 & 2 by BioFire Diagnostics, XT-8 Respiratory Viral Panel and ePlex Respiratory Pathogen Panel 1 & 2 by GenMark Diagnostics, NxTAG Respiratory Pathogen Panel and Verigene Respiratory Pathogens Flex Test by Luminex, may be useful as an adjunctive RDT. As an important intervention to reduce the use of inappropriate antibiotics, antimicrobial stewardship guidelines advocate rapid testing for broad panels of respiratory viruses.7 In a multicenter, retrospective cohort analysis of adult patients

these panels provide increased sensitivity and detect presence of resistance markers with a turnaround time of 1 to 5 hours. The BioFire FilmArray Pneumonia Panel identifies 8 viruses, 8 resistance genes, 3 atypical bacteria using qualitative targets, and 15 bacterial targets with semiquantitative analysis, which facilitates the evaluation of infection versus colonization. The Curetis Unyvero LRT Panel detects 29 bacterial pathogens and 19 resistance genes. Both panels are compatible with multiple specimen types (sputum, endotracheal aspirates, bronchoalveolar lavage [BAL] fluid). Although clinical specificity may be improved with semiquantitative analysis, neither molecular testing panels nor culture distinguish airway colonizers from invasive pathogens. Molecular testing for bacterial pathogens was not addressed by the current CAP or hospital- or ventilator-associated pneumonia guidelines because their performance and potential impact on clinical decision making have not been determined.54,70 A downstream effect of paradoxically increasing antimicrobial use should be considered a possibility. The clinical usefulness of these panels would be in situations where patients have new or worsening lung infiltrates, are moderately to severely ill, have received empiric antibiotics prior to obtaining cultures, and/or there is concern for multidrug-resistant bacteria or a polymicrobial infection.11 The BioFire FilmArray Pneumonia Panel demonstrates a PPA and an NPA of 98.1% and 96.2%, respectively, for the identification of bacterial targets in BAL specimens compared with culture.71 Similarly, a high overall agreement of 99.2% (95% CI, 98.4%-99.6%) for viral detection is observed between the BioFire FilmArray Pneumonia Panel and culture.72 In 396 endotracheal or BAL specimens, Rand et al found a sensitivity of 97.8% (95% CI, 94.3%-99.4%), specificity of 80.4% (95% CI, 74.5%-85.4%), PPV of 80% (95% CI, 75.5%-84%), and NPV of 97.8% (95% CI, 94.3%-99.1%) for the BioFire FilmArray Pneumonia Panel for bacterial pathogens compared with culture. The panel semiquantitative copy numbers were strongly correlated with the report of white blood cell (WBC) count on initial Gram stain and conventional bacterial semiquantitation.73 Bacterial targets discovered by the panel, not found in culture, had significantly higher levels of WBC reported on Gram stain, suggesting a host response and potential pathogenicity.73 Likewise, Kolenda et al observed 100% sensitivity and 88.4% to 100% specificity with the panel in 99 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) patients compared with culture.74 Of concern, 60.5% of the bacterial targets reported using

RDTs continue to advance the diagnosis of infections.

Lower Respiratory Tract Infection Panels The BioFire FilmArray Pneumonia Panel and Curetis Unyvero Lower Respiratory Tract (LRT) Panel are multiplex syndromic molecular testing panels for LRTIs, and have recently been approved by the FDA. Compared with conventional microbiology cultures,

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admitted with suspected pneumonia in 179 hospitals nationwide, only 24.5% (40,787/166,273) were tested for respiratory viruses, with most being tested for influenza.64 Viral assays were positive in 12.6% (5,133/40,787), typically for influenza and rhinovirus.64 Antibacterial courses were significantly shorter for virus-positive patients than negative patients overall (mean, 5.5 vs 6.4 days; P<0.001), but varied by bacterial testing: 8.1 versus 8.0 days (P=0.60) if bacterial tests were positive; 5.3 versus 6.1 days (P<0.001) if bacterial tests were negative; and 3.3 versus 5.2 days (P<0.001) if bacterial tests were not obtained (interaction, P<0.001).64 A minority of patients were tested for a fraction of the potential respiratory viruses. Patients with positive viral tests often received a prolonged duration of unnecessary antibacterial courses even with concurrent negative bacterial tests. Nonetheless, viral testing may have affected antibacterial use because patients with positive viral results were treated for 0.9 fewer days than those with negative viral results despite being generally older and sicker. The IDSA’s Diagnostics Committee suggests that the combination of respiratory viral testing and PCT may be more likely to exclude bacterial coinfection with confidence in a meaningful period.11 In 2 multicenter, quasi-experimental studies, the respiratory viral panel (RVP) combined with PCT and either direct or indirect (automated best practice alert) ASP intervention had a higher proportion of antibiotic discontinuation or deescalation and significantly reduced antibiotic days of therapy (mean, 2.2 days [5.8 vs 8.0 days; P<0.001]).65,66 In the absence of ASP intervention, previous evidence showed low rates of antibiotic discontinuation in patients with negative PCT and positive RVP.67 In particular, findings from Moradi et al emphasize the importance of its real-world implementation strategy by leveraging indirect ASP intervention through an automated alert, which may be especially valuable in minimal resource settings.65,68 Reduction in antibiotic days of therapy observed with RVP and PCT combination with a varying level of ASP intervention appears to be similar if not greater and more consistent compared with solely PCT or RVP use with ASP intervention, but more robust head-to-head comparisons are needed to confirm such speculation.58,61,65,66,69

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the panel were not recovered by culture and 76.9% of discordant results corresponded to bacteria belonging to commensal oral flora and/or report with 105 copies/ mL or fewer bacterial nucleic acids.74 The BioFire FilmArray Pneumonia Panel may be useful to rule out bacterial coinfections and avoid inappropriate prescribing of antibiotics, but positive results should be interpreted with caution. Although the BioFire FilmArray Pneumonia Panel can detect resistance genes with concordance with culture results, CTX-M and carbapenemase genes could not be definitively linked to the microorganism(s) detected.75 Thus, panel results should be used with culture results to confirm susceptibility or resistance. A retrospective multicenter study observed antimicrobial deescalation in 63 of 159 (40%) and escalation in 35 (22%) of hospitalized pneumonia patients based on BioFire FilmArray Pneumonia Panel results, reinforcing its potential to reduce unnecessary antimicrobial exposure and increase the appropriateness of empiric antibiotic therapy.76 The Curetis Unyvero LRT Panel has reported comparable diagnostic accuracy. Klein et al found an overall positive and negative percent agreement with culture of 93.4% and 98.3%, respectively, but 21.7% of specimens had additional potential pathogens identified by the panel. The positive percent agreement for antibiotic resistance markers compared with antibiotic susceptibility testing ranged from 80% to 100%.77 Challenges in interpretation also have been noted for the Curetis Unyvero LRT Panel—not all genes could be attributed to an organism, highlighting the essential continuation of current culture methods with antimicrobial susceptibility testing.78 Pickens et al reported an overall sensitivity of 85.7% (95% CI, 82.3%-88.7)

and specificity of 98.4% (95% CI, 98.2%-98.7%) with an NPV of 97.9% (95% CI, 97.6%-98.1%) relative to culture.79 Results predicted antibiotic deescalation from unnecessary coverage for methicillin-resistant S. aureus (MRSA) and P. aeruginosa in 65.9% (405/615) of patients.79 Challenges in interpretation of newer RDTs, especially with resistance genes, may be potentially mitigated by ASP intervention, requiring further exploration.

Clinical Utility of Surveillance Screening By MRSA Nasal PCR The MRSA nasal PCR, Cepheid GeneXpert SA Nasal, has become a robust ASP tool for deescalation from MRSA therapy, such as vancomycin and linezolid, in predominantly patients with suspected or confirmed pneumonia. Evidence for the MRSA nasal PCR to rule out MRSA pneumonia has repeatedly demonstrated an NPV of more than 95%.80 Thus, the current CAP guidelines recommend the routine use of the MRSA nasal PCR for the deescalation of MRSA coverage.54 The implementation of this tool combined with ASP intervention have been associated with a median decrease of 2.1 days of vancomycin use (P<0.01).81 A pharmacist-driven MRSA nasal PCR–based testing protocol with ASP effort had a 70% acceptance rate for vancomycin discontinuation within 24 hours of negative results, significantly reducing unnecessary vancomycin use with an estimated cost avoidance of $40 per vancomycin course.82 Vancomycin avoidance in suspected or confirmed pneumonia with MRSA nasal screening among ICU patients has been associated with an even higher cost avoidance of $108 per patient based on the cost of surveillance testing,

For GI infections, conventional testing with stool cultures has subpar sensitivity with turnaround times of 3 to 5 days. 56

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Gastrointestinal Panels Syndromic panels, FilmArray Gastrointestinal Panel (BioFire), xTAG Gastrointestinal Pathogen Panel (Luminex), and Verigene Enteric Pathogens Test (Luminex), have been developed to identify causative pathogens of infectious diarrhea. Conventional testing with stool cultures has subpar sensitivity with a turnaround time of 3 to 5 days.3 These rapid panels are highly sensitive, encompass a broad range of community-acquired bacterial, viral, and parasitic pathogens in the United States, and typically have results in 1 to 5 hours. However, most infectious diarrhea is self-limited, treatment is not recommended, and most targets lack associated antimicrobial treatment. Negative consequences of this molecular platform may be introduced through inclusion of several targets of questionable significance, including enteropathogenic E. coli (EPEC), Clostridioides difficile, and lowincidence targets, and be further exacerbated by its nonquantitative nature.90 Additionally, specimens are often positive for multiple targets, creating further difficulty in treatment selection.91 EPEC is one of the most frequently positive targets, followed by C. difficile, but may represent colonization and lead to unnecessary treatment due to its prevalence in adults in the United States.91,92 The inclusion of C. difficile toxin raises serious concern because C. difficile colonizes more than half of children younger than 12 months of age and 5% to 10% of asymptomatic adults.93 Since detection does not differentiate between infection and colonization, testing should only be performed in the appropriate clinical context, paving the way for diagnostic and ASP partnerships.1,90 Development of clinical criteria for testing, selective reporting of results, and maintenance of separate testing methods for C. difficile are potential ASP

strategies to mitigate incidental detection and inappropriate treatment.94 Although data have shown a modest decrease in the number of antibiotic days, antibiotic prescriptions, imaging studies, hospital LOS, and hospitalization cost with panel testing, these studies were retrospective without ASP intervention.95,96 In a single-center, prospective observational study, Keske et al reported that the panel post-ASP intervention, educational meetings, and activities with providers decreased antibiotic use compared with pre-ASP intervention (42.9% vs 25.8%, respectively; P=0.023).92 In a single-center, quasi-experimental study, Marcelin et al implemented a hard stop in the electronic health record as diagnostic stewardship to prevent clinicians from ordering the panel more than once per admission or in patients with diarrhea hospitalized for more than 72 hours, resulting in significant reductions in inappropriate testing and cost savings. There was an estimated 30% reduction in total ordering rates (relative risk, 0.70; 95% CI, 0.63-0.78; P<0.001), with the rate of inappropriate tests also decreasing from 21.5% to 4.9% (P<0.0001).97 Total savings calculated, factoring only orders triggering the hard stop, were about $67,000.97 Robust studies with diagnostic stewardship are needed to fully capture the impact of these panels on hospital clinical and financial outcomes.

Central Nervous System Panel Infections of the central nervous system (CNS) are associated with significant morbidity and mortality, requiring timely medical management including rapid identification of infectious etiology and administration of antimicrobial therapy. Bacterial meningitis and viral encephalitis rely heavily on cerebrospinal fluid (CSF) examination performed after lumbar puncture. In bacterial meningitis, CSF cultures are positive in 70% to 85% of patients who have not received prior antimicrobial therapy, but cultures may take up to 48 hours for organism identification.98 For viral encephalitis, more than 10% of patients can have normal CSF findings and isolation of viral causes by CSF cultures provides limited value.99 Current meningitis and encephalitis treatment guidelines support the adjunctive use of multiplex molecular diagnostics to establish the specific etiology of infection.98,99 The FilmArray Meningitis/Encephalitis Panel (BioFire) tests for 14 common communityacquired bacterial (E. coli K1, Haemophilus influenzae, Listeria monocytogenes, Neisseria meningitidis, Streptococcus agalactiae, Streptococcus pneumoniae), viral (cytomegalovirus, enterovirus, herpes simplex virus 1 [HSV-1], herpes simplex virus 2 [HSV-2], human herpesvirus 6, human parechovirus, varicella zoster virus), and fungal pathogens (Cryptococcus neoformans and Cryptococcus gattii) in about 1 hour. The panel may be most useful for excluding the diagnosis of bacterial

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vancomycin, and vancomycin therapeutic drug monitoring levels.83 During implementation, the ability of the MRSA nasal PCR to hold its NPV for 7 days after results and vancomycin exposure lacking effect on results of testing should be recognized.84,85 The clinical utility of the MRSA nasal PCR appears to extend to other indications, such as skin and soft tissue infections (SSTIs).86 A national Veterans Affairs system study has supported this notion in the largest cohort to date, which includes 561,325 clinical cultures.87 A high overall NPV was observed for all infection types (96.5%) and specific infections such as BSIs (96.5%), intra-abdominal infections (98.6%), respiratory infections (96.1%), SSTIs (93.1%), and urinary tract infections (99.2%).87 Conversely, despite gram-negative resistance surveillance using rectal swab testing (eg, Streck ARM-D resistance detections kits) being standard infection prevention and control practice, its clinical utility for antimicrobial decision making has yet to be determined.88,89

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meningitis with its 100% sensitivity and NPV.98,100 Despite the speed and ease of use of this panel, false positives, particularly for S. pneumoniae101; variable sensitivity for HSV102; and inferior sensitivity for Cryptococcus compared with antigen testing, have been seen.103,104 Patient outcomes, LOS and antimicrobial duration surrounding implementation of the panel have inconsistent results.105,106 In a review by Goodlet et al, 10 controlled studies evaluated antimicrobial use following implementation of the panel compared with usual care. Only half of the studies identified significant reductions in antibiotic duration, with 8 of 10 reporting modest reductions in acyclovir use.107 Further analytical and clinical validation, possibly with an ASP approach, may be beneficial since the panel falls short as a stand-alone test, requiring further additional tests for confirmation.108

Outpatient Antimicrobial Prescribing And Diagnostic Potential Respiratory Although the target for ASPs has been primarily the inpatient setting, the importance of ASPs in the outpatient setting has been increasingly recognized and has begun to gain widespread attention, leading to the release of the Core Elements of Outpatient Antibiotic Stewardship.109 Based on population database evaluations in the United States, at least one-third of antimicrobial prescribing is considered inappropriate, attributed to mainly respiratory infections.110 Interventions such as C-reactive protein testing, shared decision making, and PCT-guided management have shown potential to influence primary care prescribing behavior for ARIs in a systematic review. The utility of outpatient RDTs is evolving, but conclusions cannot be drawn from studies of low or very low quality.111 Molecular point-of-care testing—ID NOW and BinaxNOW (Abbott), Cobas Liat PCR (Roche Diagnostics), Xpert Xpress (Cepheid), BD Veritor Plus (BD), and FilmArray Respiratory Panel EZ (BioFire)—is widely available in the outpatient setting, but its use is limited by regulations for testing (Clinical Laboratory Improvement Amendments [CLIA] waivers) and logistical circumstances of achieving practical turnaround time during primary care visits. ID NOW influenza A & B 2 (ID NOW 2) was found to have a significantly higher sensitivity (97.8%; 95% CI, 92.2%-99.7% vs 78.9%; 95% CI, 69.0%-86.8%) compared with the rapid antigen detection test (RADT), respectively. The low analytical sensitivity of the RADT was attributed to the low viral loads in patients during the early period of 12 hours from disease onset. ID NOW 2 had high specificity as well, at better than 98%.112 In a study comparing the performance of ID NOW 2, Cobas influenza A/B nucleic acid test, and Xpert Xpress Flu for Flu A and Flu B, the overall sensitivities were 93.2%, 100%, and 100% and 97.2%, 94.4%, and 91.7%, respectively. The specificity

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for influenza A and B by all methods was higher than 97%.113 These tests outperformed the BD Veritor Flu A/B antigen test, with sensitivities of 79.5% for flu A and 66.7% for flu B. In contrast, BD Veritor Flu A/B antigen test compared with BinaxNOW influenza test had higher sensitivity (89.6%; 95% CI, 82.2%-94.3% vs 72.4%; 95% CI, 63.2%-80.0% and 98.8%; 95% CI, 92.6%99.9% vs 100%; 95% CI, 94.5%-100.0%) in the detection of influenza A and B, respectively.114 The impact of Xpert Xpress Flu on clinical decisions in the ED/urgent care clinic settings was evaluated in 339 pediatric encounters. After results were available, original plans were changed by clinicians in 44.5% of positive cases compared with 92.6% of negative cases (P<0.00001).115 Change in plans for antiviral use was observed in 26% of positive cases compared with 77% of negative cases (P<0.00001).115 A total of 135 antiviral prescriptions were avoided in patients with negative results.115 The FilmArray Respiratory Panel EZ (RPEZ) has been demonstrated to significantly improve the appropriate use of antibiotics and was associated with a decrease in clinic appointment duration in the outpatient pediatric clinic setting.116 Although promising, these results are likely limited by the test’s turnaround time of approximately 1 hour compared with the other tests. Additionally, there is uncertainty whether the implementation of RPEZ would reduce the use of downstream health care resources, including radiological and laboratory tests, telephone calls, and followup appointments.117 The significance of rapid turnaround time cannot be overemphasized in outpatient settings because this determines whether results are clinically actionable. Post hoc analysis of randomized controlled trial data on the use of RVP for patients presenting to EDs with respiratory symptoms has associated faster turnaround times with improved patient management compared with longer turnaround times.118 The logistics of primary care require technologies to accommodate the time constraints of a brief office visit for respiratory tract infections, which are on average only 15 minutes.119 Implementation of these new technologies will require consideration of appropriate patient populations and process measures, such as antibiotic avoidance, and use of antivirals, radiological and laboratory tests, and other health care resources.120 Optimal use of results may be derived through clinical decision support, because there likely is minimal prospective audit and feedback by ASPs in the outpatient setting.68

Conclusion A multitude of technological advances for the management of BSIs, invasive candidiasis, respiratory infections, infectious diarrhea, CNS infections, and outpatient respiratory infections have continued to advance the field of infectious diseases. RDTs have been recognized increasingly for their significant

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impact on clinical outcomes, antimicrobial use, and cost savings. Many of these RDTs show promise in their potential to improve patient care, but implementation of efficient evidence-based ASP interventions and diagnostic stewardship with pragmatism in mind are expected to be necessary to augment appropriate use and interpretation for translation outcomes. As clinicians, we should ensure the value of RDTs is not only increasing the accuracy and speed of diagnosis, but also changing clinical management, improving patient outcomes, and yielding overall cost-effectiveness, thus highlighting the importance of continued efficacy evaluations of these technologies.

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58. Huang DT, Yealy DM, Angus DC, the Pro ACTI. N Engl J Med. 2018;379(20):1973.

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69. Srinivas P, Rivard KR, Pallotta AM, et al. Pharmacotherapy. 2019;39(6):709-717. 70. Kalil AC, Metersky ML, Klompas M, et al. Clin Infect Dis. 2016;63(5):e61-e111. 71. Buchan BW, Windham S, Balada-Llasat JM, et al. J Clin Microbiol. 2020;58(7):e00135-20. 72. Webber DM, Wallace MA, Burnham CA, et al. J Clin Microbiol. 2020;58(7) e00343-20. 73. Rand KH, Beal SG, Cherabuddi K, et al. Open Forum Infect Dis. 2021;8(1):ofaa560. 74. Kolenda C, Ranc AG, Boisset S, et al. Open Forum Infect Dis. 2020;7(11):ofaa484. 75. Yoo IY, Huh K, Shim HJ, et al. Int J Infect Dis. 2020;95:326-331. 76. Monard C, Pehlivan J, Auger G, et al. Crit Care. 2020;24(1):434. 77. Klein M, Bacher J, Barth S, et al. J Clin Microbiol. 2021;59(3):e02497-20. 78. Collins ME, Popowitch EB, Miller MB. J Clin Microbiol. 2020;58(5):e02013-19. 79. Pickens C, Wunderink RG, Qi C, et al. Diagn Microbiol Infect Dis. 2020;98(4):115179. 80. Parente DM, Cunha CB, Mylonakis E, et al. Clin Infect Dis. 2018;67(1):1-7. 81. Willis C, Allen B, Tucker C, et al. Am J Health Syst Pharm. 2017;74(21):1765-1773. 82. Meng L, Pourali S, Hitchcock MM, et al. Open Forum Infect Dis. 2021;8(4):ofab099. 83. Smith MN, Erdman MJ, Ferreira JA, et al. J Crit Care. 2017;38:168-171. 84. Smith MN, Brotherton AL, Lusardi K, et al. Ann Pharmacother. 2019;53(6):627-638. 85. Carr AL, Daley MJ, Givens Merkel K, et al. Pharmacotherapy. 2018;38(12):1216-1228.

103. O’Halloran JA, Franklin A, Lainhart W, et al. Open Forum Infect Dis. 2017;4(4):ofx242. 104. Lewis PO, Lanier CG, Patel PD, et al. Med Mycol. 2020;58(3):408-410. 105. DiDiodato G, Bradbury N. Open Forum Infect Dis. 2019;6(4):ofz119. 106. Dack K, Pankow S, Ablah E, et al. Kans J Med. 2019;12(1):1-3. 107. Goodlet KJ, Tan E, Knutson L, et al. Diagn Microbiol Infect Dis. 2021;100(4):115394. 108. Vetter P, Schibler M, Herrmann JL, et al. Clin Microbiol Infect. 2020;26(6):706-712. 109. Sanchez GV, Fleming-Dutra KE, Roberts RM, et al. MMWR Recomm Rep. 2016;65(6):1-12. 110. Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. JAMA. 2016;315(17):1864-1873. 111. Tonkin-Crine SK, Tan PS, van Hecke O, et al. Cochrane Database Syst Rev. 2017;9:CD012252. 112. Mitamura K, Yamazaki M, Ichikawa M, et al. J Infect Chemother. 2021;27(3):450-454. 113. Kanwar N, Michael J, Doran K, et al. J Clin Microbiol. 2020;58(3):e01611-19. 114. Hassan F, Nguyen A, Formanek A, et al. J Clin Microbiol. 2014;52(3):906-910. 115. El Feghaly RE, Nolen JD, Lee BR, et al. J Pediatr. 2021;228:271277 e271. 116. Beal SG, Posa M, Gaffar M, et al. Pediatr Infect Dis J. 2020;39(3):188-191. 117. Fenton J, Posa M, Kelly M, et al. Pediatr Infect Dis J. 2020;39(9):e282-e283. 118. Brendish NJ, Malachira AK, Beard KR, et al. Eur Respir J. 2018;52(2):1800555. 119. Linder JA, Singer DE, Stafford RS. Clin Ther. 2003;25(9):2419-2430.

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Dr. Fong reported no relevant financial disclosures.

88. Lindblom A, Karami N, Magnusson T, et al. Eur J Clin Microbiol Infect Dis. 2018;37(8):1491-1497. 89. Rottier WC, Bamberg YR, Dorigo-Zetsma JW, et al. Clin Infect Dis. 2015;60(11):1622-1630. 90. Dien Bard J, McElvania E. Clin Lab Med. 2020;40(4):393-420. 91. Buss SN, Leber A, Chapin K, et al. J Clin Microbiol. 2015;53(3):915-925.

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About the Author Karen Fong, PharmD, BCIDP, is a clinical pharmacist, Infectious Diseases and Antimicrobial Stewardship, in the Department of Pharmacy, University of Utah Health, Salt Lake City, Utah.

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The Persistence of PrEP: Essential for Ending HIV BY MILENA MURRAY, PHARMD, MSC, BCIDP, AAHIVP

pproximately 30 years after the beginning of the HIV epidemic, emtricitabine–tenofovir disoproxil fumarate (FTC/TDF; Truvada, Gilead) was approved in 2012 as the first preexposure prophylaxis (PrEP) therapy. However, of the 1.2 million Americans eligible for PrEP, only an estimated 70,000 had an active prescription for PrEP as of the end of 2017.1 In 2019, FTC–tenofovir alafenamide (FTC/ TAF; Descovy, Gilead) was approved as a second PrEP therapy option. The PrEP continuum of care includes awareness of risk, uptake of therapy, and adherence and retention in care.2 Barriers to adherence and retention in care include forgetfulness, competing priorities, safety concerns, stigma, and lack of a supportive social network.3 It is well known that PrEP adherence is directly related to efficacy.4 Thus, a barrier that should be addressed is the ability to remain on PrEP after initiation, referred to as PrEP persistence. PrEP persistence is also defined as the length of time a person continues to refill PrEP prescriptions without an interruption of more than 30 days.5 Initiation of PrEP may be a poor measure because the discontinuation of PrEP at 1 month is reported to be as high as 45%.6 A study of 11,807 people with commercial insurance and 647 with Medicaid revealed a significant disparity in PrEP persistence.5 People with commercial insurance remained on PrEP for a median of 13.7 months (95% CI, 13.3-14.1 months) compared with 6.8 months (95% CI, 6.1-7.6 months) among those on Medicaid. After adjustment for covariates, female sex (hazard ratio [HR], 1.81; 95% CI, 1.6-2.1) and younger age (1824 years: HR, 2.4; 95% CI, 2.1-2.7) were predictors of nonpersistence.5

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A separate study of 300 people also showed that age affected PrEP persistence.7 In this study, 85% of participants had at least 1 behavior associated with a high risk for HIV acquisition. Of the participants, 178 (59%) were 30 years of age or older, 287 (96%) were men, and 178 (59%) identified as men who have sex with men (MSM).7 There were 57 (19%) participants who were not white. After 12 months, 44% of participants were persistent with PrEP. Only 34% attended quarterly follow-up visits. Being age 30 years or older was associated positively with PrEP persistence (odds ratio [OR], 1.04; 95% CI, 1.0-1.1). Additionally, a negative association was found with PrEP persistence and minority group status (OR, 0.33; 95% CI, 0.12-0.83).7

Understanding Changes Use Some people may stop PrEP for appropriate reasons, such as no longer being at high risk for HIV acquisition, but many discontinue due to structural issues. A study of 25 people taking PrEP and 18 providers of PrEP care identified several reasons for the PrEP discontinuation,8 including side effects and lack of perceived risk. In addition, a lack of housing caused 1 person to

stop therapy. From a provider perspective, there is often a focus on short-term clinical visits rather than long-term PrEP persistence. An analysis of 103 MSM taking PrEP found that 18% attended clinic appointments less often than the 3-month interval recommended by guidelines.9 The emergent reported barrier to PrEP adherence was insurance (39%), specifically the need for prior authorization and mailorder pharmacy mandates. In addition, systemic barriers to medical care were reported, such as poor availability of appointments, leading to medical appointment–related barriers.9 Removal of these appointment- and insurance-related barriers may help with PrEP persistence. A systematic review and metaethnography of experiences with PrEP use in cisgender men in the United States revealed interventions such as telehealth and pharmacist-prescribed approaches to PrEP distribution might reduce barriers to PrEP uptake and persistence.10 However, structural interventions were not likely to alleviate barriers in underserved communities. Of interest, a study of approximately 1,000 participants taking PrEP reported

that out-of-pocket costs for medication and clinic visits were not barriers to PrEP persistence. In this study, the average quarterly out-of-pocket cost was $34 (median, $5; interquartile range, $0-$25), and those with commercial insurance had higher costs than those without insurance.11 The authors noted that the costs were absolute and not analyzed relative to income, which may have led to a different interpretation of the data. The introduction of 2-1-1 PrEP dosing, sometimes called “on-demand PrEP,” provided an option for people who don’t want to take medication every day.12 A study of 140 men who had used the 2-1-1 dosing strategy reported high adherence to the double dose before sexual encounters. However, barriers to using this dosing strategy, such as stigma, cost, and unplanned sexual encounters, were reported.12 It should be noted that this particular PrEP dosing strategy is currently only recommended by the International Antiretroviral Society-USA for the MSM population.13 People taking PrEP may also discontinue therapy due to a low perceived risk for HIV acquisition.14 This may occur without consultation with a health care provider. Data at the 6to 12-month mark indicate discontinuations occur even though there is an ongoing risk for HIV acquisition.8 In a study of 112 Black ciswomen, PrEP persistence was 18%, with an average of 8.1 months on therapy.15 This small percentage was mainly attributed to a low perception of risk by participants and health care providers. Perceived and ongoing risk should be discussed at the initiation of therapy to avoid inappropriate discontinuation.14 While PrEP persistence is an important topic, there will be people for whom it is appropriate to discontinue therapy. It should be noted that major and international guidelines provide differing recommendations on the duration of oral therapy after the last exposure if PrEP discontinuation is desired.14 Length of therapy should be

considered based on the type of exposure, and it varies from 2 to 28 days.14 PrEP specialized services, navigation, LGBTQIA+ competent providers, and accessible clinic locations may reduce barriers to PrEP persistence. In addition, a comprehensive approach should be used; referrals for substance use, housing, and mental health services should be provided if appropriate.9 Other strategies that should be considered include 90-day prescriptions, drop-in clinic visits, and standing orders for laboratory testing. “Sameday” PrEP is also an emerging strategy to avoid delays in PrEP initiation.16 Data suggest that discontinuation with this strategy occurs at the same rate as standard prescribing practices. Understanding barriers to the initiation and persistence of PrEP is a critical factor to ending the HIV epidemic. Data on people with specific characteristics continue to expand. New PrEP options will also provide more opportunities for diverse populations. Targeted interventions based on the available data should be implemented to increase PrEP persistence.

References 1. Beymer MR, Holloway IW, Pulsipher C, et al. Current and future PrEP medications and modalities: on-demand, injectables, and topicals. Curr HIV/AIDS Rep. 2019;16(4):349-358. 2. Nunn AS, Brinkley-Rubinstein L, Oldenburg CE, et al. Defining the HIV preexposure prophylaxis care continuum. AIDS. 2017;31(5):731-734. 3. Clement ME, Kofron R, Landovitz RJ. Long-acting injectable cabotegravir for the prevention of HIV infection. Curr Opin HIV AIDS. 2020;15(1):19-26. 4. Koss CA, Liu AY, Castillo-Mancilla J, et al. Similar tenofovir hair concentrations in men and women after directly observed dosing of tenofovir disoproxil fumarate/emtricitabine: implications for preexposure prophylaxis adherence monitoring. AIDS. 2018;32(15):2189-2194. 5. Huang YA, Tao G, Smith DK, et al. Persistence with human immunodeficiency virus pre-exposure prophylaxis in the United States, 2012-2017. Clin Infect Dis. 2021;72(3):379-385. 6. Stankevitz K, Grant H, Lloyd J, et al. Oral preexposure prophylaxis continuation,

measurement and reporting. AIDS. 2020;34(12):1801-1811. 7. Keyes J, Crouse EC, DeJesus E, et al. Determinants of pre-exposure prophylaxis (PrEP) persistence in a high-risk population in central Florida. J Investig Med. 2021;69(2):397-401. 8. Laborde ND, Kinley PM, Spinelli M, et al. Understanding PrEP persistence: provider and patient perspectives. AIDS Behav. 2020;24(9):2509-2519. 9. D’Angelo AB, Lopez-Rios J, Flynn AWP, et al. Insurance- and medical provider-related barriers and facilitators to staying on PrEP: results from a qualitative study. Transl Behav Med. 2021;11(2):573-581. 10. Edeza A, Karina Santamaria E, Valente PK, et al. Experienced barriers to adherence to pre-exposure prophylaxis for HIV prevention among MSM: a systematic review and metaethnography of qualitative studies. AIDS Care. 2021;33(6):697-705. 11. Furukawa NW, Schneider JA, Coleman ME, et al. Out-of-pocket costs and HIV preexposure prophylaxis persistence in a US multicity demonstration project. Health Serv Res. 2020;55(4):524-530. 12. Camp C, Saberi P. Facilitators and barriers of 2-1-1 HIV pre-exposure prophylaxis. PLoS One. 2021;16(5):e0251917. 13. Saag MS, Gandhi RT, Hoy JF, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2020 recommendations of the International Antiviral Society–USA panel. JAMA. 2020;324(16):1651-1669. 14. Rutstein SE, Smith DK, Dalal S, et al. Initiation, discontinuation, and restarting HIV pre-exposure prophylaxis: ongoing implementation strategies. Lancet HIV. 2020;7(10):e721-e730. 15. Pyra M, Johnson AK, Devlin S, et al. HIV preexposure prophylaxis use and persistence among black ciswomen: “Women need to protect themselves, period.” J Racial Ethn Health Disparities. 2021 Mar 17: 1-10. doi: 10.1007/s40615-021-01020-9 16. Rowan SE, Patel RR, Schneider JA, et al. Same-day prescribing of daily oral pre-exposure prophylaxis for HIV prevention. Lancet HIV. 2021;8(2):e114-e120.

Dr. Murray reported being a speaker for Merck and on the advisory board for Theratechnologies and ViiV Healthcare.

About the Author Milena Murray, PharmD, MSc, BCIDP, AAHIVP, is an associate professor, College of Pharmacy, Midwestern University, in Downers Grove, Illinois.

I N F E C T I O U S D I S E A S E S P E C I A L E D I T I O N • FA L L 2 0 2 1

TREATMENT FOR NOSOCOMIAL PNEUMONIA HAS ARRIVED

In HABP/VABP and cUTI caused by susceptible Gram-negative microorganisms

OUTSMART RESISTANCE Fetroja outsmarts pathogens by using iron to gain cell entry, like a Trojan horse.1,2

Fetroja—the world’s only siderophore cephalosporin—overcomes Gram-negative antibacterial resistance1 INDICATIONS Fetroja® (cefiderocol) is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex. Fetroja is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens. USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of Fetroja and other antibacterial drugs, Fetroja should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria.

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of Fetroja. WARNINGS AND PRECAUTIONS Increase in All-Cause Mortality in Patients with CarbapenemResistant Gram-Negative Bacterial Infections An increase in all-cause mortality was observed in patients treated with Fetroja as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically ill patients with carbapenemresistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin.

Stable in vitro against all known classes of ϐ-lactamases, including serine-carbapenemases (such as KPC and OXA) and metallo-ϐ-lactamases (such as VIM, IMP, and NDM)1 Active against pathogens with porin channel deletions and efflux pump up-regulation1,3,4 The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with Fetroja than in patients treated with BAT [25/101 (24.8%) vs 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with Fetroja than in patients treated with BAT through Day 49 [34/101 (33.7%) vs 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including non-fermenters such as Acinetobacter baumannii complex, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established. Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP. Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Hypersensitivity was observed in Fetroja-treated patients in clinical trials. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins.

Fetroja has an extensive Gram-negative spectrum that includes hard-to-treat pathogens1 Fetroja has demonstrated activity against the following Gram-negative bacteria, both in vitro and in HABP/VABP: Acinetobacter baumannii complex, Escherichia coli*, Enterobacter cloacae complex*, Klebsiella pneumoniae*, Pseudomonas aeruginosa*, Serratia marcescens *Also included in cUTI indication.

In a seriously ill patient population with HABP or VABP, Fetroja exhibited non-inferiority to extended-infusion, high-dose meropenem1

Fetroja is highly active in vitro vs Gramnegative carbapenem-NS pathogens5 In this study, susceptibility of >38,000 Gram-negative clinical isolates from multiple countries (2013-2018) was tested against Fetroja

• Study highlights:

In vitro activity does not necessarily correlate with clinical efficacy.

Enterobacteralesa Overall

Enterobacterales

carbapenem-non-susceptible

P aeruginosaa

(n=25,995)

100%

(n=814)

97%

– 60% of patients were ventilated, while approximately 33% had failed empiric treatment1,5

98%

– The top 5 baseline Gram-negative pathogens were K pneumoniae, P aeruginosa, A baumannii, E coli, and E cloacae5

(n=6213)

Overall

P aeruginosaa

95%

(n=1416)

carbapenem-non-susceptible

A baumannii complexa A baumannii complexa

(n=2274)

S maltophilia b

(n=1565)

carbapenem-non-susceptible

Overall

• At Day 14, all-cause mortality (primary endpoint) in the mITT population was 12.4% for Fetroja vs 12.2% for extended-infusion, high-dose meropenem (95% CI, -7.2, 7.7)1

90%

(n=4185)

Overall

85% 100%

(inherently carbapenem-resistant)5,7

– Meropenem was used as a comparator in the trial and was optimized (2 grams IV over 3 h q8h) for seriously ill patients with a multidrug-resistant Gram-negative infection in the ICU1

PERCENT

100

In a phylogenetic reclassification performed in 2016, the nomenclature of Enterobacterales was proposed, which includes formerly established Enterobacteriaceae family and other genera such as Proteus spp, Providencia spp, Photorhabdus spp, and Serratia spp.8

In vitro susceptibility study design Clinical isolates of Gram-negative bacteria were collected from 4 global surveillance studies (SIDERO-WT-2014, SIDERO-WT-2015, SIDERO-WT-2016, and SIDERO-WT-2018) that included Enterobacterales* and non-fermenter strains. The global surveillance study (Proteeae†) collected clinical isolates from 2013-2016, and were tested centrally (IHMA Inc., Schaumburg, IL, USA). Fetroja MICs were determined by microbroth dilution using irondepleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) as approved by the Clinical and Laboratory Standards Institute (CLSI) subcommittee on antimicrobial susceptibility testing in January 2016. FDA breakpoints were used for Enterobacterales MIC ≤4 μg/mL, P aeruginosa MIC ≤1 μg/mL, and A baumannii complex‡ MIC ≤1 μg/mL, whereas CLSI investigational breakpoint was used for S maltophilia MIC ≤4 μg/mL. Carbapenem-nonsusceptible strain was defined as meropenem MIC ≥2 μg/mL for Enterobacterales strains (including Proteeae) and MIC ≥4 μg/mL for P aeruginosa and A baumannii complex.5 a FDA breakpoints used for Enterobacterales MIC ≤4 μg/mL, P aeruginosa MIC ≤1 μg/mL, and A baumannii complex MIC ≤1 μg/mL. b CLSI investigational breakpoint used for S maltophilia MIC ≤4 μg/mL. *E coli, K pneumoniae, other Klebsiella spp, Enterobacter spp, Serratia spp, and Citrobacter spp. † Morganella morganii, P mirabilis, Proteus vulgaris, and Providencia rettgeri. ‡ A baumannii complex consists of A baumannii, A calcoaceticus, A dijkshoorniae, A nosocomialis, A pittii, and A seifertii.

IMPORTANT SAFETY INFORMATION (continued) WARNINGS AND PRECAUTIONS (continued) Hypersensitivity Reactions (continued) Before therapy with Fetroja is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactam antibacterial drugs. Discontinue Fetroja if an allergic reaction occurs. Clostridioides difficile-associated Diarrhea (CDAD) Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including Fetroja. CDAD may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

• Fetroja exhibited comparable safety vs extended-infusion, high-dose meropenem in HABP/VABP1 Study Design Multicenter, double-blind, parallel-group, randomized, active-controlled Phase 3 study in approximately 300 adults with nosocomial pneumonia caused by Gramnegative bacteria. Subjects were randomized (1:1) to either cefiderocol, 2 grams, administered IV over 3 hours every 8 hours (q8h) or extended-infusion, high-dose meropenem, 2 grams, administered IV over 3 hours q8h. Randomization was performed by the stratified randomization method using their infection diagnosis (HABP, VABP, and HCABP) and Acute Physiology And Chronic Health Evaluation II (APACHE II) score (≤15 and ≥16) as allocation factors. Linezolid was administered for at least 5 days to subjects in both arms to provide coverage for methicillin-resistant Staphylococcus aureus (MRSA), and to maintain the study blind.1,5 CI=confidence interval.

FOR MORE INFORMATION, VISIT

FetrojaID.com Seizures and Other Central Nervous System (CNS) Adverse Reactions Cephalosporins, including Fetroja, have been implicated in triggering seizures. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust Fetroja dosing based on creatinine clearance. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether Fetroja should be discontinued. Development of Drug-Resistant Bacteria Prescribing Fetroja in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. ADVERSE REACTIONS The most common adverse reactions occurring in (≥2%) of patients receiving Fetroja compared to imipenem/cilastatin in the cUTI trial were: diarrhea (4% vs 6%), infusion site reactions (4% vs 5%), constipation (3% vs 4%), rash (3% vs <1%), candidiasis (2% vs 3%), cough (2% vs <1%), elevations in liver tests (2% vs <1%), headache (2% vs 5%), hypokalemia (2% vs 3%), nausea (2% vs 4%), and vomiting (2% vs 1%). The most common adverse reactions occurring in (≥4%) of patients receiving Fetroja compared to meropenem in the HABP/VABP trial were: elevations in liver tests (16% vs 16%), hypokalemia (11% vs 15%), diarrhea (9% vs 9%), hypomagnesemia (5% vs <1%), and atrial fibrillation (5% vs 3%). Please see a Brief Summary of Prescribing Information on following page.

References: 1. Fetroja (cefiderocol) [package insert]. Florham Park, NJ: Shionogi Inc.; 2020. 2. Zhanel GG, Golden AR, Zelenistky S, et al. Cefiderocol: a siderophore cephalosporin with activity against carbapenem-resistant and multidrug-resistant Gram-negative bacilli. Drugs. 2019;79(3):271-289. 3. Iregui A, Khan Z, Landman D, Quale J. Activity of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii endemic to medical centers in New York City. Microb Drug Resist. 2020;26(7):1-5. 4. Iregui A, Khan Z, Landman D, Quale J. Activity of cefiderocol against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii endemic to medical centers in New York City. Microb Drug Resist. 2020;26(7) (suppl):S1-S3. 5. Data on file. 6. Brooke JS. Stenotrophomonas maltophilia: an emerging global opportunistic pathogen. Clin Microbiol Rev. 2012;25(1):2-41. 7. Ruppé É, Woerther PL, Barbier F. Mechanisms of antimicrobial resistance in Gramnegative bacilli. Ann Intensive Care. 2015;5(1):61. doi:10.1186/s13613-015-0061-0. 8. Adeolu M, Alnajar S, Naushad S, Gupta RS. Genome-based phylogeny and taxonomy of the 'Enterobacteriales': proposal for Enterobacterales ord. nov. divided into the families Enterobacteriaceae, Erwiniaceae fam. nov., Pectobacteriaceae fam. nov., Yersiniaceae fam. nov., Hafniaceae fam. nov., Morganellaceae fam. nov., and Budviciaceae fam. nov. Int J Syst Evol Microbiol. 2016;66(12):5575-5599. © 2021 Shionogi Inc. Florham Park, NJ 07932. All Rights Reserved. Fetroja is a registered trademark of Shionogi & Co., Ltd. Osaka, Japan. USFET-0349 05/21

FETROJA (cefiderocol) for injection, for intravenous use Initial U.S. Approval: 2019 BRIEF SUMMARY: Please see package insert for full prescribing information. 1 INDICATIONS AND USAGE 1.1 Complicated Urinary Tract Infections (cUTIs), Including Pyelonephritis FETROJA®

is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex [see Clinical Studies (14.1) in the full prescribing information]. 1.2 Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) FETROJA is indicated in patients 18 years of age or older for the treatment of hospitalacquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens [see Clinical Studies (14.2) in the full prescribing information]. 1.3 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of FETROJA and other antibacterial drugs, FETROJA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. 4 CONTRAINDICATIONS FETROJA is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of FETROJA [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)]. 5 WARNINGS AND PRECAUTIONS 5.1 Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections An increase in all-cause mortality was observed in patients treated with FETROJA as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically ill patients with carbapenem-resistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin. The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with FETROJA than in patients treated with BAT [25/101 (24.8%) vs. 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with FETROJA than in patients treated with BAT through Day 49 [34/101 (33.7%) vs. 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including non-fermenters such as Acinetobacter baumannii complex, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established. Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP. 5.2 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Hypersensitivity was observed in FETROJA-treated patients in clinical trials [see Adverse Reactions (6.1)]. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins.

If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated. 5.4 Seizures and Other Central Nervous System (CNS) Adverse Reactions Cephalosporins, including FETROJA, have been implicated in triggering seizures [see Adverse Reactions (6.1)]. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust FETROJA dosing based on creatinine clearance [see Dosage and Administration (2.2) in the full prescribing information]. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether FETROJA should be discontinued. 5.5 Development of Drug-Resistant Bacteria Prescribing FETROJA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Indications and Usage (1.3)]. 6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail in the Warnings and Precautions section: • Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections [see Warnings and Precautions (5.1)] • Hypersensitivity Reactions [see Warnings and Precautions (5.2)] • Clostridioides difficile-associated Diarrhea (CDAD) [see Warnings and Precautions (5.3)] • Seizures and Other Central Nervous System Adverse Reactions [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Complicated Urinary Tract Infections (cUTIs), Including Pyelonephritis FETROJA was evaluated in an active-controlled, randomized clinical trial in patients with cUTI, including pyelonephritis (Trial 1). In this trial, 300 patients received FETROJA 2 grams every 8 hours infused over 1 hour (or a renally-adjusted dose), and 148 patients were treated with imipenem/cilastatin 1gram/1gram every 8 hours infused over 1 hour (or a renally-adjusted dose). The median age of treated patients across treatment arms was 65 years (range 18 to 93 years), with approximately 53% of patients aged greater than or equal to 65. Approximately 96% of patients were White, most were from Europe, and 55% were female. Patients across treatment arms received treatment for a median duration of 9 days. Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 1, a total of 14/300 (4.7%) cUTI patients treated with FETROJA and 12/148 (8.1%) of cUTI patients treated with imipenem/cilastatin experienced serious adverse reactions. One death (0.3%) occurred in 300 patients treated with FETROJA as compared to none treated with imipenem/cilastatin. Discontinuation of treatment due to any adverse reaction occurred in 5/300 (1.7%) of patients treated with FETROJA and 3/148 (2.0%) of patients treated with imipenem/cilastatin. Specific adverse reactions leading to treatment discontinuation in patients who received FETROJA included diarrhea (0.3%), drug hypersensitivity (0.3%), and increased hepatic enzymes (0.3%). Common Adverse Reactions Table 4 lists the most common selected adverse reactions occurring in ≥ 2% of cUTI patients receiving FETROJA in Trial 1. Selected Adverse Reactions Occurring in ≥ 2% of cUTI Patients Receiving FETROJA in Trial 1 FETROJAa Imipenem/Cilastatinb Adverse Reaction (N = 300) (N = 148)

Table 4

Before therapy with FETROJA is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactam antibacterial drugs. Discontinue FETROJA if an allergic reaction occurs.

Diarrhea

Infusion site reactionsc

5.3 Clostridioides difficile-associated Diarrhea (CDAD) Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including FETROJA. CDAD may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile.

Constipation

Rashd

< 1%

Candidiasise

Cough

< 1% < 1%

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.

Elevations in liver testsf

Headache

Hypokalemiag

3% (continued)

Table 4

Selected Adverse Reactions Occurring in ≥ 2% of cUTI Patients Receiving FETROJA in Trial 1 FETROJAa (N = 300)

Imipenem/Cilastatinb (N = 148)

Nausea

Vomiting

Adverse Reaction

cUTI = complicated urinary tract infection. a 2 grams IV over 1 hour every 8 hours (with dosing adjustment based on renal function). b 1 gram IV over 1 hour every 8 hours (with dosing adjustment based on renal function and body weight). c Infusion site reactions include infusion site erythema, inflammation, pain, pruritis, injection site pain, and phlebitis. d Rash includes rash macular, rash maculopapular, erythema, skin irritation. e Candidiasis includes oral or vulvovaginal candidiasis, candiduria. f Elevations in liver tests include alanine aminotransferase, aspartate aminotransferase, gammaglutamyl transferase, blood alkaline phosphatase, hepatic enzyme increased. g Hypokalemia includes blood potassium decreased.

Other Adverse Reactions of FETROJA in the cUTI Patients (Trial 1) The following selected adverse reactions were reported in FETROJA-treated cUTI patients at a rate of less than 2% in Trial 1: Blood and lymphatic disorders: thrombocytosis Cardiac disorders: congestive heart failure, bradycardia, atrial fibrillation Gastrointestinal disorders: abdominal pain, dry mouth, stomatitis General system disorders: pyrexia, peripheral edema Hepatobiliary disorders: cholelithiasis, cholecystitis, gallbladder pain Immune system disorders: drug hypersensitivity Infections and infestations: C. difficile infection Laboratory investigations: prolonged prothrombin time (PT) and prothrombin time international normalized ratio (PT-INR), red blood cells urine positive, creatine phosphokinase increase Metabolism and nutrition disorders: decreased appetite, hypocalcemia, fluid overload Nervous system disorders: dysgeusia, seizure Respiratory, thoracic, and mediastinal disorders: dyspnea, pleural effusion Skin and subcutaneous tissue disorders: pruritis Psychiatric disorders: insomnia, restlessness Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) FETROJA was evaluated in an active-controlled clinical trial in patients with HABP/VABP (Trial 2). In this trial, 148 patients received FETROJA 2 grams every 8 hours infused over 3 hours, and 150 patients received meropenem 2 grams every 8 hours infused over 3 hours. Doses of study treatments were adjusted based on renal function. The median age was 67 years, approximately 59% of patients were 65 years of age and older, 69% were male, and 68% were White. Overall, approximately 60% were ventilated at randomization, including 41% with VABP and 14% with ventilated HABP. The mean Acute Physiology And Chronic Health Evaluation (APACHE II) score was 16. All patients received empiric treatment for Gram-positive organisms with linezolid for at least 5 days. Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 2, serious adverse reactions occurred in 54/148 (36.5%) HABP/VABP patients treated with FETROJA and 45/150 (30%) of HABP/VABP patients treated with meropenem. Adverse reactions leading to death were reported in 39/148 (26.4%) patients treated with FETROJA and 35/150 (23.3%) patients treated with meropenem. Adverse reactions leading to discontinuation of treatment occurred in 12/148 (8.1%) of patients treated with FETROJA and 14/150 (9.3%) of patients treated with meropenem. The most common adverse reactions leading to discontinuation in both treatment groups were elevated liver tests. Common Adverse Reactions Table 5 lists the most common selected adverse reactions occurring in ≥ 4% of patients receiving FETROJA in the HABP/VABP trial. Table 5

Selected Adverse Reactions Occurring in ≥ 4% of HABP/VABP Patients Receiving FETROJA in Trial 2 FETROJAa N = 148

Meropenemb N = 150

Elevations in liver testsc

16%

Hypokalemiad

11%

15%

Diarrhea

Hypomagnesemia

< 1%

Atrial fibrillation

Adverse Reaction

HABP/VABP = hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. a 2 grams IV over 3 hours every 8 hours (with dosing adjustment based on renal function). b 2 grams IV over 3 hours every 8 hours (with dosing adjustment based on renal function). c Elevations in liver tests include the following terms: aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyl transferase increased, liver function test increased, liver function test abnormal, hepatic enzyme increased, transaminases increased, hypertransaminesemia. d Hypokalemia includes blood potassium decreased.

Other Adverse Reactions of FETROJA in HABP/VABP Patients in Trial 2 The following selected adverse reactions were reported in FETROJA-treated HABP/VABP patients at a rate of less than 4% in Trial 2:

Blood and lymphatic disorders: thrombocytopenia, thrombocytosis Cardiac disorders: myocardial infarction, atrial flutter Gastrointestinal disorders: nausea, vomiting, abdominal pain Hepatobiliary disorders: cholecystitis, cholestasis Infections and infestations: C. difficile infection, oral candidiasis Laboratory investigations: prolonged prothrombin time (PT) and prothrombin time international normalized ratio (PT-INR), activated partial thromboplastin time (aPTT) Metabolism and nutrition disorders: hypocalcemia, hyperkalemia Nervous system disorders: seizure Renal and genitourinary disorders: acute interstitial nephritis Respiratory, thoracic, and mediastinal disorders: cough Skin and subcutaneous tissue disorders: rash including rash erythematous 7 DRUG INTERACTIONS 7.1 Drug/Laboratory Test Interactions Cefiderocol may result in false-positive results in dipstick tests (urine protein, ketones, or occult blood). Use alternate clinical laboratory methods of testing to confirm positive tests. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on FETROJA use in pregnant women to evaluate for a drugassociated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Available data from published prospective cohort studies, case series, and case reports over several decades with cephalosporin use in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Developmental toxicity studies with cefiderocol administered during organogenesis to rats and mice showed no evidence of embryo-fetal toxicity, including drug-induced fetal malformations, at doses providing exposure levels 0.9 times (rats) or 1.3 times (mice) higher than the average observed in patients receiving the maximum recommended daily dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Human Data While available studies cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified an association with cephalosporin use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups. Animal Data Developmental toxicity was not observed in rats at intravenous doses of up to 1000 mg/kg/day or mice at subcutaneous doses of up to 2000 mg/kg/day given during the period of organogenesis (gestation days 6-17 in rats and 6-15 in mice). No treatment-related malformations or reductions in fetal viability were observed. Mean plasma exposure (AUC) at these doses was approximately 0.9 times (rats) and 1.3 times (mice) the daily mean plasma exposure in patients that received 2 grams of cefiderocol infused intravenously every 8 hours. In a pre- and postnatal development study, cefiderocol was administered intravenously at doses up to 1000 mg/kg/day to rats from Day 6 of pregnancy until weaning. No adverse effects on parturition, maternal function, or pre- and postnatal development and viability of the pups were observed. In pregnant rats, cefiderocol-derived radioactivity was shown to cross the placenta, but the amount detected in fetuses was a small percentage (< 0.5%) of the dose. 8.2 Lactation Risk Summary It is not known whether cefiderocol is excreted into human milk; however, cefiderocolderived radioactivity was detected in the milk of lactating rats that received the drug intravenously. When a drug is present in animal milk, it is likely that the drug will be present in human milk. No information is available on the effects of FETROJA on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FETROJA and any potential adverse effects on the breastfed child from FETROJA or from the underlying maternal condition.

Data

Patients Receiving CRRT

Cefiderocol-derived radioactivity was detected in milk following intravenous administration to lactating rats. The peak level in rat milk was approximately 6% of the peak plasma level.

A total of 16 patients treated with FETROJA received CRRT in clinical trials. Dosage adjustment of FETROJA is required in patients receiving CRRT including CVVH, CVVHD, and CVVHDF. Dosage of FETROJA should be based on the effluent flow rate in patients receiving CRRT [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. While on CRRT, a patient’s residual renal function may change. Improvements or reductions in residual renal function may warrant a change in FETROJA dosage.

8.4 Pediatric Use Safety and effectiveness of FETROJA in pediatric patients younger than 18 years of age have not been established. 8.5 Geriatric Use cUTI Of the 300 patients treated with FETROJA in the cUTI trial, 158 (52.7%) were 65 years of age and older, and 67 (22.3%) were 75 years of age and older. No overall differences in safety or efficacy were observed between these patients and younger patients. HABP/VABP Of the 148 patients treated with FETROJA in the HABP/VABP trial, 83 (56.1%) were 65 years of age and older, and 40 (27%) were 75 years of age and older. The incidence of adverse reactions in patients treated with FETROJA was similar in patients under 65 years of age as compared to older patients (65 years of age and older and 75 years of age and older). The incidence of adverse reactions in older patients (65 years of age and older and 75 years of age and older) was also similar between treatment groups. Clinical cure rates at the Test-of-Cure visit (TOC) in FETROJA-treated adult patients younger than 65 years of age, 65 years of age to younger than 75 years of age and 75 years of age and older were 60%, 77.5%, and 60%, respectively. In comparison, the clinical cure rates at the TOC visit in the meropenem-treated patients for each of these subgroups were 65.5%, 64.4%, and 70.5%, respectively. The observed all-cause mortality rates at Day 14 in the FETROJA-treated patients for each of these subgroups were 12.3%, 7.5%, and 17.5%, respectively. In comparison, in the meropenem-treated patients for each of these subgroups, they were 10.3%, 17.8%, and 9.1%, respectively.

Patients with CLcr 120 mL/min or Greater CLcr 120 mL/min or greater may be seen in seriously ill patients, who are receiving intravenous fluid resuscitation. Dosage adjustment of FETROJA is required in patients with CLcr 120 mL/min or greater [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. Monitor renal function regularly and adjust the dosage of FETROJA accordingly as renal function may change during the course of therapy. 8.7 Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of cefiderocol have not been evaluated. Hepatic impairment is not expected to alter the elimination of cefiderocol as hepatic metabolism/excretion represents a minor pathway of elimination for cefiderocol. Dosage adjustments are not necessary in patients with impaired hepatic function. 10 OVERDOSAGE There is no information on clinical signs and symptoms associated with an overdose of FETROJA. Patients who receive doses greater than the recommended dose regimen and have unexpected adverse reactions possibly associated with FETROJA should be carefully observed and given supportive treatment, and discontinuation or interruption of treatment should be considered. Approximately 60% of cefiderocol is removed by a 3- to 4-hour hemodialysis session [see Clinical Pharmacology (12.3) in the full prescribing information].

cUTI and HABP/VABP FETROJA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. No dosage adjustment is required based on age. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) in the full prescribing information]. 8.6 Renal Impairment Patients with CLcr 60 to 89 mL/min No dosage adjustment of FETROJA is recommended in patients with CLcr 60 to 89 mL/min. Patients with CLcr Less Than 60 mL/min Including Patients Receiving Intermittent HD Dose adjustment is required in patients with CLcr less than 60 mL/min, and in patients who are receiving HD. In patients requiring HD, complete HD at the latest possible time before the start of cefiderocol dosing [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. Monitor renal function regularly and adjust the dosage of FETROJA accordingly as renal function may change during the course of therapy.

Manufactured by Shionogi & Co., Ltd. Osaka 541-0045 Japan Manufactured for Shionogi Inc. Florham Park, NJ USA, 07932 FET-PI-02A USFET-0247 09/20

IDSE Review

Antibiotic Use in the Emergency Department: A 2-Door Opportunity for Stewardship BY KAREN FONG, PHARMD, BCIDP

ntibiotics are often prescribed in hospitals and ambulatory care, but most prescribing occurs in the outpatient setting.1 Primary care offices, specialty clinics, emergency departments (EDs), and urgent care comprise 80% to 90% of total antibiotic use.2 Unfortunately, approximately 30% of all outpatient antimicrobial use is deemed unnecessary.3,4 Moreover, inappropriate antibiotic use is associated with morbidity, adverse effects, Clostridioides difficile infection (CDI), and increased cost while being the most important modifiable risk factor for antibiotic resistance.2,5,6

Antimicrobial stewardship has been recognized to improve patient outcomes, reduce adverse events, including CDI, enhance rates of antimicrobial susceptibilities, and optimize resource utilization across the health care system.7 Antimicrobial stewardship programs (ASPs) traditionally have focused on hospitalized patients, but the importance of ASPs in the outpatient setting including the ED captured national attention and led to the release of the Core Elements of Outpatient Antibiotic Stewardship.2,8,9 The ED serves as a gateway between the community and hospital while harboring a unique opportunity for stewardship with the potential for downstream effects in either direction.8 A significant portion of the 139 million annual ED visits are the result of an infection, accompanied by an overwhelming 25 million prescriptions for cephalosporins, penicillins, and macrolides alone each year.10 The rate of inappropriate antimicrobial prescribing specific to the ED is estimated to be 39%, with the highest rates observed among patients with bronchitis, upper respiratory tract infections (URTIs), and skin and soft tissue infections (SSTIs).11 Antimicrobial regimens selected for initiation in the ED also have the potential to drive inpatient use, because they are often maintained after another clinician adopts care of the patient.12 There are substantial barriers to commonly used ASPs in the

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ED setting due to high rates of overcrowding, rapid rate of patient and staff turnover, quick clinical decision making, diagnostic uncertainty, and diminished continuity of care.8,12 May et al acknowledge the unique challenges faced by ASPs in the ED and suggest that there are 4 key characteristics differentiating the ED from the conventional antimicrobial stewardship approach (Table).13 Furthermore, the ED is complicated by the 2015 Centers for Medicare & Medicaid Services’ mandate to comply with the Severe Sepsis and Septic Shock Early Management Bundle as a quality measure. The Surviving Sepsis Campaign recommends rapid administration of broad-spectrum antibiotics within the first 3 hours of presentation, recently debated as a driver of antibiotic overuse by experts.14-16 We discuss current antimicrobial stewardship strategies in the ED followed by an emphasis on the performance of strategies targeting specific syndromes including urinary tract infections (UTIs), URTIs, and SSTIs.

Current Antimicrobial Stewardship Strategies in the ED Antimicrobial stewardship strategies in the ED should be adapted for the individualized setting and align to the Core Elements of Outpatient Antibiotic Stewardship to ensure feasibility and effectiveness. The MITIGATE Antimicrobial Stewardship Toolkit (A Multifaceted Intervention to Improve Prescribing for Acute Respiratory Infection for Adults and Children in Emergency Department and Urgent Care Settings) is a systematically developed ASP for use in the ED setting, specifically designed to meet the core elements and fully endorsed by the CDC. MITIGATE recommends intervention components consisting of provider education, patient education, provider commitment, departmental feedback, provider feedback and education, and peer comparison using personalized audit and feedback (PAF; Figure, page 72).17

Multifaceted interventions are the most frequent type of behavioral strategy, typically including education, implementation of guidelines or clinical pathway, and followed by PAF.8,13,18 Losier et al performed systematic review of 43 studies of ASPs in the ED. Most had an uncontrolled before-and-after design.19 Although only 6 studies described PAF, patient or provider education and guideline or clinical pathway implementation were the most common interventions. Published outcomes have been mostly limited to process measures such as reporting significant improvement in adherence to guidelines or appropriateness of antimicrobial prescribing and decreased antimicrobial use. Five studies demonstrated statistically significant improvement in clinical outcomes, including hospital and ED length of stay, admission of low-risk patients to the hospital, readmission to the ED, and mortality.19 ED pharmacist involvement was described in 13 studies, targeting continuity of care through culture follow-up programs for patients discharged, highlighting the importance of the pharmacists' role as part of a multidisciplinary team.19 Livorsi et al evaluated an audit-and-feedback intervention using a quasi-experimental interrupted time-series design at 2 intervention and 2 matched-control EDs.20 Clinicians received single, one-on-one education on antimicrobial prescribing for common infections and individualized feedback on total and condition-specific (uncomplicated acute respiratory tract infection [ARI]) antimicrobial use with peer-to-peer comparisons. Intervention sites compared with control sites had no absolute reduction in their total antimicrobial rate (incidence rate ratio, 0.99; 95% CI, 0.98-1.01).20 Antimicrobial use for uncomplicated ARIs at the intervention sites decreased (68.6%-42.4%; P<0.01) and guideline-concordant management improved (52.1%-72.5%; P<0.01), although these improvements were absent at the control sites.20 In a recent prospective quasiexperimental study of a multifaceted ASP for the main

Table. Key Aspects of Antimicrobial Stewardship in the Emergency Department Key Aspect Clinical diagnosis

Empiric therapy

Considerations

Comments

Rationale for starting antimicrobials for (tentative) diagnosis

• Application of rapid diagnostics including molecular techniques and biomarkers to reduce unnecessary antibiotic use

Timing, choice of spectrum, route, dose, and dosing interval

• Major impact on therapy further downstream (either inpatient or outpatient care settings) • Critical appraisal of the choice of empiric therapy provides an important opportunity

Microbiological cultures and tests

Relevance of appropriate culture taking and other microbiological tests before starting antimicrobial therapy

• Allows for identification of the causative pathogen for reasoned deescalation of antimicrobial therapy

Follow-up for outpatients

Evaluate clinical response to antimicrobial therapy and culture result assessment

• Logistically challenging process

IDSE.NET

Urinary Tract Infections UTIs are one of the leading causes for infections among ED patients, accounting for almost 3 million visits annually in the United States.10 Antibiotic prescriptions for asymptomatic bacteriuria (ASB) frequently occur in the ED, with the driver being positive urinalysis and urine culture rather than presence of urinary symptoms.22 There is a clear discrepancy between ED diagnoses of UTIs and the clinical and microbiological data that accumulate during hospital admission. However, these diagnoses often perpetuate the continuation of antibiotics throughout hospital admission despite the absence of clinical and microbiological evidence for infection.23 Treatment of ASB in women who were not pregnant, older patients, and patients with chronic indwelling or intermittent catheters does not confer any benefit while promoting the risk for antimicrobial resistance and CDI.24 Moreover, up to 30% of patients discharged from the ED with an antibiotic for UTI require post-discharge intervention due to detection of resistance.25,26 ASP efforts for UTIs in the ED should target reducing treatment of ASB, and improving diagnostic processes, empiric antibiotic selection, and duration of therapy.18,27,28 A clinical decision support system (CDSS) is an antimicrobial stewardship strategy that has been explored in the ED to improve guideline compliance for empiric antibiotic prescribing in UTIs. A multicenter prospective before-and-after controlled interventional study was conducted in adult ED patients diagnosed with cystitis, pyelonephritis, or acute prostatitis. CDSS was integrated into the workflow of the electronic health record and used at the point of care, which was automatically triggered when an antibiotic prescription was considered for treatment. Based on national French guidelines, the CDSS offered diagnostic and therapeutic tools, and displayed recommendations for antibiotic treatment and follow-up tailored to individual patient data. A total of 912 patients were included in the study, and the CDSS was used in 59% of cases (182/307).29 The CDSS intervention only improved the

compliance of antibiotic choice and duration prescribing in 1 ED (absolute increase, +20%; P=0.007).29 In a multivariate analysis, CDSS use was associated with only antibiotic choice improvement (odds ratio [OR], 1.94; 95% CI, 1.13-3.32; P=0.016).29 This demonstrates that CDSS alone only partially improves UTI guideline compliance in the ED, and additional strategies for antimicrobial stewardship may be needed. Quasi-experimental studies have been conducted in the ED for patients with uncomplicated UTIs. In 3 EDs, Hudepohl et al distributed local antibiotic resistance data, including a recommendation to consider nitrofurantoin in absence of contraindication. A total of 1,140 patients were included retrospectively; prescriptions for ciprofloxacin decreased (39% vs 26%; P<0.001) and prescriptions for nitrofurantoin (20% vs 30%; P=0.003) increased at the end of the study period.30 Reduction in prescribing ineffective antibiotics (7.6% vs 4.1%) was observed, but did not reach statistical significance (OR, 0.51; 95% CI, 0.17-1.52).30 Jorgensen et al performed a retrospective pre-/ post-implementation analysis in ED patients with UTIs.31 The investigators developed an empiric antimicrobial treatment algorithm based on national and professional society guidelines with an emphasis on nitrofurantoin for patients with cystitis. The ASP team disseminated the algorithm as a quick reference pocket card, an educational campaign was launched, and PAF was conducted by ASP members. The investigators included 401 and 351 patients, respectively, in the preand post-implementation cohorts.31 There was a significant increase in empiric nitrofurantoin (16%-43%; P<0.001).31 In a subgroup of patients with a positive urine culture (n=141), those discharged on nitrofurantoin had significantly fewer return visits for a UTI-related reason (4% vs 16%; P=0.032).31 More recently, Zalmanovich et al assessed their multifaceted antimicrobial stewardship intervention on 427 patients discharged from the ED with a UTI diagnosis.32 This consisted of 3 months of dissemination of guidelines, short lectures, incorporation of order sets into electronic ED charts, and weekly PAF followed by an 11-month booster period of monthly text messages of the treatment protocol. Results showed protocol adherence with antibiotic selection and duration increased from 41% to 84% (P<0.001).32 Adherence remained high in the late follow-up period (73.4% vs 41%; P<0.001).32 Fluoroquinolone use decreased from 19.1% before the intervention to 5% in the intervention and 7.4% in the late follow-up periods (P<0.001).32 Multifaceted antimicrobial stewardship strategies including promoting awareness of

Antibiotics prescribed in the ED are often continued upon admission.

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infectious syndromes in the ED, Savoldi et al found an associated reduction in antibiotic use and costs.21 Clinical outcomes included a mild but sustained decrease in hospital length of stay and significant downward trend of CDI incidence rate, but mortality did not change significantly.21 Although these studies pursued multiple syndromes, ASP studies specific to the ED often are focused on a single condition, such as UTIs, ARIs, or SSTIs.

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Commitment Core Element: Demonstrate dedication to and accountability for optimizing antibiotic prescribing and patient safety MITIGATE: Provider commitment

Action for Policy and Practice C Core El Element: t Implement at least 1 policy or practice to improve antibiotic prescribing, assess whether it is working, and modify as needed MITIGATE: Departmental feedback

Figure. Compliance with CDC Core Elements through the MITIGATE Antimicrobial Stewardship Toolkit.

Tracking and Reporting Core Element: Monitor antibiotic prescribing practices and offer regular feedback to clinicians, or have clinicians access their own antibiotic prescribing practices themselves MITIGATE: Provider feedback and education, peer comparison using personalized audit and feedback

ED-specific antibiotic resistance; development of institution-specific treatment guidelines; and encouraging these resources through education, leverage of the electronic medical record, and PAF have had important implications for UTI management in the ED.

Respiratory Tract Infections ARIs including bronchitis and pneumonia account for more than 6 million visits to the ED annually in the United States.10 Most are considered antibioticnonresponsive diagnoses, excluding pneumonia and pharyngitis, yet approximately 75% of cases of acute bronchitis are inappropriately treated with broadspectrum antibiotics.33,34 Despite ample evidence against antibiotics for acute bronchitis, this practice continues, suggesting there is substantial opportunity to reverse this trend.11,35,36 Metlay et al conducted a cluster randomized trial in 16 EDs evaluating the effectiveness of an educational program to target reduction in unnecessary antibiotic use for ARIs.37 The multidimensional educational intervention emphasized judicious antibiotic use through direct education to providers, performance feedback, and an interactive computer kiosk located in the waiting room for patient education. More than 5,500 ED patients during the 2-year study period were included, and antibiotic prescriptions for URTIs and acute

IDSE.NET

Education And Expertise Core Element: Provide resources to clinicians and patients on antibiotic prescribing, and ensure access to needed expertise for optimizing antibiotic prescribing MITIGATE: Provider and patient education

bronchitis decreased by 10% (95% CI, –18% to –2%) at the intervention sites compared with an increase of 0.5% (95% CI, –3% to 5%) at the control sites.37 There were no significant differences between control and intervention sites for return ED visits or patient satisfaction. Despite educational intervention, there is still substantial antibiotic overuse.37 In a quasi-experimental controlled study, Madaras-Kelly et al found implementation of the core elements was associated with safe reductions in antibiotic prescribing for uncomplicated ARIs across Veterans Health Administration ED and primary care clinic sites.38 Antibiotic prescribing rates pre-/postimplementation in 10 intervention sites were 59.7% and 41.5%, respectively, whereas the rates were 73.5% and 67.2%, respectively, in 40 control sites (P<0.001).38 The use of appropriate antibiotic therapy in the intervention site ORs pre-/post-implementation increased (1.67; 95% CI, 1.31-2.14). This outcome remained unchanged within the control sites (1.01; 95% CI, 0.911.19).38 No difference in ARI-related return visits postimplementation was observed (1.3% vs 2.0%; P=0.76), but all-cause hospitalization was lower within the intervention sites (–0.5% vs –0.2%; P=0.02).38 The BioFire FilmArray Respiratory Panel also has been explored in 2 randomized controlled trials in the ED as a rapid diagnostic test to reduce unnecessary

Skin and Soft Tissue Infections SSTIs lead to approximately 3.4 million ED visits annually in the United States.10 Misdiagnosed lower extremity cellulitis is common, occurring at a rate of more than 30%.43 Eighty-five percent of misdiagnosed patients do not require hospitalization and 92% receive unnecessary antibiotics.43 Cost estimates and projections indicate 50,000 to 130,000 hospitalizations and $195 million to $515 million in health care spending may be avoided annually.43 The Infectious Diseases Society of America (IDSA) guidelines for the diagnosis and management of SSTIs suggest many patients can be successfully treated with outpatient therapy and recommend either oral agents or outpatient parental antibiotic therapy (OPAT).44 However, many patients with uncomplicated SSTIs (no systemic

signs of infection or comorbidities) are still admitted to the hospital to receive IV antibiotics, commonly the sole reason for admission.45,46 The likelihood of all-cause unplanned 30-day ED visits or readmissions has also been found to be similar between admitted and non-admitted patients for acute SSTIs.47 SSTIs are most often caused by Staphylococcus aureus and Streptococcus species, but empiric antibiotic therapy frequently deviates from narrow-spectrum oral agents to incorporate coverage for methicillin-resistant S. aureus (MRSA) and Pseudomonas aeruginosa using IV agents.44,46 ASPs in the ED should target appropriate prescribing for empiric therapy, including antibiotic selection and route for SSTIs, to limit unnecessary hospital admissions and costs. For uncomplicated SSTIs, equal efficacy has been demonstrated between IV and oral antibiotic therapies, but benefits to the oral route include the potential for fewer complications and decreased cost.48,49 Therefore, oral antibiotics have been advocated as the default treatment of SSTIs unless patient factors or clinical criteria are present, such as immunocompromised status; areas affecting the hand, face, or orbit; or failure of an appropriate course of oral antibiotics.50 However, there are many perceived barriers to outpatient treatment across the spectrum of the clinician (misconceptions of bioavailability, cognitive bias, fear of litigation), patient (noncompliance, perceived severity of illness, patient expectations), and system and process (lack of clear guidelines, convenience, quick decision making).50 Barriers may be diminished through education and organizational strategies such as empiric treatment guidelines and CDSS to increase awareness surrounding antibiotic choice and route.50 Galanter et al performed a retrospective quasiexperimental study of 456 patients in the ED comparing appropriate antibiotic prescribing pre-/ post-implementation of an empiric therapy guide for inpatient and outpatient regimens based on the facility-specific antibiogram and IDSA guidelines for a variety of infections, including nonpurulent cellulitis.51 The guide was disseminated through email and pharmacists providing direct education to the ED providers. A 6-week follow-up email was sent to ED providers seeking feedback and reminding them to continue using the guide. Appropriateness of antibiotic prescribing improved significantly by 35.5% for nonpurulent cellulitis (P=0.002).51 Also, broad-spectrum antibiotic use decreased by 24.9% for nonpurulent cellulitis (P=0.025).51 Investigators have explored several other antibiotic stewardship strategies for managing SSTIs. In a non-randomized controlled trial, May et al employed CDSS and PAF with education, knowledge assessment, and implementation of a clinical treatment algorithm. They found that the interventions

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antibiotic use in patients with suspected URTIs. Rapid testing results with or without a multifaceted ASP intervention were only associated with a trend toward decreased antibiotic use in both studies.39,40 Patients were less likely to receive antibiotics if results were available before the end of the ED visit, highlighting that usefulness of rapid testing is contingent upon the timeliness of results.40 To improve compliance with pneumonia treatment guidelines, CDSSs have provided clinicians with guideline-recommended decision support for diagnosis, severity assessment, disposition, and antibiotic selection for adult ED patients. Dean et al conducted a prospective, controlled, quasi-experimental study in 7 EDs within a health care system.41 A CDSS was introduced to the ED providers at the intervention sites through emails, small group meetings, didactic lectures, and “academic detailing” one-on-one with providers during clinical shifts to raise awareness and receive feedback. A total of 4,758 ED patients with pneumonia were included; physicians used the CDSS in 62.6% of the intervention patients.41 There was no difference overall in severity-adjusted mortality (OR, 0.69; 95% CI, 0.41-1.16), but a post hoc analysis showed significantly lower mortality among patients with community-acquired pneumonia at EDs with the intervention (OR, 0.53; 95% CI, 0.28-0.99).41 In addition, Ciarkowski et al found a CDSS-driven pathway for community-acquired pneumonia initiated in the ED supplemented by active antimicrobial stewardship review led to robust improvements in antibiotic length of therapy and decreased costs by 20% with similar clinical outcomes compared with baseline.42 When active antimicrobial stewardship review was withdrawn, significant cost savings and reductions in total length of therapy were not maintained.42 There is a potential benefit to CDSSs for ED patients with pneumonia, but improved outcomes are likely only sustainable with ongoing dedicated ASP resources such as PAF.

IDSE Review

modestly improved adherence to guidelines driven by treatment duration reductions. In 583 SSTIs examined, clinical adherence to guidelines at the intervention site improved from 41% to 51% (adjusted OR, 2.13; 95% CI, 1.20-3.79).52 No changes occurred at the control site. Antibiotic duration decreased by 26% at the intervention site (adjusted geometric mean ratio, 0.74; 95% CI, 0.66-0.84), and mean antibiotic prescription duration was 1.95 days shorter (95% CI, 1.54-2.33).52 Furthermore, rapid diagnostics have emerged to mitigate the shifted prescribing of antiMRSA agents as empiric antibiotic therapy in moderate to severe SSTIs (systemic signs of infection) after incision and drainage.53 May et al conducted a prospective, randomized controlled trial of 252 patients in 2 EDs to determine whether real-time results using the Xpert MRSA/methicillin-sensitive S. aureus (MSSA) SSTI assay (Cepheid) would affect antibiotic selection for patients with abscesses after incision and drainage. Patients in the intervention group with MSSA received beta-lactams more often than those in the control group (absolute difference, 14.5%; 95% CI, 1.1%-30.1%), as did patients with MRSA who received anti-MRSA agents more often (absolute difference, 21.5%; 95% CI, 10.1%-33.0%).54 There were no differences in clinical outcomes or overall antibiotic use observed.54 In addition, ASPs should consider patients presenting with comorbidities, recurrent infection, or sepsis, because treatment strategies vary significantly for these conditions.55 Appropriate candidates among this group should be identified for oral therapy to avoid unnecessary observation use and hospital admission for IV therapy.

Conclusion The ED serves as a gateway between inpatient and outpatient settings, thus presenting ASPs with a unique opportunity to promote appropriate antibiotic prescribing and benefit both sites of care.8 When implementing an ASP, consider the 4 key aspects— clinical diagnosis, empiric therapy, microbiological cultures and tests, and follow-up for outpatients.13 Most common strategies have been reported as multifaceted, including provider education, guidelines and clinical pathways, CDSSs, and PAF, but each setting requires a tailored approach.8,13,18 Interventions focusing on UTIs, URTIs, and SSTIs should be emphasized, because these are the most common conditions associated with inappropriate prescribing in the ED and significant impact could be achieved by improving prescribing practices and outcomes.11,22 Future research for ASPs in the ED should shift away from process measures and focus on meaningful clinical and public health outcomes, such as adverse events, patient mortality, and community rates of antimicrobial resistance.13

IDSE.NET

References 1.

Suda KJ, Hicks LA, Roberts RM, et al. Antibiotic expenditures by medication, class, and healthcare setting in the United States, 2010-2015. Clin Infect Dis. 2018;66(2):185-190.

2. Sanchez GV, Fleming-Dutra KE, Roberts RM, et al. Core Elements of Outpatient Antibiotic Stewardship. MMWR Recomm Rep. 2016;65(6):1-12. 3. Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011. JAMA. 2016;315(17):1864-1873. 4. Cosgrove SE, Seo SK, Bolon MK, et al. Evaluation of postprescription review and feedback as a method of promoting rational antimicrobial use: a multicenter intervention. Infect Control Hosp Epidemiol. 2012;33(4):374-380. 5. Shehab N, Patel PR, Srinivasan A, et al. Emergency department visits for antibiotic-associated adverse events. Clin Infect Dis. 2008;47(6):735-743. 6. Srinivasan A. Antibiotic stewardship: why we must, how we can. Cleve Clin J Med. 2017;84(9):673-679. 7. Barlam TF, Cosgrove SE, Abbo LM, et al. Implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62(10):e51-77. 8. May L, Cosgrove S, L’Archeveque M, et al. A call to action for antimicrobial stewardship in the emergency department: approaches and strategies. Ann Emerg Med. 2013;62(1):69-77.e62. 9. Bishop BM. Antimicrobial stewardship in the emergency department: challenges, opportunities, and a call to action for pharmacists. J Pharm Pract. 2016;29(6):556-563. 10. Rui P, Kang K. National Hospital Ambulatory Medical Care Survey: 2017 emergency department summary tables. National Center for Health Statistics. Accessed August 24, 2021. https://bit.ly/3zBnKiS-IDSE 11. Timbrook TT, Caffrey AR, Ovalle A, et al. Assessments of opportunities to improve antibiotic prescribing in an emergency department: a period prevalence survey. Infect Dis Ther. 2017;6(4):497-505. 12. Trinh TD, Klinker KP. Antimicrobial stewardship in the emergency department. Infect Dis Ther. 2015;4(suppl 1):39-50. 13. May L, Martin Quiros A, Ten Oever J, et al. Antimicrobial stewardship in the emergency department: characteristics and evidence for effectiveness of interventions. Clin Microbiol Infect. 2021;27(2):204-209. 14. Rhodes A, Evans LE, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock: 2016. Intensive Care Med. 2017;43(3):304-377. 15. Chanu R, Chiotos K, Cosgrove SE, et al, for the Infectious Diseases Society of America Sepsis Task Force. Infectious Diseases Society of America Position Paper: recommended revisions to the National Severe Sepsis and Septic Shock Early Management Bundle (SEP-1) Sepsis Quality Measure. Clin Infect Dis. 2021;72(4):541-552. 16. Townsend SR, Rivers EP, Duseja R. Centers for Medicare and Medicaid Services Measure Stewards’ Assessment of the Infectious Diseases Society of America’s Position Paper on SEP-1. Clin Infect Dis. 2021;72(4):553-555. 17. May LKY, Gaona SD, Mistry R, et al. MITIGATE Antimicrobial Stewardship Toolkit. 2018. Accessed August 24, 2021. https://bit.ly/3CI2z0f-IDSE 18. Pulia M, Redwood R, May L. Antimicrobial stewardship in the emergency department. Emerg Med Clin North Am. 2018;36(4):853-872. 19. Losier M, Ramsey TD, Wilby KJ, et al. A systematic review of antimicrobial stewardship interventions in the emergency department. Ann Pharmacother. 2017;51(9):774-790. 20. Livorsi DJ, Nair R, Dysangco A, et al. Using audit and feedback to improve antimicrobial prescribing in emergency departments: a multicenter quasi-experimental study in the Veterans Health Administration. Open Forum Infect Dis. 2021;8(6):ofab186.

40. Durant TJS, Kubilay NZ, Reynolds J, et al. Antimicrobial stewardship optimization in the emergency department: the effect of multiplex respiratory pathogen testing and targeted educational intervention. J Appl Lab Med. 2020;5(6):1172-1183.

22. Pallin DJ, Ronan C, Montazeri K, et al. Urinalysis in acute care of adults: pitfalls in testing and interpreting results. Open Forum Infect Dis. 2014;1(1):ofu019.

41. Dean NC, Jones BE, Jones JP, et al. Impact of an electronic clinical decision support tool for emergency department patients with pneumonia. Ann Emerg Med. 2015;66(5):511-520.

23. Shallcross LJ, Rockenschaub P, McNulty D, et al. Diagnostic uncertainty and urinary tract infection in the emergency department: a cohort study from a UK hospital. BMC Emerg Med. 2020;20(1):40.

42. Ciarkowski CE, Timbrook TT, Kukhareva PV, et al. A pathway for community-acquired pneumonia with rapid conversion to oral therapy improves health care value. Open Forum Infect Dis. 2020;7(11):ofaa497.

24. Nicolle LE, Gupta K, Bradley SF, et al. Clinical practice guideline for the management of asymptomatic bacteriuria: 2019 update by the Infectious Diseases Society of America. Clin Infect Dis. 2019;68(10):1611-1615.

43. Weng QY, Raff AB, Cohen JM, et al. Costs and consequences associated with misdiagnosed lower extremity cellulitis. JAMA Dermatol. 2017;153(2):141-146.

25. Dumkow LE, Kenney RM, MacDonald NC, et al. Impact of a multidisciplinary culture follow-up program of antimicrobial therapy in the emergency department. Infect Dis Ther. 2014;3(1):45-53.

44. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis. 2014;59(2):147-159.

26. Jorgensen S, Zurayk M, Yeung S, et al. Risk factors for early return visits to the emergency department in patients with urinary tract infection. Am J Emerg Med. 2018;36(1):12-17.

45. Talan DA, Salhi BA, Moran GJ, et al. Factors associated with decision to hospitalize emergency department patients with skin and soft tissue infection. West J Emerg Med. 2015;16(1):89-97.

27. Maddali N, Cantin A, Koshy S, et al. Antibiotic prescribing patterns for adult urinary tract infections within emergency department and urgent care settings. Am J Emerg Med. 2021;45:464-471.

46. Kamath RS, Sudhakar D, Gardner JG, et al. Guidelines vs actual management of skin and soft tissue infections in the emergency department. Open Forum Infect Dis. 2018;5(1):ofx188.

28. Veillette JJ, Waters CD, Gelman SS, et al. Antibiotic prescribing for adult bacteriuria and pyuria in community hospital emergency departments. Am J Emerg Med. 2021;40:1-5. 29. Demonchy E, Dufour JC, Gaudart J, et al. Impact of a computerized decision support system on compliance with guidelines on antibiotics prescribed for urinary tract infections in emergency departments: a multicentre prospective before-and-after controlled interventional study. J Antimicrob Chemother. 2014;69(10):2857-2863. 30. Hudepohl NJ, Cunha CB, Mermel LA. Antibiotic prescribing for urinary tract infections in the emergency department based on local antibiotic resistance patterns: implications for antimicrobial stewardship. Infect Control Hosp Epidemiol. 2016;37(3):359-360. 31. Jorgensen SCJ, Yeung SL, Zurayk M, et al. Leveraging antimicrobial stewardship in the emergency department to improve the quality of urinary tract infection management and outcomes. Open Forum Infect Dis. 2018;5(6):ofy101. 32. Zalmanovich A, Katzir M, Chowers M, et al. Improving urinary tract infection treatment through a multifaceted antimicrobial stewardship intervention in the emergency department. Am J Emerg Med. 2021;49:10-13. 33. Gonzales R, Camargo CA Jr, MacKenzie T, et al. Antibiotic treatment of acute respiratory infections in acute care settings. Acad Emerg Med. 2006;13(3):288-294. 34. Kroening-Roche JC, Soroudi A, Castillo EM, et al. Antibiotic and bronchodilator prescribing for acute bronchitis in the emergency department. J Emerg Med. 2012;43(2):221-227. 35. Evans AT, Husain S, Durairaj L, et al. Azithromycin for acute bronchitis: a randomised, double-blind, controlled trial. Lancet. 2002;359(9318):1648-1654. 36. Bent S, Saint S, Vittinghoff E, et al. Antibiotics in acute bronchitis: a meta-analysis. Am J Med. 1999;107(1):62-67. 37. Metlay JP, Camargo CA Jr, MacKenzie T, et al. Clusterrandomized trial to improve antibiotic use for adults with acute respiratory infections treated in emergency departments. Ann Emerg Med. 2007;50(3):221-230. 38. Madaras-Kelly K, Hostler C, Townsend M, et al. Impact of implementation of the Core Elements of Outpatient Antibiotic Stewardship within Veterans Health Administration emergency department and primary care clinics on antibiotic prescribing and patient outcomes. Clin Infect Dis. Published online December 8, 2020. doi:10.1093/cid/ciaa1831 39. May L, Tatro G, Poltavskiy E, et al. Rapid multiplex testing for upper respiratory pathogens in the emergency department: a randomized controlled trial. Open Forum Infect Dis. 2019;6(12):ofz481.

47. Bookstaver PB, Jenkins TC, Stenehjem E, et al. Impact of outpatient vs inpatient ABSSSI treatment on outcomes: a retrospective observational analysis of medical charts across US emergency departments. Open Forum Infect Dis. 2018;5(7):ofy109. 48. Aboltins CA, Hutchinson AF, Sinnappu RN, et al. Oral versus parenteral antimicrobials for the treatment of cellulitis: a randomized non-inferiority trial. J Antimicrob Chemother. 2015;70(2):581-586. 49. Dalen D, Fry A, Campbell SG, et al. Intravenous cefazolin plus oral probenecid versus oral cephalexin for the treatment of skin and soft tissue infections: a double-blind, non-inferiority, randomised controlled trial. Emerg Med J. 2018;35(8):492-498. 50. Hamill LM, Thi YE, Keijzers G. Picking the low-hanging fruit: why not choose oral antibiotics for skin and soft-tissue infections in the emergency department. Emerg Med Australas. 2019;31(6):1119-1122. 51. Galanter KM, Ho J. Impact of an empiric therapy guide on antibiotic prescribing in the emergency department. J Hosp Infect. 2020;104(2):188-192. 52. May L, Nguyen MH, Trajano R, et al. A multifaceted intervention improves antibiotic stewardship for skin and soft tissues infections. Am J Emerg Med. 2021;46:374-381. 53. Talan DA, Krishnadasan A, Gorwitz RJ, et al. Comparison of Staphylococcus aureus from skin and soft-tissue infections in US emergency department patients, 2004 and 2008. Clin Infect Dis. 2011;53(2):144-149. 54. May LS, Rothman RE, Miller LG, et al. A randomized clinical trial comparing use of rapid molecular testing for Staphylococcus aureus for patients with cutaneous abscesses in the emergency department with standard of care. Infect Control Hosp Epidemiol. 2015;36(12):1423-1430. 55. Almarzoky Abuhussain SS, Burak MA, Adams DK, et al. Variability in emergency medicine provider decisions on hospital admission and antibiotic treatment in a survey study for acute bacterial skin and skin structure infections: opportunities for antimicrobial stewardship education. Open Forum Infect Dis. 2018;5(10):ofy206.

Dr. Fong reported no relevant financial disclosures.

About the Author Karen Fong, PharmD, BCIDP, is a clinical pharmacist, Infectious Diseases and Antimicrobial Stewardship, Department of Pharmacy, at the University of Utah Health, in Salt Lake City, Utah.

I N F E C T I O U S D I S E A S E S P E C I A L E D I T I O N • FA L L 2 0 2 1

IDSE Review

21. Savoldi A, Foschi F, Kreth F, et al. Impact of implementing a non-restrictive antibiotic stewardship program in an emergency department: a four-year quasi-experimental prospective study. Sci Rep. 2020;10(1):8194.

For challenging cases in cIAI... Reported penicillin allergy

WHEN THE RESISTANCE RISK IS HIGH,

EMPIRIC CHOICE IS CLEAR

THE

Indications and Usage XERAVA is indicated for the treatment of complicated intraabdominal infections (cIAI) caused by susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Enterobacter cloacae, Klebsiella oxytoca, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Streptococcus anginosus group, Clostridium perfringens, Bacteroides species, and Parabacteroides distasonis in patients 18 years or older. Limitations of Use XERAVA is not indicated for the treatment of complicated urinary tract infections (cUTI). Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of XERAVA and other antibacterial drugs, XERAVA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information

Long-term care resident at risk for resistant pathogens

Recent travel to an ESBL-endemic area

are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. Important Safety Information XERAVA is contraindicated for use in patients with known hypersensitivity to eravacycline, tetracycline-class antibacterial drugs, or to any of the excipients. Life-threatening hypersensitivity (anaphylactic) reactions have been reported with XERAVA. The use of XERAVA during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown) and enamel hypoplasia. The use of XERAVA during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth.

All trademarks and registered marks are the property of their respective owners. XERAVA™ is a trademark of Tetraphase Pharmaceuticals. ©2019 Tetraphase Pharmaceuticals All rights reserved. 01/19 PM-ERV-00049-US

HIGHLY EFFECTIVE NON–BETA-LACTAM ANTIBACTERIAL WITH APPROPRIATE EMPIRIC COVERAGE 1

Clinical cure rate, %

Clinical Cure Rate at TOC in Enterobacteriaceae2,a Pooled data from IGNITE1 and IGNITE4 100 90 80 70 60 50 40 30 20 10 0

89.6

88.9

87.0

88.9

43/48

32/36

40/46

40/45

90.6

86.2

Active against key Gram-negative, Gram-positive, and anaerobic bacteria, including isolates expressing a variety of multidrug resistance mechanisms 1,2 CEPH-R (n/N1)

Enterobacteriaceae (N=314) XERAVA

25/29

29/32

Enterobacteriaceae (N=325)

Confirmed ESBL (n/N1) MDRb (n/N1)

POOLED COMPARATORS

• The first fully synthetic fluorocycline antibacterial for cIAI1,3 • Proven as effective as carbapenems in cIAI1,a • Low rates of GI-related adverse reactions reported in 2 large clinical trials – Those that occurred in >2% of patients were nausea (6.5%), vomiting (3.7%), and diarrhea (2.3%)1

Study design: XERAVA was compared with carbapenems in 2 phase 3, randomized, double-blind, active-controlled, multinational, multicenter, prospective studies in 1,041 adult subjects with cIAI to demonstrate non-inferiority. Treatment was for 4 to 14 days. The primary efficacy endpoint was clinical response at the TOC visit in the micro-ITT population. IGNITE1 compared XERAVA 1 mg/kg IV q12h with ertapenem 1 g IV q24h. IGNITE4 compared XERAVA 1 mg/kg IV q12h with meropenem 1 g IV q8h.

MDR pathogens were defined as resistant to at least 1 member of 3 or more antibiotic classes.1,4,5

Important Safety Information (cont’d) Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, and may range in severity from mild diarrhea to fatal colitis. The most common adverse reactions observed in clinical trials (incidence ≥3%) were infusion site reactions (7.7%), nausea (6.5%), and vomiting (3.7%). XERAVA is structurally similar to tetracycline-class antibacterial drugs and may have similar adverse reactions. Adverse reactions including photosensitivity, pseudotumor cerebri, and anti-anabolic action which has led to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, and abnormal liver function tests, have been reported for other tetracycline-class antibacterial drugs, and may occur with XERAVA. Discontinue XERAVA if any of these adverse reactions are suspected.

CEPH-R, cephalosporin-resistant; cIAI, complicated intra-abdominal infection; ESBL, extended-spectrum beta-lactamase; GI, gastrointestinal; IV, intravenous; MDR, multidrug-resistant; micro-ITT, microbiologic intent-to-treat; q8h, every 8 hours; q12h, every 12 hours; q24h, every 24 hours; TOC, Test of Cure. References: 1. XERAVA [prescribing information]. Watertown, MA: Tetraphase Pharmaceuticals, Inc.; 2018. 2. Ditch K, Newman J, Izmailyan S, Fyfe C, Tsai L. Microbiological efficacy of eravacycline against Enterobacteriaceae and Acinetobacter baumannii, including MDR isolates: a pooled analysis from IGNITE1 and IGNITE4, two phase 3 trials of complicated intra-abdominal infection. Poster presented at: ASM Microbe; June 7-11, 2018; Atlanta, GA. Poster 629. 3. Zhanel GG, Cheung D, Adam H, et al. Review of eravacycline, a novel fluorocycline antibacterial agent. Drugs. 2016;76(5):567-588. 4. Solomkin J, Evans D, Slepavicius A, et al. Assessing the efficacy and safety of eravacycline vs ertapenem in complicated intra-abdominal infections in the Investigating Gram-Negative Infections Treated with Eravacycline (IGNITE 1) trial: a randomized clinical trial. JAMA Surg. 2017;152(3):224-232. 5. Tsai L, Horn P, Solomkin J, Evans D, Gardovskis J, Fonte A. Results of IGNITE4: a phase 3 study to evaluate the efficacy and safety of eravacycline versus meropenem in complicated intra-abdominal infections. Poster presented at: 28th European Congress of Clinical Microbiology and Infectious Diseases; April 21-24, 2018; Madrid, Spain. Encore poster presentation at: 2018 Annual Making a Difference in Infectious Diseases (MAD-ID) Meeting; May 8-11, 2018; Orlando, FL.

To report SUSPECTED ADVERSE REACTIONS, contact Tetraphase Pharmaceuticals Inc., at 1-833-7-XERAVA (1-833-793-7282) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Please see Brief Summary of full Prescribing Information on the following pages.

LEARN MORE AT XERAVA.COM/IDSE

XERAVA may be administered intravenously through a dedicated line or through a Y-site. If the same intravenous line is used for sequential infusion of several drugs, the line should be flushed before and after infusion of XERAVA with 0.9% Sodium Chloride Injection, USP.

Brief Summary XERAVATM (eravacycline) for injection Brief Summary of full Prescribing Information. See full Prescribing Information. Rx only. INDICATIONS AND USAGE Complicated Intra-abdominal Infections XERAVA is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Enterobacter cloacae, Klebsiella oxytoca, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Streptococcus anginosus group, Clostridium perfringens, Bacteroides species, and Parabacteroides distasonis in patients 18 years or older. Limitations of Use XERAVA is not indicated for the treatment of complicated urinary tract infections (cUTI). Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of XERAVA and other antibacterial drugs, XERAVA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. DOSAGE AND ADMINISTRATION Recommended Adult Dosage The recommended dose regimen of XERAVA is 1 mg/kg every 12 hours. Administer intravenous infusions of XERAVA over approximately 60 minutes every 12 hours. The recommended duration of treatment with XERAVA for cIAI is 4 to 14 days. The duration of therapy should be guided by the severity and location of infection and the patient’s clinical response. Dosage Modifications in Patients with Hepatic Impairment In patients with severe hepatic impairment (Child Pugh C), administer XERAVA 1 mg/kg every 12 hours on Day 1 followed by XERAVA 1 mg/kg every 24 hours starting on Day 2 for a total duration of 4 to 14 days. No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). Dosage Modifications in Patients with Concomitant Use of a Strong Cytochrome P450 Isoenzymes (CYP) 3A Inducer With concomitant use of a strong CYP3A inducer, administer XERAVA 1.5 mg/kg every 12 hours for a total duration of 4 to 14 days. No dosage adjustment is warranted in patients with concomitant use of a weak or moderate CYP3A inducer. Preparation and Administration XERAVA is for intravenous infusion only. Each vial is for a single dose only. Preparation XERAVA is supplied as a sterile yellow to orange dry powder in a single-dose vial that must be reconstituted and further diluted prior to intravenous infusion as outlined below. XERAVA does not contain preservatives. Aseptic technique must be used for reconstitution and dilution as follows: 1. Calculate the dose of XERAVA based on the patient weight; 1 mg/kg actual body weight. Prepare the required dose for intravenous infusion, by reconstituting the appropriate number of vials needed. Reconstitute each vial of XERAVA with 5 mL of Sterile Water for Injection, USP. When the XERAVA vial content is reconstituted with 5 mL sterile Water for Injection, USP it will deliver 50 mg (10 mg/mL) of eravacycline (free base equivalents). 2. Swirl the vial gently until the powder has dissolved entirely. Avoid shaking or rapid movement as it may cause foaming. The reconstituted XERAVA solution should be a clear, pale yellow to orange solution. Do not use the solution if you notice any particles or the solution is cloudy. Reconstituted solution is not for direct injection. 3. The reconstituted XERAVA solution is further diluted for intravenous infusion to a target concentration of 0.3 mg/mL, in a 0.9% Sodium Chloride Injection, USP infusion bag before intravenous infusion. To dilute the reconstituted solution, withdraw the full or partial reconstituted vial content from each vial and add it into the infusion bag to generate an infusion solution with a target concentration of 0.3 mg/mL (within a range of 0.2 to 0.6 mg/mL). Do not shake the bag. 4. The reconstituted and diluted solutions must be infused within 6 hours if stored at room temperature (not to exceed 25°C/77°F) or within 24 hours if stored refrigerated at 2°C to 8ºC (36ºF to 46ºF). Reconstituted XERAVA solutions and diluted XERAVA infusion solutions should not be frozen. 5. Visually inspect the diluted XERAVA solution for particulate matter and discoloration prior to administration (the XERAVA infusion solution for administration is clear and ranges from light yellow to orange). Discard unused portions of the reconstituted and diluted solution. Administration of the Intravenous Infusion The diluted XERAVA solution is administered as an intravenous infusion over approximately 60 minutes.

Drug Compatibilities XERAVA is compatible with 0.9% Sodium Chloride Injection, USP. The compatibility of XERAVA with other drugs and infusion solutions has not been established. XERAVA should not be mixed with other drugs or added to solutions containing other drugs. CONTRAINDICATIONS XERAVA is contraindicated for use in patients with known hypersensitivity to eravacycline, tetracycline-class antibacterial drugs, or to any of the excipients. WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Life-threatening hypersensitivity (anaphylactic) reactions have been reported with XERAVA. XERAVA is structurally similar to other tetracycline-class antibacterial drugs and should be avoided in patients with known hypersensitivity to tetracycline-class antibacterial drugs. Discontinue XERAVA if an allergic reaction occurs. Tooth Discoloration and Enamel Hypoplasia The use of XERAVA during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-grey-brown). This adverse reaction is more common during long-term use of the tetracycline-class drugs, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported with tetracycline class drugs. Advise the patient of the potential risk to the fetus if XERAVA is used during the second or third trimester of pregnancy. Inhibition of Bone Growth The use of XERAVA during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Advise the patient of the potential risk to the fetus if XERAVA is used during the second or third trimester of pregnancy. Clostridium difficile-Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial drug use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Tetracycline Class Adverse Reactions XERAVA is structurally similar to tetracycline-class antibacterial drugs and may have similar adverse reactions. Adverse reactions including photosensitivity, pseudotumor cerebri, and anti-anabolic action which has led to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, and abnormal liver function tests, have been reported for other tetracycline-class antibacterial drugs, and may occur with XERAVA. Discontinue XERAVA if any of these adverse reactions are suspected. Potential for Microbial Overgrowth XERAVA use may result in overgrowth of non-susceptible organisms, including fungi. If such infections occur, discontinue XERAVA and institute appropriate therapy. Development of Drug-Resistant Bacteria Prescribing XERAVA in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drugresistant bacteria. ADVERSE REACTIONS The following clinically significant adverse reactions are described in greater detail in the Warnings and Precautions section: • Hypersensitivity Reactions • Tooth Discoloration • Inhibition of Bone Growth • Clostridium difficile-Associated Diarrhea • Tetracycline Class Adverse Reactions Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

XERAVA was evaluated in 3 active-controlled clinical trials (Trial 1, Trial 2 and Trial 3) in adults with cIAI. These trials included two Phase 3 trials (Trial 1 and Trial 2) and one Phase 2 trial (Trial 3, NCT01265784). The Phase 3 trials included 520 patients treated with XERAVA and 517 patients treated with comparator antibacterial drugs (ertapenem or meropenem). The median age of patients treated with XERAVA was 56 years, ranging between 18 and 93 years old; 30% were age 65 years and older. Patients treated with XERAVA were predominantly male (57%) and Caucasian (98%). The XERAVA-treated population included 31% obese patients (BMI ≥30 kg/m2) and 8% with baseline moderate to severe renal impairment (calculated creatinine clearance 15 to less than 60 mL/min). Among the trials, 66 (13%) of patients had baseline moderate hepatic impairment (Child Pugh B); patients with severe hepatic impairment (Child Pugh C) were excluded from the trials. Adverse Reactions Leading to Discontinuation Treatment discontinuation due to an adverse reaction occurred in 2% (11/520) of patients receiving XERAVA and 2% (11/517) of patients receiving the comparator. The most commonly reported adverse reactions leading to discontinuation of XERAVA were related to gastrointestinal disorders. Most Common Adverse Reactions Adverse reactions occurring at 3% or greater in patients receiving XERAVA were infusion site reactions, nausea and vomiting. Table 1 lists adverse reactions occurring in ≥1% of patients receiving XERAVA and with incidences greater than the comparator in the Phase 3 cIAI clinical trials. A similar adverse reaction profile was observed in the Phase 2 cIAI clinical trial (Trial 3). Table 1. Selected Adverse Reactions Reported in ≥1% of Patients Receiving XERAVA in the Phase 3 cIAI Trials (Trial 1 and Trial 2) Adverse Reactions

XERAVAa N=520 n (%)

Comparatorsb N=517 n (%)

Infusion site reactionsc Nausea Vomiting Diarrhea Hypotension Wound dehiscence

40 (7.7) 34 (6.5) 19 (3.7) 12 (2.3) 7 (1.3) 7 (1.3)

10 (1.9) 3 (0.6) 13 (2.5) 8 (1.5) 2 (0.4) 1 (0.2)

Abbreviations: IV=intravenous a XERAVA dose equals 1 mg/kg every 12 hours IV. b Comparators include ertapenem 1 g every 24 hours IV and meropenem 1 g every 8 hours IV. c Infusion site reactions include: catheter/vessel puncture site pain, infusion site extravasation, infusion site hypoaesthesia, infusion/injection site phlebitis, infusion site thrombosis, injection site/vessel puncture site erythema, phlebitis, phlebitis superficial, thrombophlebitis, and vessel puncture site swelling. Other Adverse Reactions of XERAVA The following selected adverse reactions were reported in XERAVA-treated patients at a rate of less than 1% in the Phase 3 trials: Cardiac disorders: palpitations Gastrointestinal System: acute pancreatitis, pancreatic necrosis General Disorders and Administrative Site Conditions: chest pain Immune system disorders: hypersensitivity Laboratory Investigations: increased amylase, increased lipase, increased alanine aminotransferase, prolonged activated partial thromboplastin time, decreased renal clearance of creatinine, increased gamma-glutamyltransferase, decreased white blood cell count, neutropenia Metabolism and nutrition disorders: hypocalcemia Nervous System: dizziness, dysgeusia Psychiatric disorders: anxiety, insomnia, depression Respiratory, Thoracic, and Mediastinal System: pleural effusion, dyspnea Skin and subcutaneous tissue disorders: rash, hyperhidrosis DRUG INTERACTIONS Effect of Strong CYP3A Inducers on XERAVA Concomitant use of strong CYP3A inducers decreases the exposure of eravacycline, which may reduce the efficacy of XERAVA. Increase XERAVA dose in patients with concomitant use of a strong CYP3A inducer. Anticoagulant Drugs Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage. USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary XERAVA, like other tetracycline-class antibacterial drugs, may cause discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimester of pregnancy. The limited available data with XERAVA use in pregnant women are insufficient to inform drug-associated risk of major birth defects and miscarriages. Animal studies indicate that eravacycline crosses the placenta and is found in fetal plasma; doses greater than approximately 3- and 2.8-times the clinical exposure, based on AUC in rats and rabbits, respectively, administered during the period of organogenesis, were associated with decreased ossification, decreased fetal body weight, and/or increased post-implantation loss.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal Data Embryo-fetal development studies in rats and rabbits reported no treatment-related effects at approximately 3 and 2.8 times the clinical exposure (based on AUC). Dosing was during the period of organogenesis, i.e. gestation days 7-17 in rats and gestation days 7-19 in rabbits. Higher doses, approximately 8.6 and 6.3 times the clinical exposure (based on AUC) in rats and rabbits, respectively, were associated with fetal effects including increased postimplantation loss, reduced fetal body weights, and delays in skeletal ossification in both species, and abortion in the rabbit. A peri-natal and post-natal rat toxicity study demonstrated that eravacycline crosses the placenta and is found in fetal plasma following intravenous administration to the dams. This study did not demonstrate anatomical malformations, but there were early decreases in pup weight that were later comparable to controls and a non-significant trend toward increased stillbirths or dead pups during lactation. F1 males from dams treated with 10 mg/kg/day eravacycline that continued to fertility testing had decreased testis and epididymis weights at approximately Post-Natal Day 111 that may have been at least partially related to lower body weights in this group. Tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy. Lactation Risk Summary It is not known whether XERAVA is excreted in human breast milk. Eravacycline (and its metabolites) is excreted in the milk of lactating rats. Tetracyclines are excreted in human milk; however, the extent of absorption of tetracyclines, including eravacycline, by the breastfed infant is not known. There are no data on the effects of XERAVA on the breastfed infant, or the effects on milk production. Because there are other antibacterial drug options available to treat cIAI in lactating women and because of the potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, advise patients that breastfeeding is not recommended during treatment with XERAVA and for 4 days (based on half-life) after the last dose. Data Animal Data Eravacycline (and its metabolites) was excreted in the milk of lactating rats on post-natal day 15 following intravenous administration of 3, 5, and 10 mg/kg/day eravacycline. Females and Males of Reproductive Potential Infertility Based on animal studies, XERAVA can lead to impaired spermiation and sperm maturation, resulting in abnormal sperm morphology and poor motility. The effect is reversible in rats. The long-term effects of XERAVA on male fertility have not been studied. Pediatric Use The safety and effectiveness of XERAVA in pediatric patients have not been established. Due to the adverse effects of the tetracycline-class of drugs, including XERAVA on tooth development and bone growth, use of XERAVA in pediatric patients less than 8 years of age is not recommended. Geriatric Use Of the total number of patients with cIAI who received XERAVA in Phase 3 clinical trials (n=520), 158 subjects were ≥65 years of age, while 59 subjects were ≥75 years of age. No overall differences in safety or efficacy were observed between these subjects and younger subjects. No clinically relevant differences in the pharmacokinetics of eravacycline were observed with respect to age in a population pharmacokinetic analysis of eravacycline. Hepatic Impairment No dosage adjustment is warranted for XERAVA in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). Adjust XERAVA dosage in patients with severe hepatic impairment (Child Pugh C). Renal Impairment No dosage adjustment is necessary for XERAVA in patients with renal impairment. OVERDOSAGE No reports of overdose were reported in clinical trials. In the case of suspected overdose, XERAVA should be discontinued and the patient monitored for adverse reactions. Hemodialysis is not expected to remove significant quantities of XERAVA.

Distributed by: Tetraphase Pharmaceuticals, Inc. 480 Arsenal Way, Ste 110 Watertown, MA 02472 XERAVATM is a trademark of Tetraphase Pharmaceuticals, Inc. ©2018, Tetraphase Pharmaceuticals, Inc. All rights reserved. 09/18 PM-ERV-00012-US

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IDSE Review

Cutting-Edge Issues In HIV Clinical Management: No End to the Dynamism of HIV Medicine BY RAJESH T. GANDHI, MD

he field of HIV medicine continues to be dynamic and innovative, even after 40 years since the first reports of AIDS. In 2021, we saw major advances, including the approval of the first injectable long-acting antiretroviral regimen, new insights into how to treat patients who have had virologic failure, a better understanding of HIV treatment during pregnancy, an appreciation for the interaction between HIV and COVID-19, and continued progress in our knowledge of comorbidities and coinfections. Here, we review some of the highlights of the year in HIV clinical management from recent conferences.

Antiretroviral Therapy: The First Long-Acting HIV Regimen In 2021, the FDA approved CAB/RPV, the first long-acting injectable regimen for the treatment of HIV. The approval of this dosage regimen of every 4 weeks was based on 2 phase 3 clinical rials—ATLAS and FLAIR—which demonstrated that monthly injections of CAB/RPV were able to maintain virologic suppression in people with HIV at rates similar to that of oral daily antiretroviral therapy (ART).1,2 In another advance, the ATLAS-2M trial demonstrated that CAB/RPV every 8 weeks was comparable with a dosage of every 4 weeks in terms of maintaining virologic suppression.3 At the 2021 Conference on Retroviruses and Opportunistic Infections, week 96 data from ATLAS-2M were presented: 91% of those receiving the regimen every 8 weeks and approximately 90% of those receiving it every 4 weeks had HIV RNA less than 50 copies/mL.4 These data support the recent filing with the FDA for a CAB/RPV dosage regimen of every 8 weeks; we eagerly await the FDA’s decision regarding this dosage interval. What are the risk factors for virologic failure developing in people receiving CAB/RPV? In a separate analysis,

I N F E C T I O U S D I S E A S E S P E C I A L E D I T I O N • FA L L 2 0 2 1

IDSE Review

HIV Medication Abbreviation Key 3TC ABC AZT BIC

lamivudine abacavir zidovudine bictegravir

CAB/RPV DTG DRV/r EFV

cabotegravir and rilpivirine dolutegravir ritonavir-boosted darunavir efavirenz

among 1,039 participants from the ATLAS, FLAIR, and ATLAS-2M clinical trials, only 13 (1.25%) had confirmed virologic failure.5 Risk factors for confirmed virologic failure included RPV resistance–associated mutations at baseline; lower RPV trough concentration at week 8; having HIV-1 subtype A1/A6; and higher body mass index. In participants who had none or only 1 of these risk factors, the rate of confirmed virologic failure was 0.4%.5 These findings support the FDA indication for CAB/RPV, which is to replace an oral regimen in patients who are virologically suppressed and have no history of treatment failure or known/suspected resistance to CAB or RPV.

What to Use in a Person Who Has Virologic Failure? A Surprising and Important Finding Until recently, the most common first-line antiretroviral regimen in many parts of the world included an non-nucleoside reverse transcriptase inhibitor (NNRTI). What is the optimal regimen for a person who has virologic failure while receiving NNRTI-based therapy? In the NADIA trial,6 464 participants with virologic failure on TDF/3TC and an NNRTI were randomized in a 2x2 factorial design to receive DTG or DRV/r with either TDF/3TC or AZT with 3TC. Many participants in this study had advanced HIV infection: About 50% had a CD4 cell count of 200/mm3 or less, and 28% had HIV RNA of 100,000 copies/mL or higher. Nucleoside reverse transcriptase (NRTI) resistance mutations at baseline were common: 50% had K65R/N and 86% had M184V. Despite this high rate of NRTI resistance, the rates of virologic suppression on the new regimen were high: • About 90% of those randomized to received DTG and approximately 92% of those randomized to receive DRV/r achieved virologic suppression (HIV RNA <400 copies/mL). DTG resistance was detected in only 4 participants, and no participants developed DRV resistance. Even when there were no NRTIs predicted to be active in the regimen, the rate of virologic suppression was high. • About 92% of those randomized to receive TDF/3TC and approximately 90% of those randomized to receive AZT/3TC achieved virologic suppression (HIV RNA <400 copies/mL). The surprising and important conclusion from this study: In patients failing NNRTI-based therapy, DTG or DRV/r suppresses viremia even when NRTI resistance is present.

IDSE.NET

FTC FTR TAF TDF

emtricitabine fostemsavir tenofovir alafenamide tenofovir disoproxil fumarate

New Insights Into HIV Therapy During Pregnancy One of the landmark studies on HIV therapy during pregnancy is the IMPAACT 2010 or VESTED trial. This phase 3 trial compared the safety and efficacy of the following 3 regimens in 643 treatment-naive women initiating ART during pregnancy (14-28 weeks of gestation): DTG plus FTC/TAF, DTG plus FTC/TDF, and EFV/FTC/ TDF. Most of the women in this study were in sub-Saharan Africa. At the time of enrollment, the median gestational age was about 22 weeks. At the time of delivery, the rate of virologic suppression was higher in women who received a DTG-based regimen than in those who received EFV/FTC/TDF (98% vs 91%, respectively).7 As expected, the time to virologic suppression was shorter in those who received DTG, an integrase inhibitor, compared with those who received EFV, an NNRTI. Adverse pregnancy outcomes occurred in 24% of those who received DTG plus 3TC/TAF, 33% of those who received DTG plus FTC/TDF, and 33% of those who received EFV/FTC/TDF. Neonatal mortality was lower in the group that received DTG plus FTC/TAF (1% of infants) compared with those who received EFV/FTC/TDF (5% of infants). A potential reason for the lower rate of adverse pregnancy outcomes in the group that received DTG plus FTC/TAF is that their average weight gain was closest to what is considered optimal during pregnancy.8 This hypothesis is plausible because both insufficient and excessive weight gain during pregnancy have been associated with adverse pregnancy outcomes. This year also saw an update of the Department of Health and Human Services perinatal HIV guidelines.9 The main changes and some highlights include: • Based on new and reassuring data, DTG-based regimens are now considered one of the preferred choices throughout pregnancy and for those trying to conceive. • The preferred NRTI combinations during pregnancy are still TDF/FTC and ABC/3TC. However, TAF/FTC is now considered an alternative NRTI combination because of data on its safety during pregnancy. • There are as yet insufficient data with BIC or with the new antiretroviral agent FTR to endorse their use during pregnancy.

COVID-19 and HIV One of the most contentious topics of the year was whether people with HIV have worse COVID-19 outcomes than people without HIV.10

study. Lancet. 2021;396(10267):1994-2005.

Comorbidities and Coinfections In recent years, it’s been recognized that certain antiretroviral medications—specifically integrase inhibitors and TAF—are associated with excess weight gain. For example, in a retrospective study called TRIO, in people with HIV who switched to an integrase inhibitor or to a new integrase inhibitor, weight gain was associated with female sex and changing from TDF to TAF.17 Whether changing from an integrase inhibitor to another drug, like DRV, or from TAF to TDF ameliorates weight gain is not certain, but is being evaluated in the AIDS Clinical Trials Group A5391 (Do-IT) study.18 Clinicians and their patients eagerly await the results of studies to inform us how to prevent or reverse weight gain among people with HIV. Another advance from this year is the recognition that modern pangenotypic hepatitis C virus (HCV) medications make it possible to treat people with minimal monitoring. In the MINMON study, 399 participants with HCV received a 12-week course of

4. Jaeger H, Overton ET, Richmond G, et al. Week 96 efficacy and safety of cabotegravir + rilpivirine every 2 months: ATLAS-2M. Presented virtually at: Conference on Retroviruses and Opportunistic Infections 2021; March 6-10, 2021. Abstract 401. http://www.croiwebcasts. org/y/2021?link=promo 5. Cutrell AG, Schapiro JM, Perno CF, et al. Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis. AIDS. 2021;35(9):1333-1342. 6. Paton N, Musaazi J, Kityo CM, et al. Nucleosides and darunavir/dolutegravir in Africa (NADIA) trial: 48 weeks primary outcome. Presented virtually at: Conference on Retroviruses and Opportunistic Infections 2021; March 6-10, 2021. Abstract 94. http://www.croiwebcasts. org/y/2021?link=promo 7. Lockman S, Brummel SS, Ziemba L, et al. Efficacy and safety of dolutegravir with emtricitabine and tenofovir alafenamide fumarate or tenofovir disoproxil fumarate, and efavirenz, emtricitabine, and tenofovir disoproxil fumarate HIV antiretroviral therapy regimens started in pregnancy (IMPAACT 2010/VESTED): a multicentre, open-label, randomised, controlled, phase 3 trial. Lancet. 2021;397(10281):1276-1292. 8. Hoffman RM, Ziemba L, Brummel SS, et al. Antepartum weight gain and adverse pregnancy outcomes in IMPAACT 2010. Presented virtually at: Conference on Retroviruses and

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IDSE Review

Early studies suggested there was no difference in sofosbuvir-velpatasvir; of note, there was no pretreatoutcomes, but recent investigations have come to the ment genotyping and participants did not have any opposite conclusion. One example is an analysis of clinic visits or labs scheduled during the treatment the National COVID Cohort Collaborative, which evalcourse. The efficacy results were striking: Sustained uated clinical outcomes in more than 500,000 adults virologic response occurred in 95% of participants.19 with COVID-19.11 People with HIV were more likely to Conclusion be hospitalized and require hospitalization than peoEven after 40 years since the first cases of AIDS ple without HIV, even after adjusting for other facwere reported, there continues to be amazing progress tors that portend poor outcomes. Similarly, a study in the care of people with HIV. We now have a variety from the World Health Organization12 reported that, after adjustment for age, sex, disease severof effective antiretroviral regimens includity, and comorbidities, in-hospital mortality ing, for the first time, a long-acting monthly was 30% greater in people with HIV hospiinjectable regimen. We have new insights talized with COVID-19 compared with into how to achieve virologic supprespeople without HIV. Potential contribsion in people who require second-line For people with utors10 to worse COVID-19 outcomes therapy. We are learning more about HIV and COVID-19, in people with HIV include immuthe safety and efficacy of new regmortality was 30% nodeficiency or an immune dysregimens for treatment of HIV during ulation legacy effect; comorbidities pregnancy. We are making progress higher than those that increase the risk for clinical proin understanding the impact of HIV without HIV. gression; and social determinants of on COVID-19 outcomes and vaccines. health.13 These considerations, and othFinally, we’re identifying new complicaers, highlight the importance of COVIDtions of ART, like weight gain, but also sim19 prevention in people with HIV. plifying our care of coinfections, like HCV. All The most effective way to prevent COVID-19 in all, this has been a banner year for advances in among all people is, of course, vaccination. Do people HIV medicine. I can’t wait to see what the future holds! with HIV have comparable immune responses to the COVID-19 vaccine as people without HIV? Two studReferences ies—one from the United Kingdom and the other from 1. Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine for maintenance of South Africa—reported that immune responses to the HIV-1 suppression. N Engl J Med. 2020;382(12):1112-1123. AstraZeneca COVID-19 vaccine were similar in those 2. Orkin C, Arasteh K, Górgolas Hernández-Mora M, et al. Long14,15 However, the story may be with and without HIV. acting cabotegravir and rilpivirine after oral induction for different among people with HIV who are not on ART HIV-1 infection. N Engl J Med. 2020;382(12):1124-1135. and who have low CD4 cell counts: In a case report, 3. Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults a person with uncontrolled HIV did not seroconvert with HIV-1 infection (ATLAS-2M), 48-week results: a ran16 after receiving 2 doses of a COVID-19 vaccine. domised, multicentre, open-label, phase 3b, non-inferiority

IDSE Review

Opportunistic Infections 2021; March 6-10, 2021. Abstract 176. http://www.croiwebcasts.org/y/2021?link=promo 9. HIV.gov. Recommendations for the use of antiretroviral drugs in pregnant women with HIV infection and interventions to reduce perinatal HIV transmission in the United States. February 10, 2021. https://clinicalinfo.hiv.gov/en/guidelines/ perinatal/whats-new-guidelines 10. Triant VA, Gandhi RT. When epidemics collide: why people with human immunodeficiency virus may have worse coronavirus disease 2019 outcomes and implications for vaccination. Clin Infect Dis. 2021;72(12):e1030-e1034. 11. Sun J, Patel R, Madhira V, et al. COVID-19 hospitalization among people with HIV or solid organ transplant in the US. Presented virtually at: Conference on Retroviruses and Opportunistic Infections 2021; March 6-10, 2021. Abstract 103. http://www.croiwebcasts.org/y/2021?link=promo 12. Bertagnolio S, Thwin SS, Silva R, et al. Clinical characteristics and prognostic factors in people living with HIV hospitalized with COVID-19: findings from the WHO Global Clinical Platform. Presented virtually at: International AIDS Society 2021; July 18-21, 2021. Track B, 2605. https://www.natap.org/2021/ IAS/IAS_49.htm 13. Meyerowitz EA, Kim AY, Ard KL, et al. Disproportionate burden of coronavirus disease 2019 among racial minorities and those in congregate settings among a large cohort of people with HIV. AIDS. 2020;34(12):1781-1787. 14. Frater J, Ewer KJ, Ogbe A, et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 (AZD1222) vaccine against SARSCoV-2 in HIV infection: a single-arm substudy of a phase 2/3 clinical trial. Lancet HIV. 2021;8(8):e474-e485. 15. Madhi S, Koen A, Fairlie L, et al. ChAdOx1 nCoV-19 (AZD1222) vaccine in people living with and without HIV. Preprint. Posted online March 17, 2021. Research Square. doi:10.21203/rs.3.rs-322470/v1

16. Touizer E, Alrubayyi A, Rees-Spear C, et al. Failure to seroconvert after two doses of BNT162b2 SARS-CoV-2 vaccine in a patient with uncontrolled HIV. Lancet HIV. 2021;8(6):e317-e318. 17. McComsey GA, Eron JJ, Santiago S, et al. Weight gain during treatment among 3,468 treatment-experienced adults with HIV. Presented virtually at: Conference on Retroviruses and Opportunistic Infections 2021; March 6-10, 2021. Abstract 671. http://www.croiwebcasts.org/y/2021?link=promo 18. ClinicalTrials.gov. Doravirine for persons with excessive weight gain on integrase inhibitors and tenofovir alafenamide. https://clinicaltrials.gov/ct2/show/NCT04636437 19. Solomon SS, Wagner-Cardoso S, Smeaton LM, et al. A simple and safe approach to HCV treatment: findings from the A5360 (Minmon) trial. Presented virtually at: Conference on Retroviruses and Opportunistic Infections 2021; March 6-10, 2021. Abstract 135. http://www.croiwebcasts. org/y/2021?link=promo

Dr Gandhi reported having been on the scientific advisory boards for Gilead and Merck more than a year ago.

About the author Rajesh T. Gandhi, MD, is a professor of medicine at Harvard Medical School, and the director of HIV Clinical Services and Education in the Division of Infectious Diseases, Massachusetts General Hospital, in Boston, Massachusetts. He is also the immediate past chair of the HIV Medicine Association.

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with CABENUVA, the ﬁrst and only, once-monthly, long-acting, complete injectable treatment regimen for virologically suppressed adults living with HIV-1.1*

Michael, living with HIV.

CABENUVA is a

DHHS STRONGLY RECOMMENDED

(AI)† REGIMEN for appropriate patients with HIV-12‡

‡

CABENUVA is administered monthly as 2 intramuscular injections by a healthcare professional. Adherence to the dosing schedule is strongly recommended.1

Patients must have sustained viral suppression for 3 to 6 months (optimal duration is not defined), have good adherence and engagement in care, have no baseline resistance to cabotegravir or rilpivirine, have no prior virologic failures, have no active or occult HBV infection (unless receiving an oral HBV regimen), not be pregnant or plan on becoming pregnant, and not be receiving medications with significant drug interactions with oral or injectable cabotegravir or rilpivirine.2

INDICATION

IMPORTANT SAFETY INFORMATION

CABENUVA is indicated as a complete regimen for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adults to replace the current antiretroviral regimen in those who are virologically suppressed (HIV-1 RNA less than 50 copies per mL) on a stable antiretroviral regimen with no history of treatment failure and with no known or suspected resistance to either cabotegravir or rilpivirine.

CONTRAINDICATIONS • Do not use CABENUVA in patients with previous hypersensitivity

Please see additional Important Safety Information for CABENUVA throughout. Please see following pages for Brief Summary of full Prescribing Information for CABENUVA.

reaction to cabotegravir or rilpivirine

• Do not use CABENUVA in patients receiving carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, systemic dexamethasone (>1 dose), and St John’s wort

For virologically suppressed adults living with HIV-1*

ONCE-MONTHLY TREATMENT IS POSSIBLE WITH CABENUVA First and only, once-monthly, complete treatment regimen for HIV-11† Proven as effective as continuing a daily oral regimen1,3† Preferred by 9 out of 10 patients in clinical trials3-5 In an exploratory endpoint in ATLAS and FLAIR Phase 3 clinical trials, patients completed a single-item question assessing their preference for CABENUVA vs their previous oral regimen.† At Week 48, 88% (523/591) of ITT-E population preferred CABENUVA vs 2% (9/591) who preferred their previous oral regimen†; 59 patients did not respond to the question. These results are descriptive in nature and should not be used to infer clinical signiﬁcance. *HIV-1 RNA <50 copies/mL.1 † Based on a pooled analysis from two Phase 3, international, randomized, non-inferiority trials (ATLAS and FLAIR) in virologically suppressed (HIV-1 RNA <50 copies/mL) adults ≥18 years with HIV-1.1,3-5 In ATLAS, 616 treatment-experienced, virologically suppressed (for ≥6 months) patients on 2 NRTIs + an INSTI, NNRTI, or PI were randomized 1:1 to receive either CABENUVA (after a 4-week oral lead-in of daily cabotegravir 30 mg and rilpivirine 25 mg) or to remain on their current therapy.1,4 In FLAIR, patients without previous ARV exposure were given ABC/DTG/3TC (or DTG + 2 NRTIs if HLA-B*5701-positive) for 20 weeks to achieve suppression and then randomized 1:1 (N=566) to receive either CABENUVA (after a 4-week oral lead-in of daily cabotegravir 30 mg and rilpivirine 25 mg) or to remain on their current regimen.1,5 At baseline, in FLAIR and ATLAS, the median age was 34 and 40 years, respectively.1 In both studies, 7% had CD4+ cell count <350 cells/mm3.1 In ATLAS, baseline third-agents were 50% NNRTIs, 33% INSTIs, or 17% PIs.1 Patients were excluded if they were pregnant or breastfeeding, had moderate to severe hepatic impairment, or evidence of HBV infection at screening.4,5 Non-inferiority of CABENUVA would be shown if the upper bound of the 95% CI for the treatment difference was <6% for the individual studies or <4% for the pooled analysis.3-5 Primary endpoint was proportion of patients with HIV-1 RNA ≥50 copies/mL at Week 48 via FDA Snapshot Algorithm.3 Proportion of patients with HIV-1 RNA ≥50 copies/mL at Week 48 in pooled analysis was 2% for CABENUVA vs 2% for daily oral comparator (non-inferior treatment difference: 0.2% [95% CI: -1.4, 1.7]).1,3 3TC=lamivudine; ABC=abacavir; ARV=antiretroviral; CI=confidence interval; DTG=dolutegravir; FDA=Food and Drug Administration; HLA-B=human leukocyte antigen complex B; INSTI=integrase strand transfer inhibitor; ITT-E=intent-to-treat efficacy; NNRTI=non-nucleoside reverse transcriptase inhibitor; NRTI=nucleoside reverse transcriptase inhibitor; PI=protease inhibitor.

References: 1. CABENUVA [package insert]. Research Triangle Park, NC: ViiV Healthcare; 2021. 2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV. Department of Health and Human Services. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf. Accessed June 30, 2021. 3. Rizzardini G, Overton ET, Orkin C, et al. Long-acting injectable cabotegravir + rilpivirine for HIV maintenance therapy: Week 48 pooled analysis of phase 3 ATLAS and FLAIR trials. J Acquir Immune Defic Syndr. 2020;85(4):498-506. 4. Swindells S, Andrade-Villanueva JF, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med. 2020;382(12):1112-1123. 5. Orkin C, Arasteh K, Górgolas Hernández-Mora M, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 2020;382(12):1124-1135.

IMPORTANT SAFETY INFORMATION (cont’d) WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: • Hypersensitivity reactions, including cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported during postmarketing experience with rilpivirine-containing regimens. While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries • Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and could occur with CABENUVA

• Discontinue CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop. Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated. Prescribe the oral lead-in prior to administration of CABENUVA to help identify patients who may be at risk of a hypersensitivity reaction Post-Injection Reactions: • Serious post-injection reactions (reported in less than 1% of subjects) were reported within minutes after the injection of rilpivirine, including dyspnea, agitation, abdominal cramping, flushing, sweating, oral numbness, and changes in blood pressure. These events may have been associated with inadvertent (partial) intravenous administration and began to resolve within a few minutes after the injection • Carefully follow the Instructions for Use when preparing and administering CABENUVA to avoid accidental intravenous administration. Observe patients briefly (approximately 10 minutes) after the injection. If a post-injection reaction occurs, monitor and treat as clinically indicated Hepatotoxicity: • Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine with or without known pre-existing hepatic disease or identifiable risk factors • Patients with underlying liver disease or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations • Monitoring of liver chemistries is recommended and treatment with CABENUVA should be discontinued if hepatotoxicity is suspected Depressive Disorders:

• Depressive disorders (including depressed mood, depression, major depression, mood altered, mood swings, dysphoria, negative thoughts, suicidal ideation or attempt) have been reported with CABENUVA or the individual products • Promptly evaluate patients with depressive symptoms Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: • The concomitant use of CABENUVA and other drugs may result in known or potentially significant drug interactions (see Contraindications and Drug Interactions) • Rilpivirine doses 3 and 12 times higher than the recommended oral dosage can prolong the QTc interval. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes

Long-Acting Properties and Potential Associated Risks with CABENUVA: • Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). Select appropriate patients who agree to the required monthly injection dosing schedule because non-adherence to monthly injections or missed doses could lead to loss of virologic response and development of resistance • To minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen no later than 1 month after the final injection doses of CABENUVA. If virologic failure is suspected, switch the patient to an alternative regimen as soon as possible

ADVERSE REACTIONS The most common adverse reactions (incidence ≥2%, all grades) with CABENUVA were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash.

DRUG INTERACTIONS • Refer to the applicable full Prescribing Information for important drug interactions with CABENUVA, VOCABRIA, or EDURANT • Because CABENUVA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended • Drugs that are strong inducers of UGT1A1 or 1A9 are expected to decrease the plasma concentrations of cabotegravir. Drugs that induce or inhibit CYP3A may affect the plasma concentrations of rilpivirine • CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes

USE IN SPECIFIC POPULATIONS • Pregnancy: There are insufficient human data on the use of CABENUVA during pregnancy to adequately assess a drug-associated risk for birth defects and miscarriage. Discuss the benefit-risk of using CABENUVA during pregnancy and conception and consider that cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA. An Antiretroviral Pregnancy Registry has been established • Lactation: The CDC recommends that HIV-1−infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. Breastfeeding is also not recommended due to the potential for developing viral resistance in HIV-positive infants, adverse reactions in a breastfed infant, and detectable cabotegravir and rilpivirine concentrations in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA

Please see following pages for Brief Summary of full Prescribing Information for CABENUVA.

Visit CABENUVAhcp.com

BRIEF SUMMARY

CABENUVA

(cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use

The following is a brief summary only; see full prescribing information for complete product information. CONTRAINDICATIONS CABENUVA is contraindicated in patients: ∞ with previous hypersensitivity reaction to cabotegravir or rilpivirine. ∞ receiving the following coadministered drugs for which significant decreases in cabotegravir and/or rilpivirine plasma concentrations may occur due to uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1 and/or cytochrome P450 (CYP)3A enzyme induction, which may result in loss of virologic response: • Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin • Antimycobacterials: Rifabutin, rifampin, rifapentine • Glucocorticoid (systemic): Dexamethasone (more than a single-dose treatment) • Herbal product: St John’s wort (Hypericum perforatum) WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Hypersensitivity reactions have been reported during postmarketing experience with rilpivirine-containing regimens. Reactions include cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and could occur with CABENUVA. Remain vigilant and discontinue CABENUVA if a hypersensitivity reaction is suspected. Discontinue CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash, or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, mucosal involvement [oral blisters or lesions], conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated. For information regarding the long-acting properties of CABENUVA, see section below. Administer oral lead-in dosing prior to administration of CABENUVA to help identify patients who may be at risk of a hypersensitivity reaction. Post-Injection Reactions: In clinical trials, serious post-injection reactions were reported within minutes after the injection of rilpivirine, including dyspnea, agitation, abdominal cramping, flushing, sweating, oral numbness, and changes in blood pressure. These events were reported in less than 1% of subjects and began to resolve within a few minutes after the injection. These events may have been associated with inadvertent (partial) intravenous administration. Carefully follow the Instructions for Use when preparing and administering CABENUVA to avoid accidental intravenous administration. Observe patients briefly (approximately 10 minutes) after the injection. If a patient experiences a post-injection reaction, monitor and treat as clinically indicated. Hepatotoxicity: Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine with or without known pre-existing hepatic disease or identifiable risk factors. Patients with underlying liver disease or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations. Monitoring of liver chemistries is recommended and treatment with CABENUVA should be discontinued if hepatotoxicity is suspected. For information regarding long-acting properties of CABENUVA, see section below. Depressive Disorders: Depressive disorders (including depressed mood, depression, major depression, mood altered, mood swings, dysphoria, negative thoughts, suicidal ideation or attempt) have been reported with CABENUVA or the individual drug products. Promptly evaluate patients with depressive symptoms to assess whether the symptoms are related to CABENUVA and to determine whether the risks of continued therapy outweigh the benefits. Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The concomitant use of CABENUVA and other drugs may result in known or potentially significant drug interactions, some of which may lead to adverse events, loss of virologic response of CABENUVA, and possible development of viral resistance. Rilpivirine 75-mg and 300-mg once-daily oral doses (3 and 12 times the recommended oral dosage) in healthy adults resulted in mean steady-state Cmax values 4.4-fold and 11.6fold higher than Cmax values associated with the recommended 600-mg dose of rilpivirine extended-release injectable suspension and prolonged the QTc interval. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes. See the Drug Interactions section for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations. Consider the potential for drug interactions prior to and during therapy with, and after discontinuation of CABENUVA; review concomitant medications during therapy with CABENUVA. Long-Acting Properties and Potential Associated Risks with CABENUVA: Residual concentrations of both cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). It is important to carefully select patients who agree to the required monthly injection dosing schedule because non-adherence to monthly injections or missed doses could lead to loss of virologic response and development of resistance. To minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen no later than 1 month after the final injection doses of CABENUVA. If virologic failure is suspected, switch the patient to an alternative regimen as soon as possible.

ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reﬂect rates observed in practice. The safety assessment of CABENUVA is based on the analysis of pooled 48-week data from 1,182 virologically suppressed subjects with HIV-1 infection in 2 international, multicenter, open-label pivotal trials, FLAIR and ATLAS. Additional safety information from other ongoing or earlier clinical trials in the cabotegravir and rilpivirine program have been considered in assessing the overall safety proﬁle of CABENUVA. Adverse reactions were reported following exposure to CABENUVA extended-release injectable suspensions (median time exposure: 54 weeks) and data from VOCABRIA (cabotegravir) tablets and EDURANT (rilpivirine) tablets administered in combination as oral lead-in therapy (median time exposure: 5.3 weeks). Adverse reactions included those attributable to both the oral and injectable formulations of cabotegravir and rilpivirine administered as a combination regimen. Refer to the prescribing information for EDURANT for other adverse reactions associated with oral rilpivirine. The most common adverse reactions regardless of severity reported in greater than or equal to 2% of adult subjects in the pooled analyses from FLAIR and ATLAS are presented in Table 3. Selected laboratory abnormalities are included in Table 4. Overall, 4% of subjects in the group receiving CABENUVA and 2% of subjects in the control group discontinued due to adverse events. Non-injectionsite-related adverse events leading to discontinuation and occurring in more than 1 subject were headache, diarrhea, hepatitis A, and acute hepatitis B (all with an incidence less than 1%). Table 3. Adverse Reactionsa (Grades 1 to 4) Reported in at Least 2% of Subjects with HIV-1 Infection in FLAIR and ATLAS Trials (Week 48 Pooled Analyses) Cabotegravir plus Rilpivirine (n=591)

Current Antiretroviral Regimen (n=591)

All Grades

At Least Grade 2

All Grades

At Least Grade 2

Injection site reactionsb

83%

37%

Pyrexiac

Fatigued

<1%

Headache

<1%

Musculoskeletal paine

<1%

Nausea

<1%

Sleep disordersf

<1%

Dizziness

<1%

Rashg

<1%

Adverse Reactions

Adverse reactions deﬁned as “treatment-related” as assessed by the investigator. See Injection-Associated Adverse Reactions for additional information. c Pyrexia: includes pyrexia, feeling hot, chills, inﬂuenza-like illness, body temperature increased. d Fatigue: includes fatigue, malaise, asthenia. e Musculoskeletal pain: includes musculoskeletal pain, musculoskeletal discomfort, back pain, myalgia, pain in extremity. f Sleep disorders: includes insomnia, poor quality sleep, somnolence. g Rash: includes erythema, pruritus, pruritus generalized, purpura, rash, rash- erythematous, generalized, macular. b

Injection-Associated Adverse Reactions: Local Injection Site Reactions (ISRs): The most frequent adverse reactions associated with the intramuscular administration of CABENUVA were ISRs. After 14,682 injections, 3,663 ISRs were reported. One percent (1%) of subjects discontinued treatment with CABENUVA because of ISRs. Most ISRs were mild (Grade 1, 75%) or moderate (Grade 2, 36%). Four percent (4%) of subjects experienced severe (Grade 3) ISRs, and no subjects experienced Grade 4 ISRs. The most commonly reported ISR was localized pain/discomfort (79%) regardless of severity or relatedness. Other manifestations of ISRs reported in more than 1% of subjects over the duration of the analysis period included nodules (14%), induration (12%), swelling (8%), erythema (4%), pruritus (4%), bruising (3%), warmth (2%), and hematoma (2%). Abscess and cellulitis at the injection site were each reported in less than 1% of subjects. The median duration of ISR events was 3 days. Other Injection-Associated Adverse Reactions: In the ATLAS and FLAIR clinical trials, an increased incidence of pyrexia (8%) was reported by subjects receiving cabotegravir plus rilpivirine injections compared with no events among subjects receiving current antiretroviral regimen. No cases were serious or led to withdrawal and the occurrences of pyrexia may represent a response to administration of CABENUVA via intramuscular (cont’d on next page)

BRIEF SUMMARY for CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use (cont'd) injection. Reports of musculoskeletal pain (3%) and less frequently, sciatica, were also more common in subjects receiving cabotegravir plus rilpivirine compared with the current antiretroviral regimen and some events had a temporal association with injection. Vasovagal or pre-syncopal reactions were reported in less than 1% of subjects after injection with rilpivirine or cabotegravir. Less Common Adverse Reactions: The following select adverse reactions (regardless of severity) occurred in less than 2% of subjects receiving cabotegravir plus rilpivirine. Gastrointestinal Disorders: Abdominal pain (including upper abdominal pain), gastritis, dyspepsia, vomiting, diarrhea, and ﬂatulence. Hepatobiliary Disorders: Hepatotoxicity. Investigations: Weight increase (see below). Psychiatric Disorders: Anxiety (including anxiety and irritability), depression, abnormal dreams. Skin and Hypersensitivity Reactions: Hypersensitivity reactions. Weight Increase: At Week 48, subjects in FLAIR and ATLAS who received cabotegravir plus rilpivirine had a median weight gain of 1.5 kg; those in the current antiretroviral regimen group had a median weight gain of 1.0 kg (pooled analysis). In the FLAIR trial, the median weight gain in subjects receiving cabotegravir plus rilpivirine or a dolutegravir-containing regimen was 1.3 kg and 1.5 kg, respectively, compared with 1.8 kg and 0.3 kg in the ATLAS trial in subjects receiving either cabotegravir plus rilpivirine or a protease inhibitor-, non-nucleoside reverse transcriptase inhibitor (NNRTI)-, or integrase strand transfer inhibitor (INSTI)-containing regimen, respectively. Laboratory Abnormalities: Selected laboratory abnormalities with a worsening grade from baseline and representing the worst-grade toxicity are presented in Table 4. Table 4. Selected Laboratory Abnormalities (Grades 3 to 4; Week 48 Pooled Analyses) in FLAIR and ATLAS Trials

Laboratory Parameter

Cabotegravir plus Rilpivirine (n=591)

Current Antiretroviral Regimen (n=591)

ALT (≥5.0 x ULN)

<1%

AST (≥5.0 x ULN)

<1%

Total bilirubin (≥2.6 x ULN)

<1%

Creatine phosphokinase (≥10.0 x ULN)

Lipase (≥3.0 x ULN)

ULN = Upper limit of normal.

Changes in Total Bilirubin: Small, non-progressive increases in total bilirubin (without clinical jaundice) were observed with cabotegravir plus rilpivirine. These changes are not considered clinically relevant as they likely reflect competition between cabotegravir and unconjugated bilirubin for a common clearance pathway (UGT1A1). Serum Cortisol: In pooled Phase 3 trials of EDURANT (rilpivirine), the overall mean change from baseline in basal cortisol was -0.69 (-1.12, 0.27) micrograms/ dL in the group receiving EDURANT compared with -0.02 (-0.48, 0.44) micrograms/ dL in the control group. Abnormal responses to ACTH stimulation tests were also higher in the group receiving EDURANT. The clinical significance of the higher abnormal rate of ACTH stimulation tests in the group receiving EDURANT is not known. Refer to the prescribing information for EDURANT for additional information. Postmarketing Experience: The following adverse reactions have been identified during postmarketing experience in patients receiving an oral rilpivirine-containing regimen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Renal and Genitourinary Disorders: Nephrotic syndrome. Skin and Subcutaneous Tissue Disorders: Severe skin and hypersensitivity reactions, including DRESS. DRUG INTERACTIONS Concomitant Use with Other Antiretroviral Medicines: Because CABENUVA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. Use of Other Antiretroviral Drugs after Discontinuation of CABENUVA: Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). These residual concentrations are not expected to affect the exposures of antiretroviral drugs that are initiated after discontinuation of CABENUVA. Potential for Other Drugs to Affect CABENUVA: Refer to the prescribing information for VOCABRIA and EDURANT for additional drug interaction information related to oral cabotegravir and oral rilpivirine, respectively. Cabotegravir: Cabotegravir is primarily metabolized by UGT1A1 with some contribution from UGT1A9. Drugs that are strong inducers of UGT1A1

or 1A9 are expected to decrease cabotegravir plasma concentrations and may result in loss of virologic response; therefore, coadministration of CABENUVA with these drugs is contraindicated. Rilpivirine: Rilpivirine is primarily metabolized by CYP3A. Coadministration of CABENUVA and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Coadministration of CABENUVA and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine. QT-Prolonging Drugs: At mean steady-state Cmax values 4.4-fold and 11.6-fold higher than those with the recommended 600-mg dose of rilpivirine extended-release injectable suspension, rilpivirine may prolong the QTc interval. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes. Established and Other Potentially Significant Drug Interactions: Refer to the prescribing information for VOCABRIA and EDURANT for additional drug interaction information related to oral cabotegravir and oral rilpivirine, respectively. Information regarding potential drug interactions with cabotegravir and rilpivirine is provided below. These recommendations are based on either drug interaction trials following oral administration of cabotegravir or rilpivirine or predicted interactions due to the expected magnitude of the interaction and potential for loss of virologic response. The following includes potentially significant interactions but is not all inclusive. ∞ Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin— coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Antimycobacterials: rifampin, rifapentine—coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Antimycobacterial: rifabutin—coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Glucocorticoid (systemic): dexamethasone (more than a single-dose treatment)—coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Herbal product: St. John’s wort (Hypericum perforatum)—coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Macrolide or ketolide antibiotics: azithromycin, clarithromycin, erythromycin— macrolides are expected to increase concentrations of rilpivirine and are associated with a risk of Torsade de Pointes. Where possible, consider alternatives, such as azithromycin, which increases rilpivirine concentrations less than other macrolides. ∞ Narcotic analgesic: methadone—no dose adjustment of methadone is required when starting coadministration of methadone with CABENUVA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients. Drugs without Clinically Significant Interactions: Cabotegravir: Based on drug interaction study results, the following drugs can be coadministered with cabotegravir (non-antiretrovirals and rilpivirine) or given after discontinuation of cabotegravir (antiretrovirals and non-antiretrovirals) without a dose adjustment: etravirine, midazolam, oral contraceptives containing levonorgestrel and ethinyl estradiol, and rilpivirine. Rilpivirine: Based on drug interaction study results, the following drugs can be coadministered with rilpivirine (non-antiretrovirals and cabotegravir) or given after discontinuation of rilpivirine (antiretrovirals and non-antiretrovirals): acetaminophen, atorvastatin, cabotegravir, chlorzoxazone, dolutegravir, ethinyl estradiol, norethindrone, raltegravir, ritonavir-boosted atazanavir, ritonavir-boosted darunavir, sildenafil, tenofovir alafenamide, and tenofovir disoproxil fumarate. Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin. USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CABENUVA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary: There are insufficient human data on the use of CABENUVA during pregnancy to adequately assess a drugassociated risk of birth defects and miscarriage. While there are insufficient human data to assess the risk of neural tube defects (NTDs) with exposure to CABENUVA during pregnancy, NTDs were associated with dolutegravir, another integrase inhibitor. Discuss the benefit-risk of using CABENUVA with individuals of childbearing potential or during pregnancy. Cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA; therefore, consideration should be given to the potential for fetal exposure during pregnancy. Cabotegravir use in pregnant women has not been evaluated. Available data from the APR show no difference in the overall risk of birth defects for rilpivirine compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The background risk for major birth defects and miscarriage for the indicated population is unknown. The background rate for major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ (cont’d on next page)

BRIEF SUMMARY for CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use (cont'd) gestation. In animal reproduction studies with oral cabotegravir, a delay in the onset of parturition and increased stillbirths and neonatal deaths were observed in a rat pre- and postnatal development study at greater than 28 times the exposure at the recommended human dose (RHD). No evidence of adverse developmental outcomes was observed with oral cabotegravir in rats or rabbits (greater than 28 times or similar to the exposure at the RHD, respectively) given during organogenesis (see Data). No adverse developmental outcomes were observed when rilpivirine was administered orally at exposures 15 (rats) and 70 (rabbits) times the exposure in humans at the RHD (see Data). Clinical Considerations: Lower exposures with oral rilpivirine were observed during pregnancy. Viral load should be monitored closely if the patient remains on CABENUVA during pregnancy. Cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA; therefore, consideration should be given to the potential for fetal exposure during pregnancy. Data: Human Data: Cabotegravir: Data from an observational study in Botswana showed that dolutegravir, another integrase inhibitor, was associated with increased risk of NTDs when administered at the time of conception and in early pregnancy. Data from clinical trials are insufficient to address this risk with cabotegravir. Rilpivirine: Based on prospective reports to the APR of over 390 exposures to oral rilpivirine-containing regimens during the first trimester of pregnancy and over 170 during second/third trimester of pregnancy, the prevalence of birth defects in live births was 1.3% (95% CI: 0.4% to 3.0%) and 1.1% (95% CI: 0.1% to 4.0%) following first and second/third trimester exposures, respectively compared with the background birth defect rate of 2.7% in the U.S. reference population of the MACDP. In a clinical trial, total oral rilpivirine exposures were generally lower during pregnancy compared with the postpartum period. Refer to the prescribing information for EDURANT for additional information on rilpivirine. Animal Data: Cabotegravir: Cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/ kg/day from 15 days before cohabitation, during cohabitation, and from Gestation Days 0 to 17. There were no effects on fetal viability when fetuses were delivered by caesarean, although a minor decrease in fetal body weight was observed at 1,000 mg/ kg/day (greater than 28 times the exposure in humans at the RHD). No drug-related fetal toxicities were observed at 5 mg/kg/day (approximately 13 times the exposure in humans at the RHD) and no drug-related fetal malformations were observed at any dose. Cabotegravir was administered orally to pregnant rabbits at 0, 30, 500, or 2,000 mg/kg/day from Gestation Days 7 to 19. No drug-related fetal toxicities were observed at 2,000 mg/kg/day (approximately 0.7 times the exposure in humans at the RHD). In a rat pre- and postnatal development study, cabotegravir was administered orally to pregnant rats at 0, 0.5, 5, or 1,000 mg/kg/day from Gestation Day 6 to Lactation Day 21. A delay in the onset of parturition and increases in the number of stillbirths and neonatal deaths by Lactation Day 4 were observed at 1,000 mg/kg/day (greater than 28 times the exposure in humans at the RHD); there were no alterations to growth and development of surviving offspring. In a cross-fostering study, similar incidences of stillbirths and early postnatal deaths were observed when rat pups born to cabotegravir-treated mothers were nursed from birth by control mothers. There was no effect on neonatal survival of control pups nursed from birth by cabotegravir-treated mothers. A lower dose of 5 mg/kg/day (13 times the exposure at the RHD) was not associated with delayed parturition or neonatal mortality in rats. Studies in pregnant rats showed that cabotegravir crosses the placenta and can be detected in fetal tissue. Rilpivirine: Rilpivirine was administered orally to pregnant rats (40, 120, or 400 mg/kg/day) and rabbits (5, 10, or 20 mg/kg/day) through organogenesis (on Gestation Days 6 through 17, and 6 through 19, respectively). No significant toxicological effects were observed in embryo-fetal toxicity studies performed with rilpivirine in rats and rabbits at exposures 15 (rats) and 70 (rabbits) times the exposure in humans at the RHD. In a pre- and postnatal development study, rilpivirine was administered orally up to 400 mg/kg/day through lactation. No adverse effects were noted in the offspring at maternal exposures up to 63 times the exposure in humans at the RHD. Lactation: Risk Summary: The Centers for Disease Control and Prevention recommends that HIV-1−infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. It is not known if the components of CABENUVA are present in human breast milk, affect human milk production, or have effects on the breastfed infant. When administered to lactating rats, cabotegravir and rilpivirine were present in milk (see Data). If cabotegravir and/or rilpivirine are present in human milk, residual exposures may remain for 12 months or longer after the last injections have been administered. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), (3) adverse reactions in a breastfed infant similar to those seen in adults, and (4) detectable cabotegravir and rilpivirine concentrations in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA, instruct mothers not to breastfeed if they are receiving CABENUVA. Data: Animal Data: Cabotegravir: Animal lactation studies with cabotegravir have not been conducted. However, cabotegravir was detected in the plasma of nursing pups on Lactation Day 10 in the rat pre- and postnatal development study. Rilpivirine: Animal lactation studies with rilpivirine have not been conducted. However, rilpivirine was detected in the plasma of nursing pups on Lactation Day 7 in the rat pre- and postnatal development study. Pediatric Use: The safety and efficacy of CABENUVA have not been evaluated in pediatric patients. Geriatric Use: Clinical trials of CABENUVA did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently

from younger subjects. In general, caution should be exercised in administration of CABENUVA in elderly patients reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Renal Impairment: Based on studies with oral cabotegravir and population pharmacokinetic analyses of oral rilpivirine, no dosage adjustment of CABENUVA is necessary for patients with mild (creatinine clearance greater than or equal to 60 to less than 90 mL/min) or moderate renal impairment (creatinine clearance greater than or equal to 30 to less than 60 mL/min). In patients with severe renal impairment (creatinine clearance 15 to less than 30 mL/min) or end-stage renal disease (creatinine clearance less than 15 mL/min), increased monitoring for adverse effects is recommended. In patients with end-stage renal disease not on dialysis, effects on the pharmacokinetics of cabotegravir or rilpivirine are unknown. As cabotegravir and rilpivirine are greater than 99% protein bound, dialysis is not expected to alter exposures of cabotegravir or rilpivirine. Hepatic Impairment: Based on separate studies with oral cabotegravir and oral rilpivirine, no dosage adjustment of CABENUVA is necessary for patients with mild or moderate hepatic impairment (Child-Pugh A or B). The effect of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of cabotegravir or rilpivirine is unknown. OVERDOSAGE There is no known specific treatment for overdose with cabotegravir or rilpivirine. If overdose occurs, monitor the patient and apply standard supportive treatment as required, including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. As both cabotegravir and rilpivirine are highly bound to plasma proteins, it is unlikely that either would be significantly removed by dialysis. Consider the prolonged exposure to cabotegravir and rilpivirine (components of CABENUVA) following an injection when assessing treatment needs and recovery.

Manufactured for:

CABENUVA and VOCABRIA are trademarks owned by or licensed to the ViiV Healthcare group of companies. The other brand listed is a trademark owned by or licensed to its respective owner and is not a trademark owned by or licensed to the ViiV Healthcare group of companies. The maker of this brand is not afﬁliated with and does not endorse the ViiV Healthcare group of companies or its products. ©2021 ViiV Healthcare or licensor. CBRJRNA210004 July 2021 Produced in USA.

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