Infectious Disease Special Edition - Summer 2021 by McMahon Group

Volume 27 • Summer 2021

The Hunt for SARS-CoV-2 Measles: The Next Threat? Managing Weight in HIV Patients Rapid Diagnostic Testing and Biomarkers Impementation Women and HIV: Gaps in Care

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

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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EDITOR’S BLOG:

What About the Children? With U.S. cases, hospitalizations and deaths from COVID-19 on a steady decline, do we have to vaccinate younger children? It will be near impossible to reach herd immunity without vaccinating children, and the variants—particularly the more aggressive Delta variant—are concerning, experts tell me. Although children have lower rates of hospitalization and mortality from COVID-19 than adults, the rates are not zero. An estimated 521 per 100,000 children have been hospitalized for COVID-19, and more than 300 have died, according to CDC data. As of June 2, another 4,018 have had multisystem inflammatory syndrome in children (MIS-C) after a diagnosis of COVID-19, and 36 with MIS-C have died. The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) and the CDC’s Advisory Committee on Immunization Practices (ACIP) are wrestling with this question. The efficacy of the COVID-19 vaccines is not in dispute—the steady declines are attributable to vaccination. But people are concerned about preliminary reports of heart inflammation after vaccination. The reports were few, reminded Tom Shimabukuro, MD, MPH, MBA, the deputy director of the CDC’s Immunization Safety Office, but there was a higher-thanexpected number of myocarditis and pericarditis cases among young people who received a messenger RNA vaccine. By May 31, 3.26 million doses of vaccine had been given to 12- to 15-year-olds, and 19.84 million doses to those 16 to 25. In that time, two cases of myocarditis/ pericarditis were reported in children 12 to 15, 79 in those 16 to 17 and 196 in those 18 to 24 years of age. The cases that would be expected are zero to one in those 12 to 15, two to 19 in those 16 to 17 and eight to 83 in those 18 to 24 years of age. At the recent VRBPAC meeting, Cody Meissner, MD, the director of pediatric infectious diseases at Tufts University School of Medicine, in Boston, was among those who urged caution before making this decision. Others expressed concern about the pediatric cases and the spread of variants. However, almost everyone was in favor of seeing the studies continue, so they could be prepared if there was a surge in the fall when the kids go back to school. “My own feeling is that COVID-19, while more benign in general in children than adults, can still cause severe disease. Thus, I think studies should be done to assess the safety and immunogenicity in children—and possible efficacy, although this may be difficult. And if the data show safety and immunogenicity to warrant FDA authorization, then children should be vaccinated,” Walter Orenstein, MD, the director of the Emory Vaccine Center, in Atlanta, told me. I recognize the valuable contribution of vaccines in general—and the COVID19 vaccines in particular—to public health. The COVID-19 numbers are down because of vaccination. I personally traveled over 120 miles—twice—to get my shots. But this serious adverse event must be studied and analyzed before an emergency use authorization is expanded to younger kids. Vanderbilt’s William Schaffner, MD, reminded me about the deliberations to switch from oral polio vaccine (OPV) to inactivated polio vaccine (IPV) because the live vaccine was linked to vaccine-associated polio (VAP). In 1997, the ACIP recommended a switch from OPV to IPV, because roughly six U.S. children per year were getting VAP—and the risk wasn’t worth the benefit because there was no wild polio circulating in this country (MMWR Recomm Rep 1997;46[RR-3]:1-25). I hope the same care and thoughtful deliberation that went into that decision will be used when considering COVID-19 in younger patients. Many of the advisors are pediatricians and most are parents, too, Dr. Schaffner said. They understand what this recommendation will mean to public health and to the nation’s children. —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

IDSE.NET

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Summer 2021 6

Editor’s Blog: What About the Children?

MAD-ID News: Stewardship in special populations

The Hunt for SARS-CoV-2

Getting Back to Normal: What Will It Take and What Will It Look Like?

Prosthetic Joint Infections: Forgetting the Usual Suspects

Meningococcal Disease: A Threat in Decline in the U.S.

Is Measles the Next Threat?

Role of Vitamin A in Measles Management

HIV News: Training immune cells and improvements in ART

Strategies for Managing Weight Gain in HIV Patients

Better Surveillance for Serious HAIs

One-Third of Community-Onset C. diff Cases Discharged From Same Hospital

33 New Weapons in the Armamentarium Against Gram-Negative Infections 38 From Zoo to You Vector-Borne Diseases Ticking Upward; Did Plague Push Immune System Evolution?

IDSE Reviews

45 Women and HIV: Gaps in Care By Jacob Boudreaux, MD, and Julia Garcia-Diaz, MD, MSc, FACP, FIDSA, CPI

51 Rapid Diagnostic Testing and Biomarkers Implementation: The Starring Role of Antimicrobial Stewardship By Karen Fong, PharmD, BCIDP

Cabenuva: A Novel Long-Acting Injectable HIV Treatment By Sarah M. Michienzi, PharmD, BCPS, AAHIVP, and Rachel Kautz, PharmD Candidate 2022

IDSE.NET

News BY ETHAN COVEY

Stewardship and Communication Boost Appropriate Antibiotic Rx Antimicrobial stewardship programs (ASPs) that include close collaboration between the ASP team and other clinicians can optimize prescribing among patients with febrile neutropenia (FN), according to a study presented at the 2021 annual MAD-ID virtual meeting (poster A23). The results may help cut the significant morbidityy and mortality associated with FN, and clarify how best to manage patients who develop this oncologic emergency. “The duration of empiric antibiotics in FN patients remains controversial,” said Pawlose Ketema, PharmD, a PGY-2 infectious disease pharmacy resident at Boston Medical Center. “The IDSA [Infectious Diseases Society of America] guideline was last updated in 2010 [Clin Infect Dis 2011;52(4):e56-e93], and since then, there have been a number of retrospective studies to support early discontinuation of antibiotics in patients who are hemodynamically stable, irrespective of their absolute neutrophil count.” Previous data collected at Boston Medical Center found that only 27.9% of patients received appropriate antibiotics based on FN guidelines, so Dr. Ketema and her colleagues conducted a quality improvement initiative aimed at increasing the level of appropriate antibiotic management for FN to 65% by April 2021. Several interventions were enacted, including ASP pharmacist

reviews, regular education programs and updates to existing FN treatment protocols. When FN was diagnosed, the ASP included pharmacist evaluation of antibiotic choices and communication with clinical oncology and primary care team members. From November 2020 through April 2021, FN was d diagnosed 23 times. The composite outcome of aappropriate antibiotic prescribing was 70% (n=16/23). Antibiotic therapy was appropriate for 87% (n=20/23) of empiric regimens, 75% (n=12/16) of regimens with de-escalation opportunities, and 91% (n=22/23) of antibiotic durations. Dr. Ketema attributes the success to educational sessions and collaboration between the stewardship and hematology/oncology groups. Discontinuation of antipseudomonal agents in stable patients did not lead to secondary events, such as ICU care. As part of its quality improvement measures, the team also added methicillin-resistant Staphylococcus aureus risk factor indication to its antibiotic management protocols, which “allowed [for] less vancomycin therapy in FN patients,” she noted. Although the results are encouraging, Dr. Ketema stressed that work has only just begun. “We want to continue to investigate prescribing patterns and applicability on a larger scale.” She added that recurrent education programs for hematology/ oncology team members are being developed.

Thrice-Weekly Cephalosporin Dosing Eﬀective in Hemodialysis Patients

osing IV cephalosporin three times per week is safe and effective in resolving infection—and preventing reinfection—in patients receiving hemodialysis, according to a study presented at the MAD-ID virtual 2021 annual meeting (poster A04). The researchers wanted to know whether this dosing schedule would provide adequate therapeutic drug concentrations to prevent infections, while

avoiding supratherapeutic drug levels. “The findings confirm that this convenient dosing strategy is effective at preventing readmission for infection while preventing accumulation in patients noncompliant with dialysis,” said Emma Sullivan, a PharmD candidate at the University of North Carolina at Chapel Hill, Eshelman School of Pharmacy. The retrospective chart review included 42 patients admitted to Moses Cone Hospital from July 1, 2019, to June 24, 2020, who received hemodialysis and cefazolin, ceftazidime or cefepime dosed as 2 g intravenously three times weekly following dialysis. Of these patients, 67% received cefazolin, 21% received ceftazidime, and 12% received cefepime. The most common infections in the patient population were methicillin-

sensitive Staphylococcus aureus bacteremia (47.6%), osteomyelitis (23.8%), cellulitis (9.5%) and streptococcal bacteremia (9.5%). Patients had a mean age of 56 years and most were male (55%). Common comorbid conditions included type 2 diabetes mellitus (59.5%), use of a cardiac device (11.9%) and hepatitis C (9.5%). After 30 days of treatment, infection resolved in all patients, and none were readmitted to the hospital. There was one death, but the researchers ruled that it was unrelated to the effectiveness of the antibiotic therapy. “[This study] is important not only to prove our dosing strategy is effective, but that it is effective in patients with a wide range of comorbidities and in a n variety of indications,” she said.

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2021

The Hunt for SARS-CoV-2 BY MARIE ROSENTHAL, MS

iven that there are millions of wild, domestic, farmed and laboratory animals in a staggering array of habitats in China, finding the animal reservoir and/ or host of SARS-CoV-2 is the proverbial needle-in-a-haystack search. But that is exactly what President Joe Biden wants the U.S. intelligence community to find after receiving a report from the National Security Advisor. He wants to know whether it emerged from human contact with an infected animal or from a laboratory. His advisors told him a similar story that the World Health Organization found when it sent its investigators into China—there is insufficient information to assess the likelihood of one over the other. Scientists must deliberate all possibilities until hard evidence can be found to

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prove or dispute them, and people are uncomfortable with that uncertainty. “I think when scientists are communicating, sometimes our expression of our balanced uncertainty can be confusing to the general public where they like to have dogmatic answers, clear-eyed answers to questions that are important,” explained Stuart C. Ray, MD, FACP, FIDSA, the vice chair for data integrity and analytics and a professor at the John Hopkins University School of Medicine, in Baltimore. Before the security report to Mr. Biden, the WHO released a report about the origins of COVID-19, but it did not offer those clear, scientifically certain answers. Even Tedros Adhanom Ghebreyesus, MSc, PhD, the director-general of the WHO, said the report “raises further questions.” The report did explore several pathways

where the virus could have entered the human population, rated them as far as likelihood and made recommendations for how best to pursue the answers. To understand what could have led to cross-species transmission, one must understand the virus’s evolution and the factors that contributed to efficient person-to-person spread. The WHO investigators focused on reviewing SARS-CoV-2 genomic and metadata from global and Chinese databases. They analyzed early sequences (514 from China; 768 from outside) from a database containing 437,808 nonredundant sequences because they were looking for the origin. All of these sequences, which provide the backbone of the report, are publicly accessible. In addition to understanding the continued on page 16

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he CDC’s recent changes in mask guidance for those who are fully vaccinated gave many people a welcome glimpse of a post-pandemic world, a chance to see family and friends and take part in activities that had stopped for more than a year. However, there are still reminders that the pandemic is not over. One needs only to look outside the United States to see surges in India, Nepal and Japan to understand that global collaboration will be required to end COVID-19. But with more states lifting masking and social distancing rules, opening restaurants, gyms and grocery stores, and many countries allowing international travelers from areas with low COVID-19 rates, “normal” is settling into a new routine. But what will it take to get there? Infectious Disease Special Edition spoke with several specialists, who all agreed that normal may be a misnomer. “Are we going back to the old normal or are we going to a new normal? And the answer is clear: It’s a new normal at every level of society,” said William Schaffner, MD, a professor of preventive medicine and infectious diseases at Vanderbilt University School of Medicine, in Nashville, Tenn.

vaccines have been effective against the variants, but one could emerge that would not be covered by the vaccine, which puts pressure on vaccination efforts to get as close to herd immunity as possible and to reduce transmission. “I don’t think this is the answer that you want to hear, but the answer is we just don’t know [what the cold weather will bring],” admitted Shmuel Shoham, MD, an associate professor of medicine at Johns Hopkins University School of Medicine, in Baltimore. Having a widely vaccinated population could turn the virus into a “nuisance” that would result in milder disease for most people, but could be a problem for immunocompromised people, as is the case for many respiratory diseases. “I think it will ‘smooth out’ over time because we are doing a lot of things as humans to try to change the trajectory of COVID,” explained Dr. Shoham, who is a member of the Infectious Disease Special Edition editorial advisory board.

What Will It Take to Get There? To get there, Dr. Schaffner said, more people have to receive COVID-19 vaccination. “The vaccines have developed a wonderful track record of being safe and effective; and clearly in areas where the vaccine has been used intensively, cases are diminishing, and we are seeing that around the country.” With more than 52.6% of the total U.S. population receiving at least one dose of COVID-19 vaccine and 43.9% fully vaccinated as of June 16, new U.S. cases, hospitalizations and deaths fall to their lowest levels in nearly a year, according to the CDC. But these reductions must continue to enable a return to normal, according to Rajesh T. Gandhi, MD, FIDSA, a professor of medicine at Harvard Medical School and Massachusetts General Hospital, in Boston, and the chair of the HIV Medicine Association. “We need to get the case numbers down and get vaccinated,” he said. “The two go hand in hand. By vaccinating, we get case numbers down, and then by getting case numbers down, it makes it possible to be safe when we’re getting back to normal activities.” None of the experts said SARS-CoV-2 will act like its country cousin—SARS-associated coronavirus—and just disappear. They expect to see continued, sporadic disease, maybe seasonal, maybe year round. Conventional, nonpandemic human coronaviruses—the ones that cause common colds—tend to be more robust in the colder months. Last year, many people were hoping the heat of the summer would mean a drop in COVID-19 cases and yet, the United States saw a surge during the warmer months, so there is uncertainty about how SARS-CoV-2 will act this year. However, with vaccination, there is definitely downward pressure on circulating virus. The biggest caveat is the variants. To date, the COVID-19

Stuart C. Ray, MD, FACP, FIDSA, the vice chair of medicine for data integrity and analytics, and a professor in the Division of Infectious Diseases at Hopkins, is concerned that as masking and social distancing rules change, people will become complacent, the push to get people vaccinated could stall, and some locations could see a surge in the winter. (See what states are doing to incentivize vaccination at https://www.idse.net/ Covid-19/Article/06-21/Incentives-Offered-to-Boost-COVID-19Vaccination-Rates-Tackle-Hesitancy/63765) “This whole notion of approaching herd immunity, it’s not a sharp finish line. It’s a gradient of risk that we travel through from where we started—which was a high rate of infections— to nearly 100% of people immune and we have no outbreaks,” said Dr. Ray, who is a member of the IDSE editorial advisory board. “As we go through that gradient, we’ll go from widespread surges to milder cases of disease. “So, if we get more people vaccinated, then when the fall does come, rates will stay low, and things will be more normal,” Dr. Ray said, but he added that some sections of the country that are resisting vaccination could see a “horrible” surge. “There is reason to be hopeful that we will drive it down so that

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2021

it’s either milder, which would obviously be a good thing, or that there are fewer and more contained outbreaks,” said Dr. Gandhi, who is also a member of the Infectious Disease Special Edition editorial advisory board.

Back to the Future With almost 600,000 deaths in the United States alone— more than 3,000 among health care workers—and more than 3.5 million worldwide during the pandemic, people cannot just pretend this never happened, noted Susan Mashni, PharmD, BCPS, the vice president and chief pharmacy officer at Mount Sinai Health System, and an associate professor at the Icahn School of Medicine at Mount Sinai, in New York City. “There’s a lot of post-traumatic stress and psychological issues. It’s bad for health care workers out there,” said Dr. Mashni, who predicted a staff exodus when COVID-19 is finally over. “There are going to be underpinnings [from that]. We have to do better at taking care of ourselves and each other.” A recent survey from Morning Consult appears to support Dr. Mashni’s view: About 25% of health care personnel have thought about leaving the profession because of COVID-19 (bit. ly/3wU7d8B-IDSE). In addition, America’s hospitals and health systems faced historic challenges with the surge of critical COVID-19 patients and the dearth of more routine testing and procedures, such as outpatient surgeries. The costs of preparing for that surge were astronomical, and hospitals lost billions of dollars in essential revenue from the stay-at-home orders, which led to a downturn in nonemergent care and an increase in care for uninsured patients. The American Hospital Association expects losses of more than $323 billion in 2020, when all the tallies are done. At least 50 hospitals declared bankruptcy or closed in 2020, and hundreds more, especially in rural and underserved areas, are at risk. A 2021 report by the Chartis Center for Rural Health found that 77% of total revenue for rural health care facilities is tied to outpatient services (bit.ly/34LwZ2M-IDSE). “We know the toll COVID has taken in terms of the hundreds of thousands of deaths, the toll it’s taken mentally, and then the economic toll,” Dr. Gandhi said. “Financially, it’s been a big hit, and emotionally, it’s been a big hit,” Dr. Mashni agreed. The pandemic will continue a trend that was started before COVID-19, they predicted. Site-of-care optimization will continue to take people out of the hospital, and hospitals that

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want to regain their financial footing will have to adapt to changing care models, according to Bonnie Kirschenbaum, MS, FASHP, FCSHP, a pharmacy consultant and an expert in reimbursement issues. “It is not going to go back to what it used to be,” Ms. Kirschenbaum said. “There is a whole chain of events, from inpatient moving to outpatient, moving to ambulatory, moving to a freestanding facility, and moving to therapy at home,” she said. “It’s not only just infusion therapy at home, but to the whole hospital-at-home concept.” Just as health systems purchased stand-alone surgery centers, they are going to have to invest in providing home care because that is what third-party payors want to see, and pricing for those services will have to be competitive, she warned. Payors are not the only ones who like the idea of home care. Patients like it, too, and telemedicine will probably continue to be part of providing patient care. “People feel a lot more comfortable doing telehealth visits, and they’ve seen the benefits,” Dr. Mashni said. “That’s one additional tool in our tool box that we can use to improve care for patients. We’ve also done a lot more with remote patient monitoring.” Dr. Shoham, who manages immunocompromised patients, particularly those who’ve undergone a transplant, agreed that his patients loved the convenience of telemedicine. “In the past year, I’ve provided a good amount of clinical care from a distance,” he said. He discussed one patient who lived a long distance from Hopkins. “She’s a mom, so driving three hours [is] a huge disruption for something that could be done by telemedicine,” Dr. Shoham said. Now that patients and providers have gotten comfortable with telemedicine, “we are going to have to be really open to people saying, ‘I can’t do that [trip] anymore.’ “It’s more convenient [to do a telemedicine visit], and if you are really sick, the last thing you want to do is get up and go to your doctor’s office. And sometimes, you go to talk, to touch base, and a traditional visit really isn’t necessary,” he explained. However, for telemedicine to be equitable, the country has to address the digital divide, Dr. Gandhi said. “There is an inequity around access to digital technologies, and equitable distribution of care is critical. For some people, the ability to see their clinician virtually has helped, and I hope some of that persists,” he said. COVID-19 was a multisystem disease, so it has been crucial continued on page 16

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SARS-CoV-2 Origin continued from page 10

genomic similarities and differences of the viruses, the search for the origin of SARS-CoV-2 involved understanding viral circulation in animal hosts. There are many high-density and wild animal farms in China, which could have played a role in the early days of the pandemic. The team considered two typical zoonotic transmission pathways: direct introduction from a primary reservoir, and introduction through an intermediate host. The sequence of SARS-CoV-2, which was published in January 2020, showed a positive-stranded RNA coronavirus that was novel to humans but similar to the original SARS coronavirus and shares a 96.2% homology with the RaTG13 strain identified from a horseshoe bat, which also has some similarities to a strain isolated from pangolins. This RaTG13 sequence is the closest known sequence to SARSCoV-2, hinting to a natural animal origin, but it is “evolutionary distant,” that is, there were mutations in the sequence not seen in its closest relative. Bats have been identified as reservoirs for genetically

diverse coronaviruses, but the team found it less likely that the virus was directly transmitted from a bat to a person. There is a large network of domesticated wild animal farms, as well as high-density farms, “leading to complex transmission pathways that may be difficult to unravel,” the report stated. However, there have been other zoonotic outbreaks involving farm animals, and it is more likely that humans would interact with the farm animals—whether wild or domestic—than with bats, they said. “I think this is a standard paradigm or understanding to explain the emergence of viruses or other pathogens from animals to humans,” said Daniel Lucey, MD, MPH, FIDSA, FACP, a clinical professor of medicine at Dartmouth Geisel School of Medicine, in Hanover, N.H. Tens of thousands of tested animals were negative, according to Peter Ben Embarek, PhD, the leader of the WHO group, demonstrating “the difficulty of picking up a particular species as a potential intermediary host” in a country as biodiverse as China. The Chinese insist the virus was introduced through frozen food brought into

Getting Back to Normal continued from page 14

for practitioners to work closely together. Dr. Gandhi said, “We worked a lot more closely with our colleagues in other specialties just by necessity, and so that has brought us together with our pulmonary colleagues, our nephrology colleagues, our cardiology colleagues. “COVID-19 has brought the entire medical community together around a common goal,” Dr. Gandhi said, predicting that these collaborative benefits will continue.

The New Normal An important part of getting back the daily routines is having children return to in-person learning, the experts said. “Many, many schools will open fully this fall, as they should,” Dr. Schaffner said. “By now literally every adult who works in the school, not only teachers, but the administrators, the coaches, folks who work in the cafeteria, the custodians, the bus drivers—everybody should be vaccinated by now.” Moreover, with the FDA lowering the age of vaccination

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the country. This was termed a “possible pathway,” but less likely than the first two, according to the report. The most controversial pathway of transmission was a laboratory leak, which the team found to be “an extremely unlikely pathway.” This is an idea that recently resurfaced after the U.S. intelligence report. Much of the idea for this originated from a paper published last year by the Chinese virologist Li-Meng Yan (http://bit. ly/3fRdpc3-IDSE) claiming the pandemic

to 12 years, many of the children also will be vaccinated. “Now, everybody is not going to be vaccinated,” he warned. “Obviously, there are going to be hesitant parents, but I think schools can be very safe.” It will still be important to maintain disinfection and air handling, and some schools might require masks and maintain social distancing, where appropriate. Dr. Ray also thought having a highly vaccinated group will be important for the return of in-person learning. “We need to vaccinate them; that will make it possible to go back to normal classroom teaching,” he said, but he agreed that vaccine hesitancy will play a role. “My guess is we are going to have a natural experiment, where we will find out what the price [of that hesitancy] is,” he said, adding there could be sporadic cases tied to schools if the vaccination rates are not high enough. When the country was sequestered, many businesses found success working from home, and while some companies have decided to maintain that model, others have asked employees to return to the workplace. Many, however, have decided on a hybrid model: working from home some days and in the office others. “I would think virtually every company and organization

was created in a lab, but American scientists said the paper was deeply flawed (http://bit.ly/3ci8XAN-idse). In fact, there is a warning that the paper did not stand up to scientific scrutiny on the original publication site (http://bit.ly/3v3Pbj3-IDSE). The WHO report listed several arguments in favor of this pathway. Three laboratories in the area work on coronaviruses, including the Wuhan Institute of Virology, where the bat COV RaTG13 strain has been sequenced. In addition, the Wuhan CDC laboratory moved to a new location near the seafood market in the beginning of December 2019. The market was the site of early recognized cases. However, accidents are rare, the experts told Infectious Disease Special Edition. John Watson, MB BS, MSc, FRCP, FFPH, a clinical epidemiologist, who visited the three laboratories with the rest of the WHO-China team, said there were good safety protocols in place. However, they could not do a detailed audit of the facilities. Some of the arguments against a laboratory accident, according to the report, were that none of the laboratories have records of viruses closely related to SARS-CoV-2.

There were no reports of a COVID-19–like respiratory illness among laboratory staffs prior to December 2019, and no incident reports during the move of the Wuhan CDC facility. “The team did not say, ‘This is an impossible thing; forget it,’” Dr. Watson said. “What it said was that of all of the scenarios that it had the opportunity to look at and discuss and read the various bits of literature about etc., it was the least likely.” The problem with the lab theories is that they rely on circumstantial evidence and assumptions, and not scientific certainty. The only way to definitely lay this pathway to rest would be to find a frozen sample with the exact sequence of the early SARS-CoV-2 in a laboratory or to find the sequence in a wild bat that is 99.5% identical to SARS-CoV-2, Drs. Lucey and Ray said. But looking at the evolution of the two original coronavirus epidemics, the most likely scenario is the one that has been seen over and over again: People encroach on an infected animal and become exposed to an organism, they added. Some scientists worried that the WHO

is currently thinking about and wrestling with, and inquiring of their employees, ‘How is that going to work?’” Dr. Schaffner said. For many people who work in an office setting, there are quality-of-life issues to working from home: They don’t have to commute, saving time and money.

Cleanliness Is Next to Healthiness Throughout the pandemic, there was a concerted effort to keep public places—including grocery stores, subways, buses and trains—clean. “We are going to have to be more cognizant of keeping our classrooms clean. And I’ve heard a lot of people say they appreciate the benefit of how clean restaurants are. That might be part of the new normal,” Dr. Mashni said. Another positive aspect of the new normal that experts hope will continue is awareness of how respiratory diseases are transmitted, and a willingness to prevent them. Experts are hopeful that in addition to people staying home when they are sick, people will continue to wear a mask in crowded places during flu season and to practice good hand hygiene. The 2020-2021 influenza season was practically nonexistent, and experts attribute that to the mitigation actions taken

could not be independent and wrote a prescriptive open letter calling for a more independent investigation that includes Chinese language specialists, so that the group would not depend on Chinese-appointed interpreters (http://bit. ly/3xcl5LL-IDSE). After the U.S. security report, Anthony Fauci, MD, the director of the National Institutes of Allergy and Infectious Diseases, asked for the medical records of the Wuhan CDC staff, and others have asked for access to laboratory data and samples. This is not something the WHO would oppose. “We have not yet found the source of the virus, and we must continue to follow the science and leave no stone n unturned as we do,” Dr. Tedros said. The sources reported no relevant financial disclosures.

against COVID-19 (https://www.scientificamerican.com/article/ flu-has-disappeared-worldwide-during-the-covid-pandemic1/). “People’s patterns have changed,” Dr. Mashni said. “They’ve learned different ways to be able to minimize their exposures to others. I think that will be part of our new normal. People will be more cognizant about shaking hands and unnecessarily sharing germs,” she said. “If somebody pulls out a little [container of] Purell and does their hands, nobody’s going to look twice at them today. It’s just normal—and maybe even wise,” Dr. Ray said. Some people don’t want the world to be exactly the same. “We want to be in a better place. COVID has shown us what happens when you have an inadequate public health response, when you don’t have equitable health care access for all, including the most vulnerable,” Dr. Gandhi explained. “So, if that’s normal, then I don’t think we want to go back to that,” he said. Instead, “we want to build on what COVID has taught us: to take stock of what happened and build on it n so that we are in a better place next time.” The sources reported no relevant financial disclosures..

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2021

Prosthetic Joint Infections: Forgetting the Usual Suspects BY DAVID C. HOLZMAN

here are several usual suspects when patients encounter a prosthetic joint infection, but a recent case review highlights the need to keep an open mind when adding culprits to the differential. The usual suspects are bacterial—Staphylococcus aureus, coagulase-negative Staphylococcus, Streptococcus and Enterococcus—and certain aerobic gram-negative bacilli and anaerobic bacteria (Clin Microbiol Rev 2014;27[2]:302-345). Fungal infections, especially due to Histoplasma capsulatum, are an exceptionally rare occurrence. Yet, Raymund R. Razonable, MD, a professor of medicine and consultant, Division of Infectious Diseases, at Mayo Clinic College of Medicine and Science, in Rochester, Minn., and his colleagues encountered three patients in one year (Mayo Clin Proc Innov Qual Outcomes 2021;5[1]:225-229). “Infectious disease physicians should consider unusual pathogens when their workup of infections of joint prostheses is nondiagnostic for the common and usual suspects,” Dr. Razonable said. The infections “appear to be localized, limited to the joints and rarely involve other organ systems,” Dr. Razonable told Infectious Disease Special Edition. “Although one assumes it originated from the lungs.” In addition to his three patients, a literature search found four more cases, but no unifying host characteristics could guide the diagnosis, he said. “Although the infection has occurred in immunocompetent patients, it is possible that an underlying immunosuppression may predispose a patient to develop [prosthetic joint infection] due to H. capsulatum. However, in a case–control study of immunocompromised transplant patients with [prosthetic joint infection], no case of histoplasmosis was reported,” he wrote. In addition, the time to infection after the initial joint replacement varied from weeks to years. The three cases reported by Dr. Razonable all resided in the Midwest, where H. capsulatum is endemic. “Histoplasma [fungi] have been endemic to that region,” said Savyasachi C. Thakkar, MD, an assistant professor of orthopedics in the Department of Orthopedic Surgery at the Johns Hopkins Hospital, in Baltimore, who was not involved in the report. But he added they don’t usually affect joint prostheses. “Fungal infections in general are very, very rare,” Dr. Thakkar said. “We probably see one in three to five years,” Dr. Thakkar continued, noting that the three cases in Dr. Razonable’s report presented at Mayo Clinic during a single

IDSE.NET

year—2019. “Having three cases reported at the same center, in such a short duration, is very concerning,” Dr. Thakkar said. In the report, Dr. Razonable and his colleagues noted that “Histoplasma serology and urinary Histoplasma antigen were negative in all except one case in which the M band was positive, suggesting that cases were localized infections involving only joint arthroplasty.” This finding is consistent with a study reporting that most bone and joint infections due to H. capsulatum are localized (Eur J Clin Microbiol Infect Dis 2014;33[12]:2131-2140). However, the third case could have been a component of a systemic disease “because of the reported presence of mediastinal and hilar adenopathy on the chest computed tomography scan,” Dr. Razonable reported in the Mayo review. “It’s so hard to take any major lessons from three cases,” said Sandra B. Nelson, MD, who was not involved in the research. “In general, fungal prosthetic joint infections are considered worse than bacterial infections. Despite this, although the treatments were challenging, they all seemed to achieve good outcomes.” Dr. Nelson is the associate clinical director of the Division of Infectious Diseases and director of the musculoskeletal infection program at Massachusetts General Hospital, and an assistant professor at Harvard Medical School, in Boston. “Although a small study, one of the interesting insights is that the standard way in which we diagnose histoplasmosis is with urinary serologies or antigen,” Dr. Nelson said. But all three cases were negative for urinary antigen, and just one was positive—transiently—for antibodies, meaning that culture is needed for a definitive diagnosis, she said. But cultures take 12 to 14 days to become positive, Dr. Thakkar said. “Labs typically only hold the cultures for one week. The labs need to be more vigilant about holding the cultures for a longer duration.” “And even then, 7% to 12% of cases of prosthetic joint infections are culture-negative,” Dr. Razonable said. “Most commonly, this is due to antibiotic use prior to diagnostic culture. In our cases, the workup revealed Histoplasma, which is uncommon.” A misdiagnosis is not benign, Dr. Razonable reminded. “One of the cases was treated for recurrent culture-negative prosthetic infection, which led to repeated surgeries,” he said. “When we finally made the diagnosis of this unusual fungal n infection, it led to appropriate treatment.” The sources reported no relevant financial disclosures.

Meningococcal Disease: A Threat in Decline in the U.S. BY ETHAN COVEY

lthough some areas of the world regularly see meningococcal disease outbreaks, U.S. rates have been in steady decline for decades, thanks to developments in vaccination. “Historically, annual rates of meningococcal disease in the U.S. fluctuated between 0.5 and 1.5 cases per 100,000 population,” said Lee H. Harrison, MD, a professor of medicine and epidemiology at the Infectious Diseases Epidemiology Research Unit, University of Pittsburgh. According to the CDC, in 2004, just prior to the introduction of MenACWY conjugate meningococcal vaccines, rates had fallen to 0.44 cases per 100,000 population. The U.S. incidence has continued to decrease, declining by more than 75% to 0.10 cases per 100,000 by 2018 (https://www.cdc.gov/ meningococcal/surveillance/index.html). “Rates of meningococcal disease are at historical low levels,” added Dan M. Granoff, MD, the director of the Center for Immunobiology and Vaccine Development at the Children’s Hospital Oakland Research Institute, in California. The risk remains highest for subgroups, including infants, young adults and those older than 80 years.

serogroup,, Trumenba (Pfizer) and Bexsero ithKline, 2015), are (GlaxoSmithKline, approved for people between 10 and 25 years; however, the ACIP supports use of the vaccines in all people age 10 years who are at increased risk for serogroup B meningococcal disease (MMWR Morb Mortal Wkly Rep 2020;69[9]:1-41). In 2019, the ACIP recommended a MenB booster dose one year following completion of a MenB primary series, followed by MenB booster doses every two to three years thereafter, for as long as increased risk remains, among those ages 10 years and older with complement deficiency, complement inhibitor use or asplenia, or who are microbiologists. Additionally, a one-time booster dose if it has been at least a year since completion of a MenB primary series, and booster dose interval of at least six months may be considered by public health officials depending on the specific outbreak response for those ages 10 years and older (https://www.cdc. gov/vaccines/acip/recommendations.html).

The Vaccine Age

Current Vaccines Effective, If Not Ideal

The first meningococcal vaccine was approved in the United States in 1974. The 2000s brought advances resulting in the approvals of the conjugate vaccines: MenACWY (Menactra, Sanofi Pasteur, and Menveo, Novartis), as well as MenHibrix (GlaxoSmithKline), which provides additional protection against Haemophilus influenzae type b. Just last year, the FDA approved MenACWY-TT (MenQuadfi, Sanofi), which is indicated for those ages 24 months to 56 years and older. The Advisory Committee on Immunization Practices (ACIP) guidelines recommend conjugate meningococcal containing vaccine at age 11 or 12 years with a booster dose at 16 years of age. In previously unvaccinated adolescents, a single dose is recommended at age 13 through 15 years, with a one-time booster dose between 16 and 18 years. In healthy individuals who receive their first dose of meningococcal conjugate vaccine at or after age 16 years, a booster is not necessary. Routine vaccination is not recommended for healthy individuals older than 21 who are not at increased risk for exposure (MMWR Morb Mortal Wkly Rep 2020;69[9]:1-41). In addition, the ACIP recommends MenACWY for anyone 2 months of age or older who is at risk for meningococcal disease caused by the serotypes covered by the vaccine. This includes certain immunocompromised individuals. Vaccines for protection against the meningococcal B (MenB)

The efficacy of meningococcal conjugate vaccines is 80% to 85% (Ped Infect Dis J 2011;30[6]:451-455). However, protection can wane significantly over time, hence adoption of the recommended booster dose at 16 years of age (Pediatrics 2017;139[2]:e20162193. https://pediatrics.aappublications.org/ content/pediatrics/139/2/e20162193.full.pdf). “On an individual level, studies have shown that both MenACWY and serogroup B meningococcal vaccines are effective in preventing meningococcal disease caused by the corresponding serogroups,” said Lucy McNamara, PhD, an epidemiologist with the Meningitis and Vaccine Preventable Diseases Branch, National Center for Immunization and Respiratory Diseases, CDC. Dr. Harrison concurred: “Meningococcal vaccines are safe, immunogenic and effective.” However, none provide full protection from all serogroups, and rates of vaccination, while generally high, illustrate areas where improvement is needed. “Coverage rates for the first dose of MenACWY are about 86%, although it took many years to get that high,” Dr. Harrison said. Coverage rates for the second MenACWY dose are far lower, around 50%, which Dr. Harrison said is suboptimal. While the proportion of cases caused by each serogroup continued on page 25

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2021

BY BOB KRONEMYER

lthough all eyes are on vaccinating against COVID-19, experts warn against forgetting to protect against other vaccine-preventable diseases, particularly measles. The chances of an outbreak were blunted in 2020 because of shelter-inplace orders, physical distancing and travel restrictions due to the pandemic. However, routine childhood immunizations declined during that time, reminded Amesh Adalja, MD, a senior scholar in infectious diseases at Johns Hopkins Center for Health Security, in Baltimore. “We also know [even during nonpandemic years] there are pockets where measles can find a home in the United States. The 2019 outbreak truly underscores that the risk has not gone away. We need to have high levels of vaccination to keep ourselves safe.” In addition, international efforts to control measles also suffered, according to the World Health Organization (http://bit.ly/3vZrNnt-IDSE). “I think that in general, as long as we have pockets of unvaccinated individuals, we need to be really vigilant because measles is not controlled worldwide,” Dr. Adalja said. “There are numerous countries where measles is still a fairly common childhood illness, and many people travel internationally.”

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Although travel, especially internationally, is limited, countries are starting to open up, and the CDC recently updated its international travel recommendations during COVID-19 (https:// wwwnc.cdc.gov/travel/noticescovid19).

The 2019 Measles Outbreak Dr. Adalja pointed to the 2019 measles outbreak in New York and New Jersey, where the cause primarily was due to imported disease by unvaccinated individuals. Between Jan. 1 and Dec. 31, 2019, there were 1,282 confirmed cases of measles in the United States. “The virus spread explosively. Measles is the most contagious virus known to humankind. You need a very high level of vaccination to keep it at bay,” he explained. In 2020, there were 13 cases of measles, and as of June 9, there have been two cases in 2021. The trigger for a new measles outbreak in the United States “would be an infected traveler who was not vaccinated and happens to set up a chain of transmission in an unvaccinated community,” Dr. Adalja predicted. Measles is so transmissible that even traveling through airports has been linked to transmission of measles,

said Pablo Sánchez, MD, a professor of pediatrics at The Ohio State University College of Medicine and Nationwide Children’s Hospital, both in Columbus. “As people start to leave their homes and leave their safe environments as the United States reopens from the pandemic, there is an increased risk of a measles outbreak if people are not caught up with their immunizations,” he said. “This is a perfect scenario for the reintroduction of measles into communities. The most likely trigger for a measles outbreak is lack of vaccination. We also know we can prevent outbreaks by proper immunization practices,” Dr. Sánchez said.

The Future It is likely the United States will see an outbreak, defined as three or more cases, after the population no longer practices physical distancing with the same rigor as during the pandemic. “Therefore, it is important to have robust health departments to be able to find these cases quickly, to isolate those individuals and to take action to prevent spread,” Dr. Adalja said. Teaching the public about the measles vaccine is also vital to ensure “that the measles vaccine uptake is as high as

it can be,” Dr. Adalja said. “Outbreaks from any infectious agent are alarming,” Dr. Sánchez said. “But the issue with a measles outbreak is the fact that there is increasing vaccine hesitancy, including for measles, mumps and rubella.” Dr. Sánchez cited an increasing number of parents either deferring or refusing to schedule routine vaccinations for their children.

The 2019 outbreak of measles centered in Williamsburg, Brooklyn, N.Y., and spread through the Hasidic Jewish community.

“The measles outbreak that occurred in New York two years ago was related to religious sects,” he said. “There has also been increasing but unfounded concern about potential adverse events associated with measles, mumps and rubella [vaccines], including the false narrative about measles and autism.” If the current vaccine hesitancy continues, coupled with ongoing delays in current immunization schedules due to the pandemic, “we might see some measles outbreaks in the next few years,” said Dr. Sánchez, a member of the CDC’s Advisory Committee on Immunization Practices. The outbreak in 2019 was so severe that the United States almost lost its measles elimination status, which it has held for more than 20 years. Dr. Sánchez advocated for a mass media education campaign promoting timely immunization. “We cannot accept a COVID pandemic as a reason for not taking children and other individuals for appropriate immunizan tions at appropriate times,” he said.

Role of Vitamin A in Measles Management Because of the well-documented effect of vitamin A in reducing the morbidity and mortality of measles, a supplement may be a viable treatment to help manage measles, according to a report from the National Foundation for Infectious Diseases (NFID) (Infect Dis Clin Pract 2020;28[4]:181-187). “When measles occurs, it decreases the vitamin A immune function by reducing oral intake of vitamin A and decreasing vitamin A absorption,” said Patricia A. Stinchfield, MS, CPNP, the president-elect of NFID. “You also lose vitamin A in measles with diarrhea by excreting the vitamin.” Two research studies found low use of vitamin A for measles management in U.S. children hospitalized with measles, according to Ms. Stinchfield, noting there are separate recommendations from the World Health Organization, the CDC and the American Academy of Pediatrics about treating hospitalized children who have acute measles with vitamin A. “However, most hospitals prescribe vitamin A at very low doses or not at all,” Ms. Stinchfield said. “This tells us people really do not understand the importance of vitamin A during an acute measles outbreak, and when they do prescribe the supplement, they are not prescribing it accurately.” At an NFID measles summit discussion, Ms. Stinchfield advocated for vitamin A for any severity of measles, whether the person is hospitalized or not. “Dosage is based on age,” she said. uld At the time of diagnosis, vitamin A should be given by mouth once daily for two days at s the following doses: for an infant 6 months y of age or younger, 15,000 mcg retinol activity d, equivalence (RAE); for those 6 to 11 months old, nd 30,000 mcg RAE; and for those 12 months and older, 60,000 mcg RAE. Parents should be warned that more is not better, because vitamin A is stored in the liver. Too high a dose and for too long can be toxic. his “African studies indicate that by following this val rate,” said Ms. regimen, children have a much greater survival hildren’s Minnesota, Stinchfield, a pediatric nurse practitioner at Children’s wer rate of blindness in St. Paul. “These children also have a much lower ly ill.” as related to measles and fewer become acutely ase specialists and Ms. Stinchfield encouraged infectious disease tbreak by engaging pediatricians to be prepared for a measles outbreak ave vitamin A in your with their departmental pharmacists. “Do you have d how to administer pharmacy? Do you know the correct dose and easles outbreak, the it to patients?” she said. “When you have a measles one thing you do not have is time.” Ms. Stinchfield reported no relevant financial disclosures.

Drs. Adalja and Sánchez reported no relevant financial disclosures.

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2021

HI News Getting Those Immune Cells Into Training

cientists have discovered that “elite controllers” have myeloid dendritic cells that display characteristics of trained innate immune cells. This rare group of people whose immune system hout can control HIV without antiretroviral therapy have these special dendritic cells (J Clin 72/ Invest 2021;131[9]. doi:10.1172/ JCI146136). ch“Using RNA sequencing techntify one nology, we were able to identify long, noncoding RNA called MIR4435 MIR44352HG that was present at a higher level in elite controllers’ myeloid dendritic cells, which have enhanced immune and metabolic states,” said Xu Yu, MD, a core member of the Ragon Institute

of Massachusetts General Hospital, in Boston. oi dendritic cells’ primary job Myeloid is to support supp T cells, which are key to the elit elite controllers’ ability to control HIV infection. Since M MIR4435-2HG was found in higher levels only in cells from el elite controllers, it may be pa part of a learned response to infection with HIV. M Myeloid dendritic cells with increased MIR4435-2HG also had highe higher amounts of a protein called RPTOR, which drives metabolism. This increased metabolism may allow the dendritic cells to better support the T cells in controlling HIV. MIR4435-2HG might work by attaching to the DNA near the location of

the RPTOR gene, encouraging the cell’s machinery to make more of the RPTOR protein, using the instructions found in the RPTOR gene. This type of epigenetic modification—a trained response to HIV infection—would allow the dendritic cells to stay in an increased metabolic state and support the T cells long term. Understanding exactly how the immune system of elite controllers can control HIV is a key part of HIV cure research. If scientists can understand how elite controllers suppress this deadly virus, they may be able to develop treatments that enable other people living with HIV to replicate the same immune response, removing the need for daily medication to control the virus and achieving what is known as a funcn tional cure.

Time to ART Prescriptions Improving in U.S.

lthough disparities exist in how quickly people with HIV are linked to care, the CDC reported great improvement in how quickly antiretroviral therapy (ART) is prescribed, according to a study presented at CROI 2021 (abstract 104). Jun Li, MD, PhD, a senior epidemiologist with the CDC’s Division of HIV/AIDS Prevention, and colleagues tracked how many newly diagnosed people received prescriptions for ART within 30 days of entering HIV care from 2021 to 2018. They looked at data on 11,853 eligible treatment-naive people with HIV. Of the group, 48% were men who have sex with men (MSM), 77% were younger than 50 years of age, 45% were Black and 15% were Hispanic. Between 2012 and 2018, the cumulative incidence of timely entry into ART nearly doubled, increasing from 42% to 82%. From 2012 to 2015, Blacks had a lower rate of timely ART than whites; however, no such difference was observed from 2016 to 2018. A switch was observed geographically: From 2012 to 2015, the Northeast lagged behind the West in getting patients on ART quickly. Yet, from 2016 to 2018, the rate of timely prescriptions in the Northeast surpassed that of all other regions. Across all periods, rates lagged for people with addiction disorders. The epidemiologist said more work is needed to address remaining gaps. In related news, trends in time to viral suppression among people living with HIV in the Deep South are improving, a sign

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BY ETHAN COVEY

of progress for a region hard hit by the HIV epidemic, according to another CROI presentation (abstract 105). “Southern states not only have the highest incidence of HIV diagnoses but also the highest proportion of people living with HIV, and the lowest rates of viral suppression observed nationally,” said Aadia Rana, MD, an associate professor of medicine at the University of Alabama at Birmingham. The retrospective, population-based cohort study included people 13 years of age and olderr newly diagnosed with HIV 4,996), Louisiana (8,199) and from 2012 to 2019 in Alabama (4,996), Mississippi (3,623). n timee Dramatic changes in median in alll to viral suppression were seen in an states. In Mississippi, the median wtime to viral suppression followayys ing an HIV diagnosis was 331 days 6 and from 2012 to 2015. Between 2016 68 days. In 2018, that number dropped to 168 Alabama, time to suppression improved from 211 to 135 days. And in Louisiana, time to viral suppression improved from 241 to 118 days. Younger age, male sex at birth, being nonwhite and transmission that was not related to MSM were associated with a longer time to viral suppression. Shorter time to viral suppression was found in patients who presented with advanced n disease at diagnosis.

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Strategies for Managing Weight Gain in HIV Patients BY ARLENE WEINTRAUB

here was a time when HIV infection was related to wasting syndrome, but today patients face a different challenge, one that is common among all U.S. adults as they live longer lives— fending off weight gain. Managing weight gain and the health risks it poses are important considerations for people with HIV because antiretroviral therapy (ART) can affect a patient’s weight, according to John R. Koethe, MD, an associate professor of infectious diseases at Vanderbilt University Medical Center, in Nashville, Tenn. Of HIV patients who started ART between 2003 and 2015, 17% gained at least 10% in body weight, with most of that occurring in the first four years. Nearly half of patients receiving ART experienced at least a 3% weight gain (Clin Infect Dis 2020;71[6]:1379-1389). “We’re finding that a lot of people are gaining weight around the viscera, or the abdominal organs, and that can lead to problems like diabetes and hyperlipidemia down the road,” said Dr. Koethe, who also is a co-author of the analysis. The cause of the weight gain in HIV patients starting ART is not entirely clear. It could be related to the ART itself, to aging changes in metabolism or just being healthier and having an appetite again. “This could reflect the fact that patients have a higher caloric requirement when they have active HIV, because the virus needs energy to replicate,” said Amy Justice, MD, PhD, a professor of medicine and public health at Yale School of Medicine, in New Haven, Conn. “When you suppress the virus, you change the caloric requirements for patients. But if their eating stays the same, they gain weight.” Another explanation could be that newer classes of ART

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drugs, including integrase strand transfer inhibitors (INSTIs), are less likely to suppress appetite or cause gastrointestinal side effects such as nausea, than older regimens. For example, the comparison drug used in many of the studies showing weight gain with INSTIs was the non-nucleoside reverse transcriptase inhibitor efavirenz, Dr. Koethe said. “Efavirenz seems to be retarding weight gain in some studies,” possibly by suppressing appetite or another unknown mechanism, he said. “So we don’t know if integrase inhibitors are causing weight gain so much as allowing it to occur.” The study found some health risks in ART patients who gained more than 10% in body weight versus those who put on less weight. They included small increases in the rate of diabetes and levels of low-density lipoprotein cholesterol, but the differences were not significant. That may be because the trials’ duration was not long enough to find an increased risk for metabolic and heart disease, the authors explained. Still, the weight gain worries some practitioners who treat HIV patients. “I would be surprised if we don’t see continued studies in the future showing metabolic complications,” said Mary Montgomery, MD, a clinician educator at Brigham and Women’s Hospital and Harvard Medical School, in Boston. “That’s because excess weight gain has already been well established to increase the risk of diabetes and cardiovascular disease.”

Strategies for Weight Management There are some strategies that clinicians can use to fend off weight gain and its complications in patients when they

are first prescribed ART. Dr. Koethe recommended measuring waist circumference and recording key metabolic factors such as fasting blood glucose and lipids in all patients when they start treatment. Then they can be monitored for changes over time that confer an increased risk for complications from excessive weight. Dr. Justice recommended counseling patients about nutrition and exercise. “We need to tell people starting antiretroviral therapy that the good news is the virus is going to be suppressed and they’re going to live a long life. But that means they have to start thinking about taking care of their general health,” she said. “Patients need to be advised that their caloric requirement likely decreases after ART initiation and that they should start thinking about reducing portion size and regular exercise.” For ART patients who become overweight or obese, Dr. Montgomery recommended referring them to an endocrinologist to discuss options, such as prescription weight-loss drugs, and if they need bariatric surgery, a referral to a gastroenterologist might be in order.

Of patients who started ART between 2003 and 2015:

17% gained at least 10% in body weight. Source: Clin Infect Dis 2020;71(6):1379-1389

As for whether physicians should avoid prescribing INSTIs to patients who have the highest risk for weight gain, Dr. Montgomery said there are not enough data to support this strategy. “Integrase-based therapies have the least amount of drug interactions and other side effects. They’re well tolerated and have a high barrier to resistance,” she said. “The problem is our best drugs appear to be associated with the most weight gain.” Now Dr. Montgomery starts every discussion with new ART patients by warning them they might gain weight and urging them to adopt healthy habits. “The hardest thing about weight is it’s so much harder to lose it than it is to prevent gaining it,” she said. “So I tell them: ‘If you’re exercising and working on your diet now, n keep it up. If not, try to do a little more.” Dr. Koethe reported financial relationships with Janssen, Merck, Theratechnologies and ViiV Healthcare. Drs. Montgomery and Justice reported no relevant financial disclosures.

Meningococcal Disease continued from page 19

varies by age group, 73% of all cases of meningococcal disease among people 11 years of age or older are caused by serogroups C, W, or Y (https://www.cdc.gov/vaccines/pubs/pinkbook/mening. html). There is guarded hope that newer vaccines may help increase protection, but significant improvement will likely require programs aimed at increasing vaccine coverage. “The new quadrivalent vaccine [MenQuadfi] does seem to offer higher protection against group C disease than other licensed vaccines,” Dr. Granoff said. “But whether this will change current policy, such as vaccination of older adults or young children, seems unlikely unless rates increase.” For MenB vaccines, coverage rates are low, around 17% (https:// www.cdc.gov/mmwr/volumes/68/wr/mm6833a2.htm). However, Dr. Harrison said the numbers are “not unexpected given the complexity of the issue and the fact that ACIP does not recommended MenB for all children.” In addition, although vaccines are partly responsible for falling disease rates, other factors—many not fully understood—are also at play, they said. “Although vaccines have contributed to some of this dramatic decline, much of it was naturally occurring because it started well before widespread use of meningococcal vaccines,” Dr. Harrison said. Dr. McNamara agreed: “The declines in incidence of meningococcal disease due to serogroups A, C, W and Y are likely multifactorial.”

Looking to the Future As researchers continue to make headway in preventing meningococcal disease, there is hope for a pentavalent vaccine, which would combine the current types into a single vaccine capable of protecting against ACWY and B serogroups. “Meningococcal disease also continues to cause many cases and deaths each year in the meningitis belt of Africa,” Dr. McNamara commented. “There is an urgent need for inexpensive meningococcal vaccines that can protect against all of the common causes of meningococcal disease in this area, including serogroup X, which is not currently included in any licensed vaccine.” For the United States, work must continue to stay abreast of the disease threat and adjust policies accordingly. “Continued surveillance and monitoring are essential to evaluate current meningococcal vaccination policies and population impact of the n vaccines,” Dr. McNamara said. Dr. Granoff reported a financial relationship with Allopex Vaccine and Sanofi Pasteur. Dr. Harrison reported a financial relationship with GSK, Merck, Pfizer and Sanofi Pasteur, and he served as a voting member of the ACIP during 2012-2016. Dr. McNamara reported no relevant financial disclosures.

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2021

Better Surveillance For Serious HAIs BY LEAH LAWRENCE

he CDC’s hospital-onset Adult Sepsis Event (HO-ASE) surveillance definition may do a better job at detecting serious hospital-associated infections (HAIs) than the criteria set by the Centers for Medicare & Medicaid Services (CMS). Many HAIs, including central line–associated bloodstream infections, catheter-associated urinary tract infections, Clostridioides difficile infections, methicillin-resistant Staphylococcus aureus bacteremia and certain surgical site infections, are missed by CMS criteria, according to a retrospective analysis of 282,441 patients hospitalized from June 2015 to June 2018 at three hospitals. The analysis showed that almost twice as many patients met the HO-ASE criteria as had reportable HAIs (0.8% vs. 0.4%), and in-hospital mortality rates were more than twice as high for HO-ASEs (28.6% vs. 12.9%), according to Chanu Rhee, MD, MPH, a researcher at Harvard Medical School and Harvard Pilgrim Health Care Institute, and an infectious disease physician and associate hospital epidemiologist at Brigham and Women’s Hospital, in Boston (Clin Infect Dis 2021 Mar 29. doi:10.1093/cid/ciab217). Surveillance for HO-ASEs is relatively new and voluntary for hospitals, Dr. Rhee said. It stemmed from previous work that he and his colleagues did developing and validating a surveillance definition for sepsis based on objective clinical data that could be extracted from electronic health records. The ASE definition requires clinical indicators of treated infection (blood culture orders Source: CDC and antibiotics) and concurrent organ dysfunction (vasopressors, mechanical ventilation and abnormal laboratory values) and distinguishes hospital-onset from communityonset ASE based on when those criteria are met relative to a patient’s admission. “The HAIs that hospitals are required by CMS to publicly report are certainly important to track and prevent, but we knew that our current surveillance was likely missing many other important infections that occur in the hospital,” Dr. Rhee said. “About 10% to 20% of sepsis cases arise in-hospital and these tend to be very serious infections, and so we thought

On any given day,

≈1 in 31

hospital patients has

at least 1 HAI.

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it would be interesting to look at the overlap between reportable HAIs and hospital-onset sepsis events.” The in-hospital mortality rate for HO-ASEs missed by reportable HAIs was twice as high as the mortality rates for reportable HAIs missed by HO-ASEs (28.1% vs. 6.3%). Of note, Dr. Rhee said reportable HAIs were only present in 14.5% of HO-ASEs, which indicates that the other 85.5% are caused by other serious events that are not captured routinely and reported, including hospital-acquired pneumonia, non–catheter-related bloodstream infections, intraabdominal infections, and skin and soft tissue infections. Jonathan Baghdadi, MD, PhD, of the University of Maryland School of Medicine, in Baltimore, who was not part of the study, said surveillance of HO-ASEs has value. “One important reason to have an objective measure of sepsis events is to facilitate comparison of outcomes among hospitals,” Dr. Baghdadi said. “This analysis demonstrates that the HO-ASE measure is sensitive to underlying differences in patient populations and may favor community hospitals over teaching hospitals or hospitals with large oncology practices.” Specifically, the study showed that incidence of HO-ASEs and reportable HAIs were higher in the academic hospital (Brigham and Women’s) compared with the two community hospitals, but mortality rates were similar. “We don’t think that means our academic hospital does worse when it comes to infection prevention,” Dr. Rhee said. “It is likely the different patient population we care for. For example, there are a larger number of oncology patients who, even with the best of care, are prone to developing serious infections when hospitalized.” Dr. Baghdadi said if the HO-ASE measure were to be used, it would likely require risk adjustment to account for differences in the patient populations served at different hospitals. Despite this value, Dr. Baghdadi said HO-ASEs should only be used to complement HAI surveillance. “It cannot and should not replace HAI surveillance,” he said, especially given the fact that only a small proportion of sepsis deaths are likely preventable. “I suspect that hospitals conducting HO-ASE surveillance would find that only a small proportion of events were actionable or led to identification of gaps in care.” Dr. Baghdadi referred to Dr. Rhee’s paper looking at sepsisassociated mortality in U.S. acute care hospitals that examined 568 randomly selected adults who died in the hospital or were discharged to hospice (JAMA Netw Open 2021 Feb 2. doi:10.1001/ jamanetworkopen.2018.7571). Sepsis was the immediate cause

of death in 34.9% of deaths; however, only 3.7% of sepsisassociated deaths were judged definitely or moderately likely preventable with another 8.3% possibly preventable. Instead, Dr. Baghdadi said he viewed the purpose of monitoring for adult sepsis events to support performance improvement related to recognition and early management of sepsis, for example, shortening the time from order to administration of broad-spectrum antibiotics or providing bedside evaluation to clinically deteriorating patients. Dr. Rhee echoed this opinion, emphasizing that the preventability of these HO-ASE events is still unknown. “We still have to determine if they are mostly just happening in really sick patients, in whom these serious infections are sometimes inevitable,” Dr. Rhee said. “If so, that could defeat the purpose of ultimately increasing prevention and quality

improvement programs to lower rates, incidence and mortality rates of these HAIs.” However, Dr. Rhee said he believes there is likely room to make progress in preventing HO-ASEs, but more research is needed. He also noted that HO-ASE surveillance can be fully automated, which eliminates the need for time-consuming and often subjective case reviews that are needed to identify reportable HAIs. “I don’t think sepsis surveillance would be a replacement for the current reportable HAIs, but I do think there is value in this,” he said. “They could be complementary in the sense that HO-ASEs could capture a lot of serious hospital-onset infections that are currently being missed and, potentially, identify n new targets for prevention.” Drs. Baghdadi and Rhee reported no relevant financial disclosures.

One-Third of Community-Onset C. diﬀ Cases Discharged From Same Hospital BY DAVID WILD

hirty-three percent of patients admitted with community-onset Clostridioides difficile infection (CDI) were discharged from the same hospital within the previous three months, according to the CDC. The findings point to the need for better hospital antibiotic stewardship and possibly additional interventions to ensure patients do not leave the hospital colonized with C. difficile. “Interventions to reduce communityonset CDI are not typically hospitalbased. There is a common perception that community-onset CDI is often acquired outside the hospital,” said Alice Guh, MD, MPH, a researcher in the CDC’s Division of Healthcare Quality Promotion, in Atlanta. Dr. Guh, who presented the findings at IDWeek 2020 (poster 780), said her group’s results suggest that “hospitalbased and post-discharge interventions aimed at improving antibiotic use could potentially help reduce subsequent CDI hospitalizations.” The researchers reached their conclusion after examining medical records from 4,724 patients hospitalized with

CDI—including 2,984 with communityonset CDI—at 86 hospitals in 10 states. Patients with C. difficile found in stool specimens collected after the third day following admission were considered to have hospital-onset CDI, while d those with C. difficile found in stool collected within three days of admission were considered to have community-onset CDI. The investigators further classified community-onset CDI cases es into four categories: cases with onset in a long-term care th onset in facility (LTCF), cases with a long-term acute care hospital, cases that were health care facility–associated (HCFA)—medical record documented an overnight stay at a health care facility in the prior 12 weeks, but patient was admitted from a private residence—and cases with no documented overnight stays in a health care facility in the 12 weeks before hospital admission. According to Dr. Guh and her team, 1,201 cases were HCFA. An overlapping 13% of these patients also had a prior

LTCF stay during this period. Moreover, they found that 83% (978/1,174) of the patients who had been hospitalized during the 12 weeks before hospitalization for community-onset CDI had been discharged from the same h hospital where they received inpatient CDI care, 33% (978/2,984) of all patients in the study with community-onset CDI. Dr. Guh’s team also found that 84% of these individuals had received an antibiotic during the 12 prior w weeks. They were not able to pin pinpoint where the antibiotics were administered or prescribed, but they said these patients “likely received antibiotics during or soon after the previous admission.” The authors noted that medical records may be incomplete, leaving open the possibility that rates of prior hospitalizations and antibiotic exposure in this populan tion were higher than documented. Dr. Guh reported no relevant financial disclosures.

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2021

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

Enterobacteralesa 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 complex

85%

(n=2274)

carbapenem-non-susceptible

S maltophilia b

100%

(n=1565)

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

(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.

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%).

5.2 Hypersensitivity Reactions

Common Adverse 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.

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

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.

Cough

< 1%

Elevations in liver testsf

< 1%

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

New Weapons in the Armamentarium Against Gram-Negative Infections By Glenn Tillotson, PhD, FIDSA, FCCP

ram-negative pathogens remain a clinical challenge, with 3 species at the top of the World Health Organization’s (WHO’s) global priority pathogens list: carbapenem-resistant Acinetobacter baumannii, carbapenemresistant Pseudomonas aeruginosa, and extended-spectrum beta-lactamase (ESBL)-producing, carbapenemresistant Enterobacterales (CRE).1 The evolution of multidrug-resistant (MDR) pathogens and limited treatment options prompted the Infectious Diseases Society of America (IDSA) to implement the “10×20” initiative with the objective of developing 10 novel and safe antibiotics by 2020.2 Other programs have been created to augment this process, such as Generating Antibiotic Incentives Now. The predominant focus of these programs has been MDR gram-negative bacteria. In addition to escalating resistance to standard agents, there are concerns about safety and toxicity, for example, with polymyxins and renal adverse events. The goal has been to develop agents that provide an adequate spectrum of activity and are well tolerated. Since 2014, there have been several beta-lactam–beta-lactamase inhibitor (BL/BLI) combinations approved in addition to a novel siderophore cephalosporin, cefiderocol (Fetroja, Shionogi); the fluorocycline, eravacycline (Xerava, Tetraphase); and the aminoglycoside, plazomicin (Zemdri, Cipla Therapeutics) (Table 1). The BLs are a broad group of bactericidal antibiotics that are active against both gram-negative and grampositive pathogens. The development of beta-lactamase has driven the utility of the BL class by inhibiting many of the 1,300-plus beta-lactamase enzymes (http://www.bldb.eu/).3

Not all of these have clinical significance, but the complexity and evolution of these molecules represent a constantly changing clinical challenge. Typically, beta-lactamases lack antibacterial activity, and there is no regulatory pathway for independent development, so they are coformulated with a partner BL based on 2 premises: 1. activity of the inhibitor against beta-lactamases capable of hydrolyzing the BL and similarities in pharmacologic properties, such as half-life and metabolism; and 2. tissue distribution so that adequate protection is provided to the BL. The selection of the optimal dosing of the BL/BLI is complex, involving many different parameters, not least of which is the timing of dosing such as intermittent or continuous infusion. The spectrum of inhibition of the BLIs against various classes of beta-lactamase enzymes is shown in Table 2. In addition to BL/BLI combinations, cefiderocol also has activity against a range of MDR species, including those producing

metallo-beta-lactamases such as New Delhi metallo-beta-lactamases. The range of FDA-approved indications is shown in Table 3. Three drugs are approved for 4 serious infections. Complicated urinary tract infections (cUTIs) are considered generally to be the most straightforward approach to FDA approval. Other indications tend to be more difficult to design and enroll appropriate patients, especially in the era of MDR pathogens. Often the clinical development programs are incremental from the initial cUTI studies, with pneumonia and intraabdominal infections being added to the label. Ceftolozane-tazobactam (TOL/ TAZ; Zerbaxa, Merck), a combination fourth-generation cephalosporin and BLI, is active against many gramnegative pathogens, such as P. aeruginosa, Enterobacterales that produce the globally significant ESBLs, for example, CTX-M-14 and some anaerobic species.4,5 This drug has no activity against Acinetobacter species and CREs. TOL/TAZ has been studied in 4 randomized clinical trials comprising patients with cUTIs, hospital-acquired

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2021

bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP), and complicated intraabdominal infections (cIAIs); all were noninferiority studies with low mortality (<2%), except the pneumonia study, which reported around a 25% rate.6-10 Specifically, clinical data on P. aeruginosa infections were collected from 12 studies. These were either case series (often salvage) or retrospective analyses. Overall mortality was 17.6%, but a higher rate was reported in MDR/extensively drug-resistant (XDR) patients at 20.1%. Clinical and microbiological success rates were 76.6% and 75.6%, respectively, for any

P. aeruginosa and 73.4% and 74.2% for MDR/XDR infections.11 Adverse events reported across the phase 3 program showed TOL/TAZ to be similar to a range of comparators, most commonly gastrointestinal events, Clostridioides difficile, headaches, pyrexia, and abnormal liver function tests. Variable rates of resistance development have been reported to be low. Ceftazidime-avibactam (CAZ/AVI; Avycaz, AbbVie) is a third-generation cephalosporin with a novel BLI. CAZ has an increased affinity for penicillinbinding proteins found in gram-negative organisms, while AVI is a novel non-BL BLI that inactivates a range of

Table 1. New Gram-Negative Antibiotics Approved for MDR Strains Antibacterials

Brand Name

Year of Approval

Ceftolozane-tazobactam

Zerbaxa

2014

Ceftazidime-avibactam

Avycaz

2015

Vabomere

2017

Zemdri

2018

Recarbrio

2019

Cefiderocol

Fetroja

2019

Eravacycline

Xerava

2019

Meropenem-vaborbactam Plazomicin Imipenem-cilastatin-relebactam

Table 2. Beta-Lactamase Spectrum Coverage of New BL/BLI Agents Enzyme Class A KPC

CAZ/AVI

CFCD

IMI/REL

MER/VAB

TOL/TAZ

–

SHV

TEM

CTX-M

Class B MBL

–

Class C AmpC

–

Class D OXA

–

BL/BLI, beta-lactam–beta-lactamase inhibitor; CAZ/AVI, ceftazidime-avibactam; CFCD, cefiderocol; IMI/REL, imipenem-relebactam; MER/VAB, meropenem-vaborbactam; TOL/TAZ, ceftolozane-tazobactam; V, variable

IDSE.NET

different classes of enzymes12 (Table 2). As noted, CAZ/AVI has variable activity against some of the class D enzymes in A. baumannii, such as OXA24, OXA-40, and OXA-69. In addition to class B resistance other mechanisms are loss of porins, increased activity in efflux pumps, and increased expression of the KPC gene. CAZ and AVI have similar pharmacokinetic profiles, and both are excreted renally. Eight randomized clinical trials formed the basis for the initial approval of CAZ/ AVI in adults, and a pediatric indication was granted in 2019.13 Sternbach et al examined these studies in a metaanalysis and showed no difference in mortality, which was about 3%, and all studies achieved noninferiority. However, a higher microbiological cure rate was demonstrated in cUTIs at test of cure.14 Furthermore, meta-analyses did not show a significant difference with CAZ/AVI versus the comparators in efficacy or safety in infections caused by Enterobacterales. No notable adverse events have been reported with CAZ/AVI. Meropenem-vaborbactam (MER/ VAB; Vabomere, Melinta) is a combination of a carbapenem and a novel boron-containing BLI. The combination is active against most Enterobacterales except those producing MBL and OXA enzymes. Like many other BL/BLI agents, it is susceptible to porin and efflux changes.15 The TANGO I study in cUTIs was the basis for FDA approval for this indication enrolling 550 adult patients to receive either MER/VAB or piperacillin. A significant advantage to MER/ VAB was observed in the microbiological intent-to-treat population with 98.4% versus 94.0% (risk difference, 4.5; 95% CI, 0.7-9.1). However, no significant difference was observed in the clinical cure rate alone (risk difference, 2.8; 95% CI, –0.7 to 7.1).16 In a series of patients without cUTIs, non–class B or D CRE infections were examined in the TANGO II trial, which compared MER/

Table 3. FDA-Approved Indications Indication

CAZ/AVI

TOL/TAZ

MER/VAB

IMI/REL

CFCD

PLA

ERV

cUTI

–

Hospital-acquired pneumonia

–

Ventilator-associated pneumonia

–

Intraabdominal infection

–

CAZ/AVI, ceftazidime-avibactam; CFCD, cefiderocol; cUTI, complicated urinary tract infection; ERV, eravacycline; IMI/REL, imipenem-cilastatin-relebactam; MER/VAB, meropenem-vaborbactam; PLA, plazomicin; TOL/TAZ, ceftolozane-tazobactam

VAB against the best available therapy (BAT) as selected by the clinician. But it was a small trial: 77 patients (52 MER/VAB and 25 BAT). The BAT was mainly combinations of 2 or 3 antibiotics of carbapenem, polymyxin, aminoglycoside, or tigecycline. Although the cohorts were small, there were significant differences in clinical cure, microbiological cure, and mortality end points in favor of MER/VAB.17 Subgroup analysis showed improved cure among older, sicker, and immunocompromised patients with MER/VAB.18 Overall, the BL/BLI combination was well tolerated.18 The addition of relebactam to imipenem-cilastatin (IMI/REL; Recarbrio, Merck) can help patients overcome AmpC beta-lactamase resistance. In a study by Livermore et al, IMI/REL was active against AmpC or ESBL-producing Enterobacterales with impermeability phenotypes.19 In 2013-2014, a study of P. aeruginosa isolates from 11 New York hospitals showed that the addition of relebactam to imipenem decreased the minimum inhibitory concentration (MIC) 4-fold. Imipenem and relebactam exhibit very similar pharmacokinetic properties.20 IMI/REL was studied in 2 phase 2 trials using different doses (500 mg imipenem-cilastatin plus 250 mg relebactam or 500 mg imipenem-cilastatin plus 125 mg relebactam) given every 6 hours over a 30-minute period versus imipenem alone for cUTIs.21,22 The phase 3 RESTORE-IMI-1 compared IMI/REL (500 mg/250 mg) versus imipenem with colistin (500 mg/4.5 MU)

for imipenem-nonsusceptible infections. The infections included HABP/ VABP, cIAIs, and cUTIs. The overall response was 71.4% versus 70.0% (risk difference, –7.3; 95% CI, –27.5 to 21.4), and clinical response at 28 days was 71.4% versus 40.0% (risk difference, 31.4; 95% CI, 1.3-51.5). Microbiological response after 5 to 9 days after end of therapy was 72.75% versus

The goal has been to develop agents that provide an adequate spectrum of activity and are well tolerated. 100%, but these were small numbers. Mortality was 9.5% versus 30.0%.23 The RESTORE-IMI 2 study was a double-blind, phase 3 trial in which adults with HABP/VABP were randomized to 500 mg/500 mg/250 mg of IMI/REL or 4 g/500 mg of piperacillin-tazobactam (PIP/TAZ) intravenously every 6 hours for 7 to 14 days. The primary end point was 28-day all-cause mortality. IMI/ REL was noninferior (P<0.001) to PIP/ TAZ; on day 28, all-cause mortality was 15.9% with IMI/REL and 21.3% with PIP-TAZ (difference, –5.3%; 95% CI, –11.9% to 1.2%).24 The clinical response

at early follow-up was 61.0% and 55.8%, respectively (risk difference, 5.0%; 95% CI, –3.2% to 13.2%). The adverse event profile for the 2 regimens was similar. Cefiderocol has activity against all 4 classes of beta-lactamase including class B metallo-beta-lactamases, such as New Delhi metallo-beta-lactamases. The compound uses a siderophore side chain linked to a fourth-generation cephalosporin that attaches to iron molecules in the infected space.25 Like a Trojan horse, this combination is then transported into the bacterial cell where the antibiotic is released and acts directly on the organism. Cefiderocol can be susceptible to porin and efflux mutations, which applies to other agents described in this paper. Multiple in vitro studies illustrate the excellent activity against both Enterobacterales and non-fermenter gram-negative species. For example, a study of 800 ICU gram-negative isolates, including carbapenemase-producing Enterobacterales, P. aeruginosa, A. baumannii, and Stenotrophomonas maltophilia had a MIC less than 4 mg/L.26 Cefiderocol was initially approved for cUTIs, but the indication was recently expanded to include HABP/ VABP. In the cUTI study, cefiderocol (2 g) or imipenem-cilastatin (1 g each) was given 3 times daily every 8 hours for 7 to 14 days, and 371 evaluable patients (n=252 patients in the cefiderocol group; n=119 patients in the imipenem-cilastatin group) were included in the primary efficacy analysis consisting of clinical and microbiological

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2021

responses. The primary end point was achieved by 183 (73%) of 252 patients in the cefiderocol group and 65 (55%) of 119 patients in the imipenem-cilastatin group, with an adjusted treatment difference of 18.58% (95% CI, 8.23%-28.92%; P=0.0004).27 An open-label, randomized pathogen-focused study, CREDIBLE-CR, was conducted to compare cefiderocol with best available therapy for carbapenem-resistant organisms causing HABP/VABP, sepsis, or cUTIs. The primary end point was clinical cure at test of cure after the end of treatment.28 Cefiderocol performed as well as, or better, in most comparisons across the various indications. However, the only unexplained outcome was the higher mortality in the cefiderocol group (34%) compared with the BAT cohort (18%). Plazomicin is a novel synthetic aminoglycoside with activity against a range of gram-negative pathogens. It is active against more than 95% of Enterobacterales isolates but only 40% of Acinetobacter or P. aeruginosa strains isolated from North America and Europe.29 Plazomicin is active against ESBL isolates and 84.5% to 97.6% of CRE strains. Aminoglycoside-modifying enzymes have no effect on plazomicin, and it can still be used in more than half of isolates resistant to 3 aminoglycosides. Moreover, plazomicin is active against 89.5% of colistin-resistant Enterobacterales, unlike the other class members.30 Two clinical trials have been undertaken in patients with cUTIs comparing 15 mg/kg of IV plazomicin once daily with 1 g of IV meropenem and 750 mg of IV levofloxacin once daily for up to 10 days. Wagenlehner et al examined clinical cure and microbiological response as the primary end point at 15 to 19 days after the start of therapy; the response rate was 81.7% and 70.1% for plazomicin and meropenem, respectively.31 Connolly et al used the microbiological eradication rate at 12 days after therapy and showed

IDSE.NET

response rates of 60.8% and 58.6% for plazomicin and levofloxacin, respectively.32 Both studies demonstrated noninferiority of plazomicin, although the incidence of CRE or P. aeruginosa was limited in both studies. Although the FDA applied the normal black box warnings for an aminoglycoside, plazomicin was associated with decreased renal function (3.7%), diarrhea (2.3%), and hypertension (2.3%). Eravacycline is approved for the treatment of cIAIs. In vitro studies have shown the drug to have activity against Escherichia coli, including ESBL variants with MIC 50/90 values being 0.12/0.5 mg/L. Activity with Klebsiella pneumoniae is similar. Activity against P. aeruginosa is limited, but eravacycline exhibits a low MIC to Acinetobacter (0.06/0.5 mg/L). Its activity correlates well with tigecycline but is 2- to 4-fold more potent.33 In 2 trials, 1 mg/kg of IV eravacycline twice daily was compared with 1 g of IV meropenem 3 times daily or 1 g of IV ertapenem twice daily in cIAIs, 80% of whom underwent surgery. Most isolates were gram-negative, more than 70% including CRE and carbapenemase-producing strains. Less than 10% were P. aeruginosa. In patients with ESBL-producing Enterobacterales, clinical cure rates were 87.5% and 84.6% in the eravacycline and meropenem groups, respectively. Similar results were observed in eravacycline and ertapenem for cIAIs, with clinical cure rates of 87.0% and 88.8%, respectively.34,35 The adverse event profile of eravacycline is similar to carbapenems, although with a slightly higher rate of vomiting. The objective of the WHO and IDSA has been achieved in terms of developing new antibiotics, but they are extensions of existing classes. As pathogens continue to mutate, it will be paramount to develop drugs that exploit other functions within the bacterial cell that overcome the existing resistance mechanisms.

References 1. WHO publishes list of bacteria for which antibiotics are urgently needed. February 27, 2017. Accessed May 10, 2021. https:// bit.ly/3lUR9xm-IDSE 2. Infectious Diseases Society of America. Bad bugs, no drugs. July 2004. Accessed May 10, 2021. http://bit.ly/3vXVKoe-IDSE 3. Naas T, Oueslati S, Bonnin RA, et al. Betalactamase database (BLDB)—structure and function. J Enzyme Inhib Med Chem. 2017;32(1):917-919. 4. Farrell DJ, Flamm RK, Sader HS, et al. Antimicrobial activity of ceftolozane-tazobactam tested against Enterobacteriaceae and Pseudomonas aeruginosa with various resistance patterns isolated in U.S. hospitals (20112012). Antimicrob Agents Chemother. 2013;57(12):6305-6310. 5. Melchers MJB, van Mil ACHAM, Mouton JW. In vitro activity of ceftolozane alone and in combination with tazobactam against extended-spectrum-beta-lactamase-harboring Enterobacteriaceae. Antimicrob Agents Chemother. 2015;59(8):4521-4525. 6. Sader HS, Farrell DJ, Castanheira M, et al. Antimicrobial activity of ceftolozane/ tazobactam tested against Pseudomonas aeruginosa and Enterobacteriaceae with various resistance patterns isolated in European hospitals (2011-12). J Antimicrob Chemother. 2014;69(10):2713-2722. 7. Kollef MH, Novacek M, Kivistik U, et al. Ceftolozane-tazobactam versus meropenem for treatment of nosocomial pneumonia (ASPECT-NP): a randomised, controlled, double-blind, phase 3, non-inferiority trial. Lancet Infect Dis. 2019;19(12):1299-1311. 8. Lucasti C, Hershberger E, Miller B, et al. Multicenter, double-blind, randomized, phase II trial to assess the safety and efficacy of ceftolozane-tazobactam plus metronidazole compared with meropenem in adult patients with complicated intra-abdominal infections. Antimicrob Agents Chemother. 2014;58(9):5350-5357. 9. Solomkin J, Hershberger E, Miller B, et al. Ceftolozane/tazobactam plus metronidazole for complicated intraabdominal infections in an era of multidrug resistance: results from a randomized, double-blind, phase 3 trial (ASPECT-cIAI). Clin Infect Dis. 2015;60(10):1462-1471. 10. Wagenlehner FM, Umeh O, Steenbergen J, et al. Ceftolozane-tazobactam compared

with levofloxacin in the treatment of complicated urinary-tract infections, including pyelonephritis: a randomised, doubleblind, phase 3 trial (ASPECT-cUTI). Lancet. 2015;385(9981):1949-1956. 11. Haidar G, Philips NJ, Shields RK, et al. Ceftolozane tazobactam for the treatment of multidrug-resistant Pseudomonas aeruginosa infections: clinical effectiveness and evolution of resistance. Clin Infect Dis. 2017;65(1):110-120. 12. Li H, Estabrook M, Jacoby GA, et al. In vitro susceptibility of characterized betalactamase-producing strains tested with avibactam combinations. Antimicrob Agents Chemother. 2015;59(3):1789-1793. 13. Avycaz. AbbVie; 2021. Accessed May 10, 2021. https://media.allergan.com/actavis/ actavis/media/allergan-pdf-documents/ product-prescribing/Avycaz_Final_PI_ CBE-0_10_2019.pdf 14. Sternbach N, Leibovici Weissman Y, Avni T, et al. Efficacy and safety of ceftazidime/avibactam: a systematic review and meta analysis. J Antimicrob Chemother. 2018;73(8):2021-2029. 15. Castanheira M, Rhomberg PR, Flamm RK, et al. Effect of the betalactamase inhibitor vaborbactam combined with meropenem against serine carbapenemase-producing Enterobacteriaceae. Antimicrob Agents Chemother. 2016;60(9):5454-5458. 16. Kaye KS, Bhowmick T, Metallidis S, et al. Effect of meropenem-vaborbactam vs piperacillin tazobactam on clinical cure or improvement and microbial eradication in complicated urinary tract infection: the TANGO I randomized clinical trial. JAMA. 2018;319(8):788-799. 17. Wunderink RG, Giamarellos-Bourboulis EJ, Rahav G, et al. Effect and safety of meropenem-vaborbactam versus best-available therapy in patients with carbapenem-resistant Enterobacteriaceae infections: the TANGO II randomized clinical trial. Infect Dis Ther. 2018;7(4):439-455. 18. Bassetti M, Giacobbe DR, Patel N, et al. Efficacy and safety of meropenem-vaborbactam versus best available therapy for the treatment of carbapenem-resistant Enterobacteriaceae infections in patients without prior antimicrobial failure: a post hoc analysis. Adv Ther. 2019;36:1771-1777. 19. Livermore DM, Warner M, Mushtaq S, et al. Activity of MK-7655 combined with imipenem against Enterobacteriaceae and Pseudomonas aeruginosa. J Antimicrob Chemother. 2013;68(10):2286-2290.

20. Recarbrio [package insert]. Merck & Co., Inc; 2019. 21. Sims M, Mariyanovski V, McLeroth P, et al. Prospective, randomized, double-blind, phase 2 dose-ranging study comparing efficacy and safety of imipenem/cilastatin plus relebactam with imipenem/cilastatin alone in patients with complicated urinary tract infections. J Antimicrob Chemother. 2017;72(9):2616-2626. 22. Lucasti C, Vasile L, Sandesc D, et al. Phase 2, dose-ranging study of relebactam with imipenem-cilastatin in subjects with complicated intra-abdominal infection. Antimicrob Agents Chemother. 2016;60(10):6234-6243. 23. Motsch J, Murta de Oliveira C, Stus V, et al. RESTORE-IMI 1: a multicenter, randomized, double-blind trial comparing efficacy and safety of imipenem/relebactam vs colistin plus imipenem in patients with imipenem-nonsusceptible bacterial infections. Clin Infect Dis. 2020;70(9):1799-1808. 24. Titov I, Wunderink RG, Roquilly A, et al. A randomized, double-blind, multicenter trial comparing efficacy and safety of imipenem/cilastatin/relebactam versus piperacillin/tazobactam in adults with hospital-acquired or ventilator-associated bacterial pneumonia (RESTORE-IMI 2 Study). Clin Infect Dis. Published online August 12, 2020. doi:10.1093/cid/ciaa803 25. Tillotson GS. Trojan horse antibiotics— a novel way to circumvent gram-negative bacterial resistance? Infect Dis (Auckl). 2016;9:45-52. 26. Golden A, Adam HJ, Baxter M, et al. In vitro activity of cefiderocol, a novel siderophore cephalosporin, against gramnegative bacilli isolated from patients in Canadian intensive care units. Diagn Microbiol Infect. Dis. 2020;97(1):115012. 27. Portsmouth S, van Veenhuyzen D, Echols R, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infections caused by gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2018;18(12):1319-1328. 28. Bassetti M, Echols R, Matsunaga Y, et al. Efficacy and safety of cefiderocol or best available therapy for the treatment of serious infections caused by carbapenem-resistant gram-negative bacteria (CREDIBLE-CR): a randomised, openlabel, multicentre, pathogen-focused,

descriptive, phase 3 trial. Lancet Infect Dis. 2021;21(2):226-240. 29. Landman D, Kelly P, Bäcker M, et al. Antimicrobial activity of a novel aminoglycoside, ACHN-490, against Acinetobacter baumannii and Pseudomonas aeruginosa from New York City. J Antimicrob Chemother. 2011;66(2):332-334. 30. Asempa TE, Kuti JL, Seroogy JD, et al. A simulated application of the Hartford Hospital aminoglycoside dosing nomogram for plazomicin dosing interval selection in patients with serious infections caused by carbapenemresistant Enterobacterales. Clin Ther. 2019;41(8):1453-1462. 31. Wagenlehner FME, Cloutier DJ, Komirenko AS, et al. Once-daily plazomicin for complicated urinary tract infections. N Engl J Med. 2019;380(8):729-740. 32. Connolly LE, Riddle V, Cebrik D, et al. A multicenter, randomized, double-blind, phase 2 study of the efficacy and safety of plazomicin compared with levofloxacin in the treatment of complicated urinary tract infection and acute pyelonephritis. Antimicrob Agents Chemother. 2018;62(4):e01989-17. 33. Livermore DM, Mushtaq S, Warner M. In vitro activity of eravacycline against carbapenem-resistant Enterobacteriaceae and Acinetobacter baumannii. Antimicrob Agents Chemother. 2016;60(6):3840-3844. 34. 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. 35. Solomkin JS, Gardovskis J, Lawrence K, et al. IGNITE4: results of a phase 3, randomized, multicenter, prospective trial of eravacycline vs meropenem in the treatment of complicated intraabdominal infections. Clin Infect Dis. 2019;69(6):921-929. Dr. Tillotson reports consulting for Ferring, Melinta, Shionogi, Spero and Summits.

About the author Glenn Tillotson, PhD, FIDSA, FCCP, is a medical microbiologist and consultant with over 30 years of pharmaceutical experience in large pharmaceutical and biotech companies.

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2021

From

Y U

Vector-Borne Diseases Ticking Upward d BY ETHAN COVEY

ick-borne diseases are increasing as they expand their geographic range, according to the CDC. In 2017, the CDC reported a record number of cases of tick-borne diseases. Lyme disease, anaplasmosis, ehrlichiosis, spotted fever group rickettsioses, babesiosis, tularemia and Powassan virus disease all increased—to 59,349 reported cases, up from 48,610 cases in 2016. Ticks also are expanding their range. For instance, Amblyomma americanum, the lone star tick that transmits the pathogens that cause ehrlichiosis, rickettsiosis, tularemia and Heartland virus disease, continues its migration from the Southeast into the North and Midwest. And the number of counties in the Northeast and Upper Midwest that are at high risk for Lyme disease increased by more than 300% between 1993 and 2012. Ram Raghavan, PhD, MS, a professor

at the University of Missouri College of Veterinary Medicine and School of Health Professions, in Columbia, has been tracking this migration in the Midwest. He and his former graduate student Ali Hroobi, PhD, collected and identified various species of ticks on the outskirts of Pittsburg, Kan., twice a month for three years (PLoS One 2021;16[4]:e0250272). They collected 15,946 ticks; most were A. americanum (79.01%). They found that many ticks are most active in the humid spring and summer seasons, but their comprehensive documentation of what, when and where ticks are present can help public health officials better understand the threat of tick-borne diseases. “We have seen increases recently in both the number and severity of tickborne diseases in the Midwest, particularly in the humid climates of Missouri, Kansas, Oklahoma and Arkansas,” Dr. Raghavan said.

h t several Dr. Raghavan explained that factors have contributed to the rise in tick-borne diseases. Humans are increasingly relocating from densely populated urban areas to more suburban areas closer to forests and grasslands where ticks are often present. Hiking, biking, walking and other outdoor activities are more popular, especially since the COVID-19 pandemic, and particularly during the warmer spring and summer seasons in the Midwest. And global warming has created the perfect conditions for ticks and their pathogens, he said. Finally, a sharp increase in the population of white-tailed deer, the primary animal host for A. americanum, is another contributing factor. “These contributing factors will likely continue to play a role going forward, and now we have meaningful, relevant data to look back on for comparisons to see if certain trends continue in the future.”

Did Plague Push Immune System Evolution?

cientists examining the remains of 36 bubonic plague victims from a 16th-century mass grave found evidence that evolutionary adaptive processes—driven by the organism—may have conferred immunity on later generations of people (Mol Biol Evol 2021 May 18. doi:10.1093/molbev/msab147). “We found that innate immune markers increased in frequency in modern people from the town compared with plague victims,” said Paul Norman, PhD, an associate professor at the University of Colorado School of Medicine, Anschutz Medical Campus, in Aurora. “This suggests these markers might have evolved to resist the plague.” The researchers collected DNA samples from bones of people in a mass grave in Ellwangen, he 16th and Germany, which experienced plague outbreaks in the 17th centuries. They also took DNA samples from 50 current Ellwangen residents and compared their frequency spectra—the distribution of gene variants in a given sample—for a large panel of immunity-related genes. Among the current inhabitants, the team found evidence that a pathogen, likely Yersinia pestis, prompted changes in the

IDSE.NET

allele distribution for two innate pattern-recognition receptors and four human leukocyte antigen molecules, which initiate and direct immune response to infection. “We propose that these frequency changes could have resu resulted from Y. pestis plague exposure during the 16th cent tury,” Dr. Norman said. The evolutionary processes, prompted by Y. pestis, may have been shaping certain human immunityrrelevant genes in Ellwangen, and possibly throughout Europ Europe, for generations and may offer some protection during tthe COVID-19 pandemic. Later simulations showed that natural selection likely d drove these allele frequency changes. “I think this study shows that we can focus on these same families of genes in looking at immunity in modern pandemics,” Dr. Norman explained. “We know these genes were heavily involved in driving resistance to infections.” Although these genetic changes might help provide some protection during this pandemic, Dr. Norman said, people should be vaccinated against COVID-19. “It’s a much safer bet than countn ing on your genes to save you.”

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.

Michael has been compensated by ViiV Healthcare. *Prior to initiating treatment with CABENUVA, prescribe cabotegravir 30-mg and rilpivirine 25-mg oral tablets, both taken once daily with a meal, for approximately 1 month (at least 28 days) to assess tolerability.1 HIV-1=human immunodeficiency virus type 1.

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

INTRODUCING CABENUVA ONCE-MONTHLY TREATMENT HAS ARRIVED First and only, once-monthly, complete treatment regimen for HIV-11 CABENUVA is for virologically suppressed adults living with HIV-1.*†

Proven as effective as continuing a daily oral regimen1,2† Primary endpoint: proportion of patients with HIV-1 RNA ≥50 copies/mL at Week 48 via FDA Snapshot Algorithm. 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]).

Preferred by 9 out of 10 patients in clinical trials2-4 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.

Adverse Reactions1 The most common adverse reactions (Grades 1–4) observed in ≥2% of subjects receiving CABENUVA were injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. *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-1.1-4 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.1,3 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.1,4 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.3,4 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.2-4

†

3TC=lamivudine; ABC=abacavir; ARV=antiretroviral; CI=confidence interval; DTG=dolutegravir; FDA=Food and Drug Administration; HBV=hepatitis B virus; 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. Overton ET, Orkin C, Swindells S, et al. Monthly long-acting cabotegravir and rilpivirine is noninferior to oral ART as maintenance therapy for H I V -1 infection: week 48 pooled analysis from the phase 3 ATLAS and FLAIR studies. Poster presented at: 10th IAS Conference on HIV Science: July 21-24, 2019; Mexico City, Mexico. Poster MOPEB257. 3. 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. 4. 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. CBRADVT190003 January 2021 Produced in USA.

IDSE Review

Women and HIV: Gaps in Care BY JACOB BOUDREAUX, MD,

AND

JULIA GARCIA-DIAZ, MD, MSC, FACP, FIDSA, CPI

he first cases of the US HIV epidemic were recognized in 1981, primarily among men who have sex with men (MSM). By 1988, the incidence of men living with HIV was nearly 15 times the rate of women.1 At the time, HIV affected the MSM community, as well as racial and ethnic minorities, at disproportionally higher rates. In the decades since then, research into HIV treatment protocols, HIV-related disease, comorbidities, and outcomes has been heavily focused on these groups. However, the incidence of HIV among these subgroups has changed significantly in the last 40 years in relation to the incidence of women living with HIV. By 2010, a shift was seen among women who comprised 21% of total HIV cases in the United States, while the incidence rate for men dropped to 3 times the rate seen in women.1

At the end of 2016, women accounted for 23.7% of all people living with HIV in the United States, and as of 2020, women represent one-fourth of all HIV cases nationally.2 In 2017, women represented a larger percentage of people living with HIV globally, accounting for 52% of total cases, or 18.2 million women. This trend has remained stable, as women continue to represent nearly half of all cases globally each year.3 Despite being equally represented in total global cases of HIV, women continue to be underrepresented in HIV research. This gap in representation is especially shocking as HIV and HIVrelated disease are the leading causes of death among women of reproductive age (ie, 15-49 years).4 In 2019, the Department of Health and Human Services announced a new goal to reduce the incidence of HIV infections by 90% within the decade.5 To achieve this goal, the importance of addressing the health care needs of women living with HIV—both diagnosed and undiagnosed—needs a sharper focus. This review serves as an update to information published in 2019 in Infectious Disease Special

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2021

IDSE Review

Edition and examines the needs of 3 subgroups of women living with HIV, presents updated treatment regimens for pregnant women living with HIV, and discusses the areas of increased need for women in HIV research (https://www.idse.net/Review-Articles/ Article/06-19/The-Forgotten-Patient/55122). The health care needs of women living with HIV in the United States vary due to several interwoven factors—including age, race, sex, and region—that pose challenges to achieving early diagnosis, treatment, and management of comorbid conditions. Three important subgroups include women who are of reproductive age, older women, and transgender women.

Women of Reproductive Age With HIV According to a 2018 study, approximately 40% of women of reproductive age with HIV may choose to have children.6 Special attention, including comprehensive reproductive care inclusive of planning considerations, antiretroviral therapy (ART), and infant feeding practices, should be offered to this group; an estimated 5,000 American women living with HIV give birth annually.7 In the United States, the annual incidence of vertical HIV transmission has declined nearly 95% in the last 30 years with increased uptake of ART.8 This includes daily ART throughout pregnancy and neonatal ART for 4 to 6 weeks after delivery; when successfully combined, these interventions have reduced the rate of vertical HIV transmission to 1%.8 While protecting a developing fetus may be a strong incentive for encouraging and maintaining ART adherence throughout the gestational period, patient concerns of potential effects of ART contributing to adverse birth outcomes remain an important area of research. A 2019 study that explored adverse pregnancy outcomes among women who conceive on ART stated that the “relatively low risks of adverse pregnancy outcomes must be weighed against the tremendous benefit of lifelong, uninterrupted ART.”9 However, higher quality data on a large population of pregnant women with HIV into the effects of newer ART regimens in particular and potential effects are needed. In the United States, women who are initiating ART while pregnant or trying to become pregnant are recommended dolutegravir (DTG), raltegravir (RAL), atazanavir-ritonavir, and darunavir (DRV)-ritonavir as the “preferred” treatment regimens.10 In 2018, preliminary data from the Tsepamo study in Botswana indicated a slightly significant increased risk in fetal neural tube defects (NTDs) among pregnant women with HIV on DTG, which was 0.19% among women taking DTG versus 0.07% for efavirenz (EFV).10 In response to the Botswanan primary data, Sibiude et al evaluated the risk for birth defects and adverse pregnancy outcomes

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to exposure of integrase strand transfer inhibitors (INSTIs) around conception.11 Of the 808 women who were on INSTIs for ART during conception (RAL 703, DTG 57, and elvitegravir 48), 6.7% of those on RAL at conception experienced birth defects, compared with 2.9% who initiated RAL later during gestation as first-line treatment and 2.5% as second-line treatment; no NTDs were observed in the study.11 Other prenatal outcomes were not statistically significant between groups exposed to RAL or DRV, such as incidence of stillbirth (RAL 1.6%, or 2 births; DRV 1.2%, or 2 births) or preterm birth (RAL 12.8%, or 16 births; DRV 11.2%, or 14 births).11 In addition, there were no differences in weight, length, or head circumference for those with INSTI exposure.11 In response to the Botswanan data, a randomized cohort study was conducted in Brazil to evaluate whether DTG exposure increased the risk for NTDs, stillbirths, or miscarriages in pregnant women with HIV. Of 1,427 women, 382 were exposed to DTG within 8 weeks of their estimated date of conception. One hundred eighty-three women (48%) of DTG-exposed and 382 (44%) of EFV-exposed women received folic acid supplementation during pregnancy. Results suggest that neither DTG nor EFV was associated with NTDs, stillbirths, or miscarriages.12 These data are reassuring that outcomes in women on DTG-based regimens are safe, but more data are needed. At CROI 2021, 2 abstracts were presented regarding the safety of DTG in pregnancy. First, Chinula et al presented research on 643 pregnant women with HIV-1 from 9 countries randomized 1:1:1 DTG+FTC/ TAF (tenofovir alafenamide with emtricitabine; n=217), DTG+FTC/TDF (tenofovir alafenamide; n=215), or EFV/FTC/TDF (n=211) at 14 to 28 weeks’ gestational age; 607 women completed the study.13 Among the 3 arms of the study at 50 weeks’ postpartum, there were no statistical differences observed in maternal or infant adverse events, infant mortality, or infant HIV infection, although fewer women in the DTG+FTC/TAF arm (24.1%) had an adverse pregnancy outcome than in the DTG+FTC/TDF (32.9%; P=0.043) or EFV/FTC/TDF (32.7%; P=0.047) arm.13 Second, Malaba et al presented results of 268 mothers randomized to receive EFV (n=133) or DTG (n=135); viral loads were measured at 6, 12, 24, 48, and 72 weeks’ postpartum.14 Viral loads less than 50 copies/mL for efficacy and occurrence of maternal or infant drug adverse events were the primary study end points. Women randomized to DTG achieved viral suppression more quickly and maintained suppression longer than those receiving EFV. Women who received DTG achieved the viral load goal with a median time of 4.14 weeks, compared with a median time of 12.14 weeks for those receiving EFV. Regarding

Transgender women who stopped ART due to concerns about interactions with hormone therapy.

adverse events, DTG (2.2%) was better tolerated compared with EFV (3.6%). Only 3% of adverse events were related to the study drug, and no infant drugrelated events were reported.14 Breastfeeding is also an area of special concern among pregnant women with HIV. US guidelines recommend against breastfeeding during the perinatal period, yet a 2019 survey of health care workers stated that 29% have cared for a patient with HIV who chose to breastfeed and that most patients’ primary concerns for choosing to breastfeed over using formula was because of social stigma.15 This is consistent with a 2021 survey in the United Kingdom that indicated one-third of surveyed pregnant women with HIV prefer to breastfeed their infants.16 While ART throughout the gestational period significantly reduces the risk for vertical transmission, it does not eliminate the risk for transmission through breastfeeding postnatally. Further research to guide clinical and virologic monitoring is warranted for women of reproductive age in both high- and low-income countries when mothers living with HIV decide that breastfeeding is right for their children.17

Older Women and HIV Due to the wider use of ART, people with HIV are living longer, healthier lives; as of 2019, 51% of all people diagnosed with HIV in the United States were 50 years of age or older, and 1 in 6 new cases of HIV was diagnosed in those older than 50 years of age.18 While adult women have many of the same risk factors associated with younger women, there are unique risks to this subgroup: less openness to discuss sexual health or drug use, lack of knowledge of sexual risk and HIV prevention, and perceived stigma associated with HIV and aging. Due to these factors, older women are more likely to be diagnosed later than their younger cohorts and begin treatment later. In 2015, people older than 55 were most likely to have the longest delay in HIV diagnosis—4.5 years, according to the CDC. 18 For these women, increased attention to their health needs and the effects of HIV on aging is appropriate.

Transgender Women and HIV Transgender women in the United States represent an estimated 1.3% of total patients receiving care for HIV, yet represent only 0.28% of the US population.1,22 Prevalence of HIV among trans women, as of 2017, is estimated to be at 14%, which is markedly higher than their cis women counterparts, whose prevalence is less than 1%.2 Data for trans women have been historically lacking, as the CDC used to classify trans women under MSM for surveillance data collection. For trans women who already experience discrimination and physical, emotional, and sexual violence at higher rates compared with cis individuals, increasing access to comprehensive HIV treatment and consistent follow-up poses additional challenges. This is complicated by a lack of research concerning ART and hormone therapy (HT), which can be lifesaving for trans women.1 In 2017, Braun et al observed that among trans women with HIV, only 49% discussed ART–HT drug–drug interaction with their health care provider, and 40% reported not taking ART due to

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2021

IDSE Review

40%

A 2018 cross-sectional study of the symptom burden for older women living with HIV reported that postmenopausal women had higher symptom burden scores for muscle aches/pains, fatigue, and insomnia.19 A 2019 study by Frazier et al compared cardiovascular risk comorbidities between men and women with HIV in those 50 to 64 and older than 65 years of age.20 Their results indicated that women with HIV between 50 and 64 years of age were more likely to be obese, hypertensive, and have higher total cholesterol levels; women with HIV older than 65 were also more likely than men to have diabetes mellitus and higher total cholesterol levels.20 Also presented at CROI 2021, “Inflammation Could Help Predict HIV Women Cardiovascular Risks” evaluated sex-modified inflammatory predictors of cardiovascular disease (CVD) and venous thromboembolism risks in people with HIV.21 Consisting of a randomized sample of 979 patients (82% male, 18% female) from the Centers for AIDS Research Network of Integrated Clinical Systems with plasma samples after more than 1 year of viral suppression on ART, results indicated that inflammatory markers were more strongly correlated with CVD and associated events in women than men with C-reactive protein, lipopolysaccharide-binding protein, sCD14, suPAR, ICAM-1, cytomegalovirus immunoglobulin G, and soluble tumor necrosis factor receptor 2 markers, pointing toward increased risk prediction in women. The significant effect that these inflammatory markers have on CVD risk in women with HIV underscores the importance of including more women in HIV interventional research.21 Further research and systematic review into the physiologic and psychological health needs of older women with HIV are warranted to address their health care needs.

IDSE Review

concerns of drug–drug interactions.23 Enrolling trans women into larger research studies designed to evaluate potential interactions between ART and HT will help guide clinicians in counseling their patients on the safety of ART while on HT. Few trials exist. In 2017, a study reviewed Medicare fee-for-service claims data to evaluate demographic characteristics and chronic disease burden for the transgender population, which demonstrated that trans individuals experienced multiple chronic conditions at higher rates than cis individuals.24 Coupled with the disproportionality, increased prevalence of HIV among trans women, and societal factors that interfere with their care, trans women represent a uniquely vulnerable population with challenges to meet their basic health care needs. Future trials need to include trans women in their enrollments in sufficient numbers to guide clinical care for this important subgroup.

Conclusion Management protocols for treating women with HIV continue to adapt to new research, but more studies are needed that enroll women in proportion to their representation of total people living with HIV. New updates provide insight into current and future research and highlight areas of increased need. Women of reproductive age, older women, and transgender women face challenging burdens that deserve consideration and increased recruitment and enrollment in future HIV management and vaccination trials.

References 1.

Breskin A, Adimora AA, Westreich D. Women and HIV in the United States. PLoS One. 2017;12(2):e0172367.

2. CDC. HIV Surveillance Reports. Published February 3, 2021. Accessed April 7, 2021. https://www.cdc.gov/hiv/library/reports/ hiv-surveillance.html 3. UNAIDS. Global HIV & AIDS statistics—2020 fact sheet. Published December 1, 2020. Accessed April 7, 2021. https://www. unaids.org/en/resources/fact-sheet 4. Curno MJ, Rossi S, Hodges-Mameletzis I, et al. A systematic review of the inclusion (or exclusion) of women in HIV research: from clinical studies of antiretrovirals and vaccines to cure strategies. J Acquir Immune Defic Syndr. 2016;71(2):181-188. 5. Fauci AS, Redfield RR, Sigounas G, et al. Ending the HIV epidemic: a plan for the United States. JAMA. 2019;321(9):844-845. 6. Cohn SE, Haddad LB, Sheth AN, et al. Parenting desires among individuals living with human immunodeficiency virus in the United States. Open Forum Infect Dis. 2018;5(10):ofy232. 7. Nesheim SR, FitzHarris LF, Lampe MA, et al. Reconsidering the number of women with HIV infection who give birth annually in the United States. Public Health Rep. 2018;133(6):637-643. 8. CDC. Pregnant women, infants, and children. Published August 26, 2020. Accessed April 7, 2021. https://www.cdc.gov/hiv/ group/gender/pregnantwomen/index.html 9. Hoffman RM, Brummel SS, Britto P, et al. Adverse pregnancy outcomes among women who conceive on antiretroviral therapy. Clin Infect Dis. 2019;68(2):273-279. 10. Clinical Info.HIV.gov. Appendix C: antiretroviral counseling guide for health care providers. Updated February 10, 2021. Accessed

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April 7, 2021. https://clinicalinfo.hiv.gov/en/guidelines/perinatal/ appendix-d-dolutegravir-counseling-guide-health-care-providers 11. Sibiude J, Le Chenadec J, Mandelbrot L, et al. Risk of birth defects and perinatal outcomes in HIV-infected women exposed to integrase strand inhibitors during pregnancy. AIDS. 2021;35(2):219-226. 12. Pereira GF, Kim A, Jalil EM, et al. Dolutegravir and pregnancy outcomes in women on antiretroviral therapy in Brazil: a retrospective national cohort study. Lancet HIV. 2021;8(1):E33-E41. 13. Chinula L, Brummel S, Ziemba L, et al. IMPAACT 2010 Update: safety and efficacy of DTG vs EFV, TDF vs TAF in pregnancy and postpartum period [CROI abstract 177]. Top Antivir Med. 2021;28(1, theme issue):483. 14. Malaba T, Nakatudde I, Kintu K, et al. DolPHIN2 final results: dolutegravir vs efavirenz in late pregnancy to 72 wks postpartum [CROI abstract 175]. Top Antivir Med. 2021;28(1, theme issue):483. 15. Tuthill EL, Tomori C, Van Natta M, et al. “In the United States, we say, ‘no breastfeeding,’ but that is no longer realistic”: provider perspectives towards infant feeding among women living with HIV in the United States. J Int AIDS Soc. 2019;22(1):e25224. 16. Nyatsanza F, Gubbin J, Gubbin T, et al. Over a third of childbearing women with HIV would like to breastfeed: a UK survey of women living with HIV. Int J STD AIDS. 2021 Feb 25. doi:10.1177/0956462421999951 17. Moseholm E, Weis N. Women living with HIV in high-income settings and breastfeeding. J Intern Med. 2020;287(1):19-31. 18. CDC. HIV among people aged 50 and over. Published September 14, 2020. Accessed April 7, 2021. https://www.cdc.gov/hiv/group/ age/olderamericans/index.html 19. Schnall R, Jia H, Olender S, et al. In people living with HIV (PLWH), menopause (natural or surgical) contributes to the greater symptom burden in women: results from an online US survey. Menopause. 2018;25(7):744-752. 20. Frazier EL, Sutton MY, Tie Y, et al. Differences by sex in cardiovascular comorbid conditions among older adults (aged 50-64 or ≥65 years) receiving care for human immunodeficiency cirus. Clin Infect Dis. 2019;69(12):2091-2100. 21. Schnittman S, Beck-Enggeser, Shigenaga J, et al. Sex modifies the association between inflammation and vascular events in treated HIV [CROI abstract 177]. Top Antivir Med. 2021;28(1, theme issue):483. 22. Mizuno Y, Frazier EL, Huang P, et al. Characteristics of transgender women living with HIV receiving medical care in the United States. LGBT Health. 2015;2(3):228-234. 23. Braun HM, Candelario J, Hanlon CL, et al. Transgender women living with HIV frequently take antiretroviral therapy and/or feminizing hormone therapy differently than prescribed due to drug-drug interaction concerns. LGBT Health. 2017;4(5):371-375. 24. Dragon CN, Guerino P, Ewald E, et al. Transgender Medicare beneficiaries and chronic conditions: exploring fee-for-service claims data. LGBT Health. 2017;4(6):404-411.

The authors reported no relevant financial disclosures.

About the authors Jacob Boudreaux, MD, is a 2020 graduate of the University of Queensland/Ochsner Clinical School, in Brisbane, Australia. He is a first-year resident at Ochsner Medical Center, New Orleans, Louisiana. Julia Garcia-Diaz, MD, MSc, FACP, FIDSA, CPI, is the director of clinical research, and an associate professor at the University of Queensland, Ochsner Clinical School, in Brisbane, Australia; and a clinical assistant professor at Tulane University School of Medicine, Ochsner Medical Center, in New Orleans, Louisiana.

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Rapid Diagnostic Testing and Biomarkers Implementation: The Starring Role of Antimicrobial Stewardship BY KAREN FONG, PHARMD, BCIDP

n the clinical microbiology laboratory, there have been truly exciting advances in microbiological diagnoses using rapid diagnostic tests (RDTs). The management of bacterial, viral, and fungal diseases has been fundamentally transformed by providing early clinical decision making through technological growth with the prospect of significantly affecting clinical outcomes, antimicrobial use, and cost savings.1-3 Although there are still shortcomings with antimicrobial susceptibility testing for bacterial and fungal cultures, RDTs provide valuable information to the clinical presentation, facilitating selection of empiric antimicrobial coverage by the prediction of susceptibility patterns based on local antibiograms.

In the early stages of sepsis, every hour of delay in commencing effective antimicrobial therapy increases the risk for death.4 The distinction between viral and bacterial infection, determination of specific bacterial etiology, and antimicrobial susceptibility testing must be available to quickly achieve maximum clinical benefit. In a proposed series by Inglis and Ekelund, 3 linked decision-making milestones with specific goals may resolve a trade-off between diagnostic confidence and therapeutic efficacy (Figure).5 The integration of RDTs into the initial investigation for sepsis and clinical laboratory workflow may expedite optimal disease management. RDT results must be actionable and promptly addressed with appropriate clinical interpretation and corresponding antimicrobial therapy adjustment. The role of antimicrobial stewardship programs (ASPs) may be exploited to correctly interpret and rapidly communicate results, directing clinicians to appropriate antimicrobial therapy.6 ASPs have continuously demonstrated their value through the improvement of clinical outcomes and reduction of adverse events by optimizing antimicrobial use.7,8 Inpatient ASPs have concomitantly improved the rates of infection

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cures and combat challenges with Clostridioides difficile infections, antimicrobial resistance, adverse effects, length of stay (LOS), and costs.8-10 RDTs combined with ASP intervention, particularly bloodstream infections (BSIs), have consistently provided meaningful results on antimicrobial optimization and patient outcomes.1,2 Rapid testing for broad panels of respiratory viruses also has been deemed by ASP guidelines as an important intervention to reduce the inappropriate use of antibiotics.11 Bauer et al created a checklist to highlight the role of ASPs as an active messenger and educator in the implementation and incorporation of RDTs (Table).12 Among the array of newer diagnostic approaches, tests, and platforms, collaboration between clinical microbiologists and ASPs is essential to determine which tests are appropriate and which cost justification and implementation strategies are effective at an institution level.12,13 The impact of RDTs is contingent on clinical context, patient flow, and access and timing. Therefore, emphasis should be placed on deriving their maximal benefit through the implementation of efficient evidence-based ASP interventions.2,14,15 In this review, we discuss novel RDTs including respiratory, biomarkers and sepsis diagnostics, advances in blood culture testing, and prospects of outpatient point of care as well as their performance with current diagnostic stewardship practices.

Respiratory Procalcitonin and Respiratory Viral Panels In the United States, pneumonia has been a major contributor of morbidity and mortality, causing an

estimated 63,000 deaths and 1.2 million hospitalizations annually.16,17 The American Thoracic Society/ Infectious Diseases Society of America (ATS/IDSA) recommendations for empiric antimicrobial therapy in community-acquired pneumonia (CAP) are based on selecting agents targeted against the major treatable respiratory bacterial pathogens.18 Unfortunately, overuse of antibiotics is common in lower respiratory tract infections (LRTIs), as there is difficulty in distinguishing between bacterial and viral etiologies due to similar manifestations.19 Antibiotic therapy may be safely withheld in patients with isolated viral pneumonia if these infections can be easily identified from those with concomitant bacterial etiology.20 Procalcitonin (PCT) is a component of the innate pro-inflammatory response that is released in response to bacterial challenge, discriminating between viral and bacterial infections.21 The ATS/IDSA CAP guidelines for adults, updated in 2019, include recommendations for the use of PCT. Empiric antibiotic therapy is recommended for adults with clinically suspected and radiographically confirmed CAP, regardless of initial serum PCT level.18 This recommendation acknowledges the findings of an updated Cochrane review assessing the safety and efficacy of using PCT for initiating or discontinuing antibiotics among a variety of patients with acute respiratory infections (ARIs) from different clinical settings. Thirty-two randomized trials of adults with ARIs who received an antibiotic based on either a PCT-guided antibiotic stewardship algorithm or usual care were included for analysis. Most of the PCT algorithm used levels less than 0.1 mg/L to indicate a high likelihood of viral infection, whereas levels

Initial Clinical Assessment Using a clinical score (eg, qSOFA)

Goal time <10 min

➧ Initial Sepsis Investigation Baseline laboratory tests

Empiric antimicrobial therapy

Basic resuscitation

Goal time <1 h

➧ Infectious Disease Management Definitive antimicrobial susceptibility testing

Corresponding antimicrobial therapy adjustment

Goal time <8 h

Figure. Three linked decision-making milestones for sepsis in relation to infectious disease management. qSOFA, quick Sequential Organ Failure Assessment

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resulted in similar DOT (5.4 vs 5.5 days; P=0.8, respectively) without differences observed in patient outcomes.25 In a single-center, retrospective, observational pre-post study of inpatients with CAP, a standardized order set with a single dose of IV ceftriaxone followed by an automatic transition to oral cefuroxime for a total antibiotic duration of 5 days coupled with active antimicrobial stewardship and provider feedback led to significantly shorter length of IV and total antibiotic therapy and 20% cost reduction with similar clinical outcomes.26 Although PCT was ordered once on admission as part of the pathway, this was unlikely to be the driver of the robust improvements in antibiotic use and decreased costs. The respiratory viral polymerase chain reaction (PCR) assays, the FilmArray Respiratory Panel (BioFire Diagnostics) and eSensor Respiratory Viral Panel (GenMark Diagnostics), may be useful in reducing the use of inappropriate antibiotics. Antimicrobial stewardship guidelines advocate rapid testing for broad panels of respiratory viruses.11 However, use of respiratory viral testing in the inpatient and outpatient settings remains low—primarily for influenza and rhinovirus testing. Antibiotic prescribing practices based on test results were also inconsistent.27,28 Combination with PCT may be more likely to exclude bacterial coinfection with confidence in a meaningful period.14 Moradi et al explored the use of respiratory viral panel (RVP) combined with PCT and an automated ASP provider alert in a multicenter quasi-experimental study. If 3 criteria were met—PCT less than 0.25 ng/mL, virus detected on RVP, and active use of systemic antibiotics—the automated alert would prompt de-escalation.29 Antibiotic days of therapy were significantly reduced in the intervention group by a mean of 2.2 days (5.8 vs 8.0 days; P<0.001).29 In addition, antibiotics were discontinued within 24 hours of initiation for significantly more patients (37.8% vs 18.6%; P<0.001), and fewer patients were discharged on antibiotics (20.0% vs 47.8%; P<0.001).29 In the absence of ASP intervention, previous evidence observed low rates of antibiotic discontinuation in patients with negative PCT and positive RVP.30 This real-world implementation strategy leveraged indirect ASP intervention through an automated alert, which may be especially worthwhile for minimal-resource settings.29,31 Similarly, Lee et al examined the clinical effect of combining the RVP with PCT in older adults with severe ARIs through a prospective multicenter observation study.32 Outcomes were compared between the intervention group and a propensity score–matched

Respiratory viral and PCR assays may be useful in reducing antibiotic prescribing.

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greater than 0.25 mg/L indicate a high likelihood of bacterial pneumonia. Mortality was significantly lower (8.6% vs 10.0%; adjusted odds ratio [aOR], 0.83; 95% CI, 0.70-0.99; P=0.037) with PCT guidance compared with usual care, respectively.22 Procalcitonin guidance was associated with a 2.4-day reduction in antibiotic exposure (5.7 vs 8.1 days; 95% CI, –2.71 to –2.15; P<0.001) and lower risk for antibiotic-related adverse effects (16.3% vs 22.1%; aOR, 0.68; 95% CI, 0.57-0.82; P<0.001).22 Results were similar among different types of ARIs and clinical settings, supporting syndromespecific PCT use with antimicrobial stewardship. However, Self et al evaluated the association between serum PCT concentration with pneumonia etiology in a multicenter prospective surveillance study of adults hospitalized with CAP.23 The authors were unable to identify a PCT threshold that allowed perfect discrimination between viral and bacterial detection—a challenging goal. While results established that there was a lower frequency of bacterial pathogens in patients with PCT below both the 0.1-ng/mL (6%) and 0.25-ng/mL (8%) thresholds, this also indicates that clinicians cannot solely rely on PCT to guide antibiotic treatment decisions.23 This was further supported by a meta-analysis of 12 studies including 2,408 CAP patients, demonstrating that PCT sensitivity and specificity are too low and variable at 0.55 (95% CI, 0.37-0.71; I2=95.5%) and 0.76 (95% CI, 0.62-0.86; I2=94.1%), respectively. Thus, PCT is unlikely to provide reliable evidence that will enable clinicians to confidently address whether the infection is bacterial or viral.24 Furthermore, Huang et al did not demonstrate a reduction in mean antibiotic days in patients with LRTIs with PCT use compared with usual care in a multicenter randomized controlled trial. Outcomes may have been limited by subpar adherence to the PCT antibiotic prescribing guideline and lack of real-time prospective audit and feedback.19 Therefore, implementation may have failed to demonstrate benefit in the absence of ASP intervention. Serial PCT measurement also has been recognized by the ATS/IDSA as likely useful to primarily reduce duration of therapy (DOT) where the average LOS for patients with CAP exceeds the expected duration of 5 to 7 days.18 However, PCT may have little role in decreasing antibiotic duration for CAP if prospective audit and feedback is designed to target a specific DOT. In a retrospective cohort at 2 community teaching hospitals, PCT with routine audit and feedback compared with a 5-day course recommendation for uncomplicated CAP as targeted audit and feedback

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historical cohort. Patients in the intervention group had significantly more antibiotics de-escalated (21.9% vs 13.2%; P=0.007), a shorter duration of IV antibiotics used (median, 10.0 days; interquartile range [IQR], 5.3-14.6 days vs median, 14.5 days; IQR, 7.2-22.0 days; P<0.001), and shorter LOS (median, 14.0; IQR, 5.020.5 days vs median, 16.1 days; IQR, 6.0-24.5 days; P=0.030).32 The authors did not incorporate formal ASP in their study but had a study nurse promote stewardship by communicating the test results and reminding the physicians of the antibiotic treatment recommendations based on different testing results.32 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 utilization with ASP intervention, but more robust head-to-head comparisons are needed to confirm such speculations.19,22,29,32-34

LRTI Panels Multiple syndromic molecular testing panels for LRTIs, including the BioFire FilmArray Pneumonia Panel and Curetis Unyvero Lower Respiratory Tract (LRT) Panel, offer increased sensitivity over clinical cultures and provide the presence of resistance markers within as little as 1 to 5 hours from specimen collection and testing. The BioFire panel offers detection of 8 viruses, 8 resistance genes, 3 atypical bacteria using qualitative targets, and 15 bacterial targets with semiquantitative analysis that can assist in evaluating colonization versus infection. The Curetis panel includes detection of 29 bacterial pathogens and 19 resistance genes. Both panels can be used with multiple specimen types (sputum, endotracheal aspirates, and bronchoalveolar lavage fluid). Although semiquantitative analysis may improve the clinical specificity, neither molecular testing panels nor culture separate airway colonizers from invasive pathogens. The possibility of a downstream effect of paradoxically increasing antimicrobial use should be a notable concern. These panels may be most useful 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.14 The BioFire FilmArray Pneumonia Panel demonstrates a positive percent agreement (PPA) and negative percent agreement (NPA) of 98.1% and 96.2%, respectively, for the identification of bacterial targets on bronchoalveolar lavage specimens compared with culture.35 Similarly, a high overall agreement of 99.2% (95% CI, 98.4%-99.6%) for viral detection is observed between the FilmArray panel and culture.36 The excellent sensitivity of the pneumonia panel may be useful to rule out bacterial coinfections and avoid inappropriate prescribing of antibiotics, but positive

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results should be interpreted with caution. In a multinational study of 52 laboratories, the largest to date, the panel identified significantly more positive specimens (76.1%) than standard-of-care (SOC) testing (56.03%; P≤0.0001) and more potential pathogens than SOC (P≤0.0001) independent of specimen type with the largest discrepancies for fastidious pathogens.37 Lower SOC bacteria detection may be explained by local reporting guidelines and testing of specimens from patients on antibiotics.37 Yoo et al accurately detected resistance genes using the pneumonia panel, showing concordant results for the resistant organisms identified by culture; however, the genetic marker of antimicrobial resistance, particularly the CTX-M and carbapenemase genes, could not be definitively linked to the microorganisms detected.38 Thus, culture testing is essential to confirm susceptibility or resistance. In summary, the panel carries interpretation challenges including understanding the increased detection rates, colonization and infection differentiation, and the presence of resistance markers without linkage to a specific pathogen.37 A recent study prospectively examined sputum specimens in 70 patients with pneumonia, and the potential for antibiotic optimization was observed in 56 of 70 patients.39 Nine bacteria in 9 patients were not covered by empiric therapy, and 70 antibiotics in 49 patients could have been discontinued.39 Likewise, a retrospective multicenter study observed antimicrobial de-escalation in 63 of 159

Pre-implementation • Identify most useful RDT based on hospital pathogen prevalence • Identify hospital cost of infection based on ICD-10 code mortality data, LOS, and 30-day readmission • Time to effective therapy • Time to infectious diseases specialist consult

Implementation • Microbiologist-validated RDT instrument • Determine whether test is done in real time 24/7 or batch • Establish communication of RDT results from microbiology to physician and ASP pharmacist • Education of medical staff by ASP pharmacist and physician • Document interventions and acceptance rate by ASP

Post-implementation • Time to effective therapy • Time to antimicrobial discontinuation or de-escalation • Time to infectious diseases specialist consult • LOS • 30-day readmission • Mortality ASP, antimicrobial stewardship program; ICD-10, International Classification of Diseases, 10th Revision; LOS, length of stay; RDT, rapid diagnostic test

Clinical Utility of Surveillance Screening MRSA Nasal PCR MRSA nasal screens, such as the Cepheid GeneXpert SA Nasal, have evolved beyond use for infection prevention and control practice to have clinical utility for routine use in de-escalations of MRSA therapy, predominantly in patients with suspected or confirmed pneumonia. Robust evidence has reflected more than 95% negative predictive value (NPV) for the use of the test in ruling out MRSA pneumonia.45 Therefore, the ATS/ IDSA CAP guidelines endorsed the routine use of MRSA nasal PCR screening for the de-escalation of MRSA coverage.18 ASP implementation of this approach has been associated with a median decrease of 2.1 days of vancomycin (P<0.01).46 Other implementation results of nasal screening in suspected or confirmed pneumonia among ICU patients have been associated with $108 per patient in cost avoidance based on the cost of surveillance testing, vancomycin, and vancomycin therapeutic drug monitoring levels.47 Reviews of implementation considerations suggest fidelity of the nasal testing for 7 days after results and lack of impact of vancomycin exposure in affecting results of testing.48,49 Systematic reviews and meta-analyses also have supported the use of the screen for NPV beyond pneumonia, such as in

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Table. Antimicrobial Stewardship Program Checklist for Rapid Diagnostic Tests

(40%) and escalation in 35 (22%) of hospitalized pneumonia patients based on FilmArray panel results.40 This reinforces the panel’s potential to reduce unnecessary antimicrobial exposure and increase the appropriateness of empiric antibiotic therapy. The Curetis Unyvero LRT Panel also has reported robust diagnostic accuracy. In an evaluation by Collins et al, the PPA and NPA for the bacterial targets was 96.5% and 99.6%, respectively.41 Also, Klein et al found a high overall PPA and NPA with culture, but 21.7% of specimens had additional potential pathogens identified by the panel.42 The positive predictive value for antibiotic resistance markers compared with antibiotic susceptibility testing ranged from 80% to 100%.42 For the resistance targets, interpretation challenges were observed, as not all genes could be attributed to an organism, highlighting that current culture methods with antimicrobial susceptibility testing must be maintained while pursuing consistency in technological advances.41 Moreover, the Curetis panel had the potential to earlier initiation of effective antibiotic therapy in 20 of 95 patients (21%) and de-escalation in 37 patients (39%) with ventilator-associated pneumonia in a prospective study.43 Pickens et al predicted antibiotic de-escalation from unnecessary methicillinresistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa coverage in 65.9% (405/615) of patients.44 Challenges with interpretation of newer RDTs, especially with resistance genes, are of concern but may be potentially mitigated by ASP intervention, requiring further exploration.

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skin and soft tissue infections.50 A national study from the Veterans Affairs system has supported this concept in the largest cohort to date including clinical cultures (N=561,325).51 These data showed a high overall NPV for all infection types (96.5%) and among specific infections including BSIs (96.5%), intraabdominal infections (98.6%), respiratory infections (96.1%), wound cultures (93.1%), and urinary tract infections (99.2%). In contrast, while the surveillance of gramnegative resistance using rectal swab testing (eg, Streck ARM-D resistance detection kits) among some settings may be standard, the clinical utility of these tests in directing therapy has yet to show significant promise.52,53

Biomarkers and Sepsis Diagnostics Candidemia is one of the most common hospitalacquired BSIs in the United States, associated with up to 47% attributable mortality and even higher among patients who develop septic shock. Prompt initiation of appropriate antifungal therapy and source control has been associated with as much as a 50% reduction in mortality. However, this is often delayed due to blood culture insensitivity, the prolonged turnaround time (median time to positivity of 2-3 days, ranging from 1 to ≥7 days) needed to yield growth, and the possibility of negative growth with invasive abdominal candidiasis.54 These limitations propagate overuse of empiric antifungal therapy for suspected invasive candidiasis, which is a practice of unproven clinical value.55 Nonculture diagnostic tests such as the Fungitell beta-D-glucan (BDG) detection assay (Associates of Cape Cod) and the T2Candida Panel (T2 Biosystems) have a much shorter turnaround time (3-5 hours) and entered clinical practice as adjunctive RDT to cultures.54-57 BDG is a component of the cell wall in Candida species, Aspergillus species, and Pneumocystis jiroveci. Therefore, true-positive results have limited specificity for candidemia due to cross-reactivity with other organisms, and there is concern for false positivity in some circumstances.54 A few studies have explored the use of BDG in suspected candidemia and shown de-escalation of antifungal therapy through avoidance and reduction, but they did not incorporate active ASP intervention.58,59 Rautemaa-Richardson et al developed a local ASPdriven guideline for the diagnosis and management of suspected or proven invasive candidiasis in nonneutropenic adult patients.60 BDG was used as a ruleout test to guide the discontinuation of therapy in the absence of other microbiological evidence at 48 to 96 hours. The authors retrospectively evaluated the compliance of the ICU with the invasive candidiasis guideline in patients initiated on micafungin and ASP impact on mortality through a 4-month audit period, in 2014, with active ASP intervention and then without ASP intervention, in 2016.60 Antifungal consumption

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also was evaluated over a 2-year period between 2014 and 2016. Results demonstrated that there were significant changes in that time in patients categorized as “proven or probable invasive candidiasis,” “appropriately suspected but candidiasis excluded,” and “inappropriately suspected” (P=0.01). A 90% reduction in inappropriately initiated antifungal courses was observed between 2014 and 2016. All-cause mortality due to proven or probable invasive candidiasis decreased to 19% from 45% in the study period compared with the historical cohort in 2003-2007, respectively. Furthermore, a decrease in micafungin consumption by 49% was observed.60 While reduction of micafungin consumption was likely attributed to BDG, improvements in inappropriate initiation of antifungals and mortality were more likely influenced by assessment of risk factors, source removal, and further workup of invasive candidiasis, as recommended by the guideline. There was improvement with guideline compliance and micafungin use from 2014, even though active ASP intervention was withdrawn in 2016. Moreover, Ito-Takeichi et al observed mixed results in their single-center prospective cohort study evaluating the impact of implementing antifungal daily reviews by ASP through prospective audit and feedback combined with BDG monitoring on antifungal consumption and clinical outcomes of patients with candidiasis.61 The ASP recommended stopping antifungal therapy in cases with negative BDG, but testing appeared to be at the physician’s discretion. Overall antifungal use was not significantly decreased after intervention, but there was a significant reduction in 60-day clinical failure rate (80.0% vs 36.4%; P<0.001) and 60-day mortality (42.9% vs 18.2%; P=0.004) in patients with proven candidiasis. This was likely due to most ASP interventions being on choice of antifungal (104/223; 47%) followed by dosage adjustment (77/223; 35%). There were minimal interventions on BDG guidance and de-escalation (8/223; 4%).61 However, in 197 oncologic patients and solid-organ transplant recipients, a pre-post study observed that serial BDG on days 1, 3, and 5 of antifungal treatment complemented with ASP bedside advice resulted in reduced median days of empiric antifungal therapy (9 vs 5 days; P=0.04) compared with ASP bedside advice alone.62 Probable or proven fungal infections and allcause mortality were similar in both periods. Although false-negative BDG results are considered rare, a retrospective study of 148 adult patients with proven candidemia found 26 (17.6%) patients with persistently negative BDG tests. In a multivariable analysis, persistently negative BDG tests were independently associated with better prognoses (OR, 0.12; 95% CI, 0.03-0.49; P=0.003), probably due to lower systemic fungal burden.63 Molecular Candida platforms, such as the T2Candida Panel and Karius Test, detecting Candida species

DNA from whole blood have emerged. While sensitivity and specificity seem to be more promising compared with blood cultures, the role of these technologies in the early diagnosis and management of candidemia remains unclear.54 Patch et al evaluated the effect of T2Candida combined with active ASP intervention through positive culture review in a 2-phase retrospective analysis on timing of appropriate antifungal initiation for patients with candidemia and micafungin DOT in patients without microbiological evidence of invasive candidiasis. The authors observed a significant decrease in time to appropriate therapy in the post-T2Candida group (34 vs 6 hours; P=0.0147). Despite a lack of mycological evidence in the pre-T2Candida group, average DOT was 6.7 days compared with 2.4 days in patients with negative T2Candida results without mycological evidence in the post-T2Candida group. This resulted in a total antifungal cost savings of $48,440 (or $280 per tested patient).64 Of concern, discordance was observed in 3 patients with unpaired positive blood cultures and a negative T2Candida result.64 In a more recent retrospective review, Bomkamp et al found in 433 paired T2Candida cultures that overall antifungal DOT improved after implementation of the panel, but micafungin use continued to decline after the panel was removed.65 This was likely due to the concomitant increased stewardship resources including physician-directed prospective audit and feedback around implementation. In contrast, Steuber et al observed different results while retrospectively evaluating 628 T2Candida results at a large community hospital with prospective audit and feedback performed on negative results typically within 24 hours. An antifungal was ordered in 265 (42.4%) of cases, and appropriate de-escalation/optimization (ie, discontinuation) of

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In the early stages of sepsis, every hour of delay in starting effective antimicrobial therapy increases the risk for death.

therapy occurred in 143 (54%) of these cases. There were 120 (53.3%) of 225 negative results where antifungal therapy was not discontinued within 48 hours, despite being negative. In the regression model, ICU LOS was predictive of failure to discontinue antifungal therapy within 48 hours of negative results (OR, 0.96; 95% CI, 0.94-0.99; P=0.002). Patients with negative results had significantly fewer days of antifungal therapy compared with positive tests (4.9±6.3 vs 10±10 days, respectively; P=0.03).66 Unfortunately, antifungal discontinuation with negative tests was unexpectedly low even with antimicrobial stewardship intervention. Further study is warranted to assess whether negative results would provide any additional value to patients already at substantially high risk for fungal infections. In patients without microbiological evidence of candidemia, negative T2Candida results were compared with negative BDG, along with active ASP intervention in both groups, in a retrospective quasiexperimental study on their facilitation in antifungal discontinuation.56 During the study period, there was a systemwide guideline on the SOC for invasive candidiasis, which included either BDG or T2Candida. Negative results for either were encouraged to discontinue echinocandin therapy. In addition, the ASP reviewed BDG and T2Candida results for patients on anidulafungin (Eraxis, Roerig) during both periods. Among 206 ICU patients, median DOT was 2 (1-5) days compared with 1 (1-2) day in the BDG and T2Candida group, respectively (P<0.001). Moreover, T2Candida was the only independent predictor of early anidulafungin discontinuation (aOR, 3.0; 95% CI, 1.7-5.6; P<0.001).56 The T2Bacteria Panel (T2 Biosystems) recently made its debut detecting bacteria DNA by T2 magnetic resonance from whole blood to improve early initiation of appropriate antibiotic therapy in BSIs. Paired with a single set of blood cultures, T2Bacteria sensitivity and specificity in diagnosing BSIs caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, P. aeruginosa, and Escherichia coli were 90% (95% CI, 76%-96%) and 90% (95% CI, 88%-91%), respectively.67 The NPV was 99.7%. Limited to only 5 bacteria, the sensitivity and specificity for any organism was 43% (95% CI, 32%-54%) and 89% (95% CI, 87%-91%). Time from initiation of testing to detection and identification of pathogens was shorter for T2Bacteria (mean, 7.70 [SD, 1.38] hours) than for blood cultures (mean, 71.7 [SD, 39.3] hours). However, a 10% false-positive rate was observed for its targeted organisms.67 Voigt et al examined 137 emergency department patients from 2 centers in a prospective noninterventional T2Bacteria clinical study.68 Relative to blood culture, T2Bacteria showed 100% PPA and 98.4% NPA. The panel detected 25% more positive results associated with evidence of infection and identified bacteria 56.6 hours faster, on average, compared with blood culture. T2Bacteria could have potentially

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de-escalated therapy in 8 patients, reduced time to species-directed therapy in 4 patients, and reduced time to effective therapy in 4 patients.68 A substudy of a larger prospective multicenter clinical trial evaluated the significance of positive T2Bacteria cases with negative blood cultures to determine whether these results were false positives or potentially associated with an infection. Among 233 participants, 20 were identified with 21 (9%) discordant results. Eleven (52.5%) cases had probable BSIs, 4 (19%) had possible BSIs, and 6 (28.5%) were presumptive false positives.69 The discrepancies observed for probable and possible BSIs appeared to be associated with closed space and localized infections, such as pyelonephritis and abscess, and recent use of active antibiotics.69 Further prospective, ideally interventional, studies are needed to justify its role along with ASPs in patient care.70 Karius testing has offered a new potential tool in the ASP armamentarium of microbiologist testing. This novel metagenomic microbiological diagnostic test uses plasma microbial cell–free DNA sequencing to identify 1,250 bacteria, fungi, parasites, and viruses.71,72 While expensive and clinical data are fairly limited, this new technology has shown promise in diagnosing and identifying causative infectious etiologies for pneumonia, bacteremia, and general sepsis despite pretreatment with antibiotics. Next-generation sequencing (NGS) may be most useful in mitigating the delay of targeted treatment and excessive broad-spectrum antimicrobial use in immunocompromised hosts where a broader range of pathogens is on the differential. However, Niles et al observed little diagnostic value with NGS compared with conventional testing (CT).73 There was 61% positive agreement and 58% negative agreement between NGS and CT among 60, most being immunocompromised pediatric patients. On average, CT provided the same result as NGS, but 3.5 days earlier. Antimicrobial therapy was only changed 26% of the time when additional organisms were identified by NGS.73 Larger studies are needed to validate these findings.

RDTs for Blood Culture Testing Molecular RDT has fundamentally changed the management of BSIs and blood culture contaminants (eg, coagulase-negative staphylococci) by providing actionable information much earlier in the course of treatment than conventional microbiological cultures. Implementation of PCR-based technologies (eg, BioFire FilmArray BCID, GenMark ePlex BCID), nanoparticle probe technology (eg, VERIGENE BC-GP and BC-GN), or matrix-assisted laser desporption/ionization time of flight (eg, bioMérieux, BD Bruker) have been associated with decreases in time to effective therapy, hospital LOS, and mortality when associated with ASP interventions.2 Similar to the clinical

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Although there are still shortcomings, RDTs provide valuable information to the clinical presentation of patients.

impacts observed, a cost-effectiveness analysis also has reflected benefits of molecular RDTs in BSIs.74 These data also highlight the strong synergy of stewardship and RDT has an 80% chance of cost-effectiveness with an ASP, but only 41.1% without. The introduction of automated rapid phenotypic testing systems such as the Accelerate Pheno system (Accelerate Diagnostics) can yield organism identification, minimum inhibitory concentration (MIC), and susceptibility interpretation with a turnaround time of approximately 7 hours after positive blood culture. Several studies have explored the Accelerate Pheno system coupled with ASP intervention. Results of 448 patients with gram-negative BSIs in a randomized controlled trial with prospective audit and feedback in both arms reflected significantly faster antibiotic changes (median decrease of approximately 25 hours for gram-negative antibiotics; P<0.001) with the Accelerate Pheno system compared with culture. Antibiotic escalation also was significantly faster with the Accelerate Pheno system relative to culture-based methods for antimicrobial resistant BSIs (median decrease of approximately 43 hours; P=0.01). There were no differences between arms in patient outcomes, including LOS and mortality.75 Four quasi-experimental beforeand-after observational studies analyzed integration of Accelerate Pheno with ASP intervention with variable results in patient outcomes.76,77 Dare et al included 496 bacteremic episodes at a single center with routine prospective audit and feedback on positive blood cultures.77 Median LOS was significantly

Outpatient Antimicrobial Prescribing And Diagnostic Potential The focus of antibiotic stewardship on the outpatient setting is relatively new. Population database evaluations of antimicrobial prescribing in the United States suggest at least one-third of prescribing is inappropriate, the majority attributed to respiratory infections.83 Following this finding, the CDC released the Core Elements of Outpatient Antibiotic Stewardship, which recommends a variety of interventions, such as commitment posters, to decrease inappropriate antibiotic prescribing.84 A systematic review on interventions to influence prescriber behavior in ARIs in primary care demonstrated that C-reactive protein testing, shared decision making, and PCT-guided management hold promise for decreasing inappropriate use of antibiotics.85 In contrast, conclusions could not be made on the utility of respiratory diagnostics, as studies were few or of very low quality. Respiratory RDTs in outpatient settings are evolving. While influenza testing using digital lateral flow immunoassays, such as the BD Veritor Plus system, in the primary care setting are widely available, the use of point-of-care molecular testing has been limited related to regulations about where testing can be performed (Clinical Laboratory Improvement Amendments [CLIA] waivers), and by whom, as well as logistical issues of achieving turnaround time during clinic visits. The first CLIA-waived nucleic acid amplification test, Alere i influenza A&B, was approved in 2015. In 2016, the BioFire FilmArray Respiratory Panel EZ (RP EZ), a CLIA-waived respiratory panel, became available to allow for multiplex respiratory inclinic testing. These advances in technologies have the potential to change outpatient health care. A recent study implemented the BioFire FilmArray RP EZ panel in a pediatric clinic among 430 patients at 2 clinics. In clinic A, the RP EZ was used routinely at provider discretion, while in clinic B, if antigen testing was performed for influenza or respiratory syncytial virus, samples were also tested using FilmArray, but results were blinded to patients and providers. In clinic A, at least 1 organism was detected in 70.4% of patients, leading to appropriate treatment in 93.6% of patients compared with 87.9% of patients in clinic B without the panel (P=0.0445).86 Significant increases in neuraminidase inhibitor use (75% vs 31.6%; P<0.01) occurred among patients in clinic A compared with clinic B, although this may have been related to differences in patient presentations and related indication for therapy.86 The RP EZ panel was associated with a decrease in clinic appointment duration when used (mean check-in to checkout time, 48 vs 55 minutes; P<0.01).86 Although promising, these results are very likely limited by the turnaround time of the CLIAwaived test of approximately 1 hour. Additional uncertainty arises from their second-phase study where the implementation of RP EZ did not reduce the use

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shorter (6.3 and 6.7 days vs 8.1 days; P=0.001) with Accelerate Pheno with or without real-time notification (RTN) compared with the historical cohort of culture-based methods. Median antimicrobial DOT also was significantly shorter in both intervention arms compared with the historical cohort (6 each vs 7 days; P=0.011).77 Although LOS and DOT significantly improved after Accelerate Pheno implementation, the addition of RTN did not show further improvement in the setting of an active ASP, suggesting integration may omit resources to include RTN. Ehren et al observed in 204 patients that median time from Gram stain to optimal therapy (7 vs 11 hours; P=0.024) and step-down antimicrobial therapy (12 vs 27.8 hours; P=0.019) were significantly shorter in the use of Accelerate Pheno with bedside ASP intervention compared with conventional diagnostics with or without ASP intervention; however, groups did not differ in DOT or LOS.76 Similarly, Walsh et al found time to definitive therapy improved with the Accelerate Pheno system bundled with ASP intervention in 206 non-critically ill patients with gram-negative BSIs.78 Post-intervention was associated with shorter median total DOT (9.5 vs 14.2 days; P<0.001) and mean hospital LOS (5.3 vs 7.9 days; P=0.047) compared with preintervention, respectively.78 Robinson et al observed median time to institutional preferred antimicrobial therapy decrease by 21.2 hours (P<0.001) with Accelerate Pheno compared with SOC in 514 patients with gram-negative BSIs.79 Antibiotic use (days of therapy/1,000 days present) improved with Accelerate Pheno by decreasing broad-spectrum agents (655.2 vs 585.8; P=0.043) and increasing narrow-spectrum beta-lactams (69.1 vs 141.7; P<0.001).79 Of concern, discrepant results occurred in 69 of 250 cases (28%) with the Accelerate Pheno system, resulting in incorrect ASP recommendations in 10 of 69 cases (14%).79 No differences in DOT, LOS, and mortality between the groups were observed. In 55% of these cases, the most common impact was continuation of unnecessarily broad therapy. Although susceptibility interpretation may have a great deal of variability associated with MIC testing,80 the introduction of rapid phenotypic testing may be of particular importance to ASPs in the critically ill related to the ability to optimize therapeutic dosing to maximize pharmacokinetic and pharmacodynamics (PK/ PD) parameters in the setting of a known MIC. Optimal drug exposures have been associated with improved outcomes in achieving the enhanced PK/PD targets.81 Prospective evaluations of critically ill patients have reflected common underdosing for PK/PD targets.82 Therefore, the use of rapid phenotypic technologies, such as Accelerate Pheno, combined with therapeutic drug monitoring among critically ill patients likely has the potential to significantly affect patient outcomes.

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of downstream health care resources including tests, telephone calls, and follow-up appointments.87 The importance of turnaround time in yielding clinically actionable information in the outpatient setting cannot be overstated. A post hoc analysis of randomized controlled trial data of RVP use for patients presenting to emergency departments with respiratory symptoms has shown that faster turnaround times are associated with improved patient management compared with longer turnaround times.88 As mean office visit times for RTIs are often 15 minutes, the logistics of primary care require technologies that can accommodate these time constraints.89 With the development of such technologies, determination will be needed of what patient population to target, which targets provide clinical utility (antibiotic avoidance, antiviral use, lab and imaging use, and subsequent health care use), and the optimal implementation strategies of these panels.90 Clinical decision support may be of benefit in directing front-line clinicians in the optimal use of RDT results, particularly as the resources for prospective audit and feedback from antimicrobial stewardship in the outpatient setting may be limited.31

Conclusion For severe RTIs, sepsis, candidiasis, BSIs, PK/PD optimization opportunities, and outpatient respiratory infections, a multitude of advances are occurring in the realm of RDT technology. These technologies, along with evidence-based ASP interventions, have demonstrated promise in improving patient care. Since RDTs are complex interventions with their effect contingent on clinical context, patient flow, and access and timing, critical importance should be placed on performing RDT efficacy evaluations. ASPs may be successfully engaged in this essential role to maximize appropriateness and effectiveness of RDTs at the institution-specific level. The goal should be to improve diagnostic accuracy and speed, influence diagnostic thinking of clinicians, change subsequent clinical management, affect patient outcomes, and yield overall cost-effectiveness.

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2. 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. 3. Brendish NJ, Malachira AK, Armstrong L, et al. Routine molecular point-of-care testing for respiratory viruses in adults presenting to hospital with acute respiratory illness (ResPOC): a pragmatic, open-label, randomised controlled trial. Lancet Respir Med. 2017;5(5):401-411. 4. Kumar A, Zarychanski R, Light B, et al. Early combination antibiotic therapy yields improved survival compared with monotherapy in septic shock: a propensity-matched analysis. Crit Care Med. 2010;38(9):1773-1785.

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5. Inglis TJJ, Ekelund O. Rapid antimicrobial susceptibility tests for sepsis; the road ahead. J Med Microbiol. 2019;68(7):973-977. 6. 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. 7. Dellit TH, Owens RC, McGowan JE Jr, et al. Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America guidelines for developing an institutional program to enhance antimicrobial stewardship. Clin Infect Dis. 2007;44(2):159-177. 8. Davey P, Marwick CA, Scott CL, et al. Interventions to improve antibiotic prescribing practices for hospital inpatients. Cochrane Database Syst Rev. 2017;2(2):CD003543. 9. Karanika S, Paudel S, Grigoras C, et al. Systematic review and meta-analysis of clinical and economic outcomes from the implementation of hospital-based antimicrobial stewardship programs. Antimicrob Agents Chemother. 2016;60(8):4840-4852. 10. Baur D, Gladstone BP, Burkert F, et al. Effect of antibiotic stewardship on the incidence of infection and colonisation with antibiotic-resistant bacteria and Clostridium difficile infection: a systematic review and meta-analysis. Lancet Infect Dis. 2017;17(9):990-1001. 11. 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-e77. 12. Bauer KA, Perez KK, Forrest GN, et al. Review of rapid diagnostic tests used by antimicrobial stewardship programs. Clin Infect Dis. 2014;59(suppl 3):S134-S145. 13. Morency-Potvin P, Schwartz DN, Weinstein RA. Antimicrobial stewardship: How the microbiology laboratory can right the ship. Clin Microbiol Rev. 2017;30(1):381-407. 14. Hanson KE, Azar MM, Banerjee R, et al. Molecular testing for acute respiratory tract infections: clinical and diagnostic recommendations from the IDSA’s Diagnostics Committee. Clin Infect Dis. 2020;71(10):2744-2751. 15. Patel SV, Pulcini C, Demirjian A, et al. Rapid diagnostic tests for common infection syndromes: less haste, more speed. J Antimicrob Chemother. 2020;75(8):2028-2030. 16. Kung HC, Hoyert DL, Xu J, et al. Deaths: final data for 2005. Natl Vital Stat Rep. 2008;56(10):1-120. 17. Ramirez JA, Wiemken TL, Peyrani P, et al. Adults hospitalized with pneumonia in the United States: incidence, epidemiology, and mortality. Clin Infect Dis. 2017;65(11):1806-1812. 18. Metlay JP, Waterer GW, Long AC, et al. Diagnosis and treatment of adults with community-acquired 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. 19. Huang DT, Yealy DM, Angus DC, the Pro ACTI. Procalcitoninguided antibiotic use. N Engl J Med. 2018;379(20):1973. 20. Ruuskanen O, Lahti E, Jennings LC, et al. Viral pneumonia. Lancet. 2011;377(9773):1264-1275. 21. Gilbert DN. Procalcitonin as a biomarker in respiratory tract infection. Clin Infect Dis. 2011;52 Suppl4:S346-S350. 22. Schuetz P, Muller B, Christ-Crain M, et al. Procalcitonin to initiate or discontinue antibiotics in acute respiratory tract infections. Cochrane Database Syst Rev. 2012(9):CD007498. 23. Self WH, Balk RA, Grijalva CG, et al. Procalcitonin as a marker of etiology in adults hospitalized with community-acquired pneumonia. Clin Infect Dis. 2017;65(2):183-190.

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29. Moradi T, Bennett N, Shemanski S, et al. Use of procalcitonin and a respiratory polymerase chain reaction panel to reduce antibiotic use via an EMR alert. Clin Infect Dis. 2020;71(7):1684-1689. 30. Timbrook T, Maxam M, Bosso J. Antibiotic discontinuation rates associated with positive respiratory viral panel and low procalcitonin results in proven or suspected respiratory infections. Infect Dis Ther. 2015;4(3):297-306. 31. Timbrook TT. Antimicrobial stewardship and implementation of rapid multiplex respiratory diagnostics: Is there method in the madness? Clin Infect Dis. 2020;71(7):1690-1692. 32. Lee CC, Chang JC, Mao XW, et al. Combining procalcitonin and rapid multiplex respiratory virus testing for antibiotic stewardship in older adult patients with severe acute respiratory infection. J Am Med Dir Assoc. 2020;21(1):62-67. 33. Srinivas P, Rivard KR, Pallotta AM, et al. Implementation of a stewardship initiative on respiratory viral PCR-based antibiotic deescalation. Pharmacotherapy. 2019;39(6):709-717. 34. Covert K, Bashore E, Edds M, et al. Utility of the respiratory viral panel as an antimicrobial stewardship tool. J Clin Pharm Ther. 2021;46(2):277-285. 35. Buchan BW, Windham S, Balada-Llasat JM, et al. Practical comparison of the BioFire FilmArray pneumonia panel to routine diagnostic methods and potential impact on antimicrobial stewardship in adult hospitalized patients with lower respiratory tract infections. J Clin Microbiol. 2020;58(7):e00135-20. 36. Webber DM, Wallace MA, Burnham CA, et al. Evaluation of the BioFire FilmArray pneumonia panel for detection of viral and bacterial pathogens in lower respiratory tract specimens in the setting of a tertiary care academic medical center. J Clin Microbiol. 2020;58(7):e00343-20. 37. Ginocchio CC, Garcia-Mondragon C, Mauerhofer B, et al. Multinational evaluation of the BioFire(R) FilmArray(R) pneumonia plus panel as compared to standard of care testing. Eur J Clin Microbiol Infect Dis. 2021 Mar 2. doi:10.1007/s10096-021-04195-5. 38. Yoo IY, Huh K, Shim HJ, et al. Evaluation of the BioFire FilmArray pneumonia panel for rapid detection of respiratory bacterial pathogens and antibiotic resistance genes in sputum and endotracheal aspirate specimens. Int J Infect Dis. 2020;95:326-331. 39. Zacharioudakis IM, Zervou FN, Dubrovskaya Y, et al. Evaluation of a multiplex PCR panel for the microbiological diagnosis of pneumonia in hospitalized patients: experience from an academic medical center. Int J Infect Dis. 2021;104:354-360. 40. Monard C, Pehlivan J, Auger G, et al. Multicenter evaluation of a syndromic rapid multiplex PCR test for early adaptation of antimicrobial therapy in adult patients with pneumonia. Crit Care. 2020;24(1):434.

46. Willis C, Allen B, Tucker C, et al. Impact of a pharmacist-driven methicillin-resistant Staphylococcus aureus surveillance protocol. Am J Health Syst Pharm. 2017;74(21):1765-1773. 47. Smith MN, Erdman MJ, Ferreira JA, et al. Clinical utility of methicillin-resistant Staphylococcus aureus nasal polymerase chain reaction assay in critically ill patients with nosocomial pneumonia. J Crit Care. 2017;38:168-171. 48. Smith MN, Brotherton AL, Lusardi K, et al. Systematic review of the clinical utility of methicillin-resistant Staphylococcus aureus (MRSA) nasal screening for MRSA pneumonia. Ann Pharmacother. 2019;53(6):627-638. 49. Carr AL, Daley MJ, Givens Merkel K, et al. Clinical utility of methicillin-resistant Staphylococcus aureus nasal screening for antimicrobial stewardship: a review of current literature. Pharmacotherapy. 2018;38(12):1216-1228. 50. Butler-Laporte G, De L’Etoile-Morel S, Cheng MP, et al. MRSA colonization status as a predictor of clinical infection: A systematic review and meta-analysis. J Infect. 2018;77(6):489-495. 51. Mergenhagen KA, Starr KE, Wattengel BA, et al. Determining the utility of methicillin-resistant Staphylococcus aureus nares screening in antimicrobial stewardship. Clin Infect Dis. 2019;71(5)1142-1148. 52. Lindblom A, Karami N, Magnusson T, et al. Subsequent infection with extended-spectrum beta-lactamase-producing Enterobacteriaceae in patients with prior infection or fecal colonization. Eur J Clin Microbiol Infect Dis. 2018;37(8):1491-1497. 53. Rottier WC, Bamberg YR, Dorigo-Zetsma JW, et al. Predictive value of prior colonization and antibiotic use for third-generation cephalosporin-resistant enterobacteriaceae bacteremia in patients with sepsis. Clin Infect Dis. 2015;60(11):1622-1630. 54. Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-50. 55. Clancy CJ, Nguyen MH. Rapid diagnosis of invasive candidiasis: ready for prime-time? Curr Opin Infect Dis. 2019;32(6):546-552. 56. Gill CM, Kenney RM, Hencken L, et al. T2 Candida versus betaD-glucan to facilitate antifungal discontinuation in the intensive care unit. Diagn Microbiol Infect Dis. 2019;95(2):162-165. 57. Mylonakis E, Clancy CJ, Ostrosky-Zeichner L, et al. T2 magnetic resonance assay for the rapid diagnosis of candidemia in whole blood: a clinical trial. Clin Infect Dis. 2015;60(6):892-9. 58. Nucci M, Nouer SA, Esteves P, et al. Discontinuation of empirical antifungal therapy in ICU patients using 1,3-beta-d-glucan. J Antimicrob Chemother. 2016;71(9):2628-2633.

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24. Kamat IS, Ramachandran V, Eswaran H, et al. Procalcitonin to distinguish viral from bacterial pneumonia: A systematic review and meta-analysis. Clin Infect Dis. 2020;70(3):538-542.

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59. Posteraro B, Tumbarello M, De Pascale G, et al. (1,3)-beta-d-Glucan-based antifungal treatment in critically ill adults at high risk of candidaemia: an observational study. J Antimicrob Chemother. 2016;71(8):2262-2269. 60. Rautemaa-Richardson R, Rautemaa V, Al-Wathiqi F, et al. Impact of a diagnostics-driven antifungal stewardship programme in a UK tertiary referral teaching hospital. J Antimicrob Chemother. 2018;73(12):3488-3495. 61. Ito-Takeichi S, Niwa T, Fujibayashi A, et al. The impact of implementing an antifungal stewardship with monitoring of 1-3, beta-D-glucan values on antifungal consumption and clinical outcomes. J Clin Pharm Ther. 2019;44(3):454-462. 62. Machado M, Chamorro de Vega E, Martinez-Jimenez MDC, et al. Utility of 1,3 beta-d-Glucan Assay for Guidance in Antifungal Stewardship Programs for Oncologic Patients and Solid Organ Transplant Recipients. J Fungi (Basel). 2021;7(1):59. 63. Agnelli C, Bouza E, Del Carmen Martinez-Jimenez M, et al. Clinical relevance and prognostic value of persistently negative (1,3)-beta-D-glucan in adults with candidemia: a 5-year experience in a tertiary hospital. Clin Infect Dis. 2020;70(9):1925-1932. 64. Patch ME, Weisz E, Cubillos A, et al. Impact of rapid, cultureindependent diagnosis of candidaemia and invasive candidiasis in a community health system. J Antimicrob Chemother. 2018;73(suppl4):iv27-iv30. 65. Bomkamp JP, Sulaiman R, Hartwell JL, et al. Evaluation of a rapid fungal detection panel for identification of candidemia at an academic medical center. J Clin Microbiol. 2020;58(3):e01408-19. 66. Steuber TD, Tucker-Heard G, Edwards J, et al. Utilization and impact of a rapid Candida panel on antifungal stewardship program within a large community hospital. Diagn Microbiol Infect Dis. 2020;97(4):115086. 67. Nguyen MH, Clancy CJ, Pasculle AW, et al. Performance of the T2Bacteria panel for diagnosing bloodstream infections: a diagnostic accuracy study. Ann Intern Med. 2019;170(12):845-852. 68. Voigt C, Silbert S, Widen RH, et al. The T2Bacteria assay Is a sensitive and rapid detector of cacteremia that can be initiated in the emergency department and has potential to favorably influence subsequent therapy. J Emerg Med. 2020;58(5):785-796. 69. Kalligeros M, Zacharioudakis IM, Tansarli GS, et al. In-depth analysis of T2Bacteria positive results in patients with concurrent negative blood culture: a case series. BMC Infect Dis. 2020;20(1):326. 70. Weinrib DA, Capraro GA. The uncertain clinical benefit of the T2Bacteria Panel. Ann Intern Med. 2019;170(12):888-889. 71. Goggin KP, Gonzalez-Pena V, Inaba Y, et al. Evaluation of plasma microbial cell-free DNA sequencing to predict bloodstream infection in pediatric patients with relapsed or refractory cancer. JAMA Oncol. 2020;6(4):552-556. 72. Hogan CA, Yang S, Garner OB, et al. Clinical impact of metagenomic next-generation sequencing of plasma cell-free DNA for the diagnosis of infectious diseases: a multicenter retrospective cohort study. Clin Infect Dis. 2021;72(2):239-245. 73. Niles DT, Wijetunge DSS, Palazzi DL, et al. Plasma metagenomic next-generation sequencing assay for identifying pathogens: a retrospective review of test utilization in a large children’s hospital. J Clin Microbiol. 2020;58(11):e00794-20. 74. 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. 75. Banerjee R, Komarow L, Virk A, et al. Randomized trial evaluating clinical impact of RAPid IDentification and Susceptibility testing for Gram Negative bacteremia (RAPIDS-GN). Clin Infect Dis. 2020 May 7. doi:10.1093/cid/ciaa528.

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76. Ehren K, Meissner A, Jazmati N, et al. Clinical impact of rapid species identification from positive blood cultures with same-day phenotypic antimicrobial susceptibility testing on the management and outcome of bloodstream infections. Clin Infect Dis. 2020;70(7):1285-1293. 77. Dare RK, Lusardi K, Pearson C, et al. Clinical impact of Accelerate PhenoTM rapid blood culture detection system in bacteremic patients. Clin Infect Dis. 2020 May 28. doi:10.1093/cid/ciaa649 78. Walsh TL, Bremmer DN, Moffa MA, et al. Impact of an antimicrobial stewardship program-bundled initiative utilizing Accelerate Pheno system in the management of patients with aerobic gramnegative bacilli bacteremia. Infection. 2021 Feb 2. doi:10.1007/ s15010-021-01581-1 79. Robinson ED, Stilwell A, Attai AE, et al. Implementation of a rapid phenotypic susceptibility platform for gram-negative bloodstream infections with paired antimicrobial stewardship intervention: Is the juice worth the squeeze? Clin Infect Dis. 2021 Feb 13. https://doi.org/10.1093/cid/ciab126 80. Mouton JW, Muller AE, Canton R, et al. MIC-based dose adjustment: facts and fables. J Antimicrob Chemother. 2018;73(3):564-568. 81. Lodise TP Jr, Lomaestro B, Drusano GL. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extended-infusion dosing strategy. Clin Infect Dis. 2007;44(3):357-363. 82. Roberts JA, Paul SK, Akova M, et al. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58(8):1072-1083. 83. 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. 84. Sanchez GV, Fleming-Dutra KE, Roberts RM, Hicks LA. Core elements of outpatient antibiotic stewardship. MMWR Recomm Rep. 2016;65(6):1-12. 85. Tonkin-Crine SK, Tan PS, van Hecke O, et al. Clinician-targeted interventions to influence antibiotic prescribing behaviour for acute respiratory infections in primary care: an overview of systematic reviews. Cochrane Database Syst Rev. 2017;9(9):CD012252. 86. Beal SG, Posa M, Gaffar M, et al. Performance and impact of a CLIA-waived, point-of-care respiratory PCR panel in a pediatric clinic. Pediatr Infect Dis J. 2020;39(3):188-191. 87. Fenton J, Posa M, Kelly M, et al. Impact of a point-of-care respiratory PCR panel in a pediatric clinic on postvisit communication and follow-up visits. Pediatr Infect Dis J. 2020;39(9):e282-e283. 88. Brendish NJ, Malachira AK, Beard KR, et al. Impact of turnaround time on outcome with point-of-care testing for respiratory viruses: a post hoc analysis from a randomised controlled trial. Eur Respir J. 2018;52(2):1800555. 89. Linder JA, Singer DE, Stafford RS. Association between antibiotic prescribing and visit duration in adults with upper respiratory tract infections. Clin Ther. 2003;25(9):2419-2430. 90. Kozel TR, Burnham-Marusich AR. Point-of-care testing for infectious diseases: past, present, and future J Clin Microbiol. 2017;55(8):2313-2320.

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.

Cabenuva: A Novel Long-Acting Injectable HIV Treatment BY SARAH M. MICHIENZI, PHARMD, BCPS, AAHIVP, AND RACHEL KAUTZ, PHARMD CANDIDATE 2022

abenuva is the first FDA-approved long-acting (LA) injectable regimen for patients with HIV infection.1 Cabenuva (ViiV Healthcare) consists of cabotegravir (CAB), an integrase strand transfer inhibitor (INSTI), and rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI) approved to replace antiretroviral therapy (ART) in patients with HIV-RNA less than 50 copies/mL who have been on a stable ART with no history of treatment failure or suspected resistance to CAB or RPV. The approval of CAB/RPV was an important milestone in the treatment of HIV. This article provides an overview of CAB/RPV and 2 key studies leading to its approval.

About CAB/RPV1 CAB/RPV consists of an oral leadin, followed by the initial injection, which are continued monthly. The oral lead-in includes a Vocabria (CAB, ViiV

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Healthcare) 30-mg tablet once daily and an Edurant (RPV, Janssen) 25-mg tablet once daily for at least 28 days. Both medications should be taken with food. The purpose of the oral lead-in is to assess the patients’ tolerability to the regimen before the LA form is injected. If tolerated after 1 month, on the last day of oral lead-in therapy, the patient can receive the initial 600-mg CAB and 900-mg RPV injections. These are 2 separate 3-mL intramuscular (IM) injections that should be administered on opposite gluteal sites or at least 2 cm apart on the same gluteal site. The continuation injections are administered the same way but consist of a 400-mg (2-mL) CAB injection and a 600-mg (2-mL) RPV injection. Before administering the injections, the vials should be removed from the refrigerator and left for 15 minutes to allow the medication to come to room temperature. CAB/RPV can remain in the carton at room temperature for

up to 6 hours. After 6 hours at room temperature, the medication should be discarded. Both medications are suspensions that need to be shaken vigorously before being drawn into a syringe. Once drawn into the syringe, the medication should be administered immediately but can remain in the syringes for up to 2 hours. CAB/ RPV should only be administered by a health care professional. The continuation injections are to be administered monthly. For the monthly visits, the patient may receive their injections up to 7 days before or after their scheduled monthly target date. If this window is missed, and the time since the last injection was less than 2 months prior, the patient should resume the 400-mg CAB injection and 600-mg RPV injection as soon as possible. If it has been more than 2 months since their last injections, they need to reinitiate the regimen with the 600mg CAB injection and 900-mg RPV

injection. If the patient has planned to miss their injection appointment for whatever reason, they can take daily oral therapy to replace up to 2 consecutive monthly injection visits. They should start the oral therapy approximately 1 month after their last injection and continue the oral therapy until the day injection therapy is restarted. The most common side effects occurring in 2% or greater of patients receiving CAB/RPV include injection site reactions, pyrexia, fatigue, headache, musculoskeletal pain, nausea, sleep disorders, dizziness, and rash. Contraindications to receiving CAB/ RPV include taking carbamazepine, oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, systemic dexamethasone (>1 dose), and St John’s wort. These medications can decrease the concentrations of CAB and RPV and coadministration with CAB/RPV could cause potential loss of virologic response and development of resistance. FLAIR and ATLAS are 2 major phase 3 studies that evaluated the safety and efficacy of CAB/ RPV in treatment-naive and -experienced patients, respectively.

Clinical Trials FLAIR2 FLAIR was a phase 3, randomized, multicenter, open-label, noninferiority trial that compared monthly IM CAB/RPV vs oral daily dolutegravir/ abacavir/lamivudine (DTG/ABC/3TC) in treatment-naive patients. Eligible participants were older than 18 years of age, antiretroviral (ARV) naive, and had HIV-RNA levels of more than 1,000 copies/mL at baseline. All patients were assigned to take 50 mg DTG, 600 mg ABC, and 300 mg 3TC as a daily oral regimen for the initial 16 weeks. At week 16, participants whose HIV-RNA level was less than 50 copies/ mL were randomly placed into 2 treatment groups. Treatment assignments were stratified by baseline HIV-RNA levels and sex at birth. One group continued the DTG/ABC/3TC daily oral regimen for the next 100 weeks. The

other group switched to CAB/RPV with the initial 4-week oral lead-in (30 mg CAB and 25 mg RPV daily). This was followed by the one-time initiation injections (600-mg CAB injection and 900-mg RPV injection). Patients then received maintenance injections every 4 weeks, which was the 400-mg CAB injection and 600-mg RPV injection for a total of 100 weeks. Patients with confirmed virologic failure, which was indicated by 2 consecutive HIV-RNA levels of 200 copies/mL or greater, discontinued their assigned treatment.

In both the FLAIR and ATLAS trials, most people preferred the injectable regimen. The primary end point measure was the percentage of patients with an HIV-RNA level of more than 50 copies/mL at week 48, determined with the use of the FDA snapshot algorithm. The percentage of patients with an HIV-RNA level of more than 50 copies/ mL at week 48 was also evaluated as a secondary end point. The primary efficacy analysis included all participants who received at least 1 dose of the assigned trial drugs during the maintenance phase. For the primary end point, a noninferiority margin of 6 percentage points was set based on clinical considerations of the 2 regimens. There were 629 participants who initiated oral induction therapy, with 63 of those participants withdrawing before randomization because of lack of efficacy. The remaining 566 participants were randomly assigned to their maintenance phase treatment. After 48 weeks, 2.1% of patients on the LA monthly injectable regimen and 2.5% of patients on the daily oral

regimen had HIV-RNA levels more than 50 copies/mL (95% CI, -2.8 to 2.1). These results met the criteria for noninferiority. Additionally, 93.6% of patients in the LA injectable group and 93.3% of patients in the daily oral therapy group had HIV-RNA levels of less than 50 copies/mL at week 48 (95% CI, -3.7 to 4.5). Of note, 3 of 54 patients in the LA therapy group who had the L74I integrase polymorphism at baseline had confirmed virologic failure. Eighty-six percent of the patients who received LA injectable therapy reported injection site reactions (mild or moderate severity for 99% of cases and decreased throughout the study). At week 48, 98% of patients who had been assigned to the LA injectable group were satisfied with the regimen and preferred it over the oral daily regimen. Results of the FLAIR study show therapy with LA CAB/RPV was noninferior to oral therapy with DTG/ ABC/3TC at maintaining HIV suppression and was well tolerated with high satisfaction.

ATLAS3 The ATLAS study was a phase 3, randomized, multicenter, parallelgroup, open-label, noninferiority trial that compared switching to monthly IM CAB/RPV injections versus staying on a 3-drug ARV regimen in treatment experienced patients. Participants enrolled were older than 18 years of age, taking 2 nucleotide reverse transcriptase inhibitors (NRTIs) plus an INSTI, NNRTI or protease inhibitor (PI), on a stable ARV regimen for more than 6 months prior, and had HIV-RNA levels of less than 50 copies/mL for more than 6 months prior. Patients were excluded if they had a history of virologic failure, NNRTI or INSTI resistance, or chronic hepatitis B. Also, patients taking DTG/ABC/3TC were excluded to maximize generalizability, as this prior regimen was evaluated in the FLAIR trial. Participants were randomly assigned in a 1:1 ratio to either continue their 3-drug oral ARV for 52 weeks or to

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2021

switch to the oral CAB and RPV leadin for the first 4 weeks, followed by initiation and continuation IM CAB and RPV injections every 4 weeks for the remaining 48 weeks. Randomization was stratified according to class of the third ARV agent of their baseline regimen and sex at birth. There were 308 participants in each group and there were no significant differences in baseline characteristics between the 2 groups. The average patient was 42 years old, white, male, and had been on ART for 52 months. NNRTIs were the most common class of the third ARV agent, followed by INSTIs and PIs. The primary end point was the percentage of participants with an HIVRNA level of more than 50 copies/mL at week 48, determined with the use of the FDA snapshot algorithm. The percentage of participants with a HIVRNA level of less than 50 copies/mL at week 48 was also evaluated. The primary efficacy analysis included all participants who received at least 1 dose of their assigned treatment. For the primary end point, a noninferiority margin of 6 percentage points was set based on the potential clinical advantages of LA therapy. The primary end point of HIV-RNA more than 50 copies/mL occurred in 1.6% of participants in the LA injectable group compared with 1.0% in the oral therapy group (95% CI, -1.2 to 2.5). These results met the criteria for noninferiority for the primary end point. Additionally, 92.5% of participants in the LA injectable group achieved an HIV-RNA level of less than 50 copies/mL compared with 95.5% in the oral therapy group (95% CI, -6.7 to 0.7), which also met the noninferiority margin. Adverse events were more common in the LA injectable group with 83% of participants reporting injection site pain. This side effect was mild to moderate in most cases and only 1% withdrew for the study because of injection site pain. The frequency of injection site reactions declined progressively,

IDSE.NET

reaching 11% at week 48. 86% of participants who received the LA therapy preferred the regimen over previous oral therapy. The ATLAS study showed that monthly LA injections of CAB/ RPV were noninferior to standard triple oral therapy for HIV treatment and provided a high rate of treatment satisfaction despite injection related side effects.

Place in Therapy CAB/RPV is a revolutionary option for HIV treatment that has the power to improve adherence and quality of life. Current first-line regimens for HIV treatment require lifelong daily oral therapy that can be burdensome and challenging for patients. CAB/RPV reduces the treatment dosing days from 365 to 12 days per year after the oral lead-in. Additionally, while clinic visits are required for injections, CAB/RPV could give patients more privacy for their HIV treatment by not having to store medications at home. While CAB/RPV injection site reactions were common in clinical trials, these reactions significantly decreased after the first injection. Moreover, patients in clinical trials preferred injectable over oral therapy.2,3 The LATITUDE Study (Long-Acting Therapy to Improve Treatment SUccess in Daily LifE) will provide much needed information on the use of CAB/RPV in patients with a history of suboptimal adherence.4 Looking beyond the current FDA approval, an extension of the ATLAS trial, ATLAS-2M, compared CAB/ RPV injections every 4 weeks to every 8 weeks in treatment experienced patients. The results showed that the efficacy and safety profiles of dosing every 4 weeks and every 8 weeks were very similar. Although dosed every 2 months is not FDA approved, the results from ATLAS-2M support this as a therapeutic option. Also, injectable CAB demonstrated excellent results for HIV pre-exposure prophylaxis in men who have sex with men and transgender women.5

For patients interested in injectable therapy, CAB/RPV could help simplify HIV treatment in the presence of resistance (as long as susceptibility to CAB and RPV is maintained) as well as help overcome a variety challenges with daily pill taking. This could result in improve ability to maintain virologic suppression and immunologic function, thus potentially preventing complications of HIV, development of resistance, and viral transmission.

References 1. Cabenuva [package insert]. ViiV Healthcare; 2021. 2. 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. 3. 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. 4. Clinicaltrails.gov. The LATITUDE Study (LongActing Therapy to Improve Treatment SUccess in Daily LifE). Accessed June 5, 2021. http://bit. ly/3gfieL3-IDSE 5. Marzinke MA, et al. Characterization of HIV infection in cisgender men and transgender women who have sex with men receiving injectable cabotegravir for HIV prevention: HPTN 083. J Infect Dis. Published online March 19, 2021. doi:10.1093/infdis/jiab152. 6. HIV Prevention Trials Network. HPTN 084 Study Demonstrates Superiority of CAB LA to Oral FTC/TDF for the Prevention of HIV. November 20, 2020. Accessed June 5, 2021. https://bit.ly/2OEK6hu-IDSE

The authors reported no relevant financial disclosures.

About the authors: Sarah Michienzi, PharmD, BCPS, AAHIVP, is a clinical assistant professor and clinical infectious disease pharmacist in the Pharmacotherapy Section, Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, in Chicago, Illinois. Rachel Kautz, is a PharmD candidate at the College of Pharmacy, University of Illinois at Chicago, in Chicago, Illinois.

SUMMER 2021

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Infectious Disease Special Edition - Summer 2021

Articles inside

Cabenuva: A Novel Long-Acting Injectable HIV Treatment

Rapid Diagnostic Testing and Biomarkers Implementation The Starring Role of Antimicrobial Stewardship

Women and HIV: Gaps in Care