Infectious Disease Special Edition - Summer 2022

Volume 26 • Summer 2022

Hepatitis of Unknown Etiology

Rounding Up the Usual (and Unusual) Suspects CENTERS FOR DISEASE CONTROL AND PREVENTION

CENTERS FOR DISEASE CONTROL AND PREVENTION

CORONAVIRUS TROL DISEASE CON CENTERS FOR VENTION AND PRE

INFLUE1NZA J10.

HEPATITIS B

B34.2

070.30 CENTERS FOR DISEASE CONTROL AND PREVENTION

ADENOVIRUS 41 F

More 'Bandwidth' for Epidemiologists Long-COVID Learning

+ KOL Reviews : C. diff, COVID-19 and Stewardship, Diagnostic Testing & Treatment-Experienced HIV Patients

In patients with cIAI...

WHEN CHOOSING AN EMPIRIC ANTIMICROBIAL THERAPY

CHOOSE WITH CONFIDENCE

Monotherapy for some of the most serious MDR pathogens in cIAI • The first fully synthetic fluorocycline antibacterial—proven as effective as carbapenems in clinical trials1-5 • Demonstrated broad-spectrum activity against key Gram-negative, Gram-positive, and anaerobic bacteria, including isolates expressing a variety of multidrug resistance mechanisms—such as ESBL-producing pathogens2

An appropriate option for patients with penicillin allergy • Penicillin allergy—the most commonly reported drug allergy in the United States—may limit beta-lactam options6,7 • Low rates of infusion site reactions (7.7%), nausea (6.5%), and vomiting (3.7%), as seen in 2 large clinical trials1

Indications and Usage

Important Safety Information (cont’d)

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).

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.

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.

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.

Important Safety Information

CDI, Clostridioides difficile infection; cIAI, complicated intra-abdominal infection; ESBL, extended-spectrum beta-lactamase; MDR, multidrug resistance.

XERAVA is contraindicated for use in patients with known hypersensitivity to eravacycline or to 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.

XERAVA® is a trademark of Tetraphase Pharmaceuticals. ©2022 Tetraphase Pharmaceuticals, Inc. All rights reserved. 01/22 PM-ERV-00111-US

References: 1. XERAVA. Prescribing information. Tetraphase Pharmaceuticals, Inc.; Rev. 06/2020. 2. Zhanel GG, Cheung D, Adam H, et al. Review of eravacycline, a novel fluorocycline antibacterial agent. Drugs. 2016;76(5):567-588. doi:10.1007/s40265-016-0545-8 3. 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. doi:10.1001/jamasurg.2016.4237 4. 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. doi:10.1093/cid/ciy1029 5. Data on File. Waltham, MA: Tetraphase Pharmaceuticals, Inc.; 2020. 6. Macy E. Penicillin and beta-lactam allergy: epidemiology and diagnosis. Curr Allergy Asthma Rep. 2014;14(11):476. doi:10.1007/s11882-014-0476-y 7. Mazuski JE, Tessier JM, May AK, et al. The Surgical Infection Society revised guidelines on the management of intra-abdominal infection. Surg Infect (Larchmt). 2017;18(1):176. doi:10.1089/sur.2016.261

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 XERAVA® (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 or with 5 mL of 0.9% Sodium Chloride Injection, USP, which will deliver the following: a. XERAVA 50 mg vial will deliver 50 mg (10 mg/mL) of eravacycline (free base equivalents). b. XERAVA 100 mg vial will deliver 100 mg (20 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. The stability of the solution after reconstitution in the vial has been demonstrated for 1 hour at room temperature (not to exceed 25°C/77°F). If the reconstituted solution in the vial is not diluted in the infusion bag within 1 hour, the reconstituted vial content must be discarded.

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 diluted solutions must be infused within 24 hours if stored at room temperature (not to exceed 25°C/77°F) or within 10 days if stored refrigerated at 2°C to 8°C (36°F to 46°F).

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 Known hypersensitivity to eravacycline, tetracycline-class antibacterial drugs, or any of the excipients in XERAVA. 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 is 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 +ost-)atal ay 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.

®

a wholly owned subsidiary of

La Jolla Pharmaceutical Company

Distributed by: Tetraphase Pharmaceuticals, Inc. Waltham, MA 02451 XERAVA® is a registered trademark *! Tetraphase Pharmaceuticals, Inc. ©2021 Tetraphase Pharmaceuticals, Inc. All rights reserved. 1Ɲ/21 PM-ERV-00ƛƜƝ-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

East Carolina University Greenville, North Carolina Thomas M. File Jr, MD, MSc, MACP, FIDSA, FCCP

Summa Health Akron, Ohio Northeast Ohio Medical University Rootstown, Ohio Rajesh T. Gandhi, MD, FIDSA

Oregon Health & Science University Portland, Oregon

Stuart Campbell Ray, MD, FIDSA

Johns Hopkins University School of Medicine Baltimore, Maryland Michael J. Rybak, PharmD, MPH, PhD, FCCP, FIDSA, FIDP

Wayne State University Detroit, Michigan

Harvard University Center for AIDS Research Shmuel Shoham, MD, FIDSA, Massachusetts General Hospital Johns Hopkins University Medical School, Boston, Massachusetts Baltimore, Maryland Julia Garcia-Diaz, MD, MSc, FACP, FIDSA, CPI

Ochsner Health System New Orleans, Louisiana

Mark H. Wilcox, MD, FRCPath

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

EDITORIAL

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EDITOR’S BLOG:

The 5 W’s That Lead to Answers Infectious Disease Special Edition won two Azbee Awards, a gold regional and bronze national, from the American Society of Business Publication Editors for a story we published in our winter 2021 issue: “40 Years of HIV: Getting the Signal Through the Noise” (https://bit.ly/3wm4rLS-IDSE).

Something struck me when I was looking over the story—the parallels to the current cover story about the cases of pediatric hepatitis of unknown origin (see page 8).

One of the first things I learned as a journalist was the importance of answering the five W’s: who, what, when, where and why. And if you can, to also answer the question, how.

I realized these were the same questions the epidemiologists are trying to answer as they investigate these cases of pediatric hepatitis of unknown origin, and the ones that those early epidemiologists tried to answer about HIV. Who? What? When? Where? Why? And how?

You might think this would be straightforward, especially in these hepatitis cases: Many test positive for adenovirus, so that must be the answer, but as you read, you will see that it is anything but straightforward, especially because these cases are occurring in several different countries.

There are a lot of data points to consider, not least of which is the fact that just because someone tests positive for adenovirus doesn’t mean it’s causing the inflamed liver. If it was, why wouldn’t all the kids test positive?

What if adenovirus is just the noise and not a signal?

Unfortunately, epidemiologists and public health officials are stretched pretty thin in the best of times (check out the story on page 12), but right now during COVID-19, they are near the breaking point, which is increasing the challenge of finding the answers to those questions: Who? What? When? Where?

Why? And how?

They are a dedicated group of people who seem dogged in their pursuit, and I hope they do find the answers quickly.

Thankfully, they can rely on astute clinicians like you—people who recognize early on that there may be a signal of a problem, who report it to their local health departments so it can be investigated.

These clinicians and the public health officials who investigate are such an important part of our nation’s health, well-being and national security.

We also won Azbee Awards for two other stories: a bronze for “Delta Blues” (https://bit.ly/3wCqFIm-IDSE) and a silver for “The Hunt for SARS-CoV-2” (https://bit.ly/3wvm7DT-idse), which were all published in our 2021 editions.

I have to give a shout-out to the eagle eyes of our wonderful copy editors, Kristin Jannacone and Betty Zhong; my oh-so-talented art director, Matt White; as well as my editorial advisory board. The experts on the board, several of whom were quoted in these award-winning stories, are always willing to offer their perspective and help me to understand the issues so I can answer those important questions for my readers.

These behind-the-scenes folks are the reason for our success, and I so enjoy working with them. Thank you.

—Marie Rosenthal, MS The views expressed here belong to the author and do not necessarily reflect those of the publisher.

Clarification: In the “Rapid Diagnostic Tests Inform Better Diagnostic and Treatment Decisions” review article that appeared in the winter 2021 edition, the authors interpreted the time to results of the ePlex as 3.5 hours, which was the median time to results reported in the citation (Eur J Clin Microbiol Infect Dis 2018;37[3]:571-577). They were not measuring the turnaround time of the assay, which is 90 minutes, but rather how long it took to get the results to the clinical team. This reference might shed more light on turnaround time (J Clin Virol 2021;135:104737).

Continuous COVID-19 news for ID specialists at www.idse.net/Section/Covid-19/664 INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2022

5

Summer 2022 5

Editorial: The 5 W’s That Lead to Answers

8

Hepatitis of Unknown Origin: Rounding Up the Usual (and Unusual) Suspects

12

Epidemiologists Don't Have the 'Bandwidth' to Respond Quickly to Outbreaks

14

Long COVID: Learning as We Go

18

COVID-19 Roundup: Can Music Soothe the Ravaged Lung?

20

Adults 50+ With COVID-19 at Risk for Shingles

22

Could Earlier Recognition Lessen the Economic Toll of Fungal Infections?

24

Fungal Infections in People With CF Increasing, Presenting New Challenges

26

Is De-Escalation an Effective Stewardship Strategy?

28

IDSA Guidance Helps in Treating Vexing Bacteria

32

Concerns About MDR Infections Grow as Treatment Options Expand

35

As UTI Resistance Increases, Treatment Choices Are Critical

36

Does Flu Change Antibiotic Prescribing?

38

PharmDs Deemed ARTisans in HIV Rx Safety

40 Dolutegravir-Based ART Is Superior to Standard Care in Adolescents 41

Vancomycin Diagnostic Stewardship Iniative Is a Winner

42

HIV News: Pediatric HIV Guidelines Updated and More

45

From Zoo to You: Canine Coronavirus; Organisms Set Sail

46

Multidisciplinary Approach Best for Managing Chronic Wounds

71

Classifieds

14

35

65

IDSE Reviews

49

Rapid Diagnostic Methods and Technologies in the Management of Infectious Diseases

By Karen Fong, PharmD, BCIDP

60

Comparison of 2021 IDSA and ACG Recommendations for the Treatment of C. difficile Infection

By Mark H. Wilcox, MD

65

Complicated Milieu of Issues During COVID-19 Affected Stewardship

By James S. Lewis II, PharmD, FIDSA

69

Current Options for Highly Treatment-Experienced People With HIV

By Milena Murray, PharmD, MSc, BCIDP, AAHIVP, FCCP

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IDSE.NET

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Hepatitis of Unknown Etiology

Rounding Up the Usual (And Unusual) Suspects

BY MARIE ROSENTHAL, MS

CENTERS FOR DISEASE CONTROL AND PREVENTION

CENTERS FOR DISEASE CONTROL AND PREVENTION

CORONAVIRUS NTROL DISEASE CO CENTERS FOR VENTION AND PRE

INFLUE1NZA J10.

HEPATITIS B

B34.2

070.30 CENTERS FOR DISEASE CONTROL AND PREVENTION

ADENOVIRUS 41 F

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C

ases of hepatitis of unknown origin occur in healthy children, but are rare. So, when Children’s of Alabama saw three cases over the span of about four weeks, the clinicians were quick to alert public health officials.

“All of the cases presented pretty much the same way,” said Markus Buchfellner, MD, a pediatric infectious disease fellow at the University of Alabama and Children’s of Alabama, in Birmingham.

The children were all younger than 10 years of age; most were 5 or younger. “All of them presented with jaundice, all of them presented with sky-high liver enzymes, and all of them had not been feeling well for a few days prior to coming in, but not for too terribly long,” said Dr. Buchfellner, who was a coauthor of a CDC report about the cluster (MMWR Morb Mortal Wkly Rep 2022;71[18]:638-640).

Although they had nonspecific complaints such as fatigue, inappetence, abdominal pain and nausea, jaundice was the primary symptom.

“These were little kids, and all of them appeared jaundiced, so the level of suspicion for a liver injury was pretty high, even in the emergency department when the kids first presented,” Dr. Buchfellner said.

The hospital’s infectious disease division was closely involved in the care of the Alabama patients because the attending physicians wanted a hepatitis workup. They tested for all the usual suspects, Dr. Buchfellner explained, including hepatitis viruses A, B and C, as well as other viral possibilities like Epstein-Barr virus (EBV) and cytomegalovirus (CMV).

“The only thing we could find was adenovirus,” Dr. Buchfellner said. When the first child tested positive for adenovirus, the physicians thought there must be some underlying issue with the child that caused the liver failure. “The first case was on everyone’s mind, so when the second kid tested positive for adenovirus, I felt like that was the start of a pattern,” he said.

Although adenovirus can be a cause of hepatitis among children, it usually occurs in immunocompromised children instead of immunocompetent ones, according to Jay Butler, MD, the deputy director for infectious diseases at the CDC. Between October 2021 and February 2022, Alabama saw nine cases. The cases were baffling because there did not seem to be a commonality that would explain why these particular children were decompensating.

“All of these patients were previously healthy, came from different parts of the state and were hospitalized with significant liver injury without a known cause, including some with acute liver failure,” Dr. Butler said during a media briefing on May 5.

The CDC issued a nationwide health alert about the cluster, asking clinicians to report any suspected cases of hepatitis of unknown origin. By May 18, the agency was investigating 180 cases among children in 36 states and territories that occurred over the past seven months. Between 9% and 15% of the U.S. children suffered liver failure that required transplantation, and

Figure. States reporting at least one person under investigation as of May 18, 2022. Source: CDC

five children died. More than half had a confirmed adenovirus infection, some with adenovirus type 41F, according to Dr. Butler.

Similar Patterns Across the globe, Scotland and several other countries in Europe were seeing similar clusters of children. On March 31, Scotland notified the health board about five children with severe hepatitis of unknown origin not related to any of the hepatitis viruses.

By April 5, the number had doubled. Scotland reported 10 cases of hepatitis of unknown origin requiring hospitalization in previously healthy children younger than 10 years of age to the European public health officials, said Aikaterini Mougkou, of the European Centre for Disease Prevention and Control (ECDC), in Solna, Sweden, at a special virtual presentation during the annual European Congress of Clinical Microbiology & Infectious Diseases (ECCMID 2022).

The ECDC issued an alert similar to the CDC’s, and by May 19, 16 countries reported 308 cases in children 16 and younger: Austria, Belgium, Cyprus, Denmark, France, Greece, Ireland, Italy, the Netherlands, Norway, Poland, Serbia, Slovenia, Spain, Sweden and the United Kingdom. Most (176) cases are from the United Kingdom.

According to the ECDC, as of May 19, there have been 621 cases worldwide, and 14 children have died.

Since these reports, cases have also been reported in Argentina, Brazil, Canada, Costa Rica, Indonesia, Israel, Japan, Panama, Palestine, Singapore and South Korea.

“The clinical picture of all these children presenting with hepatitis—many cases reported gastrointestinal symptoms, including abdominal pain, diarrhea and vomiting in the weeks preceding the presentation with severe acute hepatitis,” Dr. Mougkou said. “Most cases did not have a fever and did not have any significant past medical history. Some of the cases required care at specialist children’s liver units, and a few had liver transplantation.”

Just as in the U.S. cases, the hepatitis viruses were not present, and different countries tested for various other

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2022

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pathogens, including adenovirus, SARS-CoV-2, enterovirus, EBV, CMV, herpesviruses, respiratory syncytial virus (RSV), parvovirus B19, influenza, HIV and the bacteria Leptospira.

Because not every country tested for the same pathogens, “the lab picture is still unclear,” Dr. Mougkou admitted.

“All the cases were negative for hepatitis A, B and C viruses, had elevated transaminases and jaundice. Adenovirus has been detected in many cases among those who have been tested for adenovirus,” she said.

Overall, 151 cases were tested for adenovirus by any specimen type, of which 90 (59.6%) tested positive. The positivity rate was the highest in whole blood specimens (68.9%), which is what the Alabama clinicians found.

Meera A. Chand, FRCPath, a consultant microbiologist with Public Health England, who is currently the incident director for the investigation of these hepatitis cases, also updated her colleagues at the meeting.

She gave more detail about the cases seen in England, some of which are still active cases.

“The clinical presentation as Aikaterini mentioned was led by jaundice and quite prominent gastrointestinal symptoms, which sometimes preceded the jaundice. There were a few respiratory symptoms noted, but much lesser in frequency,” Dr. Chand said.

The median age of the U.K. patients is 3 years. Seven he rest required transplantation. Just as is being seen in the of the world, “the cases in England are not known to be epidemiologically linked. So, they are not contactss of each other, and they are dispersed all over the country,” Dr. Chand said. nsisAlthough testing for adenovirus has been inconsistage tent, adenovirus was confirmed in a high percentage e but of all the children, and many have the 41F subtype, more work is needed before it can be definitively said that adenovirus F41 is the cause of the outbreak, the experts said.

Making the Case for Adenovirus At the beginning of any outbreak investigation, there is a lot of speculation, with many suspects put into the differential, but pinpointing the cause in a multicountry outbreak is even more complex. As Dr. Mougkou mentioned, each country performed different tests, so determining the etiology is still uncertain.

Even the working definition of the condition varied slightly among countries, mostly surrounding the ages of the patients, with some using a cutoff of 10 and others using a cutoff of 16.

The ECDC and WHO suggested a cutoff of 16 to capture as many children as possible. The CDC, however, recommended no cutoff. All agree, however, the vast number of children are very young, typically younger than 5 years of age.

In the United States, much of the investigation is a retrospective review going back seven months, so the cause of the

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U.S. Adenovirus Testing Because the potential relationship between adenovirus and acute hepatitis is still under a national epidemiological investigation, consider collection and submission of the following specimen types (if available) for adenovirus detection: • Blood specimen collected in purple top EDTA tube (whole blood, plasma) or serum; whole blood is preferred to plasma • Respiratory specimen (nasopharyngeal swab in VTM/UTM sputum, or BAL) • Stool specimen (or rectal swab in VTM/UTM); whenever possible, a stool specimen is preferred to a rectal swab • If a liver biopsy has already been performed as clinically indicated, or from native liver explant or autopsy: - FFPE liver tissue - Fresh liver tissue, frozen on dry ice or liquid nitrogen immediately or as soon as possible, and stored at ≤-70°C NAAT, e.g., PCR, is preferred for adenovirus detection (currently not available for FFPE liver biopsy or native liver explant). Testing whole blood by PCR may be more sensitive than testing plasma by PCR and is preferred.

BAL, bro bronchioalveolar lavage; FFPE, formalin-fixed, paraffin embedde NAAT, nucleic acid amplification testing; PCR, embedded; polymera chain reaction; VTM/UTM, viral media transport polymerase

Source: CDC Sourc

acute infection—if it was indeed an infectious etiology—is eeven more challenging, according to Dr. Butler.

“As severe hepatitis can take some time to develop th onset of the first symptoms and as investigaafter the tions take time, there may be a delay in the reporting of cases,” Dr. Mougkou said.

One of the first issues the disease detectives needed to determine is whether these clusters represent a higher number of hepatitis of unknown origin cases than is normally found, and although it is looking like that is the case, they are not yet entirely sure, especially in the United States. “Based on a preliminary analysis of limited data, there has not been a significant increase in pediatric hepatitis cases or liver transplants,” compared with periods before and during the COVID-19 pandemic, Dr. Butler admitted during a media briefing held on May 5.

Pinpointing adenovirus as a cause is tricky, according to Aaron Milstone, MD, a professor of pediatric infectious disease at the John Hopkins University School of Medicine, in Baltimore, who was asked to comment on the investigation.

First, it is not a reportable disease in the United States, so it’s not a routine test a physician would request during the workup of an acute “stomach flu” or cold. And because of the timing of the hepatitis, antibodies might or might not be present.

“Most kids with a respiratory illness or a ‘stomach bug’ are never formally diagnosed with adenovirus, because kids get better quickly and testing is often not done,” Dr. Milstone said.

Umesh Parashar, MD, the chief of the CDC’s Viral Gastroenteritis Branch, Division of Viral Diseases, reiterated Dr. Milstone’s observation. “It is not a reportable disease in the U.S.,” he said. “It is not a pathogen that clinicians would typically test for, and there is no specific treatment if you diagnose it. So, our surveillance really relies on passive reporting, and we don’t have very good national systems for [testing for] adenovirus 41 type, but we are working to get data from certain clinical laboratories,” Dr. Parashar explained.

Just because a sample tests positive does not mean that adenovirus is the cause, Dr. Milstone reminded. Because adenoviruses are common, a child could have had an infection weeks ago and recovered, and then presents with an inflamed liver from another cause, such as an acetaminophen or paracetamol toxicity, but they may still test positive for adenovirus. A positive test does not prove cause and effect.

“There are a lot of dots that have to get connected as they try to understand why these patients [have hepatitis] or what’s the common link,” Dr. Milstone said.

“It is quite challenging from a public health perspective to see something like this happening but not to have a clear sense of etiology, and therefore [not knowing] which control measures you might be able to put in place,” Dr. Chand admitted.

“We don’t have answers yet, but we do have hypotheses, and perhaps, the first few pieces of the puzzle as we start to test these hypotheses,” Dr. Chand added.

In some ways, the United Kingdom is set up quite nicely for this particular investigation, because the handling of pediatric liver injury cases is centralized. Hospitals all over the United Kingdom refer to one of three specialist units. The majority of cases are managed in their home hospital with support from the liver units. Sicker patients and those requiring transplants are transferred to one of the three centers.

“Using that network is actually a very good way for us for case finding on a national basis,” she said.

However, it is difficult to gather, analyze and report realtime data, admitted Dr. Chand, who played a significant role during the pandemic as a national public health incident director for COVID-19 in England.

COVID-19, of course, hangs over every investigation, not only because some of the children tested positive for SARSCoV-2 but because public health resources are still very much focused on the COVID-19 response. “Acquiring this information quickly requires a strong public health infrastructure,” Dr. Milstone reminded.

“The speed and the depth that we see investigations happen are most influenced by existing public health infrastructure,” Dr. Milstone said. “I would say that the infrastructure is better right now, but remains fragile. We’re in a better position

maybe than we were in the past, but we are in a fragile position because I can see funds getting diverted elsewhere.”

In addition to an infectious etiology, investigators are ruling out food and water sources, medications and other exposures, such as a household pet. They are looking at the families of the children to see if there is any epidemiological link, household illnesses and household occupations, which could explain the cases.

“While this trawling is going on, we have done a reasonable number now, around 60, and there really is no common exposure,” Dr. Chand said at ECCMID. If adenovirus is determined to be the cause, epidemiologists will want to determine why, explained Dr. Chand. Therefore, pathogen exceedance will be examined to determine whether there is a signal related to the pattern of adenovirus in the community, or virulence or something else that is novel about this particular subtype.

“We are seeing that in the enteric samples, adenovirus exceedance. So, it’s reasonably marked, and there is a strong effect in our age group of interest—this age 3 to 5 group,” Dr. Chand said.

Investigators also want to determine why these particular children who are infected with adenovirus decompensate.

There is some speculation being given to a possible lack of exposure, especially for the very young children. Because people were sequestered in place for two years, and many children did not attend day care or go to in-person school, there were fewer respiratory and gastrointestinal viruses in circulation, and very young children may not have encountered some of the more routine viruses.

“Young children have had less exposure to common childhood infection,” Dr. Milstone said. “But when they all got back together, each virus is new to the immune system. So, I don’t think this was an immune dysregulation.”

Another issue that they do not know is whether this will be a seasonal problem. Adenoviruses typically circulate in the winter and spring, but COVID-19 certainly broke those rules, Dr. Milstone reminded. “We used to have great ability to predict the seasonal pattern of most viruses,” he said. “COVID really ruined that. We didn’t see RSV for more than a year in kids, and then it showed up in late August. I think the COVID pandemic has, at least for now, changed when viruses circulate,” he said.

“So, where does that leave us with our hypotheses at the moment?” Dr. Chand asked. “I think our leading hypothesis, given the data that we’ve seen, would probably be that we have a normal adenovirus circulating. We may not have seen as much of it as we have for the past couple of years, but it is just one of the adenoviruses that we are familiar with. But we have a cofactor affecting a particular age group of young children, which is either rendering that infection more severe or causing ■ it to trigger some kind of immunopathology,” he said.

The sources reported no relevant financial disclosures.

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2022

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Epidemiologists Don't Have the 'Bandwidth' to Respond Quickly to Outbreaks

BY TOM ROSENTHAL

“That’s 1,000 individuals [a day] we have to interview. Then we have to get that information in the database and then that he number of epidemiologists in large health departments information has to be crunched. There’s no way you can keep need to nearly double to respond quickly to public health up with that.” threats, according to a recent report by The Big Cities Health The report clearly demonstrates the need, not only for epiCoalition (BCHC) and the Council of State and Territorial demiologists but more funding in general. "Federal resources Epidemiologists (CSTE). to fight COVID-19 are not reaching health departments on the “The shortfall puts the nation’s efforts to combat future and front lines where they are needed most," Dr. Roberts said. current pandemics at risk,” Chrissie Juliano, MPP, executive direcThe past two years have taken a tremendous toll on public tor of the BCHC, said at a media briefing releasing the report. health departments, they said. Emergency COVID-19 funding To reach full capacity, departments reported the need to will soon disappear, “presenting yet another ‘funding cliff ’ for increase their epidemiology staffs by 47% “to promote and public health,” Dr. Robert said. “Cities need direct, sustained protect the health and safety of the nearly 62 million people funding to make our nation prepared for the next pandemic they serve,” Ms. Juliano said. “Together and to fight ongoing health crises like gun these public health officials directly affect violence and the opioid epidemic.” the health and well-being of nearly one in The participants said health departments five Americans. BCHC sees the findings shifted many of their epidemiologists to of this report as vital to the health of folks manage the pandemic, leaving numerous who live in these cities.” other critical areas less than adequately Only 1,284 epidemiologists worked in the covered. “Almost half of BCHC epis are Public health 26 participating BCHC departments during working on COVID,” Ms. Juliano said, with the survey from January to May 2021. More another 27% focusing on infectious disofficials in large than 175 positions went vacant in 2021— eases and 8% working as generalists. cities affect the more than double the open positions four Local health officials are making tough health of nearly years earlier, the report found. decisions, not only diverting key staff from The need to increase the number of epichallenges like gun violence and overdoses, 1 in 5 Americans. demiologists in local health departments but also from obesity, tobacco use, sexually Source: BCHC became dire during the COVID-19 pantransmitted diseases, as well as maternal demic, according to Mysheika Roberts, MD, and child health and infant mortality.

MPH, Columbus, Ohio, health commissioner and BCHC chair, “These disease detectives collect, analyze and deliver timely and Janet Hamilton, MPH, CSTE, the executive director. outbreak data to inform both policymakers and the public Dr. Roberts said in response to a question from Infectious where outbreaks are happening and how they can be stopped,” Disease News Special Edition that calls to the Columbus Health Ms. Hamilton said. “This study makes clear what we knew Department epidemiologists about infectious diseases went anecdotally: Big cities need more staff and resources to from about 40 a day before the outbreak to more than 1,000 address the magnitude of the public health concerns in their ■ daily at the height of the COVID-19 pandemic. jurisdictions.”

“So even if you were fully staffed, you don’t have the bandwidth to expand to that volume that quickly,” Dr. Roberts said. The sources reported no relevant financial disclosures.

T

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Long COVID: Learning as We Go Patterns are beginning to emerge as more patients are being referred to post–COVID-19 clinics in the United States.

BY LANDON GRAY

T

he hallmark of the early days of the COVID-19 pandemic has been treating a large number of people who need immediate attention without having the data to support those interventions. And, unfortunately, that seems to be happening with post-acute sequelae of COVID-19 (PASC): The immediate need to treat people must be weighed with providing the best care possible, often without the data to support the interventions.

Much is still unknown about the prolonged and enduring physical and mental effects of COVID-19, but experts are studying and implementing new interventions designed to mitigate the effects of PASC, commonly known as long COVID or long-haul COVID. Patterns are beginning to emerge as more patients are being referred to post–COVID-19 clinics in the United States.

Commonly reported symptoms include fatigue, shortness of breath and brain fog.

David Beckham, MD, an associate professor of medicine,

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immunology and microbiology, and neurology at the University of Colorado Health Infectious Disease Clinic, Anschutz Medical Campus, in Aurora, told Infectious Disease Special Edition that hospitalization from SARS-CoV-2, so far, is the most prominent predictor of which patients will be affected by long COVID. Vaccinations and boosters are still key in reducing the risk for hospitalization due to COVID-19 among the general population, but crucial to those who have an increased risk.

“The people who are the highest risk for long COVID are people who are hospitalized with COVID-19,” Dr. Beckham said. “We also know, the big predictors, or risk factors for long-COVID syndromes are 1) age, 2) female sex, 3) obesity and then the other kind of comorbid conditions—diabetes, things like that. So, if we target those folks with vaccination and prevent them from getting into the hospital, then their risk of long COVID goes down significantly.”

Just as acute COVID-19 disproportionately affected certain groups, namely Blacks and Hispanics, PASC appears to be

disproportionately reported in women. However, Dr. Beckham said providers don’t know why women are more susceptible to long COVID, but it may have a correlation to autoimmunity, although more studies are needed to support that relationship.

“Definitely, there is a higher incidence of post-COVID symptoms in women than men. That’s been shown in several studies now,” said Dr. Beckham, who added that women have a higher incidence of autoimmune diseases. “We don’t know why that is, but there’s clearly a predilection for women to have a higher incidence of these kinds of immune-mediated injury responses. It’s definitely something that we need to study and understand more, because it’s important to understand what underlies those sex differences.”

While the absolute predictive factors are still unknown, Tae Chung, MD, an assistant professor of physical medicine and rehabilitation at the Johns Hopkins University School of Medicine, in Baltimore, said PASC could be an autoimmune phenomonon.

He compared long COVID with postural orthostatic tachycardia syndrome (POTS), which also affects more women than men. “[With POTS] there’s sympathetic innervation, especially to the blood vessels. That’s causing a lot of blood flow dysregulation causing brain fog, severe chronic fatigue, and exercising tolerance.”

Dr. Chung offered an explanation based on his own ongoing research as to why women appear to be at higher risk. The idea is that the COVID virus spike protein has an antigen with the molecular surface that resembles some part of the woman's autonomic nervous system. So, maybe certain populations had this kind of antigen in their autonomic nervous system that looks very similar to their spike protein. Once they get rid of COVID, their antibodies attack their own nervous system.

It’s possible.

“I think there’s a kind of genetic predisposition to make them vulnerable to this kind of autoimmune attack,” Dr. Chung told Infectious Disease Special Edition.

John Baratta, MD, the founder and a co-director of the UNC COVID Recovery Clinic, in Chapel Hill, N.C., agreed that factors such as vaccination and booster status, comorbidities, hospitalization for COVID-19, and sex are possible predictors of PASC. “The risk of long COVID is increased in those who were hospitalized and in the ICU, as well as for those who have not been fully vaccinated. Also, people with medical comorbidities, such as diabetes or obesity, have a higher risk of developing long COVID. And unfortunately, long COVID is seen more in women. In our clinic and others throughout the country, referrals for women outpace men by about a 2-to-1 ratio,” he said.

However, not everyone is seeing this trend toward women, according to Alexandra Kadl, MD, the director of UVA Health’s Post-COVID Clinic, in Charlottesville, Va., who said referrals to

her clinic have been somewhat equal between men and women.

She offered a more nuanced hypothesis for the skewed ratio that some are seeing: Some people are just more reluctant to go to the doctor.

“I think there’s a big concern from the patient side to actually ‘confessing’ some of their symptoms, because it might affect how they work, could affect how they are seen in public, and I think it’s really important that we provide COVID care to all these patients and really listen to the symptoms patients come up with, and take them for real, because those symptoms are very vague.”

Similarly, Nahid Bhadelia, MD, the founding director of the Boston University Center for Emerging Infectious Diseases Policy and Research, described the patients referred to her clinic during an Infectious Diseases Society of America (IDSA) media briefing on long COVID. “I work at Boston Medical Center, and up to 40% of our patients in the acute setting are patients who are from socially disadvantaged backgrounds. In the worst months of this pandemic, we know when 70% of our inpatient wards were filled with COVID patients, that’s who we were seeing—front-line essential workers from many communities that were hard-hit.

Most Common Characteristics of Hospitalized Patients With Long COVID

82.7% Non-Hispanic 44.4% Black 55.4% Female 43.9% 46-65 years 20.1% Diabetes Lancet Digital Health 2022 May 16. https://doi.org/10.1016/S25897500(22)00048-6

“But we’ve had a long COVID clinic now for a few months, and we’re not seeing many of those patients actually coming in for care. And that raises a big question, not just for clinical care, but also for research in terms of understanding the burden of long COVID and other post-acute sequelae of SARSCoV-2 among populations, among communities that were heavily hit,” Dr. Bhadelia said.

On-the-Job Training Complements and contradictions are not uncommon to doctors studying and treating COVID-19 survivors, the experts said. Post–COVID-19 centers and clinics all over the country have allowed doctors to observe and treat long-haulers in real time, learning as they go. With the broad symptoms ranging from mild to severe, experts are having to learn how to distinguish the ones directly linked to COVID-19 survivors’

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2022

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5 Major Risk Factors for PASC

1

Vaccination status

2

Hospitalization

3

initial infections, separating out what could be undiagnosed chronic conditions.

Dr. Baratta explained that since the symptoms are wideranging, it can be difficult to tease out which symptoms are directly linked to COVID-19. “Long COVID is a heterogeneous syndrome, and that makes it challenging to delineate clearly.

The most common symptoms that we see include fatigue; respiratory discomfort, such as shortness of breath and cough; brain fog, including memory and attention impairments; pain; and psychological issues, including anxiety, depression and PTSD [post-traumatic stress disorder].”

He added fatigue is the most commonly reported symptom associated with PASC, and almost without exception, every treated patient suffers from it.

Dr. Baratta said rigorous, targeted testing is crucial to determine whether symptoms stem from a COVID-19 infection.

In the instance of fatigue, he said, his clinic looks for other conditions that could contribute to fatigue, including anemia, thyroid complications, cardiovascular disease, etc. When these other potential causes are ruled out, they can assume COVID-19 is their likely culprit; and in the case of fatigue, a “structured activity program” would be initiated to boost energy and endurance.

Dr. Beckham also addressed fatigue as the most commonly reported symptom of PASC, and found rehab—for example, pulmonary rehab approaches—has been the best intervention.

He theorized that a good portion of PASC-related fatigue may be a result of COVID-19–related lung injuries.

“It’s interesting, because in the studies of post-COVID syndromes, fatigue tends to track with shortness of breath, and then also [with] severity of disease. Probably what’s going on, is the fatigue is a symptomatic outcome of lung injury.

And so, people have [fatigue], and that’s why it’s tracking with hospitalization. People that have more lung injury are more likely to be hospitalized, and then in their recovery, they have decreased lung function. So, that results in fatigue and shortness of breath and extra decreased exercise tolerance.”

Dr. Kadl also advised fellow clinicians to focus on rehab therapy when discussing lung components, but not to become frustrated when some patients aren’t so easily categorized. She also specifically advised against the empiric use of antifibrotics,

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Age

4

Being female

5

Obesity, heart disease and other comorbid conditions

due to lack of evidence of clinical benefit and high cost.

Evidence-based treatment does n0t exist for patients who are not suffering from pulmonary-related symptoms but still reporting fatigue, anxiety, depression and similar complaints.

However, Dr. Kadl said, occupational therapy—where patients learn how to manage their day-to-day issues—may be a viable option along with treating depression and sleep disturbances.

Dr. Kadl hypothesized that if 10% to 30% of COVID-19 survivors develop long COVID, these patients won’t be treated by subspecialists, but by their primary care physicians, which would put a major strain on doctors.

“I do think that we have to be very open-minded and try to reinforce and provide acceptance to those patients [with vague symptoms]. I do think that it’s not going to be subspecialties in the future that will treat them because there’s just too many patients out there. So, it is a big burden on family practitioners and primary care doctors that will see a good load of patients with non-COVID symptoms.”

Kathleen Bell, MD, a professor and the chair of the Department of Physical Medicine and Rehabilitation at The University of Texas Southwestern Medical Center, in Dallas, also spoke during the IDSA briefing about new systems in place to help clinicians and medical providers keep track of PASC patients.

“One of the things that’s been extremely helpful to practicing physicians and researchers alike is that the [Centers for Medicare & Medicaid Services] has established a set of codes that specifically allow us to code visits to post-COVID symptoms, so that we can actually now track patients and treatment through the line—longitudinally following patients across the healthcare system, for instance, which is going to make it much easier to really track these patient populations and figure out what’s going on with them.” (Find out more about the codes at https://go.cms.gov/3OU0JjU.) No matter how broad or vague, a good number of longhaulers, regardless of age and sex, are experiencing debilitating symptoms. Recognition and validation are important to the treatment of these patients; their symptoms are real, Dr. ■ Chung warned.

Dr. Chung is a consultant to Argenx Pharmaceuticals. The other sources reported no relevant financial disclosures.

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News Can Music Soothe The Ravaged Lung?

A new study looks at just why some people become sicker with COVID-19 than others: It might have to do with the types of macrophages they produce. Speaking of the immune system, one might think cancer patients would be at higher risk for severe disease because they are immunocompromised, but a new study says that is not necessarily true. Many Black and Hispanic women who are pregnant suffer more severe illness if they become infected with COVID-19. The folks at Children’s Hospital of Philadelphia looked into why. And finally, music might soothe the ravaged lung.

—Marie Rosenthal, MS

Why Do Some People Get Sicker Than Others?

A new study suggests those who escape the worst symptoms of COVID-19 might have the right balance of a type of macrophages (Cell Rep 2022 Apr 3. doi:https://doi.org/10.1016/j. celrep.2022.110714).

Using a mouse model, researchers at Boston and Princeton Universities found a set of genes that determine whether immune cells mount a solid defense or turn rogue and land someone on a ventilator.

The team developed a new animal model: a mouse engrafted with human lung tissue and bolstered with a human immune system derived from stem cells to monitor the different stages of SARS-CoV-2 infection and COVID-19 disease. Mice with human lung tissue, but without the human immune system, don’t react well to infection—the model lung tissues are damaged similarly to the lungs of people with a severe case of the disease. But when the investigators studied mice that also had a humanized immune system, it was different.

“We were barely seeing any virus in the lungs,” said Florian

Douam, PhD, an assistant professor of microbiology at BU School of Medicine. “The lung was protected. Then we asked the question, ‘Why is the lung protected?’ And this is where we found the macrophages.”

There was a lack of macrophage diversity in the damaged lungs, and the overactive immune response was dominated by pro-inflammatory macrophages called M1. “It seems they drive this hyperinflammatory response, and it leads to a more severe disease state,” said Devin Kenney, a PhD candidate in Dr. Douam’s lab.

By contrast, those immune systems that mixed in more M2 or regulatory macrophages, which typically help in wound repair, fared better. The researchers linked this positive antiviral response to a set of 11 genes they called “protection-defining genes.”

“We now know not only that macrophages can promote protection in the lung tissue, we also know the key set of genes that these macrophages need to express to protect the lung,” Dr. Douam said.

Can Online Singing Program Improve COVID-19–Related Breathlessness?

An online breathing program, similar to one used by opera singers, helps improve quality of life and breathlessness for people recovering from COVID-19 (Lancet Respir Med 2022 Apr 27. doi:https://doi. org/10.1016/S2213-2600[22]00125-4).

The ENO Breathe program was developed by the English National Opera (ENO) and respiratory clinicians at Imperial College Healthcare NHS Trust, in London. It uses singing techniques to help patients with persistent

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breathlessness due to COVID-19.

A clinical trial involving 150 participants with continuing breathlessness, for an average of 320 days since the onset of COVID-19 symptoms, was conducted by researchers at Imperial College London alongside the program team at Imperial College Healthcare. Most (81%) of the participants were female.

Participants were divided into two groups. One group (n=74) took part in the six-week ENO Breathe program

and a control group (n=76) continued with their usual care as directed by their post-COVID-19 assessment clinic. Both groups were assessed after six weeks, at which time the control group was also offered the opportunity to take part in the program.

The researchers collected information about participants’ health and well-being via online questionnaires, and used focus groups and feedback questions to assess participant experience. They measured

Neighborhood Crowding, Poverty Associated With Higher Rates of COVID-19 in Pregnancy

Cancer History Not Associated With Higher Risk for Severe COVID-19

Neighborhood characteristics, including poverty and crowding, were associated with higher rates of SARS-CoV-2 in pregnancy before the COVID-19 vaccine was available (Obstet Gynecol 2022 June. doi: 10.1097/AOG.0000000000004791).

Investigators at the Children’s Hospital of Philadelphia (CHOP) had reported that positivity for SARS-CoV-2 was five times higher among pregnant Black and Hispanic patients than pregnant white females.

To better understand the role that neighborhood environments might play in driving these disparities, the researchers analyzed a cohort of 5,991 pregnant patients who gave birth at two hospitals in Philadelphia between April 13 and Dec. 31, 2020. They tested serum samples for antibodies to SARS-CoV-2, which would indicate current or prior infection, given that vaccines were not yet available and antibodies persist for some time after infection.

Race and ethnicity were determined based on patients’ self-reported answers in their medical record. The researchers also geocoded patients’ residential addresses to assess three census tract variables: community deprivation, based on factors such as the proportion of residents with income below the federal poverty line, without a high school diploma and lacking health insurance; racial segregation, based on the extent to which a neighborhood was all Black or all White or something in between; and crowding, defined as the proportion of residences with more occupants than rooms in the house.

Examining the entire cohort, the researchers found 9.4% of all patients tested positive for SARS-CoV-2 antibodies. Higher rates of positivity were seen among Hispanic (19.3%) and Black (14%) patients than Asian (3.2%) and white (2.7%) patients, as well as those of another race or ethnicity (5.9%). Using statistical tools, the researchers found that deprivation and crowding were associated with positivity for SARS-CoV-2, whereas racial segregation was not.

Their statistical analysis showed crowded housing might explain 6.7% of the Hispanic-white disparity and neighborhood deprivation might explain 10.2% of the Black-white disparity.

Timing of a patients’ past cancer diagnosis and ongoing treatment state is critical in the response to COVID-19, according to a new study led by UTHealth Houston (PLoS One 2022 May 4. https://doi.org/10.1371/ journal.pone.0267584).

Using electronic health records from more than 700 hospitals and 700 clinics in the United States, a multiinstitutional team assessed the association between COVID-19 outcomes and existing cancers.

“We found that recent cancer diagnoses were associated with a 17% increased risk for death and 10% increased risk for hospitalization,” said Youngran Kim, PhD, in the Department of Neurology at McGovern Medical School, UTHealth Houston.

“However, a history of cancer more than one year before COVID-19 diagnosis was not significantly associated with increased mortality or hospitalization.”

The researchers analyzed 271,639 adults diagnosed with COVID-19 between June 1 and Dec. 31, 2020; 18,460 also had at least one cancer diagnosis, including 10,426 patients diagnosed with cancer within a year before their COVID-19 infection.

Multiple outcomes were examined, including allcause 30-day mortality, hospitalization, admission to the ICU and ventilator use, which were compared using relative risks according to cancer status and treatments.

Recent cancer diagnoses were associated with higher risks for worse COVID-19 outcomes, particularly for metastatic hematologic, liver and lung cancers, compared with the noncancer group. Among COVID19 patients with a recent cancer diagnosis, a higher chance of death was related to chemotherapy or radiation treatments within three months before SARSCoV-2 infection.

physical and mental components of a validated Health-Related Quality of Life tool that assesses key indicators of quality of life, including difficulties resulting from health problems, social impacts, pain and effects on daily activities. The researchers also examined other disease effects including breathlessness, anxiety and many other symptoms.

The ENO Breathe participants experienced a 10.48-point (out of 100 points) reduction in breathlessness while running compared with people who

continued with usual care alone. They also had a 2.42-point improvement in the mental component of quality of life.

Participants who attended all the sessions found improvements in a wider range of respiratory symptoms and anxiety, and larger quality-of-life improvements. For example, 40% of program participants experienced a 5-point improvement in the mental component of quality of life, compared with 17% in the usual care group. However, the physical component of quality of life did

not improve more in either group.

ENO Breathe uses weekly online group sessions and digital resources, developed with the support of healthcare professionals, to empower participants with tools and techniques to improve the way they breathe and how they engage with their breathing. The program is led by professional singers from the ENO and focuses on breathing retraining through singing techniques, using lullabies as its musical starting point. No experience or ■ interest in singing is required.

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2022

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Adults Aged 50+ Diagnosed With COVID-19 At Greater Risk for Developing Shingles

BY RENÉE BACHER

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here is a significantly increased risk for developing herpes zoster, or shingles, in adults aged 50 years and older who have been diagnosed with COVID-19, according to a retrospective cohort study (Open Forum Infect Dis 2022;9[5]:ofac118).

“The COVID-19 pandemic exposed how vulnerable older adults are to infectious disease,” said lead author Amit Bhavsar, MBBS, MHA, a physician and the director of clinical research and development at GSK in Belgium.

“We wanted to expand research to further understand the impacts of the pandemic on adults aged 50 or older, which led to this first-of-its-kind observational study between COVID-19 and zoster,” he added.

The researchers performed a large retrospective cohort study to assess the risk for developing shingles after a COVID19 diagnosis. They compared the incidence of shingles in people 50 years of age and older diagnosed with COVID19 versus those without COVID-19. They used data from the MarketScan Commercial Claims and Encounters and Medicare Supplemental (March 2020 to February 2021) as well as the Optum Clinformatics Data Mart (March to December 2020) databases.

A Higher Risk Seen According to the study, the researchers exact-matched individuals with COVID-19 1:4 to those without COVID-19 by age, sex, presence of risk factors for shingles and healthcare cost level. They estimated adjusted incidence rate ratios (aIRRs) by Poisson regression. They matched a total of 394,677 individuals 50 and older with COVID-19 to 1,577,346 without COVID19. They balanced mean follow-up time after COVID-19 diagnosis and baseline characteristics between cohorts. Those diagnosed with COVID-19 had a 15% higher risk for developing shingles than those without COVID-19 (aIRR, 1.15; 95% CI, 1.07-1.24; P<0.001). The increased shingles risk was more pronounced (21%) following COVID-19 hospitalization (aIRR, 1.21; 95% CI, 1.03-1.41; P=0.02).

“Interestingly, the study showed that not only were people aged 50 or older who contracted COVID-19 15% more likely to develop shingles compared [with those who did not have COVID-19], but the risk of shingles was elevated for up to six months after a COVID-19 diagnosis,” Dr. Bhavsar said.

Prior to this study, a series of case reports and descriptive analyses showed a possible association between COVID-19 and shingles in older people during the first year of the pandemic (Dermatol Ther [Heidelb] 2021; 11:1119–26).

It was hypothesized that after initial infection with COVID19, if sufficient levels of varicella-zoster virus (VZV)-specific

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T-cell immunity weren’t maintained and cell-mediated immunity declined, VZV reactivation leading to herpes zoster could be triggered (J Clin Virol 2010; 48:S2–7). (Older people, for example, could be more vulnerable due to immunosenescence or immunosuppressive conditions.) But until this study, the evidence wasn’t yet there.

Abinash Virk, MD, an infectious disease specialist at Mayo Clinic in Rochester, Minn., finds the outcome of this study unsurprising and yet also very interesting. “We do know that COVID-19 does likely cause short-term relative T-cell immunosuppression, which can then result in reactivation of some viral infection or other opportunistic infections,” she said, adding that “it’s important to realize that there are other vaccine-preventable diseases that can occur in these patients and alert primary care providers.”

Although the study design controlled for possible confounding, other factors may have affected the observed shingles risk, according to Dr. Bhavsar. For example, the analyzed databases contain no information on race and ethnicity. As COVID-19 has disproportionately affected the Black population, the COVID-19 cohort in this study may include proportionately more Black adults than the non–COVID-19 cohort. This may have led to an underestimation of the effect of COVID-19 on shingles, given that Black adults have a lower risk for shingles than those who are white.

Dr. Virk said she would have expected higher rates of herpes zoster in patients who receive tocilizumab (Actemra, Genentech) and other immunosuppressive regimens for the management of COVID-19, but the researchers did not identify this particular patient group separately.

“Therefore, it would be particularly helpful to look at patients who received immunosuppressive regimens for hospitalized COVID-19 infection,” she said. “Additionally, [it is] also important to look at older patients and those with immunosuppression.” Dr. Virk said she would like to know whether the shingles vaccine is still protective in these patients.

According to Dr. Bhavsar, an Avalere Health report showed that cumulatively, from January 2020 to July 2021, adults and teens may have missed an estimated 37.1 million doses of recommended vaccines compared with 2019 (https://avalere.com/ insights).

“It is critical that we, as infectious disease specialists, work to educate and vaccinate patients with all the recommended vaccines,” Dr. Bhavsar said, “so that the COVID-19 pandemic ■ does not continue to impact routine preventative care.”

Drs. Bhavsar and Virk reported no relevant financial disclosures outside of their employment.

Improving Outcomes for Drug Use–Associated Endocarditis

BY IDSE NEWS STAFF standard treatment compared with the standard approach. Of utpatient parenteral antimicrobial therapy (OPAT) and all four strategies, the addition of oral antibiotics and OPAT partial oral antibiotic therapy regimens were as effective led to the greatest cure rates (80.3% and 78.8%, respectively, and less expensive than admitting patients with injection drug compared with 77.6% for inpatient IV antibiotic therapy plus use–associated endocarditis for six weeks of IV antibiotics. addiction care services and 77.6% for inpatient IV antibiotic A new modeling study suggested that when patients who inject therapy only). opioids continue an antibiotic treatment for infective endocarThe strategy that included OPAT also cost less than the ditis outside of the hospital, they experience better other strategies. The researchers suggest that these stratelong-term health outcomes than those who receive gies could save the U.S. healthcare system more than $6 the standard inpatient IV antibiotic therapy. In billion per year in hospitalizations alone. addition to reducing infective endocarditis–related One in 10 hospitalizations for endocarditis is assocideaths and extending life expectancy, these outated with injection drug use, and these numbers conpatient strategies are more cost-effective than tinue to rise. Inadequate access to sterile injection the standard approach (JAMA Network Open equipment is common, and dramatically increases 2022;5[2]:e220541). risk for infection in people who use drugs.

Twenty percent of patients admitted with Research estimates that if current trends drug use–associated endocarditis leave the hoscontinue, more than 250,000 Americans will pital before completing treatment. Fewer than die of drug use–associated endocarditis from 8% are subsequently connected with addiction 2020 to 2030. care services that provide further healthcare and “Endocarditis is one of the numerous harms support upon discharge. associated with injecting drugs,” said National 1 in 10 The researchers investigated the efficacy of Institute on Drug Abuse Director Nora D. outpatient treatment for infective endocarditis.

MD. “Developing effective, patienthospitalizations Volkow, They created a robust model that simulated the centered treatment for this potentially fatal for infective condition is critical. It is also imperative to natural history of injection opioid use in 5 million individuals. The population for this model and implement harm reduction strateendocarditis embrace had a mean age of 42 years and 70% were male, gies, such as syringe services programs, which reflecting the age and gender demographics for are associated we know can help prevent endocarditis in the the U.S. population of people who inject opioids, place.” with injection first informed by previous studies and the U.S. Census.

The results still need to be tested in randomdrug use. ized clinical trials that include people who inject They compared life expectancies, rates of treatment completion, endocarditis and overdose deaths, drugs. The researchers also emphasize the need for and average costs across four treatment strategies in these a national surveillance system for injection drug use–related individuals. Two of the treatment strategies offered the standard endocarditis, based on existing surveillance strategies for four to six weeks of inpatient IV antibiotics, either with or with- HIV and hepatitis C. Expanding research in this area could out inpatient addiction care services. The other two strategies strengthen evidence for patient-centered decision making provided three weeks of inpatient IV antibiotics and addiction when offering treatment strategies for endocarditis. care services followed by either OPAT or oral antibiotics after “Outpatient treatment approaches for endocarditis may discharge. not only save lives, but also save money that could then be Of note, the scientists accounted for socioeconomic chal- allocated to evidence-based programs for the opioid crisis,” lenges such as homelessness by assuming that only half of the said Joshua Barocas, MD, of the Unversity of Colorado School hospitalized patients could receive OPAT. of Medicine in Denver.

In individuals hypothesized to contract infective endocardiStrategies should also include the promotion of safer injectis according to the model, the researchers found a substantial tion practices, access to medications for opioid use disorder ■ increase in life expectancy and decrease in mortality caused and funding for outpatient support services, he said. by endocarditis or overdose for individuals who received OPAT, oral antibiotics or inpatient addiction care services with Dr. Barocas reported no relevant financial disclosures.

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INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2022

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Could Earlier Recognition Lessen The Economic Toll of Fungal Infections?

BY BOB KRONEMYER

H

ealthcare costs for fungal infections are staggering in the United States.

In 2018 alone, the estimated expenditure was $6.7 billion for roughly 666,235 infections, according to a recent study in Open Forum Infectious Diseases (2022 Jan 10. doi:org/10.1093/ ofid/ofab593).

“Many of the current diagnostic methods take days and can still fail to specify a specific pathogen,” said lead investigator Emily Rayens, PhD, a postdoctoral research associate in the Center for Vaccines and Immunology and Department of Infectious Diseases at the University of Georgia, in Athens.

“This means that fungal infections are chronically underdiagnosed, and the number of infections that occur in the U.S. is even higher than current estimates.”

Apart from the challenges of diagnosis and treatment in the clinical setting, “there are few estimates on the burden of fungal disease,” Dr. Rayens said. “These estimates have primarily been limited to clinical observations because there are almost no coordinated surveillance [methods] for fungal disease.

However, we can use national anonymized patient data sets to make an educated estimate of the burden of disease, as well as the impact on patients.”

The study assessed hospital discharge data from the most recent Healthcare Cost and Utilization Project National Inpatient Sample, and outpatient visit data from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey, all conducted in 2018.

Aspergillus, Pneumocystis and Candida infections represented 76.3% of all fungal infections diagnosed, and 81.1% of connected costs.

Roughly 32,000 deaths were reported in patients with any fungal diagnosis, of which about 1,440 deaths were hospital

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admission for fungal infections.

“Most invasive infections—whether they are fungal, bacterial or viral—will have a serious toll on patients, especially those with compromised immune function,” Dr. Rayens said.

“However, the extent to which fungal infections impact these patients and the magnitude of the associated healthcare costs may be surprising.”

Quick Response Best The findings will hopefully reinforce ongoing research efforts to improve diagnostic and treatment options, Dr. Rayens noted. “Further, the demonstrated frequency of these infections, particularly among patients who are immunocompromised, should raise awareness of the clinical risk,” she said.

“The sooner we can identify and treat a fungal infection, the better the outcome for the patient.”

One strategy to reduce the incidence of fungal infections is ongoing public health efforts; for instance, since the early 2000s, there has been a dramatic decrease in the number of fatal cases, due to efforts that help people with unmanaged HIV/AIDS. “Nonetheless, the current and growing population that we see as ‘high risk’ for fungal infections cannot be reduced,” Dr. Rayens said. “This includes many transplant recipients, cancer patients undergoing chemotherapy or radiation treatments, and patients on medications to treat autoimmune or inflammatory disorders.”

A broader prevention strategy is an antifungal vaccine that targets multiple fungal infections, which Dr. Rayens’ laboratory is developing and that would reduce both the incidence of disease and the associated healthcare costs.

“But the quickest way to decrease healthcare costs for fungal

infections is simply treating them sooner, or even preventing allowing for antifungal treatment that could prevent poor them from occurring at all,” Dr. Rayens said. “These include outcomes.” improvements in diagnostic testing to decrease the time to In addition, bolstering public awareness about these disidentification of specific fungi, increased physician awareness eases and clinician education can lead to better diagnosis and and screening for fungal infections, and identification and treatment. “We also need to ensure we are detecting emerging monitoring of patients that may be at a particularly high risk.” threats to prevent them from becoming bigger problems,” Dr. A second study in Open Forum Infectious Diseases (2022 Mar Jackson said.

23. doi:10.1093/ofid/ofac097) conservatively estimated that the Tom Chiller, MD, the chief of the CDC’s Mycotic Diseases U.S. economic burden of fungal diseases was $11.5 billion in Branch, noted there is great potential for future disease caused 2019, with direct medical costs totaling $7.5 billion, productiv- by fungi. “Fungi represent a kingdom of organisms,” he said. ity loss due to absenteeism pegged at $3.2 billion and prema- “It is estimated there are around 5 million species. However, ture deaths costing $3.2 billion. we have identified perhaps only 125,000 species, of which An alternative “value of statistical life” calculation came in probably less than a few hundred cause human disease and at more than $48 billion in 2019. less than 100 species cause the majority of human disease.”

“Because fungal diseases are diverse, there is no one-sizeEnvironmental changes are also making new fungi emerge fits-all solution for mitigating their substantial health and because fungi largely live in the human environment. “Fungi economic burden,” said co-author Brendan Jackson, MD, a are very sensitive to the changes that are happening with medical epidemiologist in the CDC’s Mycotic Diseases Branch. temperature and weather,” Dr. Chiller said. “Therefore, they “Fortunately, there are several different strategies that can can outcompete their friends and neighbors for the highest save lives, prevent hospitalizations and reduce costs.” position on the totem pole, so to speak.”

Besides fungal vaccines being developed, “we need to The good news is that most emerging fungi tend to be rare. learn more about where some of these fungi live and how to “But as patient populations become more immunosuppressed reduce exposures,” Dr. Jackson said. “For high-risk patients, from COVID-19, these are the same populations where fungal improved evidence-based prophylaxis approaches could diseases can really wreak havoc,” Dr. Chiller said. reduce infections.”

In general, fungal diseases are extremely difficult to diagFor immunosuppressed patients, more targeted therapy nose, he noted, because of the lack of great diagnostic tests for that still treats their conditions without predisposing them many of these infections. “We are struggling and need more to fungal infections could help, Dr. Jackson noted. “Because financial investment in diagnostics,” he said. “Diagnostics antibiotic use can disrupt the bacterial flora and allow fungal are key. We know for a fact that the earlier you diagnose a overgrowth and infection, antimicrobial fungal infection, the better patients do. stewardship can also reduce fungal infecConversely, the later the infection is tions,” he said. diagnosed, the worst the outcome.”

Reducing exposures to fungi in healthFungi are also complex, eukaryotic care settings are important as well, for organisms like humans. “Fungi share a lot example, decreasing invasive candidiamore in common with us than do other sis via improved central line care and pathogens,” Dr. Chiller said. “This makes decreasing invasive mold infections by it more challenging to develop specific reducing exposures via indoor air and tests to identify fungi and not humans.” linens. Improved infection control in Effective treatments are equally forlong-term care facilities also can reduce midable, partly because the investment the spread of the emerging and resistant community is reluctant to wager on pathogen Candida auris. developing an antifungal drug that can Source: Open Forum Infectious Diseases Another focus should be on preventtake decades to bring to market. Also, the ing poor outcomes such as hospitalmarket may not be as large as for a lipization and death once infection hapid-lowering agent or hypertensive drug. pens. For instance, coccidioidomycosis, “There has been a dearth of investment histoplasmosis and blastomycosis “are in the whole anti-infective space over the widely misdiagnosed as other illnesses, past two decades,” Dr. Chiller said. such as bacterial pneumonia, and can Currently, only three major classes lead to severe disease and death,” Dr. of antifungals kill invasive fungal infecJackson said. “Improved diagnostics and tions: polyenes (amphotericin B), azoles continued on page 25 more testing identify infections earlier,

U.S. economic burden of fungal diseases was $11.5 billion in 2019.

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2022

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Fungal Infections in CF Patients Appear to Be Increasing, Presenting New Challenges

BY NEAL LEARNER

T

hose who see cystic fibrosis (CF) patients expect to o treat respirare commonly tory bacterial infections, as the two conditions are linked. Today, however, many clinicians are seeingg more CF patients present with fungal infections, exacerbating diagnosis and treatment. n among Fungal colonization of the respiratory tracts is common most CF patients, but fungal infections appear to be on the hologia rise, according to a growing body of research (Mycopathologia ease in 2021;186[5]:639-653), including studies that show an increase atients beta-D-glucan, a biomarker for fungal infections, in CF patients (BMC Pulm Med 2018. PMID: 29587700).

A substantial minority of CF patients, perhaps 20%, will be adversely affected by true fungal infections and may benefitt from antifungal therapy (Pediatr Pulmonol 2018;53[S3]:S75-S85)..

However, many physicians are uncertain how to treat the ts, expanding list of fungal species showing up in lab results, m, including Aspergillus, Candida, Exophiala, Scedosporium, Trichosporon and Rasamsonia. d According to the article, “the clinician pauses and thinks, does that mean something significant? Shall I ld ignore it, or treat it? If so, what might work best? Should ore I wait or act? It is an old dilemma, but it is becoming more frequent.”

Aspe Aspergillus fum ost fumigatus, the most co n common fungus in cy fibrosis, ranges nges cystic fro 12% to 35%. from Experts are trying to answer these questions.

“With regard to the scope of the problem, it seems to be increastrics and ing,” said Richard Moss, MD, a professor emeritus of pediatrics dicine, in pulmonary medicine at Stanford University School of Medicine, California, and a co-author of the article. nition of The rise could be due to increased awareness and recognition creasing the infections, he noted. But it also could stem from an increasing

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age of the CF population, heavy use of antibiotics and inhaled corticosteroids, and increased environmental exposures, or some combination of these factors, Dr. Moss told Infectious Disease Special Edition.

Diagnosis of an acute fungal infection among CF patients is still challenging, according to Dr. Moss. Most clinicians will commence treatment if several factors are present: • Fungal respiratory cultures are repeatedly positive.

• The patient is not doing well based on a complex set of factors, such as history, physical exam findings, lab results, lung function tests, chest imaging and blood tests.

• The patient has a poor or no response to treatment for other potential causes, especially bacterial infection using antibiotics.

Fungal Costs continued from page 23

Gina Hong, MD, MHS, an assistant professor of medicine at the Hospital of the University of Pennsylvania, treats CF patients in Philadelphia, where she finds the presence of fungi creates a more complicated treatment scenario than bacteria.

Bacterial microbes are classically seen as either a colonization or an infection, Dr. Hong said. “But when it comes to fungi, there also is allergy and sensitization,” she added.

Sometimes the role of the fungi is very clear. Patients with CF and allergic fungal disease—including allergic bronchopulmonary aspergillosis or other mycoses—may have increased sputum production, wheezing, lung function decline and radiographic changes, including bronchiectasis, she said.

“But the role of fungi is less clear in the absence of allergy/sensitization, which makes the approach to identifying when to treat as active or chronic infection in CF quite challenging,” Dr. Hong said.

Some fungi in CF are rare, including Scedosporium apiospermum, Lomentospora prolificans, Exophiala dermatitidis and Apiotrichum mycotoxinivorans (formerly Trichosporon mycotoxinivorans).

But other fungi are commonly seen in CF patients. Depending on the epidemiological study, the prevalence of Aspergillus fumigatus, the most common fungus in CF, ranges from 12% to 35%, Dr. Hong said.

Observational data suggest that the chronic presence of A. fumigatus is associated with increased pulmonary exacerbation rates, increased radiographic changes and possibly worse health-related quality of life, Dr. Hong explained.

But she added a caveat. “These studies are limited because it could be that Aspergillus is present in the setting of more advanced lung disease associated with these characteristics.”

The choice of therapy is often triazole antifungals, Dr. Hong noted. But she cautions these compounds have potential drug–drug interactions with a class of drugs called cystic fibrosis transmembrane conductance regulator modulators. Furthermore, antifungal treatments last, on average, two to three months, “which is quite lengthy,” she said.

Ultimately, the poor state of understanding around fungi in CF mandates the need for large research agenda. “There is a pressing need to standardize mycology culture protocols in much the same way that the CF community has done in monitoring our patients for pathogenic bacteria,” Dr. Moss’ study concluded. ■

and echinocandins. “But C. auris, which has emerged over the past decade, has developed resistance to all three classes, but thankfully still rarely,” Dr. Chiller said. “Nonetheless, C. auris is pan-resistant, for which there are not really any treatment options.”

Resistance is a major concern, as it is across the infectious disease spectrum, Dr. Chiller noted. “Resistance is not just coming from human use but agricultural use as well,” he said. “For instance, using pesticides in the environment have now been linked to the development of a specific resistance within Aspergillus, a fungus that can cause respiratory infections and death.”

Moreover, many available drugs are static, meaning they do not kill the fungus but rather stop it from growing. “In fact, the whole azole class, which is a great class of drugs, is a static class,” Dr. Chiller said. “Therefore, you generally need to treat people for prolonged periods of time, because you eventually want the human immune response to kick in. However, many of these patients do not have an immune response because they are immunosuppressed from an implant or taking various medicines.”

Two new classes of drugs that show promise in improving treatment and outcomes are the tetrazoles and glucan synthase inhibitors. Another new class of antifungal agents, the orotomides, also has been discovered with a distinct mechanism of action: selectively targeting fungal dihydroorotate dehydrogenase, a key enzyme in the biosynthesis pathway. “This is a new target not seen in any other antifungals,” Dr. Chiller said.

Overall, clinicians need to consider how antifungal drugs are used in the environment, animals and humans.

“In the past, it was the era of the bacteria, and we are now in the era of the virus,” Dr. Chiller said. “The future, though, could be ■ the era of the fungi.”

Dr. Moss reported relationships with Mayne Pharma, Nob Hill Therapeutics and Zambon Pharma. Dr. Hong reported no relevant financial disclosures.

The sources reported no relevant financial disclosures.

Fungi Are More Complicated Than Bacteria

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2022

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Is De-Escalation an Effective Stewardship Strategy?

BY DAVID WILD

W

hile a number of organizations recommend narrowing the spectrum of antibiotic therapy in hospitalized patients in light of laboratory findings, some are questioning the primacy of the practice, including one expert who said there are no convincing data concerning spectrum de-escalation to judge whether it improves outcomes.

“I would question whether it really should be the standard of practice based on the available data,” said Meghan Jeffres, PharmD, an associate professor in the Department of Clinical Pharmacy at Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, in Aurora.

Transitioning from a broad-spectrum antibiotic to that of a narrower spectrum based on culture results is one form of antibiotic de-escalation, a broader term encompassing, for example, discontinuing redundant or unnecessary antibiotics or switching from IV to oral antibiotics.

While Dr. Jeffres said she does not dispute that use drives antibiotic resistance, she said the data behind “spectrum de-escalation” have not convinced her that it is necessary to pursue this measure to prevent resistance. For example, a single-center retrospective study of 7,118 patients with severe sepsis or septic shock showed that each additional day of treatment with antipseudomonal beta-lactams increased the chances of developing new resistance by 4% (Pharmacotherapy 2019;39[3]:261270), and a follow-up analysis of those data found resistance to these broad-spectrum agents increased from around 2% during the first three days to roughly 10% between 10 and 18 days,

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rising slightly more between 19 and 21 days (Infect Control Hosp Epidemiol 2020;41[4]:484-485).

“While the authors’ theory is that resistance continues to increase with prolonged duration of these broad-spectrum agents, I would suggest the same phenomenon would be present if they looked at a different narrower spectrum antibiotic,” Dr. Jeffres asserted.

“Why would we assume this relationship to be unique to the antipseudomonal beta-lactams?”

Other studies supporting the practice of spectrum de-escalation may not have adequately accounted for possible confounding variables, she said, pointing to findings that show administering antipseudomonal beta-lactams for longer than 48 hours in patients with Enterobacteriaceae bloodstream infections leads to a higher risk for Clostridioides difficile infection (CDI) within 90 days (7% for >48 hours vs.

1.8% for ≤48 hours) (Clin Infect Dis 2019;69[3]:414-420).

In this case, Dr. Jeffres said, the risk factors for longer treatment—such as older age, female sex, more comorbidities and bacteremia, and longer lengths of hospital stays prior to bloodstream infections—are some of the same established risk variables for CDI. “Arguably, this study does not support the early discontinuation of antipseudomonal beta-lactams in decreasing CDI risk,” Dr. Jeffres said.

Other data are “at best, indifferent to the idea that spectrum de-escalation is important,” she said.

For example, a trial of 116 patients with severe sepsis who received empiric treatment and were then randomly assigned to undergo spectrum de-escalation or continue with this treatment

found that ICU stays were longer among the de-escalation group (median 3.4 days longer), that de-escalation was associated with more days of antibiotic use (14 vs. 10 days) and that the practice was linked with higher rates of superinfections (27% vs. 11%; P=0.03) (Intensive Care Med 2014;40[10]:1399-1408). The authors’ finding that 44% of those who underwent de-escalation and had a superinfection developed resistance to the index pathogen, compared with 67% of those who continued empiric treatment, provides insight into the mechanism behind these results, she said.

“It looks like when you de-escalate and expose patients to a second antibiotic, you may raise the risk of developing resistance to additional pathogens,” said Dr. Jeffres, noting the study’s small size and that results need to be validated in larger trials.

Shorten Duration Rather than focusing on spectrum de-escalation efforts, Dr. Jeffres suggested implementing other stewardship interventions, such as shortening the duration of antibiotic exposure.

“We know that shortening the length of antibiotic administration is arguably the highest-impact measure we can take to prevent antibiotic resistance and improve patient outcomes,” she said.

Jonathan Ryder, MD, a fellow in the Division of Infectious Diseases at the University of Nebraska Medical Center, in Omaha, said the evidence supporting use of spectrum de-escalation is hampered by design limitations, such as small sample sizes and observational research that has yielded conflicting results, but well-designed randomized controlled trials are underway. continued on page 41

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IDSA Guidance Helps in Treating Vexing Bacteria

BY BOB KRONEMYER

T

hree common gram-negative bacteria can be particularly vexing for clinicians: extended-spectrum beta-lactamase– producing Enterobacterales (ESBL-E), carbapenem-resistant Enterobacterales (CRE) and Pseudomonas aeruginosa with difficult-to-treat resistance (DTR-P. aeruginosa).

Using the available data and exercising good clinical judgment, a panel of six infectious disease specialists with expertise in managing antibiotic-resistant infections formulated numerous questions, followed by suggested answers and corresponding rationales to help improve prescribing practices for infections from these bacteria (Clin Infect Dis 2021 Dec 5. doi:10.1093/cid/ciab1013) (Table).

“This effort is part of a priority that IDSA [Infectious Diseases Society of America] made in 2019 to provide more timely updates to treatment recommendations,” said coauthor Cornelius Clancy, MD, a professor of medicine at the University of Pittsburgh. “These three specific infections were chosen because difficult-to-treat gram-negative antimicrobialresistant infections have become an increasing problem in the United States.”

Dr. Clancy noted the lack of good randomized controlled clinical trial data to guide therapy and provide definitive answers. “It is simply infeasible to conduct large randomized trials,” he said.

“The new IDSA guidance is meant to provide the type of guidance that cannot be easily found by clinicians looking in

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the literature,” Dr. Clancy said. “We try to interpret the body of literature and offer our best recommendations. That is why it is called a guidance document rather than a guideline.

We simply do not have the level of evidence to offer formal, evidence-based guidelines to clinicians.”

Not a Surprise, but Still Interesting The guidance shares about nine different treatments for each of the three bacteria.

For ESBL-E, the guidance advocates that the carbapenems remain the first-line drugs for treatment. “There have been a number of studies trying to define whether non-carbapenem agents could be recommended for those infections,” Dr. Clancy said. “But the data at this point in time to support alternatives are not robust enough.”

For CRE, the guidance strongly endorses the new antibiotics, particularly the beta-lactamase inhibitors (e.g., ceftazidime-avibactam [Avycaz, Allergan] and meropenem-vaborbactam [Vabomere, Melinta]), “which are superior to the older options of primarily polymyxin and aminoglycoside-based treatments,” Dr. Clancy said.

For DTR-P. aeruginosa, there is often an antibiotic that is active against Pseudomonas species, Dr. Clancy noted. “But the data are going to differ from center to center, so for Pseudomonas you need to make treatment decisions that are more specific to an individual patient,” he said.

Table. Suggested Dosing of Antibiotics for the Treatment of Infections Caused by Antimicrobial-Resistant Organismsa Target organismsb,c

Agent

Adult dosage (assuming normal renal and liver function)

Amikacin

Cystitis: 15 mg/kg/dosed IV once ESBL-E, AmpC-E, CRE, All other infections: 20 mg/kg/dosed IV ✕ 1 dose; subsequent doses and dosing interval DTR-Pseudomonas aeruginosa based on pharmacokinetic evaluation

Ampicillinsulbactam

9 g IV q8h over 4 hours or 27 g IV q24h as a continuous infusion For mild infections caused by CRAB isolates susceptible to ampicillin-sulbactam, it is reasonable to administer 3 g IV q4h—particularly if intolerance or toxicities precludes the use of higher dosages.

CRAB

Cefepime

Cystitis: 1 g IV q8h All other infections: 2 g IV q8h, infused over 3 hours

AmpC-E

Cefiderocol

2 g IV q8h, infused over 3 hours

CRE, DTR-P. aeruginosa, CRAB, Stenotrophomonas maltophilia

Ceftazidimeavibactam

2.5 g IV q8h, infused over 3 hours

CRE, DTR-P. aeruginosa

Ceftazidimeavibactam and aztreonam

Ceftazidime-avibactam: 2.5 g IV q8h, infused over 3 hours Plus Aztreonam: 2 g IV q8h, infused over 3 hours, administered at the same time as ceftazidime-avibactam, if possible

Metallo-beta-lactamase– producing CRE, S. maltophilia

Ceftolozanetazobactam

Cystitis: 1.5 g IV q8h, infused over 1 hour All other infections: 3 g IV q8h, infused over 3 hours

DTR-P. aeruginosa

Ciprofloxacin

ESBL-E or AmpC infections: 400 mg IV q8h-q12h or 500-750 mg PO q12h

ESBL-E, AmpC-E

Colistin

Refer to international consensus guidelines on polymyxinse

CRE cystitis, DTR-P. aeruginosa cystitis, CRAB cystitis

Eravacycline

1 mg/kg/dose IV q12h

CRE, CRAB

Ertapenem

1 g IV q24h, infused over 30 minutes

ESBL-E, AmpC-E

Fosfomycin

Cystitis: 3 g PO ✕ 1 dose

ESBL-Escherichia coli cystitis

Gentamicin

Cystitis: 5 mg/kg/dosed IV once All other infections: 7 mg/kg/dosed IV ✕ 1 dose; subsequent doses and dosing interval based on pharmacokinetic evaluation

ESBL-E, AmpC-E, CRE, DTR-P. aeruginosa

Imipenemcilastatin

Cystitis (standard infusion): 500 mg IV q6h, infused over 30 minutes All other ESBL-E or AmpC-E infections: 500 mg IV q6h, infused over 30 minutes All other CRE and CRAB infections: 500 mg IV q6h, infused over 3 hours

ESBL-E, AmpC-E, CRE, CRAB

Imipenemcilastatinrelebactam

1.25 g IV q6h, infused over 30 minutes

CRE, DTR-P. aeruginosa

Levofloxacin

750 mg IV/PO q24h

ESBL-E, AmpC-E, S. maltophilia

Meropenem

Cystitis (standard infusion): 1 g IV q8h infused over 30 minutes All other ESBL-E or AmpC-E infections: 1-2 g IV q8h, infused over 30 minutes All other CRE and CRAB infections: 2 g IV q8h, infused over 3 hours

ESBL-E, AmpC-E, CRE, CRAB

Meropenemvaborbactam

4 g IV q8h, infused over 3 hours

CRE

Minocycline

200 mg IV/PO q12h

CRAB, S. maltophilia

Nitrofurantoin

Cystitis: macrocrystal/monohydrate (Macrobid) 100 mg PO q12h Cystitis: Oral suspension: 50 mg PO q6h

ESBL-E cystitis, AmpC-E cystitis

Plazomicin

Cystitis: 15 mg/kgd IV ✕ 1 dose ESBL-E, AmpC-E, CRE, All other infections: 15 mg/kgd IV ✕ 1 dose, subsequent doses and dosing interval based DTR-P. aeruginosa on pharmacokinetic evaluation

Polymyxin B

Refer to international consensus guidelines on polymyxinse

Tigecycline

200 mg IV ✕ 1 dose, then 100 mg IV q12h

CRE, CRAB, S. maltophilia

Tobramycin

Cystitis: 5 mg/kg/dosed IV ✕ 1 dose All other infections: 7 mg/kg/dosed IV ✕ 1 dose; subsequent doses and dosing interval based on pharmacokinetic evaluation

ESBL-E, AmpC-E, CRE, DTR-P. aeruginosa

Trimethoprimsulfamethoxazole

Cystitis: 160 mg (trimethoprim component) IV/PO q12h Other infections: 8-12 mg/kg/day (trimethoprim component) IV/PO divided q8-12h (consider maximum dose of 960 mg trimethoprim component per day)

ESBL-E, AmpC-E, S. maltophilia

DTR-P. aeruginosa, CRAB

AmpC-E, AmpC-producing Enterobacterales; CRAB, carbapenem-resistant Acinetobacter baumannii; CRE, carbapenem-resistant Enterobacterales; DTR-P. aeruginosa, Pseudomonas aeruginosa with difficult-to-treat resistance; ESBL-E, extended-spectrum beta-lactamase–producing Enterobacterales; MIC, minimum inhibitory concentration; PO, per os (by mouth); q4h, every 4 hours. a

Dosing suggested for several agents differs from FDA-recommended dosing.

Target organisms limited to the following organisms and generally only after susceptibility has been demonstrated: ESBL-E, AmpC-E, CRE, DTR-P. aeruginosa, CRAB and Stenotrophomonas maltophilia. c For additional guidance on the treatment of ESBL-E, CRE and DTR-P. aeruginosa, refer to: https://www.idsociety.org/practice-guideline/amr-guidance/. d Use adjusted body weight for patients >120% of ideal body weight for aminoglycoside dosing. b

e

Pharmacotherapy 2019;39(1):10-39.

Source: Clin Infect Dis 2021 Dec 5. doi:10.1093/cid/ciab1013. (Used with permission.)

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2022

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Dr. Clancy noted that the three infections account for tens of thousands of infections yearly in the United States; however, the epidemiology differs by geographic location and from hospital to hospital. “You cannot draw only on personal experience in knowing what is the best treatment,” he said.

The uncertainty and confusion over treatment among clinicians who do not normally treat gram-negative infections “often stem from the fact that we just don’t have definitive conclusive data,” Dr. Clancy said. “For that reason, you really need to use your clinical judgment and best decision making. The guidance explains what might be done in cases where there is uncertainty about what to treat.”

There is also an interactive component to the guidance, whereby clinicians can provide comments, feedback and debate for incorporation into future iterations of the guidance document. “It is meant to be an active document that can be readily updated as more data and feedback emerges,” Dr. Clancy said. “Clinicians can feel confident that they are doing the right thing by their patients.”

Alex Lepak, MD, an associate professor of infectious diseases at the University of Wisconsin–Madison School of Medicine and Public Health, noted that many infectious disease experts “will be familiar with the organisms and therapeutic difficulties presented here, although may not be up to date on some of the more recent evidence, especially with newer therapies.”

Dr. Lepak personally found the carbapenem-resistant Acinetobacter baumannii (CRAB) and Stenotrophomonas sections enlightening because they presented data and studies that he was aware of, yet he had not necessarily codified them all together in his mind.

For other providers, much of the guidance “may be new and, therefore, while extremely helpful, may be a lot to digest,” said Dr. Lepak, who was not a co-author. “Overall, I think the authors did a nice job walking the line for both audiences in providing up-to-date evidence and expert advice. It is a very pragmatic approach and useful guidance document to optimize therapy for these difficult infections.”

The SPACE/SPICE (Serratia, Providencia/Pseudomonas, Acinetobacter/indole-positive Proteus, Citrobacter, and Enterobacter) review and modification, including the recommendation for cefepime use, will likely come as a surprise to many clinicians, according to Dr. Lepak, who also is the medical director of antimicrobial stewardship at the University of Wisconsin–Madison. “Most providers, even those we see in training today, as well as those trained specifically in infectious diseases, often quote the SPACE or SPICE acronym, which denotes a group of organisms that, despite the susceptibility testing results, may be induced

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SPACE/SPICE

The guidance unpacks the SPACE/SPICE organisms, describing the limitations of the aforementioned acronym and defining a more clinically relevant group of organisms.

Serratia

Providencia/

Pseudomonas

Acinetobacter/ Indole-positive Proteus

Citrobacter

Enterobacter

into becoming resistant while on therapy.” our attention where AmpC overexpression is most clinically Dr. Lepak said the authors did a wonderful job unpacking relevant,” he said. this group of organisms, describing the limitations of the Dr. Gallagher suspects that the biggest surprise to cliniaforementioned acronym and defining a more clinically rel- cians will be that they “can throw out SPACE and SPICE as evant group of organisms. useful mnemonics and treat Proteus and Serratia infections “They identify Enterobacter cloacae, Klebsiella aerogenes and with ceftriaxone again when it is reported to be susceptible Citrobacter freundii as the three organisms for which the in vitro. Other people may be surprised to see the high doses occurrence of inducible AmpC [Ambler class C enzymes] is of ampicillin-sulbactam recommended for CRAB infections.” moderate to high risk,” he said. “The guidance supports using The guidance will provide a go-to reference for clinicians cefepime in most situations for any of these three organisms.” who rarely treat CRAB and S. maltophilia infections and do From Dr. Lepak’s own experience in clinical and antimicro- not follow the difficult and methodologically challenged bial stewardship, “the clinical uncertainty of inducible AmpC literature, according to Dr. Gallagher, who was not on the resistance is often overapplied to all cephalosporins and guidance panel. “The guidance will also support clinicians penicillin-related compounds.” who already make these types of treatDr. Lepak also noted that the recent ment decisions but encounter colleagues Merino trial results and/or ESBL treatwho are skeptical or nervous about givment guidance are sometimes misaping large doses of ampicillin-sulbactam, plied to AmpC organisms. or are unaware that carbapenems are “The combined result is overuse of unnecessary for many traditional AmpCcarbapenems for a number of organisms producing organisms,” he said. in which more narrow therapy would be Dr. Gallagher also hopes that the recappropriate and efficacious,” he said. ommendations for AmpC producers lead The guidance that ceftriaxone should to better streamlined therapy choices for be considered for use in organisms that these infections. were previously included in the SPACE/ “However, new guidelines and guidSPICE acronym, such as Serratia marcance always take time to disseminate escens, but are not one of the three into practice,” said Dr. Gallagher, a cliniSource: CDC high-risk organisms for inducible resiscal pharmacy specialist in infectious distance, will likely be challenging for some eases at Temple University Hospital, in clinicians to embrace, according to Lepak, because they have Philadelphia. “But I think this guidance is likely to be used learned to essentially never use third-generation cephalospo- sooner than most guidelines because there is so little guidance rins for SPACE/SPICE. published for clinicians to follow.”

The paucity of data on CRAB and Stenotrophomonas, even in However, Dr. Gallagher pointed out that some of the recomthe preclinical environment, also is underscored in the guid- mendations will be more difficult to implement, due to a lack ance. “It is striking to see how little we know about old and of in vitro on-site testing to support them, such as cefiderocol new drugs for these organisms,” Dr. Lepak said. “Although the (Fetroja, Shionogi) and high-dose ampicillin-sulbactam. guidance document does a very nice job walking through the “One of the issues with providing guidance for these knowns and unknowns, and lays out treatment recommenda- organisms is that they cause many different types of infections very well, I believe this also highlights the need for effec- tions, ranging from mild to severe,” he said. “Also, CRAB and tive stewardship and infectious disease expertise for these S. maltophilia are often colonizers of patients in hospitals who infections to help those clinicians that might be less familiar have received antibiotics previously. Still, when they do cause with the nuance of CRAB and Stenotrophomonas.” infection, they are very hard to eradicate.”

Jason Gallagher, PharmD, a clinical professor of pharmacy Dr. Gallagher looks forward to future updates of this practice at Temple University, in Philadelphia, called the guidance. “However, no matter how quickly the guidance is guidance “excellent. It will be helpful to a wide variety of updated, S. maltophilia is likely to have another name change ■ practitioners.” by then,” he said.

Dr. Gallagher noted that mnemonics like SPACE for AmpCproducing Enterobacterales “have taken on a life of their own, Dr. Clancy serves as an advisory board member for Astellas, Cidara and the authors provide a rationale for refocusing our atten- and Scynexis, and is a consultant to Needham & Associates. He also receives research funding from Astellas and Merck. Dr. Gallagher tion on three key organisms instead.” receives grant support from Merck, and is a consultant to Merck, Because the SPACE organisms are relatively common, Shionogi, Spero Therapeutics and Qpex. Dr. Lepak has done scientific “unnecessary carbapenem use can be avoided by focusing consulting for Spero.

AMR pathogens caused

>2.8 million

infections from 2012-2017.

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2022

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Concerns About MDR Infections Grow as Treatment Options Expand

BY MYLES STARR

T

he narrow range of treatments available for multidrugresistant (MDR) gram-negative infections—a leading cause of morbidity and mortality in the United States—poses a grave threat to patients in healthcare settings.

More than 2.8 million people become infected with antibiotic-resistant infections in the United States each year, and more than 35,000 people die as a result, according to the CDC (http://www.cdc.gov/DrugResistance/Biggest-Threats.html).

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However, six new drugs have proven effective at treating many of these pathogens: 1. cefiderocol (Fetroja, Shionogi) 2. ceftazidime-avibactam (Avycaz, AbbVie) 3. ceftolozane-tazobactam (Zerbaxa, Merck) 4. eravacycline (Xerava, Tetraphase) 5. imipenem-cilastatin-relebactam (Recarbrio, Merck) 6. meropenem-vaborbactam (Vabomere, Merck)

Abinash Virk, MD, an infectious disease specialist at Mayo Clinic in Rochester, Minn., was particularly concerned about Pseudomonas and New Delhi metallo-beta-lactamase (NDM) infections.

“Pseudomonas is common in the hospital, and even after days of appropriate treatment, these infections can develop resistance. They have slightly different enzymes and mechanisms than other gram-negative microorganisms. Therefore, P. aeruginosa can require different antibiotics. There are a couple of new drugs, namely, ceftolozane in combination with tazobactam, which are more effective against multidrug-resistant P. aeruginosa infections.”

Pseudomonas in particular can present challenges to healthcare systems beyond drug resistance. It has the ability to survive in circumstances that would be inhospitable to other bacteria’s growth (Med Microbiol 2021;32[3]:169-175). For this reason, Pseudomonas puts an extra burden on healthcare systems and requires extra vigilance of hospital staff, from doctors to orderlies.

Dr. Virk also noted that the imipenem-cilastatin-relebactam combination can be used against Pseudomonas, and it has better activity against these infections than the use of imipenem alone. She pointed out that this combination is “active against organisms that exhibit class A and C beta-lactamases and has improved minimum inhibitory concentration for Klebsiella pneumoniae carbapenemase (KPC)-producing bacteria.”

Although ceftazidime-avibactam works well against the carbapenem-susceptible microbes, they are less effective when used alone against NDM infections (Antimicrob Agents Chemother 2017;61[4]:e02243-16).

“A combination of ceftazidime-avibactam with aztreonam is a preferred treatment option for NDM infections. Avibactam has the ability to inhibit ESBL [extendedspectrum beta-lactamase], which many of the MDR produce and used with aztreonam, which retains activity against NDM,” Dr. Verk said. “Aztreonam [can be used] alone if it is certain the microorganism does not produce ESBLs or AmpC beta-lactimades. Other combinations of aztreonam [can be used], such as with plazomicin or cefiderocol, if [there’s] evidence of ESBL production.”

Dr. Russo discussed the possible use of eravacycline and cefiderocol as new agents to use against gram-negative MDR infections, but also warned of the limitations of tetracycline derivatives. “They have some activity against carbapenemresistant strains that produce class B metallo-beta-lactamase such as New Delhi metallo-beta-lactamase. But pharmacokinetic/pharmacodynamic limitations exist with bloodstream and urinary concentrations.” Dr. Russo said.

Despite these potential downsides, several studies have

35,000

people die each year in the U.S. from resistant infections.

Infectious Disease Special Edition spoke with three experts about which MDR infections are most concerning; when and why each of the aforementioned antibiotics should be prescribed; and how to combat the emergence of new microbial resistance to drugs. The experts and the CDC agree that gramnegative infections, pathogens that have an outer membrane that protects them from neutralization by white blood cells, are the most challenging.

Infections of Greatest Concern “In the healthcare setting, the most problematic extensively drug resistant gram-negative infections, in terms of overall resistance, are those with carbapenem resistance, like Enterobacteriaceae, which produce serine carbapenemases,” said Tom Russo, MD, an infectious diseases specialist at the University at Buffalo Jacobs School of Medicine and Biomedical Sciences, in New York. “We now have good drugs for the treatment of infections, such as ceftazidime-avibactam and meropenem-vaborbactam.”

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2022

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shown high cure rates of gram-negative infections using tetracycline derivatives. For example, a 2017 study of the use of eravacycline in complicated gram-negative abdominal infections showed a cure rate of greater than 86% (JAMA Surg 2017;152[3]:224-232).

Due to evidence of limited bloodstream-concentration reliability, Dr. Russo recommended that tetracycline derivatives only be used in settings where a patient is stable and the monitoring of their drug concentration levels is possible.

Causes and Solutions to Growing MDR Infections The increase in MDR infections is driven by two main factors, according to experts. First, overprescribed antibiotics lead to a scenario where microbes are exposed to new antibiotics so frequently that they have a high likelihood of developing resistance to any new class of drug. In fact, antibiotic overprescribing is so common that in 2016, the CDC determined that more than 30% of antibiotic prescriptions in the United States were unnecessary (https://www.cdc.gov/media/releases/2016/p0503-unnecessary-prescriptions.html). Second, MDR developed by bacteria, due to overprescribing, is compounded by insufficient local, national and global strategies to use antibiotics more responsibly and effectively.

In 2016, the CDC determined that >30% of U.S. antibiotic prescriptions were unnecessary.

COVID’s Impact on the Increases Overprescribing of antibiotics for viral respiratory infections predates COVID-19, but the pandemic has greatly exacerbated the problem. Since the beginning of the pandemic, there has been an increase in the empiric use of broad-spectrum antimicrobials in patients hospitalized with COVID-19.

Of 16,000 patients admitted to the hospital with confirmed SARS-CoV-2 and treated for bacterial or fungal coinfections, an estimated 24% had a resistant bacterial coinfection, and 0.3% were infected with resistant fungal organisms, indicating overprescribing of antimicrobial therapy (Int J Antimicrob Agents 2021;57[4]:106324).

This increase in infections can be attributed to a wide range of MDR organisms including methicillin-resistant Staphylococcus aureus; carbapenem-resistant Acinetobacter

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baumannii, K. pneumoniae and P. aeruginosa; and MDR Candida auris (Int J Antimicrob Agents 2021;57[4]:106324). The uptick in detection of carbapenem-resistant NDM infections is of particular concern, according to Drs. Virk and Russo.

Combating the Growth of Gram-Negative MDR Infections Despite the proven effectiveness of new pharmaceutical agents against MDR gram-negative infections, there are already reports of microbes with increasing resistance to these drugs (Clin Infect Dis 2021;73[11]:e4472-e4474). Therefore, doctors and public health officials, such as the CDC and World Health Organization, acknowledge that the use of currently available antibiotics and the development of new pharmaceutical agents will be insufficient to prevent the spread of these infections.

The importance of more sensible use of antimicrobial agents in human and animal populations, as well as the strengthening of surveillance and lab capacities, have been emphasized concurrently with the recommendation to develop new antibiotic drugs (Bull World Health Organ 2011;89[5]:390-392). Lab analysis, particularly testing an agent’s effectiveness against a microbe before clinical use, can help combat the spread of MDR infections by dramatically reducing the overuse of infective agents that aid bacteria in developing drug resistance.

Unfortunately, this is only possible if a patient is not critically ill, in which case, empiric prescriptions of broad-spectrum antimicrobial agents are widespread.

“When we want to treat a particular MDR infection, our microbiology lab conducts a test, and we use whatever novel agent the microbe is susceptible to,” said Emily Sydnor Spivak, MD, the director of the antimicrobial stewardship programs at the University of Utah School of Medicine, in Salt Lake City.

Dr. Spivak cautioned that even though her lab can help patients by analyzing organisms that they previously encountered, to look for patterns of drug susceptibility and resistance, there is no standardized surveillance system in the United States for antibiotic-resistant infections, “so there is no specific way to track infections nationally. Also, there are various rates of antibiotic-resistant infections across the country.” More coordination of data collection and analysis, both nationally and internationally, will be needed to effectively counter and combat the growth of MDR infections.

New antibiotics are being proven effective at treating many gram-negative MDR infections, but their overuse and development of resistance to these agents suggest doctors and public health officials need to continue to implement steps to fight these infections: promoting antibiotic stewardship, increasing use of laboratory tests before therapy, and continuing to fund ■ and develop new classes of antibiotics.

Drs. Russo, Spivak and Verk reported no relevant financial disclosures.

As UTI Drug Resistance Increases, Treatment Choices Are Critical

BY DAVID WILD

W

ith recent data indicating that roughly 60% of antibiotics prescribed for urinary tract infections (UTIs) in the outpatient setting do not conform to clinical guidelines, and some UTI drug resistance rates markedly rising, one expert urged clinicians to carefully review the appropriateness of UTI prescriptions.

“With a lot of UTI infections comes a lot of antibiotic prescribing, and sometimes our providers don’t do the greatest job [with stewardship],” said Ryan Moenster, PharmD, a clinical pharmacy specialist in infectious diseases, VA St. Louis Health Care System.

One recent analysis included 44.9 million female outpatient visits for uncomplicated UTIs from 2015 to 2019 and found that only 58.4% of prescriptions for these infections were concordant with treatment guidelines (Am J Obstet Gynecol 2021;225[3]:272. e1-272.e11). “That’s not fanstastic data,” Dr. Moenster said.

Coinciding with those prescribing patterns has been a rise in the prevalence of extended-spectrum cephalosporin-resistant urinary Escherichia coli, which increased from 14% to 19% of UTI isolates between 2013 and 2017, he noted (Clin Infect Dis 2021;73[11]:e4552-e4559).

Dr. Moenster urged healthcare providers to review their “go-to stable” of outpatient antibiotics for this indication. “We all know about the unacceptably high rates of fluoroquinolone resistance and the limitations of using that as empiric antibiotic therapy, but less is discussed about trimethoprim-sulfamethoxazole [TMP-SMX], nitrofurantoin and fosfomycin,” he said.

Regarding TMP-SMX, a hospital study conducted in South Carolina revealed that roughly 20% of 351 patients with community-onset UTIs had Enterobacterales isolates with resistance to TMP-SMX (J Glob Antimicrob Resist 2020;21:218-222).

Use of TMP-SMX in the prior 12 months was associated with a 2.58-fold increased risk for Enterobacterales resistance to the drug, the researchers found (P=0.02).

A randomized controlled trial shed light on the efficacy of nitrofurantoin and fosfomycin for the treatment of lower UTIs (JAMA 2018;319[17]:1781-1789). Specifically, 70% of patients who received a five-day course of nitrofurantoin and 58% given a single dose of fosfomycin experienced a clinical response at 28 days (P=0.004), while 74% and 63%, respectively, experienced a microbiological response (P=0.04).

However, “we can’t talk about these agents without talking about some of their notable limitations,” Dr. Moenster

The prevalence of extended-spectrum cephalosporin-resistant urinary E. coli between 2013 and 2017 increased from 14% to 19%.

Source: Clin Infect Dis 2021;73(11):e4552-e4559.

stressed. For example, some patients have an allergy to TMPSMX, while there is a risk for renal dysfunction with the drug, he said. As for nitrofurantoin, one limitation is its “relatively high” creatinine clearance cutoff (<60 mL per minute), as indicated in the package insert. Additionally, nitrofurantoin and fosfomycin are not recommended for pyelonephritis, he noted.

Furthermore, only the single-dose regimen of fosfomycin is FDA approved, “although clinicians do use alternative dosing recommendations for certain patients,” he said.

Keeping It Local Dr. Moenster also urged attendees to consider their own local resistance rates when choosing treatment. For example, in 2020, the VA St. Louis Health Care System identified high levels of E. coli susceptibility to nitrofurantoin (92%) but lower levels of susceptibility to TMP-SMX (72%). “This is one of the best examples I can think about in terms of basing your decisions on your local antibiogram,” Dr. Moenster said.

Lisa Dumkow, PharmD, the antimicrobial stewardship program director at Mercy Health Saint Mary’s, in Grand Rapids, Mich., echoed the importance of selecting outpatient UTI treatments based on local antibiograms.

“We try to avoid treating asymptomatic bacteriuria and stress the importance of using nitrofurantoin as first-line therapy whenever possible, limiting the use of cephalosporin agents to patients who do not qualify for nitrofurantoin,” she said. “It’s a delicate balance with our first-generation cephalosporins, because while their empiric chance of targeting our urinary pathogens is high—based on our local antibiogram— there is also a big risk of increasing ESBL [extended-spectrum ■ beta-lactamase] rates with overuse.”

Dr. Moenster reported financial relationships with Allergan-AbbVie and Shionogi.

He spoke at the 2021 annual meeting of the American College of Clinical Pharmacy.

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Does Flu Change Antibiotic Prescribing?

BY GINA SHAW

A

ntibiotic resistance of common infectious bacteria, both gram-positive and gram-negative, matches up with influenza season in the United States, according to recent findings from an ecological analysis conducted by scientists with BD (Becton, Dickinson and Company), in Franklin Lakes, N.J. “These data can help stewardship teams improve antibiotic use and establish standardizations in care during surges in influenza activity,” said lead author Vikas Gupta, PharmD, BD’s director of medical affairs, in an interview with Infectious Disease Special Edition. “Particularly, it can help inform guidelines and protocols during severe influenza seasons.”

Viral infections are often treated with empiric antibiotics due to suspected bacterial coinfection, which does occur in 11% to 35% of patients with laboratory-confirmed influenza (Influenza Other Respir Viruses 2016; 10[5]:394-403). But many patients with respiratory conditions receive empiric treatment with antibiotics despite the lack of bacterial coinfection.

A 2018 study found 41% of patients treated with empiric antibiotics for respiratory symptoms did not have an appropriate diagnosis for antibiotic use (JAMA Netw Open 2018;1:e180243).

“The higher rates of both bacterial infections and antibiotic use during influenza seasons are thought to play a role in seasonal antibiotic resistance (ABR), particularly in respiratory isolates,” Dr. Gupta and his colleagues noted.

The researchers used the BD Insights US Research Database to evaluate antibiotic susceptibility profiles in 30-day bacterial isolates collected at 257 U.S. healthcare institutions from 2011 to 2019. For each 20% increase in positive influenza tests at a center, approximately 90 additional patients per 1,000 admissions entered the hospital with macrolide-nonsusceptible Streptococcus pneumoniae, 12 with penicillin-nonsusceptible S. pneumoniae, and seven with S. pneumoniae not susceptible to extended-spectrum cephalosporins. A 20% rise in influenza rates also was associated with a smaller but still significant rise in gram-negative bacteria, including approximately 1% more Enterobacterales and Pseudomonas aeruginosa not susceptible to fluoroquinolones and a 4% increase in Acinetobacter baumannii not susceptible to carbapenems.

“Generally, it is known that gram-positive pathogens would be the primary ones that would be associated with coinfection in patients with influenza,” Dr. Gupta said. “While we did not evaluate coinfection in this study, we were surprised to see

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gram-negative pathogens to be associated with influenza activity—although it was a generally mild association. This finding underscores the need for clinicians to be more diligent in diagnostic evaluation when selecting antimicrobial therapy, which would better support appropriate medication utilization.”

The increase in gram-negative pathogens is “collateral damage” from antibiotic use, said Katherine Yang, PharmD, MPH, a health sciences clinical professor in the Department of Clinical Pharmacy at the University of California, San Francisco (UCSF) School of Pharmacy and an infectious diseases clinical pharmacist at the UCSF Medical Center. “When you’re pressuring your flora, you also pressure the other bacteria that could be around. You could give one antibiotic that doesn’t have any activity against a specific gram-negative, but nonetheless pressure that bacteria to form resistance.”

As an example, she cited AmpC (ampicillin C)-driven betalactam resistance in P. aeruginosa. “Ampicillin itself doesn’t have activity against Pseudomonas, but the presence of it turns on Pseudomonas,” Dr. Yang said. “Pseudomonas is really flexible, and the more flexible these bacteria are, the harder they are to treat.

Because antibiotic resistance is so complicated, utilizing an antibiotic against one bacteria can also pressure another to become resistant. That’s one of the reasons we want to go as narrow as possible with our antibiotics, because we don’t want to pressure growth.”

The researchers suggested that their study supports the expansion of influenza vaccine coverage further upstream to help mitigate the inciting viral infection and reduce secondary bacterial coinfections and antibiotic use. “We concur with the World Health Organization Action Framework on leveraging vaccines to reduce antibiotic use and prevent ABR that vaccines and vaccination should be considered core components of stewardship policies and strategies,” they wrote.

“Antibiotic resistance is complicated and multifactorial, so one intervention is not going to do it,” Dr. Yang cautioned.

“This study is also a good reminder that when we get to the time of year when we expect to see antibiotic usage go up, as in winter months when there are increases in respiratory infections, it’s time for reminders in our institutions about ■ prescribing guidelines and antimicrobial stewardship.”

BD was contracted by Sanofi Pasteur to conduct the study, and two of the study co-authors are employees of Sanofi Pasteur and may hold shares or stock options in that company. Dr. Gupta and two of his co-authors are employees of BD and own stock in that company.

Free CE/CME now available!

1.0 AMA PRA Category 1 Credit™ 1.0 ACPE credit

Ensuring Optimal Management of Antibiotic-Resistant Hospital- and VentilatorAcquired Pneumonia RELEASE DATE: JUNE 8, 2021 EXPIRATION DATE: DECEMBER 31, 2022

CHAIR Keith S. Kaye, MD, MPH

Jointly provided by Postgraduate Institute for Medicine and Applied Clinical Education

Professor Infectious Diseases, Internal Medicine University of Michigan Taubman Center Ann Arbor, Michigan

FACULTY Andrew F. Shorr, MD, MPH, MBA

Supported by an independent educational grant from Shionogi Inc.

Head of Pulmonary and Critical Care Medicine MedStar Washington Hospital Center Professor of Medicine Georgetown University Washington, DC

David P. Nicolau, PharmD, FCCP, FIDSA Distributed by Infectious Disease Special Edition, Pharmacy Practice News, and cmezone.com

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PharmDs Deemed ARTisans in HIV Rx Safety

BY DAVID WILD

E

xpanding inpatient medication stewardship efforts to encompass antiretroviral therapy (ART) can slash medication errors and 30-day hospital readmission rates by more than 50% in people living with HIV, recent studies suggest.

“ARVSPs [antiretroviral stewardship programs] improve outcomes for patients because they ensure patients get the right medications, at the right time, in the right doses,” said Elizabeth Sherman, PharmD, an associate professor of pharmacy practice at Nova Southeastern University, in Fort Lauderdale, Fla., who helped launch her own institution’s program.

Inpatient medication errors related to ART or opportunistic infection (OI) treatments occur in up to 72% of hospitalized patients with HIV (Open Forum Infect Dis 2020;7[8]:ofaa073), making medication monitoring imperative in this population, Amber Ladak, PharmD, an HIV pharmacist in the Division of Infectious Disease at the Medical College of Georgia at Augusta University, said during a session on ARVSPs at the 2021 annual meeting of the American College of Clinical Pharmacy (ACCP).

“Hospitalized patients with HIV require careful medication review and management, both because of their complex antiretroviral regimens and because they are receiving increasingly more medications for non-HIV comorbidities,” Dr. Ladak said.

Part of the reason the error rate is so high is that many

hospitalists do not have expertise in HIV treatment and can make mistakes when initiating or modifying complex HIV regimens, Dr. Ladak said. “There are just so many different combinations of antiretrovirals that it’s quite easy for physicians to start a regimen without a booster, for example, or to prescribe a regimen that doesn’t match the patient’s outpatient treatment,” she explained.

The good news is that pharmacists can help reduce these errors by implementing simple ARVSP interventions. For example, adding clear instructions in computerized physician order entry (CPOE) systems can guide accurate dosing and prompt physicians to double-check the regimen they are prescribing, Dr. Ladak said.

Another low-cost measure that Dr. Ladak and her colleagues have found helpful in mitigating errors for ART orders has been to add brand names alongside single-tablet multidrug treatments in their CPOE system. “If someone is ordering quickly and looking only at the first couple of drugs of a regimen, they can easily confuse it for another regimen,” she said.

Reducing Mix-Ups

Although Dr. Ladak did not share details on the effectiveness of adding brand names to the CPOE system at her institution, she said it has reduced the number of mix-ups between ART treatments that share some of the same components. She also cited data ‘Hospitalized patients with HIV require showing CPOE-based tools such as this careful medication review and manage- have reduced inpatient ART-related errors by more than 40% (Clin Infect Dis ment, both because of their complex 2020;70[11]:2241-2246). antiretroviral regimens and because Other stewardship tools pharmacists can use include HIV-specific clinical they are receiving increasingly more checklists, Dr. Ladak said. Checklists medications for non-HIV comorbidities.’ can augment medication reviews at the —Elizabeth Sherman, PharmD time of admission and discharge and can

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Table. ARVSP Initiatives Clinical checklist—ART-specific medication review • Conducted by HIV/ID specialist • What is patient’s most recent outpatient regimen?

Order entry • Guided ordering instructions • Removal/alert of outdated ARV/inappropriate doses • Including brand names for combination products.

Example: emtricitabine/tenofovir disoproxil fumarate versus emtricitabine/tenofovir alafenamide

Leveraging EHR capabilities • Generating patient lists of admitted people with HIV • Notification of ARV orders

Formulary management • Ensure most commonly used products available • Restriction of ARV prescribing to ID team

Education • Common ART pearls (incomplete regimens, drug interactions) • Who to reach for questions/consults ARV, antiretroviral; ARVSP, antiretroviral stewardship program; EHR, electronic health record; ID, infectious disease.

Source: Amber Ladak, PharmD, based on material presented at the 2021 annual meeting of the American College of Clinical Pharmacy.

be tailored to the specific institution. Common components in use by Dr. Ladak and her colleagues, and described in a 2020 study she co-authored, include patients’ outpatient and inpatient ART and non-ART medications, drug allergies, interactions with non-ART drugs, OI prophylaxis and a review of their most recent HIV viral loads, to verify treatment efficacy (J Int Assoc Provid AIDS Care 2020;19:2325958219898457).

In a separate study examining the impact of an ARVSP with a strong emphasis on medication reviews, investigators found that 17% of patients admitted with HIV had medication errors prior to an ARVSP (Open Forum Infect Dis 2020;7[8]:ofaa073).

These included omissions of OI treatment or ART, drug– drug interactions and incorrect therapy. After the program’s implementation, the error rate dropped to 6%. All errors were resolved prior to discharge and the 30-day all-cause readmission rate fell from 27% to 12% (P=0.03).

To ensure they don’t miss any opportunity to conduct a thorough medication review and use their checklist, Dr. Ladak said she and her colleagues have set their electronic health record (EHR) to generate a daily list of patients admitted with HIV. They use the checklist at the time of admission and discharge, when they also educate patients on any new medications, document changes to their treatment regimens and contact patients’ outpatient providers to notify them of these changes.

Errors Slashed at Nova Southeastern University Reviewing thrice-weekly EHR-generated reports of inpatients receiving an ARV has had a profound effect on medication error rates at Nova Southeastern University, noted Dr. Sherman, who served as one of four pharmacists in the nation selected to author the ASHP Guidelines on Pharmacist Involvement in HIV Care (bit.ly/3vEb2kR). Her team implemented their ARVSP in January 2020 and found that the program significantly reduced the number of uncorrected ART errors. Six months before rollout, the error rate was 64% versus 31% six months after implementation (P<0.05) (J Am Pharm Assoc 2022;62[1]:264-269). Moreover, the proportion of patients with at least one medication error fell from 55.5% to 32.6%, reported Dr. Sherman, who was not part of the ACCP session.

Taking It Slow Institutions interested in launching their own ARVSP can set themselves up for success by implementing the program gradually, Dr. Ladak advised. “Perform a baseline evaluation and identify areas with the greatest need, whether that’s improving medication reviews at the time of admission or educating physicians,” she said. “Focus on one or two stewardship activities first, do them well and then add more activities as needed.”

It is also important to designate a program lead with expertise in HIV or other infectious diseases who can provide oversight, assume responsibility for the ARVSP, spearhead the development of policies and review the program’s results after implementation, Dr. Ladak said. In addition, one of the most important steps the ARVSP program lead can take is to provide prescriber education, she said.

“Sharing ART pearls, educating prescribers about the most common prescribing errors and drug interactions, and providing regular updates on available treatments can go a long way,” Dr. Ladak said.

Dr. Sherman echoed this sentiment, urging institutions that may not have the resources to implement a full ARVSP to focus on education as one way of improving ART use in hospitals. “Educating healthcare staff about clinical pearls and using medication errors as learning lessons, or even just having a dedicated person the staff can call with questions about ARV regimens, can be very helpful in preventing ARV medication ■ errors.”

Dr. Ladak reported serving on an advisory board for Theratechnologies.

Dr. Sherman reported no relevant financial disclosures.

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2022

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Dolutegravir-Based ART Is Superior to Standard Care in Adolescents

BY AARON TALLENT

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esults from a multicountry, phase 3 basket trial found that antiretroviral therapy (ART) based on dolutegravir (DTG; ViiV Healthcare) was superior to standard-of-care regimens in preventing treatment failure for children living with HIV-1, according to results of the ODYSSEY trial.

“Dolutegravir-based therapy, used as either first- or secondline [ART], resulted in fewer treatment failures compared with medication combinations currently used as standard of care. Also, fewer participants receiving dolutegravir developed major drug-resistance mutations,” said Carolyn Chu, MD, MSc, AAHIVS, an associate professor of clinical family and community medicine at the University of California, San Francisco School of Medicine.

An estimated 1.8 million people younger than 15 years of age are living with HIV worldwide. In the United States, adolescents and children make up about 7% of the 1.1 million people living with HIV. To date, the FDA approved 26 individual antiretroviral drugs and 22 combination therapies made up of two or more antiretrovirals for treating adults with HIV. However, these treatments are not indicated for children, especially young children and infants. The side effect profile and formulation may affect their overall tolerability and durability with the treatment, according to Dr. Chu, who is also the chief medical officer of the American Academy of HIV Medicine.

“With children, careful attention needs to be paid to whether use of a medication potentially affects growth and development. Dose selection and formulation are also important considerations. For example, medication availability as a liquid is often a desirable—and sometimes necessary—factor,” she said.

Dolutegravir, an integrase strand transfer inhibitor, blocks the integrase viral enzyme from inserting the HIV-1 genome into the host DNA. It is available as a pill or liquid formulation and was approved by the FDA in 2013 for treating adults and children who are 12 years of age and older and weigh at least 88 pounds.

In 2020, the agency expanded the approved indication to include adolescents who weigh at least 44 pounds and infants who are 1 month of age or older and weigh at least 6.5 pounds.

Dolutegravir is also on the World Health Organization’s Model Lists of Essential Medicines.

For the ODYSSEY trial, researchers in Germany, Portugal,

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South Africa, Spain, Thailand, Uganda, the United Kingdom and Zimbabwe compared a three-drug DTG-based ART with standard-of-care non–DTG-based ART in children and adolescents with a median age of 12.2 years who weighed at least 31 pounds. From September 2016 through June 2018, 350 participants received DTG-based ART, while 357 received the standard-of-care treatment, which was a combination of three to four antiretroviral drugs based on the countries’ guidelines (N Engl J Med 2021;385[27]:2531-2543).

“We had a lot of questions. We wanted to see if dolutegravirbased ART worked as a first-line therapy in patients who had never been treated for HIV and as second-line therapy for patients who had experienced treatment failure,” said lead author Anna Turkova, MD, a research clinician at the MRC Clinical Trials Unit at UCL and consultant pediatrician at Great Ormond Street Hospital, in London.

The investigators used a basket trial approach to study therapies across multiple populations. Patients were started on first-line ART or switched to second-line ART after experiencing treatment failure. The primary end point was the proportion of participants with virologic or clinical treatment failure.

At the set follow-up of 96 weeks, 47 patients who had received DTG-based ART experienced treatment failure, compared with 75 who were given the standard of care.

“These results show that dolutegravir is superior in terms of preventing children from developing treatment failure. This was shown in the first line and also in the second line as we applied our analysis to each basket,” Dr. Turkova said.

Dr. Chu said the ODYSSEY results provided sufficient evidence for updating simplified WHO dosing guidance and pediatric licensing recommendations, as well as expediting global access to DTG for children living with HIV. She also said additional studies of pediatric DTG use should further explore psychiatric side effects and associated events based on studies and real-world experience of DTG in adults.

“I also hope experiences and findings of this trial might pave the way for greater availability of effective, well-tolerated and easily administered medication formulations for pediatric ■ HIV treatment,” Dr. Chu said.

The study was funded by ViiV Healthcare. Dr. Chu reported no relevant financial disclosures. Dr. Turkova reported financial relationships with Mylan, Penta Foundation and ViiV Healthcare.

De-escalation continued from page 26

“For now, physicians should know that antibiotic spectrum de-escalation has an important role in clinical practice and antimicrobial stewardship programs, although many questions persist in how best to incorporate this efficiently in antimicrobial stewardship programs and what the broader ecologic consequences are,” Dr. Ryder said.

Dominic Chan, PharmD, an infectious diseases specialist and the director of

pharmacy at Legacy Emanuel Medical Center, in Portland, Ore., said evidence on the practice of spectrum de-escalation is lacking, specifically on “the outcomes we care about: mortality, notable resistance rates and long-term consequences of microbiota disruption.”

Additionally, he said, there are cases where spectrum de-escalation following use of a broad-spectrum antibiotic does not significantly alleviate the antibiotic pressure on the microbiota.

“For example, the difference in bacterial spectrum of activity between

meropenem and ceftriaxone-metronidazole may be large, but the collateral damage that ceftriaxone-metronidazole has on commensal bacteria is still tremendous,” Dr. Chan said.

“The questions we likely should be asking are, ‘Does this patient need any antibiotics, or are they on the correct, most valuable, antibiotic,’ rather than, ‘Should we decrease the spectrum of the ■ antibiotics?’” he said.

Much of this information was presented at IDWeek 2021.

Vancomycin Diagnostic Stewardship Initiative Is a Winner

BY DAVID WILD A successful stewardship initiative requires robust planning, needs buy-in from stakeholders and should demonstrate its impact after implementation. According to one stewardship expert, data should be at the center of every stewardship project.

“There are a million ways to improve patient care and only so much time during the day, and I’m a firm believer in letting the data drive what you do,” said Erin McCreary, PharmD, an infectious diseases pharmacist at UPMC, a clinical assistant professor of medicine at the University of Pittsburgh School of Medicine and the director of Stewardship Innovation for Infectious Disease Connect, in Pittsburgh.

During the midst of the COVID-19 pandemic in June 2020, Dr. McCreary and her colleagues still managed to implement several diagnostic stewardship initiatives.

These were targeted toward decreasing vancomycin usage in light of data gathered over a 16-month onth pre-pandemic period showing the duration n of vancomycin treatment was “through the roof” oof” and that 31% of vancomycin recipients experiperienced acute kidney injury because they received ed a high dose or underwent treatment for too long, g, for example.

To shorten duration of therapy in patients receiving vancomycin for pneumonia, Dr. McCreary’s team proposed moving from chromogenic agar–based methicillin-resistant Staphylococcus aureus nares testing g to polymerase chain reaction (PCR) testing,, whic would reduce the turnaround time from m 48 hours to one hour and increase testing g sensitivity from 65.7% to 91.8%. However, itt would also raise the cost per test from $5/$6 6 to $25/$35.

“We launched the project as a small-scale pilot to see if outcomes would justify the increase in testing expenditures,” she said. They collaborated with infection prevention staff to create a unique pharmacy-placed order for the rapid diagnostic test, and provided education and tracked outcomes.

The initiative proved successful, as post-implementation data gathered over a six-month period after implementation in June 2020 showed. Vancomycin was discontinued for nearly all patients with a negative test, and 15% were able to avoid vancomycin altogether because of the fast turnaround of PCR testing. Of note, the median number of days on vancomycin fell from three to one, Dr. McCreary said.

“This led to a drop in demand for vancomycin monitoring, less lab time due to less vancomycin levels being sent, less pharmacy time spent on pharmacokinetics consults, fewer instances of acute kidney injury, and it dec decreased the overall cost of patient care,” Dr. McCreary said. She did not share cost data but said McCr the program’s success has led to the intervention p being implemented at other sites across UPMC. Dr. D McCreary noted that educating stakeholders er about the stewardship initiative was “really challenging, especially at a larger center like c ours where you have to keep making adjusto ments to your protocol. m “But over time, all providers have embraced the policy of PCR testing when initiatb ing i vancomycin in patients with pneumonia,” she s said.

Dr. McCreary served on the advisory boards for AbbVie, Cidara, Entasis, Ferring, MeMed, Merck, Shionogi and Summit.

S

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2022

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HI News HHS Updates Pediatric HIV Guidelines

T

he Department of Health and Human Services updated its guidelines on treating children with HIV (https://bit. ly/3yMwVjJ-IDSE).

One of the biggest updates was the inclusion of longacting, injectable cabotegravir and rilpivirine (Cabenuva, ViiV Healthcare/Janssen), after the FDA changed the indication to include children and adolescents 12 years of age and older and weighing at least 35 kg.

Other antiretroviral therapy (ART) recommendations for naive patients were made after the FDA updated the pediatric indications for the medications, including making bictegravir-emtricitabine-tenofovir alafenamide (BIC/ FTC/TAF; Biktarvy, Gilead) a preferred integrase strand transfer inhibitor (INSTI)-based regimen for those ages 24 months and older and weighing at least 14 kg, and moving doravirine (DOR) plus a two-nucleoside reverse transcriptase inhibitor (NRTI) backbone to an alternative choice as a nonnucleoside reverse transcriptase inhibitor (NNRTI)based regimen for children and adolescents weighing 35 kg and more.

In addition, FTC/TAF (Descovy, Gilead) was made a preferred dual-NRTI combination for children and adolescents weighing at least 14 kg when used with an INSTI or NNRTI. However, the HHS panel has not yet updated the guidelines to include another FDA approval: the dispersible

tablet formulation of the fixed-dose combination of abacavirdolutegravir-abacavir-lamivudine (Triumeq, ViiV) for use in children weighing 10 to 25 kg, although HHS said it would be addressed later.

The panel recommends abacavir (ABC) plus lamivudine (3TC) or FTC as a preferred dual-NRTI combination for children at least 3 months old, and now recommends it from birth in full-term infants younger than 3 months. The healthcare provider should obtain a negative test for the HLAB5701 allele before starting ABC, regardless of age, according to the panel.

The panel also made slight changes to the clinical and laboratory monitoring section of the guidelines calling for periodic measurements of body weight, which it said was important to ensure the dosing was correct as the child grows.

The panel said some healthcare providers might want to monitor glycosylated hemoglobin, or HbA1C, in children who were at risk for prediabetes or diabetes, instead of just doing a routine blood glucose.

It was also suggested that children with HIV who emigrate to this country might benefit from thyroid function tests or other screenings, such as for tuberculosis, hepatitis and parasites. Lead level might also be checked.

Other changes include a discussion of substance use disorders in adolescents and managing drug toxicities.

Reprogramming CD8+ Cells Could Help Suppress Viral Loads

C

D8+ T cells play a critical role in enabling HIV controllers to suppress their viral loads in the long term even without antiretroviral therapy (ART), and reprogramming these immune cells might someday make more people HIV controllers.

In 2007, scientists at the Institut Pasteur described how, unlike non-controllers’ CD8+ T cells, those of controllers are able to rapidly destroy infected CD4+ T cells. Asier Sáez-Cirión’s group also demonstrated in a previous study that the cells from controllers use a different molecular program. Their research shows anti-HIV CD8+ T cells in controllers not only have huge antiviral potential, they are also programmed to survive, whereas in non-controllers, the cell program predisposes them to apoptosis.

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In continuation of this work, the scientists at the HIV, Inflammation and Persistence Unit at the institute reprogrammed non-controllers’ CD8+ T cells to acquire key characteristics of controllers’ cells—namely their ability for memory, survival, expansion, resistance to exhaustion and polyfunctionality, including an enhanced ability to suppress HIV infection. The ability of CD8+ T cells to acquire and maintain such properties appears crucial to achieving natural control of HIV (J Clin Invest 2022 Apr 5. doi:10.1172/JCI157549).

This reprogramming was performed in vitro through temporary exposure of HIV non-controllers’ cells to a GSK 3 inhibitor, a small molecule targeting two signaling pathways identified as essential to optimal functioning of CD8+ T cells. The reprogramming promoted

functional capacities associated with natural control of infection.

CD8+ T cells (red) of a controller in contact with HIV-infected CD4+ T cells (viral protein gp120 stained green). The cell nuclei are in blue. The cytotoxic molecule granzyme B is shown in pink.

Confocal microscopy.

Source: Institut Pasteur/Anastassia Mikhailova

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HI News Keeping Kaposi Sarcoma Herpesvirus Dormant

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team of researchers at the University of California, Davis has identified a protein in the cancer cell’s nucleus as a critical agent keeping Kaposi sarcoma-associated herpesvirus (KSHV) dormant and undetected by the body’s immune system. This virus is linked to Kaposi sarcoma and other illnesses.

The number of people infected with KSHV varies around the world. Less than 10% of people in the United States are infected with the virus, compared with 50% of the population in some parts of Africa. Not everyone with KSHV will rally are develop Kaposi sarcoma (KS). Those who do generally immunocompromised. roducKS used to be an AIDS-defining illness, but the introducated tion of antiretrovirals significantly reduced AIDS-related een prevalence in Western countries, although it is still seen cin parts of the United States (https://bit.ly/3M53xJcIDSE). However, in sub-Saharan Africa, the diseasee continues to have a poor prognosis. dWhen the virus enters a human cell, it causes a hidus den infection in the nucleus. During this stage, the virus d not is latching onto parts of the cell’s chromosomes and producing viral offspring.

Researchers looked at KSHV’s latent-lytic switch, a process in which the virus exits its dormant state to replicate in the host cell. This lytic cycle ends with the disintegration of the cell and the release of the viruses, infecting neighboring cells (Cell Rep 2022 May 10. doi:10.1016/j.celrep.2022.110788).

The researchers wanted to uncover the mechanisms of this latent-lytic switch and the role the host cell environment played in this process.

“Where the virus latches onto the host cell, how it manages to stay dormant and what triggers its activation were very exciting and important puzzles to solve,” said Yoshihiro Izumiya, DVM, PhD, the study’s senior author. Dr. Izumiya is a professor in the Department of Dermatology and the director of the Viral and Pathogens Associated Malignancies Program at UC Davis Comprehensive Cancer Center.

Dr. Izumiya and his team used Capture Hi-C and DNA fluorescence in situ hybridization to profile and analyze chromosomal interactions on three cancer cell lines naturally infected with KSHV. They located the virus’s preferred docking sites inside the host chro chromosomes. The binding patterns, similar amon among the three cancer cell lines, showed a nucle nuclear ecosystem that can attract and help ke keep the virus in its silent form.

The team also found chromodomain h helicase DNA-binding protein 4 (CHD4) b binds to the virus’s genomic elements.

C CHD4, a protein in the host cell’s chrom mosomes, suppresses the work of the gen gene responsible for viral replication. The study sshowed CHD4 is a key regulator of the KSHV latent-lytic switch.

“The location where the virus genome attaches to the host chromosome is not random,” said Ashish Kumar, a postdoctoral researcher in Dr. Izumiya’s lab and the paper’s first author.

“Without having enriched CHD4 protein, the virus starts to replicate, kicking in a cell-destructive mode. For the virus to select CHD4 among many other host proteins, CHD4 must play a unique and important role in host cells.”

ART Does Not Alter Microbiome Richness of Breast Milk

A

ntiretroviral therapy (ART) alone does not cause disruption in breast milk from mothers with HIV in terms of microbiome richness, diversity or bacterial composition, whereas the use of antibiotics produces distinct changes in the microbiome (Microbiol Spectr 2022 Apr 6. doi:10.1128/spectrum.02080-21).

Breast milk provides developing infants with a nutritious blend of essential microbes, antibodies and human milk oligosaccharides. Nursing infants use breast milk to establish the suite of microbes that begin to develop in their gut immediately after birth.

Microbes acquired from the mother’s

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breast milk can be detected in infant stool samples.

Disruptions in the breast milk microbiome are a serious concern due to the potential negative effect on infant health and subsequent development.

Previous studies have implicated alterations in the infant microbiome in a broad range of chronic disorders, including Crohn’s disease, diabetes mellitus and obesity. The new study suggests that babies of HIV-positive mothers on combined ART can enjoy the many benefits associated with breastfeeding, without adverse effects on the ■ infant’s microbiome.

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Protein Shift Helps Canine Coronavirus Jump to Humans

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shift occurring in canine coronavirus points to a possible pattern that may provide clues about zoonotic transmission.

Cornell and Temple University researchers identified a pattern that occurs in the terminus of canine coronavirus, which was first identified in 2017 in two Malaysian human patients with pneumonia. The virus shifted from infecting both the gastrointestinal and respiratory tracts of the animal host to infecting only the respiratory tract in the human host.

The researchers identified a change in the terminus of the spike protein—known as the N-terminus—a region of the molecule with alterations also detected in another coronavirus, which jumped from bats to humans, where it causes respiratory symptoms (Viruses 2022;14[5]:853).

In humans, the main receptor that the Alphacoronavirus spike protein binds with is called APN, but there are also coreceptors. One of these is sialic acid, which is found in GI cells.

The researchers identified a region of the spike protein in the N-terminus called the O-domain. The canine coronavirus found in the Malaysian patients appeared to be losing its O-domain.

The researchers found evidence of “relaxed evolution,” where the pressures of natural selection become reduced, which facilitated the shift.

The researchers compared this shift and loss of the O-domain

to other related coronaviruses. One, called transmissible GI virus (TGEV), infects pigs and causes respiratory and GI disease. A variant called porcine respiratory coronavirus, is almost identical to TGEV, but it has lost its O-domain and is entirely a respiratory pathogen. Similarly, another coronavirus originated in bats as a GI virus, lost its O-domain and jumped to a human host as a respiratory virus.

“So, this is a pattern that seems to be repeating itself in coronavirus evolution and, in particular, in coronavirus evolution associated with these tropism shifts, where we go from a gastrointestinal infection originally and then jumping to an alternate host, where it’s now respiratory,” Michael Stanhope, PhD, a professor of public and ecosystem health at Cornell University College of Veterinary Medicine, in Ithaca, N.Y.

Pathogen Stowaways Hitch a Ride to Sea

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icroplastics are a pathway for pathogens found on land to reach the ocean, with likely consequences for human and wildlife health, according to a study from the University of California, Davis (Sci Rep 2022;12[1]:6532).

The pathogens studied, Toxoplasma gondii, Cryptosporidium and Giardia, are underestimated causes of illness from shellfish consumption and are found throughout the ocean.

The study’s findings indicate that by hitchhiking on microplastics, pathogens can disperse throughout the ocean,

reaching places a land parasite would normally never be found. For instances, T. gondii, a parasite found only in cat feces, has caused toxoplasmosis in many ocean species. UC Davis and its partners have connected the parasite to sea otter deaths.

It’s also killed critically endangered wildlife, including Hector’s dolphins and Hawaiian monk seals.

For the study, the researchers tested whether the selected pathogens can be associated with plastics in seawater. They used two different types of microplastics: polyethylene microbeads and polyester microfibers. Microbeads are often found in cosmetics, such as exfoliants and cleansers, while microfibers are in clothing and fishing nets.

The scientists found that more parasites adhered to microfibers than to microbeads, although both types of plastic can carry pathogens. The wispy particles of microfibers are common in California’s waters and have been found in shellfish.

Microplastics that float along the surface can travel long distances, spreading pathogens far from their sources on land.

Plastics that sink may concentrate pathogens in the benthic environment, near the bottom of the sea. That’s where filterfeeding animals like zooplankton, clams, mussels, oysters, abalone and other shellfish live, increasing the likelihood of their ingesting both plastic and pathogens.

Microfibers are commonly shed in washing machines and can reach waterways via wastewater systems, according to the researchers.

“This is very much a problem that affects both humans and animals,” said first author Emma Zhang, a fourth-year veterinary student with the UC Davis School of Veterinary Medicine. “It highlights the importance of a One Health approach that requires collaboration across human, wildlife and environmental disciplines. We all depend on the ocean ■ environment.”

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Multidisciplinary Approach Best For Managing Chronic Wounds

By CHASE DOYLE

A

s the treatment of nonhealing wounds continues to evolve, multidisciplinary care is playing an increasingly important role in the management of complicated patients.

During the 2021 virtual American College of Surgeons Clinical Congress, Nicolas J. Mouawad, MD, the chief of vascular and endovascular surgery at McLaren Health Care, in Bay City, Mich., discussed the benefits of multidisciplinary wound care and how to incentivize institutional collaboration.

“Patients with difficult wounds who would often be considered for amputation with a single-specialty approach can now be managed successfully with a multidisciplinary wound team,” he said.

As Dr. Mouawad explained, chronic wounds are generally wounds that fail to heal through the body’s natural healing process (less than approximately 30% closure in four weeks).

Whether due to anatomic site, concurrent illness or medical comorbidities, the reasons for lack of healing are often complex, with these wounds posing a significant challenge to both patients and providers.

“Patients with long-term chronic wound abnormalities, particularly those with venous leg ulcers and diabetic ulcers, can suffer for months or even years, and there are significant costs to the healthcare system,” Dr. Mouawad said. “Based on Medicare data, the management of chronic wounds costs between $28.1 billion to $98.6 billion per year.”

The Core Problem According to Dr. Mouawad, a major problem affecting treatment is that wounds are not considered an actual disease. This misperception leads to a lack of standardization in wound care management, a lack of reproducibility of clinical and research outcomes, an overwhelming array of similar products, and outdated measurement tools for wound evaluation. Moreover, if chronic wounds are to become a disease entity, he noted, there’s the question of who should manage the patient, given multiple stakeholders.

“The management of patients with chronic wounds involves a wide range of specialties,” Dr. Mouawad said. “Taking ownership of the wound requires a multidisciplinary routine approach or a network.”

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Multidisciplinary Teamwork The concept of multidisciplinary teamwork in the management of chronic wounds has been around for decades and is supported by numerous professional associations and organizations. The American Diabetes Association and American College of Foot and Ankle Surgeons, for example, promote a team approach, particularly for diabetic wounds. Importantly, this approach can benefit myriad aspects of healthcare.

“The primary outcomes are to increase wound healing rates and ultimately decrease amputation rates,” Dr. Mouawad said.

“Secondary outcomes involve patient satisfaction, compliance with orthotic and prosthetic management, and ultimately health-related quality of life.”

These outcomes have been repeatedly demonstrated in the global literature. A study showed an improvement in healing rates from 23% with a single-discipline approach to 82% after the implementation of a team approach in patients with diabetic disease (Acta Derm Venereol 1995;75[2]:133-135). In addition, Gottrup et al showed healing rates of 60% over 12 months for chronic recalcitrant leg ulcers (Arch Surg 2001;136[7]:765772), while Valdes et al reported an average eight-week healing time for venous ulcers (Ostomy Wound Manage 1999;45[6]:3036). Finally, a 2011 study noted that 72% of patients healed in an average of 12 weeks following a team approach (Wound Pract Res 2011;19[4]:229-233).

Many studies have also reported a reduction in amputation rates associated with a multidisciplinary care strategy.

In patients with diabetes, for example, the results of a fiveyear prospective study showed an 82% decrease in major amputations (from 36.4% to 6.7%) with use of a team approach (Diabetes Res Clin Pract 2007;75[2]:153-158). The authors also reported a 45.7% reduction in below-the-knee amputations and a significant decrease in high-to-low amputation ratio.

“We’ve seen this over and over again, not just within the United States, but globally. Involvement of a multidisciplinary team, particularly for the diabetic foot, is associated with a reduction in the incidence of major amputations,” Dr. Mouawad said.

“Importantly, between 45% and 85% of all lower-extremity amputations can be avoided by using a multidisciplinary approach.”

In addition to clinical excellence, the multidisciplinary team allows for psychosocial factors that are important to patients.

Patients have reported increased quality-of-life scores, particularly in the domains of physical and emotional functioning, when treated with a team approach. A study in Denmark found 91% of patients were satisfied with the quality of technical care and empathy when a multidisciplinary wound team was put in place (Int J Low Extrem Wounds 2009;8[3]:153-156).

“It’s difficult and involves a lot of people, but multidisciplinary wound teams lead to the best management and the best ■ outcomes for these patients,” Dr. Mouawad concluded.

Choosing the Right Dressings for Chronic Wounds Matthew Murphy, MD, PhD, an assistant professor of plastic and reconstructive surgery at Stanford University School of Medicine, in California, noted that choosing the right dressing for chronic wounds can shorten time to healing, relieve pain and suffering, and reduce the economic burden on both the patient and healthcare system. Dr. Murphy highlighted these three types of dressings that can aid the healing process:

1. Hydrocolloids, an occlusive dressing composed of a hydrocolloid matrix bonded to a vaporpermeable film or foam backing, are known to many wound care physicians, and consist of two main types: hydrocolloid and fibrous hydrocolloid (reserved for moderate to severe wounds). Hydrocolloids absorb exudate, provide thermal insulation, promote a moist wound healing environment, prevent bacterial contamination, reduce friction and shear, and promote epithelial migration.

2. Matrices are tissue-engineered products that act as a tissue scaffold and provide a supporting structure into which cells can migrate. Matrices may be sourced from biologic tissue (animal, human or plants), synthetic materials, and composite materials containing two or more components. “The ideal matrix is one that most closely approximates the structure and function of the native extracellular matrix that it is replacing.”

3. Amniotic products are those obtained from normal amnion/chorionic membrane or umbilical tissue of live newborns. These products undergo proprietary processing for sterility, preservation and retention of growth factors. “Within these dressings, there is a host of regulatory proteins, growth factors, cytokines and chemokines that participate in healing.”

INFECTIOUS DISEASE SPECIAL EDITION • SUMMER 2022

47

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Copyright © 2022 Accelerate Diagnostics, Inc. All Rights Reserved.

“Accelerate Diagnostics” and diamond shaped logos and marks are registered trademarks of Accelerate Diagnostics, Inc. Any trade, product or service name referenced in this document using the name “Accelerate” is a trademark and/or property of Accelerate Diagnostics, Inc. All other company and product names may be trademarks, registered trademarks, or service marks of the companies with which they are associated

IDSE Review

Rapid Diagnostic Methods and Technologies in the Management Of Infectious Diseases

BY KAREN FONG, PHARMD, BCIDP

I

n the realm of infectious diseases management, rapid diagnostic tests (RDTs) have modernized the field profoundly by providing microbiological diagnoses more quickly and robustly. Modern molecular techniques include direct-specimen rapid amplification and detection platforms and next-generation sequencing, which provide more rapid, sensitive, and comprehensive laboratory diagnoses never before possible compared with conventional microbiology.1 RDTs have revolutionized the microbiological diagnostic pathway, serving as the cornerstone for pathogen identification and resistance testing.

Despite significant progress in diagnostic technologies, broad-spectrum antimicrobials continue to be heavily overused during empiric treatment of infectious disease syndromes.2,3 The detection of genotypic markers of resistance has been made available through newer technologies, but rapid phenotypic antimicrobial susceptibility testing (AST) has been accessible only recently. Genotypic (nucleic acid-based) methods are limited by detecting only searchable resistance patterns and potentially finding resistance genes that are not necessarily from the pathogenic organism.4 According to the Clinical Laboratory Standards Institute (CLSI) and European

Committee on Antimicrobial Susceptibility Testing (EUCAST) guidelines, reliable antibiotic resistance diagnostics requires phenotypic testing. Thus, these commercial advances are not yet a replacement for bacterial and fungal cultures, but could provide information to the clinical presentation and support empiric antimicrobial selection by facilitating the anticipation of susceptibility patterns based on local antibiograms.1 Classic AST techniques include broth microdilution, disk diffusion, gradient tests, agar dilution and breakpoint tests, which are based on continuous exposure of a bacterial isolate to a set of

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antimicrobials, followed by visual detection of growth.

For conventional growth-based AST, several cultivation rounds are required, including enrichment cultivations (ie, blood specimens) to increase the quantity of bacteria, plate cultivations to acquire pure cultures, identification with matrix-assisted laser desorption/ ionization time of flight (MALDI-TOF) mass spectrometry if available, and finally AST and minimum inhibitory concentration (MIC) determination, according to CLSI or EUCAST standards. This entire process may require up to several days for complete results.4 Commercial systems like VITEK 2 (bioMérieux) and BD Phoenix have streamlined and partly automated the follow-up of AST cultures, with turnaround times as short as 2 hours for identification and 4 to 8 hours for susceptibility testing.5-7 These systems use a fluorogenic methodology for organism identification and a turbidimetric method for susceptibility testing.

Standardized AST cassettes containing positive controls and wells with increasing concentrations of antibiotic continuously monitor growth and analyze MIC patterns for a large group of organisms through their extensive databases.

The effectiveness of RDTs in the diagnosis and treatment of infectious disease syndromes depends on the benefits and limitations of the methods and compatibility with clinical practice, including antimicrobial stewardship programs (ASPs). In this review, we discuss diagnostic methods and technologies that enable rapid identification and AST for blood culture testing, respiratory infections, and outpatient point of care with current antimicrobial stewardship practices. See the Table for a synopsis of RDT samples, method, specimen, turnaround time, pathogens, and resistance markers.

Blood For bloodstream infections (BSIs) and blood culture contaminants (eg, coagulase-negative staphylococci), MALDI-TOF (eg, bioMérieux, BD Bruker), polymerase chain reaction (PCR)-based technologies (eg, BioFire FilmArray BCID, GenMark ePlex BCID), and nanoparticle probe technology (eg, Verigene BC-GP and BC-GN) are molecular RDTs that have changed management fundamentally by providing identification much earlier in the course of empiric treatment compared with conventional microbiology cultures.

Organism identification using MALDI-TOF is a routine diagnostic component for infectious diseases in current clinical laboratories, first successfully introduced in the early 2000s.8 The analytical strategy using this technique is to reflect the composite proteome of a bacterial cell.9 Bacterial and fungal colonies are applied directly onto a MALDI target plate with matrices for cocrystallizations. Analytes are cocrystallized within the matrix, and then a laser beam provides energy to ionize the analyte to generate

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Classic AST techniques include broth microdilution, disk diffusion, gradient tests, agar dilution and breakpoint tests. separate protonated ions. These ions are accelerated at a fixed potential and separated from one another based on their weights when they fly along the separation tube. The flight time of each ion is measured at the detection panel placed at the end of the flight tube.8 A characteristic spectrum called peptide mass fingerprint (PMF) is generated for the analytes. Identification of the organisms is completed by comparing the PMF of the unknown organism with the PMFs contained in the database or by matching the masses of biomarkers of the unknown organism with the proteome database.9 MALDI-TOF has become the standard protocol for the identification of bacterial and fungal species based on its speed (<1 minute per sample), accurate identification of clinically relevant pathogens, and cost-effectiveness.8 The BioFire FilmArray BCID2 Panel is a multiplexed nucleic acid test performed directly on positive blood culture samples for the simultaneous qualitative detection and identification of multiple bacterial and yeast nucleic acids and selected genetic determinants associated with antimicrobial resistance. This test has an approximate turnaround time of 1 hour. There are 4 main steps when running the BioFire System: 1. lysing the sample by agitation (bead beating) in addition to chemical lysis mediated by the sample buffer; 2. extracting and purifying all nucleic acids from the sample using magnetic bead technology; 3. conducting nested multiplex PCR by performing a single, large-volume, massively multiplex reaction (PCR1) and then performing multiple singleplex second-stage PCR reactions (PCR2) to amplify

changes (median decrease, 25 hours for gram-negative antibiotics; P<0.001) and antibiotic escalation (median decrease, 43 hours; P=0.01) with Accelerate Pheno, but there were no differences in clinical outcomes, including mortality and hospital LOS, compared with culture-based methods.18 Five quasiexperimental before-and-after observational studies, analyzing the integration of Accelerate Pheno with ASP intervention, had variable results in patient outcomes. Although median time to optimal or targeted therapy and step-down antimicrobial therapy were significantly shorter with the use of Accelerate Pheno, LOS and duration of therapy (DOT) were not consistently shorter despite ASP intervention.19-24 Nevertheless, Accelerate Pheno seemed to have no benefit on mortality compared with culture-based methods.18-24 Future studies on a larger scale with ASP intervention are needed to assess its impact on clinical outcomes.

The T2Candida Panel and T2Bacteria Panel by T2 Biosystems are 2 nonculture diagnostic tests that use T2 magnetic resonance (T2MR) to identify pathogens in whole blood samples by directly detecting DNA from multiple species of Candida and bacteria, respectively, without the need for cultivating organisms. This platform amplifies microbial cell-associated DNA using a thermostable polymerase and target-specific primers, and detects signals by amplicon-induced agglomeration of superparamagnetic particles and T2MR.25 Candidemia, one of the most common hospital-acquired BSIs in the United States, is associated with high mortality, especially among patients who develop septic shock. Prompt initiation of appropriate antifungal therapy and source control are limited by blood culture insensitivity, prolonged turnaround time (median time to positivity, 2-3 days; range, 1 to ≥7 days) needed to yield growth, and the possibility of negative growth with invasive abdominal candidiasis.26 This delay has led to an overuse of empiric antifungal therapy for suspected invasive candidiasis, a practice of unproven clinical value.27 The T2Candida Panel (T2 Biosystems) is a nonculture diagnostic test with a much shorter turnaround time (3-5 hours), and has entered clinical practice as an adjunctive RDT to cultures.26,28,29 While sensitivity and specificity seem to be much more promising compared with blood cultures, the role of the T2Candida Panel in the early diagnosis and management of candidemia remains unclear.26,29 Based on retrospective, single-center cohort studies, the T2Candida Panel decreased time to appropriate therapy in patients with proven candidemia while shorter antifungal DOT and cost savings were observed in patients without microbiological evidence of invasive candidiasis. However, antifungal discontinuation with negative tests has been inconsistent despite antimicrobial stewardship interventions such as prospective audit and feedback being performed on negative results.30-32 The

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sequences within the PCR1 products; and 4. using end point melting curve data to detect and generate a result for reach target on the BioFire BCID2 Panel array.10 Similarly, the ePlex BCID Panels are automated, qualitative multiplex nucleic acid in vitro diagnostic tests for the simultaneous detection and identification of gram-positive, gram-negative, and fungal pathogens as well as antibiotic resistance genes in positive blood cultures in approximately 1.5 hours.

This test uses electrowetting to perform multiplex nucleic acid extraction, amplification, and digestion, and Genmark’s eSensor technology to detect analyte targets.11,12 Finally, Verigene BC-GP and BC-GN use nanogrid technology, a unique gold nanoparticle probe chemistry, which is the driving force behind its platform with a turnaround time of 2.5 hours. Identification of causative pathogens is accompanied by their associated resistance markers. Each nanoparticle is functionalized with either a defined number of oligonucleotides (ie, short pieces of DNA or RNA) or a defined number of antibodies that are specific to a particular protein of interest. The detection of DNA or RNA targets on the Verigene System involves automating nucleic acid extraction and PCR amplification (if necessary) from positive blood culture, automating transfer of eluted nucleic acids for hybridization, primary hybridization of target DNA to capture oligonucleotides on a microarray, secondary hybridization of specific mediator oligonucleotides and gold nanoparticle probes, signal amplification of hybridized probes via a silver staining process, and automated qualitative analysis of results.13 These platforms for BSIs have been associated with decreases in time to effective therapy, hospital length of stay (LOS), and mortality when paired with actionable ASP interventions.14 Benefits of molecular RDTs in BSIs appear cost effective.15 There is a robust synergism between antimicrobial stewardship and RDT in these data, with an 80% chance of cost-effectiveness but only 41.1% in the absence of ASP. The Accelerate Pheno system from Accelerate Diagnostics has introduced further potential changes in the management of BSIs through an automated rapid phenotypic testing system. This system can yield organism identification and susceptibility interpretation with an MIC, and turnaround time of approximately 2 hours and 7 hours after positive blood culture, respectively. The platform uses automated fluorescence in situ hybridization technology with morphokinetic cellular analysis—a method that tracks, analyzes, and interprets different morphology and kinetic data to determine mass, division rate, anomalous growth patterns, and even detect heterogeneity.16,17 A randomized controlled trial of patients with gramnegative BSIs combined with prospective audit and feedback demonstrated significantly faster antibiotic

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Positive blood culture

Whole blood Whole blood

Fluorescencelabeled nucleic acid probe, morphokinetic cellular analysis

mPCR, magnetic resonance

mPCR, magnetic resonance

Next-generation sequencing

Accelerate Pheno (Accelerate Diagnostics)

T2Bacteria Panel (T2 Biosystems)

T2Candida Panel (T2 Biosystems)

Karius Test

Whole blood

Positive blood culture

mPCR, gold nanoparticle technology

Positive blood culture

mPCR, electrowetting, eSensor technology

ePlex Blood Culture Identification (GenMark)

Verigene Blood Culture Test (Luminex)

Positive blood culture

Pure culture

Specimen

mPCR

Mass spectrometry

Method

FilmArray Blood Culture Identification (BioFire)

Blood MALDI-TOF (bioMérieux, Brucker)

1d

3-5 h

3-5 h

Identification: 2 h Susceptibility: 7 h

2.5 h

1.5 h

1h

<1 min

Turnaround time

1,250 bacteria, fungi, parasites, and viruses

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

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

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

Resistance markers: mecA, vanA, vanA/B, CTX-M, IMP, KPC, NDM, OXA, VIM

E. faecalis, E. faecium, Listeria spp, Micrococcus spp, Staphylococcus spp, S. aureus, S. epidermidis, S. lugdunensis, Streptococcus spp, S. agalactiae, S. anginosus, S. pneumoniae, S. pyogenes, Acinetobacter spp, Citrobacter spp, E. coli, Enterobacter spp, K. oxytoca, K. pneumoniae, Proteus spp, P. aeruginosa, S. marcescens

Resistance markers: mecA, mecC, vanA, vanA/B, CTX-M, IMP, KPC, NDM, OXA, VIM

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

Resistance markers: mecA, mecC, vanA, vanA/B, CTX-M, IMP, KPC, mcr-1, NDM, OXA-48-like, OXA

Enterococcus faecalis, Enterococcus faecium, Listeria monocytogenes, Staphylococcus spp, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus lugdunensis, Streptococcus spp, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes, Acinetobacter baumannii, Bacteroides fragilis, Escherichia coli, Enterobacter cloacae complex, Haemophilus influenzae, Klebsiella aerogenes, Klebsiella oxytoca, Klebsiella pneumoniae, Neisseria meningitidis, Proteus spp, Pseudomonas aeruginosa, Salmonella, Serratia marcescens, Stenotrophomonas maltophilia, Candida albicans, Candida auris, Candida glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis, Cryptococcus neoformans

All organisms

Pathogens/resistance markers

Table. Sample of RDTs With Turnaround Time and Pathogens/Resistance Markers

IDSE Review

NPS or throat

mPCR

Real-time PCR

Isothermal nucleic acid amplification

Unyvero Lower Respiratory Tract Panel (Curetis)

Xpert MRSA NxG test, GeneXpert (Cepheid)

mPCR

FilmArray Respiratory Panel EZ (BioFire)

NPS

NPS or throat

Tracheal aspirate, BAL

Tracheal aspirate, BAL

1h

18-36 min

6-13 min

1h

<5 h

1h

<2 h

<3 h

<2 h

6h

45 min

Adenovirus, coronavirus, human metapneumovirus, influenza A, influenza A subtype H1, influenza A subtype H3, influenza A subtype H1-2009, influenza B, parainfluenza virus, human rhinovirus/enterovirus, respiratory syncytial virus, B. pertussis, C. pneumoniae, M. pneumoniae

SARS-CoV-2, influenza A/B, respiratory syncytial virus, GAS

SARS-CoV-2, influenza A/B, respiratory syncytial virus A/B, GAS

MRSA

Pathogens: Acinetobacter spp, C. pneumoniae, Citrobacter freundii, E. coli, E. cloacae complex, Haemophilus influenza, K. oxytoca, K. pneumoniae, Klebsiella variicola, Legionella pneumophila, Moraxella catarrhalis, Morganella morganii, M. pneumoniae, Proteus spp, P. aeruginosa, S. marcescens, S. aureus, S. maltophilia, S. pneumoniae Resistance markers: CTX-M, KPC, mecA, NDM, OXA-23, OXA-24, OXA-48, OXA-58, TEM, VIM

Pathogens: Acinetobacter calcoaceticus-baumannii complex, K. oxytoca, S. marcescens, E. cloacae complex, K. pneumoniae group, S. aureus, E. coli, Moraxella catarrhalis, S. agalactiae H. influenzae, Proteus spp, S. pneumoniae, K. aerogenes, P. aeruginosa, S. pyogenes, C. pneumoniae, L. pneumophila, M. pneumoniae, adenovirus, human rhinovirus/wnterovirus, parainfluenza virus, coronavirus, influenza A, respiratory syncytial virus, human metapneumovirus, influenza B Resistance markers: CTX-M, NDM, mecA/C and MREJ, IMP, OXA-48 like, KPC, VIM

Adenovirus, human metapneumovirus, influenza A subtypes, influenza B, parainfluenza types 1-4, respiratory syncytial virus A/B, rhinovirus, Bordetella parapertussis/ bronchiseptica, Bordetella holmesii, B. pertussis

Adenovirus, human metapneumovirus, influenza A subtypes, influenza B, parainfluenza types 1-4, respiratory syncytial virus A/B, rhinovirus/enterovirus, coronavirus subtypes, human bocavirus, C. pneumoniae, M. pneumoniae, Legionella pneumophila

Adenovirus; coronavirus types 229E, HKU1, NL63, and OC43; SARS-CoV-2; metapneumovirus; rhinovirus/enterovirus; influenza A; influenza A H1; influenza AvH12009; Influenza A H3; influenza B; parainfluenza types 1-4; respiratory syncytial virus A and B; C. pneumoniae, M. pneumoniae

Adenovirus groups B, C, and E; coronavirus types 229E, HKU1, OC43, and NL63; influenza A virus subtypes; influenza B virus; human metapneumovirus; parainfluenza virus types 1-4; respiratory syncytial virus types A and B; and rhinovirus

Adenovirus; coronavirus types 229E, HKU1, NL63, and OC43; SARS-CoV-2; human metapneumovirus; human rhinovirus/enterovirus; influenza A, including subtypes H1, H3, and H1-2009; influenza B; parainfluenza virus types 1-4; respiratory syncytial virus; Bordetella parapertussis; Bordetella pertussis; Chlamydia pneumoniae; Mycoplasma pneumoniae

BAL, bronchoalveolar lavage; GAS, group A Streptococcus; MRSA, methicillin-resistant S. aureus; NPS, nasopharyngeal swab

Real-time PCR

Xpert Xpress CoV-2/ Flu/RSV plus (Cepheid)

ID NOW (Abbott)

Nasal

mPCR

FilmArray Pneumonia Panel (BioFire)

NPS

mPCR

Verigene Respiratory Pathogens Flex Test (Luminex)

NPS

NPS

mPCR, electrowetting, eSensor technology

ePlex Respiratory Pathogen Panel 2 (GenMark Diagnostics)

mPCR

NPS

mPCR, electrowetting, eSensor technology

eSensor XT-8 Respiratory Viral Panel (GenMark Diagnostics)

NxTAG Respiratory Pathogen Panel (Luminex)

NPS

mPCR

FilmArray Respiratory Panel 2.1 (BioFire)

Respiratory

IDSE Review

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stewardship potential of the T2Candida Panel, if any, appears minimal and heavily contingent on the effectiveness of the ASP intervention as clinicians are particularly apprehensive about de-escalation in patients already at substantially high risk for fungal infections.

The T2Bacteria Panel by T2 Biosystems has a similar turnaround time of 3 to 5 hours for the detection of BSIs caused by 5 bacteria: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli. Its sensitivity, specificity, negative predictive value (NPV), positive percent agreement, and negative percent agreement, paired with blood cultures, are all more than 90%.25,33,34 Compared with blood cultures (mean, 71.7 [SD, 39.3] hours), there was a shorter time from initiation of testing to detection and identification of pathogens (7.70 [SD, 1.38] hours), but a 10% false-positive rate was observed for its targeted organisms.25 Additionally, the T2Bacteria assay appeared to detect 25% more positives than blood culture in a small, prospective noninterventional study in the emergency department, which were deemed to be associated with evidence of infection, but true positivity remains unclear.33 Interestingly, 20 patients were identified in a study of 233 participants with 21 (9%) discordant results, positive T2Bacteria cases and negative blood cultures. Eleven (52.5%) cases had probable BSI, 4 (19%) had possible BSI, and 6 (28.5%) were presumed false positives.35 Closed-space and localized infections (mostly pyelonephritis and abscess) and recent use of antimicrobial agents were characteristics among the probable and possible BSIs with discrepancies.35 In a recent evaluation of both platforms, Giannella et al conducted a systematic review of 14 controlled studies, the majority being observational, comparing T2MR with blood culture for the detection of bacterial and fungal BSIs. Patients testing positive were found to have received targeted antimicrobial therapy faster (by 42 hours; P<0.001). Patients who tested negative were de-escalated from empiric therapy faster (by 7 hours; P=0.02).36 Length of stay in the ICU (mean difference, –5.0 days; P=0.03) and hospital LOS (–4.8 days; P=0.03) were shorter with T2MR, but no difference was observed for mortality (28.9% vs 29.9%; RR [rate ratio], 1.02; P=0.86).36 Further prospective, ideally interventional, studies are needed to justify the role of T2MR along with ASPs in patient care.37 The Karius Test is a novel metagenomic microbiological diagnostic test that uses next-generation sequencing (NGS) to detect degraded microbial DNA released into the plasma, also known as cell-free DNA,

from 1,250 bacteria, fungi, parasites, and viruses to facilitate the improvement of infectious disease diagnosis by elevating diagnostic yield, shortening time to diagnosis, and avoiding invasive testing for specimen collection.38-40 Given its noninvasive nature and that only 5 mL of whole blood is required, NGS has been coined “liquid biopsy” by the company. Once the sample is received in the laboratory, quantitative results in molecules per microliter with a reference range based on pooled results from 167 asymptomatic donors are available by the next day.40 Plasma proceeds to processing through DNA extraction; sequencing, where billions of DNA fragments are simultaneously and independently sequenced with the goal to interrogate all genetic sequences present in the specimen; and analyze against a database of pathogen genomes.40 While clinical data are still limited, this new technology may have a particular niche in the diagnosis and identification of infectious etiologies for pneumonia, bacteremia, endovascular infections, and febrile neutropenia (FN) despite pretreatment with antibiotics.38,39,41 For complicated community-acquired pneumonia (CAP), NGS results were retrospectively compared with standard culture methods and found to be pathogen positive in 45 (98%) of 46 hospitalized children with the causative pathogen identified in 41 (89%). In 32 (70%) children, NGS was the only method for pathogen identification. Management changed in 36 (78%) children based on NGS results, with antibiotic spectrum narrowing in 29 (81%).42 In a prospective study of 55 patients with FN, NGS sensitivity and specificity for definite, probable, and possible cases of infection were 85% (41/48) and 100% (14/14%), respectively.

Real-time NGS results could have optimized antimicrobials earlier in 47% of patients, by addition of antibacterials (20%; mostly against anaerobes, 12.7%), antivirals (14.5%), and/or antifungals (3.6%), and antimicrobial de-escalation in 27.3% of cases.43 Furthermore, NGS was assessed retrospectively in 31 patients with either hematologic malignancy or hematopoietic stem cell transplant (HSCT) who had persistent fever and/or imaging suspicious for infection. NGS results escalated antibiotics in 28% of cases (9/32) and de-escalated antibiotics in 31% of cases (10/32) with overall management changed in 59% (19/32) of patients. Sensitivity and specificity were 80% and 58% for clinically significant infection, respectively. Some notable uncommon and difficult-to-diagnose organisms detected were Nocardia, Legionella, Toxoplasma, and Pneumocystis jirovecii.44 In 3 studies of mostly HSCT recipients

Pneumonia is a major contributor to morbidity and mortality in the United States, accounting for 1.3 million hospitalizations and 63,000 deaths annually.

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Respiratory Infections Respiratory Viral Panels Pneumonia is a major contributor to morbidity and mortality in the United States, accounting for 1.2 million hospitalizations and 63,000 deaths annually.48,49 Although recommendations from the American Thoracic Society/Infectious Diseases Society of America (IDSA) for empiric antibiotic therapy in CAP are based on targeting the major treatable respiratory bacterial organisms, hospitalized patients are more than twice as likely to harbor respiratory viruses as bacteria, and influenza only marginally accounts for the respiratory viruses with the propensity to cause pneumonia.50-53 Antibiotics are commonly overused, because distinguishing between bacterial and viral etiologies in lower respiratory tract infections (LRTIs) is difficult due to similar manifestations.54 Antibiotic therapy may be withheld safely in patients diagnosed with only viral pneumonia as long as these infections may be discriminated from those with concomitant bacterial etiologies.55 As an important intervention to reduce the inappropriate use of antibiotics, antimicrobial stewardship guidelines advocate rapid testing for broad panels of respiratory viruses.56 The BioFire FilmArray Respiratory Panel 2.1 is a PCR-based multiplex nucleic acid test intended for use with the BioFire System, which simultaneously identifies nucleic acids from 18 different viruses and 4 bacteria associated with acute respiratory tract infections from a single nasopharyngeal specimen.57 The eSensor XT-8 Respiratory Viral Panel (GenMark Diagnostics) is based on the principles of competitive DNA hybridization and electrochemical detection. This panel includes assays for 8 viruses, including adenovirus groups, coronavirus types, influenza A virus, influenza B virus, human metapneumovirus, parainfluenza virus types, respiratory syncytial virus types, and rhinovirus. Nucleic acids first are extracted from the specimen for real-time PCR assays.

The target DNA is mixed with the signal probe solution specific for the different viral targets, and hybridization to signal probes occurs immediately if the applicable target DNA is present. The solution is pumped through the cartridge’s microfluidic chamber and the target DNA/signal probe complex reacts with the preassembled capture probe specific for individual viral targets.

An electrical current is swept across each electrode and target DNA is analyzed by electrochemical detection.58,59 The ePlex Respiratory Pathogen Panel 2 (GenMark Diagnostics) is a qualitative nucleic acid multiplex test that detects 19 of the most common viruses and 2 bacterial respiratory pathogens in nasopharyngeal specimens. As described for the eSensor XT-8 Respiratory Viral Panel, this test uses GenMark’s eSensor technology, based on the principles of competitive DNA hybridization and electrochemical detection, combined with electrowetting microfluidics.60 The NxTAG Respiratory Pathogen Panel (Luminex) is also a qualitative test that simultaneously detects and identifies nucleic acids from 18 respiratory viruses and 3 bacteria in nasopharyngeal swabs collected from individuals with clinical signs and symptoms of an acute respiratory tract infection. Nucleic acid extraction is followed by loading extracted nucleic acid to pre-plated test wells, and then multiplex reverse transcriptase PCR and hybridization occurs with data acquisition on the MAGPIX instrument.61,62 Lastly, the Verigene Respiratory Pathogens Flex Test (Luminex) uses reverse transcription, PCR, and microarray hybridization to detect gene sequences of 13 viruses (adenovirus, human metapneumovirus, influenza A subtypes, influenza B, parainfluenza 1-4, respiratory syncytial virus A and B, and rhinovirus), and 3 bacteria (Bordetella parapertussis/bronchiseptica, Bordetella holmesii, and Bordetella pertussis).63 According to a multicenter, retrospective cohort analysis of adult patients admitted with suspected pneumonia in 179 hospitals nationwide, only a minority of patients were tested for a fraction of the potential respiratory viruses, with most tested for influenza.

Patients with positive viral test results often received a prolonged duration of unnecessary antibacterial courses even with concurrent negative bacterial tests.64 The IDSA’s Diagnostics Committee suggests that the combination of respiratory viral testing and procalcitonin (PCT) may be more likely to exclude bacterial coinfection with confidence in a meaningful time frame.65 The respiratory viral panel (RVP) combined with PCT and either direct or indirect (automated best practice alert) ASP intervention had a higher proportion of antibiotic discontinuation or deescalation and significantly reduced antibiotic days of therapy, but this effect was observed only with ASP intervention.66-68 Reduction in antibiotic days of therapy observed with RVP and PCT combination with a varying level of ASP intervention appears to be similar, if not greater, and more consistent compared with solely PCT or RVP use with ASP intervention, but more robust head-to-head comparisons are needed to confirm these speculations.54,66,67,69,70

Lower Respiratory Tract Infection Panels The BioFire FilmArray Pneumonia Panel and Curetis

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and leukemia or lymphoma patients, the sensitivity of NGS for biopsy-proven/probable Aspergillus and non-Aspergillus invasive mold infections (IMI) was found to be 51%.45-47 The specificity and PPV were estimated to be 100% based on no findings of false positives in 19 controls, while NPV was estimated to be 81% to 99%. 45 When combined with serum galactomannan, NGS had an improved sensitivity of 84%.45 Future larger studies are needed to validate the utility of this test in these patient populations.

IDSE Review

Unyvero Lower Respiratory Tract (LRT) Panel are multiplex nucleic acid panels for the simultaneous detection and identification of nucleic acid sequences from microorganisms and resistance markers in sputumlike or bronchoalveolar lavage (BAL)-like specimens obtained from patients suspected to have LRTIs.71,72 The BioFire FilmArray Pneumonia Panel is intended for use with the BioFire System, identifying 8 viruses, 8 resistance genes, and 3 atypical bacteria using qualitative targets. Fifteen typical bacterial targets are reported semiquantitatively with bins of 104, 105, 106, or 107 or more genomic copies/mL of bacterial nucleic acid in the specimen to estimate the relative abundance of nucleic acid from common bacteria in a sample.71 Although semiquantitative analysis may improve clinical specificity, airway colonizers cannot be distinguished from invasive pathogens. The Curetis Unyvero LRT Panel is purely qualitative, and able to detect 29 bacterial pathogens and 19 resistance genes. This panel automates and integrates DNA purification, 8 parallel multiplex end point PCR reactions, and detection of nucleic acid using hybridization on PCR chamber arrays in a single-use cartridge from LRTI pathogens in a single respiratory specimen.72 Molecular testing for bacterial pathogens was not addressed by the current pneumonia guidelines, because their performance and potential impact on clinical decision making are still undetermined.53,73 The clinical applicability of these panels is likely to be in patients who have new or worsening lung infiltrates, are moderately to severely ill, and/or have received empiric antibiotics prior to obtaining cultures.65 Rand et al found a sensitivity of 97.8% (95% CI, 94.3%-99.4%), specificity of 80.4% (95% CI, 74.5%85.4%), PPV of 80% (95% CI, 75.5%-84%), and NPV of 97.8% (95% CI, 94.3%-99.1%) for the BioFire FilmArray Pneumonia Panel for bacterial pathogens compared with endotracheal and BAL cultures.74 Kolenda et al observed similar sensitivity and specificity for the panel, but 60.5% of bacterial targets detected by the panel were not recovered by culture. Also, 76.9% of discordant results corresponded to commensal oral flora bacteria and/or 105 copies/mL or less of bacterial nucleic acids.75 The high sensitivity may be useful to deter inappropriate prescribing of antibiotics by ruling out bacterial coinfections, but positive results should be interpreted with caution. Resistance genes can be detected in concordance with results by culture but cannot be linked definitively to the microorganism(s) detected. Culture results are still required in conjunction with panel results to confirm susceptibility or resistance.76 The BioFire FilmArray Pneumonia Panel may have the potential to reduce unnecessary antimicrobial exposure and increase the appropriateness of empiric antibiotic therapy based on observed antimicrobial de-escalation in 63 of 159 (40%) and escalation in 35 (22%) hospitalized pneumonia patients.77 The

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Curetis Unyvero LRT Panel has reported similar diagnostic accuracy, but there are comparable interpretation challenges and not all genes could be attributed to an organism, highlighting the necessary continuation of current culture methods with antimicrobial susceptibility testing.78,79 Results from Pickens et al predicted antibiotic de-escalation from unnecessary methicillin-resistant Staphylococcus aureus (MRSA) and P. aeruginosa coverage in 65.9% (405/615) of patients.80 Interpretation challenges with pneumonia panels, especially with resistance genes, may be assisted by ASPs, but this requires further exploration.

Clinical Utility of Screening for MRSA With Nasal PCR The Xpert MRSA NxG test, from GeneXpert Cepheid, has become a robust ASP tool for de-escalation from MRSA therapy in predominantly patients with suspected or confirmed pneumonia.81 This serves as a qualitative ancillary test to rule out MRSA pneumonia by detecting MRSA DNA directly in nasal swabs from patients at risk for nasal colonization. The technology involves real-time PCR for the amplification of MRSA-specific DNA targets and fluorogenic targetspecific hybridization probes for the real-time detection of the amplified DNA.82 Current guidelines for CAP recommend the routine use of the MRSA nasal PCR for the de-escalation of MRSA coverage.53 With an NPV of more than 95% combined with ASP implementation, the MRSA nasal PCR was found to significantly reduce unnecessary vancomycin use and associated costs.83-85

Outpatient Antimicrobial Prescribing And Diagnostic Potential Respiratory Infections The RDTs have been used mainly in the inpatient setting, but millions of patients are affected by respiratory tract infections (RTIs) in the outpatient setting annually, resulting in millions of outpatient antibiotic prescriptions.86-88 Based on population database evaluations in the United States, up to half of prescriptions are considered inappropriate based on indication, drug, dose, or duration prescribed.87,88 If RDTs could be performed closer to healthcare providers, this could cause a paradigm shift from presumptive to definitive treatments of infectious disease syndromes in outpatient clinics.4 Primary care logistics require RDT technologies to accommodate the time constraints of brief office visits for RTIs, which on average are only 15 minutes.89 Common RDT platforms such as agglutination or lateral flow tests are very simple, require minimal familiarity and almost no equipment, and provide rapid results in a few minutes. In a lateral flow test, the specimen is placed onto a strip to migrate across the zone where the antigen or antibody is captured, and visual

Conclusion As the field of infectious disease management continues to evolve, RDTs have been increasingly recognized for their significant impact on clinical outcomes, antimicrobial use, and cost savings. For the management of BSIs, invasive candidiasis, and inpatient and outpatient respiratory infections, there is a multitude of technological advances. A comprehensive chart of the RDTs discussed with respect to detection method, sample type required, turnaround time, pathogen identification, and resistance gene detection is shown in the Table. Evaluations of the efficacy of these technologies are imperative and should ensure their value is not only increasing the accuracy and speed of diagnosis, but also changing clinical management, improving patient outcomes, and yielding overall cost-effectiveness.

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24. Bhalodi AA, et al. Clin Infect Dis. 2021;ciab921.

25. Nguyen MH, et al. Ann Intern Med. 2019;170(12):845-852.

26. Pappas PG, et al. Clin Infect Dis. 2016;62(4):e1-e50.

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28. Gill CM, et al. Diagn Microbiol Infect Dis. 2019;95(2):162-165.

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identification occurs after a certain period. The sensitivity and qualitative nature of these results may limit their interpretation.90 Agglutination assays work by observing carrier particles binding to target analytes in visible clumps. Interpretation may be limited by low sensitivity and inconclusive results in weak reactions.90 Molecular point-of-care testing, using ID NOW and BinaxNOW (Abbott), Cobas Liat PCR (Roche Diagnostics), Xpert Xpress (Cepheid), BD Veritor Plus (BD), and FilmArray Respiratory Panel EZ (BioFire), is increasingly available in the outpatient setting, but their use is limited by regulations for testing (Clinical Laboratory Improvement Amendments [CLIA] Act waivers). If CLIA-waived, these tests may have limited implementation due to cost, lack of laboratory oversight, and even achieving practical turnaround time (<20 minutes) during primary care visits.91 ID NOW is an automated multiplex assay that uses isothermal nucleic acid amplification technology for the qualitative detection of influenza A/B, respiratory syncytial virus (RSV) A/B, SARS-CoV-2, and Group A Strep nucleic acids from nasal, nasopharyngeal, and/or throat swabs. Templates, similar to primers, designed to target viral RNA or bacterial DNA are used for amplification. Fluorescent-labeled molecular beacons are used to identify each of the amplified RNA or DNA targets. Results are available within 6 to 13 minutes.92-95 The Xpert Xpress CoV-2/Flu/RSV Plus qualitatively detects RNA from SARS-CoV-2, influenza A/B, and/or RSV in nasopharyngeal swabs in approximately 36 minutes.96,97 Also, the Xpert Xpress Strep A test is available in the same platform for Group A Strep DNA detection in throat specimens in 18 minutes.98 The Cepheid GeneXpert Xpress instrument automates and integrates preparation, nucleic acid extraction, amplification, and detection of the target sequences by using real-time PCR. The BioFire FilmArray Respiratory Panel EZ, a simplified version of the BioFire FilmArray Respiratory Panel, was demonstrated to significantly improve the appropriate use of antibiotics and was associated with a decrease in clinic appointment duration in an outpatient pediatric clinic.99 The turnaround time of 1 hour likely will limit the clinical utility of this test compared with the other tests. Additionally, this simplified test is uncertain to reduce the use of downstream healthcare resources, including radiological and laboratory tests, telephone calls, and follow-up appointments.100 A major limitation of molecular diagnostic tests is appropriate utilization and interpretation.101,102 When an organism is detected, pathogenicity may not necessarily be reflected; colonization or prolonged shedding also should be considered.88,103 Clearly, there is an opportunity for collaboration between the laboratory and clinicians to incorporate these tests into ASP and diagnostic stewardship efforts to mitigate the risk for overtesting and misinterpretation.101,102

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29. Mylonakis E, et al. Clin Infect Dis. 2015;60(6):892-899.

30. Patch ME, et al. J Antimicrob Chemother.

2018;73(suppl_4):iv27-iv30.

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Steuber TD, et al. Diagn Microbiol Infect Dis. 2020;97(4):115086.

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BioFire FilmArray Pneumonia Panel. https://www.biofiredx. com/products/the-filmarray-panels/filmarray-pneumonia/

72. Unyvero Application Manual - Lower Respiratory Tract (LRT).

2021.

73. Kalil AC, et al. Clin Infect Dis. 2016;63(5):e61-e111.

32. Bomkamp JP, et al. J Clin Microbiol. 2020;58(3):e01408-e01419.

74. Rand KH, et al. Open Forum Infect Dis. 2021;8(1):ofaa560.

33. Voigt C, et al. J Emerg Med. 2020;58(5):785-796.

75. Kolenda C, et al. Open Forum Infect Dis. 2020;7(11):ofaa484.

34. Drevinek P, et al. Microbiologyopen. 2021;10(3):e1210.

76. Yoo IY, et al. Int J Infect Dis. 2020;95:326-331.

35. Kalligeros M, et al. BMC Infect Dis. 2020;20(1):326.

77. Monard C, et al. Crit Care. 2020;24(1):434.

37. Weinrib DA, et al. Ann Intern Med. 2019;170(12):888-889.

78. Klein M, et al. Multicenter Evaluation of the Unyvero Platform for Testing Bronchoalveolar Lavage Fluid. J Clin Microbiol.

2021;59(3):e02497.

38. Goggin KP, et al. JAMA Oncol. 2020;6(4):552-556.

79. Collins ME, et al. J Clin Microbiol. 2020;58(5):e02013-e02019.

39. Hogan CA, et al. Clin Infect Dis. 2021;72(2):239-245.

80. Pickens C, et al. Diagn Microbiol Infect Dis. 2020;98(4):115179.

40. Morales M. Clinical Microbiology Newsletter. 2021;43(9):69-79.

81.

36. Giannella M, et al. Expert Rev Med Devices. 2021;18(5):473-482.

Parente DM, et al. Clin Infect Dis. 2018;67(1):1-7.

42. Dworsky ZD, et al. Hosp Pediatr. 2022;12(4):377-384.

82. Xpert MRSA NxG 2019. https://www.cepheid.com/Package%20 Insert%20Files/Xpert-MRSA-NxG-US-IVD-ENGLISH-PackageInsert-301-4055-Rev-E.pdf

43. Benamu E, et al. Clin Infect Dis. 2021 Apr 19;ciab324.

83. Willis C, et al. Am J Health Syst Pharm. 2017;74(21):1765-1773.

44. Yu J, et al. Transplant Cell Ther. 2021;27(6):500 e501-500 e506.

84. Meng L, et al. Open Forum Infect Dis. 2021;8(4):ofab099.

45. Hill JA, et al. Clin Infect Dis. 2021;73(11):e3876-e3883.

85. Smith MN, et al. J Crit Care. 2017;38:168-171.

46. Hong DK, et al. Diagn Microbiol Infect Dis. 2018;92(3):210-213.

86. Drekonja DM, et al. Infect Control Hosp Epidemiol.

2015;36(2):142-152.

41.

To RK, et al. Pediatr Infect Dis J. 2021;40(5):486-488.

47. Armstrong AE, et al. Pediatr Blood Cancer. 2019;66(7):e27734.

48. Kung HC, et al. Natl Vital Stat Rep. 2008;56(10):1-120.

87. Fleming-Dutra KE, et al. JAMA. 2016;315(17):1864-1873.

88. King LM, et al. BMJ. 2018;363:k3047.

49. Agency for Healthcare Research and Quality. http://www.ahrq. gov/research/sep08/0908RA40.htm

89. Linder JA, et al. Clin Ther. 2003;25(9):2419-2430.

50. Burk M, et al. Eur Respir Rev. 2016;25(140):178-188.

90. Rapid Diagnostic Test (RDT). http://www.globalhealthprimer. emory.edu/targets-technologies/rapid-diagnostic-test.html

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52. Jain S, et al. N Engl J Med. 2015;373(24):415-427.

53. Metlay JP, et al. Am J Respir Crit Care Med. 2019;200(7):e45-e67.

54. Huang DT, et al. N Engl J Med. 2018;379(20):1973.

55. Ruuskanen O, et al. Lancet. 2011;377(9773):1264-1275.

Cawcutt KA, et al. Clin Infect Dis. 2021;72(12):e1115-e1121.

92. ID NOW Influenza A & B 2 [product insert]. https://www. globalpointofcare.abbott/en/product-details/id-nowinfluenza-ab-2.html 93. ID NOW RSV [package insert]. https://www.globalpointofcare. abbott/en/product-details/id-now-rsv.html

56. Barlam TF, et al. Clin Infect Dis. 2016;62(10):e51-77.

94. ID NOW COVID-19 [product insert]. https://www.fda.gov/ media/136525/download

57. BioFire Respiratory Panel 2.1 (RP2.1). https://www.fda.gov/ media/142696/download

95. ID NOW Strep A 2 [package insert]. https://www.globalpointofcare.abbott/en/product-details/id-now-strep-a-2.html

58. Technology. https://www.genmarkdx.com/education/ technology/

96. Xpert Xpress CoV-2/Flu/RSV plus. https://www. cepheid.com/en_US/tests/Critical-Infectious-Diseases/ Xpert-Xpress-CoV-2-Flu-RSV-plus

59. Pierce VM, et al. J Clin Microbiol. 2012;50(11):3458-3465.

60. Babady NE, et al. J Clin Microbiol. 2018;56(2):e01658.

61.

NxTAG Respiratory Pathogen Panel. https://www.luminexcorp. com/nxtag-respiratory-pathogen-panel-2/

62. NxTAG Respiratory Pathogen Panel + SARS-CoV-2 [package insert]. https://www.fda.gov/media/146495/download 63. VERIGENE Respiratory Pathogens Flex Test. https://www. luminexcorp.com/respiratory-pathogens-flex-test/#overview

97. Xpert Xpress CoV-2/Flu/RSV plus. 2021. https://www. cepheid.com/en_US/tests/Critical-Infectious-Diseases/ Xpert-Xpress-CoV-2-Flu-RSV-plus 98. Xpert Xpress Strep A. https://bit.ly/3NjiKqs-IDSE 99. Beal SG, et al. Pediatr Infect Dis J. 2020;39(3):188-191.

100. Fenton J, et al. Pediatr Infect Dis J. 2020;39(9):e282-e283.

101. Patel R, et al. Clin Infect Dis. 2018;67(5):799-801.

102. Messacar K, et al. J Clin Microbiol. 2017;55(3):715-723.

64. Klompas M, et al. Infect Control Hosp Epidemiol.

2021;42(7):817-825

103. Caliendo AM, et al. Clin Infect Dis. 2013;57 suppl 3:S139-S170.

65. Hanson KE, et al. Clin Infect Dis. 2020;71(10):2744-2751.

Dr. Fong reported no relevant financial disclosures.

66. Moradi T, et al. Clin Infect Dis. 202;71(7):1684-1689.

67. Lee CC, et al. J Am Med Dir Assoc. 2020;21(1):62-67.

About the author

68. Timbrook T, et al. Infect Dis Ther. 2015;4(3):297-306.

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

69. Schuetz P, et al. Cochrane Database Syst Rev. 2012(9):CD007498.

70. Srinivas P, et al. Pharmacotherapy. 2019;39(6):709-717.

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IF YOU SUSPECT CANDIDA, ASPERGILLUS, PNEUMOCYSTIS Order A Fungitell® Assay Fungitell Fungitell F ungitell®® can ccan an provide provide proviide aa rapid rrapid apid indication iindication ndication of o off fungal ffungal ungal infection iinfection nfection –– including including Candida, Aspergillus and Pneumocystis.

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IDSE Review

Comparison of 2021 IDSA and ACG Recommendations for the Treatment Of C. difficile Infection

BY MARK H. WILCOX, MD

C

lostridioides difficile infection (CDI) remains a considerable challenge to diagnose accurately, prevent, and treat, especially with respect to minimizing the risk for recurrent infection. In 2021, the Infectious Diseases Society of America (IDSA) and the American College of Gastroenterology (ACG) each updated its own CDI management guideline,1,2 from previous versions published in 2018 (but confusingly noted as a “2017 update”) and 2013, respectively.3,4 Both guidelines used the GRADE criteria to determine the strength of evidence underpinning the recommendations. While the ACG 2021 update is a full series of recommendations covering prevention, diagnosis, treatment, prevention of recurrence, and special populations, the IDSA 2021 update is more focused, given the shorter gap since its previous guidelines. Hence, the IDSA 2021 guideline addresses 3 specific questions (Table 1).1 This review compares and contrasts how the ACG and IDSA cover these 3 key practice points for the treatment of CDI.

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Treatment of Initial Episode of CDI The IDSA 2021 guideline recommends fidaxomicin (Dificid, Merck) (200 mg orally given twice daily for 10 days) instead of vancomycin (125 mg orally given 4 times daily for 10 days) to treat an initial episode of CDI (conditional recommendation, moderate certainty of evidence), which is a shift from its previous position.1,3 Furthermore, it is noted this recommendation “places a high value in the beneficial effects and safety of fidaxomicin, but its implementation depends upon available resources. Vancomycin remains an acceptable alternative.”1 Continuing its stance from 2018,3 the IDSA guideline prefers both fidaxomicin and vancomycin to metronidazole, commenting that metronidazole (500 mg orally 3 times daily for 10-14 days) is an alternative for nonsevere CDI, if the former agents are unavailable.1 The IDSA recommendation in favor of fidaxomicin was based on a pooled analysis of 4 studies,5-8 including 2 trials7,8 that were not considered in the 2018 version.3 The Guery

IDSE Review

et al clinical trial is considered below in more detail.7 The 2021 IDSA guideline panel acknowledged the relatively high acquisition cost of fidaxomicin, but noted that cost-effectiveness analyses probably support its use due to superior sustained clinical response rates compared with vancomycin at 4 weeks after end of therapy (risk ratio, 1.16; 95% CI, 1.09-1.24).1 However, the panel noted that uncertainty remains regarding costeffectiveness estimates. Given the assumptions made, the conclusions are based data inputted into the models, and risk for publication bias, including secondary to commercial sponsorship. Also, the IDSA guideline notes there is a chance that implementing this recommendation “probably reduces equity due to variation in medical insurance coverage.”1 The 2021 ACG guideline is more circumspect in its recommendations for the treatment of primary CDI, with no stated preference for vancomycin or fidaxomicin, and even stating that metronidazole remains a reasonable choice, which is somewhat strange given it reviewed the same evidence demonstrating inferiority of the latter option.2 Instead, this guideline only recommends avoiding metronidazole in severe CDI.2 The key randomized controlled trials (RCTs) that compared the efficacy of vancomycin and metronidazole found that the latter was inferior regardless of CDI severity.9 The ACG guideline is similarly cautious regarding the comparative cost-effectiveness of vancomycin and fidaxomicin: “Although vancomycin is less expensive, lower recurrence rates of fidaxomicin imply overall similar cost-effectiveness for both agents.”2 Therefore, regarding question 1 (and 2) in Table 1, the IDSA and ACG 2021 guidelines agree and disagree, which appears to reflect a different interpretation of the available evidence. On this point, there is a puzzling anomaly; the IDSA 2021 guideline1 does not consider a notable, high-impact 2018 network metaanalysis of studies examining the treatment of nonrecurrent CDI.10 The ACG 2021 guideline discusses this meta-analysis, but states: “In a network meta-analysis comparing 13 agents across 24 trials comprising 5,361 patients, vancomycin was rated the best option for achieving primary cure of severe infection, although fidaxomicin had higher sustained cure (ie, fewer recurrences).”2 Actually, the stated conclusion of this meta-analysis was that “among the treatments for non-multiply recurrent infections by C. difficile, the highest quality evidence indicates that fidaxomicin provides a sustained symptomatic cure most frequently. Fidaxomicin is a better treatment option than vancomycin for all patients except those with severe infections with C. difficile and could be considered as a first-line therapy. Metronidazole should not be recommended for treatment of C. difficile.”10 The higher sustained cure associated with fidaxomicin may be especially beneficial in patients at greater

Table 1. Three Specific Questions Addressed In the 2021 IDSA CDI Guideline 1.

In patients with an initial CDI episode, should fidaxomicin be used rather than vancomycin?

2.

In patients with recurrent CDI episode(s), should fidaxomicin be used rather than vancomycin?

3.

In patients with a CDI episode, should bezlotoxumab be used as a cointervention along with standard-of-care antibiotics rather than standard-of-care antibiotics alone?

CDI, Clostridioides difficile infection; IDSA, Infectious Diseases Society of America.

risk for recurrence of CDI,11,12 including those with a history of prior CDI; who are at least 65 years of age; with prior hospitalization, severe CDI, concurrent antibiotics and hypervirulent ribotype (027/078/244) infections.13,14 Given that the high acquisition cost of fidaxomicin remains a potential barrier to its widespread use, further cost-effectiveness analyses are needed that measure the total (patient and insurance) cost savings from reduced CDI recurrences to determine how much the greater initial drug price is offset. Of note, the nonfinancial benefits of reducing CDI recurrences need to be quantified, noting the considerable impacts on patients’ quality of life and families.15-17

Treatment of Recurrent CDI The ACG 2021 guideline states: “We suggest tapering/pulsed-dose vancomycin for patients experiencing a first recurrence after an initial course of fidaxomicin, vancomycin, or metronidazole (strong recommendation, very low quality of evidence).” In addition, “we recommend fidaxomicin for patients experiencing a first recurrence after an initial course of vancomycin or metronidazole (conditional recommendation, moderate quality of evidence).”2 The recommendation in favor of tapering/pulsed-dose vancomycin, which comes before the one recommending fidaxomicin, is puzzling given the very modest evidence base, including no RCTs, and noting the relatively high cost of a 4- to 6-week course of oral vancomycin. Conversely, the IDSA 2021 guideline states: “The panel suggests the use of fidaxomicin as the preferred therapy for patients with recurrent CDI episode(s) to improve sustained response after therapy. More well-designed RCTs for patients with recurrent CDI, particularly multiply recurrent CDIs, are needed to improve the strength of recommendations. In particular, studies with more appropriate controls for extended-pulsed fidaxomicin should help clarify the role of this dosing strategy for patients with recurrent CDI both in terms of efficacy and quality of life.”1 The latter point follows on from a phase 3b clinical trial in adults older than 60 years of age, 80% of

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whom had primary CDI, that compared vancomycin with an extended-dosing fidaxomicin regimen.7 The extended-pulsed regimen comprised the same total dosage as in a standard fidaxomicin course of 200 mg twice daily for 10 days, but instead was 200 mg of fidaxomicin twice daily for 5 days followed by 200 mg once daily on alternate days until day 25. This longer period of fidaxomicin dosing had been shown in a clinically reflective gut model to be associated with less risk for CDI recurrence, likely due to the extended period during which C. difficile inhibitory levels of antibiotic are present in the large intestine.18 The clinical trial found a very low and significantly reduced rate of CDI recurrence in patients receiving the extendedpulsed regimen (4% vs 17% at day 30 after the end of treatment; P<0.001).7 However, the open study design and absence of comparator groups (extended-pulsed vancomycin and standard-dosage fidaxomicin) limit the full interpretation of the study results. Nevertheless, this is further evidence of the reduced risk of CDI recurrence (increased chance of sustained cure) in fidaxomicin versus vancomycin recipients.

Treatment of CDI With Bezlotoxumab and SOC Antibiotics Bezlotoxumab (Zinplava, Merck) is a monoclonal antibody against C. difficile toxin B given as an IV infusion at any point during the first 10 days of standard-ofcare (SOC) antibiotic therapy for CDI.19 Bezlotoxumab was the first agent to be licensed for the prevention of CDI recurrence. The ACG 2021 guideline states: “We suggest bezlotoxumab be considered for prevention of CDI recurrence in patients who are at high risk of recurrence (conditional recommendation, moderate quality of evidence).”2 The IDSA 2021 guideline is similar: “For patients with a recurrent CDI episode within the last 6 months, we suggest using bezlotoxumab as a cointervention along with SOC antibiotics rather than SOC antibiotics alone (conditional recommendation, very low certainty of evidence).”1

More than three-fourths of patients recruited to the 2 MODIFY phase 3 trials of bezlotoxumab had 1 or more risk factors for poor CDI outcome, including recurrent infection (Table 2).19-21 Analysis of the treatment outcomes for those with risk factors showed that the benefits of bezlotoxumab were greatest for patients 65 years of age or older, for those experiencing a recurrent episode of CDI, in immunocompromised patients, and in severe CDI.20 More than 30% of patients with any 1 of the risk factors who received placebo (plus SOC antibiotics) had recurrent CDI, compared with about 21% of those without a risk factor.

Also, the risk for recurrent CDI was higher for those with more risk factors. Those with 1 risk factor had an increased risk for recurrent CDI of 31.3%, while those with 3 or more risk factors had an increased risk of 46.1%. Conversely, recurrent CDI was not reduced significantly in bezlotoxumab recipients who had none of these predefined risk factors for recurrence. Of note, recurrent CDI, use of fecal microbiota transplants (FMTs), and CDI-associated 30-day readmissions were all reduced in bezlotoxumab recipients who had risk factors for recurrence.20 Both guideline panels reviewed the cost-effectiveness data for the use of bezlotoxumab and broadly agreed that such analyses favor the addition of bezlotoxumab to SOC antibiotics in patients with a high risk for recurrence, particularly those with a recurrent CDI episode within the last 6 months.1,2 The number needed to treat (NNT) with bezlotoxumab to prevent a case of recurrent CDI is low for patients with risk factors for recurrence, especially for those who have had a recurrent CDI in the previous 6 months (NNT=2.5) (Table 2).21 However, it was noted that the high acquisition cost of bezlotoxumab means that “implementing this recommendation also probably reduces equity due to variation in medical insurance coverage.”1 For patients with multiple CDI recurrences, both guidelines consider a role for FMT. While the use of FMT is beyond the scope of this review, safety concerns

Table 2. Effectiveness of Bezlotoxumab With SOC Antibiotics, According to Risk Factors for CDI Recurrence CDI recurrence risk factor

Number needed to treat to prevent a CDI recurrence

Patients aged ≥65 y

3.8

Patients who are immunocompromised

4.7

Patients with severe CDI on presentation

5.1

Patients aged ≥65 y and ≥1 previous episode in prior 6 mo

2.5

Patients who are immunocompromised and ≥1 previous episode in prior 6 mo Patients with severe CDI on presentation and ≥1 previous episode in prior 6 mo CDI, Clostridioides difficile infection; SOC, standard of care.

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3 2.5

References 1.

2.

Johnson S, Lavergne V, Skinner AM, et al. Clinical practice guideline by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA): 2021 focused update guidelines on management of Clostridioides difficile infection in adults. Clin Infect Dis. 2021;73(5):e1029-e1044.

Kelly CR, Fischer M, Allegretti JR, et al. ACG clinical guidelines: prevention, diagnosis, and treatment of Clostridioides difficile infections. Am J Gastroenterol. 2021;116(6):1124-1147. Erratum in: Am J Gastroenterol. 2022;117(2):358.

3. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66:e1-e48.

4. Surawicz CM, Brandt LJ, Binion DG, et al. Guidelines for diagnosis, treatment, and prevention of Clostridium difficile infections.

Am J Gastroenterol. 2013;108(4):478-498.

5.

Louie TJ, Miller MA, Mullane KM, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431.

14. Davies K, Lawrence J, Berry C, et al. Risk factors for primary Clostridium difficile infection; results from the observational study of risk factors for Clostridium difficle infection in hospitalized patients with infective diarrhea (ORCHID). Front Public Health. 2020;17(8):293.

15. Garey KW, Aitken SL, Gschwind L, et al. Development and validation of a Clostridium difficile health-related quality of life questionnaire. J Clin Gastroenterol. 2016;50:631-637.

16. Wilcox MH, Ahir H, Coia JE, et al. Impact of recurrent Clostridium difficile infection: hospitalization and patient quality of life.

J Antimicrob Chemother. 2017;72(9):2647-2656.

17. Barbut F, Galperine T, Vanhems P, et al. Quality of life and utility decrement associated with Clostridium difficile infection in a French hospital setting. Health Qual Life Outcomes. 2019;17(1):6.

18. Chilton CH, Crowther GS, Todhunter SL, et al. Efficacy of alternative fidaxomicin dosing regimens for treatment of simulated Clostridium difficile infection in an in vitro human gut model.

J Antimicrob Chemother. 2015;70(9):2598-2607.

19. Wilcox MH, Gerding DN, Poxton IR, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376(4):305-317.

20. Gerding DN, Kelly CP, Rahav G, et al. Bezlotoxumab for prevention of recurrent Clostridium difficile infection in patients at increased risk for recurrence. Clin Infect Dis. 2018;67(5):649-656.

21. Prabhu VS, Dubberke ER, Dorr MB, et al. Cost-effectiveness of bezlotoxumab compared with placebo for the prevention of recurrent Clostridium difficile infection. Clin Infect Dis. 2018;66(3):355-362.

22. DeFilipp Z, Bloom PP, Torres Soto M, et al. Drug-resistant E. coli bacteremia transmitted by fecal microbiota transplant. N Engl J Med. 2019;381:2043-2050.

23. FDA. Important safety alert regarding use of fecal microbiota for transplantation and risk of serious adverse reactions due to transmission of multi-drug resistant organisms. 2019. Accessed May 10, 2022. https://bit.ly/3gKXZEDidse

6. Cornely OA, Crook DW, Esposito R, et al. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomized controlled trial. Lancet Infect Dis. 2012;12(4):281-289.

24. FDA. Update to March 12, 2020 safety alert regarding use of fecal microbiota for transplantation and risk of serious adverse events likely due to transmission of pathogenic organisms. 2020.

Accessed May 10, 2022. https://bit.ly/3yx1REnIDSE

7.

25. FDA. Safety alert regarding use of fecal microbiota for transplantation and additional safety protections pertaining to SARS-CoV-2 and COVID-19. 2020. Accessed May 10, 2022. https://bit.ly/2U0DUAbIDSE

Guery B, Menichetti F, Anttila VJ, et al. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomized, controlled, open-label, phase 3b/4 trial. Lancet Infect Dis. 2018;18(3):296-307.

8. Mikamo H, Tateda K, Yanagihara K, et al. Efficacy and safety of fidaxomicin for the treatment of Clostridioides (Clostridium) difficile infection in a randomized, double-blind, comparative phase III study in Japan. J Infect Chemother. 2018;24(9):744-752.

9. Johnson S, Louie TJ, Gerding DN, et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014;59(3):345-354.

10. Beinortas T, Burr NE, Wilcox MH, et al. Comparative efficacy of treatments for Clostridium difficile infection: a systematic review and network meta-analysis. Lancet Infect Dis. 2018;18(9):1035-1044.

11. Madoff SE, Urquiaga M, Alonso CD, et al. Prevention of recurrent Clostridioides difficile infection: a systematic review of randomized controlled trials. Anaerobe. 2020;61:102098.

12. Crook DW, Walker AS, Kean Y, et al. Fidaxomicin versus vancomycin for Clostridium difficile infection: meta-analysis of pivotal randomized controlled trials. Clin Infect Dis. 2012;55(suppl 2):S93-S103.

13. Wilcox MH. Progress with a difficult infection. Lancet Infect Dis. 2012;12(4):256-257.

26. European Centers for Disease Control. Increase in severe acute hepatitis cases of unknown aetiology in children. April 28, 2022.

Accessed May 10, 2022. https://bit.ly/3stbOitIDSE

About the author Mark H. Wilcox, MD, is a consultant/ the head of microbiology research & development and the infection lead of the NIHR Leeds Diagnostic Technologies Medical Technology and In Vitro Diagnostics Co-operative, Leeds Teaching Hospitals National Health Service (NHS) Trust; a professor of medical microbiology and the Sir Edward Brotherton Chair of Bacteriology, the University of Leeds, in the United Kingdom; the lead on Clostridioides difficile infection for Public Health England; and the national clinical director, Antimicrobial Resistance & Infection Prevention and Control, for the NHS England.

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remain regarding the potential for inadvertent transmission of pathogens via donor fecal samples.22-24 Such concerns have been extended to SARS-CoV-225 and, most recently, adenoviruses that are associated with severe hepatitis.26 While the newly recognized severe hepatitis cases have occurred primarily in children, the epidemiology and transmission of potential viral cause(s) are poorly characterized. The need for extensive screening/testing of donors/samples adds to the associated costs of FMT. It is probable that the regulatory position on FMT will change as defined microbiome-based products become available.

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IDSE Review

Complicated Milieu of Issues During COVID-19 Affected Stewardship

BY JAMES S. LEWIS II, PHARMD

A

ntibiotic stewardship is a core tenet in hospital and public health as a tool to minimize the emergence of antibacterial resistance.1 Great strides have been made during the past decade to increase awareness of the overuse of antibiotics in medicine. Randomized trials have facilitated a “shorter is better” mindset in medical practice that has allowed for improved antibiotic use in many commonly encountered infections.2 In addition, a variety of other tools and data reporting structures now exist to improve the use of this critical class of medicines.3

Since its arrival in 2020, COVID-19 has created a complicated milieu of issues resulting in a step backward for many antibiotic stewardship programs: Diagnostic uncertainty while managing critically ill patients, the recognition that many moderately ill patients with COVID-19 would need ICU care, and the reemergence of the long-held perception that antibiotics can only help have coalesced around COVID19 patients in the ICU. These issues combined with a new and unknown infectious entity have led clinicians to an uncomfortable space where a patient’s clinical syndrome could be COVID-19; however, it could be a bacterial infection, and providers are very

aware of the deleterious effects of delayed effective antibacterial therapy on bacterial infection–related mortality.4 This scenario affected antibiotic stewardship programs in many clinical settings, as clinicians often were reassigned to assist in the implementation of COVID-19 therapeutic plans and strategies.5 These efforts, while certainly important and worthy of the dedicated resources, have resulted in marked reductions in the time dedicated to antibiotic stewardship rounds and responsibilities. Furthermore, early in the pandemic, there was considerable concern about bacterial superinfections that have historically

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been associated with influenza infections.6-8 This concern combined with the recognition that many hospitalized patients with COVID-19 rapidly decompensate to ICU care led to worries that bacterial superinfections similar to that reported with influenza would be a real clinical challenge.

However, similar rates of bacterial superinfection were not observed early in the pandemic, and many early reports did not identify bacterial superinfections until late in the ICU stay of COVID-19 patients.9,10 Many of these data identified nosocomial gram-negative bacteria such as Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter species as common pathogens in late-onset infections in the ICU. Whether these isolates were infections or colonization of upper and lower airways with common ICU pathogens highlighted the clinical challenge presented by diagnostic uncertainty in critically ill patients. With the margin of error sometimes razor thin for critically ill patients, providers justifiably prescribed just-in-case antibiotics.

In the early months of the pandemic, emerging literature described high rates of ventilator-associated pneumonia in patients who required ICU care.6,8 These studies were limited by small numbers but widely cited and discussed, as they arrived at a time when the medical community was desperate for information surrounding the management and implications of this new virus. These and other data instilled in providers a concern that COVID-19 patients could often develop bacterial superinfections, so antibacterial treatment would likely be needed. An editorial published several months later discussed this belief and sounded a word of caution that an “appreciable minority of critically ill” patients would develop superinfections, and that as risk factors such as age, comorbidities, and length of stay accumulated, this problem would become more prevalent and recognized.11 Reports from early in the pandemic quickly resulted in the realization that influenza pneumonia and post– COVID-19 pneumonia were markedly different in their epidemiology. Likely causative pathogens associated with influenza superinfections, such as Staphylococcus aureus and Streptococcus pneumoniae of community origin, were infrequently identified in COVID-19 patients in whom superinfections often occurred late in the hospital course and associated with gram-negative nosocomial pathogens.6,10,11 Recent data also have suggested a markedly different cytokine profile in COVID-19 patients compared with those with influenza, which may contribute to these differences.12 Also, the onset for post–COVID-19 bacterial pneumonia appeared to be approximately 17 days after symptom onset or 8 days after intubation.11 In hospitalized patients, this immediately raises the question of colonization versus true infection, a discussion that was largely overlooked in many early data sets. This lack of discussion was understandable, given the novelty

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Early in the pandemic, concerns about bacterial superinfections and the fact that many ICU patients rapidly decompensated were among the reasons just-in-case antibiotics were prescribed. of COVID-19 and the high mortality rates observed early in the pandemic. However, it set a precedent that these infections were not uncommon and that mortality was high—the ideal scenario to create excessive antibiotic use.

Discussions regarding the importance and apparent lack of antibiotic stewardship in COVID-19 patients began early in the pandemic with the recognition that this viral infection was leading to frequent antibiotic use, particularly in hospitalized patients.9 Cultures obtained on day 1 or 2 of hospitalization in COVID19 patients frequently remained negative or only occasionally grew community-associated organisms.

However, in COVID-19 patients requiring ICU care, P. aeruginosa appeared after the first week and quickly became the predominant pathogen along with a rapid shift to nosocomial pathogens.9

Bacteria, Fungus, or Virus?

Ominously, reports of invasive fungal infections began to appear in COVID-19 patients. Early reports of invasive aspergillosis in COVID-19 patients drove early empiric antifungal therapy in critically ill COVID-19 patients.13 The recurring theme in bacterial and fungal infections in this space was the difficulty in distinguishing between true infections and colonization. However, the high mortality rates reported in these series created a situation in which providers were often justifiably unwilling or unable to remove antibacterial/ antifungal coverage.

Once again, as often seen in the critical care/sepsis literature, the difficulty facing clinicians in distinguishing between viral and bacterial infections in critically ill patients leads to antibiotic use. The lack of a widely available diagnostic test that clearly and reliably differentiates between the 2 creates uncertainty and leads to the use of just-in-case antibiotics. Procalcitonin (PCT), while initially promising in the outpatient respiratory infection arena, has proven to be

References 1.

CDC. Antibiotic Use in the United States, 2021 Update: Progress and Opportunities. Accessed April 25, 2022. https://www.cdc. gov/antibiotic-use/pdfs/stewardship-report-2021-H.pdf

2. Spellberg B, Rice LB. The shorter is better movement: past, present, future. Clin Microbiol Infect. 2022 Apr 15. doi:10.1016/ j.cmi.2022.04.00 3. Jenkins TC, Tamma PD. Thinking beyond the “core” antibiotic stewardship interventions: shifting the onus for appropriate antibiotic use from stewardship teams to prescribing clinicians.

Clin Infect Dis. 2021;72(8):1457-1462.

4. Ferrer R, Martin-Loeches I, Phillips G, et al. Empiric antibiotic treatment reduces mortality in severe sepsis and septic shock from the first hour: results from a guideline-based performance improvement program. Crit Care Med. 2014;42(8):1749-1755.

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of limited value during the pandemic. The test had already begun to fall out of favor in some institutions after international guidelines for nosocomial pneumonia were unable to firmly recommend its use and recent US data suggesting that the test was of limited benefit in stewardship.14,15 These diagnostic limitations combined with the uncertainties of a new clinical entity with a high mortality rate created a situation in which clinicians would be slow to stop antibiotics, even when presented additional data such as a negative PCT result.

This lack of clarity coupled with a new clinical entity at a time when antibiotic stewardship teams were redirected to COVID-19 responsibilities highlights the need for improved diagnostic capabilities in this space. A recent publication evaluating host–gene expression as a way to distinguish between bacterial and viral infections is encouraging, but previous diagnostic platforms promised to improve the situation and were overshadowed by the clinical realities.16,17 Similar challenges have arisen in the arena of antifungal stewardship in COVID-19 patients, particularly in the realm of invasive Aspergillus infections and the diagnosis of COVID-19–associated pulmonary aspergillosis. Reports of invasive aspergillosis in patients with COVID-19 appeared early in the pandemic; rates of the dreaded condition varied markedly across institutions.13 Similar to trends observed for bacterial infections, considerable difficulty exists in determining between colonization and infection. Standard radiographic findings typically identified in invasive aspergillosis patients with hematologic malignancies often are not present, and other diagnostic tests such as galactomannan and 1,3-beta-D-glucan are of questionable value and have not been evaluated in COVID19 patients.18 Again, this placed stewardship programs in a difficult position: Faced with critically ill patients with positive cultures, radiological results complicated by the presence of COVID-19–induced lung

damage and acute respiratory distress syndrome, and the increasing use of immunosuppressive regimens for COVID-19 management, antifungals were often initiated based on the literature from other disease states suggesting high mortality rates and the importance of early effective antifungal therapy.

Candidemia also has been increasingly recognized in critically ill COVID-19 patients; recent data have painted a bleak picture of the clinical outcomes in these patients.19 One-fourth of patients with candidemia in the CDC’s Emerging Infections Program were COVID-19–positive between April and August 2020. In-hospital mortality was 2 times higher in COVID-19 patients with candidemia compared with controls (62.5%), and the fact that these patients were candidemic left no doubt as to the question of colonization or infection. However, many of these patients lacked the usual risk factors associated with the development of candidemia. Instead, it was reported by the authors that the use of factors associated with COVID-19 care, such as immunosuppressive medications, appeared to play a larger role. In an accompanying editorial, it was noted that almost all of these patients had received antibiotics in the 2 weeks prior to their candidemia diagnosis, despite bacterial coinfections with COVID-19 at presentation being rare. The author noted the importance of understanding that viral sepsis is a real entity and that antibiotic stewardship was largely lacking in these patients, underscoring the important role of diagnostic uncertainty and the challenges this has created for stewardship programs.20 COVID-19 has presented numerous hurdles for antibiotic stewardship programs during the last 2 years of the pandemic. Hopefully the peak of the pandemic has passed, and more routine activities and duties for antibiotic stewardship personnel can resume. COVID-19 has reminded us that we have a long way to go in optimizing the use of antibiotics in critically ill patients, and diagnostic uncertainty often results in unnecessary and potentially harmful antibiotic use.

IDSE Review

5. Wimmer MR. The impact of coronavirus disease 2019 (COVID-19) on the antimicrobial stewardship pharmacist workforce: a multicenter survey. Antimicrobial Stewardship Healthcare Epidemiol.

2022;2(1):e56.

6. Zhou F, Yu T, Du R, et al. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054-1062.

7. Sharifipour E, Shams S, Esmkhani M, et al. Evaluation of bacterial co-infections of the respiratory tract in COVID-19 patients admitted to ICU. BMC Infect Dis. 2020;20(1):646.

8. Quartuccio L, Sonaglia A, McGonagle D, et al. Profiling COVID-19 pneumonia progressing into the cytokine storm syndrome: results from a single Italian centre study on tocilizumab versus standard of care. J Clin Virol. 2020;129:104444.

9. Stevenson DR, Sahemey M, Cevallos Morales J, et al. Improving antimicrobial stewardship in critically-ill patients with COVID-19.

Clin Infect Dis. 2021;72(11):e926.

10. Hughes S, Troise O, Donaldson H, et al. Bacterial and fungal coinfection among hospitalized patients with COVID-19: a retrospective cohort study in a UK secondary-care setting.

Clin Microbiol Infect. 2020;26(10):1395-1399.

11. Clancy CJ, Nguyen MH. Coronavirus disease 2019, superinfections, and antimicrobial development: what can we expect?

Clin Infect Dis. 2020;71(10):2736-2743.

12. Karaba AH, Zhou W, Hsieh LL, et al. Differential cytokine signatures of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza infection highlight key differences in pathobiology. Clin Infect Dis. 2022;74(2):254-262.

13. Thompson III GR, Cornely OA, Pappas PG, et al. Invasive aspergillosis as an under-recognized superinfection in COVID-19.

Open Forum Infect Dis. 2020;7(7):ofaa242.

14. Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the Infectious Diseases Society of America and the American Thoracic Society.

Clin Infect Dis. 2016;63(5):e61-e111.

15. Huang DT, Yealy DM, Filbin MR, et al. Procalcitonin-guided use of antibiotics for lower respiratory tract infection. N Engl J Med. 2018;379(3):236-249.

16. Ko ER, Henao R, Frankey K, et al. Prospective validation of a rapid host gene expression test to discriminate bacterial from viral respiratory infection. JAMA Netw Open. 2022;5(4):e227299.

17. Wils J, Saegeman V, Schuermans A. Impact of multiplexed respiratory viral panels on infection control measures and antimicrobial stewardship: a review of the literature. Eur J Clin Microbiol Infect Dis. 2022;41(2):187-202.

18. Koehler P, Bassetti M, Chakrabarti A, et al. Defining and managing COVID-19-associated pulmonary aspergillosis: the 2020 ECMM/ISHAM consensus criteria for research and clinical guidance. Lancet Infect Dis. 2021;21(6):e149-e162.

19. Seagle EE, Jackson BR, Lockhart SR, et al. The landscape of candidemia during the coronavirus disease 2019 (COVID-19) pandemic. Clin Infect Dis. 2022;74(5):802-811.

20. McCarty T. Candidemia and severe coronavirus disease 2019: which risk factors are modifiable? Clin Infect Dis. 2022;74(5):812-813.

About the author James S. Lewis II, PharmD, FIDSA, is the ID pharmacy supervisor and an associate professor in the departments of Pharmacy and Infectious Diseases, at Oregon Health & Science University, in Portland, Oregon.

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Current Options for Highly Treatment-Experienced People With HIV

BY MILENA MURRAY, PHARMD, MSC, BCIDP, AAHIVP, FCCP

T

he treatment of HIV has dramatically advanced over the past 40 years. Clear data show a decreased occurrence of AIDS and an increased life expectancy.1,2 However, a small percentage of the overall population with HIV cannot achieve treatment goals. People with HIV who are highly treatment-experienced (HTE) may have limited antiretroviral therapy (ART) options due to resistance or tolerability issues. This population may have problems with virologic suppression, immune function, toxicities, and drug–drug interactions. These challenges may lead to an overall decrease in health-related quality of life (HRQOL).3 HTE people with HIV need novel ART options and classes with improved tolerability and no crossresistance to current ART classes.

Transmitted and acquired resistance must be considered in the HIV treatment discussion. In a World Health Organization survey report, there was more than 10% resistance to nevirapine or efavirenz in people with HIV initiating therapy.4 This global prevalence of resistance to the nonnucleoside reverse transcriptase inhibitors emphasizes the need to use ART with long-term efficacy and durability.4 There is also a need to retain these patients in care and encourage adherence. Global access to HIV RNA testing is needed to ensure that ART is effective and to rapidly identify cases of virologic failure.4 Overall resistance rates to 4 ART classes are thought to be low; however, reported prevalence rates to 3 and 4 ART classes are estimated to be 5% to 10% in Europe and less than 3% in North America.1,5 In the United States, approximately 12,000 people with multidrug-resistant HIV need novel agents.2,6 When HIV RNA

undetectability cannot be achieved, a secondary goal is to reduce the HIV RNA levels as much as possible and maintain immunologic function. 7 Entry inhibitors are second-line agents that prevent HIV-1 cellular entry by binding a cellular target.1 Enfuvirtide (Fuzeon, Genentech) and maraviroc were the first agents in this class; however, there are several disadvantages to these agents, including the route of administration, pill burden, and lower virologic efficacy compared with other ART options.1 The newest agents in the entry inhibitor class are fostemsavir (Rukobia, ViiV) and ibalizumab-uiyk (Trogarzo, Theratechnologies).

Fostemsavir is an HIV-1 attachment inhibitor that binds the gp120 envelope glycoprotein and prevents viral connection to CD4 T cells. The drug was approved in July 2020 and has no apparent cross-resistance to other ART classes.3 Within the same drug class, there is no cross-resistance with ibalizumab-uiyk or maraviroc.8,9 Fostemsavir

is dosed as 600-mg tablets orally twice daily without regard to food.1 One concern with twice-daily administration is that nonadherence may have led to virologic failure, and adhering to a twicedaily regimen may be an issue for some people with HIV.6 Common adverse reactions with fostemsavir include nausea, diarrhea, headache, abdominal pain, dyspepsia, fatigue, rash, and sleep disturbances.6 Fostemsavir was studied in people with HIV who failed to respond to their current ART, and this agent also may be used for tolerability issues.10 This drug, combined with optimized background therapy, showed robust and sustained virologic and immunologic responses.11 Patient-reported outcomes from the BRIGHTE trial showed improved HRQOL outcomes.3 These improved outcomes are thought to increase overall adherence to ART, leading to better health outcomes. A case report of the use of fostemsavir to overcome a drug–drug interaction issue also has been published.12

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Ibalizumab-uiyk is a long-acting post-attachment inhibitor.13 It is a humanized immunoglobulin G4 (IgG4) monoclonal antibody targeting CD4 receptors of T cells to interfere with the binding of HIV-1 gp120.1 The medication was approved in March 2018 and is given as a twice-monthly parenteral infusion (2,000-mg loading dose, followed by subsequent doses of 800 mg every 2 weeks).2 The most common adverse reactions reported in trials were diarrhea, dizziness, nausea, and rash. Monotherapy with ibalizumab-uiyk is not recommended due to the development of resistance in 1 to 2 weeks.2 The parenteral administration of ibalizumab-uiyk presents logistical barriers to patient care implementation. Adherence may be an issue when clinic visits or home infusions are needed every 2 weeks.2 Missed infusions may lead to resistance.

Several clinical trials reported a decrease in HIV RNA and virologic suppression after therapy with ibalizumab-uiyk.2,14 Pharmacoeconomic studies have reported that ibalizumabuiyk represents a cost-effective and affordable option for HTE people due to an increase in quality-adjusted lifeyears.13,15 Successful treatment of panresistant HIV has been described with ibalizumab-uiyk used as an “induction treatment” followed by an optimized “maintenance treatment.”5 A case report of a switch to ibalizumab as a “bridge therapy” due to a drug–drug interaction with chemotherapy showed an alternative use when other ART options are not available.16 Another novel therapy is lenacapavir (Gilead) in the newest ART class of capsid inhibitors, which works by disrupting the functioning of the HIV capsid across multiple steps in the viral life cycle.17 Lenacapavir is an investigational agent and can be administered orally, either daily or weekly, and subcutaneously up to every 6 months.17 It is being investigated in both HTE and treatment-naive people with HIV. No overlapping resistance with other classes or preexisting resistance

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mechanisms is known; however, emergent resistance during treatment has been reported.17,18 Results from the CAPELLA and CALIBRATE studies reported a rapid reduction in HIV RNA and no serious adverse events.17 After submission to the FDA, the manufacturer received a complete response letter in March 2022 detailing chemistry, manufacturing, and controls concerns relating to the compatibility of lenacapavir with the proposed borosilicate glass vial.19 Gilead is working with the FDA to resolve the issues.19 Transmitted and acquired resistance leading to virologic failure remain a global issue in the treatment of HIV. Recently approved agents represent a step forward toward virologic control for all people with HIV, including those who are HTE. However, there is still a need for more options in novel classes to overcome resistance, tolerability, and drug–drug interaction issues.

References 1.

Berruti M, Pincino R, Taramasso L, et al. Evaluating fostemsavir as a therapeutic option for patients with HIV. Expert Opin Pharmacother.

2021;22(12):1539-1545.

2.

Chahine EB, Durham SH. Ibalizumab: the first monoclonal antibody for the treatment of HIV-1 infection. Ann Pharmacother.

2021;55(2):230-239.

3.

Anderson SJ, Murray M, Cella D, et al. Patientreported outcomes in the phase III BRIGHTE trial of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced individuals. Patient. 2022;15(1):131-143.

treatment of people with human immunodeficiency virus-1 (HIV-1): current evidence and place in therapy. Drug Des Devel Ther.

2022;16:297-304.

9. Rose R, Gartland M, Li Z, et al. Clinical evidence for a lack of cross-resistance between temsavir and ibalizumab or maraviroc. AIDS. 2022;36(1):11-18.

10. Hiryak K, Koren DE. Fostemsavir: a novel attachment inhibitor for patients with multidrug-resistant HIV-1 infection.

Ann Pharmacother. 2021;55(6):792-797.

11. Ackerman P, Thompson M, Molina JM, et al. Long-term efficacy and safety of fostemsavir among subgroups of heavily treatment-experienced adults with HIV-1. AIDS. 2021;35(7):1061-1072.

12. Pecora Fulco P, Nixon D, Gomes DC. Novel use of fostemsavir for 2 multidrug-resistant persons with human immunodeficiency virus.

Ann Pharmacother. 2022;56(4):501-502.

13. Brogan AJ, Talbird SE, Davis AE, et al. The cost-effectiveness and budget impact of ibalizumab-uiyk for adults with multidrug-resistant HIV-1 infection in the United States. Pharmacoeconomics. 2021;39(4):421-432.

14. Gathe JC, Hardwicke RL, Garcia F, et al. Efficacy, pharmacokinetics, and safety over 48 weeks with ibalizumab-based therapy in treatment-experienced adults infected with HIV-1: a phase 2a study. J Acquir Immune Defic Syndr.

2021;86(4):482-489.

15. Millham LRI, Scott JA, Sax PE, et al. Clinical and economic impact of ibalizumab for people with multidrug-resistant HIV in the United States. J Acquir Immune Defic Syndr.

2020;83(2):148-156.

16. Dickter JK, Martin AL, Ho S, et al. Ibalizumabuiyk as a bridge therapy for a patient with drug-resistant HIV-1 infection receiving chemotherapy: a case report. J Clin Pharm Ther.

2021;46($):1185-1187.

17. Dvory-Sobol H, Shaik N, Callebaut C, et al.

Lenacapavir: A first-in-class HIV-1 capsid inhibitor. Curr Opin HIV AIDS. 2022;17(1):15-21.

4.

World Health Organization. HIV drug resistance. November 22, 2021. Accessed April 26, 2022. https://www.who.int/news-room/ fact-sheets/detail/hiv-drug-resistance

18. Margot N, Vanderveen L, Naik V, et al. Phenotypic resistance to lenacapavir and monotherapy efficacy in a proof-of-concept clinical study. J Antimicrob Chemother.

2022;77(4):989-995.

5.

Canetti D, Muccini C, Spagnuolo V, et al. Achieving virological control in panresistant HIV-1 infection: a case series.

EBioMedicine. 2022;77:103906. doi:10.1016/j. ebiom.2022.103906

19. Gilead receives complete response letter from U.S. FDA for investigational lenacapavir due to vial compatibility issues [press release]. Business Wire; March 1, 2022. Accessed April 26, 2022. https://bwnews.pr/3yWvaAi

6. Chahine EB. Fostemsavir: the first oral attachment inhibitor for treatment of HIV-1 infection.

Am J Health Syst Pharm. 2021;78(5):376-388.

7.

Department of Health and Human Services.

Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents With HIV. Updated January 20, 2022. Accessed April 26, 2022. https://bit.ly/38ybb0p-IDSE

8. Muccini C, Canetti D, Castagna A, et al. Efficacy and safety profile of fostemsavir for the

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

CLASSIFIEDS

SUMMER 2022

Penn State Health is seeking a BC/BE Infectious Disease physician to join our team as we proudly expand our services in Lancaster County Pennsylvania. Penn State Health is a multihospital health system serving patients and communities across Central Pennsylvania.

This is an exciting opportunity to join our health system and our brand new, state-of-the-art facility, Penn State Health Lancaster Medical Center, opening Fall 2022. Come grow with us!

What We’re Offering: • Inpatient/Outpatient position • We’ll foster your passion for patient care and cultivate a collaborative environment rich with diversity • Competitive Salary • Relocation Assistance • Comprehensive Benefits & Retirement package

What We’re Seeking: • MD, DO, or foreign equivalent • Completion of accredited Infectious Disease Fellowship • BC/BE Infectious Disease • Ability to acquire license in the State of Pennsylvania No J1 visa waiver opportunities available

Photo was taken before March 2020 when COVID-19 precautionary measures were not in place.

What the Area Offers: Central PA is rich in history and offers a diverse culture. Our local neighborhoods boast a reasonable cost of living whether you prefer a more suburban setting or thriving city rich in theater, arts, and culture.

Nearby mountains host various ski slopes and the Appalachian Trail and rambling rivers are in our backyard, offering many outdoor activities for all seasons. Conveniently located within a short distance to major cities such as Philadelphia, Pittsburgh, NYC, Baltimore, and Washington DC, the area is rich with activity and is waiting for you to explore.

FOR MORE INFORMATION PLEASE CONTACT: Heather Peffley, PHR CPRP Lead Physician Recruiter Penn State Health hpeffley@pennstatehealth.psu.edu careers.pennstatehealth.org

Penn State Health is fundamentally committed to the diversity of our faculty and staff. We believe diversity is unapologetically expressing itself through every person’s perspectives and lived experiences. We are an equal opportunity and affirmative action employer. All qualified applicants will receive consideration for employment without regard to age, color, disability, gender identity or expression, marital status, national or ethnic origin, political affiliation, race, religion, sex (including pregnancy), sexual orientation, veteran status, and family medical or genetic information.

For classified advertising, contact Craig Wilson 212-957-5300 x235 • cwilson@mcmahonmed.com

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A VICIOUS CYCLE WITH SIGNIFICANT BURDEN WHAT COULD BE THE CONSEQUENCES OF RECURRENT C. DIFFICILE INFECTION?

Learn why it requires aggressive action

THE CDC ACKNOWLEDGES C. DIFFICILE INFECTION AS A MAJOR AND URGENT THREAT.1

IT RECURS IN UP TO 35% OF CASES WITHIN 8 WEEKS AFTER INITIAL DIAGNOSIS.2,3

THE CONSEQUENCES OF RECURRENCE ARE SIGNIFICANT, POTENTIALLY DEADLY.2

Now is the time to learn how Ferring is shedding light on the link between disease and disruptions in the gut microbiome, exploring the potential for repopulating its diversity and restoring hope to patients.

References: 1. Centers for Disease Control and Prevention. 2019 Antibiotic Resistance Threats Report: Clostridioides Difficile. https://www.cdc. gov/drugresistancxqe/pdf/threats-report/clostridioides-difficile-508.pdf. Accessed April 8, 2021. 2. Lessa FC, Mu Y, Bamberg WM, et al. Burden of Clostridium difficile infection in the United States. N Engl J Med. 2015;372(9):825-834. 3. Cornely OA, Miller MA, Louie TJ, Crook DW, Gorback SL. Treatment of first recurrence of Clostridium difficile infection: fidaxomicin versus vancomycin. Clin Infect Dis. 2012;55(suppl 2):s154-s161.

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