Infectious Disease Special Edition - Winter 2021

Volume 25 • Winter 2021

Are Test Providers Profiteering From The Pandemic?

Managing Refractory CMV New Paradigms in HIV, Latest ACIP Recommendations, + Editorial Reviews From ID Experts

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Winter 2021 4

Editorial: My Wish for 2022

6

40 Years of HIV: Getting the Signal Through the Noise

15

Are COVID-19 Test Providers Profiteering From the Pandemic?

18

Masking in Schools: What Is the Evidence?

20

Managing Post-Transplant Refractory/Resistant CMV

22

Do Nonantibiotic Medications Increase the Risk for C. difficile Infections?

24

Will Restrictions at the Border Lead to IG Shortages?

26

Jury Still Out on Premedicating Kawasaki Disease Patients Before IVIG Therapy

27

New Paradigms in HIV Therapy

32

Should INSTI- or TAF-Related Weight Gain Prompt a Switch?

34

As UTI Drug Resistance Increases, Treatment Choices Critical

35

FDA Expands Indication for Flucelvax Quadrivalent to Children 6 Months and Older

36

ACIP Recommends Pneumococcal Vaccine for 65+ and Immunocompromised Adults

37

ACIP Recommends Recombinant Zoster Shot for Immunocompromised Adults

38

Hepatitis D Pipeline Looks Promising

40 ACIP Recommends 'Universal' Adult HBV Vaccine—But Not for All 44

Hitchhikers' Guide to the Galaxy?

IDSE Reviews

55

Updates in the Pipeline of HIV Therapy

By Daniel A. Solomon, MD, and Jonathan X. Li, MD, MMSc

61

Rapid Diagnostic Tests Inform Better Diagnostic and Treatment Decisions

By Amy K. Feehan, PhD; Julia Carcia-Diaz, MD, MSc, FACP, FIDSA, CPI; and Andrea J. Linscott, PhD, D(ABBM)

72

Implementing Injectables: Considerations for Cabotegravir-Rilpivirine Long-Acting Therapy

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

75

Antimicrobial Efficacy

By Devin M. Donnelly, PharmD; Gurminder M. Sanghera, PharmD; Maryrose Laguio-Vila, MD; and Sean M. Stainton, PharmD

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

3

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

Debra A. Goff, PharmD

Medical University of South Carolina Charleston, South Carolina

The Ohio State University Wexner Medical Center Columbus, Ohio

Philip A. Brunell, MD

Nancy D. Hanson, PhD

Emeritus, National Institutes of Health Bethesda, Maryland

Creighton University School of Medicine Omaha, Nebraska

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

Oregon Health & Science University Portland, Oregon

East Carolina University Greenville, North Carolina

Jonathan Z. Li, MD, MMSc

Brian Currie, MD, MPH

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

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

Johns Hopkins University School of Medicine Baltimore, Maryland

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

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

Rajesh T. Gandhi, MD, FIDSA

Wayne State University Detroit, Michigan

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

Shmuel Shoham, MD, FIDSA,

Julia Garcia-Diaz, MD, MSc, FACP, FIDSA, CPI

Mark H. Wilcox, MD, FRCPath

Ochsner Health System New Orleans, Louisiana

Johns Hopkins University Medical School, Baltimore, Maryland Leeds Teaching Hospitals NHS Trust University of Leeds Leeds, United Kingdom

EDITORIAL

McMAHON GROUP

Marie Rosenthal, MS

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Circulation Manager POSTMASTER: Send address changes to: Infectious Disease Special Edition McMahon Publishing Group | 545 W. 45th Street, 8th Fl. | New York, NY 10036 We endeavor to obtain relevant financial disclosures from all interviewees and rely on our sources to accurately provide this information, which we believe can be important in evaluating the research discussed in this publication.

EDITOR’S BLOG:

My Wish for 2022 I’m a little tired of COVID-19, and I’m sure you are, too, so we decided to end our year talking about a different pandemic. This year commemorates the publication of the first case report of what would become AIDS 40 years ago, and our coverage begins on page 6.

I was fortunate to be able to interview some of the pioneers who were there since the beginning—and are still treating people with HIV or researching this disease—as well as the people who began their practices a little later and are contributing to this field.

I have to give a special thank you to Dr. Anthony Fauci for taking time away from fighting COVID-19 to talk with me for this story. To be honest, I think he agreed because I promised not to talk about COVID-19, although we did end up talking about it. How could you not in 2021?

However, it was in the context of fighting both pandemics.

The last time I talked with Dr. Fauci was when he announced the plan to end HIV in the United States at the CROI meeting in 2019, and during our conversation for this 40th commemoration story, we talked about the effects that COVID-19 had on that effort. COVID-19 has certainly put that lofty goal behind schedule, but it has not derailed it, he assured me.

And money and resources have been diverted from HIV to COVID-19, others told me, which is understandable. Although HIV has killed more people overall—about 36 million—it has done so over 40 years. COVID-19 has killed more than 5.3 million people in under two years.

Both are staggering statistics to think about, and the efforts to fight both pandemics have been Herculean.

The time line for the two pandemics is noteworthy for something else—the lack of technology during the early days of the HIV pandemic. There was no internet when HIV was discovered, so physicians and researchers had to rely on peer-reviewed print publications, presentations at scientific meetings and landline telephones to disseminate information quickly. Even faxes were far from ubiquitous. Dr. Paul Volberding told me that writing a letter to the editor of a journal was a “quick” way to get the word out in the early days, and of course, the Morbidity and Mortality Weekly Report was crucial to stay updated.

An important thing to remember is that research done in the field of HIV has helped develop COVID-19 vaccines and treatments. For instance, the adenovirus-based COVID-19 vaccine was first tested for HIV. When people say the vaccine was developed too quickly, it was actually years in the making. And that research will come back around; researchers are already looking at mRNA technology to see whether it could be used to make an HIV vaccine.

Two unfortunate issues were prevalent in the early days of HIV, and are also a problem with COVID-19. One is equity, Drs. Rajesh Gandhi and Jonathan Li reminded me. That is a lesson that HIV can teach COVID-19.

Access to treatment and vaccines is crucial everywhere.

You cannot fight a pandemic in just one country. You can’t cure it here and expect it to stay over there because, as we are reminded all the time, organisms do not observe country or state borders.

The second is the noise, and separating the signal from that noise is crucial. Although the internet is a wonderful tool for quickly disseminating data, it can spread misinformation even more quickly. I don’t envy any physician today trying to separate the signal from the noise.

So, my wish for 2022 is that you all succeed in this and end both pandemics, before many more die.

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

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

4

IDSE.NET

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BY MARIE ROSENTHAL, MS

A

t first, it was a puzzle—a 33-year-old man, formerly healthy with a two-month history of fevers of unknown origin, elevated liver enzymes, oral mucosa candidiasis and cytomegalovirus —who presented to the emergency room at UCLA Medical Center, in Los Angeles, with dyspnea.

He died shortly afterward, and on post-mortem was found to have an unusual pneumonia, caused by Pneumocystis carinii —later renamed P. jirovecii —which typically affected people who were severely immunocompromised. But there was no evidence of a condition that would have impaired his immune system.

One patient.

An infectious disease curiosity, nothing more.

But then there were others.

6

IDSE.NET

In 1981, Michael S. Gottlieb, MD, and his colleagues published what is regarded as the first paper on HIV, which reported on five patients—all young, previously healthy men (MMWR Morb Mortal Wkly Rep 1981;30[21];1-3).

“It started with one patient who had something unusual and quickly became several patients, then dozens of patients with unexplained illness,” said Dr. Gottlieb, a staff physician at APLA Health in Los Angeles, and an associate Kaposi's sarcoma. clinical professor of medicine at Source: NCI the University of California, Los Angeles Geffen School of Medicine.

These patients appeared to have nothing in common except their gender and sexual orientation. They came from different socioeconomic backgrounds and shared no known contacts.

They all reported being gay, but only two reported having several partners. All five reported using “poppers,” inhaled psychoactive amyl nitrite that was thought might play a role in weakening their immune systems. (Eventually, it was realized that poppers had a role in behaviors that put them at risk [Ann N Y Acad Sci 1984;437:192-199]).

Other reports were published of men with unusual conditions, such as Mycobacterium intracellulare infection, which typically affects severely immunocompromised people.

One month later, there was a report of 26 cases of Kaposi sarcoma (KS) among homosexual men in New York City and California (MMWR Morb Mortal Wkly Rep 1981;30[25]:305-308).

It might have taken longer to put the puzzle together if the cases were not seen in academic medical centers, noted Dr. Gottlieb, an allergist and immunologist, who helped found the American Foundation for AIDS Research with Elizabeth Taylor in 1985, after his AIDS patient, actor Rock Hudson, died.

That first MMWR report was published because “it happened at an academic medical center—UCLA—where this first patient stumbled into the emergency room, and then word traveled to the community,” Dr. Gottlieb said. After that publication, people began looking at their own patients, and the dots started to connect.

The CD4 T-lymphocyte deficiency in the first patients was identified in the laboratory of Dr. John Fahey at UCLA, and the patients reported in MMWR were described in greater detail in December 1981 (N Engl J Med 1981;305[24]:1425-1431). “Thus, CD4 was identified early on as the target of a putative retrovirus, suggesting to the Pasteur and other groups that they look for a virus that attacked CD4 cells using cultured CD4 T cells,” Dr. Gottlieb said. “CD4 typing was a research tool at the time at UCLA and not clinically available, another reason why

Dr. Anthony Fauci in 1984.

Source: NIAID

being at an academic center allowed these early observations.

Identification of CD4 as the target facilitated the discovery of the virus within three years of the initial case reports.”

Dr. Gottlieb was on the front line because of his specialty, he explained. It was obvious that the immune systems of these patients were not working. “It was exciting, on one hand, to be involved with something new,” he said. “On the other hand, it quickly dawned on me that it was a very serious and probably irreversible immune deficiency.”

Powerless Against This New Disease Cases like these are what intrigues infectious disease specialists, which is why they are called the disease detectives and the people whom specialists call when they’ve run out of differentials in their own field. The curiosity of many young doctors and researchers was sparked as these reports started appearing.

“I can remember very clearly sitting in my office at the NIH [National Institutes of Health] Clinical Center in June 1981, when the first MMWR landed on my desk reporting five young gay men from Los Angeles with Pneumocystis pneumonia. I thought that it was either a one-off kind of curiosity or a fluke,” said Anthony Fauci, MD, who took time from fighting the COVID-19 pandemic to talk with Infectious Disease Special Edition. “I thought maybe they were sniffing some poppers to enhance sexual pleasure or something, but I didn’t make much of it.”

Then the MMWR reported the KS cases, he said, and his interest was piqued. “This time, 26 curiously all gay men, not only from L.A., but now from New York City and from San Francisco, reporting not only Pneumocystis, but Kaposi’s sarcoma and other opportunistic infections [OIs], and that is when my career and my life changed,” Dr. Fauci said, because he realized that “this is a brand-new disease.”

Dr. Fauci said that during his ID fellowship and subsequent nine years at the National Institute of Allergy and Infectious

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

7

Diseases, he had seen many OIs among chemotherapy patients. For these young men to come down with OIs such as Pneumocystis and KS, “something” had to be wreaking havoc with their immune systems.

“I made a decision that I was going to totally change the direction of my career. Up to that point, I had been successful publishing in the field of immunoregulation and looking at how the immune system gets suppressed when you give therapies such as prednisone and cytotoxic agents. I said, Discovery of HIV ‘I am going to now start studying this amazingly One of the more contentious issues surrounding HIV was the discovery scary and brand-new disease.’” of the virus. Drs. Jean-Claude Chermann and Françoise Barré-Sinoussi This was before the virus was discovered, he at Dr. Luc Montagnier’s lab at the Pasteur Institute, in Paris; Dr. Robert reminded.

Gallo at the National Cancer Institute, in “My mentors thought I was crazy. They said, Bethesda, Md.; and Dr. Jay A. Levy in San ‘Why in God’s name would you want to divert Francisco were looking at human retroviyourself from a successful career trajectory to start ruses. Dr. Gallo had pioneered the detection studying a disease in a group of gay men that is of RNA viruses with the discovery of interleuprobably going to go away and not amount to anykin-2 and human T-cell leukemia virus (HTLV). thing?’” Dr. Fauci recalled.

Each scientist isolated a virus that Another young man, who was studying the link they believed was the cause of AIDS. Dr. between viruses and cancer, was also intrigued. He Montagnier identified it as lymphadenopahad moved to San Francisco to study that connecthy-associated virus (LAV); Dr. Gallo called it tion in the laboratory of Jay A. Levy, MD, one of HTLV-III; and Dr. Levy, AIDS-associated retroDr. Françoise Barréthe discoverers of HIV. “I really liked taking care virus (ARV). All of them were correct, and the Sinoussi in 2008.

Source: Wikimedia Commons of cancer patients when I was a medicine resident, virus became known as human immunodefiand so I decided to have my clinical focus be oncolciency virus, or HIV. ogy, although I always planned to still work with But there was a bitter and very public dispute between the viruses in the lab,” said Paul A. Volberding, MD, Americans and the French over who first discovered the cause of HIV—a the director of the AIDS Research Institute at the dispute that wound up in court.

University of California, San Francisco.

In 1987, President Ronald Reagan and French Prime Minister Jacques “I think, for me, the issue was that it was absoChirac reached a joint agreement: They would share scientific credit lutely new. No one had ever seen anything like this and patent royalties. However, when the Nobel Committee handed before—it was out of the blue,” Dr. Volberding said. out its 2008 prize for the discovery, it went to Drs. Barré-Sinoussi and “Obviously, it was not the first new disease that Montagnier of the Pasteur Institute. people had come across—that’s part of the history of medicine—but it was really very remarkable.”

Donna Mildvan, MD, was an infectious disease physician at study enteric pathogens as a sexually transmitted infection Beth Israel Medical Center, in New York City. In the late 1970s, (STI) and began to notice that many of the men also had she saw a young man hospitalized with multiple gastrointesti- unexplained lymphadenopathy. But it wasn’t until 1980 that nal infections. There was no history of travel, but Shigella and Dr. Mildvan saw her first patient who subsequently was diagGiardia were found in his stool, she said. nosed with AIDS. Then a second patient came into the hospital with a similar “It was a very unfortunate case of a 33-year-old man who pattern. She reported both cases to the city health department, had a series of infections and wasting and eventually died,” she where she met Daniel C. Williams, MD, whose practice brought said. “You just don’t lose a 33-year-old. It was extraordinary.” a perspective on the gay community. “Dan explained that the And like Dr. Gottlieb, a second and then a third patient sexual practices of gay men could have led to the development came in with fulminant disease and died. of these GI infections,” said Dr. Mildvan, a clinical professor “We realized, maybe all that lymph node enlargement we’d of medicine at the Icahn School of Medicine at Mount Sinai, in been seeing in gay males had something to do with this fulmiNew York. Both patients were gay and had multiple partners. nant manifestation,” Dr. Mildvan said. So they began following continued on page 13 Drs. Williams and Mildvan collaborated with the CDC to

8

IDSE.NET

AVYCAZ® (ceftazidime and avibactam) for injection, for intravenous use INDICATIONS AND USAGE Complicated Intra-abdominal Infections (cIAI) AVYCAZ (ceftazidime and avibactam) in combination with metronidazole, is indicated for the treatment of complicated intra-abdominal infections (cIAI) in adult and pediatric patients 3 months or older caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, and Pseudomonas aeruginosa.

Complicated Urinary Tract Infections (cUTI), including Pyelonephritis AVYCAZ (ceftazidime and avibactam) is indicated for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis in adult and pediatric patients 3 months or older caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii complex, Proteus mirabilis, and Pseudomonas aeruginosa.

Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) AVYCAZ (ceftazidime and avibactam) is indicated for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) in patients 18 years or older caused by the following susceptible Gram-negative microorganisms: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa, and Haemophilus influenzae.

Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of AVYCAZ and other antibacterial drugs, AVYCAZ should be used to treat only indicated 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.

CONTRAINDICATIONS AVYCAZ is contraindicated in patients with known serious hypersensitivity to the components of AVYCAZ (ceftazidime and avibactam), avibactamcontaining products, or other members of the cephalosporin class [see Warnings and Precautions].

WARNINGS AND PRECAUTIONS Decreased Clinical Response in Adult cIAI Patients with Baseline Creatinine Clearance of 30 to Less Than or Equal to 50 mL/min In a Phase 3 cIAI trial in adult patients, clinical cure rates were lower in a subgroup of patients with baseline CrCl of 30 to less than or equal to 50 mL/min compared to those with CrCl greater than 50 mL/min (Table 1).

The reduction in clinical cure rates was more marked in patients treated with AVYCAZ plus metronidazole compared to meropenem-treated patients.

Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCl 30 to less than or equal to 50 mL/min.

The decreased clinical response was not observed for patients with moderate renal impairment at baseline (CrCl of 30 to less than or equal to 50 mL/min) in the Phase 3 cUTI trials or the Phase 3 HABP/VABP trial.

Monitor CrCl at least daily in adult and pediatric patients with changing renal function and adjust the dosage of AVYCAZ accordingly [see Adverse Reactions].

Table 1. Clinical Cure Rate at Test of Cure in a Phase 3 cIAI Trial,

by Baseline Renal Function – mMITT Populationa AVYCAZ + Metronidazole % (n/N) Normal function / mild impairment (CrCl greater than 50 mL/min) Moderate impairment (CrCl 30 to less than or equal to 50 mL/min) a

85% (322/379)

Meropenem % (n/N)

Development of Drug-Resistant Bacteria Prescribing AVYCAZ 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 drug-resistant bacteria [see Indications and Usage].

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in the Warnings and Precautions section: t Hypersensitivity Reactions [see Warnings and Precautions] t Clostridium difficile-Associated Diarrhea [see Warnings and Precautions] t Central Nervous System Reactions [see Warnings and Precautions] 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.

Clinical Trials Experience in Adult Patients AVYCAZ was evaluated in six active-controlled clinical trials in patients with cIAI, cUTI, including pyelonephritis, or HABP/VABP. These trials included two Phase 2 trials, one in cIAI and one in cUTI, as well as four Phase 3 trials, one in cIAI, one in cUTI (Trial 1), one in cIAI or cUTI due to ceftazidime non-susceptible pathogens (Trial 2) and one in HABP/VABP. Data from cUTI Trial 1 served as the primary dataset for AVYCAZ safety findings in cUTI as there was a single comparator. cUTI Trial 2 had an open-label design as well as multiple comparator regimens which prevented pooling, but provided supportive information. The six clinical trials included a total of 1809 adult patients treated with AVYCAZ and 1809 patients treated with comparators.

Complicated Intra-abdominal Infections The Phase 3 cIAI trial included 529 adult patients treated with AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered intravenously over 120 minutes every 8 hours plus 0.5 grams metronidazole administered intravenously over 60 minutes every 8 hours and 529 patients treated with meropenem. The median age of patients treated with AVYCAZ was 50 years (range 18 to 90 years) and 22.5% of patients were 65 years of age or older. Patients were predominantly male (62%) and Caucasian (76.6%).

Treatment discontinuation due to an adverse reaction occurred in 2.6% (14/529) of patients receiving AVYCAZ plus metronidazole and 1.3% (7/529) of patients receiving meropenem. There was no specific adverse reaction leading to discontinuation.

Adverse reactions occurring at 5% or greater in patients receiving AVYCAZ plus metronidazole were diarrhea, nausea and vomiting.

Table 2 lists adverse reactions occurring in 1% or more of patients receiving AVYCAZ plus metronidazole and with incidences greater than the comparator in the Phase 3 cIAI clinical trial.

Table 2. Incidence of Selected Adverse Reactions Occurring in 1% or more of Patients Receiving AVYCAZ in the Phase 3 cIAI Trial Preferred term

74% (26/35)

Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Before therapy with AVYCAZ is instituted, careful inquiry about previous hypersensitivity reactions to other cephalosporins, penicillins, or carbapenems should be made. Exercise caution if this product is to be given to a penicillin or other beta-lactam-allergic patient because cross sensitivity among beta-lactam antibacterial drugs has been established.

Discontinue the drug if an allergic reaction to AVYCAZ occurs.

Clostridium difficile-associated Diarrhea Clostridium difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial drugs, including AVYCAZ, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial drugs alters the normal flora of the colon and may permit 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 use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial drugs.

If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

Central Nervous System Reactions Seizures, nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported in patients treated with ceftazidime, particularly in the setting of renal impairment. Adjust dosing based on creatinine clearance.

Meropenemb (N=529)

Headache

3%

2%

Dizziness

2%

1%

Diarrhea

8%

3%

Nausea

7%

5%

Vomiting

5%

2%

Abdominal Pain

1%

1%

Gastrointestinal disorders

86% (321/373)

Microbiological modified intent-to-treat (mMITT) population included patients who had at least one bacterial pathogen at baseline and received at least one dose of study drug.

AVYCAZ plus metronidazolea (N=529)

Nervous system disorders

a

45% (14/31)

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

b

2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) IV over 120 minutes every 8 hours (with metronidazole 0.5 grams IV every 8 hours) 1 gram IV over 30 minutes every 8 hours

Increased Mortality In the Phase 3 cIAI trial, death occurred in 2.5% (13/529) of patients who received AVYCAZ plus metronidazole and in 1.5% (8/529) of patients who received meropenem. Among a subgroup of patients with baseline CrCl 30 to less than or equal to 50 mL/min, death occurred in 19.5% (8/41) of patients who received AVYCAZ plus metronidazole and in 7.0% (3/43) of patients who received meropenem. Within this subgroup, patients treated with AVYCAZ received a 33% lower daily dose than is currently recommended for patients with CrCl 30 to less than or equal to 50 mL/min [see Warnings and Precautions]. In patients with normal renal function or mild renal impairment (baseline CrCl greater than 50 mL/min), death occurred in 1.0% (5/485) of patients who received AVYCAZ plus metronidazole and in 1.0% (5/484) of patients who received meropenem. The causes of death varied and contributing factors included progression of underlying infection, baseline pathogens isolated that were unlikely to respond to the study drug, and delayed surgical intervention.

Complicated Urinary Tract Infections, Including Pyelonephritis The Phase 3 cUTI Trial 1 included 511 adult patients treated with AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered intravenously over 120 minutes every 8 hours and 509 patients treated with doripenem; in some patients parenteral therapy was followed by a switch to an oral antimicrobial agent. Median age of patients treated with AVYCAZ was 54 years (range 18 to 89 years) and 30.7% of patients were 65 years of age or older. Patients were predominantly female (68.3%) and Caucasian (82.4%). Patients with CrCl less than 30 mL/min were excluded.

There were no deaths in Trial 1. Treatment discontinuation due to adverse reactions occurred in 1.4% (7/511) of patients receiving AVYCAZ and 1.2% (6/509) of patients receiving doripenem. There was no specific adverse reaction leading to discontinuation.

The most common adverse reactions occurring in 3% of cUTI patients treated with AVYCAZ were nausea and diarrhea.

Table 3 lists adverse reactions occurring in 1% or more of patients receiving AVYCAZ and with incidences greater than the comparator in Trial 1.

Table 3. Incidence of Selected Adverse Drug Reactions Occurring in 1% or more of Patients Receiving AVYCAZ in the Phase 3 cUTI Trial 1 AVYCAZa (N=511)

Doripenemb (N=509)

Nausea

3%

2%

Diarrhea

3%

1%

Constipation

2%

1%

Upper abdominal pain

1%

< 1%

Preferred Term Gastrointestinal disorders

a b

2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) IV over 120 minutes every 8 hours 0.5 grams IV over 60 minutes every 8 hours

Hospital-acquired Bacterial Pneumonia/Ventilator-associated Bacterial Pneumonia The Phase 3 HABP/VABP trial included 436 adult patients treated with AVYCAZ 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered intravenously over 120 minutes and 434 patients treated with meropenem. The median age of patients treated with AVYCAZ was 66 years (range 18 to 89 years) and 54.1% of patients were 65 years of age or older.

Patients were predominantly male (74.5%) and Asian (56.2%).

Death occurred in 9.6% (42/ 436) of patients who received AVYCAZ and in 8.3% (36/434) of patients who received meropenem. Treatment discontinuation due to an adverse reaction occurred in 3.7% (16/436) of patients receiving AVYCAZ and 3% (13/434) of patients receiving meropenem.

There was no specific adverse reaction leading to discontinuation.

Adverse reactions occurring at 5% or greater in patients receiving AVYCAZ were diarrhea and vomiting.

Table 4 lists selected adverse reactions occurring in 1% or more of patients receiving AVYCAZ and with incidences greater than the comparator in the Phase 3 HABP/VABP clinical trial.

Table 4. Incidence of Selected Adverse Drug Reactions Occurring in 1% or more of Patients Receiving AVYCAZ in the Phase 3 HABP/VABP Trial Preferred Term

AVYCAZa (N=436)

Meropenemb (N=434)

3%

2%

2%

1%

Gastrointestinal disorders Nausea Skin and subcutaneous tissue disorders Pruritus a b

2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) IV over 120 minutes every 8 hours 1 gram IV over 30 minutes every 8 hours

Other Adverse Reactions of AVYCAZ and Ceftazidime in Adults The following selected adverse reactions were reported in AVYCAZ-treated patients at a rate of less than 1% in the Phase 3 trials and are not described elsewhere in the labeling.

Blood and lymphatic disorders - Thrombocytopenia, Thrombocytosis, Leukopenia General disorders and administration site conditions - Injection site phlebitis Infections and infestations - Candidiasis Investigations - Increased aspartate aminotransferase, Increased alanine aminotransferase, Increased gamma-glutamyltransferase Metabolism and nutrition disorders - Hypokalemia Nervous system disorders - Dysgeusia Renal and urinary disorders - Acute kidney injury, Renal impairment, Nephrolithiasis Skin and subcutaneous tissue disorders - Rash, Rash maculo-papular, Urticaria Psychiatric disorders - Anxiety Additionally, adverse reactions reported with ceftazidime alone that were not reported in AVYCAZ-treated patients in the Phase 3 trials are listed below: Blood and lymphatic disorders - Agranulocytosis, Hemolytic anemia, Lymphocytosis, Neutropenia, Eosinophilia General disorders and administration site conditions - Infusion site inflammation, Injection site hematoma, Injection site thrombosis Hepatobiliary disorders – Jaundice Investigations - Increased blood lactate dehydrogenase, Prolonged prothrombin time Nervous system disorders - Paresthesia Renal and urinary disorders - Tubulointerstitial nephritis Reproductive and breast disorders - Vaginal inflammation Skin and subcutaneous tissue disorders - Angioedema, Erythema multiforme, Stevens-Johnson syndrome, Toxic epidermal necrolysis Laboratory Changes in Adults In the Phase 3 trials, seroconversion from a negative to a positive direct Coombs’ test result among patients with an initial negative Coombs’ test and at least one follow up test occurred in 3.0% (cUTI), 12.9% (cIAI), and 21.4% (HABP/VABP) of patients receiving AVYCAZ and 0.9% (cUTI), 3% (cIAI) and 7% (HABP/VABP) of patients receiving a carbapenem comparator.

No adverse reactions representing hemolytic anemia were reported in any treatment group.

Clinical Trials Experience in Pediatric Patients AVYCAZ was evaluated in 128 pediatric patients aged 3 months to < 18 years in two single-blind, randomized, active-controlled clinical trials, one in patients with cUTI and the other in patients with cIAI. Safety data from the two studies were pooled. The AVYCAZ dosing regimen was the same in each

trial with a mean treatment duration of 6 days, and a maximum of 14 days.

The regimen was selected to result in pediatric drug exposure comparable to that of adults, and in the cIAI trial, metronidazole was administered concurrently with AVYCAZ. Patients were randomized 3:1 to receive AVYCAZ or comparator, which was meropenem or cefepime in the cIAI and cUTI trials, respectively. The median age of patients treated with AVYCAZ was 8.6 years, and in the comparator group 7.4 years. The majority of patients treated with AVYCAZ were female (57%) and Caucasian (80%).

The safety profile of AVYCAZ in pediatric patients was similar to adults with cIAI and cUTI, treated with AVYCAZ. There were no deaths reported in either trial. Treatment discontinuation due to adverse reactions occurred in 2.3% (3/128) of patients receiving AVYCAZ and 0/50 of patients receiving comparator drugs.

The most common adverse reactions occurring in greater than 3% of pediatric patients treated with AVYCAZ were vomiting, diarrhea, rash, and infusion site phlebitis.

DRUG INTERACTIONS Probenecid In vitro, avibactam is a substrate of OAT1 and OAT3 transporters which might contribute to the active uptake from the blood compartment, and thereby its excretion. As a potent OAT inhibitor, probenecid inhibits OAT uptake of avibactam by 56% to 70% in vitro and, therefore, has the potential to decrease the elimination of avibactam when co-administered. Because a clinical interaction study of AVYCAZ or avibactam alone with probenecid has not been conducted, co-administration of AVYCAZ with probenecid is not recommended.

Drug/Laboratory Test Interactions The administration of ceftazidime may result in a false-positive reaction for glucose in the urine with certain methods. It is recommended that glucose tests based on enzymatic glucose oxidase reactions be used.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary There are no adequate and well-controlled studies of AVYCAZ, ceftazidime, or avibactam in pregnant women. Neither ceftazidime nor avibactam were teratogenic in rats at doses 40 and 9 times the recommended human clinical dose. In the rabbit, at twice the exposure as seen at the human clinical dose, there were no effects on embryofetal development with avibactam.

The background risk of major birth defects and miscarriage for the indicated population is unknown. The background risk of major birth defects is 2-4% and of miscarriage is 15-20% of clinically recognized pregnancies within the general population. Because animal reproduction studies are not always predictive of human response, this drug should be used in pregnancy only if clearly needed.

Data Animal Data Ceftazidime Reproduction studies have been performed in mice and rats at doses up to 40 times the human dose and showed no evidence of harm to the fetus due to ceftazidime.

Avibactam Avibactam was not teratogenic in rats or rabbits. In the rat, intravenous studies with 0, 250, 500 and 1000 mg/kg/day avibactam during gestation days 6-17 showed no embryofetal toxicity at doses up to 1000 mg/kg/day, approximately 9 times the human dose based on exposure (AUC). In a rat pre- and post-natal study at up to 825 mg/kg/day intravenously (11 times the human exposure based on AUC), there were no effects on pup growth and viability. A dose-related increase in the incidence of renal pelvic and ureter dilatation was observed in female weaning pups that was not associated with pathological changes to renal parenchyma or renal function, with renal pelvic dilatation persisting after female weaning pups became adults.

Rabbits administered intravenous avibactam on gestation days 6-19 at 0, 100, 300 and 1000 mg/kg/day showed no effects on embryofetal development at a dose of 100 mg/kg, twice the human exposure (AUC). At higher doses, increased post-implantation loss, lower mean fetal weights, delayed ossification of several bones and other anomalies were observed.

Lactation Risk Summary Ceftazidime is excreted in human milk in low concentrations. It is not known whether avibactam is excreted into human milk, although avibactam was shown to be excreted in the milk of rats. No information is available on the effects of ceftazidime and avibactam on the breast-fed child or on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for AVYCAZ and any potential adverse effects on the breastfed child from AVYCAZ or from the underlying maternal conditions.

Data In a rat pre- and post-natal study at doses up to 825 mg/kg/day intravenously (11 times the human exposure based on AUC), the exposure to avibactam was minimal in the pups in comparison to the dams. Exposure to avibactam was observed in both pups and milk on PND 7.

Pediatric Use The safety and effectiveness of AVYCAZ in the treatment of cUTI and cIAI have been established in pediatric patients 3 months to less than 18 years.

Use of AVYCAZ in these age groups is supported by evidence from adequate and well-controlled studies of AVYCAZ in adults with cUTI and cIAI and additional pharmacokinetic and safety data from pediatric trials.

The safety profile of AVYCAZ in pediatric patients was similar to adults with cIAI and cUTI, treated with AVYCAZ [see Adverse Reactions].

Safety and effectiveness in pediatric patients below the age of 3 months with cUTI or cIAI have not been established. There is insufficient information to recommend dosage adjustment for pediatric patients younger than 2 years of age with cIAI and cUTI and renal impairment.

Safety and effectiveness in pediatric patients less than 18 years of age with HABP/VABP have not been established.

Geriatric Use Of the 1809 patients treated with AVYCAZ in the Phase 2 and Phase 3 clinical trials 621 (34.5%) were 65 years of age and older, including 302 (16.7 %) patients 75 years of age and older.

In the pooled Phase 2 and Phase 3 cIAI AVYCAZ clinical trials, 20% (126/630) of patients treated with AVYCAZ were 65 years of age and older, including 49 (7.8%) patients 75 years of age and older. The incidence of adverse reactions in both treatment groups was higher in older patients (≥ 65 years of age) and similar in both treatment groups; clinical cure rates for patients 65 years of age or older were 73.0% (73/100) in the AVYCAZ plus metronidazole arm and 78.6% (77/98) in the meropenem arm.

In the Phase 3 cUTI trial, 30.7% (157/511) of patients treated with AVYCAZ were 65 years of age or older, including 78 (15.3%) patients 75 years of age or older. The incidence of adverse reactions in both treatment groups was lower in older patients (≥ 65 years of age) and similar between treatment groups. Among patients 65 years of age or older in the Phase 3 cUTI trial, 66.1% (82/124) of patients treated with AVYCAZ had symptomatic resolution at Day 5 compared with 56.6% (77/136) of patients treated with doripenem.

The combined response (microbiological cure and symptomatic response) observed at the test-of-cure (TOC) visit for patients 65 years of age or older were 58.1% (72/124) in the AVYCAZ arm and 58.8% (80/136) in the doripenem arm.

In the Phase 3 HABP/VABP trial, 54.1% (236/436) of patients treated with AVYCAZ were 65 years of age or older, including 129 (29.6%) patients 75 years of age or older. The incidence of adverse reactions in patients ≥ 65 years of age was similar to patients < 65 years of age. The 28-day all-cause mortality was similar between treatment groups for patients 65 years of age or older (12.7% [29/229] for patients in the AVYCAZ arm and 11.3% [26/230] for patients in the meropenem arm).

Ceftazidime and avibactam are known to be substantially excreted by the kidney; therefore, the risk of adverse reactions to ceftazidime and avibactam may be greater in patients with decreased renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function.

Healthy elderly subjects had 17% greater exposure relative to healthy young subjects when administered the same single dose of avibactam, which may have been related to decreased renal function in the elderly subjects.

Dosage adjustment for elderly patients should be based on renal function.

Renal Impairment Dosage adjustment is required in adult patients with moderately or severely impaired renal function (CrCl 50 mL/min or less). For patients with changing renal function, CrCl should be monitored at least daily, particularly early in treatment, and dosage of AVYCAZ adjusted accordingly. Both ceftazidime and avibactam are hemodialyzable; thus, AVYCAZ should be administered after hemodialysis on hemodialysis days.

Dosage adjustment is also required in pediatric patients with cIAI or cUTI and renal impairment from 2 years to < 18 years with eGFR 50 mL/min/1.73 m2 or less. There is insufficient information to recommend a dosing regimen for pediatric patients younger than 2 years of age with cIAI or cUTI and renal impairment.

OVERDOSAGE In the event of overdose, discontinue AVYCAZ and institute general supportive treatment.

Ceftazidime and avibactam can be removed by hemodialysis. In subjects with end-stage renal disease (ESRD) administered 1 gram ceftazidime, the mean total recovery in dialysate following a 4-hour hemodialysis session was 55% of the administered dose. In subjects with ESRD administered 100 mg avibactam, the mean total recovery in dialysate following a 4-hour hemodialysis session started 1 hour after dosing was approximately 55% of the dose.

No clinical information is available on the use of hemodialysis to treat AVYCAZ overdosage.

Distributed By: Allergan USA, Inc., Madison, NJ 07940 Manufactured by: GlaxoSmithKline Manufacturing S.p.A., Verona, 37135 Italy AVYCAZ® is a registered trademark of Allergan Sales, LLC. Allergan® and its design are trademarks of Allergan, Inc. All other trademarks are the property of their respective owners. © 2020 Allergan. All rights reserved.

Ref: v1.1USPI2700 Revised: December 2020 US-AVY-210260 MASTER US-AVY-210253

40 Years

“We had no clue what was going on at first, and I didn’t expect it to be a new virus,” Dr. Volberding said, so he had continued from page 8 no qualms about caring for these patients. Then the blood the lymphadenopathy patients longitudinally. “A large number transfusion cases started to appear, so it became clear it was of them progressed to develop AIDS-defining events.” an infectious agent.

Being around the same age as one’s patients—Dr. Gottlieb “That is when it became real to me, and I was really terrified was 33 when be published that first MMWR article—was dis- of it because we didn’t know the nature of it. We didn’t know concerting. “I was in my 30s; they were in their 30s. All of our how it was transmitted. We had no way to diagnose it, and so patients died within that first year after diagnosis. It quickly that was a pretty fraught period,” Dr. Volberding said. became scary and disheartening to see these men die, and not It was a time of worry for physicians caring for these men be able to tell their parents, in some cases, lovers, and others until about 1983-1984, Dr. Gottlieb agreed. Several doctors what was wrong with them because we didn’t know what had treating HIV/AIDS patients reported unexplained illnesses. Dr. caused their immune systems to fail,” Dr. Gottlieb said.

Gottlieb had a scare when he developed a mononucleosis-like “We were powerless in the face of this new disease,” he illness that lasted a couple of months with extreme fatigue and added. low-grade fever. “It was before there was an HIV test, so I trav“I saw my first KS patient literally at my first day on the eled to Paris, where virologists Jean-Claude Chermann and faculty at San Francisco General Hospital, and the patient Françoise Barré-Sinoussi cultured my blood for HIV, because was my age. I had just turned 31,” Dr. Volberding said. “The I was concerned about this unexplained illness,” Dr. Gottlieb patients were coming in in their 20s and 30s with really bad said. Fortunately, the result was negative. diseases, really bad cancers that tended to be diseases of aging.

Dr. Mildvan had her own HIV scare. “We were afraid when So nothing prepared us for what looked like an epidemic of we realized that it was transmissible,” she said. “At one point, cancer appearing in young people.

I looked at my arm and there was a funny lesion on it, and I thought, ‘Oh, God, it’s Kaposi sarcoma.’” It faded eventually, and she finally Difficult but Important Conversations remembered her cat using her arm as a When the second patient with multiple enteric diseases presented to Donna launching pad. “Just about everyone has Mildvan, MD, and reported he was gay and had more than one partner, she a story like that,” Dr. Mildvan said. realized she had to go back to the first patient and ask about his sexual In 1982, the CDC published a case behavior—a difficult doctor–patient conversation in the 1970s. definition, calling the disease “acquired “I had never thought to ask these questions. We would take sexual hisimmunodeficiency syndrome (AIDS)” tories from patients who presented with venereal or sexually transmitted (Morb Mortal Wkly Rep MMWR diseases, but nobody really made the connection that amebiasis or Shigella 1982;31[37]:507-508; 513-514), and by 1983, or Campylobacter could be a sexually transmitted disease,” she said. “These the virus was isolated, which changed were enteric GI diseases that you get from travel or contaminated food.” everything, because now there was a tarDr, Mildvan’s team reported the cases (JAMA 1977;238[13]:1387-1389), and an get for diagnostic tests and treatments. accompanying editorial emphasized the importance of inquiring about sexual With a test, the physicians felt safer, preference in the workup of these patients. because they could at least find out if “Back then, this was news,” she said. that odd headache or malaise was HIV. Today, Julia Garcia-Diaz, MD, MSc, teaches medical students how to have However, needlesticks were a concern; these awkward conversations with patients. “It’s not just getting a sexual they were rare, but they still occurred, history,” said Dr. Garcia-Diaz. “[They need to know] how to talk to the the expert said. patient. You need to feel comfortable with the things that you’re asking your Universal precautions would not be patients. How many partners, and beyond that, are they male or female? Is it put into place until 1984, and they were both? implemented largely due to HIV, accord“Now some patients share a little more than I w would like,” she joked, but ing to the CDC. that is because they feel comfortable discuss discussin these issues. discussing In addition to a sexual histo ory a thorough drug hishistory, ant “It’s not just ‘Do you tory is also importa important. do drugs?’ B But But, ‘Do you use needles or sh share them? How do you ccook your meth?’” she said.

Early Patient Management The story of HIV/AIDS is more than a story of medical advancement. It is a story of fear, activism, education, disparities and prejudices. It is the story of a pandemic that has spanned 40 years,

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

13

infected 79.3 million people and killed almost 40 million. It is treatments that could be expensive, Dr. Garcia-Diaz noted. But a story of life and death. it was even more important then, when patients became so sick In the first two years, AIDS appeared to be a problem of gay they could no longer work, she stressed. men, so the public did not give it much attention. However, Even within the hospital, some staff were reluctant to intermany of these men were already isolated, often estranged from act with HIV patients. They didn’t even want to enter the room family and friends because they were gay, and AIDS added to to deliver or pick up food trays. Some surgeons refused to do the stigma. surgeries for these patients.

“There was nothing so heartbreaking as watching patients “Back then, if you referred a patient with HIV for cardiac with AIDS in those early days suffer and die,” said Paul Sax, surgery or orthopedic surgery, you had to choose your surgeon MD, who was a medical student when HIV was discovered. very carefully, because most of them didn’t want to do it,” Dr. “The combination of the absence of effective therapy and the Sax explained. “They didn’t want to do it for a combination of societal stigma and isolation they felt—it really tore you up their own personal risk—and I don’t want to diminish that, they and you wanted to do everything you could for them.” had more personal risk than we did—but they also felt, ‘What’s He remembered one patient who epitomized the early iso- the point?’ The average life expectancy of someone with AIDS lation some patients felt. He had come from Cuba with the in 1986 was 12 months.

Mariel boatlift in 1980, and he was dying of AIDS. “He had no “Today, they want to operate on everyone [with HIV],” said family, and he wouldn’t tell his friends, so he gradually became Dr. Sax, which just demonstrates the strides made in HIV care more and more isolated,” Dr. Sax explained. and education.

When cases occurred in men who were not gay, women, “Whenever there is a new disease and there is uncertainty infants or children, Americans started to take notice, and they about how it’s transmitted, I think the public and medical prowere afraid, which isolated AIDS fessionals—who are just like other patients even more. people in terms of worry—will iniOne of the most notable tially be concerned about whether patients outside the gay comthey may be at risk,” said Rajesh T. munity was an Indiana teenager Gandhi, MD, the director of HIV with hemophilia. In 1985, Ryan Clinical Services at Massachusetts White contracted AIDS from General Hospital, in Boston, and the a blood transfusion, and fear past president of the HIV Medicine drove his expulsion from middle Association. Dr. Gandhi was a medischool. Ryan and his parents cal resident in the 1980s. ended up moving to another Dr. Gandhi added that, soon after town because of the bigotry he the discovery of HIV, he was reasencountered, and he spent the sured by the fact that people with rest of his short life teaching HIV who lived in a household with An early AIDS testing kit in1985. Source: FDA people about HIV/AIDS. He died others who were not sexual partners in 1990. That year, Congress did not infect their relatives and enacted the Ryan White Comprehensive AIDS Resources friends. “So, obviously, eating, drinking and being in a family Emergency (CARE) Act, which is the largest federal program is typically a closer interaction than being a person’s doctor, focused on providing HIV care and treatment services to low- and that reassured me in those early days after HIV was disincome people living with HIV. (For more on the Ryan White covered,” Dr. Gandhi said. program today, see bit.ly/31Ld6L4-IDSE.) Education and communication were crucial, they all said.

“The Ryan White Care Act created a pathway for the federal support of AIDS care across the country … similar to the way the All on the Same Team … Almost The signal-to-noise ratio—a measurement from radio engigovernment covers dialysis treatments,” Dr. Volberding said.

The occurrence of HIV outside the gay community led to neering that separates the noise-free radio signal from backanother milestone: the Social Security Administration’s deci- ground white noise—serves as a good analogy for the early sion to allow people with AIDS to apply for disability ben- days of HIV on many levels, from discerning the transmissible efits, according to Julia Garcia-Diaz, MD, MSc, an associate agent to figuring out how that agent was transmitted and getprofessor, University of Queensland/Ochsner Clinical School, ting research funding.

The fact that most patients were gay, and there was bigotry Oschsner Health, in New Orleans, who began providing care for patients in the early 1990s as a medical student. These surrounding same-sex relationships, made them easy for the continued on page 46 benefits are important today because they keep people on

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Are COVID-19 Test Providers Profiteering From the Pandemic?

BY ARLENE WEINTRAUB

O

n Oct. 14, Premera Blue Cross, based in suburban Seattle, sued GS Labs alleging that the Omaha, Neb.–based medical testing company is exploiting the COVID-19 pandemic by overcharging for COVID-19 testing. It was the second Blue Cross plan to file suit against GS Labs over its COVID-19 test prices in six months.

Premera alleged that GS charges prices ranging from $380 to $979 per test, which often amounts to 10 times more than what other labs are charging. Virtually every claim from GS indicates that patients have reported COVID-19 symptoms or exposures, Premera said in its complaint. “But GS Labs does not perform individual patient assessments, and includes these false diagnoses in an effort to obtain higher payments,” the lawsuit alleged.

Insurers are far from alone in their complaints about COVID-19 test pricing. Some consumers have faced unexpected out-of-pocket charges, despite the fact that two federal laws passed at the start of the pandemic—the Coronavirus Aid, Relief, and Economic Security (CARES) Act and Families First Coronavirus Response Act (FFCRA)—mandated free testing for insured patients and provided reimbursement mechanisms for the uninsured.

“A crisis can become a profiteering opportunity, and some providers may be attempting to take advantage of the pandemic,” said Ge Bai, PhD, a professor of accounting, health policy and management at the Johns Hopkins University, in Baltimore.

Premera’s suit alleges that GS Labs has improperly filed

claims for more than $26 million worth of COVID-19 tests.

Blue Cross and Blue Shield of Kansas City, which filed a lawsuit against GS Labs in July, alleged that the lab provider billed $9.2 million in improper charges for COVID-19 testing.

GS countersued the Kansas City insurer, demanding the entire $9 million owed plus damages, interest and legal fees.

Under the CARES Act, insurance companies are responsible for paying for COVID-19 tests, the company said. “This is a perfect example of Big Insurance trying to make things absurdly complicated to avoid paying what they owe,” said GS Labs partner Kirk Thompson in a statement. The company calls the allegations in the Premera suit “patently false” and “a blatant attempt to disregard the CARES Act and the intentions of Congress.”

On Oct. 29, GS filed suit against Medica, a health insurer in Minnesota, alleging failure to pay $10 million in COVID-19 testing charges.

Under the two federal laws passed at the start of the pandemic, insurers have to pay the full list prices for COVID-19 testing and related services. They can negotiate those prices with providers that are in network but not with those that are out of network, the latter of which can become onerous for payors, said Loren Adler, the associate director of the University of Southern California-Brookings Schaeffer Initiative for Health Policy.

“For out-of-network tests, insurers have to pay any ‘cash price’ that a lab or hospital lists on its website, without any restrictions,” Mr. Adler said. Medicare pays $50 for a standard

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

15

COVID-19 polymerase chain reaction test, but most hospitals and labs are charging much more than that, he added.

The Kaiser Family Foundation (KFF) searched COVID-19 test prices for 102 hospitals in 50 states in early 2021 and found 203 different prices ranging from $20 to $1,419 per test. Nearly half of hospitals charged between $100 and $199, KFF found.

Hospitals that administer COVID-19 tests also can bill for specimen collection and office visits. Only 30 of the hospitals that KFF sampled posted those charges, which ranged from $18 to $240, the foundation reported.

Further complicating the debate over COVID-19 test prices are loopholes in the CARES Act and FFCRA that some COVID19 test providers can leverage, said Cynthia Cox, a vice president at KFF and the director of the Peterson-KFF Health System Tracker. For example, insurers can deny claims or impose cost sharing on people who are tested for COVID-19 but have not experienced symptoms or had known exposures to the virus.

The feds released guidance early this year stating that insurers must fully cover testing of asymptomatic people, but there are still some notable exceptions, Ms. Cox said. “There are starting to be more situations where COVID-19 testing is required by schools, employers or for travel,” she said. “For this routine screening, insurers can say, ‘Sorry, that’s not medically necessary, so we’re not going to pay for any of it, or we’re only going to pay part of it.’”

Such refusals to pay for testing could increase as prices continue to rise. AHIP (America’s Health Insurance Plans), a national association of health insurers, surveyed members over the summer to find out what they’re being charged for COVID-19 testing and concluded in a report that price gouging “continues as a significant problem.” The survey found that in-network providers were charging $130 on average for COVID-19 tests.

More than half of out-of-network providers charged $185 or more per test in March 2021, which was about 12% more than they charged a year before, AHIP reported. The share of tests that cost 50% or more than the average commercial price has doubled to 36% since the start of the pandemic, according to the study.

The share of “egregiously priced COVID tests,” those costing $390 or more, fell from 12% in spring 2020 to 7% at the start of this year, likely reflecting the fact that the share of tests performed at health clinics—many of which would be charging negotiated in-network prices—has increased, AHIP said.

Up to Lawmakers Still, AHIP called on lawmakers to stem COVID-19 test overcharges. “COVID-19 testing price gouging threatens the progress we are making against this deadly virus, and we urge the administration, Congress and policymakers to take deliberate steps to ensure testing is accessible and affordable for all Americans,” said Jeanette Thornton, a senior vice president at AHIP, in a statement.

16

IDSE.NET

Johns Hopkins public health researchers wondered whether there is a correlation between surging demand for COVID19 testing and an increase in test prices. So, they examined more than 182,000 insurance claims filed by 2,324 providers between March and July 2020. They found no correlation between state-level testing rates and charges. (J Gen Intern Med 2020 Sep 15. doi:10.1007/s11606-020-06198-y).

But they found a “huge variation” in charges depending on the type of facility where the testing occurred and the state where it was based, Dr. Bai said. For example, independent laboratories charged on average $140.41 for a COVID-19 diagnostic test, while hospital outpatient clinics charged $168.87 on average. The average price on the state level for diagnostic testing ranged from a low of $64.98 in Utah to a high of $505.65 in Washington, D.C. The limited negotiating power granted to insurers likely fueled those differences, Dr. Bai said. “Some providers charged high amounts because they could,” she said.

The insurance industry continues to push lawmakers to find solutions to COVID-19 test price gouging. The Blue Cross Blue Shield Association (BCBSA) asked policymakers to allow the Centers for Medicare & Medicaid Services to establish a “fair price” for COVID-19 testing, a spokesperson said in an email. That would move “away from posted cash prices for out-of-network facilities, which often have little bearing on the actual costs of the test or their administration,” BCBSA said.

So far, there have been few reports of high COVID-19 test prices being passed along directly to consumers, but that could change as more asymptomatic people seek testing.

Some employers are mandating regular testing for employees who refuse to get vaccinated, for example. “Once employers impose these kinds of requirements, employees are exposed to the risk of high COVID-19 test prices,” Dr. Bai said.

Additional protection for consumers is coming in 2022 with the enactment of the No Surprises Act, a federal law that will make it illegal to pass surprise out-of-network bills along to patients. Under the law, any patient who unknowingly receives out-of-network care will not be responsible for cost sharing beyond their in-network rate. So, if an in-network hospital performs a COVID-19 test that’s sent to an out-of-network lab for processing, insurers will only be able to impose cost sharing on patients at their contracted in-network rates.

Even with those consumer protections, high COVID-19 test pricing could ultimately have a negative long-term impact on health care costs, Mr. Adler said, because insurers will likely pass the costs along to patients by hiking premiums, or in the case of employer-sponsored health plans, slashing wages. “If insurers pay more for these tests, those costs will ultimately ■ be borne by consumers and patients,” he said.

Mr. Adler, Dr. Bai and Ms. Cox reported no relevant financial disclosures.

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MASKING IN SCHOOLS: What Is the Evidence?

BY KATE O’ROURKE

S

tate school systems have taken different approaches to the CDC’s recommendations for universal indoor masking by all students (ages 2 years and older), staff, teachers and visitors to K-12 schools, regardless of COVID-19 vaccination status.

According to Burbio, a data monitoring service, states such as California, Illinois and New York have mandated masks in schools; states such as Oklahoma and Utah have banned masks in schools; states such as Arizona, Florida, Texas and Utah have banned mask mandates in schools and then had these bans overturned; states such as Nevada have mandated masks for schools in counties with more than 100,000 people or with a schoolwide COVID-19 outbreak; and other states, such as Colorado, Georgia and Maine have issued no policy, leaving it to local regulators to decide.

So, what do we know about masks in schools?

According to Jade Fulce, a spokesperson for the CDC, as COVID-19 cases began increasing nationally in mid-June 2021, driven by the delta variant, protection against exposure remained essential in school settings. She said the CDC recommends universal indoor masking in the school setting because of the highly transmissible nature of the delta variant, the mixing of vaccinated and unvaccinated people in schools, the fact that not all children are eligible for vaccination, and the low levels of vaccination among youth who are eligible. As of Dec. 12, 1.3% of children 5 to 11 years and 6.5% of children 12 to 17 are fully vaccinated against COVID-19.

Vaccination rates among educators appear to be higher. The National Education Association, the nation’s largest union representing nearly 3 million educators, said 90% of members have received at least one COVID-19 vaccine as of Sept. 9.

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“I strongly agree with the CDC guidance that recommends masking in schools because masks have been shown to decrease COVID-19 transmission in the school setting across several studies. This should be part of [a] multipronged, layered approach to protect children and school staff from COVID-19 infection, including vaccination, physical distancing, ventilation, testing, cleaning and disinfection,” said Ishminder Kaur, MD, an assistant professor of pediatrics in the Division of Infectious Diseases at the David Geffen School of Medicine and the medical director of the Pediatric Antimicrobial Stewardship Program at UCLA Mattel Children’s Hospital, in Los Angeles.

In September, the CDC released three studies in its Morbidity and Mortality Weekly Report that highlighted the importance of using layered prevention strategies, including universal masking to stop the spread and minimize disruptions to school operations for safe in-person education (MMWR Morb Mortal Wkly Rep 2021;70[39]:1372-1378). These studies found that school districts without a universal masking policy in place were more likely to have COVID-19 outbreaks.

Nationally, counties without masking requirements saw the number of pediatric COVID-19 cases increase nearly twice as quickly during this same period. One report from Arizona revealed that schools in two of the state’s most populous counties were 3.5 times more likely to have COVID-19 outbreaks if they did not have a mask requirement at the start of school compared with schools that required universal masking on the first day (MMWR Morb Mortal Wkly Rep 2021;70[39]:13721373). Another report that looked at national data found that during the two weeks following the start of school, the average change in pediatric COVID-19 case rates was lower among

counties with school mask requirements (16.32/100,000 per day) compared with counties lacking school mask requirements (34.85/100,000 per day) (MMWR Morb Mortal Wkly Rep 2021;70[39]:1377-1378). A third report studied COVID-19– related school closures and found that despite an estimated 1,801 school closures so far this school year, 96% of public schools have been able to remain open for full in-person learning (MMWR Morb Mortal Wkly Rep 2021;70[39];1374-1376).

According to the CDC, the continued focus on providing students with a safe environment for in-person learning is one of the main priorities for the CDC’s COVID-19 guidance, and can be best achieved by following a layered prevention strategy that includes both vaccination and masking.

While some have argued that face masks can hinder emotion recognition and interpersonal connection (PLoS One 2021;16[9]:e0257740; Front Public Health 2020;8:582191), and are bothersome in that they can muffle speech and fog up eyeglasses, still most argue that masking in schools is the correct thing to do.

“Overall, the benefits of masking really outweigh the potential risks of delays in social and language development,” said Michelle Durham, MD, MPH, a clinical associate professor of psychiatry at Boston University School of Medicine and a physician specializing in pediatric and adult psychiatry at Boston Medical Center.

Tina Tan, MD, an attending physician in the Division of Infectious Diseases at Ann & Robert H. Lurie Children’s Hospital of Chicago, and a professor of pediatrics at Northwestern University Feinberg School of Medicine, said she absolutely agreed with the CDC guidance that recommends masking in schools. “We know that masking in addition to other protective mitigation protocols works to decrease transmission and spread of COVID-19,” she said.

“Masking in schools is also important because the majority of children in the K-12 space are not vaccinated; there remain many teachers and staff who are not vaccinated; and the COVID-19 delta variant continues to circulate in the community,” and omnicron cases are increasing.

“There is very strong evidence that masks reduce the transmission of not only COVID-19, but also other respiratory viruses in children,” Dr. Tan added. “States that do not have mask mandates in schools have higher rates of COVID cases in the overall population and in the school setting than those that have mask mandates in place.”

Dr. Tan said the COVID-19 delta variant is different from other variants in that it is significantly more transmissible.

“COVID infection in children tends to be milder with cough and fever being the most common symptoms, and [children]

are less likely to die compared with adults. However, children can become severely ill with COVID, especially those younger than 24 months of age, children with underlying conditions, and Black and Latino children. Because of the increased transmissibility and the significant increase in the number of children infected, this has resulted in a significant increase in children requiring hospitalization for their COVID disease.”

Some people have questioned whether continuous use of face masks by teachers and other adults may harm their children’s speech and language development, the American Academy of Pediatrics (AAP) points out that visually impaired children develop speech and language skills at the same rate as their peers. According to the AAP, there is no known evidence that use of face masks interferes with speech and language development or social communication. Plus, the AAP argued, children can still get plenty of face time at home with maskfree family members.

According to a study by psychologists at the University of Wisconsin-Madison, the proliferation of face coverings to keep COVID-19 in check isn’t keeping kids from understanding facial expressions (PLoS One 2020;15[12]:e0243708). The study concluded that children were still able to make accurate inferences about emotions, even when parts of the faces were covered, and that masks are unlikely to dramatically impair children’s social interactions in their everyday lives. Other studies have shown a shift has occurred in how people perceive faces such that the more people are interacting with others who are wearing masks, the more they have learned to focus on visual cues from the eye area of the face (PLoS One 2021;16[10]:e0258470).

The United States differs from England in that most children in England are not mandated to wear masks. It has been argued that one reason that Britain can take such risks is nearly all adults older than 65—a high-risk population—have been fully vaccinated and this is not the case in the United States. One of the biggest reasons for masking children is their possibility of infecting high-risk populations. “The benefits of masking up protect a lot of people in the community, in the family, and in any of the places we are going, and that is a good thing to do from a public health standpoint. The consequence of not masking can be very deadly as we have seen over the course of the pandemic,” Dr. Durham said. In England, cases surged this fall and are surging again this winter, more so the ■ United States and many other countries.

Only 1.3% of children 5-11 are fully vaccinated against COVID-19.

Drs. Durham, Kaur and Tan, and Ms. Fulce reported no relevant financial disclosures.

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

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Managing Post-Transplant Refractory/Resistant CMV Older antivirals for these severely immunocompromised patients are associated with serious toxicities; New agents look like better options.

BY CONNI B. KOURY

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ytomegalovirus (CMV) infection is the most common infectious complication in solid organ transplant and hematopoietic stem cell transplant (HSCT) recipients.

The incidence varies depending on the type of transplant, CMV serostatus of the donor and recipient, and the level of immunosuppression. Overall, about one-third of transplant patients will have CMV infection, which when left untreated, can progress to clinically severe and sometimes life-threatening disease. CMV infection more than doubles the risk for transplant loss and mortality, according to studies (Virology [Auckl] 2019;10:1178122X19840371. doi: 10.1177/1178122X19840371. eCollection 2019).

Resistant, Refractory Infection Some post-transplant CMV patients will develop infection or disease that is refractory and/or resistant (R/R) to previous anti-CMV treatment. Outside of CMV retinitis, there had been no FDA antiviral drugs approved for post-transplant CMV infection and disease, including R/R CMV. These patients, therefore, have been treated empirically with existing antivirals that include the IV agents ganciclovir, foscarnet and cidofovir, and oral valganciclovir. The older agents have significant challenges to their use, including toxicities, that may lead to premature discontinuation, predisposition to development of resistance, and ultimately failure to control CMV infection.

One agent, letermovir (Prevymis, Merck), was approved in

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2017 for CMV prophylaxis. It has a favorable safety profile and is available in IV and oral dosage forms, but is only indicated for adult recipients of an allogeneic HSCT. “Fortunately, with appropriate use of antiviral therapy, both as prophylaxis and as treatment, R/R disease is rare,” said Camille Nelson Kotton, MD, FIDSA, FAST. “But when it does occur, there is significant morbidity and mortality associated with it as these patients are the most vulnerable and immunocompromised and at the highest risk for complications. It is a dreaded and challenging situation,” said Dr. Kotton, who is the clinical director, Transplant & Immunocompromised Host Infectious Disease Group, Infectious Diseases Division at Massachusetts General Hospital, and an associate professor at Harvard Medical School, both in Boston. She presented an overview of posttransplant R/R CMV infection and unmet needs to the FDA’s Antimicrobial Drugs Advisory Committee (ADAC) in October, when they gave the nod to maribavir (Takeda), which is now approved to treat refractory CMV infection and disease.

Patients with R/R CMV have increased morbidity and mortality compared with patients who do not have R/R infection (Transplantation 2016;100[10]:e74-80). The treatment options have historically involved switching from oral valganciclovir to ganciclovir, increasing the dose of ganciclovir, or switching to foscarnet or cidofovir. High-dose ganciclovir is poorly tolerated due to neutropenia/cytopenias; forcarnet is associated with a risk for serious renal toxicity and electrolyte abnormalities;

and cidofovir carries serious renal and ocular toxicity risks.

There is a significant unmet need for antiviral agents that are more effective, safer, more tolerable and easier to administer.

“Until now, as per the [CDC] guidelines, we would recommend either high-dose ganciclovir for mild to moderate disease. This, in my experience, does not work very well because many of the CMV mutations convey a high level of resistance to ganciclovir,” Dr. Kotton explained. “We’d have to use foscarnet, which has a high level of toxicity and requires hospitalization. Then you end up having to go among these treatments to see if something else is going to work better, but they all have the same framework of side effects and toxicities.”

Newer Antivirals Letermovir and maribavir work by unique mechanisms of action and are not associated with significant myelotoxicity or nephrotoxicity. Letermovir targets the subunit pUL56 of the terminase enzyme complex, thereby inhibiting the terminal phase of the virus life cycle (Clin Infect Dis 2021;73[1]:156-160).

When the FDA approved letermovir in 2017, for CMV prevention in CMV-seropositive HSCT recipients, it marked the first approval of a new anti-CMV agent since 2003.

In a pivotal phase 3 randomized, multicenter, double-blind, placebo-controlled study of adult CMV-seropositive people who had an allogeneic HSCT, patients were randomized 2:1 to letermovir or placebo and stratified by study site and high versus low risk (N=565) (N Engl J Med 2017;377[25]:24332444). Letermovir significantly lowered the risk for clinically significant CMV infection compared with placebo through week 48. Fewer patients in the letermovir arm (37.5%; 122/235) compared with the placebo arm (60.6%) developed significantly clinical CMV infection (defined as CMV disease or CMV viremia that required preemptive treatment), discontinued treatment or required an antiviral for CMV infection through week 24 post-transpant (P<0.001), the primary end point. Due to the agent’s specificity to CMV, additional prophylaxis would be required to prevent herpes simplex virus (HSV).

Maribavir is a competitive inhibitor of adenosine triphosphate binding to pUL97, a protein kinase essential for viral replication, and maribavir is now approved for R/R posttransplant patients. It shows antiviral activity against CMV, but not HSV 1 and 2, varicella-zoster virus, human herpesvirus-6 (HHV) and HHV-8 (Antiviral Res 2019;163:91-105). The ADAC unanimously recommended the approval of maribavir for patients with R/R post-transplant CMV, both those with and without genotypic resistance to the standard-of-care antivirals. It is currently the only agent approved for posttransplant CMV infections in R/R patients.

“I think many of us will very quickly switch away from foscarnet with the associated high toxicity, need for blood work to monitor electrolytes and creatinine, and sometimes three weeks or more in the hospital. All of this is phenomenally

challenging for the patient and very expensive,” Dr. Kotton said.

The safety and efficacy of maribavir have been established across multiple phase 2 and 3 studies involving more than 1,500 subjects, according to data the company presented to the FDA advisory panel. The pivotal phase 3 study included a total of 352 patients with R/R CMV who were treated with 400 mg of maribavir twice daily (n=235) compared with those receiving investigator-assigned therapy (IAT) with ganciclovir, valganciclovir, cidofovir or foscarnet.

The primary end point, endorsed by the FDA, was confirmed CMV viremia clearance at week 8, according to Martha Fournier, MD, the executive medical director, Clinical Sciences, Takeda, who presented the efficacy data. The key secondary end point was a composite of CMV viremia clearance and symptom control. The comparator arm was designed to mimic real-world care, she said. Investigators were allowed to use one or two of the available CMV antivirals; however, combined therapy with cidofovir and foscarnet was prohibited, Dr. Fournier noted.

Maribavir demonstrated superior CMV clearance versus IAT at week 8, (56% vs. 24%; P<0.001). Dr. Fournier showed sensitivity analyses to support the robustness of the primary end point. These data included the finding that CMV viremia clearance at week 8 or at the time of study discontinuation or treatment switch was 60% in the maribavir group compared with 43.6% in IAT group (P=0.001). CMV viremia clearance at any time during treatment was 74% in the study group versus 52.1% in IAT (P<0.001), and CMV viremia clearance at week 8 regardless of alternate CMV antiviral strategy was 59.1% in maribavir-treated subjects versus 42.7% in IAT subjects (P=0.002). Dr. Fournier said results were consistent across subgroups. In the key secondary end point, the maintenance of viremia clearance and symptom control was 19% for maribavir compared with 10% in the IAT group (P=0.013).

Dr. Kotton noted that maribavir has an excellent safety profile as seen in the phase 3 study and previous studies, with the most common side effect being dysgeusia. Because it was well tolerated, patients were able to stay on maribavir 50% longer than with standard of care.

“Having led creation of international consensus guidelines on CMV for solid organ transplant for over a decade and a half, and understanding the intrinsic challenges in the field—especially with resistant/refractory disease—I am thrilled to have new therapeutic options,” Dr. Kotton said. “For the first time, we might be able to consider clinical trials involving combination therapy, especially in higher-risk situations. Anytime we have a new antiviral agent in the CMV sphere, we are very happy and excited as this is sure to be a game changer, and hopefully will save lives and improve the overall quality of ■ many lives as well.”

Dr. Fournier is an employee of Takeda Dr. Kotton is a consultant to Merck, Takeda, Roche Diagnostics and Hookipa.

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

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Do Nonantibiotic Medications Increase The Risk for C. difficile Infections?

BY DAVID WILD

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wo recent studies have shed light on the impact of nonantibiotic medications on the risk for Clostridioides difficile infection (CDI). In one study, researchers found a twofold increased risk for CDI during proton pump inhibitor (PPI) use, with a lingering risk up to one year after PPI discontinuation, while a separate study found no association between use of nonsteroidal anti-inflammatory drugs (NSAIDs) and CDI. “Studies like these are important as we seek to understand environmental influences on gut microbiota which might increase risk for C. difficile infections,” said CDI expert Colleen Kelly, MD, an associate professor of medicine in the Division of Gastroenterology at the Warren Alpert Medical School of Brown University, in Providence, R.I., who was not involved in the research.

Malin Inghammar, MD, an associate professor of infection medicine at Lund University, in Sweden, and his co-investigators studied the link between community-acquired CDI and PPIs (Clin Infect Dis 2021;72[12]:e1084-e1089). They noted that prior observational studies have identified a link between PPI use and CDI risk, but that association has remained controversial “due to the absence of data from randomized controlled trials, considerable variability between studies, and insufficient adjustment for confounding in previous studies.”

To address these shortcomings, the researchers examined nationwide registry data in Denmark and found 3,583 incident episodes of CDI that occurred between 2010 and 2013 in patients who were not hospitalized within 12 weeks before infection and who did not have a positive C. difficile test in the prior eight weeks. The CDI cases were identified through a positive culture, molecular assay or toxin test, and by definition.

Their data set also included C. difficile test results in the Danish Microbiology Database, prescription information and patient characteristics, allowing them to perform analyses

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controlling for the effects of chronic disease, genetics, socioeconomic status, hospital stay, and antibiotic and corticosteroid use.

The researchers reported that 964 cases of CDI were diagnosed in patients during PPI treatment; 324 occurred in patients who had discontinued treatment within the previous six months; and 123 occurred six to 12 months after PPI cessation. The remaining patients had not received a PPI during or the year before CDI onset.

Dr. Inghammar and his colleagues found the risk for CDI was more than twice as high among current PPI users than for individuals not receiving PPIs (adjusted incidence rate ratio [IRR], 2.03; 95% CI, 1.74-2.36). The PPI-CDI association persisted, with a 54% higher risk for CDI during the six months after PPI cessation (adjusted IRR, 1.54; 95% CI, 1.31-1.80) and a 24% higher risk in the six to 12 months after PPI cessation (adjusted IRR, 1.24; 95% CI, 1-1.53).

Sex, age and hospitalization one or more years before CDI did not affect the risk for infection in PPI users, the authors found.

“This large study with thorough control for confounding significantly adds to the body of evidence that increased risk of CDI, even in the community setting, should be considered when prescribing PPIs,” the investigators noted.

Although Dr. Kelly said these results confirm prior findings, the observational nature of the study is a limitation. She also said the observed increased risks for CDI with PPIs “are extremely small in comparison with known CDI risk factors, and discontinuing antisecretory therapy may leave patients at risk of harm by leaving acid-related conditions, such as peptic ulcer disease and reflux esophagitis, untreated.”

Dr. Kelly emphasized that “when used for appropriate indications, the benefits of PPI are clear, and therapy should not be interrupted in patients being treated for CDI or at higher risk of this infection.”

In another study, Adam Ressler, MD, from the Department of Internal Medicine, Division of Infectious Disease, at the University of Michigan, in Ann Arbor, and his co-investigators identified 628 CDI cases from a previously published cohort continued on page 33

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Will Restrictions At the Border Lead To IG Shortages?

BY GINA SHAW

F

or well over a year, pharmacists, physicians and patients have been dealing with sporadic shortages of immune globulin (IG) products, as the COVID-19 pandemic led to a significant decline in donations of the blood plasma that is the primary component of these therapies.

According to the Plasma Protein Therapeutics Association (PPTA), plasma donations fell by 20% in 2020. Because the fractionation process that turns donated plasma into IG can take nine to 12 months from “needle to needle,” they expected the shortages to be much worse, but the IG supply in the United States remained relatively robust compared with other countries.

A lack of cross-border plasma donations is not helping.

Because Mexico does not allow monetary compensation for plasma donations, many Mexican citizens cross the border regularly to donate plasma in the United States. On June 15, the U.S. Customs and Border Patrol (CBP) agency announced that it was stopping that practice and would no longer permit Mexican citizens to cross the border on temporary visas to sell blood plasma.

“Selling plasma constitutes labor for hire in violation of B-1 nonimmigrant status, as both the labor (the taking of the plasma) and accrual of profits would occur in the U.S. with no principal place of business in the foreign country,” the agency said in a statement.

The U.S.–Mexico border was closed to nonessential travel through much of the pandemic, so plasma donation centers at the border already experienced significant declines in donations, said Matthew Hotchko, PhD, the president of the Marketing Research Bureau, which supplies market data and intelligence on the global blood and plasma industry. “There

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had already been a steep dropoff. I don’t have exact figures, but I believe somewhere between 70% to 80% of plasma donors coming from Mexico had already dropped out of the regular donor pool because of the challenge of getting across the border.”

Before the pandemic, the approximately 40 border centers contributed about 10% to 12% of total U.S. plasma collections, with most coming from those living in Mexico, Dr. Hotchko said.

He estimated that between the border closures and the new CBP ruling, plasma donations at border centers have been reduced by more than half. “I would say that probably about 3% to 4% of total plasma collections in the U.S. are now coming from those border centers after the recent CBP policy change.”

Organizations that advocate for patients with primary immunodeficiencies (PIs), such as the Immune Deficiency Foundation, have urged the Biden administration to rethink this policy change. “This action could reduce the plasma supply used to make lifesaving therapies by 5% to 10%,” said IDF vice president of public policy Lynn H. Albizo, JD, in a letter sent in June, to Health and Human Services Secretary Alejandro Mayorkas.

“If these changes are implemented, we will see further pressure on the supply of plasma that will jeopardize the health of Americans with PI and other conditions.”

The PPTA, which represents manufacturers of IG and other plasma products such as CSL Behring, Grifols and Takeda, also issued a statement. “The change by U.S. Customs and Border Protection to limit the ability of people to cross the border to donate plasma is bad policy that risks American lives. Nearly 125,000 people in the U.S. with rare diseases, as well as countless others facing trauma and emergency medical needs every day, rely on medicines that are only available because of the com‘I would have said [plasma mitment of dedicated plasma donors, and this new policy collections would stabilize] by end risks hindering the availability of these lifesaving medicines.”

As of Dec.15, the policy was still in place. “PPTA conof this year but the delta variant has tinues to be actively engaged with policymakers and the thrown a monkey wrench into that, administration to reverse CBP's policy change, as do sevand it might be mid-2022 before we eral national and international patient advocacy groups see supply growing again.’ and PPTA member companies. PPTA feels strongly that —Matthew Hotchko, PhD this restriction risks patients' lives by stopping dedicated

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individuals from Mexico from donating plasma, which is the unique starting material for lifesaving plasma-derived therapies. The longer this policy change remains in effect, the greater the likelihood that more than 125,000 U.S. patients (and countless others who rely on these therapies every day via emergency medical needs) will experience challenges accessing the treatments that enable them to live full, healthy lives,” PPTA told Infectious Disease Special Edition in an email.

The Gorilla in the Field The United States is the 1,000 lb gorilla of the plasma therapeutics field, so supplies affect it less than other countries. “The reimbursement for a gram of plasma in the United States is so much more than in any other country, the manufacturers moved all that they possibly could from the rest of the world into the U.S. to meet that demand, because economically that just makes the most sense for them,” said Stacey Ness, PharmD, the vice president of clinical services at Managed Health Care Associates, and president of the Immunoglobulin National Society (IgNS).

Not only does the United States pay more for plasma products than other countries, but it supplies most of it as well. “The U.S. supplies approximately 70% of the source plasma used to manufacture plasma therapies for the entire world,” said Peter Jawoski, PhD, an associate teaching professor in strategy, ethics, economics and public policy at Georgetown University’s McDonough School of Business, in Washington, D.C., and an advocate of compensation for plasma donors. “Virtually the entire world is dependent on the U.S.” There are U.S. shortages of certain products. (A complete list is regularly updated at the ASHP [https://bit.ly/33lVHtkIDSE]), but many foreign supply issues are dire. “The reduction in plasma collections has resulted in countries with lower prices for plasma products not getting enough supply, including many European countries and many other countries around the world,” Dr. Hotchko said.

in Redaccion Medica on July 12, Teresa Lluch, the vice president of GBS/CIDP Espana, reported that La Paz Hospital, in Madrid, had to suspend all IG treatments, while La Fe Hospital, in Valencia, was receiving 30% of its normal IG supply.

The National Health Service in the United Kingdom, which reinstated plasma donations in April 2021 after banning them in 1998 due to fears of Creutzfeldt-Jakob disease, initiated its first national campaign calling for plasma donations. “They are perilously short of supply,” Dr. Jaworski said.

The CBP order just makes the current trend even more negative, Dr. Hotchko said. “Countries that are struggling now will struggle even more, but the U.S. will still have a prioritized supply because of our pricing and because we are the location of most of the source plasma. We still may see lowered supplies in the U.S. if the suppliers cannot redirect enough supply to the United States for various reasons, but I don’t see that, yet.”

Although this country has avoided severe shortages so far, Sohail Masood, PharmD, the founder and CEO of KabaFusion, which specializes in IV and subcutaneous IG therapies and operates 28 accredited home infusion specialty pharmacies nationally, thinks that is likely to change. “We do still have ample supplies of IG now, but if the border restrictions continue, I think it’s unavoidable that shortages will hit us in the U.S., as well. It will tend to impact companies that are more dependent on the border centers first.”

Dr. Hotchko predicted that collections will rebound with time, however. “I would have said by the end of this year but the delta variant has thrown a monkey wrench into that, and it might be mid-2022 before we see supply growing again,” he said. “There are now more places to donate and a lot more marketing with higher donor compensation offered. There were about 100 new centers added nationwide last year, and there will be about the same number added by the end of this year.”

Because the cost of collecting plasma is also going up, including increased remuneration to donors, Dr. Hotchko also predicted rising prices for IG therapies. “They are likely to rise faster than inflation, probably around the 3% to 5% per year ■ range in the U.S., and faster in other markets.”

Before the pandemic, about 10% to 12% of total U.S. plasma collections came from border collection centers—and most of the donors were from Mexico.

‘The Canary in the Coal Mine’ Spain, which began reporting shortages of IG products in early July in local and regional news outlets, may be the “canary in the coal mine” for other countries, Dr. Jaworski suggested. The newspaper La Razon reported on July 5, 2021, that hospitals were significantly lowering doses of IG products given to patients with chronic neuropathies to preserve supplies for those with PIs. In an opinion piece published

The sources reported no relevant financial disclosures beyond their stated employment/affiliation.

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

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P

remedicating children with Kawasaki disease (KD) using hydration and agents such as acetaminophen, antihistamines, histamine 2 receptor antagonists or corticosteroids to prevent infusion-related reactions associated with IV immune globulin (IVIG) may not necessarily be helpful, according to a recent study by pharmacists from Jersey Shore University Medical Center, in Neptune, N.J. The researchers reviewed records for 66 children with KD who were given a total of 81 IVIG administrations between January 2014 and June 30, 2019. This included 42 boys and 24 girls, ages 4 months to 15 years. Sixty-four patients (97%) were premedicated prior to infusion. However, 17 in 66 patients (26%) experienced IVIG-related adverse events, most commonly chills, vomiting and spiking fever. Despite appropriate medication management, five patients (7.6%) developed coronary abnormalities (Pediatr Allergy Immunol 2021;32[4]:750-755).

There were strong patterns in premedication, said lead study author Elaine Liu, PharmD, a PGY-2 infectious diseases pharmacy resident at Hartford Hospital, in Connecticut.

She was a pharmacy student at the Ernest Mario School of Pharmacy at Rutgers, the State University of New Jersey, at the time of the study, and continued her PGY-1 training at the N.J. medical center. The most common premedication regimen seen in the study was a combination of acetaminophen and diphenhydramine, which accounted for 65% of regimens used and was given prior to 63% of IVIG infusions.

Other commonly used regimens were diphenhydramine alone, and a triple combination of acetaminophen, diphenhydramine and famotidine. Of the 25 documented adverse events, 16 were immediate, occurring within six hours of starting IVIG, and nine were delayed, occurring after six hours.

Overall, she said, patients demonstrated appropriate clinical outcomes, with an average fever duration of eight days and average hospital stay of about four days, similar to national data.

Although premedication was not shown to adversely affect patient outcomes, Dr. Liu said, “we didn’t really observe much

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of a benefit when looking at a reduction in adverse events, at least compared with historically reported incidences of adverse event profiles with IVIG” of about 20%.

More Studies Needed Due to a lack of formal guidelines or recommendations on premedication regimens prior to IVIG therapy, more studies are needed, said senior study author Anita Siu, PharmD, BCPS, the neonatal and pediatric pharmacy clinician at K. Hovnanian Children’s Hospital at Jersey Shore, in Neptune, and a clinical professor of pharmacy practice and administration at the Ernest Mario School of Pharmacy, in Piscataway.

Published studies on the use of premedication agents have been conflicting, Dr. Siu said. Ultimately, the efficacy of premedication continues to pose a clinical question, she added.

Secondary consequences of premedication, such as unnecessary drug exposure, IVIG treatment delays and increased costs, are issues to be considered in the face of what could be a questionably beneficial yet widely used practice, she said. “We really hope that more larger randomized controlled trials will come out of this.”

Dr. Liu added, “This encourages us to reevaluate our practices and supports the need to have further large, potentially prospective studies, given that the literature available right now is so mixed. Ours was a single-center study, but there are many other patient demographics and a lot of other institutions. We would love to see more data arise to get a bigger picture of overall practice and really discern if there is a benefit in this strategy at all.”

In the pediatric population, Drs. Liu and Siu said, adverse events from IVIG occur in an estimated 1% to 40% of patients (Eur Ann Allergy Clin Immunol 2017;49[1]:11-14). Other than premedication, common mitigation strategies include slowing the infusion rate, switching from IV to subcutaneous immune globulin, changing to another IG product or discontinuing ■ infusion.

The authors reported no relevant financial disclosures.

New Paradigms in HIV Therapy

BY GINA SHAW

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ear the end of the first act of Jonathan Larson’s iconic musical “Rent,” which opened on Broadway in New York City in 1996, a beeper goes off loudly. Mimi, an exotic dancer struggling with heroin addiction, tells her date (who unknown to her also has HIV), “AZT break!”

Twenty-five years later, living with HIV no longer requires constant reminders to take multiple daily pills with potentially debilitating side effects. These and other advances represent a paradigm shift in HIV management, according to interviews with HIV experts.

“The biggest news in HIV management isn’t just how good our therapies are—they are great. But we’ve been there for a long time,” said Eric Daar, MD, the chief of the Division of HIV Medicine at Harbor-UCLA Medical Center in Los Angeles. For virtually everyone who starts taking their HIV regimen as prescribed, their viral load will drop to undetectable levels within six months, maintaining their health and preventing transmission of the virus to sexual partners, Dr. Daar noted, citing data from the National Institute of Allergy and Infectious Diseases (bit.ly/3jHIDnV).

What is new, he said, is how easy the latest drugs are to take. “Our current regimens are incredibly well tolerated, very safe, with limited drug-drug and drug-food interactions [JAMA 2020;324(16):1651-1669]. They also come in increasingly smaller and smaller single tablets that need to be taken only once a day, and we have several regimens, so those who are unlucky to have some side effects can usually go on to one of the others with all the same advantages. It just continues to get easier and easier for people to take these medications.”

For most people with newly diagnosed HIV, clinicians should start by reviewing the latest information from the Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents (updated June 2021; bit.ly/37TXbKi).

The guidelines recommend starting treatment with two nucleoside reverse transcriptase inhibitors administered in combination with a third active antiretroviral (ARV) drug from one of three drug classes: an integrase strand transfer inhibitor (INSTI), a nonnucleoside reverse transcriptase inhibitor, or a protease inhibitor with a pharmacokinetic enhancer. (See box for more details.)

The latest guidelines removed raltegravir (RAL)-based regimens as initial therapy for most people because RAL has a lower barrier to resistance than bictegravir (BIC) and dolutegravir (DTG), and RAL-based regimens have a higher pill burden than other INSTI-based regimens. In addition, new study data (Lancet 2021;397[10281]:1276-1292) showed the risk for neural tube defects associated with DTG use during conception is much lower than previously understood, so women of childbearing age no longer need to choose RAL over DTG.

“We’ve known for several years that people whose viral load is already suppressed on a three-drug regimen can switch to two, but now it is possible even in people starting therapy for the first time,” Dr. Daar said. “Now, it’s open to debate just how big an advantage this is. Yes, fewer drugs mean smaller pills, fewer interactions and less toxicity, but most of the other first-line therapies have pretty small pills, few interactions and few side effects already. Cost is another issue. While that’s not necessarily defined by how many drugs are in a regimen, DTG/3TC did come in at a lower cost than other standard regimens.” A 2016 analysis found that DTG/3TC could save more than $500 million in antiretroviral treatment (ART) costs in the United States over five years (Clin Infect Dis 2016;62[6]:784-791).

One of the most recent paradigm shifts in HIV therapy is the option for a long-acting regimen. In January 2021, the FDA approved cabotegravir and rilpirivine (CAB-RIL; Cabenuva, ViiV Healthcare/Janssen)—the first long-acting, once-monthly injectable HIV treatment.

“This simplifies therapy in many ways,” said Roger Bedimo, MD, the chief of the Infectious Diseases Section at the VA North Texas Health Care System. “It addresses issues such as pill fatigue and the daily stigma of oral medications, and because it is administered by a health care provider, it offers ease of documenting adherence.”

The once-monthly treatment cycle for CAB-RIL might even be extended to once every two months soon, Dr. Daar said. The FDA is considering a supplemental New Drug Application based on results from the phase 3b ATLAS-2M study. According to the data, the antiviral activity and safety of the antiviral combination administered once every two months was noninferior to once-monthly administration (Lancet 2020;396[10267]:1994-2005). “That’s pretty amazing,” he said. “Patients will go from multiple pills a day, every day, to coming in six days a year and being assured that not only

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will your disease be suppressed, but you won’t transmit it to your partner.”

But there are limitations. Patients must first be virologically suppressed on a stable ARV regimen with no previous treatment failure, so this combination can’t be used as a first-line therapy or in treatment-resistant patients. There also is some inconvenience. “You have to come in to see your health care provider; it can’t be self-administered,” Dr. Daar said. In addition, “if you skip an injection, you’re at pretty big risk for developing resistance. Both drugs have pretty long half-lives, but one is significantly longer than the other.

Skipping a dose translates into using monotherapy, and we know that always selects for resistance.”

Other products are in the pipeline, including a subcutaneous agent that could be given at home once every six months. “That would be a home run, but we know you can’t do this with one drug, so you need to find another you can give every six months,” Dr. Daar said. “That’s the challenge: finding drugs that have promise to be long-acting, then figuring out how to pair them.”

Treatment Resistance Today’s ARV regimens are more effective and easier to take than ever, but there is still a small percentage of people living with HIV who are heavily treatment-experienced and are resistant to multiple classes of drugs (AIDS 2020;34[14]:20512059). “The proportion of people with HIV who have two or fewer drug classes available to them has declined significantly since 2000, and represents about 1% of the population today,” Dr. Bedimo said. “This group includes patients who are highly adherent but were started on nonsuppressive regimens that led to selection of highly resistant HIV—fortunately, this is a smaller group—and a somewhat larger group of patients who do not have multidrug resistance, but are nonadherent to therapy due to various challenges and still have viremia.”

There is also a pediatric cohort among treatment-resistant patients. A 2019 study of young people who recently transitioned from pediatric to adult HIV care found that 56% of participants had at least one incident of unsuppressed viremia in the year before the transition (Clin Infect Dis 2020;71[1]:133-141).

“Some of these new therapies may be able to reduce the treatment-resistant population further,” Dr. Bedimo said. “For the second group—those with nonadherence issues—we can try to simplify the pill burden, reduce frequency of dosing with long-acting injectables, or if vascular or renal tolerability is

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an issue, try to find agents that mitigate the impact to these organs. As our population ages, they have other non-HIV medications they have to take, so we also need to mitigate potential drug-drug interactions.”

For adherent patients who have failed second-line regimens and beyond, the challenges are even greater. “We can use past and current genotypic and phenotypic resistance and ART history in designing a new regimen,” Dr. Bedimo said. “These patients should be on at least two, and preferably three, fully active agents, but partially active drugs may be used when no other options are available as they can partially suppress progression even if they don’t totally suppress viremia.”

He cited several novel agents that either have been recently approved or are in the pipeline, as possible options. They include the monoclonal antibody ibilizumab (Trogarzo, TaiMed Biologics), approved in March 2018 for heavily pretreated adults with HIV, administered intravenously every two weeks and used in combination with other ARV drugs; and fostemsavir (Rukobia, ViiV Healthcare), a first-inclass HIV attachment inhibitor approved in July 2020, for people with extensive drug resistance. It’s a twice-daily oral therapy also used with other ARV drugs.

“New mechanisms of action and additional long-acting regimens are also coming soon,” Dr. Bedimo noted. For example, in early August, data on Gilead’s twice-yearly, long-acting injectable lenacapavir, the first HIV capsid inhibitor, were reported at the 11th International AIDS Society Conference on HIV Science in July. The phase 2 Capella study found that lenacapavir in combination with an optimized background regimen produced sustained virologic suppression in 81% of heavily pretreated patients at week 26. In the phase 2 Calibrate study (theprogramme.ias2021.org/Abstract/Abstract/2211), it also produced high rates of virologic suppression in treatmentnaive patients in combination with emtricitabine/tenofovir alafenamide (F/TAF).

“The group of people who need new options for treatment because of side effects or underlying resistance is not a huge number, but for those who are dealing with it, it’s their life,” Dr. Daar said. “These new options offer huge promise for these people, and it’s rewarding to see that companies have invested ■ in developing treatments for them.”

Dr. Bedimo reported that he serves on the advisory committees/boards for Merck, Theratechnologies and ViiV Healthcare. Dr. Daar reported financial relationships with Gilead Sciences, Merck and ViiV Healthcare.

DALVANCE® (dalbavancin) for injection, for intravenous use INDICATION AND USAGE Acute Bacterial Skin and Skin Structure Infections DALVANCE® is indicated for the treatment of adult and pediatric patients with acute bacterial skin and skin structure infections (ABSSSI) caused by designated susceptible strains of the following Gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillinresistant isolates), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus group (including S. anginosus, S. intermedius, S. constellatus) and Enterococcus faecalis (vancomycin susceptible isolates).

Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of DALVANCE and other antibacterial agents, DALVANCE 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.

CONTRAINDICATIONS DALVANCE is contraindicated in patients with known hypersensitivity to dalbavancin.

WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Serious hypersensitivity (anaphylactic) and skin reactions have been reported in patients treated with DALVANCE. If an allergic reaction to DALVANCE occurs, discontinue treatment with DALVANCE and institute appropriate therapy for the allergic reaction. Before using DALVANCE, inquire carefully about previous hypersensitivity reactions to other glycopeptides. Due to the possibility of cross-sensitivity, carefully monitor for signs of hypersensitivity during treatment with DALVANCE in patients with a history of glycopeptide allergy [see Patient Counseling Information].

Infusion-Related Reactions DALVANCE is administered via intravenous infusion, using a total infusion time of 30 minutes to minimize the risk of infusion-related reactions. Rapid intravenous infusions of DALVANCE can cause flushing of the upper body, urticaria, pruritus, rash, and/or back pain. Stopping or slowing the infusion may result in cessation of these reactions.

Hepatic Effects In Phase 2 and 3 clinical trials, more DALVANCE than comparator-treated subjects with normal baseline transaminase levels had post-baseline alanine aminotransferase (ALT) elevation greater than 3 times the upper limit of normal (ULN). Overall, abnormalities in liver tests (ALT, AST, bilirubin) were reported with similar frequency in the DALVANCE and comparator arms [see Adverse Reactions].

Clostridioides difficile-Associated Diarrhea Clostridioides difficile-associated diarrhea (CDAD) has been reported in users of nearly all systemic antibacterial drugs, including DALVANCE, with severity ranging from mild diarrhea to fatal colitis. Treatment with antibacterial agents can alter the normal flora of the colon, and may permit 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 antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.

If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile should be discontinued, if possible. Appropriate measures such as fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Development of Drug-Resistant Bacteria Prescribing DALVANCE in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

ADVERSE REACTIONS The following clinically significant adverse reactions are also discussed elsewhere in the labeling: t Hypersensitivity Reactions [see Warnings and Precautions] t Infusion Related Reactions [see Warnings and Precautions] t Hepatic Effects [see Warnings and Precautions] t Clostridioides difficile-associated Diarrhea [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of DALVANCE cannot be directly compared to rates in the clinical trials of another drug and may not reflect rates observed in practice.

Clinical Trials Experience in Adult Patients Adverse reactions were evaluated for 2473 patients treated with DALVANCE: 1778 patients were treated with DALVANCE in seven Phase 2/3 trials comparing DALVANCE to comparator antibacterial drugs and 695 patients were treated with DALVANCE in one Phase 3 trial comparing DALVANCE single and two-dose regimens. The median age of patients treated with DALVANCE was 48 years, ranging between 16 and 93 years. Patients treated with DALVANCE were predominantly male (59.5%) and White (81.2%).

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation Serious adverse reactions occurred in 121/2473 (4.9%) of patients treated with any regimen of DALVANCE. In the Phase 2/3 trials comparing DALVANCE to comparator, serious adverse reactions occurred in 109/1778 (6.1%) of patients in the DALVANCE group and 80/1224 (6.5%) of patients in the comparator group.

In a Phase 3 trial comparing DALVANCE single and two-dose regimens, serious adverse reactions occurred in 7/349 (2.0%) of patients in the DALVANCE single dose group and 5/346 (1.4%) of patients in the DALVANCE two-dose group.

DALVANCE was discontinued due to an adverse reaction in 64/2473 (2.6%) patients treated with any regimen of DALVANCE. In the Phase 2/3 trials comparing DALVANCE to comparator, DALVANCE was discontinued due to an adverse reaction in 53/1778 (3.0%) of patients in the DALVANCE group and 35/1224 (2.9%) of patients in the comparator group. In a Phase 3 trial comparing DALVANCE single and two-dose regimens, DALVANCE was discontinued due to

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

an adverse reaction in 6/349 (1.7%) of patients in the DALVANCE single dose group and 5/346 (1.4%) of patients in the DALVANCE two-dose group.

Most Common Adverse Reactions The most common adverse reactions in patients treated with DALVANCE in Phase 2/3 trials were nausea (5.5%), headache (4.7%), and diarrhea (4.4%).

The median duration of adverse reactions was 3.0 days in patients treated with DALVANCE. In the Phase 2/3 trials comparing DALVANCE to comparator, the median duration of adverse reactions was 3.0 days for patients in the DALVANCE group and 4.0 days in patients in the comparator group. In a Phase 3 trial comparing DALVANCE single and two-dose regimens, the median duration of adverse reactions was 3.0 days for patients in the DALVANCE single and two-dose group.

Table 1 lists selected adverse reactions occurring in 2% or more of patients treated with DALVANCE in Phase 2/3 clinical trials.

Table 1. Selected Adverse Reactions Occurring in ≥ 2% of Patients Receiving DALVANCE in Phase 2/3 Trials (Number (%) of Patients) Adverse Reactions DALVANCE Comparator* (N = 1778) (N = 1224) Nausea 98 (5.5) 78 (6.4) Diarrhea 79 (4.4) 72 (5.9) Headache 83 (4.7) 59 (4.8) Vomiting 50 (2.8) 37 (3) Rash 48 (2.7) 30 (2.4) Pruritus 38 (2.1) 41 (3.3) * Comparators included linezolid, cefazolin, cephalexin, and vancomycin.

In the Phase 3 trial comparing the single and two-dose regimen of DALVANCE, the adverse reaction that occurred in 2% or more of patients treated with DALVANCE was nausea (3.4% in the DALVANCE single dose group and 2% in the DALVANCE two-dose group).

The following selected adverse reactions were reported in DALVANCE treated patients at a rate of less than 2% in these clinical trials: Blood and lymphatic system disorders: anemia, hemorrhagic anemia, leucopenia, neutropenia, thrombocytopenia, petechiae, eosinophilia, thrombocytosis Gastrointestinal disorders: gastrointestinal hemorrhage, melena, hematochezia, abdominal pain General disorders and administration site conditions: infusion-related reactions Hepatobiliary disorders: hepatotoxicity Immune system disorders: anaphylactic reaction Infections and infestations: Clostridioides difficile colitis, oral candidiasis, vulvovaginal mycotic infection Investigations: hepatic transaminases increased, blood alkaline phosphatase increased, international normalized ratio increased, blood lactate dehydrogenase increased, gamma-glutamyl transferase increased Metabolism and nutrition disorders: hypoglycemia Nervous system disorders: dizziness Respiratory, thoracic and mediastinal disorders: bronchospasm Skin and subcutaneous tissue disorders: rash, pruritus, urticaria Vascular disorders: flushing, phlebitis, wound hemorrhage, spontaneous hematoma Alanine Aminotransferase (ALT) Elevations Among patients with normal baseline ALT levels treated with DALVANCE 17 (0.8%) had post baseline ALT elevations greater than 3 times the upper limit of normal (ULN) including five subjects with post-baseline ALT values greater than 10 times ULN. Among patients with normal baseline ALT levels treated with non-DALVANCE comparators 2 (0.2%) had post-baseline ALT elevations greater than 3 times the upper limit of normal. Fifteen of the 17 patients treated with DALVANCE and one comparator patient had underlying conditions which could affect liver enzymes, including chronic viral hepatitis, history of alcohol abuse and metabolic syndrome. In addition, one DALVANCE-treated subject in a Phase 1 trial had post-baseline ALT elevations greater than 20 times ULN. ALT elevations were reversible in all subjects with follow-up assessments. No comparatortreated subject with normal baseline transaminases had post-baseline ALT elevation greater than 10 times ULN. Clinical Trials Experience in Pediatric Patients Adverse reactions were evaluated in one Phase 3 pediatric clinical trial which included 161 pediatric patients from birth to less than 18 years of age with ABSSSI treated with DALVANCE (83 patients treated with a single dose of DALVANCE and 78 patients treated with a two-dose regimen of DALVANCE) and 30 patients treated with comparator agents for a treatment period up to 14 days. The median age of pediatric patients treated with DALVANCE was 9 years, ranging from birth to <18 years. The majority of patients were male (62.3%) and White (89.0%).

The safety findings of DALVANCE in pediatric patients were similar to those observed in adults.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation Serious adverse reactions (SARs) occurred in 3/161 (1.9%) of patients treated with DALVANCE, all in the single-dose arm. There were no adverse reactions leading to DALVANCE discontinuation.

Most Common Adverse Reactions Most common adverse reaction occuring in more than 1% of pediatric patients 2/161 (1.2%) was pyrexia.

Other Adverse Reactions The following selected adverse reactions were reported in DALVANCE-treated patients at a rate of less than 1% in this pediatric clinical trial: Gastrointestinal disorders: diarrhea Nervous system disorders: dizziness Skin and subcutaneous tissue disorders: pruritus Post Marketing Experience The following adverse reaction has been identified during post-approval use of dalbavancin. Because the reaction is reported voluntarily from a population of uncertain size, it is not possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

General disorders and administration site conditions: Back pain as an infusion-related reaction [See Warnings and Precautions].

DRUG INTERACTIONS Drug-Laboratory Test Interactions Drug-laboratory test interactions have not been reported. DALVANCE at therapeutic concentrations does not artificially prolong prothrombin time (PT) or activated partial thromboplastin time (aPTT).

Drug-Drug Interactions No clinical drug-drug interaction studies have been conducted with DALVANCE. There is minimal potential for drug-drug interactions between DALVANCE and cytochrome P450 (CYP450) substrates, inhibitors, or inducers.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary There are no adequate and well-controlled studies with DALVANCE use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or adverse developmental outcomes.

No treatment-related malformations or embryo-fetal toxicity were observed in pregnant rats or rabbits at clinically relevant exposures of dalbavancin.

Treatment of pregnant rats with dalbavancin at 3.5 times the human dose on an exposure basis during early embryonic development and from implantation to the end of lactation resulted in delayed fetal maturation and increased fetal loss, respectively [see Data].

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 No evidence of embryo or fetal toxicity was found in the rat or rabbit at a dose of 15 mg/kg/day (1.2 and 0.7 times the human dose on an exposure basis, respectively). Delayed fetal maturation was observed in the rat at a dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis).

In a rat prenatal and postnatal development study, increased embryo lethality and increased offspring deaths during the first week post-partum were observed at a dose of 45 mg/kg/day (3.5 times the human dose on an exposure basis).

Lactation Risk Summary There are no data on the presence of dalbavancin or its metabolite in human milk, the effects on the breast-fed child, or the effects on milk production.

Dalbavancin is excreted in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for DALVANCE and any potential adverse effects on the breast-fed child from DALVANCE or from the underlying maternal condition.

Pediatric Use The safety and effectiveness of DALVANCE for the treatment of ABSSSI has been established in pediatric patients aged birth to less than 18 years. Use of DALVANCE for this indication is supported by evidence from adequate and wellcontrolled studies in adults with additional pharmacokinetic and safety data in pediatric patients aged birth to less than 18 years [see Adverse Reactions].

There is insufficient information to recommend dosage adjustment for pediatric patients with ABSSSI and CLcr less than 30 mL/min/1.73m2.

Geriatric Use Of the 2473 patients treated with DALVANCE in Phase 2 and 3 clinical trials, 403 patients (16.3%) were 65 years of age or older. The efficacy and tolerability of DALVANCE were similar to comparator regardless of age. The pharmacokinetics of DALVANCE was not significantly altered with age; therefore, no dosage adjustment is necessary based on age alone.

DALVANCE is substantially excreted by the kidney, and the risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection in this age group.

Renal Impairment In patients with renal impairment whose known CLcr is less than 30 mL/min and who are not receiving regularly scheduled hemodialysis, the recommended regimen for DALVANCE is 1125 mg, administered as a single dose, or 750 mg followed one week later by 375 mg. No dosage adjustment is recommended for patients receiving regularly scheduled hemodialysis, and DALVANCE can be administered without regard to the timing of hemodialysis. There is insufficient information to recommend dosage adjustment for pediatric patients younger than 18 years with CLcr less than 30 mL/min/1.73m2.

Hepatic Impairment No dosage adjustment of DALVANCE is recommended for patients with mild hepatic impairment (Child-Pugh Class A). Caution should be exercised when prescribing DALVANCE to patients with moderate or severe hepatic impairment (Child-Pugh Class B or C) as no data are available to determine the appropriate dosing in these patients.

OVERDOSAGE Specific information is not available on the treatment of overdose with DALVANCE, as dose-limiting toxicity has not been observed in clinical studies. In Phase 1 studies, healthy volunteers have been administered cumulative doses of up to 4500 mg over a period of up to 8 weeks (not an approved dosing regimen), with no signs of toxicity or laboratory results of clinical concern.

Treatment of overdose with DALVANCE should consist of observation and general supportive measures. Although no information is available specifically regarding the use of hemodialysis to treat overdose, in a Phase 1 study in patients with renal impairment less than 6% of the recommended dalbavancin dose was removed.

Distributed by: Allergan USA, Inc. Madison, NJ 07940 Patented. See www.allergan.com/patents.

DALVANCE® is a registered trademark of Allergan Pharmaceuticals International Limited. © 2021 Allergan. All rights reserved.

Ref: v2.0USPI0100 Revised: 7-2021 US-DAV-210213 MASTER

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Should INSTIor TAFRelated Weight Gain Prompt a Switch?

BY DAVID WILD

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oughly 15% of people living with HIV gain more than 10% of their body weight in the first one to two years of treatment with an integrase strand transfer inhibitor (INSTI) or tenofovir alafenamide (TAF) regimen, leaving clinicians with the clinical question of whether to switch to a non-INSTI or non-TAF regimen. The answer is unclear, experts said.

“I would argue that physicians should generally not switch patients from an INSTI regimen only in light of weight gain, mainly because we don’t know what regimen we should switch these patients to, or if it will help,” said Kristine Erlandson, MD, MS, an associate professor in the Division of Infectious Disease at the University of Colorado Denver, Anschutz Medical Campus.

To be sure, a pooled analysis that her team conducted suggests that switching to an INSTI or TAF regimen does appear to contribute to the problem of weight gain, regardless of the regimen type (Clin Infect Dis 2021;73[8]:1440-1451). Her group found that 6.4% of individuals who switched from a variety of regimens to a newer regimen gained at least 10% of their body weight, compared with 2.2% of those who remained on their regimen.

“While switching from abacavir to TAF was associated with somewhat less weight gain, it should be noted that abacavir is not a great option for patients with numerous cardiovascular disease risk factors like diabetes, hypertension and hyperlipidemia,” Dr. Erlandson said.

For clinicians considering a change to a protease inhibitor (PI)based regimen, Dr. Erlandson said observational data from a cohort of almost 23,000 antiretroviral treatment (ART)-naive patients with HIV showed that patients treated with a PI-based regimen gained only slightly less weight than using an INSTI-based regimen (J Int AIDS Soc 2020;23:e25484), while her group’s pooled analysis showed switching from a PI to an INSTI was similar in terms of weight gain as remaining on a PI (Clin Infect Dis 2021;73[8]:1440-1451).

“So, weight changes with protease inhibitors really aren’t that impressively better than integrase inhibitors,” Dr. Erlandson said.

While she has seen an increase in practitioners switching patients from an INSTI to a doravirine (DOR) regimen because of the concern about weight gain, Dr. Erlandson cautioned that “we really don’t have a lot of data to support that switch.”

Existing findings are mixed, with DOR initiation studies showing similar weight gains as would be expected in people without HIV (AIDS 2021;35[1]:91-99). In a single-switch study in ART-naive individuals randomized to start either DOR with a tenofovir disoproxil fumarate (TDF) backbone or efavirenz (EFV) with a TDF backbone, those who started EFV switched to DOR after 96 weeks. Participants experienced a 1- to 1.2-kg weight increase in either group at 96 weeks and 2 to 3 kg by week 192 (IAS 2021, abstract 709).

“These weight gains are definitely less than what we saw in some of the other studies, but it’s also a different patient population, including fewer women and fewer racial and ethnic minorities,” Dr. Erlandson said.

Switching from a three-drug regimen to a two-drug regimen does not appear to limit weight gain, Dr. Erlandson

added. Specifically, a recently presented study found that patients switching from one of several three-drug regimens to DTG/3TC experienced an average 2.1-kg weight gain, compared with an average weight gain of 0.6 kg among those who continued on their baseline three-drug regimen (IAS 2021, abstract 1457).

“One reason that some patients might experience impressive weight gain after a switch from some three-drug regimens is in part because we remove a weight-suppressive effect of EFV or TDF,” said Dr. Erlandson, adding that TDF-related weight suppression can be detrimental in pregnant women with HIV. Research indicates these patients gain less weight than recommended during pregnancy and can have more adverse pregnancy outcomes, including preterm delivery and neonatal mortality (Lancet 2021;397[10281]:1276-1292).

Rather than proceeding with a switch, Dr. Erlandson urged clinicians to first work with patients to institute lifestyle changes, including exercise and dietary modification.

“These modifications can have not only a significant effect on weight, but on physical function, strength and endurance as patients are aging, as well as control of metabolic issues like diabetes and hypertension, and they can reduce other comorbidities, such as sleep impairments or mood impairments,” Dr. Erlandson said.

The effects of INST-related weight gain can be significant, according to Darcy Wooten, MD, MS, an associate professor of medicine in the Division of Infectious Disease and Global Public Health at the University of California, San Diego.

She pointed to recent research showing higher 10-year risk for cardiovascular illness among patients on an INSTI-based regimen who gain weight (Conference on Retroviruses and Opportunistic Infections [CROI] 2021, abstract 117) and other data revealing a 22% increased likelihood of developing diabetes mellitus and hyperglycemia within six months of INSTI treatment, compared with similar patients not receiving an INSTI (hazard ratio, 1.22; 95% CI, 1.131.32), with the effect most pronounced among individuals receiving dolutegravir (CROI 2021, abstract 516).

Dr. Wooten does not encourage clinicians to switch patients to another regimen because of weight gain, but she said that “in certain patients who have gained a substantial amount of weight and have tried all the interventions, are still not able to lose weight or maintain their weight, and are considering stopping their medications, it would be appropriate to consider switching to an alternative regimen.

“That requires taking a patient-centered approach and explaining to the patient what’s known about this area, what the gaps are in the literature, and doing active and deep listening to understand what this person values, what their priorities are, and then developing a plan that utilizes shared decision making,” Dr. Wooten said. ■ Drs. Erlandson and Wooton spoke at the same session during the IDWeek 2021 virtual meeting. Dr. Erlandson reported relationships with Gilead, Janssen and ViiV Healthcare. Dr. Wooten reported no relevant financial disclosures.

C. diff Medications continued from page 22

of patients treated at Michigan Medicine and 628 controls also treated at Michigan Medicine for diarrhea suspicious for CDI but who were negative for CDI (Anaerobe 2021 Sep 8. https://doi.org/10.1016/j. anaerobe.2021.102444).

They analyzed data for prescribed and over-thecounter non-aspirin NSAIDs within 30 days of CDI as well comorbidities and baseline laboratory findings. Patients with CDI and NSAID use were closely matched with non-CDI NSAID users according to sex, presence of back pain and arthritis, baseline serum creatinine, serum albumin, and use of anticoagulants or antiplatelet medications.

There was a 2-fold increased risk for CDI during PPI use.

Source: Clin Infect Dis 2021;72(12):e1084-e1089

The results showed that 22% to 26% of those with or without CDI had used non-aspirin NSAIDs during the previous month, with analyses confirming there was no elevated CDI risk among those receiving NSAIDs (odds ratio [OR], 0.97; 95% CI, 0.72-1.29; P=0.816).

The only significant CDI risk factors they found were older age (OR, 1.09; CI, 1.01-1.17; P=0.02), scores on the weighted Elixhauser Comorbidity Index, a measure of comorbidity burden (OR, 0.98; 95% CI, 0.97-0.99) and prior CDI (OR, 2.64; 95% CI, 1.96-3.56).

“Both on unadjusted and adjusted modeling, our findings do not support an association between NSAID use and an increased risk for CDI,” according to the investigators.

Prior research on the topic that has found an association between NSAID use and CDI “had two major limitations, [including] inadequate assessment of over-the-counter NSAID use and failure to account for treatment assignment bias,” the team noted. “To our knowledge this is the first study of NSAID use as a risk factor for CDI to account for treatment assignment bias utilizing propensity score matching,” they added.

“This is significant as it increases our confidence that our modeled risk of CDI is causally related to NSAID use itself, rather than the underlying indication for the ■ NSAID use.”

The sources reported no relevant financial disclosures.

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

33

As UTI Drug Resistance Increases, Treatment Choices 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 with clinical guidelines, and some UTI drug resistance rates markedly rising over the past several years, one expert urged pharmacists to carefully review the appropriateness of UTI prescriptions.

“With a lot of UTI infections comes a lot of prescribing of antibiotics, and sometimes our providers don’t do the greatest job,” said Ryan Moenster, PharmD, a clinical pharmacy specialist in infectious diseases, VA St. Louis Health Care System, during a virtual session at the 2021 American College of Clinical Pharmacy Virtual Annual Meeting.

The most recent data on the epidemiological burden of outpatient UTI treatment, as cited by Dr. Moenster, indicated there were 10.5 million office visits in 2007 for UTIs and 2 to 3 million emergency department visits in that year (Nat Rev Microbiol 2015;13[5]:269-284). Moreover, an analysis published in 2021 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 fantastic data,” said Dr. Moenster, also a professor of pharmacy practice at University of Health Sciences and Pharmacy in St. Louis.

Rise in E. coli Resistance 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, Dr. Moenster said (Clin Infect Dis 2020 Jul 23).

Room for improvement in UTI medical treatment prompted Dr. Moenster to urge attendees 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 [TMPSMX], nitrofurantoin and fosfomycin.”

Regarding TMP-SMX, a hospital study conducted in South Carolina revealed that roughly 20% of 351 patients with

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community-onset UTIs had Enterobacterales isolates with resistance to the agent (J Glob Antimicrob Resist 2020;21:218-222). Use of TMP-SMX in the prior 12 months was associated with a 2.58fold increased risk for Enterobacterales resistance to the drug, the researchers found (adjusted odds ratio, 2.58; 95% CI, 1.135.89; P=0.02).

Dr. Moenster said a randomized controlled trial shed light on the relative efficacy of nitrofurantoin and fosfomycin for the treatment of lower UTIs (JAMA 2018;319[17]:1781-1789).

Specifically, those findings showed that 70% of patients who received a five-day course of nitrofurantoin and 58% of recipients of a single dose of fosfomycin experienced a clinical response at 28 days (P=0.004), while 74% and 63%, respectively, experienced a microbiological response at the same time (P=0.04).

“We can’t talk about these agents without talking about some of their notable limitations,” Dr. Moenster stressed. For example, some patients have an allergy to TMP-SMX, 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, while nitrofurantoin and fosfomycin are not recommended for the management of pyelonephritis, Dr. Moenster noted. Furthermore, only the single-dose regimen of fosfomycin is FDA approved, “although clinicians do use alternative dosing recommendations for certain patients,” he said.

In addition to general considerations of antibiotic resistance and safety and efficacy, he urged attendees to consider their own local resistance rates when choosing an outpatient UTI 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 TM-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.

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

FDA Expands Indication for Flucelvax Quadrivalent to Children 6 Months and Older

BY IDSE NEWS STAFF

T

he FDA expanded the indication for a cell-based quadrivalent influenza vaccination (QIVc; Flucelvax Quadrivalent, Seqirus) for children as young as 6 months old.

The expanded age indication is supported by a phase 3 clinical study demonstrating that ccIIV4 was as safe and immunogenic as a standard quadrivalent seasonal influenza vaccine (QIV) in children 6 months to younger than 4 years of age during the U.S. 2019-2020 influenza season, according to data presented at the Pediatric Academic Society (PAS) virtual annual meeting on May 1, 2021.

This observer-blinded, controlled study randomized 2,414 U.S. children to receive QIVc or QIV. Participants received one or two vaccine doses 28 days apart, based on vaccination history, and were followed for at least 180 days.

Noninferiority of QIVc to QIV was concluded if the upper bound of the two-sided 95% confidence interval for the postvaccination geometric mean titer (GMT) ratio did not exceed 1.5 and the seroconversion rate (SCR) difference did not exceed 10% for each of the four strains tested (A/H1N1, A/ H3N2, B/Yamagata and B/Victoria), which was reached.

Safety profiles also were comparable between QIVc and QIV. The most common adverse events were similar between vaccinated groups, and included tenderness, erythema at the injection site, irritability and sleepiness.

The vaccine is produced with a cell-based manufacturing process, an alternative to traditional egg-based manufacturing, which can cause the strain to mutate at several steps throughout the manufacturing process, and may lead to an antigenic mismatch between the circulating strains and the inactivated influenza strains contained within the seasonal influenza vaccine, according to the CDC. Cell-based influenza vaccines are designed to produce a better match to the World Health Organization selected influenza virus strains by avoiding egg-adapted changes, and therefore may be more effective, according to the CDC, and may offer additional advantages over the standard manufacturing process, including increased scalability and production speed in the event of an influenza pandemic.

Children younger than 5 years old, particularly those younger than 24 months, are at increased risk for developing serious influenza-related complications, including pneumonia. According to the CDC, almost 50,000 hospitalizations occurred in children during the 2019-2020 U.S. influenza season, and there were more than 486 influenza-related deaths in this age group.

The CDC recommends everyone 6 months of age and older

without contraindications receive an influenza vaccine annually.

In related news, the FDA granted supplemental approval of a multidose vial of Influenza A(H5N1) Monovalent Vaccine, Adjuvanted (Audenz, Seqirus), the first adjuvanted, cell-based influenza vaccine designed to help protect people 6 months of age and older against influenza A(H5N1) in the event of a pandemic.

The approval marks an important milestone in pandemic preparedness, the company said. “Producing Audenz in multidose vials allows for increased speed and efficiency, which is absolutely critical to help protect public health in the case of an influenza pandemic,” said Marc Lacey, the executive director of Pandemic Response Solutions at Seqirus.

“According to the CDC, the influenza A(H5N1) virus is highly pathogenic and has high pandemic potential, so it’s critical to be prepared.”

Adjuvanted, Cell-Based Technology Audenz combines Seqirus’ proprietary MF59 adjuvant technology, designed to create broad, cross-reactive antibodies, with its cell-based manufacturing platform. This adjuvant is an important part of pandemic preparedness planning because it reduces the amount of antigen required to produce an immune response, increasing the number of doses of vaccine developed, so that a large number of people can be vaccinated as quickly as possible (Vaccine 2014;32:5027-5034).

Under the terms of the public-private partnership with the Biomedical Advances Research and Development Authory, and the Department of Health and Human Services, established in 2009, Seqirus would deliver 150 million influenza vaccine doses to the U.S. government to support an influenza pan■ demic response within six months.

The sources work for Seqirus.

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

35

ACIP Recommends Pneumococcal Vaccines For Those 65+ and Immunocompromised Adults

BY GINA SHAW

A

moderately divided Advisory Committee on Immunization Practices (ACIP) recommended that adults 65 years of age and older, and those aged 19 years and older with certain underlying medical conditions or other risk factors, should receive a pneumococcal conjugate vaccine (either PCV20 or PCV15). If PCV15 is used, they recommended, the vaccine should be followed by a dose of pneumococcal polysaccharide vaccine (PPSV23).

The risk factors in younger people include alcoholism, chronic heart, liver or lung disease, cigarette smoking, diabetes mellitus, chronic renal failure, nephrotic syndrome, immunodeficiency, iatrogenic immunosuppression, generalized malignancy, HIV, Hodgkin disease, leukemia, lymphoma, multiple myeloma, solid-organ transplants, congenital or acquired asplenia, sickle cell disease or other hemoglobinopathies, cerebrospinal fluid leak, or having a cochlear implant.

At the Oct. 20 ACIP meeting, all panel members agreed that these two recommendations should go forward, but four of 15 voted yes on a prior recommendation that the age-based guideline should be brought down to age 50, noting that it could reduce disparities in disease burden in adults aged 50 to 64 years, and could open up opportunities to vaccinate adults before they develop underlying conditions.

“This age group already has a lot of comorbid conditions, and it would be much easier to simplify the vaccination process to include this group,” said panel member Helen Keipp Talbot, MD, an associate professor of medicine at Vanderbilt University, in Nashville, Tenn.

“This is an age group that will respond to a vaccine and create a lasting vaccine response much better than someone aged 70. The majority of physicians who

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take care of adults really were interested in starting at age 50.

“While I do recognize that we do not know the duration of protection if we start at this age, as adult physicians, we are more than happy to evaluate a booster in the future because we hope that our patients live long enough to require that booster. We would like to capture people when they are most likely to respond to a vaccine and reduce current disease disparities,” Dr. Talbot said.

But the ACIP found that placing the age-based recommendation for a PCV vaccine at 65 years of age consistently lowered the cost and provided better health outcomes, said Miwako Kobayashi, MD, MPH, a CDC epidemiologist in the Pneumococcal Vaccines Work Group, who presented the recommendations to the full panel. “When we reviewed the data for cost-effectiveness at 65 and older, there was consistent cost savings, which means lower cost and better health outcomes compared with current recommendations, in all costeffectiveness analyses,” she said. “Our analyses found that while recommending PCV20 at age 65 consistently showed that the intervention was cost-saving, PCV20 at age 50 resulted in worse health in some CDC scenarios.”

Dr. Kobayashi noted that more than 90% of the infectious pneumococcal disease burden in the United States is in those who are 65 years of age and older, and in those who are 19 to 64 years of age with risk-based indications.

After the unanimous vote to support the PCV vaccine in adults 65 and older and those aged 19 and older with certain underlying risk factors, members noted the importance of further data. “I do have some concerns that the disparities in outcomes related to invasive PCV disease may not be totally addressed by our vote,” said Oliver Brooks, MD,

the chief medical officer for the Watts HealthCare Corp., in Los Angeles, and a past president of the National Medical Association, who pointed out that hypertension and obesity were not included among the underlying risk factors.

“Although there seems to be evidence suggesting that hypertension and obesity are not risk factors for PCV disease, I’d like to revisit these conditions at some time in the near future.”

Many patients will still have invasive pneumococcal disease with serotypes that are not covered by the existing vaccines, noted Sarah Long, MD, a professor of pediatrics at Drexel University College of Medicine and the chief of the Section of Infectious Diseases at St. Christopher’s Hospital for Children, in Philadelphia.

“It is increasingly important, in adults with invasive pneumococcal disease, that those isolates be saved and sent for serotyping. This is not a completely preventable disease, and in immunocompromised patients specifically, the likelihood that they have non-vaccine serotypes of invasive disease is quite high. Our clinical observations of what we are seeing, and how that is or isn’t covered by the vaccine, will only be relevant if we have ■ serotyping of those isolates.”

The sources reported no relevant financial disclosures.

ACIP Recommends Recombinant Zoster Shot For Immunocompromised Adults

BY GINA SHAW

A

dults 19 years of age and older who are immunosuppressed due to disease or therapy should receive the recombinant zoster vaccine (RZV; Shingrix, GlaxoSmithKline) in two doses given at least four weeks apart, the Advisory Committee on Immunization Practices (ACIP) recommended in a unanimous vote on Oct. 20.

This population includes, but is not limited to, hematopoietic stem cell transplant (HSCT) recipients; patients with hematologic malignancies and solid tumor malignancies; solid-organ transplant recipients; people living with HIV; patients with primary immunodeficiencies, autoimmune and inflammatory conditions; and those taking immunosuppressive therapies.

Taken together, these groups account for approximately 22 million people, said Tara Anderson, DVM, MPH, PhD, who leads the ACIP’s zoster workgroup

and presented a summary of the evidence in support of the recommendation. “Herpes zoster incidence is common in U.S. adults and increases with age, with approximately 1 million U.S. cases per year in the pre-vaccine era,” she noted.

The FDA first approved RZV in 2017; in that same year, ACIP recommended it for use in all immunocompetent adults ages 50 and older. In July 2021, the agency expanded RZV’s indication to include immunosuppressed adults ages 19 and over; at ACIP’s September meeting, the panel discussed the economics of vaccinating immunocompromised adults ages 19 to 49 and developed preliminary evidence for a recommendation framework regarding the use of the vaccine in this group.

Dr. Anderson noted that recent research found the median incidence of herpes zoster in immunosuppressed people exceeds that in individuals older continued on page 44

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Hepatitis D Pipeline Looks Promising

BY MICHAEL VLESSIDES

I

nterim results from a new phase 3 trial support the safety and efficacy of monotherapy with bulevirtide (Hepcludex, Gilead) in patients who have chronic infection with the hepatitis delta virus (HDV). Coupled with recent data on oral HDV regimens, the pipeline for treating this rare, challenging form of hepatitis looks promising.

The interim phase 3 study, an international, multicenter investigation, concluded that treatment with bulevirtide for 24 weeks was associated with significant decreases in viral RNA and improvements in biochemical disease activity. The researchers said the findings confirm the August 2020 conditional approval by the European Commission of bulevirtide.

The first-in-class entry inhibitor has received a breakthrough therapy designation from the FDA in the United States.

Bulevirtide is a peptide derived from the hepatitis B surface antigen (HBsAg). “In previous phase 2 trials [MYR202/ MYR203], we showed that if you inject hepatitis D patients with this peptide [daily] with different doses, you get a linear decline in HDV RNA over time, which reflects a loss of infected cells,” said Heiner Wedemeyer, MD, the chair of the Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical Hospital, in Germany.

The current study was a 24-week analysis of the MYR301 trial, which comprised 150 patients (57% men; mean age, 41.8 years) coinfected with hepatitis B virus (HBV) and HDV. Participants in the trial were randomized to one of three groups: no antiviral treatment for 48 weeks followed by 10 mg daily of bulevirtide for 96 weeks (control arm A; n=51), 2 mg daily of bulevirtide (arm B; n=49), or 10 mg daily of bulevirtide (arm C; n=50).

Patients in arms B and C received the drug for 144 weeks, with a treatment-free follow-up of 96 weeks. The

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DAVID BRONSTEIN

primary end point of the trial was a combined response of undetectable HDV RNA or HDV RNA reduction of at least 210 IU/mL and normalization of alanine aminotransferase (ALT) at week 48. Secondary end points included undetectable HDV RNA, a fall in HDV RNA of at least 210 IU/mL, normalization of ALT and a reduction in HBsAg of at least 110 IU/mL. In a presentation at the 2021 International Liver Congress (abstract LBP-2730), Dr. Wedemeyer reported that after 24 weeks, none of the patients in the control group (arm A) achieved a combined virologic and biochemical response, whereas 36.7% of patients in arm B and 28.0% of those in arm C did so (P<0.0001). Similar results were observed for HDV RNA, which fell by at least 210 IU/mL between baseline and week 24 in 3.8% of patients in arm A, 55.1% in arm B and 68% in arm C (P<0.0001). At week 24, normalization of ALT was achieved by 53.1% of patients in arm B and 38% in arm C, compared with 5.9% in arm A (P<0.0001). The level of HBsAg did not show relevant declines in all but one patient at week 24.

“The important message is that the findings of the phase 2 trials were exactly confirmed,” Dr. Wedemeyer said.

Safety analyses found that treatment-related adverse events were much more common in patients who received the study drug. “As was expected, bile acids increased because bulevirtide’s mode of action blocks a bile salt transporter,” Dr. Wedemeyer said. “But there were no unexpected serious adverse events.”

The researchers acknowledged that only a small proportion of patients had completely undetectable HDV RNA, but they were encouraged by the results. “This confirms that we can use the drug in a real-world setting,” Dr. Wedemeyer said.

“These are exciting times for hepatitis delta patients.” continued on page 42

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ACIP Recommends ‘Universal’ Adult HBV Vaccine— But Not for All

BY MARIE ROSENTHAL, MS

A

risk-based strategy for adult hepatitis B (HepB) vaccination just hasn’t worked, according to Kevin A. Ault, MD, FACOG, FIDSA, the division director of the Department of Obstetrics and Gynecology, University of Kansas Medical Center, in Kansas City.

“The risk-based strategy has been given over a decade to prove itself, and that hasn’t panned out because of the complex list of risk factors,” Dr. Ault told the CDC’s Advisory Committee on Immunization Practices (ACIP).

The list for at-risk adults is indeed complex. There are four risks under those who might be exposed through sexual contact, such as having multiple partners or living with someone who is hepatitis B surface antigen–positive, and six under the category of those at risk from percutaneous or mucosal exposure to blood, such as injection drug users, those with diabetes and hemodialysis patients. In addition, there are “others”: those at risk because of HIV, chronic liver disease, hepatitis C virus (HCV), incarceration or international travel. And finally, there is a catchall—“all other persons seeking protection from HBV infection.”

Determining whether the patient in front of you should be vaccinated is challenging in the time constraints of an office or clinic visit, Dr. Ault said. It’s especially difficult because many patients do not report a risk, added Mark K. Weng, MD, MSc, FAAP, the lead of the ACIP’s Hepatitis Vaccine Work Group.

“It’s important to recall that only one-third of people with reported acute hepatitis B actually recorded any risk factors,” said Dr. Weng, who is a medical epidemiologist in the Hepatitis Branch of the CDC. “The current risk-based vaccination strategy provides no advantages in identifying and vaccinating [those] people.”

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It has not been a total wash, he added, because the has been partially successful with initial decreases, but new hepatitis B virus (HBV) infections began to plateau 10 years ago, according to Dr. Weng.

The problem is not insignificant.

An estimated 1.89 million people live with chronic HBV, and up to 25% of them are at risk for premature death from cirrhosis or liver cancer. About 20,700 acute infections occur annually. Each year, the United States spends more than $1 billion on HBV-related hospitalizations, and this figure does not include indirect costs, according to Dr. Weng, who is a medical epidemiologist at the CDC. “The HepB immunization strategy has evolved over the past four decades,” he said. “Risk-based strategies were first introduced among the adults and perinatally exposed infants in the early 1980s. Then universal infant vaccination was introduced in 1991 with catch-up vaccination recommendations for adolescents in 1999, followed by the introduction of a universal birth dose among all newborns in 2005. All of these steps toward routine HepB vaccination resulted in large declines,” Dr. Weng explained. “However, hepatitis B incidents have plateaued over the past 10 years, with more than 20,000 new infections estimated to occur each year.”

HepB vaccination has had the most success among children, because the recommendation is part of the universal childhood immunization schedule, he said.

Rates are now highest among adults and have increased among adults 40 years of age and older.

The Department of Health and Human Services called for the elimination of viral hepatitis in the United States by 2030,

according to Dr. Ault, and the plan emphasizes the role of vaccination. The Viral Hepatitis Plan focuses on the three most common hepatitis viruses in the United States: hepatitis A, HBV and HCV. According to HHS, “the nation faces unprecedented hepatitis A outbreaks, progress on preventing hepatitis B has stalled, and hepatitis C rates nearly tripled from 2011 to 2018” (https://bit.ly/3EMOvUO-IDSE).

Another problem with the risk-based strategy was health inequity, according to Dr. Weng. Risk-based recommendations favor people with consistent access to preventive health services, who trust their health care provider enough to disclose potentially stigmatizing risk factors, are aware of their risk and enjoy a high degree of health literacy.

“Right now, acute infection rates among Black American adults were up to three times the rates of Asian/Pacific Islanders and Hispanics,” he said, and all minorities have higher rates of disease than whites.

The universal strategy for children and adolescents eliminated most of the racial disparities among children when it came to HepB vaccination. “Rates of HBV infection for children and adolescents of all races/ethnicities converged to a lower rate when a universal vaccination strategy was implemented for children 18 and younger,” Dr. Weng explained.

A universal vaccination strategy has been successful in increasing the uptake of several vaccines: In 2010, almost 27% of adults were vaccinated under a risk-based recommendation, and that increased to 51% of adults during the 2020-2021 flu season under a universal recommendation. The same was seen for pneumococcal vaccination going from 23.3% in 2018 to 69% when the vaccine was universal for those 65 years of age and older.

“The past decade has illustrated that risk-based screening among adults has gotten us as far as it can take us,” Dr. Weng said.

The hepatitis work group recommended a universal strategy for all adults because universal vaccination would: • reduce stigma and barriers; • make the recommendation simpler and easier to implement for providers; • help eliminate HBV both here and abroad; and • advance health equity goals.

But everything has a cost. The Institute for Clinical and Economic Review, which provides independent evaluations about the value of medical interventions, found that universal HepB vaccination would cost $153,000 per quality-adjusted life-year (QALY). However, the QALY estimate would decrease as more people were vaccinated, according to Dr. Weng.

Acute HBV infections should be reduced by 24% and HBVrelated deaths by 23%, he found.

The ACIP agreed with the need for a change in strategy, but disagreed that all older adults needed to be included in a universal recommendation.

“I agree that the risk-based strategy has taken us as far as we can go, and the universal strategy is appropriate. But I have

concerns about having a recommendation for adults over the age of 60,” said ACIP Member James Loehr, MD, FAAFP, a family practitioner in Ithaca, N.Y. “I feel there’s diminishing return,” he said. “If you only give it to people under 59 years old, you’ll be giving 298 million doses.

If you give it to all adults, it should be about 352 million doses.

That’s an additional 54 million doses, an extra 18%. You are increasing the percentage of people who are protected by 28%, but you’re reducing the acute infections by only 1%,” he said.

Many on the panel had concerns both for and against vaccinating those 60 and older. “I just like to highlight that as a clinician who sees hundreds of patients as they are being evaluated for organ transplant, who have both kidney and liver failure, I am shocked at the number of people who are on dialysis or who have cirrhosis who are not yet vaccinated against hepatitis B,” said Camille Nelson Kotton, MD, FISDA, FAST, the clinical director of transplant and immunocompromised host infectious diseases in the Infectious Diseases Division at Massachusetts General Hospital, in Boston. “So, we have a very large population, some under the age of 16, many over the age of 60, who would benefit from vaccination.”

However, most agreed that the most beneficial group to target would be those younger than 60. “It doesn’t seem to me like a 90-, 95-year-old, an 85-year-old may be the person who really needs to be vaccinated,” said Pablo J. Sanchez, MD, a professor of pediatrics at The Ohio State University Nationwide Children’s Hospital, in Columbus. “And that’s what would happen with this universal recommendation. So, I tend to agree that the age cutoff needs to be relooked at.”

In the end, the committee voted 15-0 to recommend HepB vaccination for all adults 19 to 59 years of age. The committee added caveats for those 60 and older: Those with known risk factors should be vaccinated against HBV; and those who do not know their risk may be vaccinated against HBV. This recommendation comes with a growing “toolbox,” Dr. Weng said. There are now two single-antigen vaccines given on a three-dose schedule (Engerix, GlaxoSmithKline and Recombivax HB, Merck) and a two-dose vaccine (Heplisav-B, Dynavax). In addition, another vaccine is in the pipeline.

And by late 2022, the CDC is expecting to release recommendations calling for one-time HBV screening for all adults.

Although he supported a universal recommendation that included older adults, Jason M. Goldman, MD, FACP, the liaison representative for the American College of Physicians, said that making the recommendations less complex would help clinicians vaccinate more people. “I try to teach my colleagues nationally on how to implement vaccine programs, and the biggest barrier to implementation is how confusing and detailed these recommendations are, so streamlining it, making it universal and easy to implement as possible is key to success.” ■ The sources reported no relevant financial disclosures.

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

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Hepatitis D Pipeline continued from page 38

Hepatitis D: FAQs

Tobias Böttler, MD, an attending physician at the University Hospital Freiburg, in Germany, commented that bulevirtide has the potential to make a significant difference in managing patients with active HDV infection. “We still need to learn a lot with regard to dosing, treatment duration and possible combination therapies, [because] some data suggest that combination with interferon is even more potent,” he said. “It appears to be well tolerated with little side effects, based on the data we currently have. Going forward, we might even be able to use the drug in hepatitis B–monoinfected patients, but that requires a lot more data from clinical trials.”

Q: What are some of the key distinguishing features of the hepatitis D virus (HDV) and its associated illness?

Oral Formulation Option

A: HBV/HDV coinfection occurs when a person simultaneously becomes infected with both HBV and HDV, whereas HDV superinfection occurs when a person who is already chronically infected with HBV acquires HDV. Although acute HBV/HDV coinfections can resolve, HDV superinfection can lead to rapid progression of the already present HBV infection, resulting in liver cirrhosis and liver failure. These outcomes occur within five to 10 years in 70% to 80% of affected people and within one to two years in 15% with chronic HBV/HDV infection.

For patients and providers who prefer orally administered therapy, another investigational agent, lonafarnib (Zokinvy, Eiger Biopharmaceuticals), may be an option if it succeeds in its pipeline journey. Lonafarnib is a late-stage, orally active inhibitor of farnesyl transferase, an enzyme involved in the modification of proteins through a process called prenylation.

The FDA approved the drug in 2020, to reduce the risk for death from Hutchinson-Gilford progeria syndrome and for the treatment of certain processing-deficient progeroid laminopathies in patients 1 year of age and older.

Lonafarnib has been evaluated in several clinical trials for the treatment of HDV, either as monotherapy or with pegylated interferon alfa-2a (PEG IFN-alfa-2a) or ritonavir. In a proof-ofconcept study that explored optimal treatment regimens, the addition of ritonavir to a twice-daily oral lonafarnib regimen of 100 mg yielded optimal antiviral responses, with significantly fewer gastrointestinal side effects than lonafarnib monotherapy (Hepatology 2018;67[4]:1224-1236). The reduced GI side effects likely are due to ritonavir’s ability to inhibit lonafarnib metabolism, allowing for higher concentrations of the farnesyl transferase inhibitor to build up in the liver and systemic circulation, the researchers noted.

In 2018, the FDA granted lonafarnib breakthrough therapy designation for the treatment of HDV infection. The drug currently is being investigated in D-LIVR, a global phase 3 trial evaluating so an all-oral arm of lonafarnib boosted with ritonavir. The trial also ir includes a combination arm of ritonavir boosted with ritonavir aplus PEG IFN-alfa-2a. Each arm is to be compared with a plar: cebo arm in HDV-infected patients (ClinicalTrials.gov identifier: NCT03719313). The estimated study completion date is April 1,, ■ 2023, according to the ClinicalTrials.gov listing.

Dr. Böttler reported that he served on an advisory committee for Gilead Sciences. Dr. Wedemeyer reported financial relationships with Abbott, AbbVie, Altimmune, Biotest, Bristol Myers Squibb, BTG, Dicerna, Gilead, Janssen, Merck/MSD, MYR GmbH, Novartis, Roche, Siemens and Transgene.

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A: HDV is known as a “satellite virus,” because it can only infect people who are also infected by the hepatitis B virus (HBV). HDV infection can be acute or lead to chronic, long-term illness. The infection can be acquired either simultaneously with HBV as a coinfection, or as a superinfection in people who are already chronically infected with HBV.

Q: What is the difference between hepatitis B/ HDV coinfection and HDV superinfection?

Q: How common is HDV in the United States?

A: HDV infection is uncommon in the United States; most U.S. cases occur among people who migrate or travel here from countries where HDV is endemic. Because hepatitis D is not a nationally notifiable condition, the actual number of hepatitis D cases in the United States is unknown.

Q: Where is HDV most common?

A: Hepatitis D is most common in Eastern Europe, Southern Europe, the Mediterranean region, the Middle East, West and Central Africa, East Asia, and the Amazon Basin in South America.

Q: Are there different genotypes of HDV, and where do they circulate?

A: Eight different HDV genotypes can be found around the world, all of which share the same transmission routes and risk groups. HDV genotype 1 circulates mainly in North America, Europe, the Middle East, and North Africa. Genotypes 2 and 4 can be found in East Asia. Genotype fou 3 iis found exclusively in the Amazon Basin in South America. Genotypes 5, 6, 7 and 8 are found in West and Central Africa.

Source: CDC (bit.ly/3jOmrI2).

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Hitchhikers’ Guide to the Galaxy?

BY IDSE NEWS STAFF

A

n organism travels on a returning space craft and spreads around the world causing a widespread and deadly pandemic. Sound like something from a sci-fi movie? It might not be, if good biosecurity measures are not taken— especially now that private companies are in the space program.

Scientiss are calling for greater recognition of the biosecurity risks ahead of the private space industry (BioScience 2021 Nov 17. doi:10.1093/biosci/biab115 https:// bit.ly/31TgweG-idse).

“In addition to government-led space missions, the arrival of private companies such as SpaceX has meant there are now more players in space exploration than ever before,” said Phill Cassey, an associate professor and the head of the Department of Ecology and Evolutionary Biology at the University of Adelaide, in Australia.

“We need to take action now to mitigate those risks.” Space biosecurity concerns itself with both the transfer of organisms from Earth to space (forward contamination) and vice versa (backward contamination). While the

research points out that the risk for alien organisms surviving the journey is low, it’s not impossible. (See the Infectious Disease Special Edition article “The Final ID Frontier” about NASA’s infectious disease concerns and studies in space. https://bit.ly/30g31Fw-IDSE).

“Risks that have low probability of occurrence, but have the potential for extreme consequences, are at the heart of biosecurity management, because when things go wrong, they go really wrong,” Dr. Cassey said.

The research provides clear evidence of how humans have spread organisms to the most remote regions of the Earth and sea, and even into space.

To address the risks for invasive species from space travel, the scientists suggest the emerging field of “invasion science,” which deals with the causes and consequences of introducing organisms into new environments, could offer valuable knowledge. This includes the fact that insular systems, such as islands, lakes and remote habitats, are most vulnerable to invasion threats.

Further insights that could be applied include protocols for early detection,

ACIP Zoster Shot continued from page 37

than 50 (Clin Infect Dis 2020;71[7]:e125-e134). “The risk of herpes zoster and … complications is generally higher in immunocompromised populations, although there is variability across and within these groups,” she said. The workgroup found the desired anticipated effects of RZV in immunocompromised adults were substantial and unfavorable anticipated effects were small.

“Given the burden of [herpes zoster] and its complications in these patients, it is anticipated that more immunocompromised patients would pursue vaccination with RZV if recommended by ACIP and their provider,” Dr. Anderson said.

“Despite lack of a recommendation from ACIP, many physicians are already recommending RZV to patients with these

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hazard assessment, rapid response and containment procedures currently used in response to threats of invasive species.

“It is far cheaper to prevent biological contamination by implementing protocols on Earth than it is on Mars, for example.” Despite the value to space biosecurity, the authors stated that invasion biologists have yet to be involved in Committee on Space Research Planetary Protection planning. In the research they argue this should change because “greater collaboration between invasion biologists and astrobiologists would enhance existing international protocols for planetary biosecurity—both for Earth and for extraterrestrial bodies that ■ could contain life.”

The sources reported no relevant financial disclosures.

conditions. Physicians need more direction on which patients are eligible for RZV.” ACIP Committee member Katherine Poehling, MD, a professor of pediatrics and epidemiology and prevention and the director of pediatric population health in the Department of Pediatrics at Wake Forest School of Medicine, in Winston-Salem, N.C., noted the importance of pharmacy communication as this recommendation is rolled out. “The data presented today show that 60% to 65% of recombinant zoster vaccine is distributed through pharmacies,” she said. “This highlights the importance of making sure that information flows between pharmacies and providers so that all are clearly aware of what the patient’s vaccination status is, and highlights the importance of having a ■ universal adult immunization registry that all can see.”

The sources reported no relevant financial disclosures.

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40 Years continued from page 14

establishment to ignore. And gay people were getting fed up: They wanted answers faster than their friends and lovers were dying, and they weren’t getting them.

“It was hard to work. It was hard to get money. It was hard to generate any empathy from the public, and the Reagan administration chose to leave these people behind,” Dr. Gottlieb said.

“The gay community was deathly afraid,” Dr. Volberding said, “and that fear translated into anger when the community felt that not enough was being done to help understand it [the disease]. It took a while for the research grants to start moving.”

Groups such as ACT UP (AIDS Coalition to Unleash Power) and The Gay Men’s Health Crisis were crucial in getting those research grants, as well as being integral partners in HIV research, they said.

In addition to demonstrations in cities around the world, activists also were a vocal presence at the AIDS medical conferences. Several people interviewed for this story told about presentations being disrupted by activists, of speakers at the podium when demonstrators entered and threw symbolic blood—red paint—on them, and researchers who had guards outside their hotel room doors during the conference because

COVID-19 Versus HIV B

Y

Because they are both viral pandemics, COVID-19 was compared quite a bit with HIV, especially in the beginning of the pandemic. Both are seeing a high morbidity, but is that where the similarities end? The answer is yes and no.

“Well, they’re both viruses, but apart from that, they are very different,” said Paul Volberding, MD, of San Francisco.

“The epidemiology is completely different. What we learned is that COVID-19 can, but rarely, kills people, and HIV always kills people. HIV is very difficult to transmit; COVID is very easy to transmit. Everyone is susceptible to COVID, and most people have no great risk for HIV, even before treatments were developed just by nature of how the virus is commonly transmitted.”

Michael S. Gottlieb, MD, agreed: “The modes of transmission are so different. HIV resembles type B hepatitis

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they were afraid. Dr. Mildvan thought some of that anger, disruption and theater was misdirected at the physicians and researchers who were just trying to help.

“Those of us who were working in HIV became to some degree the heroes, but also to some degree the villains,” Dr. Volberding explained. “We were seen as complicit with the government in not responding adequately because we weren’t able to do anything. We couldn’t cure the disease.”

But there was also unity.

During the Sixth International Conference on AIDS in San Francisco, protesters drowned out then Health and Human Services Secretary Louis W. Sullivan, MD, while he was delivering the closing address. Dr. Mildvan remembers all of the physicians also turned their back on him, and everyone was shouting.

“Everybody, to a person, all the delegates were on our feet with our backs turned to the stage where he was trying to speak,” Dr. Mildvan said. “It was just so loud and so overpowering, and everybody was unified in our dismay at what the government had been doing—or not doing—with Sullivan as the representative.

“So, we were grateful to the activists because as delegates, we would not have protested without them,” she said.

“Their [AIDS activists’] role was huge in moving the ball forward,” Dr. Gottlieb said. “Larry Kramer and his associates were prophets in their day, said things that other people

MARIE ROSENTHAL, MS

in its transmission, whereas COVID-19 represents common respiratory viruses.

COVID-19 affects everyone. Theoretically speaking, everyone is at risk for HIV, but only through certain routes of transmission. COVID-19 is out there for everyone to contract,” said Dr. Gottlieb, of Los Angeles.

The high mortality rates are certainly similar, but the time line is very different, with h HIV killing millions over 40 years, k and COVID-19 killing millions in just two, said Jonathan Z. Li, MD, of Boston, but there is more stigma attached to HIV—even today—because iit is a sexually transmitted infection. infe However, the groundwork set for a drug approval during the early days of HIV was certainly used during COVID-19, “allowing the FDA to be more flexible

in a time of emergency. Without those early HIV activists pushing against the initial, ossified way that the FDA used do things, I’m not sure that to d tthey would be able to be as nimble as the FDA and the U.S. government have been for the current pandemic.”

The treatments have a commonality, too, he said. ““Some of the vaccines and treat treatments for COVID-19 were built on a foundation of HIV research,” Dr. Li said. “If you look at the J & J vaccine, that was an adenoviral-based vaccine that was developed in Dan Barouch’s lab and built off of a platform that he’s been studying for 20 years for HIV vaccine. There’s no way that that vaccine could have been created in such a short time frame without the two decades of research that had gone into it as part of HIV research.”

In addition, the research in neutralizing antibodies that has been done for

An ACT-UP organized protest outside of the FDA's headquarters in Rockville, Md., in 1988. Source: FDA

didn’t want to hear about safe sex, and ACT UP was incredibly important in getting to where we are now—in pushing the federal government, the NIH to study treatments for people with HIV and liberalizing access to experimental therapies.”

Dr. Fauci was one person who was instrumental in bringing the communities together, several people said, and brought the gay community, pharmaceutical companies and the government together as partners in research. He worked with

HIV treatment led to monoclonal antibodies, and Pfizer is working on a protease inhibitor, another HIV technology, for COVID-19.

The biggest difference is the time line, according to Julia B. Garcia-Diaz, MD, of New Olreans. “HIV lasted for years and years, and COVID was rapid, and so the time line was very different,” she said.

“These are different times with different technology. I think that we did things for HIV as quickly as we could have done it, but that is a span of 15-plus years; research did not start until the mid-, late 80s. We did not have HAART [highly active antiretroviral therapy] until about the mid-90s, and here we have remdesivir within six months. [In contrast,] COVID just spread like a wildfire throughout the world,” Dr. Garcia-Diaz said.

So many infectious diseases are diseases of poverty and vulnerable populations, such as HIV and tuberculosis, observed Dr. Rajesh T. Gandhi, MD, of

activists and changed the way clinical trials were done to include patient input. He also helped them get access to experimental drugs and helped speed up the approval process within the FDA. In 1984, he became the director of the National Institute of Allergy and Infectious Diseases, where he made sure HIV was a major research concern. He was also instrumental in developing the plan, “Ending the HIV Epidemic in the U.S.,” in 2019 (bit.ly/3pLfn1n-IDSE).

“At first he was criticized by activists, but then he worked together with activists in a very meaningful way,” Dr. Gandhi said.

“I have to hand it to Tony Fauci, because he partnered with them rather than excluded them,” Dr. Sax added.

“The signal-to-noise finally got through as a signal, and they made all the difference once they arrived. They made an enormous amount of contributions,” Dr. Mildvan explained.

Breakthroughs and Challenges Azidothymidine (AZT), also known as zidovudine, developed for HIV by Burroughs Wellcome, was approved in 1987—25 months after demonstrating activity against HIV in the lab—one of the shortest periods of drug development until COVID-19. It did not prevent viral replication, but slowed the progression to AIDS. “It was a groundbreaker because it was the first effective

Boston, and COVID-19 highlighted that by disproportionately affecting vulnerable populations. “I don’t think we learned the lesson, though.”

Both are global infections. “I think it’s highlighted to the extreme with COVID, but this idea that we can attempt to treat HIV here and not be concerned about it globally. … In the late 1990s, it became clear that it just was totally unethical to have treatments that were available to Americans, but not to people in resource-limited settings,” he said.

COVID-19 has had a direct effect on the HIV pandemic, however, in that many resources were diverted from HIV research and care to the COVID-19 response, they said.

This is especially true for the federal plan for ending HIV in America, Anthony Fauci, MD, admitted. “Well, I think COVID has upended everything everyone does on the planet,” he said. “So, you can’t say it hasn’t interfered with the plans to end HIV because it interfered with access to health care on the part of

some people who otherwise would get tested and put on therapy early, [and] it interferes with people getting the counseling that gets them into PrEP or preexposure prophylaxis.

“It interferes in the developing world who has supply chain issues of getting drugs to people. So, I think anyone who has anything that requires a stability in society has actually been upended,” he said.

“The impact of COVID on HIV, TB, malaria and probably every aspect of medical care has been substantial,” Dr. Volberding said.

People have decreased their uptake of PrEP; there is less testing; and it probably has affected adherence because patients were not seeing their physicians regularly.

“I think that COVID has delayed research in all areas,” Dr. Garcia-Diaz added. “HIV research has slowed down because the big companies have diverted their focus to COVID-19 [therapeutics and vaccines].”

And money for research is finite, she reminded, “very finite.”

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

47

drug,” Dr. Fauci said. “We had nothing before AZT. It saved a lot of lives. It wasn’t a durable effect in most people, but it saved a lot of lives.”

Dr. Volberding agreed. “The fact that it wasn’t very potent is almost not as important as that it opened the door. It did not reverse the disease, but it slowed it down.”

Dr. Gandhi added that one of most important contributions of AZT was that it gave patients hope.

Treatment took a huge leap forward again in 1996, with research presented at the Vancouver International AIDS Conference on combination antiretroviral therapy.

It was not only groundbreaking, it was thrilling, according to Dr. Sax, who quickly saw the benefits of treatment in his patients. “The treatment group made remarkable recoveries.

Patients who had lost 30, 40 pounds and looked as if they were at death’s door, within six to eight to 12 weeks they gained weight, put color in their cheeks and went back to work. Wow.” Today HIV is a very different disease from what it was 40 years ago because it is considered a chronic condition, not a death sentence. There have been so many breakthroughs in treatment—preexposure prophylaxis, one-pill-daily treatments and injectables that last weeks between doses—and all with fewer adverse events. Many of these treatments make viral loads so low they are undetectable, and undetectable means untransmissible, Dr. Fauci reminded.

“The pills are much smaller, the regimens are more tolerable, and the side effects are better,” Dr. Garcia-Diaz said.

“HIV in my mind is very dynamic and the treatments are continually evolving,” Dr. Gandhi said. “They’ve gotten better and better since those days of AZT.” But there is still much work to be done, and many challenges lie ahead, they said.

“We want the cure,” said Dr. Garcia-Diaz, who is a member of the Infectious Disease Special Edition editorial advisory board.

“I don’t know if it is going to be in my lifetime, but I am hoping that I could have that conversation with my patients, ‘Hey, this is the pill that is going to cure you,’” she said.

“I’m an optimistic person,” said Jonathan Z. Li, MD, an associate professor of medicine at Harvard Medical School and the Brigham and Women's Hospital, in Boston. “First of all, there have already been a couple of instances of HIV cures, but of course, both of those instances required a bone marrow transplantation, which has a high up-front mortality, so it’s not broadly applicable. But it is a proof of principle that HIV cure is possible.”

Dr. Li, who also is a member of the Infectious Disease Special Edition editorial advisory board, studies elite controllers— those HIV patients who control viral replication without antiretroviral therapy—and hopes they will help promote cure research. The Esperanza patient, an elite controller who appeared to have cleared HIV without antiretroviral therapy, is a very exciting development, he said (Ann Intern Med 2021 Nov

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16. https://doi.org/10.7326/L21-0297). Researchers are taking a close look at her cells to see if that information could translate to treatment and the eventual cure of HIV infection.

Dr. Li began his medical career in the 2000s—later than the other physicians interviewed for this story—but he said his early work spent in Mexico and China gives him a better understanding of what patients and physicians were going through in the early 1980s. “Those were regions of the world you still saw stigma and lack of access to care and end-stage HIV, and the kind of desperation of the patients [that was seen in the United States in the 1980s],” he said.

It also helped him to understand the importance of making sure that breakthroughs in the West make it to developing countries.

“These are challenges, but also opportunities,” Dr. Li said.

“One pill once a day for the vast majority of patients is phenomenal, but making sure that these pills are available around the world, including sub-Saharan Africa, where the vast majority of patients are, I think that is a priority.”

Dr. Gandhi agreed. “We need to give equal attention to making sure there is equitable distribution of life-saving technologies,” he said.

Vaccination is another challenge, they said, but one that still has a lot of interest, despite disappointing results in the past. As Infectious Disease Special Edition was going to press, there was a report that the messenger RNA technology used for the COVID-19 vaccines was successful in preventing simian immunodeficiency in primates (Nature Med 2021 Dec 9. doi:10.1038/s41591-021-01574-5). So, there is some hope in that area, too.

Despite all the education and knowledge, there is still stigma attached to being gay and having HIV, Dr. Sax said. “It is maddening,” he said, that some patients still won’t take their medications because of that stigma. “I think if the stigma was removed completely, they would be able to do it because they take their medicines for other conditions, but they just don’t take their HIV medications.”

Despite all the challenges, not one physician interviewed for this article said they were sorry they went into the field of HIV. They all agreed that caring for this special group of patients is its own reward.

Yet, all of the early pioneers in HIV, who have treated thousands of patients, remember those early young men who started them on their career paths, and those first patients are particularly special, the early HIV doctors told Infectious Disease Special Edition.

“The patients trusted us,” Dr. Gottlieb said. “We had a bond with them. Those first patients I remember better than the patients I saw last week. I remember them by name, and I remember their faces.

“And people still tell me they remember where they were ■ when they read that first report,” he said.

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

Michael, living with HIV.

CABENUVA is a

DHHS STRONGLY RECOMMENDED

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

‡

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

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

INDICATION

IMPORTANT SAFETY INFORMATION

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

CONTRAINDICATIONS • Do not use CABENUVA in patients with previous hypersensitivity

Please see additional Important Safety Information for CABENUVA throughout.

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

reaction to cabotegravir or rilpivirine

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

For virologically suppressed adults living with HIV-1*

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

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

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

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

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

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

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

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

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

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

Visit CABENUVAhcp.com

BRIEF SUMMARY

CABENUVA

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

The following is a brief summary only; see full prescribing information for complete product information.

CONTRAINDICATIONS CABENUVA is contraindicated in patients: ∞ with previous hypersensitivity reaction to cabotegravir or rilpivirine. ∞ receiving the following coadministered drugs for which significant decreases in cabotegravir and/or rilpivirine plasma concentrations may occur due to uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1 and/or cytochrome P450 (CYP)3A enzyme induction, which may result in loss of virologic response: • Anticonvulsants: Carbamazepine, oxcarbazepine, phenobarbital, phenytoin • Antimycobacterials: Rifabutin, rifampin, rifapentine • Glucocorticoid (systemic): Dexamethasone (more than a single-dose treatment) • Herbal product: St John’s wort (Hypericum perforatum) WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Hypersensitivity reactions have been reported during postmarketing experience with rilpivirine-containing regimens. Reactions include cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS). While some skin reactions were accompanied by constitutional symptoms such as fever, other skin reactions were associated with organ dysfunctions, including elevations in hepatic serum biochemistries. Serious or severe hypersensitivity reactions have been reported in association with other integrase inhibitors and could occur with CABENUVA. Remain vigilant and discontinue CABENUVA if a hypersensitivity reaction is suspected. Discontinue CABENUVA immediately if signs or symptoms of hypersensitivity reactions develop (including, but not limited to, severe rash, or rash accompanied by fever, general malaise, fatigue, muscle or joint aches, blisters, mucosal involvement [oral blisters or lesions], conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver transaminases, should be monitored and appropriate therapy initiated. For information regarding the long-acting properties of CABENUVA, see section below. Administer oral lead-in dosing prior to administration of CABENUVA to help identify patients who may be at risk of a hypersensitivity reaction.

Post-Injection Reactions: In clinical trials, serious post-injection reactions were reported within minutes after the injection of rilpivirine, including dyspnea, agitation, abdominal cramping, flushing, sweating, oral numbness, and changes in blood pressure. These events were reported in less than 1% of subjects and began to resolve within a few minutes after the injection. These events may have been associated with inadvertent (partial) intravenous administration. Carefully follow the Instructions for Use when preparing and administering CABENUVA to avoid accidental intravenous administration. Observe patients briefly (approximately 10 minutes) after the injection.

If a patient experiences a post-injection reaction, monitor and treat as clinically indicated.

Hepatotoxicity: Hepatotoxicity has been reported in patients receiving cabotegravir or rilpivirine with or without known pre-existing hepatic disease or identifiable risk factors. Patients with underlying liver disease or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations. Monitoring of liver chemistries is recommended and treatment with CABENUVA should be discontinued if hepatotoxicity is suspected. For information regarding long-acting properties of CABENUVA, see section below. Depressive Disorders: Depressive disorders (including depressed mood, depression, major depression, mood altered, mood swings, dysphoria, negative thoughts, suicidal ideation or attempt) have been reported with CABENUVA or the individual drug products. Promptly evaluate patients with depressive symptoms to assess whether the symptoms are related to CABENUVA and to determine whether the risks of continued therapy outweigh the benefits.

Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The concomitant use of CABENUVA and other drugs may result in known or potentially significant drug interactions, some of which may lead to adverse events, loss of virologic response of CABENUVA, and possible development of viral resistance.

Rilpivirine 75-mg and 300-mg once-daily oral doses (3 and 12 times the recommended oral dosage) in healthy adults resulted in mean steady-state Cmax values 4.4-fold and 11.6fold higher than Cmax values associated with the recommended 600-mg dose of rilpivirine extended-release injectable suspension and prolonged the QTc interval. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes. See the Drug Interactions section for steps to prevent or manage these possible and known significant drug interactions, including dosing recommendations.

Consider the potential for drug interactions prior to and during therapy with, and after discontinuation of CABENUVA; review concomitant medications during therapy with CABENUVA. Long-Acting Properties and Potential Associated Risks with CABENUVA: Residual concentrations of both cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer).

It is important to carefully select patients who agree to the required monthly injection dosing schedule because non-adherence to monthly injections or missed doses could lead to loss of virologic response and development of resistance. To minimize the potential risk of developing viral resistance, it is essential to initiate an alternative, fully suppressive antiretroviral regimen no later than 1 month after the final injection doses of CABENUVA. If virologic failure is suspected, switch the patient to an alternative regimen as soon as possible.

ADVERSE REACTIONS Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect rates observed in practice. The safety assessment of CABENUVA is based on the analysis of pooled 48-week data from 1,182 virologically suppressed subjects with HIV-1 infection in 2 international, multicenter, open-label pivotal trials, FLAIR and ATLAS. Additional safety information from other ongoing or earlier clinical trials in the cabotegravir and rilpivirine program have been considered in assessing the overall safety profile of CABENUVA. Adverse reactions were reported following exposure to CABENUVA extended-release injectable suspensions (median time exposure: 54 weeks) and data from VOCABRIA (cabotegravir) tablets and EDURANT (rilpivirine) tablets administered in combination as oral lead-in therapy (median time exposure: 5.3 weeks). Adverse reactions included those attributable to both the oral and injectable formulations of cabotegravir and rilpivirine administered as a combination regimen.

Refer to the prescribing information for EDURANT for other adverse reactions associated with oral rilpivirine. The most common adverse reactions regardless of severity reported in greater than or equal to 2% of adult subjects in the pooled analyses from FLAIR and ATLAS are presented in Table 3. Selected laboratory abnormalities are included in Table 4. Overall, 4% of subjects in the group receiving CABENUVA and 2% of subjects in the control group discontinued due to adverse events. Non-injectionsite-related adverse events leading to discontinuation and occurring in more than 1 subject were headache, diarrhea, hepatitis A, and acute hepatitis B (all with an incidence less than 1%).

Table 3. Adverse Reactionsa (Grades 1 to 4) Reported in at Least 2% of Subjects with HIV-1 Infection in FLAIR and ATLAS Trials (Week 48 Pooled Analyses) Cabotegravir plus Rilpivirine (n=591)

Current Antiretroviral Regimen (n=591)

All Grades

At Least Grade 2

All Grades

At Least Grade 2

Injection site reactionsb

83%

37%

0

0

Pyrexiac

8%

2%

0

0

Fatigued

5%

1%

<1%

<1%

Headache

4%

<1%

<1%

<1%

Musculoskeletal paine

3%

1%

<1%

0

Nausea

3%

<1%

1%

<1%

Sleep disordersf

2%

<1%

<1%

0

Dizziness

2%

<1%

<1%

0

Rashg

2%

<1%

0

0

Adverse Reactions

a

Adverse reactions defined as “treatment-related” as assessed by the investigator.

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

Injection-Associated Adverse Reactions: Local Injection Site Reactions (ISRs): The most frequent adverse reactions associated with the intramuscular administration of CABENUVA were ISRs. After 14,682 injections, 3,663 ISRs were reported. One percent (1%) of subjects discontinued treatment with CABENUVA because of ISRs. Most ISRs were mild (Grade 1, 75%) or moderate (Grade 2, 36%). Four percent (4%) of subjects experienced severe (Grade 3) ISRs, and no subjects experienced Grade 4 ISRs. The most commonly reported ISR was localized pain/discomfort (79%) regardless of severity or relatedness. Other manifestations of ISRs reported in more than 1% of subjects over the duration of the analysis period included nodules (14%), induration (12%), swelling (8%), erythema (4%), pruritus (4%), bruising (3%), warmth (2%), and hematoma (2%).

Abscess and cellulitis at the injection site were each reported in less than 1% of subjects. The median duration of ISR events was 3 days.

Other Injection-Associated Adverse Reactions: In the ATLAS and FLAIR clinical trials, an increased incidence of pyrexia (8%) was reported by subjects receiving cabotegravir plus rilpivirine injections compared with no events among subjects receiving current antiretroviral regimen. No cases were serious or led to withdrawal and the occurrences of pyrexia may represent a response to administration of CABENUVA via intramuscular (cont’d on next page)

BRIEF SUMMARY for CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use (cont'd) injection. Reports of musculoskeletal pain (3%) and less frequently, sciatica, were also more common in subjects receiving cabotegravir plus rilpivirine compared with the current antiretroviral regimen and some events had a temporal association with injection. Vasovagal or pre-syncopal reactions were reported in less than 1% of subjects after injection with rilpivirine or cabotegravir.

Less Common Adverse Reactions: The following select adverse reactions (regardless of severity) occurred in less than 2% of subjects receiving cabotegravir plus rilpivirine. Gastrointestinal Disorders: Abdominal pain (including upper abdominal pain), gastritis, dyspepsia, vomiting, diarrhea, and flatulence. Hepatobiliary Disorders: Hepatotoxicity. Investigations: Weight increase (see below). Psychiatric Disorders: Anxiety (including anxiety and irritability), depression, abnormal dreams. Skin and Hypersensitivity Reactions: Hypersensitivity reactions.

Weight Increase: At Week 48, subjects in FLAIR and ATLAS who received cabotegravir plus rilpivirine had a median weight gain of 1.5 kg; those in the current antiretroviral regimen group had a median weight gain of 1.0 kg (pooled analysis). In the FLAIR trial, the median weight gain in subjects receiving cabotegravir plus rilpivirine or a dolutegravir-containing regimen was 1.3 kg and 1.5 kg, respectively, compared with 1.8 kg and 0.3 kg in the ATLAS trial in subjects receiving either cabotegravir plus rilpivirine or a protease inhibitor-, non-nucleoside reverse transcriptase inhibitor (NNRTI)-, or integrase strand transfer inhibitor (INSTI)-containing regimen, respectively.

Laboratory Abnormalities: Selected laboratory abnormalities with a worsening grade from baseline and representing the worst-grade toxicity are presented in Table 4.

Table 4. Selected Laboratory Abnormalities (Grades 3 to 4; Week 48 Pooled Analyses) in FLAIR and ATLAS Trials

Laboratory Parameter

Cabotegravir plus Rilpivirine (n=591)

Current Antiretroviral Regimen (n=591)

ALT (≥5.0 x ULN)

2%

<1%

AST (≥5.0 x ULN)

2%

<1%

Total bilirubin (≥2.6 x ULN)

<1%

<1%

Creatine phosphokinase (≥10.0 x ULN)

8%

4%

Lipase (≥3.0 x ULN)

5%

3%

ULN = Upper limit of normal.

Changes in Total Bilirubin: Small, non-progressive increases in total bilirubin (without clinical jaundice) were observed with cabotegravir plus rilpivirine. These changes are not considered clinically relevant as they likely reflect competition between cabotegravir and unconjugated bilirubin for a common clearance pathway (UGT1A1). Serum Cortisol: In pooled Phase 3 trials of EDURANT (rilpivirine), the overall mean change from baseline in basal cortisol was -0.69 (-1.12, 0.27) micrograms/ dL in the group receiving EDURANT compared with -0.02 (-0.48, 0.44) micrograms/ dL in the control group. Abnormal responses to ACTH stimulation tests were also higher in the group receiving EDURANT. The clinical significance of the higher abnormal rate of ACTH stimulation tests in the group receiving EDURANT is not known. Refer to the prescribing information for EDURANT for additional information.

Postmarketing Experience: The following adverse reactions have been identified during postmarketing experience in patients receiving an oral rilpivirine-containing regimen. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Renal and Genitourinary Disorders: Nephrotic syndrome.

Skin and Subcutaneous Tissue Disorders: Severe skin and hypersensitivity reactions, including DRESS. DRUG INTERACTIONS Concomitant Use with Other Antiretroviral Medicines: Because CABENUVA is a complete regimen, coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended. Use of Other Antiretroviral Drugs after Discontinuation of CABENUVA: Residual concentrations of cabotegravir and rilpivirine may remain in the systemic circulation of patients for prolonged periods (up to 12 months or longer). These residual concentrations are not expected to affect the exposures of antiretroviral drugs that are initiated after discontinuation of CABENUVA. Potential for Other Drugs to Affect CABENUVA: Refer to the prescribing information for VOCABRIA and EDURANT for additional drug interaction information related to oral cabotegravir and oral rilpivirine, respectively. Cabotegravir: Cabotegravir is primarily metabolized by UGT1A1 with some contribution from UGT1A9. Drugs that are strong inducers of UGT1A1

or 1A9 are expected to decrease cabotegravir plasma concentrations and may result in loss of virologic response; therefore, coadministration of CABENUVA with these drugs is contraindicated. Rilpivirine: Rilpivirine is primarily metabolized by CYP3A. Coadministration of CABENUVA and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Coadministration of CABENUVA and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine.

QT-Prolonging Drugs: At mean steady-state Cmax values 4.4-fold and 11.6-fold higher than those with the recommended 600-mg dose of rilpivirine extended-release injectable suspension, rilpivirine may prolong the QTc interval. CABENUVA should be used with caution in combination with drugs with a known risk of Torsade de Pointes.

Established and Other Potentially Significant Drug Interactions: Refer to the prescribing information for VOCABRIA and EDURANT for additional drug interaction information related to oral cabotegravir and oral rilpivirine, respectively. Information regarding potential drug interactions with cabotegravir and rilpivirine is provided below. These recommendations are based on either drug interaction trials following oral administration of cabotegravir or rilpivirine or predicted interactions due to the expected magnitude of the interaction and potential for loss of virologic response. The following includes potentially significant interactions but is not all inclusive. ∞ Anticonvulsants: carbamazepine, oxcarbazepine, phenobarbital, phenytoin— coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Antimycobacterials: rifampin, rifapentine—coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Antimycobacterial: rifabutin—coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Glucocorticoid (systemic): dexamethasone (more than a single-dose treatment)—coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Herbal product: St. John’s wort (Hypericum perforatum)—coadministration is contraindicated with CABENUVA due to potential for loss of virologic response and development of resistance. ∞ Macrolide or ketolide antibiotics: azithromycin, clarithromycin, erythromycin— macrolides are expected to increase concentrations of rilpivirine and are associated with a risk of Torsade de Pointes. Where possible, consider alternatives, such as azithromycin, which increases rilpivirine concentrations less than other macrolides. ∞ Narcotic analgesic: methadone—no dose adjustment of methadone is required when starting coadministration of methadone with CABENUVA. However, clinical monitoring is recommended as methadone maintenance therapy may need to be adjusted in some patients.

Drugs without Clinically Significant Interactions: Cabotegravir: Based on drug interaction study results, the following drugs can be coadministered with cabotegravir (non-antiretrovirals and rilpivirine) or given after discontinuation of cabotegravir (antiretrovirals and non-antiretrovirals) without a dose adjustment: etravirine, midazolam, oral contraceptives containing levonorgestrel and ethinyl estradiol, and rilpivirine. Rilpivirine: Based on drug interaction study results, the following drugs can be coadministered with rilpivirine (non-antiretrovirals and cabotegravir) or given after discontinuation of rilpivirine (antiretrovirals and non-antiretrovirals): acetaminophen, atorvastatin, cabotegravir, chlorzoxazone, dolutegravir, ethinyl estradiol, norethindrone, raltegravir, ritonavir-boosted atazanavir, ritonavir-boosted darunavir, sildenafil, tenofovir alafenamide, and tenofovir disoproxil fumarate. Rilpivirine did not have a clinically significant effect on the pharmacokinetics of digoxin or metformin.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to CABENUVA during pregnancy.

Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary: There are insufficient human data on the use of CABENUVA during pregnancy to adequately assess a drugassociated risk of birth defects and miscarriage. While there are insufficient human data to assess the risk of neural tube defects (NTDs) with exposure to CABENUVA during pregnancy, NTDs were associated with dolutegravir, another integrase inhibitor.

Discuss the benefit-risk of using CABENUVA with individuals of childbearing potential or during pregnancy. Cabotegravir and rilpivirine are detected in systemic circulation for up to 12 months or longer after discontinuing injections of CABENUVA; therefore, consideration should be given to the potential for fetal exposure during pregnancy.

Cabotegravir use in pregnant women has not been evaluated. Available data from the APR show no difference in the overall risk of birth defects for rilpivirine compared with the background rate for major birth defects of 2.7% in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) (see Data). The rate of miscarriage is not reported in the APR. The background risk for major birth defects and miscarriage for the indicated population is unknown. The background rate for major birth defects in a U.S. reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP) is 2.7%. The estimated background rate of miscarriage in clinically recognized pregnancies in the U.S. general population is 15% to 20%. The APR uses the MACDP as the U.S. reference population for birth defects in the general population. The MACDP evaluates women and infants from a limited geographic area and does not include outcomes for births that occurred at less than 20 weeks’ (cont’d on next page)

BRIEF SUMMARY for CABENUVA (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for intramuscular use (cont'd) gestation. In animal reproduction studies with oral cabotegravir, a delay in the onset of parturition and increased stillbirths and neonatal deaths were observed in a rat pre- and postnatal development study at greater than 28 times the exposure at the recommended human dose (RHD). No evidence of adverse developmental outcomes was observed with oral cabotegravir in rats or rabbits (greater than 28 times or similar to the exposure at the RHD, respectively) given during organogenesis (see Data).

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

Pediatric Use: The safety and efficacy of CABENUVA have not been evaluated in pediatric patients. Geriatric Use: Clinical trials of CABENUVA did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently

from younger subjects. In general, caution should be exercised in administration of CABENUVA in elderly patients reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Renal Impairment: Based on studies with oral cabotegravir and population pharmacokinetic analyses of oral rilpivirine, no dosage adjustment of CABENUVA is necessary for patients with mild (creatinine clearance greater than or equal to 60 to less than 90 mL/min) or moderate renal impairment (creatinine clearance greater than or equal to 30 to less than 60 mL/min). In patients with severe renal impairment (creatinine clearance 15 to less than 30 mL/min) or end-stage renal disease (creatinine clearance less than 15 mL/min), increased monitoring for adverse effects is recommended. In patients with end-stage renal disease not on dialysis, effects on the pharmacokinetics of cabotegravir or rilpivirine are unknown. As cabotegravir and rilpivirine are greater than 99% protein bound, dialysis is not expected to alter exposures of cabotegravir or rilpivirine. Hepatic Impairment: Based on separate studies with oral cabotegravir and oral rilpivirine, no dosage adjustment of CABENUVA is necessary for patients with mild or moderate hepatic impairment (Child-Pugh A or B). The effect of severe hepatic impairment (Child-Pugh C) on the pharmacokinetics of cabotegravir or rilpivirine is unknown.

OVERDOSAGE There is no known specific treatment for overdose with cabotegravir or rilpivirine.

If overdose occurs, monitor the patient and apply standard supportive treatment as required, including monitoring of vital signs and ECG (QT interval) as well as observation of the clinical status of the patient. As both cabotegravir and rilpivirine are highly bound to plasma proteins, it is unlikely that either would be significantly removed by dialysis. Consider the prolonged exposure to cabotegravir and rilpivirine (components of CABENUVA) following an injection when assessing treatment needs and recovery.

Manufactured for:

ViiV Healthcare Research Triangle Park, NC 27709 by: GlaxoSmithKline Research Triangle Park, NC 27709 ©2021 ViiV Healthcare group of companies or its licensor.

CBN:1PI

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

IDSE Review

Updates in the Pipeline of HIV Therapy

BY DANIEL A. SOLOMON, MD,

M

AND

JONATHAN Z. LI, MD, MMSC

odern antiretroviral therapy (ART) for HIV is well tolerated and highly effective. Most people with HIV (PWH) achieve virologic suppression with currently available options. So, where is the room for improvement? The recent advances in HIV therapy focus on new options for both treatment-naive and treatment-experienced patients, simplified drug regimens, and novel treatment strategies that do not rely on adherence to daily oral medication.

In this article, we review the newest wave of ART, provide an update on 2-drug oral regimens, and discuss how treatment strategies may change with the approval of long-acting oral and injectable therapies.

The Most Exciting New Agents Recently Approved by the FDA Fostemsavir (FTR; Rukobia, ViiV Healthcare), the prodrug of temsavir, was approved in July 2020. FTR is a first-in-class glycoprotein 120 (gp120) attachment inhibitor that works by blocking viral attachment to the host CD4 cell. Compared with maraviroc (Selzentry, ViiV Healthcare), a CCR5 attachment inhibitor, it is active regardless of viral tropism, and there is no cross-resistance to any existing ART.1 The current role of FTR in HIV treatment is for patients with extensive antiviral resistance and limited therapeutic options. The BRIGHTE study was a phase 3 trial of patients experiencing virologic failure with multiclass resistance and no fully viable combination ART regimens available. When FTR was added to an optimized backbone for patients with 1 or 2 remaining active ART classes, 57% of individuals achieved a viral load less than 40 copies/mL at 48 weeks, compared with 45% in the placebo arm. For patients with no remaining antiretroviral options, 38% achieved a viral load less than 40 copies/mL at week 48, and participants demonstrated a mean increase in the CD4 cell count of 64 cells/mm3.2 FTR is an important addition to

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

55

IDSE Review

the armamentarium of salvage therapy for patients with multiclass antiviral resistance.

Submitted for Approval by the FDA Lenacapavir (LEN), developed by Gilead, is a highly potent, long-acting capsid inhibitor. Pharmacokinetic studies support subcutaneous injections every 6 months.3 Similar to FTR, as a first-in-class medication, this drug holds particular promise for patients with heavy treatment experience. In the CAPELLA study of patients with a long history of treatment with antiviral resistance (≤2 fully active agents from 4 main ART classes), the addition of subcutaneous LEN to an optimized backbone regimen led to virologic suppression in 81% of patients at week 26.4 Based on the preliminary data, in July 2021, Gilead submitted a New Drug Application to the FDA to be used for heavily treatment-experienced patients with multidrug-resistant (MDR) HIV. Due to its novel mechanism of delivery, LEN also holds promise as a long-acting first-line therapy for treatment-naive patients, and as a long-acting agent for HIV pre-exposure prophylaxis (PrEP). In CALIBRATE, a phase 2 study of treatment-naive patients, individuals treated with subcutaneous LEN in addition to emtricitabine (FTC) and tenofovir alafenamide (TAF) achieved rates of viral suppression greater than 90% by week 16. The subcutaneous injection was generally well tolerated with no grade 3 or 4 adverse events (AEs) related to LEN. The most frequent AEs were local erythema, pain, or swelling at the injection site.5

In Development Islatravir (ISL), a nucleoside reverse transcriptase translocation inhibitor being developed by Merck, is an adenosine analog that acts as a reverse transcriptase chain terminator and prevents DNA translocation.6 A key feature of the medication is its prolonged half-life.

As an oral medication, it may be an appealing strategy to decrease pill burden and is being tested as a oncemonthly oral agent in multiple phase 3 PrEP studies.7,8 Moreover, pharmacokinetic studies show that therapeutic levels of ISL can be sustained for longer than 6 months when the drug is administered by long-term drug-eluting implants.9 The implants hold promise for both HIV PrEP when used as monotherapy, and as treatment when used in combination with other medications. In a phase 1 study, the implant was found to be well tolerated and maintained adequate levels of ISL throughout the 12-week implantation period.10 The focus of the ISL drug development program also includes the evaluation of ISL-based 2-drug regimens, either as daily or weekly oral therapy, as reviewed later.

Albuvirtide (ABT), which is being developed by Frontier Biotechnologies, is a novel fusion inhibitor that binds to the gp41 envelope protein, preventing

56

IDSE.NET

HIV from fusing with the host cell membrane and entering the cell. Like the other medication in this class, enfuvirtide (Fuzeon, Genentech), it is administered by subcutaneous injection, but due to its prolonged half-life, it can be given just once weekly. Currently, the target population for this medication is people with multiclass resistance or intolerance of multiple classes of medications. The TALENT study is a phase 3 trial comparing ritonavir-boosted lopinavir plus either ABT or 2 nucleoside reverse transcriptase inhibitors (NRTIs) (second-line treatment recommended by the World Health Organization) in treatment-experienced participants in China experiencing virologic failure. An interim analysis at week 48 found that 80% of patients in the ABT arm had a viral load less than 50 copies/mL compared with 66% in the NRTI arm.11 ABT is approved for second-line therapy in China where access to alternative oral medications, like integrase strand transfer inhibitors (INSTIs), may be more limited.

Maintenance therapy for individuals with good virologic control is another potential use for ABT when combined with other agents. There are ongoing phase 2 studies of ABT plus 3BNC117 (a broadly neutralizing antibody) either as long-acting maintenance therapy in virologically suppressed patients12 or for those with MDR HIV.13

Promising Daily Oral 2-Drug Regimens Long-held dogma that effective ART must consist of 3 active antiretrovirals has been challenged by several recent studies suggesting that 2-drug therapy may be adequate for selected combinations. Two single-tablet, 2-drug regimens have been approved, and other combinations of oral medications are under investigation.

Approved Combinations Combination dolutegravir-rilpivirine (DTG/RPV; Juluca, ViiV Healthcare), approved in November 2017, was the first complete single-tablet regimen consisting of only 2 drugs. The combination has proven effective as a switch regimen in treatment-experienced patients who are virologically suppressed. In 2 identical phase 3, open-label trials, SWORD-1 and SWORD-2, treatment-experienced participants without non-NRTI (NNRTI) resistance and with good virologic control were randomly assigned to switch to DTG/RPV or remain on their current ART. Participants who were switched to DTG/RPV maintained virologic

suppression at 48 weeks, and experienced fewer AEs with better renal and bone outcomes than participants who remained on their current ART.14 Multiple observational studies have confirmed that patients maintain durable virologic suppression after switching to DTG/RPV.15,16 Coformulated DTG/RPV is a promising NRTI-sparing regimen for patients with side effects to current ART, contraindications to NRTIs, or who are just looking for regimen simplification. It is a particularly good option for patients with renal impairment, as exposure to DTG and RPV is not affected by decreased renal function. This combination has only been studied as a switch regimen in patients who are already virologically suppressed with no history of treatment failure or major drug resistance, and has not been assessed in treatment-naive individuals.

Coformulated DTG-lamivudine (DTG/3TC; Dovato, ViiV Healthcare) was approved in April 2019, making it the second complete regimen consisting of a single-tablet, 2-drug combination. In contrast to DTG/RPV, DTG/3TC has proven effective as initial therapy in treatment-naive individuals. GEMINI-1 and GEMINI-2 were identically designed large phase 3 studies comparing the 2-drug regimen of DTG/3TC with the 3-drug regimen DTG/FTC/tenofovir disoproxil fumarate (TDF) in ART-naive participants. At week 48, the 2-drug regimen was found to be noninferior to the 3-drug regimen, with fewer AEs. Of note, DTG/3TC was not associated with emergence

Under Investigation

Two-drug therapy is a focus of the ISL drug development program. The combination that is farthest along in clinical trials is ISL-doravirine (DOR), a highly potent NNRTI with a distinct resistance pathway from earlier generation NNRTIs. In a phase 2 clinical trial, DRIVE2SIMPLIFY, treatmentnaive patients underwent a 24-week leadin period with ISL/DOR/3TC. Participants who were then simplified to the daily 2-drug regimen ISL/DOR maintained high rates of virologic suppression.23 Preliminary results from 2 phase 3 switch studies also reported that daily treatment with the combination once-daily regimen of ISL/DOR maintained virologic suppression.24 ISL/DOR is also being evaluated in phase 3 studies of treatment-naive25 and treatment-experienced PWH.26 In addition, leveraging the long half-life of oral ISL, a dose-ranging study for once-weekly ART with ISL plus MK8507, a novel NNRTI also being developed by Merck, is underway,27 as is a phase 2 switch study of weekly oral ISL with oral LEN in PWH with virologic suppression.28

Long-Acting Injectable Therapy Long-acting injectable ART has been on the horizon for several years and holds promise as a paradigm shift for HIV treatment. Similar to monthly injections of other medications such as the contraceptive medroxyprogesterone acetate (Depo-Provera, Pfizer), long-acting injectable ART would preclude the need for daily oral medications. After a prolonged wait, Cabenuva, a monthly injection of cabotegravir (CAB; ViiV Healthcare), a novel INSTI, and RPV (Edurant, Janssen) were approved by the FDA in January 2021 for patients who are virologically suppressed on a stable ART regimen with no history of treatment failure and no known or suspected resistance to either CAB

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Recent advances in HIV therapy focus on new options for both treatment-naive and treatment-experienced patients, simplified drug regimens, and improved adherence.

of treatment-associated mutations.17 Multiple switch studies have demonstrated maintenance of viral suppression when patients with virologic control are transitioned to DTG/3TC, including a large phase 3 switch study called TANGO, which showed that DTG/3TC was noninferior in maintaining virologic suppression compared with TAFbased regimens.18-21 DTG/3TC is the first 2-drug regimen to be included as an option for treatment-naive individuals with a baseline viral load less than 500,000 copies/mL in the National Institutes of Health HIV/AIDS treatment guidelines.22 Because tenofovir is not included in the regimen, hepatitis B coinfection is a contraindication to this 2-drug regimen.

IDSE Review

or RPV. Patients are instructed to first switch to an oral formulation of CAB (Vocabria, ViiV Healthcare) and RPV for 1 month to assess tolerability before starting long-acting CAB/RPV. CAB/RPV has been studied in both treatment-naive and treatment-experienced individuals. The FLAIR trial included treatment-naive patients who were all given a 20-week period of oral DTG/abacavir/3TC. Participants who achieved virologic suppression after the oral lead-in period were randomized to continue the oral regimen or switch to monthly CAB/RPV injections. Using the primary end point of HIV-1 RNA viral load of no more than 50 copies/mL HIV-1 RNA, switching to CAB/RPV was found to be noninferior to continuing oral treatment. At week 48, 2.1% of patients in the long-acting injectable arm had HIV-1 RNA of no more than 50 copies/mL, compared with 2.5% of patients who continued oral therapy.29 Of note, individuals randomized to the switch arm first received oral CAB/RPV for 4 weeks to assess tolerability before starting the injections.

The ATLAS trial included treatment-experienced patients with virologic control and no baseline NNRTI or INSTI resistance who were randomized to remain on their current oral therapy or switch to monthly injections of CAB/RPV. In a similar outcome to the FLAIR trial, the long-acting injectable arm was noninferior at week 48, with 1.6% of participants found to have HIV-1 RNA of at least 50 copies/mL compared with 1.0% in the oral arm.30 The medication is administered every 4 weeks, but in ATLAS-2M, a recently published phase 3b study, rates of virologic suppression were noninferior when doses were administered every 8 weeks compared with every 4 weeks in a week 96 analysis.31 Injectable CAB/RPV also may shift the paradigm for HIV PrEP. Multiple studies have demonstrated that the injection is safe and well tolerated in HIV-uninfected individuals.32,33 Two paired studies, HPTN 083 (which enrolled cisgender men and transgender women who have sex with men) and HPTN 084 (which enrolled cisgender women in sub-Saharan Africa), compared the efficacy of CAB injections with oral TDF/FTC for PrEP. Both studies were stopped early by the data safety monitoring board when long-acting CAB administered every 8 weeks was found to be statistically superior to daily oral TDF/FTC.34,35

Conclusion In 2021, most patients with HIV who are engaged in care are virologically suppressed, but advances have led to simplified regimens, decreased cumulative drug exposure, and expanded therapeutic options for patients with multiclass resistance. The field continues to evolve with the recent approval of the first long-acting injectable combination, as well as drugs from novel classes and drug-eluting implants on the horizon.

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References 1.

Nowicka-Sans B, Gong Y-F, McAuliffe B, et al. In vitro antiviral characteristics of HIV-1 attachment inhibitor BMS-626529, the active component of the prodrug BMS-663068. Antimicrob Agents Chemother.

2012;56(7):3498-3507.

2. Kozal M, Aberg J, Pialoux G, et al. Fostemsavir in adults with multidrug-resistant HIV-1 infection. N Engl J Med. 2020;382(13):1232-1243.

3. Begley R, Lutz J, Rhee M, et al. GS-6207 sustained delivery formulation supports 6-month dosing interval.

Presented virtually at: International AIDS Conference; July 6-10, 2020. Abstract 8533.

4. Molina JM, Segal-Maurer S, Stellbrink HJ, et al. Efficacy and safety of long-acting subcutaneous lenacapavir in phase 2/3 in heavily treatment-experienced people with HIV: week 26 results (Capella study). Presented at: International AIDS Conference; July 18-21, 2021; Berlin, Germany. Abstract 2605.

5. Gupta SK, Berhe M, Crofoot G, et al. Long-acting subcutaneous lenacapavir dosed every six months as part of a combination regimen in treatment-naive people with HIV: interim 16-week results of a randomized, open-label, phase 2 induction-maintenance study (CALIBRATE).

J Int AIDS Soc. 2021;24:13.

6. Michailidis E, Huber AD, Ryan EM, et al. 4’-Ethynyl-2fluoro-2’-deoxyadenosine (EFdA) inhibits HIV-1 reverse transcriptase with multiple mechanisms. J Biol Chem.

2014;289(35):24533-24548.

7. Oral Islatravir (MK-8591) Once-Monthly as Preexposure Prophylaxis (PrEP) in Men and Transgender Women Who Have Sex With Men and Are at High Risk for HIV-1 Infection (MK-8591-024) (Impower-024). Accessed October 26, 2021. https://clinicaltrials.gov/ct2/show/ NCT04652700 8. Oral ISL QM as PrEP in Cisgender Women at High Risk for HIV-1 Infection (MK-8591-022) (Impower-022).

Accessed October 26, 2021. https://clinicaltrials.gov/ct2/ show/NCT04644029 9. Barrett SE, Teller RS, Forster SP, et al. Extended-duration MK-8591-eluting implant as a candidate for HIV treatment and prevention. Antimicrob Agents Chemother.

2018;62(10). doi:10.1128/AAC.01058-18 10. Matthews RP, Patel M, Barrett SE, et al. Safety and pharmacokinetics of islatravir subdermal implant for HIV-1 pre-exposure prophylaxis: a randomized, placebo-controlled phase 1 trial. Nat Med. 2021;27(10):1712-1717.

11. Su B, Yao C, Zhao Q-X, et al. Efficacy and safety of the long-acting fusion inhibitor albuvirtide in antiretroviral-experienced adults with human immunodeficiency virus-1: interim analysis of the randomized, controlled, phase 3, non-inferiority TALENT study. Chin Med J. 2020;133(24):2919-2927.

12. Albuvirtide and 3BNC117 as Long-Acting Maintenance Therapy in Virologically Suppressed Subjects (ABL).

Accessed October 15, 2021. https://clinicaltrials.gov/ct2/ show/NCT03719664 13. Albuvirtide in Combination With 3BNC117 in Patients With Multi-Drug Resistant (MDR) HIV-1 Infection.

Accessed October 26, 2021. https://clinicaltrials.gov/ct2/ show/NCT04560569 14. Llibre JM, Hung C-C, Brinson C, et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for the maintenance

(HIV-1) Infection (MK-8591A-020). Accessed October 27, 2021. https://clinicaltrials.gov/ct2/show/NCT04233879

15. Capetti AF, Cossu MV, Sterrantino G, et al. Dolutegravir plus rilpivirine as a switch option in cART-experienced patients: 96-week data. Ann Pharmacother.

2018;52(8):740-746.

26. Doravirine/Islatravir (DOR/ISL) in Heavily Treatment-Experienced (HTE) Participants for Human Immunodeficiency Virus Type 1 (HIV-1) Infection (MK-8591A-019). Accessed October 27, 2021. https://clinicaltrials.gov/ct2/show/NCT04233216

16. Palacios R, Mayorga M, González-Domenech CM, et al. Safety and efficacy of dolutegravir plus rilpivirine in treatment-experienced HIV-infected patients: the DORIVIR study. J Int Assoc Provid AIDS Care.

2018;17:2325958218760847.

27. Dose Ranging, Switch Study of Islatravir (ISL) and MK-8507 Once-Weekly in Virologically-Suppressed Adults With Human Immunodeficiency Virus Type 1 (HIV1) [MK-8591-013]. Accessed October 15, 2021. https:// clinicaltrials.gov/ct2/show/NCT04564547

17. Cahn P, Madero JS, Arribas JR, et al. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet.

2019;393(10167):143-155.

28. Study Evaluating the Safety and Efficacy of Islatravir in Combination With Lenacapavir in Virologically Suppressed People With HIV. Accessed October 26, 2021. https://clinicaltrials.gov/ct2/show/NCT05052996

18. Joly V, Burdet C, Landman R, et al. Dolutegravir and lamivudine maintenance therapy in HIV-1 virologically suppressed patients: results of the ANRS 167 trial (LAMIDOL). J Antimicrob Chemother. 2019;74(3):739-745.

19. Li JZ, Sax PE, Marconi VC, et al. No significant changes to residual viremia after switch to dolutegravir and lamivudine in a randomized trial. Open Forum Infect Dis. 2019;6(3):ofz056.

20. Taiwo BO, Marconi VC, Berzins B, et al. Dolutegravir plus lamivudine maintains human immunodeficiency virus-1 suppression through week 48 in a pilot randomized trial.

Clin Infect Dis. 2018;66(11):1794-1797.

21. van Wyk J, Ajana F, Bisshop F, et al. Efficacy and safety of switching to dolutegravir/lamivudine fixed-dose 2-drug regimen vs continuing a tenofovir alafenamidebased 3- or 4-drug regimen for maintenance of virologic suppression in adults living with human immunodeficiency virus type 1: phase 3, randomized, noninferiority TANGO study. Clin Infect Dis. 2020;71(8):1920-1929.

22. National Institutes of Health. Guidelines for the use of antiretroviral agents in adults and adolescents living with HIV. Accessed November 3, 2021. https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/ whats-new-guidelines 23. Molina J-M, Yazdanpanah Y, Afani Saud A, et al. Islatravir in combination with doravirine for treatment-naive adults with HIV-1 infection receiving initial treatment with islatravir, doravirine, and lamivudine: a phase 2b, randomised, double-blind, dose-ranging trial. Lancet HIV. 2021;8(6):e324-e333.

24. Merck announces positive top-line results from pivotal phase 3 trials evaluating investigational, once-daily oral fixed dose combination of doravirine/islatravir for the treatment of people with HIV-1 infection. Merck; October 25, 2021. Accessed November 1, 2021. https://www. merck.com/news/merck-announces-positive-top-lineresults-from-pivotal-phase-3-trials-evaluating-investigational-once-daily-oral-fixed-dose-combination-of-doravirine-islatravir-for-the-treatment-of-people-with-hiv-1/ 25. Randomized, Double-blind, Efficacy, and Safety Study of Doravirine/Islatravir (DOR/ISL) in Treatment-naïve Participants With Human Immunodeficiency Virus Type 1

29. Orkin C, Arasteh K, Górgolas, et al. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 2020;382(12):1124-1135.

30. Swindells S, Andrade-Villanueva J-F, Richmond GJ, et al. Long-acting cabotegravir and rilpivirine for maintenance of HIV-1 suppression. N Engl J Med. 2020;382(12):1112-1123.

31. Jaeger H, Overton ET, Richmond G, et al. Long-acting cabotegravir and rilpivirine dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 96-week results: a randomised, multicentre, open-label, phase 3b, noninferiority study. Lancet HIV. Published online October 11, 2021. doi:10.1016/S2352-3018(21)00185-5 32. Landovitz RJ, Li S, Grinsztejn B, et al. Safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in low-risk HIV-uninfected individuals: HPTN 077, a phase 2a randomized controlled trial. PLoS Med. 2018;15(11):e1002690.

33. Markowitz M, Frank I, Grant RM, et al. Safety and tolerability of long-acting cabotegravir injections in HIVuninfected men (ECLAIR): a multicentre, double-blind, randomised, placebo-controlled, phase 2a trial. Lancet HIV. 2017;4(8):e331-e340.

34. Landovitz RJ, Donnell D, Clement ME, et al. Cabotegravir for HIV prevention in cisgender men and transgender women. N Engl J Med. 2021;385(7):595-608.

35. Marzinke MA, Delany-Moretlwe S, Agyei Y, et al. Longacting injectable PrEP in women. Accessed October 18, 2021. https://www.hptn.org/sites/default/files/inlinefiles/210708%20HPTN%20084%20Poster%20final.pdf

About the authors Daniel A. Solomon, MD, is an infectious disease specialist with the Division of Infectious Diseases at Brigham and Women’s Hospital; and an instructor of medicine at Harvard Medical School, in Boston, Massachusetts.

Jonathan Z. Li, MD, MMSc, is an infectious disease specialist with the Division of Infectious Diseases at Brigham and Women’s Hospital; and an associate professor of medicine at Harvard Medical School, in Boston, Massachusetts.

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of virological suppression in adults with HIV-1: phase 3, randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018;391(10123):839-849.

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IDSE Review

Rapid Diagnostic Tests Inform Better Diagnostic and Treatment Decisions

BY AMY K. FEEHAN, PHD; JULIA GARCIA-DIAZ, MD, MSC, FACP, FIDSA, CPI; AND ANDREA J. LINSCOTT, PHD, D(ABMM)

R

apid diagnostic testing (RDT) provides convenient and immediate diagnostic results for patients in inpatient, outpatient, and home settings. RDTs allow treatment teams and patients to make quick, informed decisions about health care and limit unnecessary treatment regimens. Overall, faster diagnostic results improve patient outcomes, mitigate disease spread, decrease hospital length of stay (LOS), and aid in the fight against unnecessary antibiotic use and/or antibiotic resistance.

Respiratory infections from viral and bacterial pathogens are a major cause of morbidity and mortality, especially during the COVID-19 pandemic.

Prior to the pandemic, the World Health Organization estimated the global burden of acute respiratory illness at roughly 3.9 million people annually,1 with an additional 269.4 million infections and more than 5.3 million deaths due to the pandemic as of December 13, 2021.2 The National Foundation for Infectious Diseases reported that respiratory syncytial virus (RSV) in older patients was responsible for 177,000 hospitalizations and 14,000 deaths in the United States annually.3 Etiologies vary depending on the season and patient demographics, especially within

specific populations such as the elderly, infants, and the immunocompromised where there are high rates of complications.4 The pandemic has affected older individuals in particular, with an estimated infection fatality ratio of more than 8% for those older than 80 years of age.5 Aside from these vulnerable populations, most respiratory infections are self-limited and will resolve without treatment, although unnecessary antibiotic use is still rampant.6 Rapid tests are especially crucial for infections that require rapid treatment, such as influenza, or in the case of public health outbreak control when containing an infection in someone who is not particularly vulnerable, such tests can protect those who

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would be most at risk, such as with COVID-19. Rapid assessment can also keep providers from handing out unnecessary antibiotic prescriptions to be taken until test results are available.

Bloodstream infections (BSIs) are another major cause of preventable hospital-related deaths, which in addition to increased morbidity, exacerbate LOS and increase excess costs. With more than 60,000 BSI episodes per year7 and $10,000 to $20,000 per patient in excess hospital costs,8 the cost burden of these infections in the United States ranges from $600 million to $1.2 billion annually. Septicemia was noted as the most expensive reason for hospitalization (approximately $15.4 million) by Buehler et al.9 Bouza et al found that 58% of patients receive inadequate therapy with initial empiric treatment, leading to increased mortality rates.10 Results from antimicrobial susceptibility testing (AST) usually take a few days for blood cultures. However, recent developments in technological advancements can substantially improve the diagnostic yield and turnaround time, ultimately improving patient care.11 Although RDTs have been recommended by the Infectious Diseases Society of America, some have not yet been widely implemented due to the high initial costs of RDTs and uncertainty of the potential savings.12 However, rapid diagnosis may lead to lower costs, improved quality of health care, and reduced antimicrobial resistance.13 This update covers rapid testing methods that can reduce the time to identification and/or susceptibilities of respiratory infections and blood cultures.

Rapid Identification for Respiratory Infections Multiplex polymerase chain reaction (PCR) testing platforms amplify multiple targets using multiple primer sets in a reaction mixture.14 Multiplex PCR can identify and differentiate a range of viral and bacterial targets, often with only 1 specimen collected from a patient.15,16 Most multiplex PCR diagnostic tests must be performed by a laboratory. On the other hand, point-of-care (POC) testing use automated technologies and can be used in clinics or other outpatient settings (eg, pop-up testing events).17 Due to the pandemic, more than 250 molecular tests have been used under an emergency use authorization (EUA) for detection of SARS-CoV-2 at the time of writing this article,18 and those that give rapid results are discussed here.

Multiplex PCR Testing Platforms BioFire Respiratory Panel 2.1 (RP2.1; bioMérieux) covers 22 viral and bacterial targets in a single reaction, including SARS-CoV-2, and was the first diagnostic to be fully (rather than EUA) approved for detection of SARS-CoV-2 through the FDA’s de novo

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Developments in testing technology substantially improves the diagnostic yield and turnaround time for antimicrobial susceptibility testing.

premarket review pathway.18,19 The RP2.1 has a run time of 45 minutes.19 Madigan et al found that the RP2 had a significant diagnostic yield of 57.3% compared with the in-house PCR at 39.5%.20 In immunocompromised hosts undergoing bronchoscopy, the results showed that lower airway samples were comparable to nasopharyngeal swabs; however, this specimen type has not been FDA approved but could play an important role for management of respiratory illness.21 In a headto-head test of the BioFire RP2.1 panel, Roche cobas, Cepheid Xpert Xpress, BioFire Defense COVID19, and NECoV19, the BioFire RP2.1 consistently detected SARS-CoV-2—even at low viral titers (cycle threshold values >30).22 The ePlex Respiratory Pathogen Panel (GenMark Diagnostics) covers 18 viral targets and 3 bacterial targets, and is a cartridge-based assay using electrowetting technology followed by nucleic acid extraction and amplification, allowing rapid results.23 The ePlex has regulatory approval in the United States, including a recent EUA approval of a second version of the cartridge that has the ability to detect SARS-CoV-2 in addition to the other 21 targets.24,25 Compared with real-time PCR results, the ePlex provided 99.1% agreement and showed good detection rates with lower viral and bacterial loads.23 Minimal hands-on time and quick results reduce costs and aid clinicians with appropriate therapies.23 The ePlex provides results in just under 3.5 hours, nearly 8 times faster than laboratory-developed real-time PCR, which clocks in at around 27 hours.26 Babady et al performed a multicenter evaluation and found that the ePlex has equivalent performance to the BioFire RP for all targets.27 Another set of multiplex PCR testing panels are the NxTAG Respiratory Pathogen Panel (RPP) and NxTAG

POC Testing The Abbott ID NOW (Abbott Laboratories, formerly Alere i) influenza rapid test was the first Clinical Laboratory Improvement Amendments–waived molecular POC test available.32 The ID NOW has become a household name thanks to the pandemic and the ability of the ID NOW to produce results within 15 minutes for SARS-CoV-2, which has been critical for stopping outbreaks.32 The ID NOW influenza A/B assay also provides results in less than 15 minutes, the strep A test in less than 8 minutes, and RSV assay within 13 minutes.32 The ID NOW RSV assay has shown high sensitivity (98%) and specificity (97.5%) in young children and older adults with likely respiratory infections, and detects 25% more true positives than rapid antigen detection tests.33,34 However, more research is needed to confirm the accuracy of these results for the older population.33 Abbott also has a BinaxNOW lateral flow card similar to the SARS-CoV-2 test covered later in the at-home testing section, but this card must be read by the DIGIVAL device, making it inaccessible for at-home use.35 The cobas Liat System (Roche Diagnostics) has approved tests for SARS-CoV-2 and influenza A/B, influenza A/B, influenza A/B and RSV, and group A strep.36 It works in 3 easy steps with minimal handson time and results in under 20 minutes. In a retrospective study, the cobas influenza A/B showed 100% specificity for both and sensitivity of 96% and 100%, respectively.37 However, a study in a large emergency department comparing cobas versus Fast Track Diagnostics Respiratory pathogens 21 multiplex PCR and Xpert Xpress Flu/RSV assay found that the detection for influenza A or B had a sensitivity of 85% and specificity of 98% (positive predictive value, 95%; negative

predictive value, 94%).38 The cobas Liat SARS-CoV-2 and influenza A/B assays performed as accurately as the Xpress SARS-CoV-2 assay for SARS-CoV-2 detection with nasopharyngeal and posterior oropharyngeal samples.39 Compared with the Alere i (now the ID NOW influenza A/B POC, the cobas influenza A/B had a sensitivity and specificity of 97.9% and 97.5% versus the Alere I (63.8% and 97.5%, respectively).40 In this and another study, the cobas assay performed more like a laboratory-based PCR.40,41 The cobas influenza A/B and RSV assay had a sensitivity and specificity of 100% for both influenza A and B and 99.5% and 100% for RSV, respectively.42 The cobas, the Luminex xTAG respiratory pathogen panel, and the ePlex panel resulted in 20 minutes, 6 hours, and 2 hours, respectively.42 One study did a head-to-head comparison of 4,981 PCR-tested samples collected at the same time as 6 rapid POC tests for SARS-CoV-2: the ID NOW, Atila iAMP, AQ-TOP Plus COVID-19 Rapid Detection Kit, Genechecker UF-300 real-time PCR (RT-PCR) system, cobas Liat System SARS-CoV-2 and influenza A/B nucleic acid test, and the POCKIT SARS-CoV-2 (orf lab) (RT insulated isothermal PCR) assay.43 Compared with non-rapid PCR, the AQ-TOP was the most sensitive (98%) followed by Genechecker (95.23%) and the ID NOW (95.18%). The Genechecker system, ID NOW, and cobas Liat were the best-performing tests compared with non-rapid RT-PCR for SARS-CoV-2 detection.43 Cepheid Inc has 3 assays for SARS-CoV-2, influenza, and RSV: the Xpert Xpress CoV-2/Flu/RSV plus, Xpert Flu/RSV Extended Coverage (XC), and the Xpert Xpress Flu/RSV (Xpress).44 The new 4-in-1 test, the Xpert Xpress CoV-2/Flu/RSV plus, was compared with the Xpert Xpress SARS-CoV-2 and Xpert Xpress Flu/RSV, which demonstrated agreement for SARSCoV-2, influenza A, influenza B, and RSV at 99.64%, 100%, 99.64%, and 100%, respectively, which suggests that accuracy is lost in the combined assay. A study on both Cepheid Flu/RSV assays found that the accuracy of the Xpress assay was 100% and the XC assay was 97.4% for influenza A, 100% for influenza B, and 98.7% for RSV when both assays were compared with the laboratory-developed tests as a reference.45 Schmidt et al compared the cobas and Xpress assays and found the cobas to have significantly higher detection rates for influenza B.46 The sensitivity and specificity reported for influenza A were 98.80% and 99.12%, and 98.76% and 96.33% for influenza B, respectively.46 The Xpress versus XC assays differ in the time to results (32 vs 63 minutes, respectively).45 However, the Xpress assay can give a 20-minute early callout for positive samples for flu- and RSV-only assays.44 Wabe et al found that use of the XC assay was associated with an 8.9-hour reduction in LOS for all patients, and a 21.5hour reduction in LOS in positive patients.47 Reduced

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RPP + SARS-CoV-2 from Luminex Corporation, with 18 viral and 2 bacterial targets (plus SARS-CoV-2 in the latter), a run time of less than 4 hours, and total handson time of 7 minutes per 24 samples.28 These tests are scalable; 96 samples can be tested with results in fewer than 3 hours post-extraction. The NxTAG RPP + SARS-CoV-2 demonstrated a 97.8% sensitivity and 100% specificity for SARS-CoV-2, and was greater than 85% sensitive, even at low viral titers.29 Finally, the Abbott Alinity m Resp-4-Plex assay simultaneously tests for RNA from influenza A and B, RSV, and SARS-CoV-2 in a single nasal or nasopharyngeal swab.30 The time to first results is less than 115 minutes, and the test can be scaled to produce 1,080 within 24 hours, depending on lab practices. Accuracy is high and agreed with results from the Xpert Xpress SARS-CoV-2/Flu/RSV.31 These particular multiplex diagnostics will be extremely useful as pandemic restrictions ease and respiratory viruses start to circulate again because COVID-19, the flu, and RSV have such similar presentations.

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testing of blood cultures, sputum cultures, bacterial serology, and viral serology was an added benefit of rapid viral detection by the XC assay.47 Further

research is needed regarding an economic analysis to assess the effect that rapid PCR testing has on clinical decision making.47 Further enhancements to these

Table 1. At-Home SARS-CoV-2 Diagnostic Testing Approved for Emergency Use by the FDA (As of October 2021) Date EUA Issued or Last Updated

Date EUA Originally Issued

Diagnostic Name

Entity

Ellume COVID-19 Home Test

Ellume Limited

2/11/2021

12/15/2020

Lateral Flow, Fluorescence, Instrument Read, Over the Counter (OTC) Home Testing, Screening

BinaxNOW COVID-19 Ag Card Home Test

Abbott Diagnostics Scarborough, Inc.

4/12/2021

12/16/2020

Lateral Flow, Visual Read, Prescription Home Testing

QuickVue At-Home COVID-19 Test

Quidel Corporation

3/1/2021

3/1/2021

Lateral Flow, Visual Read, Prescription Home Testing

QuickVue At-Home OTC COVID-19 Test

Quidel Corporation

10/21/2021

3/31/2021

Lateral Flow, Visual Read, Over the Counter (OTC) Home Testing, Serial Screening

BinaxNOW COVID-19 Antigen Self Test

Abbott Diagnostics Scarborough, Inc.

8/10/2021

3/31/2021

Lateral Flow, Visual Read, Over the Counter (OTC) Home Testing, Serial Screening

BinaxNOW COVID-19 Ag Card 2 Home Test

Abbott Diagnostics Scarborough, Inc.

3/31/2021

3/31/2021

Lateral Flow, Visual Read, Over the Counter (OTC) Home Testing, Telehealth Proctor Supervised, Serial Screening

InteliSwab COVID-19 Rapid Test Rx

OraSure Technologies, Inc.

6/4/2021

6/4/2021

Lateral Flow, Visual Read, Prescription Home Testing

InteliSwab COVID-19 Rapid Test

OraSure Technologies, Inc.

6/4/2021

6/4/2021

Lateral Flow, Visual Read, Over the Counter (OTC) Home Testing, Serial Screening

CareStart COVID-19 Antigen Home Test

Access Bio, Inc.

8/23/2021

8/2/2021

Lateral Flow, Visual Read, Over the Counter (OTC) Home Testing, Serial Screening

BD Veritor At-Home COVID19 Test

Becton, Dickinson and Company (BD)

8/24/2021

8/24/2021

Lateral Flow, Digital Read, Over the Counter (OTC) Home Testing, Serial Screening

Flowflex COVID-19 Antigen Home Test

ACON Laboratories, Inc

10/19/2021

10/4/2021

Lateral Flow, Visual Read, Over the Counter (OTC) Home Testing

Celltrion DiaTrust COVID-19 Ag Home Test

Celltrion USA, Inc.

10/21/2021

10/21/2021

Lucira CHECK-IT COVID-19 Test Kit

Lucira Health, Inc.

4/9/2021

4/9/2021

RT, LAMP, Over the Counter (OTC) Home Testing, Screening

Cue COVID-19 Test for Home and Over The Counter (OTC) Use

Cue Health Inc.

3/5/2021

3/5/2021

RT, Isothermal amplification, Over the Counter (OTC) Home Testing, Screening

Lucira COVID-19 All-In-One Test Kit

Lucira Health, Inc.

11/18/2020

11/17/2020

Reproduced from fda.gov.18,51

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Attributes

Lateral Flow, Visual Read, Over the Counter (OTC) Home Testing, Serial Screening

Prescription Home Testing

At-Home Testing

MALDI-TOF There are 2 different manufacturers for MALDI-TOF used in the clinical laboratory: Bruker MALDI-TOF and bioMérieux VITEK MS. Positive blood cultures are taken using fluid from the positive blood culture bottle and processed using a specialized kit, such as the Bruker MBT Sepsityper, or using organism growth on an agar plate.57 MALDI-TOF rapidly identifies pathogen protein biomarkers with molecular mass profiling.

Because of the pandemic, numerous companies have attempted to make rapid at-home testing kits to detect SARS-CoV-2. While the gold standard for sensitivity and specificity is still PCR, experts have 53 argued that in the battle to reduce transmission, rapid 49 The combination of MALDI-TOF with positive blood at-home tests like BinaxNOW can be used to detect the infectious period.50 PCR testing can remain posicultures can identify pathogens in less than 1 hour,58 tive for a month or beyond, but a with a success rate of 81.8% for person is only infectious for about MALDI-TOF MS used after pos10 days, which the rapid tests can itive blood cultures.59 The success rate by bacterial type varied: generally detect. As of the writgram-negative aerobes at 85%, ing of this article, 12 home antigen gram-positive aerobes at 78.2%, tests have an EUA and are listed in and anaerobes at 67%.59 Using a the Table.51 In addition to approved home rapid AST such as the Alifax Alfred diagnostics for SARS-CoV-2, the 60AST (light-scattering technolpandemic has caused a proliferogy), currently not available in ation of home collection kits18 for the United States, after the direct respiratory testing that could pave MALDI-TOF MS identification the way for home-collected samyielded agreement with Thermo ARIs, acute respiratory infections. ples sent to laboratories for tradiScientific SensiTitre (Thermo Source: WHO. tional molecular testing or rapid Fisher Scientific) technology for multiplex testing. Home collecgram-negative organisms at 91.1% tions could mitigate the spread and gram-positive organisms at of respiratory infections in doctors’ offices and make 95.7%.60 By contrast, a large clinical laboratory tested 100 positive blood cultures for gram-negative bacilli testing more convenient and available for patients. using the VITEK MS, which correctly identified 86% Rapid Identification for Blood Cultures of the samples.61 The MALDI-TOF MS portion takes up Blood cultures are the universal gold standard for to 10 minutes, but the total time—including the initesting blood-borne pathogens, established in 1940.52 tial positive blood cultures required to complete the The testing methods discussed here illustrate the benprocess—takes up to 25 hours.59 These early results assist physicians in making informed decisions regardefits of rapid tests when used in addition to blood ing patient care earlier than the gold-standard method cultures. Matrix-assisted laser desorption/ionization of using blood cultures alone.59 There is also an added time-of-flight (MALDI-TOF) technology has been most benefit of the low cost per isolate at $0.20.59 commonly used in laboratories and uses mass spec53 Osthoff et al found that rapid identification of trometry (MS) to profile organisms. Depending on the blood culture results, certain peptide nucleic acid blood-borne pathogens led to a shorter duration of fluorescence in situ hybridization (PNA-FISH) methIV antibiotics (4.6 vs 7.5 days), but rapid identification ods can identify pathogens by binding a fluorescently using MALDI-TOF on positive blood cultures did not labeled probe to specific targets for visual identificaaffect the duration.62 However, another study showed a decrease in mortality rates just 30 days after impletion.54 Multiplex PCR also is used after positive blood culture results, and can amplify and identify a range of menting MALDI-TOF with antimicrobial stewardship blood pathogens. program (ASP) pharmacist real-time review (21%T2Biosystem Panels directly identifies pathogens 12%), even without a statistical difference in hospital from whole blood by measuring the reaction of water LOS.63 This method also resulted in an annual savings of $2.34 million for the hospital at a rate of $2,439 per molecules in a magnetic field independent of blood BSI.63 culture.55 Lastly, the Accelerate Pheno System (AccelLimitations of MALDI-TOF include the high initial erate Diagnostics) is a fully automated system using cost for instrumentation, the need for improvement morphokinetic cellular analysis with fully automated and expansion of reference databases, and the lack of FISH to identify and generate the minimum inhibitory ability to differentiate certain species, such as Escheconcentration and uses dynamic dilution to produce richia coli from Shigella.64 MALDI-TOF MS is not easily AST results from positive blood cultures.56

Global burden for ARIs:

3.9

million people annually

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

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tools, especially the addition to the SARS-CoV-2 test, may be more beneficial in acute care settings and have a greater impact on decision making.44,48

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accessible to all laboratories, but some have suggested developing an instrument that could separate the blood culture into a cartridge, lyse and filter the sample, and then load the sample into wells with panels of antibiotics and controls before using the MALDI-TOF MS target.65 MALDI-TOF MS also can detect betalactamase and carbapenemase production57 and identify yeasts directly from positive blood culture bottles in 30 minutes without a subculture.66

PNA-FISH PNA-FISH by OpGen allows rapid identification of bacteria and yeast directly from positive blood cultures.67 This method covers pathogens for the majority of BSIs such as Staphylococcus aureus/coagulase-negative staphylococci (CoNS), Enterococcus faecalis/ other enterococci, gram-negatives (panel: E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa), and Candida species.67 The turnaround time is less than 90 minutes, versus 48 hours for standard conventional methods, improving clinical management and lowering costs.67 Although the hands-on time is only 10 minutes, this technique requires a skilled technologist for interpretation.

A 7-year study performed at a single institution with the Yeast Traffic Light PNA FISH (OpGen) panel yielded 92% growth for 5 Candida species with mono- and polymicrobial growth blood culture bottles.68 The results were 98.9% correct and did not show any false-positive results compared with MALDI-TOF MS, which correctly identifies yeast in 91.3% of cases.68 PNA-FISH with an ASP, including the cost of the blood culture, did not show any differences in terms of cost or effectiveness.12 PNA-FISH without an ASP was associated with a higher effectiveness but also a higher cost at baseline.12 The Yeast Traffic Light PNA FISH panel is an FDA-cleared 3-probe system that can identify Candida albicans, Candida parapsilosis, Candida glabrata, Candida krusei, and Candida tropicalis within 90 minutes.67 The total time to identification can be reduced to 9.5 versus 44 hours with standard testing methods, and a reduction in cost per patient of roughly $2,000.66

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Multiplex PCR Multiplex PCR methods can perform fast pathogen identification and detection of a few antimicrobial resistance genes but do not offer AST. The BioFire FilmArray Blood Culture Identification Panel (BCID; bioMérieux) has 27 targets in 1 panel consisting of 8 gram-positive, 11 gram-negative, 5 yeast, and 3 resistance markers.19 The system is easy to use with 2 minutes of hands-on time and a rapid turnaround time of about 1 hour.19 Implementing BCID with real-time ASP decision support intervention in a pediatric population caused a significant decrease in time to therapy (26.7 hours vs standard methods at 60.2 hours).69 However, real-time ASP decision support depends on the resources available, as time constraints due to staffing may exist.69 In another study, 44 patients were switched to new treatments based on the rapid test results, which accurately identified 91% of cases for on-panel organisms, with an average 2.4hour turnaround time.70 Other studies have agreed that BCID allows for faster identification of BSIs and can reduce the duration of therapy with broad-spectrum antibiotics.71 BCID correctly identified 81 of 83 isolates, with roughly 97.6% covered by the panel in a significantly shorter time versus conventional methods.72 The BioFire FilmArray BioThreat-E test performed well in the field of West Africa, and the results in this population were comparable to the conventional methods; among the 37 symptomatic patients tested, the sensitivity and specificity were 95.7% and 100%, respectively.73 With results and interpretations within an hour, this method would be particularly beneficial in an epidemic or during postoutbreak surveillance.73 This technique covers a wide variety of common pathogens with good sensitivity and specificity, but only 1 sample can be run at a time.66 Further assessment of BCID in larger populations is needed to assess the benefit it can provide.74 It is possible that BCID may lead to ineffective treatments or missed opportunities if physician interpretation of the results is suboptimal.75 Surveys regarding discontinuing or de-escalating antibiotic therapy indicated poor performance on interpretation of the test, suggesting a need for improved BCID reporting of results to assist physicians with clinical decision making.75

The financial burden of BSIs ranges from $600 million to $1.2 billion in the U.S.

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

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The VERIGENE consists of a gram-positive panel krusei, C. glabrata, and C. parapsilosis. There is an (3 resistance markers, 9 organisms with speciation, added benefit with a low limit of detection of 1 col4 genera) and a gram-negative panel (5 organisms ony-forming unit/mL.55 However, the main limita76 tion of this technology is that pathogen detections with speciation, 4 genera, 6 resistance markers). The processing to identification time is roughly 2.5 hours, dependent on panels. The sensitivity and specificwith a hands-on time of approximately 5 minutes per ity are reported at 90% and 98%, respectively, for the sample.76 The VERIGENE gram-positive blood culT2Bacteria panel and 91% and 99%, respectively, for ture correctly identified the target organisms in 94% the T2Candida panel.55 Results are available within 3 77 to 5 hours as opposed to blood cultures, which take of cases with susceptibility. Hayakawa et al showed a significant increase in prescription changes with the about 1 to 5 days for results.55 T2MR also is different 78 from the previously discussed methods as it directly use of the VERIGENE test. Arroyo and Denys evaluated the Sepsityper versus VERIGENE gram-negative assesses blood, limiting the number of cross-contamblood culture test and found that although the Sepsiination and false-positive results. There is no interfertyper had a longer hands-on time, it allows for untarence from antimicrobial exposure, allowing patients to geted testing and has a broader capability than the be empirically treated prior to testing.

VERIGENE, which only targets 9 A clinical trial that used the gram-negative bacilli.79 T2Bacteria panel showed that this The Cepheid Xpert MRSA/SA technology could identify infectest was evaluated for positive tions 3 times faster compared blood cultures in the neonatal ICU with the standard method of testsetting and found that rapid testing.55 T2 Biosystems overcomes the common blood culture variing was nonsignificant for reduced able of antimicrobial interference length of admission and durafrom patients already undergoing tion of antimicrobials.80 In a single institution, 35 obstetric patients antibiotic therapy.55 The T2Candida panel takes with positive blood cultures were 4.2 hours to identify 5 species of assessed with the Xpert MRSA/SA Candida by category in a rapid and found a reduction in median BSIs, bloodstream infections and efficient, culture-independent duration of IV antimicrobials by 12 Source: Am J Infect Control manner that can help with transhours and LOS by 10.5 hours.81 2008;36(10):S172e1-e3.

At the end of December 2018, mission and infection control.68,83 Ibáñez-Martínez et al estimated GenMark received FDA clearance a cost savings of roughly 48.8% in candidemia costs for its ePlex BCID bacterial and fungal panels. The with the T2Candida panel at approximately $26,887 ePlex BCID Gram-Positive, Gram-Negative and Funand a reduction in mortality of 60.6%.66 Moreover, the gal Pathogen panels were developed for the diagnopotential savings in empirical therapy in non candisis and disease management of BSIs that can lead to demic patients would be $4,521,081 (42.8%) in total sepsis. The panels identify bacterial and fungal organcosts or $886 per tested patient. 66 isms, along with resistance genes within about 1.5 hours from positive culture.82 The fungal panel idenAccelerate PhenoTest tifies a wide array of fungal organisms, including mulThe Accelerate PhenoTest is capable of identifying tidrug-resistant Candida auris, which is increasing in blood pathogens with AST through automated FISH hospitals.82 technology.56 It is a fully automated system and proT2 Biosystems duces results within 7 hours for the most common T2 Biosystems Panels run on the T2Dx Instrument, organisms in BSIs (gram-positive bacteria: S. aureus, use T2 Magnetic Resonance (T2MR) Technology to Staphylococcus lugdunensis, CoNS, E. faecalis, E. faedetect and identify pathogens direct-from-wholecium, and Streptococcus species [6 antibiotics and blood K2EDTA samples.55 It is an automated system resistance markers for methicillin-resistant S. aureus, with low operator variability; thus, the instrument inducible clindamycin]; gram-negative bacteria: E. is easy to operate and not labor-intensive. 55 The coli, Klebsiella species, Enterobacter species, Proteus T2Dx Instrument is FDA cleared as are the T2Bacspecies, Citrobacter species, Serratia marcescens, P. teria and T2Candida panels.55 The T2 Bacteria panel aeruginosa, and Acinetobacter baumannii [12 antibicovers some of the ESKAPE (Enterococcus faecium, otics]; and yeast: C. albicans and C. glabrata).43 It has the ability to produce a full phenotypic susceptibilS. aureus, K. pneumoniae, P. aeruginosa), and E. coli ity result.84 pathogens found in BSIs, which covers 70% of bacteThe Accelerate Pheno System improved the turnrial pathogens seen in the emergency department. The around time for blood culture identification and AST T2Candida panel covers C. albicans, C. tropicalis, C.

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of gram-negative organisms by approximately 27.49 and 40.39 hours.85 Gram-negative pathogens were identified correctly in 88.7% of blood samples, and 97.1% were correctly identified with proper identification panels.85 Of those samples correctly identified, 91% yielded AST results.85 There is room for improvement, as this device has limited capabilities with a selected number of organism identification (grampositive bacteria: S. aureus, S. lugdunensis, CoNS, E. faecalis, E. faecium, and Streptococcus species; gramnegative bacteria: E. coli, Klebsiella species, Enterobacter species, Proteus species, Citrobacter species, S. marcescens, P. aeruginosa, and A. baumannii; yeast: C. albicans and C. glabrata) and processing size (eg, 1 sample at a time per system module). The Accelerate PhenoTest correctly identified 95.6% of bloodstream pathogens with overall gram-positive and gram-negative sensitivity and specificity at 95.6% and 99.5%, respectively.84 This system also has 95.1% overall essential agreement and 95.5% categorical agreement compared with standard methods.84 The system is easy to use with quick access to clinically actionable results.84 Charnot-Katsikas et al discovered limitations such as AST results for the dominant organism in polymicrobial cultures containing multiple on-panel AST-eligible organisms.84 One of the greater challenges identified in this study was with Streptococcus species, where the interpretations varied greatly depending on the present species.84 Pancholi et al performed a multicenter evaluation comparing the Accelerate PhenoTest with the VITEK2.86 They assessed the Accelerate PhenoTest using the updated 2017 software, which showed that the new algorithm had reduced the invalid results.86 The sensitivity and specificity reported with the update showed 97.5% and 99.5%, respectively. When they were substratified by morphology, the sensitivity and specificity reported were gram-positive bacteria at 96.7% and 99%, gram-negative bacteria at 98.5% and 99.8%, and yeasts at 97.9% and 99.6%, respectively.86 The positive predictive value for monomicrobial samples was 97.3%; however, polymicrobial samples would have resulted in a monomicrobial call. 86 The Accelerate PhenoTest may prove the most beneficial for hospitals that have limited access to physicians trained in infectious diseases and/or pharmacists.86 Despite the benefits, Giordano et al found that rapid AST combined with MALDI-TOF MS proved faster and more cost-effective than the Accelerate PhenoTest.60 Compared with MALDI-TOF MS, the Accelerate PhenoTest correctly identified 99% of monomicrobial samples; however, it only identified 40% for polymicrobial ones.86 There is an overall AST agreement at 93.7%. They also discovered impaired functioning in certain areas that impaired the performance of the Accelerate PhenoTest, such as with beta-lactams, Enterobacterales, and P. aeruginosa.87

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Conclusion Rapid testing methods for common respiratory viruses have performance characteristics on par with non-rapid PCR testing, and POC testing in particular could stop the chain of transmission, even in settings that do not have a full molecular lab. Rapid testing for blood pathogens is increasingly becoming culture-independent to expedite results, although timeto-identification varies by device. However, further studies should explore how effectively clinicians use the information to manage patients, and cost-effectiveness should be evaluated in various care settings.

Rapid testing can help to reduce antimicrobial usage, antimicrobial resistance, and morbidity and mortality.

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27. Babady NE, England MR, Jurcic Smith KL, et al. Multicenter evaluation of the ePlex Respiratory Pathogen Panel for the detection of viral and bacterial respiratory tract pathogens in nasopharyngeal swabs. J Clin Microbiol. 2018;56(2). doi:10.1128/JCM.01658-17 28. Luminex. NxTAG Respiratory Pathogen Panel + SARS-CoV-2 (EUA). Accessed October 26, 2021. https://www.luminexcorp. com/nxtag-respiratory-pathogen-panel-sars-cov-2/ 29. Chen JH, Yip CC, Chan JF, et al. Clinical performance of the Luminex NxTAG CoV Extended Panel for SARS-CoV-2 detection in nasopharyngeal specimens from COVID-19 patients in Hong Kong. J Clin Microbiol. 2020;58(8). doi:10.1128/JCM.00936-20 30. Abbott. ALINITY m RESP-4-PLEX Assay. Accessed October 26, 2021. https://www.molecular.abbott/int/en/ alinity-m-resp-4-plex-assay 31. Cheng A, Riedel S, Arnaout R, et al. Verification of the Abbott Alinity m Resp-4-Plex Assay for detection of SARS-CoV-2, influenza A/B, and respiratory syncytial virus. Diagn Microbiol Infect Dis. 2021:115575. doi.org/10.1016/j.diagmicrobio.2021.115575 32. Abbott. Your Rapid Respiratory Testing Solutions. Accessed October 21, 2021. https://www.globalpointofcare.abbott/en/products-solutions/solutions/respiratory-solutions.html 33. Hassan F, Hays LM, Bonner A, et al. Multicenter clinical evaluation of the Alere i respiratory syncytial virus isothermal nucleic acid amplification assay. J Clin Microbiol. 2018;56(3):e01777-17.

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39. Tsang HF, Leung WMS, Chan LWC, et al. Performance comparison of the Cobas(R) Liat(R) and Cepheid(R) GeneXpert(R) systems on SARS-CoV-2 detection in nasopharyngeal swab and posterior oropharyngeal saliva. Expert Rev Mol Diagn.

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44. Cepheid. Critical Infectious Disease. Accessed October 22, 2021. https://www.cepheid.com/en_US/tests/ Critical-Infectious-Diseases 45. Popowitch EB, Miller MB. Comparison of the Xpert Flu/ RSV XC and Xpress Flu/RSV assays. J Clin Microbiol.

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48. Cohen DM, Kline J, May LS, et al. Accurate PCR detection of influenza A/B and respiratory syncytial viruses by use of Cepheid Xpert Flu+RSV Xpress assay in point-of-care settings: comparison to Prodesse ProFlu. J Clin Microbiol. 2018;56(2):e01237-17.

49. Abbott Diagnostics. BinaxNOW: what you need to know.

Accessed October 25, 2021. https://bit.ly/3e3Ax5r-IDSE 50. Mina M. Coronavirus (COVID-19): press conference with Michael Mina, 04/01/21. Harvard School of Public Health; 2021.

51. FDA. In vitro diagnostics EUAs - antigen diagnostic tests for SARS-CoV-2. Accessed October 25, 2021. (This website is updated regularly.) https://bit.ly/3mZqqDW-idse 52. Bryan CS. Clinical implications of positive blood cultures.

Clin Microbiol Rev. 1989;2(4):329-353.

53. Creative Proteomics. MALDI-TOF mass spectrometry. Accessed October 22, 2021. https://www.creative-proteomics.com/technology/maldi-tof-mass-spectrometry.htm 54. Dogan O, Inkaya AC, Gulmez D, et al. Evaluation of PNA-FISH method for direct identification of Candida species in blood culture samples and its potential impact on guidance of antifungal therapy [in Turkish]. Mikrobiyol Bul. 2016;50(4):580-589.

55. T2 Biosystems. T2Direct Diagnostics. Accessed October 21, 2021. www.t2biosystems.com 56. Accelerate Diagnostics. Accelerate Pheno System. Accessed October 21, 2021. www.acceleratediagnostics.com/products/ accelerate-pheno-system/#features 57. Bruker. MBT Sepsityper IVD kit. Accessed October 22, 2021. https://bit.ly/3klzUaM-IDSE

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17. Quesada-Gonzalez D, Merkoci A. Nanomaterial-based devices for point-of-care diagnostic applications. Chem Soc Rev. 2018;47(13):4697-4709.

IDSE Review

58. Candel FJ, Borges Sa M, Belda S, et al. Current aspects in sepsis approach. Turning things around. Rev Esp Quimioter.

2018;31(4):298-315.

59. Lin JF, Ge MC, Liu TP, et al. A simple method for rapid microbial identification from positive monomicrobial blood culture bottles through matrix-assisted laser desorption ionization time-of-flight mass spectrometry. J Microbiol Immunol Infect.

2018;51(5):659-665.

60. Giordano C, Piccoli E, Brucculeri V, et al. A prospective evaluation of two rapid phenotypical antimicrobial susceptibility technologies for the diagnostic stewardship of sepsis. Biomed Res Int. 2018;2018:6976923.

61. Seco BMS, Campos JC, da Costa Rocha DA, et al. Improved blood culture workflow for faster identification of KPC-producing Enterobacterales. Braz J Microbiol. 2019;50(1):127-132.

62. Osthoff M, Gurtler N, Bassetti S, et al. Impact of MALDI-TOFMS-based identification directly from positive blood cultures on patient management: a controlled clinical trial. Clin Microbiol Infect. 2017;23(2):78-85.

63. Patel TS, Kaakeh R, Nagel JL, et al. Cost analysis of implementing matrix-assisted laser desorption ionization-time of flight mass spectrometry plus real-time antimicrobial stewardship intervention for bloodstream infections. J Clin Microbiol. 2017;55(1):60-67.

64. Plongla R MM. Molecular testing for diseases associated with bacterial infections. In: Coleman WB, Tsongalis GJ, eds. Diagnostic Molecular Pathology: A Guide to Applied Molecular Testing.

Academic Press; 2016:139-150.

65. Faron ML, Buchan BW, Ledeboer NA. Matrix-assisted laser desorption ionization-time of flight mass spectrometry for use with positive blood cultures: methodology, performance, and optimization. J Clin Microbiol. 2017;55(12):3328-3338.

66. Ibanez-Martinez E, Ruiz-Gaitan A, Peman-Garcia J. Update on the diagnosis of invasive fungal infection. Rev Esp Quimioter.

2017;30(suppl 1):16-21.

67. OpGen. FISH Product Inserts. Accessed October 22, 2021. https://www.opgen.com/resources-search/fish-product-inserts/ 68. Klingspor L, Lindback E, Ullberg M, et al. Seven years of clinical experience with the yeast traffic light PNA FISH: assay performance and possible implications on antifungal therapy. Mycoses.

2018;61(3):179-185.

78. Hayakawa K, Mezaki K, Kobayakawa M, et al. Impact of rapid identification of positive blood cultures using the Verigene system on antibiotic prescriptions: a prospective study of community-onset bacteremia in a tertiary hospital in Japan. PLoS One. 2017;12(7):e0181548.

79. Arroyo MA, Denys GA. Parallel evaluation of the MALDI Sepsityper and Verigene BC-GN assays for rapid identification of gram-negative bacilli from positive blood cultures. J Clin Microbiol. 2017;55(9):2708-2718.

80. Koh LL, O’Rourke S, Brennan M, et al. Impact of a rapid molecular test for positive blood cultures from neonatal intensive care patients on clinical management: a retrospective audit. Ir J Med Sci. 2018;187(2):423-427.

81. Page A, O’Rourke S, Brennan M, et al. Impact of Xpert MRSA/SA blood culture PCR assay on management of positive blood cultures in obstetric patients: a retrospective audit. Ir J Med Sci. 2017;186(4):995-998.

82. Huang TD, Melnik E, Bogaerts P, et al. Evaluation of the ePlex Blood Culture Identification panels for detection of pathogens in bloodstream infections. J Clin Microbiol. 2019;57(2):e01597-18.

83. Sexton DJ, Bentz ML, Welsh RM, et al. Evaluation of a new T2 Magnetic Resonance assay for rapid detection of emergent fungal pathogen Candida auris on clinical skin swab samples.

Mycoses. 2018;61(10):786-790.

84. Charnot-Katsikas A, Tesic V, Love N, et al. Use of the Accelerate Pheno System for identification and antimicrobial susceptibility testing of pathogens in positive blood cultures and impact on time to results and workflow. J Clin Microbiol.

2018;56(1):e01166-17.

85. Marschal M, Bachmaier J, Autenrieth I, et al. Evaluation of the Accelerate Pheno System for fast identification and antimicrobial susceptibility testing from positive blood cultures in bloodstream infections caused by gram-negative pathogens. J Clin Microbiol.

2017;55(7):2116-2126.

86. Pancholi P, Carroll KC, Buchan BW, et al. Multicenter evaluation of the Accelerate PhenoTest BC Kit for rapid identification and phenotypic antimicrobial susceptibility testing using morphokinetic cellular analysis. J Clin Microbiol. 2018;56(4):e01329-17.

69. Messacar K, Hurst AL, Child J, et al. Clinical impact and provider cceptability of real-time antimicrobial stewardship decision support for rapid diagnostics in children with positive blood culture results. J Pediatric Infect Dis Soc. 2017;6(3):267-274.

87. Descours G, Desmurs L, Hoang TLT, et al. Evaluation of the Accelerate Pheno system for rapid identification and antimicrobial susceptibility testing of gram-negative bacteria in bloodstream infections. Eur J Clin Microbiol Infect Dis. 2018;37(8):1573-1583.

70. Payne M, Champagne S, Lowe C, et al. Evaluation of the FilmArray Blood Culture Identification Panel compared to direct MALDI-TOF MS identification for rapid identification of pathogens. J Med Microbiol. 2018;67(9):1253-1256.

About the authors

71. Bookstaver PB, Nimmich EB, Smith TJ 3rd, et al. Cumulative effect of an antimicrobial stewardship and rapid diagnostic testing bundle on early streamlining of antimicrobial therapy in gram-negative bloodstream infections. Antimicrob Agents Chemother. 2017;61(9). doi:10.1128/AAC.00189-17 72. Szymankiewicz M, Nakonowska B. Rapid detection of bloodstream pathogens in oncologic patients with a FilmArray Multiplex PCR assay: a comparison with culture methods. Pol J Microbiol. 2018;67(1):103-107.

73. Gay-Andrieu F, Magassouba N, Picot V, et al. Clinical evaluation of the BioFire FilmArray(R) BioThreat-E test for the diagnosis of Ebola virus disease in Guinea. J Clin Virol. 2017;92:20-24.

74. Buss BA, Baures TJ, Yoo M, et al. Impact of a multiplex PCR assay for bloodstream infections with and without antimicrobial stewardship intervention at a cancer hospital. Open Forum Infect Dis. 2018;5(10):ofy258.

75. Donner LM, Campbell WS, Lyden E, et al. Assessment of rapidblood-culture-identification result interpretation and antibiotic prescribing practices. J Clin Microbiol. 2017;55(5):1496-1507.

76. Luminex. VERIGENE Bloodstream Infection testing panels. October 22, 2021. https://www.luminexcorp.com/ bloodstream-infection-tests/ 77. Dekmezian M, Beal SG, Damashek MJ, et al. The SUCCESS model for laboratory performance and execution of rapid molecular diagnostics in patients with sepsis. Proc (Bayl Univ Med Cent).

2015;28(2):144-150.

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Amy K. Feehan, PhD, is a clinical research scientist in the Department of Infectious Diseases at Ochsner Health and the University of Queensland, Ochsner Clinical School, in Brisbane, Australia.

Julia Garcia-Diaz, MD, MSc, FACP, FIDSA, CPI, is the director of clinical infectious diseases research, the director of medical student research, and an associate professor at the University of Queensland, Ochsner Clinical School, in Brisbane, Australia; and a clinical assistant professor at Tulane University School of Medicine, Ochsner Medical Center, in New Orleans, Louisiana.

Andrea J. Linscott, PhD, D(ABMM), is a clinical microbiologist in the Department of Pathology and Laboratory Medicine at Ochsner Medical Center, New Orleans, Louisiana. She is a contributing author in the Manual of Clinical Microbiology, Clinical Microbiology Procedures Handbook, and Clinical Laboratory Management.

Evidence?

Yeah, we’ve got that.

Super-fast phenotypic MIC results and the evidence to back them up.

Get the data: axdx.com/evidence © 2021 Accelerate Diagnostics, Inc. All Rights Reserved. “ACCELERATE DIAGNOSTICS,” “ACCELERATE PHENO,” “ACCELERATE PHENOTEST” and diamond shaped logos and marks are registered trademarks of Accelerate Diagnostics, Inc.

Implementing Injectables: Considerations for CabotegravirRilpivirine Long-Acting Therapy

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

L

ong-acting cabotegravir and rilpivirine injections are approved in Canada, Europe, and the United States.1 The unique pharmacokinetic and pharmacodynamics properties of long-acting cabotegravir and rilpivirine injectables allow them to be administered once monthly2; the most prominent of these are long elimination half-lives with intramuscular administration (cabotegravir = 5.6-11.5 weeks and rilpivirine = 13-28 weeks).1 The drug–drug interaction profile of the injectable and oral formulations are different; each formulation should be checked for interactions before initiation of therapy. The 96-week results of the FLAIR study mirrored the 48-week data showing that this regimen was noninferior to the standard of care for maintaining viral suppression.3 In addition, 256-week data

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from the LATTE-2 trial demonstrated long-term efficacy, tolerability, and durability of long-acting cabotegravir-rilpivirine (Cabenuva, ViiV Healthcare) injection therapy.4 Virologic control is entwined with quality of life.5 There is the potential for once-monthly injectable agents to improve quality of life by incorporating patient treatment preferences and removing stigma-related concerns. In a survey of 688 people with HIV, almost two-thirds were interested in long-acting injectable therapy.5 Most of these respondents noted that injectable treatment would fulfill an unmet need, such as suboptimal adherence, confidentiality concerns, and the emotional burden of daily dosing.

Physicians noted different levels of likelihood to recommend injectable therapy depending on individual

patient factors.5 They were more likely to offer injectable therapy in cases of dysphagia or malabsorption. However, the majority would also recommend this treatment strategy for suboptimal adherence.5 Of note, these data were collected before drug approval and evaluated as an every 2-month dosing regimen. Benefits that were perceived with injectable therapy included being able to travel without worrying about forgetting medication. Physicians noted that there would be increased patient contact (once monthly) compared with a lower frequency of encounters.5 Data are also available for an every 2-month dosing regimen.6 Patient satisfaction data collected during treatment indicate that an every 8-week regimen is preferred over an every 4-week regimen; however, patient

satisfaction scores were high for both dosing regimens.7 In addition, approximately 80% of respondents noted that local injection site reactions were acceptable after 48 weeks of therapy.

Implementation Opportunities exist with injectable agents to improve adherence and outcomes, including less frequent dosing, avoidance of pill fatigue and HIVrelated stigma, and decreased pill burden.8 However, the requirement of an oral lead-in and management of missed doses present barriers to treatment initiation.

Implementation concerns to be considered include workflow, procurement, reimbursement, and nonadherence.9 Operationally, a multidisciplinary group should form a clinic-specific protocol and outline each identification, initiation, and maintenance process step. Health care professional training also may be necessary because the Z-track injections cannot be self-administered.9

Observe patients for 10 minutes after injections.

Refrigerated storage and availability of examination rooms for injection also should be considered.9 At least 15 minutes are needed for the vials to be allowed to come to room temperature before injection. A 10-minute observation period also is recommended postinjection. Overall, this represents at least a 30-minute appointment.9 From a payment standpoint, the medication may be covered by either pharmacy or medical benefits. A full

investigation and precertification or prior authorization should be completed to ensure the exact cost is known before initiating therapy. Financial assistance and benefits investigation can be facilitated through the ViiV Connect Portal (https://bit.ly/306wEsm-IDSE).9 The oral lead-in of both medications is available through TheraCom, LLC Specialty Pharmacy at no cost.9 Appointments for injections should be easily distinguished from other types of clinic visits. This will allow identification of missed or canceled appointments for injections to perform outreach as soon as possible for rescheduling. Delayed or missed doses should be addressed immediately.8 A screening process should be considered to identify people for injectable therapy appropriately. Many people initiating injectable therapy will increase their number of clinic visits per year, raising other issues such as parking fees or the need for time off work. Transportation also should be addressed.9 Patients should immediately report any changes in insurance status to ensure an uninterrupted supply of medication.

Implementation strategies for an every 8-week regimen will differ slightly from every an 4-week regimen. Direct-to-injection (no oral leadin) data are available; however, this is not yet an approved strategy.8 In addition, attending an injection appointment 6 times per year versus 12 times per year may allow a larger population to initiate therapy. These data support the need to offer injectable therapy to patients with an appropriate indication, as it is challenging to predict confidentiality concerns or emotional burdens. The overall interest of people with HIV to use injectables is an essential piece of data to allow clinicians to allocate appropriate resources.

References 1. Hodge D, Back DJ, Gibbons S, et al. Pharmacokinetics and drug-drug interactions of long-acting intramuscular cabotegravir and rilpivirine. Clin Pharmacokinet.

2021;60(7):835-853.

2. Podany AT, Scarsi KK, Pham MM, et al.

Comparative clinical pharmacokinetics and pharmacodynamics of HIV-integrase strand transfer inhibitors: an updated review. Clin Pharmacokinet.

2020;59(9):1085-1107.

3. Orkin C, Oka S, Philibert P, et al. Longacting cabotegravir plus rilpivirine for treatment in adults with HIV-1 infection: 96-week results of the randomised, openlabel, phase 3 FLAIR study. Lancet HIV. 2021;8:e185-e196.

4. Smith GHR, Henry WK, Podzamczer D, et al. Efficacy, safety, and durability of long-acting cabotegravir and rilpivirine in adults with human immunodeficiency virus type 1 infection: 5-year results from the LATTE-2 study. Open Forum Infect Dis. 2021;8:ofab439.

5. Akinwunmi B, Buchenberger D, Scherzer J, et al. Factors associated with interest in a long-acting HIV regimen: perspectives of people living with HIV and healthcare providers in four European countries. Sex Transm Infect. Published online February 25, 2021. doi:http://dx.doi.org/10.1136/ sextrans-2020-054648 6. Swindells S, Lutz T, van Zyl L, et al.

Long-acting cabotegravir + rilpivirine for HIV-1 treatment: ATLAS week 96 results. AIDS. Publsihed online July 13, 2021. doi:http://dx.doi.org/10.1097/ qad.0000000000003025 7. Chounta V, Overton ET, Mills A, et al.

Patient-reported outcomes through 1 year of an HIV-1 clinical trial evaluating long-acting cabotegravir and rilpivirine administered every 4 or 8 weeks (ATLAS2m). Patient. 2021;14(6):849-862.

8. Scarsi KK, Swindells S. The promise of improved adherence with long-acting antiretroviral therapy: what are the data? J Int Assoc Provid AIDS Care.

2021;20:23259582211009011.

9. Howe ZW, Norman S, Lueken AF, et al.

Therapeutic review of cabotegravir/rilpivirine long-acting antiretroviral injectable and implementation considerations at an HIV specialty clinic. Pharmacotherapy.

2021;41:686-699.

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

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

73

For challenging cases in cIAI...

Reported penicillin allergy

WHEN THE RESISTANCE RISK IS HIGH,

EMPIRIC CHOICE IS CLEAR

THE

Indications and Usage XERAVA is indicated for the treatment of complicated intraabdominal infections (cIAI) caused by susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Enterobacter cloacae, Klebsiella oxytoca, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Streptococcus anginosus group, Clostridium perfringens, Bacteroides species, and Parabacteroides distasonis in patients 18 years or older.

Limitations of Use XERAVA is not indicated for the treatment of complicated urinary tract infections (cUTI).

Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of XERAVA and other antibacterial drugs, XERAVA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information

Long-term care resident at risk for resistant pathogens

Recent travel to an ESBL-endemic area

are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

Important Safety Information XERAVA is contraindicated for use in patients with known hypersensitivity to eravacycline, tetracycline-class antibacterial drugs, or to any of the excipients. Life-threatening hypersensitivity (anaphylactic) reactions have been reported with XERAVA. The use of XERAVA during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown) and enamel hypoplasia.

The use of XERAVA during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth.

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

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

Clinical cure rate, %

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

89.6

88.9

87.0

88.9

43/48

32/36

40/46

40/45

90.6

86.2

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

Enterobacteriaceae (N=314) XERAVA

25/29

29/32

Enterobacteriaceae (N=325)

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

POOLED COMPARATORS

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

a

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

b

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

Important Safety Information (cont’d) Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, and may range in severity from mild diarrhea to fatal colitis.

The most common adverse reactions observed in clinical trials (incidence ≥3%) were infusion site reactions (7.7%), nausea (6.5%), and vomiting (3.7%).

XERAVA is structurally similar to tetracycline-class antibacterial drugs and may have similar adverse reactions. Adverse reactions including photosensitivity, pseudotumor cerebri, and anti-anabolic action which has led to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, and abnormal liver function tests, have been reported for other tetracycline-class antibacterial drugs, and may occur with XERAVA. Discontinue XERAVA if any of these adverse reactions are suspected.

CEPH-R, cephalosporin-resistant; cIAI, complicated intra-abdominal infection; ESBL, extended-spectrum beta-lactamase; GI, gastrointestinal; IV, intravenous; MDR, multidrug-resistant; micro-ITT, microbiologic intent-to-treat; q8h, every 8 hours; q12h, every 12 hours; q24h, every 24 hours; TOC, Test of Cure.

References: 1. XERAVA [prescribing information]. Watertown, MA: Tetraphase Pharmaceuticals, Inc.; 2018. 2. Ditch K, Newman J, Izmailyan S, Fyfe C, Tsai L. Microbiological efficacy of eravacycline against Enterobacteriaceae and Acinetobacter baumannii, including MDR isolates: a pooled analysis from IGNITE1 and IGNITE4, two phase 3 trials of complicated intra-abdominal infection. Poster presented at: ASM Microbe; June 7-11, 2018; Atlanta, GA. Poster 629. 3. Zhanel GG, Cheung D, Adam H, et al. Review of eravacycline, a novel fluorocycline antibacterial agent. Drugs. 2016;76(5):567-588.

4. Solomkin J, Evans D, Slepavicius A, et al. Assessing the efficacy and safety of eravacycline vs ertapenem in complicated intra-abdominal infections in the Investigating Gram-Negative Infections Treated with Eravacycline (IGNITE 1) trial: a randomized clinical trial. JAMA Surg. 2017;152(3):224-232.

5. Tsai L, Horn P, Solomkin J, Evans D, Gardovskis J, Fonte A. Results of IGNITE4: a phase 3 study to evaluate the efficacy and safety of eravacycline versus meropenem in complicated intra-abdominal infections. Poster presented at: 28th European Congress of Clinical Microbiology and Infectious Diseases; April 21-24, 2018; Madrid, Spain. Encore poster presentation at: 2018 Annual Making a Difference in Infectious Diseases (MAD-ID) Meeting; May 8-11, 2018; Orlando, FL.

To report SUSPECTED ADVERSE REACTIONS, contact Tetraphase Pharmaceuticals Inc., at 1-833-7-XERAVA (1-833-793-7282) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see Brief Summary of full Prescribing Information on the following pages.

LEARN MORE AT XERAVA.COM/IDSE

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

Brief Summary XERAVATM (eravacycline) for injection Brief Summary of full Prescribing Information. See full Prescribing Information. Rx only.

INDICATIONS AND USAGE Complicated Intra-abdominal Infections XERAVA is indicated for the treatment of complicated intra-abdominal infections (cIAI) caused by susceptible microorganisms: Escherichia coli, Klebsiella pneumoniae, Citrobacter freundii, Enterobacter cloacae, Klebsiella oxytoca, Enterococcus faecalis, Enterococcus faecium, Staphylococcus aureus, Streptococcus anginosus group, Clostridium perfringens, Bacteroides species, and Parabacteroides distasonis in patients 18 years or older.

Limitations of Use XERAVA is not indicated for the treatment of complicated urinary tract infections (cUTI).

Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of XERAVA and other antibacterial drugs, XERAVA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

DOSAGE AND ADMINISTRATION Recommended Adult Dosage The recommended dose regimen of XERAVA is 1 mg/kg every 12 hours. Administer intravenous infusions of XERAVA over approximately 60 minutes every 12 hours.

The recommended duration of treatment with XERAVA for cIAI is 4 to 14 days. The duration of therapy should be guided by the severity and location of infection and the patient’s clinical response.

Dosage Modifications in Patients with Hepatic Impairment In patients with severe hepatic impairment (Child Pugh C), administer XERAVA 1 mg/kg every 12 hours on Day 1 followed by XERAVA 1 mg/kg every 24 hours starting on Day 2 for a total duration of 4 to 14 days. No dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B).

Dosage Modifications in Patients with Concomitant Use of a Strong Cytochrome P450 Isoenzymes (CYP) 3A Inducer With concomitant use of a strong CYP3A inducer, administer XERAVA 1.5 mg/kg every 12 hours for a total duration of 4 to 14 days. No dosage adjustment is warranted in patients with concomitant use of a weak or moderate CYP3A inducer.

Preparation and Administration XERAVA is for intravenous infusion only. Each vial is for a single dose only.

Preparation XERAVA is supplied as a sterile yellow to orange dry powder in a single-dose vial that must be reconstituted and further diluted prior to intravenous infusion as outlined below. XERAVA does not contain preservatives. Aseptic technique must be used for reconstitution and dilution as follows: 1. Calculate the dose of XERAVA based on the patient weight; 1 mg/kg actual body weight.

Prepare the required dose for intravenous infusion, by reconstituting the appropriate number of vials needed. Reconstitute each vial of XERAVA with 5 mL of Sterile Water for Injection, USP. When the XERAVA vial content is reconstituted with 5 mL sterile Water for Injection, USP it will deliver 50 mg (10 mg/mL) of eravacycline (free base equivalents).

2. Swirl the vial gently until the powder has dissolved entirely. Avoid shaking or rapid movement as it may cause foaming. The reconstituted XERAVA solution should be a clear, pale yellow to orange solution. Do not use the solution if you notice any particles or the solution is cloudy. Reconstituted solution is not for direct injection.

3. The reconstituted XERAVA solution is further diluted for intravenous infusion to a target concentration of 0.3 mg/mL, in a 0.9% Sodium Chloride Injection, USP infusion bag before intravenous infusion. To dilute the reconstituted solution, withdraw the full or partial reconstituted vial content from each vial and add it into the infusion bag to generate an infusion solution with a target concentration of 0.3 mg/mL (within a range of 0.2 to 0.6 mg/mL). Do not shake the bag.

4. The reconstituted and diluted solutions must be infused within 6 hours if stored at room temperature (not to exceed 25°C/77°F) or within 24 hours if stored refrigerated at 2°C to 8ºC (36ºF to 46ºF). Reconstituted XERAVA solutions and diluted XERAVA infusion solutions should not be frozen.

5. Visually inspect the diluted XERAVA solution for particulate matter and discoloration prior to administration (the XERAVA infusion solution for administration is clear and ranges from light yellow to orange). Discard unused portions of the reconstituted and diluted solution.

Administration of the Intravenous Infusion The diluted XERAVA solution is administered as an intravenous infusion over approximately 60 minutes.

Drug Compatibilities XERAVA is compatible with 0.9% Sodium Chloride Injection, USP. The compatibility of XERAVA with other drugs and infusion solutions has not been established. XERAVA should not be mixed with other drugs or added to solutions containing other drugs.

CONTRAINDICATIONS XERAVA is contraindicated for use in patients with known hypersensitivity to eravacycline, tetracycline-class antibacterial drugs, or to any of the excipients.

WARNINGS AND PRECAUTIONS Hypersensitivity Reactions Life-threatening hypersensitivity (anaphylactic) reactions have been reported with XERAVA. XERAVA is structurally similar to other tetracycline-class antibacterial drugs and should be avoided in patients with known hypersensitivity to tetracycline-class antibacterial drugs.

Discontinue XERAVA if an allergic reaction occurs.

Tooth Discoloration and Enamel Hypoplasia The use of XERAVA during tooth development (last half of pregnancy, infancy and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-grey-brown). This adverse reaction is more common during long-term use of the tetracycline-class drugs, but it has been observed following repeated short-term courses. Enamel hypoplasia has also been reported with tetracycline class drugs. Advise the patient of the potential risk to the fetus if XERAVA is used during the second or third trimester of pregnancy.

Inhibition of Bone Growth The use of XERAVA during the second and third trimester of pregnancy, infancy and childhood up to the age of 8 years may cause reversible inhibition of bone growth. All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in fibula growth rate has been observed in premature infants given oral tetracycline in doses of 25 mg/kg every 6 hours. This reaction was shown to be reversible when the drug was discontinued. Advise the patient of the potential risk to the fetus if XERAVA is used during the second or third trimester of pregnancy.

Clostridium difficile-Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, and may range in severity from mild diarrhea to fatal colitis.

Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

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

If CDAD is suspected or confirmed, ongoing antibacterial drug use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial drug treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated.

Tetracycline Class Adverse Reactions XERAVA is structurally similar to tetracycline-class antibacterial drugs and may have similar adverse reactions. Adverse reactions including photosensitivity, pseudotumor cerebri, and anti-anabolic action which has led to increased BUN, azotemia, acidosis, hyperphosphatemia, pancreatitis, and abnormal liver function tests, have been reported for other tetracycline-class antibacterial drugs, and may occur with XERAVA. Discontinue XERAVA if any of these adverse reactions are suspected.

Potential for Microbial Overgrowth XERAVA use may result in overgrowth of non-susceptible organisms, including fungi. If such infections occur, discontinue XERAVA and institute appropriate therapy.

Development of Drug-Resistant Bacteria Prescribing XERAVA in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drugresistant bacteria.

ADVERSE REACTIONS The following clinically significant adverse reactions are described in greater detail in the Warnings and Precautions section: • Hypersensitivity Reactions • Tooth Discoloration • Inhibition of Bone Growth • Clostridium difficile-Associated Diarrhea • Tetracycline Class Adverse Reactions Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

XERAVA was evaluated in 3 active-controlled clinical trials (Trial 1, Trial 2 and Trial 3) in adults with cIAI. These trials included two Phase 3 trials (Trial 1 and Trial 2) and one Phase 2 trial (Trial 3, NCT01265784). The Phase 3 trials included 520 patients treated with XERAVA and 517 patients treated with comparator antibacterial drugs (ertapenem or meropenem). The median age of patients treated with XERAVA was 56 years, ranging between 18 and 93 years old; 30% were age 65 years and older. Patients treated with XERAVA were predominantly male (57%) and Caucasian (98%). The XERAVA-treated population included 31% obese patients (BMI ≥30 kg/m2) and 8% with baseline moderate to severe renal impairment (calculated creatinine clearance 15 to less than 60 mL/min). Among the trials, 66 (13%) of patients had baseline moderate hepatic impairment (Child Pugh B); patients with severe hepatic impairment (Child Pugh C) were excluded from the trials.

Adverse Reactions Leading to Discontinuation Treatment discontinuation due to an adverse reaction occurred in 2% (11/520) of patients receiving XERAVA and 2% (11/517) of patients receiving the comparator. The most commonly reported adverse reactions leading to discontinuation of XERAVA were related to gastrointestinal disorders.

Most Common Adverse Reactions Adverse reactions occurring at 3% or greater in patients receiving XERAVA were infusion site reactions, nausea and vomiting.

Table 1 lists adverse reactions occurring in ≥1% of patients receiving XERAVA and with incidences greater than the comparator in the Phase 3 cIAI clinical trials. A similar adverse reaction profile was observed in the Phase 2 cIAI clinical trial (Trial 3).

Table 1. Selected Adverse Reactions Reported in ≥1% of Patients Receiving XERAVA in the Phase 3 cIAI Trials (Trial 1 and Trial 2) Adverse Reactions

XERAVAa N=520 n (%)

Comparatorsb N=517 n (%)

Infusion site reactionsc Nausea Vomiting Diarrhea Hypotension Wound dehiscence

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

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

Abbreviations: IV=intravenous a XERAVA dose equals 1 mg/kg every 12 hours IV. b Comparators include ertapenem 1 g every 24 hours IV and meropenem 1 g every 8 hours IV. c Infusion site reactions include: catheter/vessel puncture site pain, infusion site extravasation, infusion site hypoaesthesia, infusion/injection site phlebitis, infusion site thrombosis, injection site/vessel puncture site erythema, phlebitis, phlebitis superficial, thrombophlebitis, and vessel puncture site swelling.

Other Adverse Reactions of XERAVA The following selected adverse reactions were reported in XERAVA-treated patients at a rate of less than 1% in the Phase 3 trials: Cardiac disorders: palpitations Gastrointestinal System: acute pancreatitis, pancreatic necrosis General Disorders and Administrative Site Conditions: chest pain Immune system disorders: hypersensitivity Laboratory Investigations: increased amylase, increased lipase, increased alanine aminotransferase, prolonged activated partial thromboplastin time, decreased renal clearance of creatinine, increased gamma-glutamyltransferase, decreased white blood cell count, neutropenia Metabolism and nutrition disorders: hypocalcemia Nervous System: dizziness, dysgeusia Psychiatric disorders: anxiety, insomnia, depression Respiratory, Thoracic, and Mediastinal System: pleural effusion, dyspnea Skin and subcutaneous tissue disorders: rash, hyperhidrosis DRUG INTERACTIONS Effect of Strong CYP3A Inducers on XERAVA Concomitant use of strong CYP3A inducers decreases the exposure of eravacycline, which may reduce the efficacy of XERAVA. Increase XERAVA dose in patients with concomitant use of a strong CYP3A inducer.

Anticoagulant Drugs Because tetracyclines have been shown to depress plasma prothrombin activity, patients who are on anticoagulant therapy may require downward adjustment of their anticoagulant dosage.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary XERAVA, like other tetracycline-class antibacterial drugs, may cause discoloration of deciduous teeth and reversible inhibition of bone growth when administered during the second and third trimester of pregnancy. The limited available data with XERAVA use in pregnant women are insufficient to inform drug-associated risk of major birth defects and miscarriages. Animal studies indicate that eravacycline crosses the placenta and is found in fetal plasma; doses greater than approximately 3- and 2.8-times the clinical exposure, based on AUC in rats and rabbits, respectively, administered during the period of organogenesis, were associated with decreased ossification, decreased fetal body weight, and/or increased post-implantation loss.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data Animal Data Embryo-fetal development studies in rats and rabbits reported no treatment-related effects at approximately 3 and 2.8 times the clinical exposure (based on AUC). Dosing was during the period of organogenesis, i.e. gestation days 7-17 in rats and gestation days 7-19 in rabbits.

Higher doses, approximately 8.6 and 6.3 times the clinical exposure (based on AUC) in rats and rabbits, respectively, were associated with fetal effects including increased postimplantation loss, reduced fetal body weights, and delays in skeletal ossification in both species, and abortion in the rabbit.

A peri-natal and post-natal rat toxicity study demonstrated that eravacycline crosses the placenta and is found in fetal plasma following intravenous administration to the dams. This study did not demonstrate anatomical malformations, but there were early decreases in pup weight that were later comparable to controls and a non-significant trend toward increased stillbirths or dead pups during lactation. F1 males from dams treated with 10 mg/kg/day eravacycline that continued to fertility testing had decreased testis and epididymis weights at approximately Post-Natal Day 111 that may have been at least partially related to lower body weights in this group.

Tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity also has been noted in animals treated early in pregnancy.

Lactation Risk Summary It is not known whether XERAVA is excreted in human breast milk. Eravacycline (and its metabolites) is excreted in the milk of lactating rats. Tetracyclines are excreted in human milk; however, the extent of absorption of tetracyclines, including eravacycline, by the breastfed infant is not known. There are no data on the effects of XERAVA on the breastfed infant, or the effects on milk production. Because there are other antibacterial drug options available to treat cIAI in lactating women and because of the potential for serious adverse reactions, including tooth discoloration and inhibition of bone growth, advise patients that breastfeeding is not recommended during treatment with XERAVA and for 4 days (based on half-life) after the last dose.

Data Animal Data Eravacycline (and its metabolites) was excreted in the milk of lactating rats on post-natal day 15 following intravenous administration of 3, 5, and 10 mg/kg/day eravacycline.

Females and Males of Reproductive Potential Infertility Based on animal studies, XERAVA can lead to impaired spermiation and sperm maturation, resulting in abnormal sperm morphology and poor motility. The effect is reversible in rats.

The long-term effects of XERAVA on male fertility have not been studied.

Pediatric Use The safety and effectiveness of XERAVA in pediatric patients have not been established.

Due to the adverse effects of the tetracycline-class of drugs, including XERAVA on tooth development and bone growth, use of XERAVA in pediatric patients less than 8 years of age is not recommended.

Geriatric Use Of the total number of patients with cIAI who received XERAVA in Phase 3 clinical trials (n=520), 158 subjects were ≥65 years of age, while 59 subjects were ≥75 years of age.

No overall differences in safety or efficacy were observed between these subjects and younger subjects.

No clinically relevant differences in the pharmacokinetics of eravacycline were observed with respect to age in a population pharmacokinetic analysis of eravacycline.

Hepatic Impairment No dosage adjustment is warranted for XERAVA in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). Adjust XERAVA dosage in patients with severe hepatic impairment (Child Pugh C).

Renal Impairment No dosage adjustment is necessary for XERAVA in patients with renal impairment.

OVERDOSAGE No reports of overdose were reported in clinical trials. In the case of suspected overdose, XERAVA should be discontinued and the patient monitored for adverse reactions.

Hemodialysis is not expected to remove significant quantities of XERAVA.

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

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IDSE Review

Antimicrobial Efficacy DEVIN M. DONNELLY, PHARMD

GURMINDER M. SANGHERA, PHARMD

MARYROSE LAGUIO-VILA, MD

SEAN M. STAINTON, PHARMD

PGY-1 Resident Department of Pharmacy Rochester General Hospital Rochester, New York

PGY-1 Resident Department of Pharmacy Rochester General Hospital Rochester, New York

Internal Medicine, Infectious Diseases Department of Infectious Diseases Rochester General Hospital Rochester, New York

Clinical Pharmacy Specialist Department of Infectious Diseases Rochester General Hospital Rochester, New York

T

his review is intended to be a reference to describe the potential in vivo activity of various antimicrobial agents when the identity of the infecting organism is known. Because the early initiation of appropriate therapy has been noted to improve clinical outcomes in patients with serious infections, empiric therapy frequently demands the use of a broad-spectrum antimicrobial agent until the specific infecting bacteria have been identified.

Given continuing concerns of increasing antimicrobial resistance among gram-positive and gram-negative bacteria, and the lack of new antibiotics coming to market, knowledge of microbiological activity and clinical treatment guidelines will permit the highest likelihood of providing appropriate antibiotic therapy to patients while minimizing use of unnecessary agents.

Of note, antimicrobial susceptibilities can be highly variable based on institution-specific and geographic factors, including various institutional sites (eg, outpatient vs inpatient, ICU versus ward). Therefore, awareness of local susceptibility data is essential to ensure the highest probability of successful clinical outcomes.

Although the use of various dosing techniques, especially for beta-lactams, may potentiate in vivo activity, the information contained herein pertains only to standard dosing regimens. This review reflects the opinions of the authors and is intended to be a general guide to antimicrobial applications, with the appreciation that host factors (eg, site of infection, clinical picture, and comorbid conditions) could greatly affect antimicrobial selection.

Key 1 First-line agent based

on clinical efficacy, susceptibility patterns, and consideration of antimicrobial stewardship and cost of care.

2 Alternative drug based

on clinical efficacy and susceptibility patterns.

3 Drug with limited clinical

efficacy data, a low level of activity against this organism, or both.

Either there are insufficient clinical data or this drug should not be used for this organism.

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

79

Monobactam

Carbapenems Penicillins

Aztreonam

Amoxicillin-clavulanate

1 2

Ampicillin-sulbactam

1 2

Piperacillin-tazobactam

2

Doripenem

2

Ertapenem

2

Meropenem

2 2 2

Imipenem-cilastatin

2

2

2 2 1 2 2 2 2 3 1

2 2 1 2 2 2 2 2 2ab 1

2 2 2 2 2 2 2 2 2 2 2 2

2 2 2 1 1 2 2 2 2 2 2 2

2 1 1 2 2 2 2 2 2

2 2 1 1 2 2 2 2 2 2 2 2 2 2 1

2

2

1

1

2

2

2

2

2

2

2

2

2

2

1

Imipenem-cilastatinrelebactam

2

2

2

2

Meropenemvaborbactam

3

2

2

3

3

2

2

2

2

80

IDSE.NET

2

Ampicillin

Penicillin G

2

Amoxicillin

Penicillin V

2 3

3

2 1

Cloxacillin/dicloxacillin

Nafcillin/oxacillin

1 3 3

1 3 2 3

2 2

2 2 3

2 2

2

2 2 2 2

2

2

2

Salmonella typhi

Salmonella spp.

Providencia stuartii

Proteus vulgaris

Proteus mirabilis

Morganella morganii

Klebsiella spp.f,g,ad

3 2 2 3

3 2 2 3

2

3

2

2 2 3 2

2 2 1

2 3

1

3

1

2

2

3

3

Stenotrophomonas maltophilia

Pseudomonas aeruginosa h

Burkholderia cepacia complex h

Ferment-Positive

Ferment-Negative

Enterobacteralesf

Acinetobacter spp.h

Shigella spp.

Serratia spp.

Vibrio cholerae

3

3

Escherichia coli f,g

Chlamydiae

Coccobacilli

Pasteurella multocida

3

3

Enterobacter spp.e,f

Citrobacter spp.e

Legionella pneumophila

Haemophilus influenzae d

Haemophilus ducreyi

Helicobacter pylori c

Francisella tularensis

Chlamydia trachomatis

Cocci

Chlamydophila psittaci

Chlamydophila pneumoniae (TWAR)

Campylobacter jejuni

Brucella spp.b

Bordetella pertussis

Neisseria meningitidisag

Neisseria gonorrhoeae a

Moraxella catarrhalis

IDSE Review

Table 1.

Penicillins, Carbapenems, Monobactam Gram-Negative Aerobes

Other Bacilli (non-Enterobacterales)

1 1

2

1 2

1 2

1

2

1 Streptococcus Group D (eg, S. bovis) Streptococcus Group F (eg, S. anginosus) Streptococcus pneumoniae i

Viridans streptococci Actinomyces israelii

3 1 1 1 2 1 2k 3 1

3 1 1 1 2 1 1

Enterococcus

3

3 3 3 3

1 1 3 3 3 3 3 3

2 3 1 1 1 1 1 3 1 2

2 3 1 1 1 1 1 3 2 2

2 3 2 2 2 2 2 3 2 3 2 3 2 2 2 2 2 2 2

2 3 2 2 2 2 2 3 2 2k 2 2 3 2 1 2 2 2 2 2

2 3 2 2 2 2 2 3 2 2 2 1 2 2 2 2 2

2 2 2 2 2 2 2 2 3 2 2 2 2 2 2

2 2 2 2 2 2

3 2 2 2 2 2 2

3

2

2 2

2

2

2

2

2

3 3 2 2 2

3 3 2 2 2 2 2 2 2 2 2

3

3

2

2

2

2

2

2

2

2

2 3

3 2

2 2

Listeria monocytogenes o

Gardnerella vaginalis n

Corynebacterium jeikeium

Corynebacterium diphtheriae m

1 2 3 2 2 2

1 2 3 2 2 2

2 2 3 1 2 1

2 3 1 2 1

2 2

2 1

Treponema pallidum

Leptospira spp.

Borrelia recurrentis

Borrelia burgdorferi (Lyme disease)q Spiral Organisms

Mycoplasma

GramPositive

Ureaplasma urealyticum

GramNegative

Mycoplasma pneumoniae

Clostridioides difficilep

Prevotella melaninogenica

Fusobacterium spp.

Bacilli

Bacteroides fragilis

Peptostreptococcus spp.

3 2

Clostridium tetani

1 Bacillus anthracis l

Actinomycetes

Cocci

Clostridium perfringens

1 Nocardia spp.

Penicillin-resistant Streptococcus pneumoniae j,k

Methicillin-susceptible Staphylococcus epidermidis

Staphylococcus epidermidis

Methicillin-resistant Staphylococcus aureus

Methicillin-susceptible Staphylococcus aureus

Vancomycin-resistant Enterococcus faecium

Enterococcus faecium

Vancomycin-resistant Enterococcus faecalis

Streptococcus Group B (S. agalactiae)

1 Streptococcus Group A (S. pyogenes)

1

Anaerobes

IDSE Review

Enterococcus faecalis

Gram-Positive Aerobes

2

2

1

2

2

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

81

Gram-Negative Aerobes Other Bacilli (non-Enterobacterales)

3

3

Cephalexin 3 Cefaclor 2

2nd

2

Cefotetan 2

3 3

2

2 2

Cefoxitin 3

3 3

2

2 2

Cefprozil 2

3

3

2

3 3

2

2

Cefuroxime 2

Generations

3

Cefdinir 2

Cefpodoxime proxetil 2

3

3

3

Ferment-Positive

2

2 2 3 2 2 2

Pasteurella multocida

3 3

2

Stenotrophomonas maltophilia

3

2 3

Pseudomonas aeruginosa h

3 3

2

Shigella spp.

3 3

1 2

Serratia spp.

3

2

Salmonella typhi

2 2 3 2

1 2

Salmonella spp.

2 3

Proteus mirabilis

3 3

2

Acinetobacter spp.h

Morganella morganii

3

Klebsiella spp.f,g,ad

2 2 3 2

1 2

2 2

1

2

2 3

2

1

Cefditoren Cefotaxime 2

3

Providencia stuartii

Cefazolin 3

Proteus vulgaris

1st

Escherichia coli f,g

Enterobacter spp.e,f

Citrobacter spp.e

Legionella pneumophila

Haemophilus influenzae d

Haemophilus ducreyi

Helicobacter pylori c

Francisella tularensis

Chlamydia trachomatis

Chlamydophila psittaci

Chlamydophila pneumoniae (TWAR)

Campylobacter jejuni

Brucella spp.b

Neisseria meningitidisag

Bordetella pertussis

Neisseria gonorrhoeae a

Moraxella catarrhalis

Cefadroxil 3

Vibrio cholerae

Enterobacterales

Ferment-Negative

Coccobacilli

Burkholderia cepacia complex h

Cocci

Chlamydiae

IDSE Review

Table 2.

Cephalosporins

2 2

2

2

2 1

2

2

1

1 1 1 1

1

2 1

2 2

2 2

2

3

3

3

2 2 2 2

2

2 2

2 2

2 2 2 2

2

3

3

1 1 1 1

1

2 1 1

2 2

3

2 2

3rd Ceftazidime 3 Ceftibuten 2

Other

2

3 2

2

2

2 2

2 2

2

2 1

Ceftriaxone 2

1 2

2

1 1

Cefepime 2

2 2

2

2

2ae 2ae 1 1 1 1 2ae 2 1 1 1

1

2 2 1 1

1

1 2

1 2

2

3

3

2 2 3 3

3

3

3

Ceftazidime-avibactam

2

2

2

2 2 3 2

3

3

2

Ceftolozane-tazobactam

2

2

2

2 2 3 2

3

2

2

2 2

Ceftaroline 2

IDSE.NET

3

2

3 1 2 2 2

3

2ae 2 3ae

2

Cefiderocol

82

2

Ceftizoxime 2

4th AntiMRSA

3 3

2af

2 3

3

3 1

3

2 2 3 2

2

2 3

2

Enterococcus

Streptococcus Group A (S. pyogenes)

2 3 2 2 3 2 2x 2 3 3

2 3 2 2 3 2

2 2 3

3 3 3 3

2 3 2 2 2 2

2 3 2 2 3 1 2x 2 2 3

2

3

2 2

3 2

2 2

2 2 1 2 2 2 2

3 2

2

3 3

2 3 3

1 2 2 2 2 2 2 2

1 1 1 2 2 3 2 2

1 2 2 2 2 3 2 2

3 3 2 2 2 2 2

3 3 3 3 3 3 3 2 2 2 2 3 2

3 3 3 3 3 3 3 2 2 2 2 3 2

3 2 2 2 3 2 2

2 2 2 2 3 2 2

2 2 3 2 2

2 2 2 3

3 2 2

3 3

3

3

2

3 2 2 2 3 2

2 2 2 3 2

3 2

3 2 1

2 3 2 2 2

1 2

3

2

Treponema pallidum

Leptospira spp.

Borrelia recurrentis

Borrelia burgdorferi (Lyme disease)q

Ureaplasma urealyticum

Spiral Organisms

Mycoplasma

GramPositive

Mycoplasma pneumoniae

Peptostreptococcus spp.

Clostridium tetani

GramNegative

Clostridium perfringens

Clostridioides difficile p

Prevotella melaninogenica

Fusobacterium spp.

Bacilli

Bacteroides fragilis

Listeria monocytogenes o

Gardnerella vaginalis n

Corynebacterium jeikeium

Corynebacterium diphtheriae m

Actinomycetes

Cocci

Bacillus anthracis l

Nocardia spp.

Actinomyces israelii

Viridans streptococci

Penicillin-resistant Streptococcus pneumoniae j,k

Streptococcus pneumoniae i

Streptococcus Group F (eg, S. anginosus)

Streptococcus Group D (eg, S. bovis)

Streptococcus Group B (S. agalactiae)

Anaerobes

IDSE Review

3

Methicillin-resistant Staphylococcus epidermidis

Methicillin-susceptible Staphylococcus epidermidis

Vancomycin-intermediate Staphylococcus aureus (VISA)

Methicillin-resistant Staphylococcus aureus

Methicillin-susceptible Staphylococcus aureus

Vancomycin-resistant Enterococcus faecium

Enterococcus faecium

Vancomycin-resistant Enterococcus faecalis

Enterococcus faecalis

Gram-Positive Aerobes

2

2

2

3

3

2

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

83

Gram-Negative Aerobes

Aminoglycosides

1

1

1

Macrolides

Clarithromycin 1

1 1

1 3 2

2

1

2

2 2 1 2

Quinolonesr

Dirithromycin 2 Erythromycin 2 3 3

1 3 2

2

Ciprofloxacin 2 2 2

2 3 2

2

2

2 2

2

2

2

2 1 3

1

Tetracyclines 3 3 3 (eg, Doxycycline, Minocycline)t

2

FermentPositive

2 2 3 3 3 3 2

3

2

2 2

2

3

2 2 2 1 2 2 2 2 2 2 2 2 2

2 2 2

1

3

2 1 2 2 2 2 2 2 2

3 2 3

2

2

3 3

3 3

2

2

2 1

2

2

2 1 2 1

2 2

3

2

2 3 3

2

2 2 3 2 3 2

2

2 2 2 2 2 2 2

2

2 2 2 2 2 2 2 2

Vancomycin Dalbavancinz Oritavancin

Telavancin

3

Linezolid Tedizolid Chloramphenicol 3

2 2 2

2 3

Clindamycin

3 2

3

3

3 3

3 2 2 3 3

3

3

3 2 2 2

Colistin/polymyxin B

2

2

Other Antibiotics

Daptomycins Fidaxomicin

2

Lefamulin

2

Metronidazole

3

Rifampin 2 2 2

3 2

Telithromycin 2 Trimethoprim-sulfamethoxazole 1 UTI

2 2

Quinupristin-dalfopristin 3

Agentsu

Vibrio cholerae

Pasteurella multocida

Stenotrophomonas maltophilia

Pseudomonas aeruginosa g

Shigella spp.

Acinetobacter spp.g

Serratia spp.

Salmonella typhi

Burkholderia cepacia complex g

1

3 2

2 2 2 2 2

Tigecycline 2

2 3 1

1 1

Eravacycline Omadacycline 3

3

1

2 2 2

2

Salmonella spp.

1 1 1 1 1 1 1 2 1

2 2

3

3

2 2 1 2 2 2 2 2 2 2 2 2 1 2 2 2

2 3

Providencia stuartii

2

2 3 1

3 3

Moxifloxacin 2 2 2

Proteus vulgaris

2 2 2 2 3 3 3 3

2 1 1 1

Levofloxacin 2 2 2

Proteus mirabilis

1

Delafloxacin Gemifloxacin 2

Tetracyclines/ Glycylcyclines

Morganella morganii

1

1 3 1

3 2

Klebsiella spp. f,g,ad

2 3 3

1 1 1 1 1 1 1 2 2

2

Tobramycin 3

1 3 1

Escherichia coli

2 2 2 2 2 2 2 2 2

3

Plazomicin

Azithromycin 1 2 2

Enterobacter spp.e

3

ac

Streptomycin

Citrobacter spp.e

Legionella pneumophila

FermentNegative

2

Haemophilus influenzae d

Haemophilus ducreyi

Helicobacter pylori c

Francisella tularensis

Chlamydia trachomatis

Chlamydophila psittaci

Campylobacter jejuni

Chlamydophila pneumoniae (TWAR)

Brucella spp.b

Bordetella pertussis

Neisseria meningitidisag

Neisseria gonorrhoeae a

Amikacin 3 Gentamicin 3

Oxazolidi- Glycopeptide/ nones Lipoglycopeptides

Other Bacilli (non-Enterobacterales)

Enterobacteralesf

Coccobacilli Chlamydiae

Cocci

Moraxella catarrhalis

IDSE Review

Table 3.

Aminoglycosides, Macrolides, Quinolones, Other Antibiotics

2 1

84

IDSE.NET

2 2

3

3 3

3

3

2 2 3

Fosfomycin (oral formulation only) Nitrofurantoin

1

2

3

1

1 2 2 2 3 2

2 2 2 2 2 2 2

3 3 2 2 3 3 3

3

3 3 1 3 3 2 3 3

3

1

1 3

Enterococcus faecium Vancomycin-resistant Enterococcus faecium

2 3 3 3

3 3 3 3

3

2

2

2

3

2

2 2 2

1

2 3

2 2 3y 3 3y 2 1 3 3 2 2 2 2 2 2 2 2 2 3

2 3 3 3 2 1 3 3 2 2 2 2 3 2 2 2 3

2 3 2 3 2 2 2 1 2 2 2 2 2 2 2 2

2 1 1 1 2 2 1 1 2 2 2 2 3 2 2 2 2

3 3 2 2 2 2 3 3 2 2

2 2 3 2 3 3 3 3 3 3

3 2 3 3 3 2 2 2 2 2 2 3 3

2 2 2 2 2 2 2 2 3 3 2

3

1

2

2 2

2

3

2 1aa

1 3

3 2

2

Methicillin-resistant Staphylococcus epidermidis

2

Methicillin-susceptible Staphylococcus epidermidis

Enterococcus

2 3

2 3

2 3 3 2 2 3 2 3 3 3

2 3 3 2 2 2 3 3 3

3 3 2 2 3 3

2 3 3 3 2

3 3 1

2 2 2 2 2 2 2

2 1

2

2

2 3

3

2

1 3

3 3

2 2

3 3

1 2

2 2 2 2

3 3 2 2 2

2 1 2 2 2

2 1 1

3 3

3

3 2

2

2

2

2

2

2

2

2 2

2

2

2 3

3

3 2 2

3 2 3 3

2

3

2

2

2

2

3

2

2

2 3

3

2 2

2

1

2

2

3

3

3 3

2

3

3

2 3

2 3

2 2

3 3

2

2 2 2 2 2 2

1 2 2 2 2 2 2 2 2 2

2 1 2 3 3 2 2 1 2 2

2

2

2 3 2

1 3

3

3

1

2

2

2 2

1

1

2

3

3 3 2

2 2 2 3 1 2 2

3 3 2 3 1 2 2

3 3 3 1

3 3 3 1 3 3

2 3

3 1

3

3

3 2 2

2 3 3 2 2 2 1 2 3 3

2 3 3 2 2 2 2 1 2 3 3 2 3

3 2

2

3 2

3 3 3 3 3 2 2 2 2

2

2 2 2 2

2 2 2 3 2

2 2

1

3 3 2 2

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

Treponema pallidum

Leptospira spp.

Mycoplasma

Borrelia recurrentis

Borrelia burgdorferi (Lyme disease) q

Clostridium tetani

Clostridium perfringens

Clostridioides difficile p

Ureaplasma urealyticum

2

Mycoplasma pneumoniae

3

Peptostreptococcus spp.

3

Prevotella melaninogenica

Fusobacterium spp.

Actinomycetes

Bacilli

Bacteroides fragilis

Listeria monocytogenes o

Gardnerella vaginalis n

Corynebacterium jeikeium

Corynebacterium diphtheriae m

Bacillus anthracis l

Nocardia spp.

Actinomyces israelii

Viridans streptococci

Penicillin-resistant Streptococcus pneumoniae j,k

Streptococcus pneumoniae i

Streptococcus Group F (eg, S. anginosus)

Streptococcus Group D (eg, S. bovis)

Streptococcus Group B (S. agalactiae)

Streptococcus Group A (S. pyogenes)

Vancomycin-intermediate Staphylococcus aureus (VISA)

Hospital-associated methicillin-resistant Staphylococcus aureusw

Community-associated methicillin-resistant Staphylococcus aureus v

Cocci

Anaerobes GramGramNegative Positive Spiral Organisms

3

3

2

2 3 2 2

1 3 3 3

1

2

3

2 2 2 2

1

2

1 1 1 2 2 2 2

2

2

1

2 2

85

IDSE Review

2 Methicillin-susceptible Staphylococcus aureus

Vancomycin-resistant Enterococcus faecalis

2

Enterococcus faecalis

Gram-Positive Aerobes

IDSE Review

Footnotes a Resistance to penicillin, tetracycline, and ciprofloxacin may be as high as 16.2%, 25.3%, and 19.2%, respectively, according to a 2014 report; dual therapy with ceftriaxone plus azithromycin is the only recommended gonorrhea treatment. b Use a combination, eg, doxycycline with gentamicin or rifampin or doxycycline with trimethoprim-sulfamethoxazole and chloramphenicol. c Combination therapies with high eradication rates include omeprazole + clarithromycin + amoxicillin as well as bismuth subsalicylate + metronidazole + tetracycline. However, metronidazole resistance has risen significantly. d Up to 50% of Haemophilus influenzae strains are capable of producing beta-lactamases.

r

Fluoroquinolone resistance rates can vary greatly against P. aeruginosa, Acinetobacter spp., and the Enterobacteriaceae.

Use as empiric therapy against these organisms should be based on local susceptibilities.

s

Despite its potent in vitro activity against S. pneumoniae, daptomycin is not indicated for the treatment of pneumonia, due to extensive binding to pulmonary surfactant, which results in clinical failure.

t

The specific tetracycline recommended varies. For methicillinresistant Staphylococcus aureus, minocycline is most active among class. Consult specific references.

u These agents generally are recommended for urinary tract infections (UTIs) only. Use of the “1” to “3” scale refers to activity for treatment of UTI. v

e Citrobacter spp. and Enterobacter spp. may differ in susceptibility patterns. Consult individual test results for appropriate choice. f

Carbapenem-resistant Enterobacteriaceae (CRE) are increasing and are endemic in certain geographic regions.

Viable treatment options are limited and should be based on susceptibilities. For serious CRE infections, ceftazidimeavibactam or meropenem-vaborbactam should be preferred.

Due to poor clinical outcomes with monotherapy, combination therapy with an aminoglycoside, including plazomicin (see footnote ac), colistin/polymyxin B, or tigecycline, based on local susceptibility results, is encouraged.

g A significant number of strains are capable of producing extended-spectrum beta-lactamases (ESBL). Consider this possibility according to antibiogram, patient’s history, and local resistance patterns. In suspected or proven cases, use carbapenems or proper non–beta-lactam antibiotics based on susceptibility studies.

w Vancomycin is considered first-line when IV therapy is required.

Notably, in recent years, vancomycin MICs have gradually increased for S. aureus and have included an increased occurrence of heteroresistance. Clinical reports have associated this loss of in vitro potency with vancomycin clinical failures in a number of patients. Alternative therapies such as ceftaroline, daptomycin, linezolid, telavancin, and tigecycline should be considered in the appropriate clinical setting. Consult specific references. x

Effective choice for meningeal infections if the ceftriaxone/ cefotaxime MIC <0.5 mcg/mL.

h Combination therapy is suggested, particularly during empiric treatment until susceptibility results are finalized.

y

Dalbavancin is not active against vancomycin-resistant enterococci (VRE) exhibiting vanA resistance.

i

z

Dalbavancin may be given as either a single dose of 1,500 mg or as 1,000 mg administered on day 1 followed by 500 mg on day 8 for patients with normal kidney function.

When parenteral penicillin is used to treat a non-CNS pneumococcal infection, 94.8% of isolates are susceptible, 3.1% are intermediate, and 2.1% are resistant. Approximately 10% and 24% of Streptococcus pneumoniae strains in the United States are resistant to clindamycin and macrolides, respectively.

j

PRSP (penicillin-resistant S. pneumoniae) is defined as nonsusceptible to penicillin with an MIC _> 8 mcg/mL for nonCNS infections (parenteral therapy), _> 2 mcg/mL for non-CNS infections (oral therapy), and _> 0.12 mcg/mL for CNS infections.

k Amoxicillin doses of 80-90 mg/kg/d may be effective against non-meningeal PRSP infections. l

For updates, see https://bit.ly/2JMRyQf.

m Membranous pharyngitis treated with antitoxin and IV erythromycin (antimicrobials used to decrease toxin production and bacterial spread). n New classification: Bacteria are gram-variable. o Aminoglycosides (gentamicin) may be synergistic with betalactams. p Oral vancomycin is recommended as first-line therapy for initial episodes of Clostridioides difficile infection (CDI), regardless of the severity of presentation. Fidaxomicin was found to be noninferior to oral vancomycin in treating CDI and superior in preventing recurrences of non-NAP1/BI/027 strains; therefore, it is also a first-line option. Metronidazole is no longer recommended for first episodes of CDI unless vancomycin and fidaxomicin are contraindicated or unavailable. q Stage of disease determines choice of treatment. Consult specific references.

86

Vancomycin is considered first-line when IV therapy is required.

Dalbavancin or oritavancin may be considered first-line treatment for acute bacterial skin and skin structure infections caused by CA-MRSA in EDs with adequate clinical pathways for follow-up. Ceftaroline, daptomycin, linezolid, tedizolid, telavancin, and tigecycline may be suitable alternatives in specified patients. Tetracyclines, clindamycin, trimethoprim-sulfamethoxazole, macrolides, tedizolid, and linezolid are viable alternatives when oral therapy can be used. In the face of erythromycin resistance, clindamycin should be considered only if the isolate is D-test–negative.

IDSE.NET

aa Higher doses of daptomycin (>8 mg/kg) have resulted in reduced mortality and may be associated with improved microbiological outcomes in the setting of VRE bacteremia. ab The sulbactam component of ampicillin-sulbactam has in vitro activity against some Acinetobacter baumannii and has been used successfully to treat serious Acinetobacter infections when the organism was reported to be susceptible. ac Plazomicin is approved for the treatment of adults with complicated UTIs, including pyelonephritis due to certain Enterobacteriaceae. Due to limited clinical and safety data, it should be reserved for patients with limited or no alternative treatment options. In particular, plazomicin is active against CRE that produce most aminoglycoside-modifying enzymes that inactivate other aminoglycoside antibiotics. Data from patients with bloodstream infections due to CRE suggest it may play a role when combined with another antibiotic. ad Enterobacter aerogenes now reclassified as Klebsiella aerogenes. ae Inducible AmpC resistance genes may render this agent ineffective against this organism. af In clinical trials, the use of cefiderocol among patients with Serratia infections was limited to those with ventilator-associated pneumonia only. ag Agents used to treat this organism should be optimized to achieve therapeutic concentrations within the central nervous system. ah This recommendation is based on preclinical studies alone i.e. in vitro studies and in vivo animal models.

IDSE Review

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2017;19:1-10.

Morrill HJ, Morton JB, Caffrey AR, et al. Antimicrobial resistance of Escherichia coli urinary isolates in the Veterans Affairs health care system. Antimicrob Agents Chemother. 2017;61(5). pii:e02236-16.

Bassetti M, Giacobbe DR, Giamarellou H, et al. Management of KPC-producing Klebsiella pneumoniae infections. Clin Microbiol Infect. 2018;24(2):133-144.

Nordmann P, Cuzon G, Naas T. The real threat of Klebsiella pneumoniae carbapenemase producing bacteria. Lancet Infect Dis. 2009;9(4):228-236.

Brook I. Spectrum and treatment of anaerobic infections.

J Infect Chemother. 2016;22(1):1-13.

Ofosu A. Clostridium difficile infection: a review of current and emerging therapies. Ann Gastroenterol. 2016;29(2):147-154.

Datta R, Juthani-Mehta M. Nitrofurantoin vs fosfomycin: rendering a verdict in a trial of acute uncomplicated cystitis.

JAMA. 2018;319(17):1771-1772.

Petersen PJ, Bradford PA, Weiss WJ, et al. In vitro and in vivo activities of tigecycline (GAR-936), daptomycin, and comparative antimicrobial agents against glycopeptideintermediate Staphylococcus aureus and other resistant gram-positive pathogens. Antimicrob Agents Chemother.

2002;46(4):2595-2601.

Ferrara AM. Potentially multidrug-resistant nonfermentative gram-negative pathogens causing nosocomial pneumonia.

Int J Antimicrob Agents. 2006;27(3):183-195.

Gordon KA, Biedenbach DJ, Jones RN. Comparison of Streptococcus pneumoniae and Haemophilus influenzae susceptibilities from community-acquired respiratory tract infections and hospitalized patients with pneumonia: five-year results for the SENTRY Antimicrobial Surveillance Program.

Diagn Microbiol Infect Dis. 2003;46(4):285-289.

Hackel M, Kazmierczak KM, Hoban DJ, et al. Assessment of the in vitro activity of ceftazidime-avibactam against multidrugresistant Klebsiella spp. Collected in the INFORM Global Surveillance Study, 2012 to 2014. Antimicrob Agents Chemother. 2016;60(8):4677-4683.

Hansen GT, Blondeau JM. Comparison of the minimum inhibitory, mutant prevention and minimum bactericidal concentrations of ciprofloxacin, levofloxacin and garenoxacin against enteric gram-negative urinary tract infection pathogens.

J Chemother. 2005;17(5):484-492.

Pitout JD, Laupland KB. Extended-spectrum beta-lactamaseproducing Enterobacteriaceae: an emerging public-health concern. Lancet Infect Dis. 2008;8(3):159-166.

Pollack CV Jr, Amin A, Ford WT Jr, et al. Acute bacterial skin and skin structure infections (ABSSSI): practice guidelines for management and care transitions in the emergency department and hospital. J Emerg Med. 2015;48(4):508-519.

Rhomberg PR, Fritsche TR, Sader HS, et al. Comparative antimicrobial potency of meropenem tested against gramnegative bacilli: report from the MYSTIC surveillance program in the United States (2004). J Chemother. 2005;17(8):459-469.

Sader HS, Farrell DJ, Flamm RK, et al. Antimicrobial susceptibility of gram-negative organisms isolated from patients hospitalised with pneumonia in US and European hospitals: results from the SENTRY Antimicrobial Surveillance Program, 2009-2012. Int J Antimicrob Agents. 2014;43(4):328-334.

Hawser SP, Bouchillon SK, Hoban DJ, et al. In vitro susceptibilities of aerobic and facultative anaerobic Gramnegative bacilli from patients with intra-abdominal infections worldwide from 2005-2007: results from the SMART study.

Int J Antimicrob Agents. 2009;34(6):585-588.

Sutherland CA, Nicolau DP. Potency of parenteral antimicrobials including ceftolozane/tazobactam against nosocomial respiratory tract pathogens: considerations for empiric and directed therapy.

J Thorac Dis. 2017;9(1):214-221.

Howard A, O’Donoghue M, Feeney A, et al. Acinetobacter baumannii: an emerging opportunistic pathogen. Virulence.

2012;3(3):243-250.

Trampuz A, Zimmerli W. Antimicrobial agents in orthopaedic surgery: prophylaxis and treatment. Drugs.

2006;66(8):1089-1105.

Kuti JL, Florea NR, Nightingale CH, et al. Pharmacodynamics of meropenem and imipenem against Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa.

Pharmacotherapy. 2004;24(1):8-15.

Unemo M, Shafer WM. Antimicrobial resistance in Neisseria gonorrhoeae in the 21st century: past, evolution, and future.

Clin Microbiol Rev. 2014;27(3):587-613.

Linder KE, Nicolau DP, Nailor MD. Epidemiology, treatment, and economics of patients presenting to the emergency department for skin and soft tissue infections. Hosp Pract (1995).

2017;45(1):9-15.

Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52:e18-e55.

Miller WR, Murray BE, Rice LB, et al. Vancomycin-resistant enterococci: therapeutic challenges in the 21st century.

Infect Dis Clin North Am. 2016;30(2):415-439.

Van Bambeke F, Michot JM, Van Eldere J, et al. Quinolones in 2005: an update. Clin Microbiol Infect. 2005;11(4):256-280.

Erratum in: Clin Microbiol Infect. 2005;11(6):513.

Yamaguchi T, Hashikita G, Takahashi S, et al. In vitro activity of beta-lactams, macrolides, telithromycin, and fluoroquinolones against clinical isolates of Streptococcus pneumoniae: correlation between drug resistance and genetic characteristics.

J Infect Chemother. 2005;11(5):262-264.

Zhanel GG, Chung P, Adam H, et al. Ceftolozane/tazobactam: a novel cephalosporin/beta-lactamase inhibitor combination with activity against multidrug-resistant gram-negative bacilli.

Drugs. 2014;74(1):31-51.

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2021

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