Infectious Disease Special Edition (Winter 2020)

Volume 25 • Winter 2020

COVID-19: Which Boat Are You In? More Options for HIV Resistance Mark Wilcox on Managing C. diff Julia Garcia-Diaz, et al, on Today’s ART New Column: Antibiotic Answers Why Won’t MDs Prescribe New Antibiotics?

THE MORE YOU DETECT THE BETTER YOU PROTECT Improve care for more patients with ePlex® Blood Culture Identification Panels, the only BCID panels that can detect >95% of organisms that cause sepsis Sepsis is a common complication of COVID-19 and rapid diagnosis is key to effective treatment. ePlex BCID Panels rapidly detect more of the organisms that cause sepsis. Armed with this critical information, you can prescribe the right treatment within hours – rather than days – improving patient care.

The ePlex BCID Panels can identify >95% of the pathogens that cause sepsis. Combine this with order-to-report integration and templated comments and you’re ready to fast-track treatment intervention, enabling earlier escalation for resistant organisms or de-escalation of empirical antimicrobials.

To learn more, scan or visit GenMarkDX.com/DetectMore

Winter 2020 4 Editor’s Blog: A Societal Responsibility 6 COVID-19: Great Debates, Sweden and Herd Immunity 10 Was the Swedish Experiment a Success?

12 Not Everyone Riding in the Same Boat With COVID-19 19 IDSA Gives Bamlanivimab a Conditional No-Go in COVID-19 Treatment Guidelines 20 Is One Quadrivalent Influenza Vaccine Better Than Others for Seniors?

22 Better Options Available for Multidrug-Resistant HIV 24 C. diff: Old Disease, New Changes in Management 29

Why Won’t Physicians Prescribe New Antibiotics?

75 Classifieds

12

24

68

IDSE Reviews

32 Updated Evidence for Optimal Management of C. diff Infection

By Mark H. Wilcox, MD, FRCPath

39 Rapid Diagnostics Revolutionize Management of Hospital Infections

By Maya Beganovic, PharmD, MPH, BCIDP; and Sarah M. Wieczorkiewicz, PharmD, FIDSA, BCPS, BCIDP

55 Antimicrobial Efficacy

By Sean M. Stainton, PharmD; Mary Staicu, PharmD, BCIDP; and MaryRose Laguio-Vila, MD

68 What’s New in HIV Therapy?

By Hind Alrowais, MD; Amy K. Feehan, PhD; and Julia Garcia-Diaz, MD

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2020

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 at East Carolina University Greenville, North Carolina

Oregon Health & Science University Portland, Oregon

Brian Currie, MD, MPH

Jonathan Z. Li, MD

Emeritus, Albert Einstein College of Medicine Montefiore Medical Center New York, New York

Harvard Medical School Brigham and Women’s Hospital Boston, Massachusetts

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

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

Summa Health Akron, Ohio Northeast Ohio Medical University Rootstown, Ohio Julia Garcia-Diaz, MD

Ochsner Health System New Orleans, Louisiana

Wayne State University Detroit, Michigan Mark H. Wilcox, MD, FRCPath

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

EDITORIAL

McMAHON GROUP

Marie Rosenthal, MS

Van Velle

Managing Editor mrosenthal@mcmahonmed.com James Prudden

Group Editorial Director Katherine Reider

Editorial Director, Projects Elizabeth Zhong

Senior Copy Editor Kristin Jannacone

Copy Editor

SALES Joe Malichio

Publication Director, IDSE Director, Medical Education jmalichio@mcmahonmed.com (212) 957-5300, ext. 286

ART/PRODUCTION Michele McMahon Velle

Creative Director, MAX Graphics

President, Partner Matthew McMahon

General Manager, Partner Lauren Smith Michael McMahon Michele McMahon Velle

Partners Ray & Rosanne McMahon

Co-founders

McMAHON PUBLISHING Sales, Production, and Editorial Offices: 545 W. 45th Street, 8th Fl. New York, NY 10036 Telephone: (212) 957-5300 Fax: (888) 200-6787 Single Copies/Subscriptions: $70 per issue ($90 outside the USA)

Matt White

Associate Art Director, MAX Graphics Ron Redfern

Production Manager Rob Sinclair

Copyright © 2020 McMahon Publishing, New York, New York All rights reserved, including the right of reproduction in any form.

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.

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

4

IDSE.NET

EDITOR’S BLOG:

A Societal Responsibility

C

OVID-19 fatalities are surpassing 3,300 a day. By the time you read this, more than 300,000 people will have died from the disease in the United States. During the most recent surge, more Americans are dying daily from COVID-19 than were killed in the 9/11 or Pearl Harbor attacks, said CDC Director Robert Redfield, MD, during an event hosted by the Council on Foreign Relations on Dec. 10.

And it is likely to get worse before it gets better, Anthony Fauci, MD, the director of the National Institute of Allergy and Infectious Diseases, warned the attendees of the ASHP 2020 Midyear Clinical Meeting & Exhibition.

But there are actions that every person can take to reduce the number of hospitalizations and deaths until the new vaccines can be widely distributed: socially distance, wear a mask and wash your hands frequently.

These actions are difficult only because we are tired of doing them. We long to send our children to the classroom, meet friends and family, go to the gym, visit the hairdresser and attend religious services. Many of us would much rather pop over to our favorite restaurant than eat another meal alone at the kitchen counter.

But we realize these small actions are nothing compared with the sacrifices made by people like you, who are risking your lives to care for COVID-19 patients. (Thank you, thank you, thank you!)

People who refuse to practice mitigation are the real concern here. They loosely fall into two camps: people who don’t believe the pandemic is a personal threat and those who believe it is fake news. It can be difficult to convince some people to take this pandemic seriously, Fauci said. A younger person’s sense of invincibility might apply here, especially younger people who believe that they won’t be very sick if they are infected. What’s the big deal?

The big deal is transmission, he explained at ASHP. And it is near impossible to convince someone to take measures who won’t even acknowledge there is a problem, he added. “I get baffled by the response of some of the people in the country … where a public health crisis becomes politicized, where wearing a mask or not becomes a political statement, where there are people in certain areas of our country who feel—even though their hospitals are almost overrun with patients, many in critical care as a result of COVID19 illness—who still believe that this is fake news or that this is a hoax,” he said.

A friend and colleague recently married amid the pandemic. Although the wedding was much different from the one originally planned, the pictures (taken outdoors) show a smiling, beautiful bride and a very happy groom.

Listening to the accommodations she made because of the pandemic reminded me of the stories my mother told of her wedding, which occurred during World War II, when everyone in the family had to pool their ration books for the small reception.

Having survived the Great Depression and in the middle of fighting a tyrant in Europe, my mother then—and my friend now during this pandemic—understand that they have a responsibility to society at large.

We all do, Fauci said.

“You can’t operate in a vacuum, because even though you may get infected and have no symptoms, you are part of the propagation of the outbreak. What you want to be is a dead end for the virus. You don’t want to be a vehicle that the virus uses to spread to someone else.

“You have to have what I call a societal responsibility, not only responsibility to yourself and to your family, but to all of society. You don’t want to be part of the problem. You want to be part of the solution,” Fauci said.

I could not have said it better myself. We really are in this together.

Our cover story looks at a parallel idea being circulated about allowing herd immunity to develop. Check it out on page 6.

—Marie Rosenthal, MS

The views expressed here belong to the author and do not necessarily reflect those of the publisher.

Learn what our portfolio of products can do for your patients.

Contact your Allergan representative or call 800-678-1605 for more information.

Brought to you by Allergan, Inc.

!LLERGANš AND ITS DESIGN ARE TRADEMARKS OF !LLERGAN )NC -/.52/,š AND ITS DESIGN ARE REGISTERED TRADEMARKS OF :AMBON 3P! !69#!:š AND ITS DESIGN ARE TRADEMARKS OF !LLERGAN 3ALES ,,# 4%&,!2/š AND ITS DESIGN ARE REGISTERED TRADEMARKS OF !LLERGAN 3ALES ,,# $!,6!.#%š AND ITS DESIGN ARE TRADEMARKS OF !LLERGAN 0HARMACEUTICALS )NTERNATIONAL ,IMITED ¥ !LLERGAN !LL RIGHTS RESERVED -"$

COVID-19: Great Debates, Sweden and Herd Immunity

BY MARIE ROSENTHAL, MS

O

ne would be hard-pressed to find someone who doesn’t long to return to normal, rather than practicing mitigation strategies against COVID-19, so the idea that natural herd immunity should be allowed to develop is gaining traction in some circles. The virus already is widespread; why not just let herd immunity develop and reduce the threat?

In addition, some argue, the non–COVID-19 effects are as devastating as the hospitalizations and deaths caused by the virus, because the pandemic has adversely touched just about every aspect of society. Although it will be some time

6

IDSE.NET

before all these consequences are appreciated, preliminary data about two serious COVID-19–related gaps in care give an idea of what is to come.

The first, a major decline in vaccination rates, is staggering, putting the country at risk for infectious outbreaks in the coming months and years (MMWR Morb Mortal Wkly Rep 2020;69[19]:591-593). In Michigan alone, fewer than 50% of young infants were up-to-date on their routine childhood vaccinations (MMWR Morb Mortal Wkly Rep 2020;69[20]:630-631). Adults also saw declines in

vaccination with the highest declines among those aged 65 years and older, according to the National Foundation for Infectious Diseases.

These missed opportunities were seen everywhere. In July 2020, the World Health Organization and UNICEF warned of declining vaccination rates during COVID-19 as immunization programs around the world were halted. “The likelihood that a child born today will be fully vaccinated with all the globally recommended vaccines by the time she reaches the age of 5 is less than 20%,” WHO said in a statement.

Cancer care also was seriously affected by the pandemic.

Between March and July 2020, there was a substantial decline in cancer screenings and care in the United States compared with the same period in 2019 (JCO Clin Cancer Inform 2020;4:1059-1071). In April, screenings for breast cancer were down 85%, for colon cancer 75%, for prostate cancer 74% and for lung cancer 56%. There also was a 74% drop in outpatient visits for cancer evaluation and management among new and existing patients.

The mental health costs—increased substance abuse, domestic violence, homelessness, anxiety, depression, loneliness and suicides—also will be felt long after the pandemic is controlled. Increases in unemployment also have affected the mental and physical health and well-being of many Americans.

And just as is evident with the infection itself, all of these problems are worse among the most vulnerable populations.

“We have underemphasized the disparities associated with this infection that disproportionately affect people of color and other populations that have been marginalized in our health care system,” said Stuart C. Ray, MD, FACP, FIDSA, the vice chair of medicine for data integrity and analytics, and a professor in the Division of Infectious Diseases at the Johns Hopkins University School of Medicine, in Baltimore.

“Poverty is one of the things that plays into this.”

The Great Debate This desire to mitigate the societal costs of COVID-19 is spawning ideas such as the Great Barrington Declaration, which proposes that governments allow natural herd immunity to develop, while protecting vulnerable groups (https:// gbdeclaration.org). “As immunity builds in the population, the risk of infection to all—including the vulnerable—falls.

We know that all populations will eventually reach herd immunity—i.e. the point at which the rate of new infections is stable—and that this can be assisted by (but is not dependent upon) a vaccine. Our goal should therefore be to minimize mortality and social harm until we reach herd immunity,” the declaration says.

At first glance, this idea might have wide appeal because people are desperate to return to normal. In fact, much has been written about the way the Swedes managed the outbreak because the country kept more businesses open than other European nations (see sidebar, page 10).

However, experts said the appeal would be misplaced for

By April, cancer screenings in the U.S. were down: 85% for breast cancer, 75% for colon cancer, 74% for prostate cancer and 56% for lung cancer compared with the same period last year.

Source: JCO Clin Cancer Inform 2020;4:1059-1071

In Michigan, fewer than 50% of young infants were up-to-date on their routine childhood vaccinations. Adults also saw declines in vaccination of 60% to 83%.

Source: MMWR Morb Mortal Wkly Rep 2020; 69[20]:630-631

many reasons, including the transmissibility of SARS-CoV-2, its potential for serious morbidity and mortality, the sheer number of people who would need to become infected before natural herd immunity would be attained, and the difficulty identifying everyone who might be at risk for serious consequences and death.

“Achieving herd immunity through natural infection, to me, is very dangerous,” said Walter A. Orenstein, MD, the associate director of the Emory Vaccine Center and director of Emory Vaccine Policy and Development, in Atlanta. “And I don’t see how that would be protective, because basically you are allowing uncontrolled infection to go on. And when infection is uncontrolled, it can hit vulnerable populations, like nursing home residents, because all you need is one introduction.”

Rajesh T. Gandhi, MD, FIDSA, a professor of medicine at Harvard Medical School and Massachusetts General Hospital, in Boston, and the chair of the HIV Medicine Association, agreed, adding that current measures are a better choice until a vaccine is widely available. “A safe and effective vaccine is much better than relying on natural infection to result in herd immunity,” he said. “Given that COVID19 can be fatal and that many people have risk factors for severe disease, it is just too risky to let COVID spread. We will lose too many people, and it will devastate our country.”

Many people shared their criticism, and the Great Barrington Declaration resulted in an almost immediate response: the John Snow Memorandum (https://www.johnsnowmemo. com). “Any pandemic management strategy relying upon immunity from natural infections for COVID-19 is flawed.

Uncontrolled transmission in younger people risks significant morbidity and mortality across the whole population. In addition to the human cost, this would impact the workforce as a whole and overwhelm the ability of health care systems to provide acute and routine care,” the memorandum says.

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2020

7

Success or Failure?

Another argument against the mitigation strategies is that measures, such as sheltering in place and closing nonessential businesses, do not work. And this assumption seems to be supported by the numbers—more than 16 million positive cases and more than 300,000 deaths in the United States (as of Dec. 14)—until one observes the statistical models available early in the pandemic, which predicted a more devastating toll without the mitigation strategies.

In March, the White House Coronavirus Task Force held a briefing where Deborah L. Birx, MD, the global AIDS

Figure. Dates of Statewide Stay-at-Home Orders, as of 4/7

went back up. And the country saw one wave after another in response to tightening and lifting restrictions.

“When I testified before a Senate hearing in July, when we were at 40,000 cases a day, I said, if we did not take seriously the implementation of public health measures, like washing hands, wearing masks, keeping distance, avoiding contact, avoiding crowds—everyone thought I was being hyperbolic,” Fauci said, but he predicted more than 100,000 cases a day without mitigation.

“Our country has been hit terribly,” he said. “Just think of that—267,000 deaths, and it isn’t even one year.”

By 3/20: CA By 3/22: IL, NJ, NY By 3/24: LA, OH, OR, WA, CT, DE, IN, MI, WV, MA, NM By 3/26: HI, ID, WI, VT, KY By 3/28: MN, NH, AK, RI, MT, WY By 3/30: KS, MD, NC, VA By 4/1: AZ, TN, PA, DC, NV By 4/3: ME, TX, GA, FL, MS

By 4/7: SC None as of 4/7: UT, OK, NE, ND, SD, IA, AR

coordinator and special representative for global health at the State Department, and Anthony Fauci, MD, the director of the National Institute of Allergy and Infectious Diseases, showed statistical models that had predicted 1 to 2 million deaths if the country did nothing. In contrast, they predicted up to 200,000 deaths if the country shut down until at least May. The purpose of the mitigation strategies was not to end the disease, but to mitigate the conditions that supported transmission and to reduce deaths and hospitalizations, so that hospitals would not be overrun until treatments and vaccines could be developed and implemented, Orenstein reminded.

“Social distancing and masking were not going to get rid of the virus, and were just going to try and limit the numbers of cases at any one time,” he explained.

Although there are difficulties in proving the success of something that did not happen, in any other circumstance, it would be hard to call a strategy that saves 700,000 to more than 1 million American lives a failure.

Fauci spoke at the ASHP Midyear Clinical Meeting & Exhibition on Dec. 9. He said that mitigation strategies implemented early in the season did bring down cases—down to 20,000 a day, but as soon as restrictions were lifted, cases

8

IDSE.NET

Mitigation Success It is also difficult to discern what the effects would have been if there had been a unified response across the country, experts said, but the administration left the shutdown implementation to the states. As a result, hard-hit states such as California, New York and New Jersey closed more nonessential activities for longer than some others. In fact, seven states—Arkansas, Iowa, Nebraska, North and South Dakota, Utah and Wyoming—never issued stay-at-home orders.

“I think one could describe what happened as sort of a whack-a-mole [approach], where we had restrictions in some areas, but not in others, and so the ‘mole’ just sort of reappeared in different places,” Ray said. “And for a virus as infectious as this, and [with] borders as porous as ours between states, it’s hard to know whether anything but a simultaneous lockdown would have prevented those other states from having a problem [today].”

Orenstein called the approach then—and now— “haphazard” and lacking national leadership. “National policies would be very helpful,” he told Infectious Disease continued on page 10

Source: CDC

By 4/5: AL, MO

I N T R OD U CI N G ™ F U N G I T E L L STAT ™

A Single Sample Format (1J3)-`-D-Glucan Detection Assay For Rapid Invasive Fungal Infection (IFI) Screening.

Fungitell STAT™ is the first and only single sample format FDA-cleared and CE marked rapid in vitro diagnostic screening test for IFI (including Candida, Aspergillus and Pneumocystis) that detects (1J3)- ` - D -Glucan in serum.

MKT#20-043

w w w. f u n g i t e l l . c o m • 8 8 8 . 3 9 5 . 2 2 2 1

COVID-19 Debates continued from page 8

Special Edition. “To me, we have to think of this in a global context. If we, in Atlanta, do a super job” but people outside the city do not, “people from Atlanta will interact with those people, and you will have spread.”

Protecting the Vulnerable Although deaths have occurred among all ages, most are among older people. As of Dec. 9, provisional numbers released by the CDC found 209,110 deaths from COVID-19 occurred in those aged 65 years and older.

Orenstein said he is concerned about the adverse effects the Great Barrington Declaration would have on the elderly and other vulnerable populations. “It is not like the elderly are completely isolated from younger populations. Clearly there are interactions between the younger and the older populations,” Orenstein said. Although he acknowledged the many problems with shelter-in-place mandates, this mitigation strategy, along with wearing masks, is the best way to reduce spread until a vaccine is widely available, he said.

SARS-CoV-2 is easily transmissible through respiratory droplets and close contact with an infected person, even if that person is currently asymptomatic, according to the CDC. This asymptomatic or presymptomatic transmission is especially problematic if one is trying to protect vulnerable people, Orenstein said.

The difference between SARS-CoV-2 and other

coronaviruses with pandemic potential, such as SARS (severe acute respiratory syndrome) and MERS (Middle East respiratory syndrome), is that SARS-CoV-2 fully adapted to human-to-human spread, where SARS and MERS were virulent but not as contagious, explained Orenstein, who is also the former director of the U.S. Immunization Program at the CDC. The reproduction number (R0; pronounced R naught) of SARS-CoV-2 is estimated to be between 2 and 4, with the best estimate believed to be 2.5, according to the CDC. If it’s 2.5, that means a person with COVID-19 is likely to infect slightly more than two people, he explained, in a 100% susceptible population. The herd immunity threshold is the immunity level when the average case infects one person. When the immunity level exceeds the herd immunity threshold, the average case infects less than one person and transmission stops. The herd immunity level is calculated by the following formula: R0-1/R0. As a comparison, the R0 for the 2009 pandemic influenza A H1N1 was 1.7 (Lancet Infect Dis 2020;20[9]:e238-e244).

With an R0 of 2.5, about 65% of the population would need to be exposed to the virus before achieving herd immunity; at an R0 of 2, about 50% of the population would need to be infected to develop herd immunity—in raw numbers, this would be more than 164 million people in the United States alone.

“I think we are talking probably on the order of 60% to 70% immunity, but an R0 can be misleading in the sense that it is a general population level, but in certain subpopulations

Was the Swedish Experiment a Success?

When Europe was implementing stayat-home orders, shutting down nonessential businesses and telling people to avoid gatherings, Sweden took a different, more open approach. Some people in the United States point to that approach as a better one than the shutdown practiced by the rest of the world.

Sweden implemented some restrictions. Although elementary schools and day care centers remained open, high schools and colleges were closed, and people were asked to work from home if they could. Large gatherings of more than 50 people were prohibited, and people were advised to avoid nonessential travel, encouraged social distancing, and seniors were asked to shelter in place, if possible.

10

IDSE.NET

However, businesses, including restaurants, were largely permitted to remain open.

“When the EU [European Union] was saying that people should wear masks, and there should be broad restrictions on movement activity, Sweden and some leaders there expressed doubts about that message,” explained Stuart

C. Ray, MD, FACP, FIDSA, the vice chair of medicine for data integrity and analytics, and a professor in the Division of Infectious Diseases at the Johns Hopkins University School of Medicine, in Baltimore.

“They tended to keep things more open than their neighbors did, hoping to preserve the economy, while still prote tecting vulnerable people,” he said.

“I think their intent was to try to move to toward herd immunity in their young po population, so they could mitigate future sp spread, and the reality is they have no not succeeded in that. They have not re reached herd immunity,” Ray said.

Sweden has seen just 7,514 deaths as of Dec. 14, and compared with the more than 299,737 seen in the United States, this approach might look like a grand success. However,

>70% of COVID-19 deaths in the U.S. occurred in those aged 65 years and older.

with closer contact rates, you may need even higher levels of immunity,” Orenstein said. “For example, we still see measles even though we meet our R0 immunity threshold, and there are entire populations that are able to sustain its transmission.”

Herd immunity is the point at which the effective R0 falls below 1, added Ray, and there is little evidence that says natural herd immunity could even be achieved. About 30% of common colds are caused by coronaviruses that circulate every season, and despite wide transmission, herd immunity to them has not developed, Ray pointed out.

“This notion that natural herd immunity is a given [after exposure], I think, is based on hope. We don’t have evidence that herd immunity would develop, even if we allowed spread, even if 60% of the population got the virus,” he told Infectious Disease Special Edition.

“In fact, for what infectious diseases can we say herd immunity occurred through natural infection without a

experts said it is hard to compare Sweden with a country like the United States. The total population of Sweden is 10.3 million and they live in the fifth-largest country in Europe by area (173,860 square miles). By comparison, the population of New York City alone is 8.39 million and they live in an area of 302 square miles.

“The much lower population density in Sweden compared with many other European countries may be a key factor in reducing the virus transmission pressure at a population level,” explained Mark Wilcox, MD, FRCPath, a consultant and the head of microbiology research and development at Leeds Teaching Hospitals NHS Trust, and a professor of medical microbiology and the Sir Edward Brotherton Chair of Bacteriology at the University of Leeds, in England.

vaccine?” Ray asked. “I absolutely would love to wave a magic wand and to have herd immunity, but the challenge at the feet of people who advocate that as a strategy is [to show] me the evidence that says we will get there.”

About 10% to 20% of the U.S. population has had COVID-19, Ray said. Even if natural herd immunity were achievable among 300 million or so Americans, “we would need a huge number of people to get infected. That is a lot of deaths,” he said.

The long-term sequelae experienced by COVID-19 survivors, including impaired cognition, are not being considered, either. “We don’t know how long these will last. We don’t know how much downstream morbidity will occur due to these infections. When we talk about herd immunity, we have to acknowledge that we cannot currently measure these, and the only way to protect against them is to reduce the number of infections,” Ray said.

“I’m not convinced this virus is going to wipe itself out,” Orenstein added. Until a vaccine can be distributed widely, “the only strategy we have is mitigation strategies, which are masking and social distancing, for the most part,” he said.

As Infectious Disease Special Edition went to press, the FDA granted an emergency use authorization for the Pfizer/ BioNTech COVID-19 vaccine and was considering an EUA for another. Several more are in clinical trials. However, it will be well into spring 2021 before they become widely n available.

The sources reported no relevant financial disclosures.

“The complexity of devising, delivering and compliance with public health measures is clearly more complex in the United States than in considerably smaller countries with less diverse and lower density populations,” Wilcox added.

A better comparison might be to look at Sweden’s Scandinavian neighbors, which did issue shutdown orders.

Compared with them, Sweden did not fare all that well. Denmark has seen 950 deaths; Finland has seen 461 deaths; and Norway has seen 393 from COVID19, as of Dec. 14. In fact, the rate of death in Sweden at 567 per 1 million people is actually closer to Italy’s rate of death, which is 581 deaths per 1 million.

Similar to other countries, the majority of deaths in Sweden occurred in the elderly, especially nursing home

residents, and other vulnerable populations. “It does not seem reasonable to conclude that this has been a success, especially noting the outcomes in care home residents, and the overall mortality data compared with other Scandinavian countries,” Wilcox said.

In addition to not developing herd immunity—only about 10% of the population has developed infection—the Swedes were not able to spare their economy: Unemployment is around 9%, much higher than the United States, which is 6.7%, and the Swedish economy is expected to continue to contract, according to the European Central Bank.

“I think the concern in taking a laxer approach to preventive measures as a strategy does not seem to be success—M.R. ful—at least not yet,” Ray said.

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2020

11

COVID-19: Not Everyone Is In the Same Boat

BY ETHAN COVEY

I

n the United States, Black people are dying at 2.5 times the ethnicity and economic status. rate of whites, according to data from the COVID Tracking Generally, men who have been exposed to COVID-19 Project. Nearly one in five Black adults today know someone have fared worse than women, a trend that was also identiwho has died of COVID-19. fied with severe acute respiratory syndrome and Middle Some experts say one reason why the COVID-19 pan- Eastern respiratory sydrome. demic has had a disproportionate effect on Blacks and other “One hypothesis has been that estrogens have a protecminorities, such as Native Americans, is the long history tive effect, and others have suggested there is a higher of racial segregation in the United States, which is partly concentration of ACE2 [angiotensin-converting enzyme 2] responsible for the health disparities seen today. receptors in men,” Del Rio said. “Finally, some have thought “When people say we are all in the same boat confronting that lifestyle differences, such as smoking prevalence, may COVID, some of us are in a yacht and others a dinghy,” said play a role.”

Carlos Del Rio, MD, a distinguished professor of medicine at Emory University School of Medicine, in Decatur, Ga. “When people say we are all in the “We are not in the same boat.”

Racial inequalities in access to health care in the United same boat confronting COVID, some of States are not new, yet they have been highlighted by the us are in a yacht and others a dinghy.”

COVID-19 pandemic, Del Rio noted in a presentation dur—Carlos Del Rio, MD ing IDWeek’s Chasing the Sun COVID-19 session.

“COVID-19 is having a strong, disproportionate impact on persons in the U.S. who are of racial/ethnic minorities,” Additionally, studies have shown that men are more likely said William Schaffner, MD, a professor of preventive medi- to be employed outside of the home, more likely to not shelcine, Department of Health Policy at Vanderbilt University in ter in place, and less likely to engage in social distancing.

Nashville, Tenn.

“We still need to define what is social, what’s behavioral and “This disturbing circumstance is the result of many factors, what is biological,” Del Rio added. including less public health awareness as well as a variety Health disparities become starker when studying how of barriers to accessible medical care. These are the down- COVID-19 has affected people of color, he said. Case rates stream consequences of past and, sadly, still current explicit are far higher than among people of color, and the disease has and implicit racial bias,” Schaffner told Infectious Disease been shown to affect minorities at younger ages than whites.

Special Edition.

“This racial disparity in mortality among COVID-19, particAccording to the Department of Health and Human ularly among African Americans and Indigenous Americans, Services Office of Disease Prevention and Health Promotion’s is really significant,” Del Rio said. “If Blacks, Latinos and publication, “Healthy People 2020,” health disparities are Indigenous people had died at the same rate as whites, there defined as issues that adversely affect groups of people who would be almost 20,000 Blacks, almost 10,000 Latinos and have systematically experienced greater social or economic over 600 Indigenous people alive today.” obstacles to health.

An interesting fact is that much of this mortality is occurring Health disparities that have been identified during the before these patients go to the hospital. Once hospitalized, continued on page 26 COVID-19 pandemic include issues related to gender, race,

12

IDSE.NET

APPROVED FOR ADULTS APP PROVED FO F OR A DULTS LTS

STARTING STARTING & SWITCHING SWITCHING ARV REGIMENS

Visit dovatohcp.com to Learn More

ARV=antiretroviral.

INDICATION DOVATO is indicated as a complete regimen to treat HIV-1 infection in adults with no antiretroviral (ARV) treatment history or to replace the current ARV regimen in those who are virologically suppressed (HIV-1 RNA <50 copies/mL) on a stable ARV regimen with no history of treatment failure and no known resistance to any component of DOVATO.

IMPORTANT SAFETY INFORMATION BOXED WARNING: PATIENTS CO-INFECTED WITH HEPATITIS B VIRUS (HBV) AND HIV-1: EMERGENCE OF LAMIVUDINE-RESISTANT HBV AND EXACERBATIONS OF HBV All patients with HIV-1 should be tested for the presence of HBV prior to or when initiating DOVATO. Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. If DOVATO is used in patients co-infected with HIV-1 and HBV, additional treatment should be considered for appropriate treatment of chronic HBV; otherwise, consider an alternative regimen.

Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued lamivudine, a component of DOVATO. Closely monitor hepatic function in these patients and, if appropriate, initiate anti-HBV treatment.

Contraindications

• Do not use DOVATO in patients with previous hypersensitivity reaction to dolutegravir or lamivudine • Do not use DOVATO in patients receiving dofetilide Please see additional Important Safety Information for DOVATO on the following pages.

Please see Brief Summary of Prescribing Information for DOVATO, including Boxed Warning, on the following pages.

Not an actual patient.

Powe erful Ressultss Wiith Durrable Virrologiic Suppre essiion TANGOâ&#x20AC;&#x201D;Noninferior Virologic Response in Virologically Suppressed Patients3

HIV-1 RNA <50 copies/mL (Virologic Suppression)

HIV-1 RNA <50 copies/mL (Virologic Suppression)

91%

93%

86%

80

60

40

20

0

100

90% Proportion of Patients, %

Proportion of Patients, %

100

GEMINI 1 & 2 Pooledâ&#x20AC;&#x201D;Noninferior Virologic Response in Treatment-NaĂŻve Patients1,2

48 Weeks (Primary Endpoint)

96 Weeks (Secondary Endpoint)

7UHDWPHQW 'LÎ?HUHQFH â&#x20AC;&#x201C;1.7% (95% CI; â&#x20AC;&#x201C;4.4%, 1.1%)

7UHDWPHQW 'LÎ?HUHQFH â&#x20AC;&#x201C;3.4% (95% CI; â&#x20AC;&#x201C;6.7%, 0.0%)

+Î&#x2013;9 51$ Ȳ FRSLHV P/ (Secondary Endpoint)

3%

2%

3%

93%

93%

80

60

40

20

0

48 Weeks (Secondary Endpoint) 7UHDWPHQW 'LÎ?HUHQFH 0.2% (95% CI; â&#x20AC;&#x201C;3.4%, 3.9%) +Î&#x2013;9 51$ Ȳ FRSLHV P/ (Primary Endpoint)

2%

DOVATO (n=716) DTG + TDF/FTC (n=717)

<1%

<1%

DOVATO (n=369) TAF-containing regimens (n=372)

7UHDWPHQW 'LÎ?HUHQFH â&#x20AC;&#x201C;0.3% (95% CI; â&#x20AC;&#x201C;1.2%, 0.7%)

GEMINI 1 & 2 NaĂŻve Trial Design: Identically designed, Phase 3, randomized, double-blind (to Week 96, open-label from Week 96 to Week 144), noninferiority trials in treatment-naĂŻve adult patients with HIV-1. At baseline across both treatment arms, 9% were CDC Stage 3 (AIDS), 20% had HIV-1 RNA >100,000 copies/mL, and 8% had CD4+ 7 FHOO FRXQW Čą FHOOV PP3. Patients with HBV or major resistance-associated mutations were excluded from the clinical trials. Primary endpoint was the proportion of patients with HIV-1 RNA <50 copies/mL at Week 48 using FDA snapshot analysis (ITTâ&#x20AC;&#x201C;E) with 10% noninferiority margin.2,4 TANGO Virologically Suppressed Trial Design: An ongoing, Phase 3, randomized, noninferiority trial in virologically suppressed adults with HIV-1.

At baseline across both treatment arms, 5% were CDC Stage 3 (AIDS), 98% had CD4+ T-cell count >200 cells/mm3, all participants were virologically suppressed (HIV-1 RNA <50 copies/mL) for >6 months, and all were taking a TAF-containing regimen.* Patients included in the trial had no virologic failure, no documented NRTI or INSTI resistance, and were HBV negative. Primary endpoint was the proportion of patients with HIV-1 RNA Ȳ FRSLHV P/ DW :HHN XVLQJ )'$ VQDSVKRW DQDO\VLV Î&#x2013;77Č&#x201A;( ZLWK QRQLQIHULRULW\ PDUJLQ Č&#x201A; QRQLQIHULRULW\ PDUJLQ IRU VHFRQGDU\ HQGSRLQW 3,4 *TAF/FTC + EVG/c, DTG, RAL, RPV, NVP, EFV, bATV, or bDRV.4

IMPORTANT SAFETY INFORMATION (contâ&#x20AC;&#x2122;d) Warnings and precautions Hypersensitivity Reactions:

â&#x20AC;˘ +\SHUVHQVLWLYLW\ UHDFWLRQV KDYH EHHQ UHSRUWHG ZLWK GROXWHJUDYLU DQG ZHUH FKDUDFWHUL]HG E\ UDVK FRQVWLWXWLRQDO Č´QGLQJV DQG VRPHWLPHV RUJDQ dysfunction, including liver injury â&#x20AC;˘ Discontinue DOVATO immediately if signs or symptoms of severe skin or hypersensitivity reactions develop, as a delay in stopping treatment may result in a life-threatening reaction. Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated Hepatotoxicity: â&#x20AC;˘ Hepatic adverse events have been reported, including cases of hepatic toxicity (elevated serum liver biochemistries, hepatitis, and acute liver IDLOXUH LQ SDWLHQWV UHFHLYLQJ D GROXWHJUDYLU FRQWDLQLQJ UHJLPHQ ZLWKRXW SUH H[LVWLQJ KHSDWLF GLVHDVH RU RWKHU LGHQWLČ´DEOH ULVN IDFWRUV â&#x20AC;˘ Patients with underlying hepatitis B or C or marked elevations in transaminases prior to treatment may be at increased risk for worsening or development of transaminase elevations with use of DOVATO. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or hepatitis B reactivation, particularly in the setting where anti-hepatitis therapy was withdrawn â&#x20AC;˘ Monitoring for hepatotoxicity is recommended Embryo Fetal Toxicity: â&#x20AC;˘ $OWHUQDWLYH WUHDWPHQWV WR '29$72 VKRXOG EH FRQVLGHUHG DW WKH WLPH RI FRQFHSWLRQ WKURXJK WKH Č´UVW WULPHVWHU RI SUHJQDQF\ GXH WR WKH ULVN RI neural tube defects â&#x20AC;˘ 3HUIRUP SUHJQDQF\ WHVWLQJ EHIRUH XVH RI '29$72 DQG FRXQVHO WKDW FRQVLVWHQW XVH RI HÎ?HFWLYH FRQWUDFHSWLRQ LV UHFRPPHQGHG ZKLOH XVLQJ DOVATO in individuals of childbearing potential Lactic Acidosis and Severe Hepatomegaly with Steatosis: Fatal cases have been reported with the use of nucleoside analogs, including lamivudine. Discontinue DOVATO if clinical or laboratory Č´QGLQJV VXJJHVWLYH RI ODFWLF DFLGRVLV RU SURQRXQFHG KHSDWRWR[LFLW\ GHYHORS LQFOXGLQJ KHSDWRPHJDO\ DQG VWHDWRVLV LQ WKH DEVHQFH RI PDUNHG Please see additional Important Safety Information for transaminase elevations.

DOVATO on the previous page.

Please see Brief Summary of Prescribing Information for Please see additional Important Safety Information for DOVATO on the previous page.

DOVATO, BoxedofWarning, onInformation the following Please seeincluding Brief Summary Prescribing forpages.

DOVATO, including Boxed Warning, on the following pages.

Hig gh Barrriierr to Resiistan nce Based on 0 cases of treatment-emergent resistance in treatment-naĂŻve adults at 96 weeks and virologically suppressed adults at 48 weeks1,3â&#x20AC; â&#x20AC;

$PRQJ WUHDWPHQW QDÂąYH DGXOWV LQ WKH *(0Î&#x2013;1Î&#x2013; WULDOV FRQČ´UPHG YLURORJLF ZLWKGUDZDO RFFXUUHG LQ SDWLHQWV IRU '29$72 IRU '7* 7') )7& DQG QR patients in either arm had treatment-emergent INSTI or NRTI resistance substitutions through Week 96. Among 741 virologically suppressed adults in the TANGO trial, SDWLHQWV LQ WKH '29$72 DUP DQG SDWLHQW LQ WKH 7$) FRQWDLQLQJ UHJLPHQV DUP KDG FRQČ´UPHG YLURORJLF ZLWKGUDZDO +Î&#x2013;9 51$ Ȳ FRSLHV P/ IROORZHG E\ D VHFRQG FRQVHFXWLYH +Î&#x2013;9 51$ DVVHVVPHQW Ȳ FRSLHV P/ 7KHUHIRUH QR SDWLHQWV LQ WKH '29$72 DUP ZHUH HYDOXDWHG IRU WUHDWPHQW HPHUJHQW UHVLVWDQFH 2QH SDWLHQW RQ '29$72 ZKR ZDV ZLWKGUDZQ IRU SURWRFRO GHYLDWLRQ QRQ FRPSOLDQFH ZLWK VWXG\ WUHDWPHQW DQG KDG D ODVW RQ WUHDWPHQW YLUDO ORDG RI Ȳ FRSLHV P/ ZDV WHVWHG DQG no INSTI- or NRTI-emergent resistance was detected.1,3,4

Adverse Drug Reactions

â&#x20AC;˘ 7UHDWPHQW HPHUJHQW $'5V LQFLGHQFH Ȳ DOO JUDGHV LQ *(0Î&#x2013;1Î&#x2013; WKURXJK ZHHNV ZHUH KHDGDFKH YV

nausea (2% vs 5%), diarrhea (2% vs 3%), insomnia (2% vs 3%), fatigueâ&#x20AC;Ą (2% vs 2%), dizziness (1% vs 2%), and anxiety (2% vs <1%) for patients receiving DOVATO and DTG + TDF/FTC, respectively 4 â&#x20AC;˘ The ADRs of DOVATO in virologically suppressed adults in TANGO through 48 weeks were similar to those of treatment-naĂŻve adults in GEMINI 1 & 23 Includes fatigue, asthenia, and malaise.

â&#x20AC;Ą

ADR=adverse drug reaction; bATV=boosted atazanavir; bDRV=boosted darunavir; CDC=Centers for Disease Control and Prevention; DTG=dolutegravir; EFV=efavirenz; EVG/c=elvitegravir-cobicistat; FTC=emtricitabine; HBV=hepatitis B virus; INSTI=integrase strand transfer inhibitor; ITTâ&#x20AC;&#x201C;E=intent-to-treatâ&#x20AC;&#x201C;exposed; NVP=nevirapine; NRTI=nucleoside reverse transcriptase inhibitor; RAL=raltegravir; RPV=rilpivirine; TAF=tenofovir alafenamide fumarate; TDF=tenofovir disoproxil fumarate.

IMPORTANT SAFETY INFORMATION (contâ&#x20AC;&#x2122;d) Warnings and precautions (contâ&#x20AC;&#x2122;d)

Adverse Reactions or Loss of Virologic Response Due to Drug Interactions with concomitant use of DOVATO and other drugs may occur (see Contraindications and Drug interactions).

Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported with the use of DOVATO.

Adverse reactions 7KH PRVW FRPPRQ DGYHUVH UHDFWLRQV LQFLGHQFH Ȳ DOO JUDGHV ZLWK '29$72 ZHUH KHDGDFKH QDXVHD GLDUUKHD LQVRPQLD

fatigue (2%), and anxiety (2%).

Drug interactions â&#x20AC;˘ &RQVXOW IXOO 3UHVFULELQJ Î&#x2013;QIRUPDWLRQ IRU '29$72 IRU PRUH LQIRUPDWLRQ RQ SRWHQWLDOO\ VLJQLČ´FDQW GUXJ LQWHUDFWLRQV â&#x20AC;˘ DOVATO is a complete regimen. Coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended â&#x20AC;˘ 'UXJV WKDW LQGXFH RU LQKLELW &<3 $ RU 8*7 $ PD\ DÎ?HFW WKH SODVPD FRQFHQWUDWLRQV RI GROXWHJUDYLU â&#x20AC;˘ Administer DOVATO 2 hours before or 6 hours after taking polyvalent cation-containing antacids or laxatives, sucralfate, oral supplements FRQWDLQLQJ LURQ RU FDOFLXP RU EXÎ?HUHG PHGLFDWLRQV $OWHUQDWLYHO\ '29$72 DQG VXSSOHPHQWV FRQWDLQLQJ FDOFLXP RU LURQ FDQ EH WDNHQ ZLWK IRRG

8VH LQ VSHFLČ´F SRSXODWLRQV â&#x20AC;˘ Pregnancy: 7KHUH DUH LQVXÉ?FLHQW KXPDQ GDWD RQ WKH XVH RI '29$72 GXULQJ SUHJQDQF\ WR GHČ´QLWLYHO\ DVVHVV D GUXJ DVVRFLDWHG ULVN IRU ELUWK GHIHFWV DQG PLVFDUULDJH $Q $QWLUHWURYLUDO 3UHJQDQF\ 5HJLVWU\ KDV EHHQ HVWDEOLVKHG Î&#x2013;I SODQQLQJ D SUHJQDQF\ RU LI SUHJQDQF\ LV FRQČ´UPHG ZKLOH WDNLQJ '29$72 GXULQJ WKH Č´UVW WULPHVWHU DVVHVV WKH ULVNV DQG EHQHČ´WV RI FRQWLQXLQJ '29$72 YHUVXV VZLWFKLQJ WR DQRWKHU DQWLUHWURYLUDO UHJLPHQ )RU individuals actively trying to become pregnant, initiation of DOVATO is not recommended unless there is no suitable alternative â&#x20AC;˘ Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission, developing viral resistance in HIV-positive infants, and adverse reactions in a breastfed infant â&#x20AC;˘ Females and Males of Reproductive Potential: Perform pregnancy testing before initiation of DOVATO. Advise individuals of childbearing SRWHQWLDO WR FRQVLVWHQWO\ XVH HÎ?HFWLYH FRQWUDFHSWLRQ ZKLOH WDNLQJ '29$72 â&#x20AC;˘ Renal Impairment: DOVATO is not recommended for patients with creatinine clearance <50 mL/min â&#x20AC;˘ Hepatic Impairment: DOVATO is not recommended in patients with severe hepatic impairment (Child-Pugh Score C) References: 1. &DKQ 3 0DGHUR -6 $UULEDV -5 HW DO 'XUDEOH HÉ?FDF\ RI GROXWHJUDYLU SOXV ODPLYXGLQH LQ DQWLUHWURYLUDO WUHDWPHQWČ&#x201A;QDLYH DGXOWV ZLWK +Î&#x2013;9 infection: 96 week results from the GEMINI-1 and GEMINI-2 randomized clinical trials. - $FTXLU Î&#x2013;PPXQH 'HČ´F 6\QGU. 2020;83(3):310-318. 2. Cahn P, Madero JS, Arribas JR, et al; and GEMINI Study Team. 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. 3. van Wyk J, Ajana F, %LVVKRS ) HW DO (É?FDF\ DQG VDIHW\ RI VZLWFKLQJ WR GROXWHJUDYLU ODPLYXGLQH Č´[HG GRVH GUXJ regimen vs continuing a tenofovir alafenamideâ&#x20AC;&#x201C;based 3- or 4-drug regimen for maintenance RI YLURORJLF VXSSUHVVLRQ LQ DGXOWV OLYLQJ ZLWK KXPDQ LPPXQRGHČ´FLHQF\ YLUXV W\SH SKDVH randomized, noninferiority TANGO study [published online ahead of print January 6, 2020].

Clin Infect Dis. 2020;ciz1243. doi:10.1093/cid/ciz1243. 4. 'DWD RQ Č´OH 9LL9 +HDOWKFDUH JURXS RI companies. Research Triangle Park, NC.

BRIEF SUMMARY

DOVATO (dolutegravir and lamivudine) tablets, for oral use

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

WARNING: PATIENTS CO-INFECTED WITH HEPATITIS B VIRUS (HBV) AND HUMAN IMMUNODEFICIENCY VIRUS (HIV-1): EMERGENCE OF LAMIVUDINE-RESISTANT HBV AND EXACERBATIONS OF HBV All patients with HIV-1 should be tested for the presence of HBV prior to or when initiating DOVATO. Emergence of lamivudine-resistant HBV variants associated with lamivudine-containing antiretroviral regimens has been reported. If DOVATO is used in patients co-infected with HIV-1 and HBV, additional treatment should be considered for appropriate treatment of chronic HBV; otherwise, consider an alternative regimen.

Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued lamivudine, a component of DOVATO. Closely monitor hepatic function in these patients and, if appropriate, initiate anti-HBV treatment.

CONTRAINDICATIONS DOVATO is contraindicated in patients: with prior hypersensitivity reaction to dolutegravir or lamivudine; receiving dofetilide due to the potential for increased dofetilide plasma concentrations and the risk for serious and/or life-threatening events.

WARNINGS AND PRECAUTIONS Patients Co-infected with HIV-1 and HBV: Emergence of LamivudineResistant HBV and the Risk of Posttreatment Exacerbations of HBV: All patients with HIV-1 should be tested for the presence of HBV prior to or when initiating DOVATO. Emergence of Lamivudine-Resistant HBV: Safety and efficacy of lamivudine have not been established for treatment of chronic HBV in subjects dually infected with HIV-1 and HBV. Emergence of HBV variants associated with resistance to lamivudine has been reported in HIV-1–infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with HBV. If a decision is made to administer DOVATO to patients co-infected with HIV-1 and HBV, additional treatment should be considered for appropriate treatment of chronic HBV; otherwise, consider an alternative regimen.

Severe Acute Exacerbations of HBV in Patients Co-infected with HIV-1 and HBV: Severe acute exacerbations of HBV have been reported in patients who are co-infected with HIV-1 and HBV and have discontinued products containing lamivudine, and may occur with discontinuation of DOVATO. Patients who are co-infected with HIV-1 and HBV who discontinue DOVATO should be closely monitored with both clinical and laboratory follow-up for at least several months after stopping treatment with DOVATO. If appropriate, initiation of anti-HBV therapy may be warranted, especially in patients with advanced liver disease or cirrhosis, since posttreatment exacerbation of hepatitis may lead to hepatic decompensation and liver failure.

Hypersensitivity Reactions: Hypersensitivity reactions have been reported with the use of dolutegravir, a component of DOVATO, and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury. These events were reported in <1% of subjects receiving dolutegravir in Phase 3 clinical trials. Discontinue DOVATO 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 or peeling of the skin, oral blisters or lesions, conjunctivitis, facial edema, hepatitis, eosinophilia, angioedema, difficulty breathing). Clinical status, including liver aminotransferases, should be monitored and appropriate therapy initiated. Delay in stopping treatment with DOVATO or other suspect agents after the onset of hypersensitivity may result in a life-threatening reaction. Hepatotoxicity: Hepatic adverse events have been reported in patients receiving a dolutegravir-containing regimen. Patients with underlying hepatitis B or C may be at increased risk for worsening or development of transaminase elevations with use of DOVATO. In some cases, the elevations in transaminases were consistent with immune reconstitution syndrome or HBV reactivation particularly in the setting where anti-hepatitis therapy was withdrawn. Cases of hepatic toxicity, including elevated serum liver biochemistries, hepatitis, and acute liver failure, have also been reported in patients receiving a dolutegravir-containing regimen who had no pre-existing hepatic disease or other identifiable risk factors. Drug-induced liver injury leading to liver transplant has been reported with TRIUMEQ (abacavir,

dolutegravir, and lamivudine). Monitoring for hepatotoxicity is recommended.

Embryo-Fetal Toxicity: An observational study showed an association between dolutegravir, a component of DOVATO, and an increased risk of neural tube defects when dolutegravir was administered at the time of conception and in early pregnancy. As there is limited understanding of reported types of neural tube defects associated with dolutegravir use and because the date of conception may not be determined with precision, an alternative treatment to DOVATO should be considered at the time of conception through the first trimester of pregnancy. Perform pregnancy testing before initiation of DOVATO in individuals of childbearing potential to exclude use of DOVATO during the first trimester of pregnancy.

Initiation of DOVATO is not recommended in individuals actively trying to become pregnant unless there is no suitable alternative. Counsel individuals of childbearing potential to consistently use effective contraception. In individuals of childbearing potential currently on DOVATO who are actively trying to become pregnant, or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing DOVATO versus switching to another antiretroviral regimen and consider switching to an alternative regimen. DOVATO may be considered during the second and third trimesters of pregnancy if the expected benefit justifies the potential risk to the pregnant woman and the fetus. Lactic Acidosis and Severe Hepatomegaly with Steatosis: Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine (a component of DOVATO). A majority of these cases have been in women. Female sex and obesity may be risk factors for the development of lactic acidosis and severe hepatomegaly with steatosis in patients treated with antiretroviral nucleoside analogues. Monitor closely when administering DOVATO to any patient with known risk factors for liver disease. Treatment with DOVATO should be suspended in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis even in the absence of marked transaminase elevations. Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The coadministration of DOVATO and other drugs may result in known or potentially significant drug interactions, some of which may lead to: Loss of therapeutic effect of DOVATO and possible development of resistance; Possible clinically significant adverse reactions from greater exposures of coadministered drugs. See Drug Interactions 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 DOVATO, review coadministered drugs during therapy with DOVATO, and monitor for the adverse reactions associated with the coadministered drugs. Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including DOVATO. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Graves’ disease, polymyositis, and Guillain-Barré syndrome) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.

ADVERSE REACTIONS Clinical Trials Experience: Clinical Trials in Adults with No Antiretroviral Treatment History: The safety assessment of DOVATO in HIV-1–infected adults with no antiretroviral treatment history and with a plasma viral load ≤500,000 HIV-1 RNA copies/mL at the screening visit, is based on the pooled primary Week 96 analyses of data from 2 identical, multicenter, double-blind, controlled trials, GEMINI-1 and GEMINI-2. A total of 1,433 HIV-1–infected adults with no antiretroviral treatment history received either dolutegravir (TIVICAY) 50 mg plus lamivudine (EPIVIR) 300 mg, as a complete regimen once daily, or TIVICAY 50 mg plus fixed-dose combination tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) (TRUVADA), administered once daily. The rates of adverse events leading to discontinuation in the pooled analysis were 3% of subjects in both treatment arms. The most common adverse events leading to discontinuation were psychiatric disorders: 1% of subjects in both treatment arms. Adverse reactions (all grades) observed in at least 2% of subjects in either treatment arm of the Week 96 pooled analysis from GEMINI-1 and GEMINI-2 trials are provided in Table 2. The adverse reactions observed for TIVICAY plus EPIVIR in the Week 96 analysis of the pooled data from GEMINI-1 and GEMINI-2 were generally consistent with the adverse reaction profiles and severities for the individual components when administered with other antiretroviral agents.

(cont’d on next page)

BRIEF SUMMARY for DOVATO (dolutegravir and lamivudine) tablets (cont’d) Table 2. Adverse Reactions (All Grades) Reported in ≥2% of Subjects in Any Treatment Group in Adults with No Antiretroviral Treatment History in GEMINI-1 and GEMINI-2 (Week 96 Pooled Analysis) Adverse Reaction

TIVICAY plus EPIVIR TIVICAY plus TRUVADA (n = 716) (n = 717)

Headache Nausea Diarrhea Insomnia Fatiguea Anxiety Dizziness

3% 2% 2% 2% 2% 2% 1%

4% 5% 3% 3% 2% 1% 2%

a

Fatigue: includes fatigue, asthenia, and malaise.

Adverse reactions of at least Grade 2 occurring in ≥1% of subjects treated with TIVICAY plus EPIVIR were headache, anxiety, and suicidal ideation (all at 1%). Less Common Adverse Reactions: The following adverse reactions occurred in <2% of subjects receiving dolutegravir plus lamivudine or are from studies described in the prescribing information of the individual components, TIVICAY (dolutegravir) and EPIVIR (lamivudine). Some events have been included because of their seriousness and assessment of potential causal relationship. – Blood and Lymphatic Systems Disorders: Anemia, neutropenia, thrombocytopenia. – Gastrointestinal Disorders: Abdominal discomfort, abdominal pain, flatulence, upper abdominal pain, vomiting. – General: Fever.

– Hepatobiliary Disorders: Hepatitis. – Immune System Disorders: Hypersensitivity, immune reconstitution syndrome. – Musculoskeletal Disorders: Myositis. – Nervous System Disorders: Somnolence. – Psychiatric Disorders: Abnormal dreams, depression. Suicidal ideation, attempt, behavior, or completion; these events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness. – Renal and Urinary Disorders: Renal impairment. – Skin and Subcutaneous Tissue Disorders: Pruritus, rash.

Clinical Trials in Virologically Suppressed Adults: The safety of DOVATO in virologically suppressed adults was based on Week 48 data from 740 subjects in a randomized, parallel-group, open-label, multicenter, non-inferiority controlled trial (TANGO). Subjects who were on a stable suppressive tenofovir alafenamide-based regimen (TBR) were randomized to receive DOVATO once daily or continue with their TBR for up to 200 weeks. Overall, the safety profile of DOVATO in virologically suppressed adult subjects in the TANGO trial was similar to that of TIVICAY plus EPIVIR in subjects with no antiretroviral treatment history in the GEMINI trials.

Laboratory Abnormalities: Selected laboratory abnormalities with a worsening grade from baseline and representing the worst-grade toxicity are presented in Table 3. The mean change from baseline observed for selected lipid values is presented in Table 4.

Table 3. Selected Laboratory Abnormalities (Grades 2 to 4; Week 96 Pooled Analyses) in GEMINI-1 and GEMINI-2 Trials Laboratory Parameter Abnormality Alanine aminotransferase (ALT) Grade 2 (2.5 to <5.0 x ULN) Grade 3 to 4 (≥5.0 x ULN) Aspartate aminotransferase (AST) Grade 2 (2.5 to <5.0 x ULN) Grade 3 to 4 (≥5.0 x ULN) Total bilirubin Grade 2 (1.6 to <2.6 x ULN) Grade 3 to 4 (≥2.6 x ULN) Creatine kinase Grade 2 (6.0 to <10 x ULN) Grade 3 to 4 (≥10.0 x ULN) Hyperglycemia (glucose) Grade 2 (126 to 250 mg/dL) Grade 3 to 4 (>250 mg/dL) Hypophosphatemia (phosphate) Grade 2 (1.4 to <2.0 mg/dL) Grade 3 to 4 (<1.4 mg/dL) Lipase Grade 2 (1.5 to <3.0 x ULN) Grade 3 to 4 (≥3.0 x ULN) ULN = Upper limit of normal.

TIVICAY plus EPIVIR (n = 716)

TIVICAY plus TRUVADA (n = 717)

3% 3%

4% 3%

4% 3%

4% 3%

2% 1%

3% 1%

4% 6%

4% 7%

9% 1%

6% 1%

9% 1%

10% 1%

6% 2%

6% 4%

Table 4. Mean Change from Baseline in Fasted Lipid Values (Week 96 Pooled Analysesa) in GEMINI-1 and GEMINI-2 Trials Laboratory Parameter Preferred Term Cholesterol (mg/dL)

TIVICAY plus EPIVIR (n = 716)

TIVICAY plus TRUVADA (n = 717)

15

-6

HDL cholesterol (mg/dL)

7

3

LDL cholesterol (mg/dL)

6

-7

Triglycerides (mg/dL) Total cholesterol/HDL cholesterol ratio

11

-11

-0.1

-0.4

a Subjects on lipid-lowering agents at baseline are excluded (TIVICAY plus EPIVIR, n = 30; TIVICAY plus TRUVADA, n = 23). The last available fasted, on-treatment lipid value prior to initiation of a lipid-lowering agent was carried forward in place of observed values after initiation of a lipid-lowering agent. A total of 40 and 16 subjects receiving TIVICAY plus EPIVIR and TIVICAY plus TRUVADA, respectively, initiated lipid-lowering agents post-baseline.

Changes in Serum Creatinine: Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function. Increases in serum creatinine occurred within the first 4 weeks of treatment in both arms and remained stable through 96 weeks.

A mean change from baseline of 0.138 mg/dL and 0.176 mg/dL was observed after 96 weeks of treatment with TIVICAY plus EPIVIR and TIVICAY plus TRUVADA, respectively. These changes are not considered to be clinically relevant. Postmarketing Experience: The following adverse reactions have been identified during postmarketing experience in patients receiving a dolutegravir- or lamivudine-containing regimen. Because postmarketing 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. Body as a Whole: Redistribution/accumulation of body fat. Endocrine and Metabolic: Hyperglycemia. General: Weakness.

Hemic and Lymphatic: Anemia (including pure red cell aplasia and severe anemias progressing on therapy). Hepatic and Pancreatic: Lactic acidosis and hepatic steatosis, pancreatitis, posttreatment exacerbations of HBV. Hepatobiliary Disorders: Acute liver failure, hepatotoxicity. Hypersensitivity: Anaphylaxis, urticaria. Investigations: Weight increased. Musculoskeletal: Arthralgia, CPK elevation, muscle weakness, myalgia, rhabdomyolysis.

Nervous System: Paresthesia, peripheral neuropathy. Skin: Alopecia.

DRUG INTERACTIONS Coadministration with Other Antiretroviral Drugs: DOVATO is a complete regimen for the treatment of HIV-1 infection; therefore, coadministration with other antiretroviral drugs for the treatment of HIV-1 infection is not recommended. Information regarding potential drug-drug interactions with other antiretroviral drugs is not provided. Potential for DOVATO to Affect Other Drugs: Dolutegravir, a component of DOVATO, inhibits the renal organic cation transporters (OCT)2 and multidrug and toxin extrusion transporter (MATE)1; thus, it may increase plasma concentrations of drugs eliminated via OCT2 or MATE1 such as dofetilide, dalfampridine, and metformin. Potential for Other Drugs to Affect the Components of DOVATO: Dolutegravir is metabolized by uridine diphosphate (UDP)-glucuronosyl transferase (UGT)1A1 with some contribution from cytochrome P450 (CYP)3A. Dolutegravir is also a substrate of UGT1A3, UGT1A9, breast cancer resistance protein (BCRP), and P-glycoprotein (P-gp) in vitro. Drugs that induce those enzymes and transporters may decrease dolutegravir plasma concentrations and reduce the therapeutic effect of DOVATO. Coadministration of DOVATO and other drugs that inhibit these enzymes may increase dolutegravir plasma concentrations. Coadministration of dolutegravir with polyvalent cation-containing products may lead to decreased absorption of dolutegravir. Established and Other Potentially Significant Drug Interactions: No drug interaction studies were conducted with DOVATO. The drug interactions described are based on studies conducted with dolutegravir or lamivudine when administered alone.

Information regarding potential drug interactions with DOVATO are provided below. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss of efficacy. Established and Other Potentially Significant Drug Interactions for DOVATO: Alterations in dose may be recommended based on drug interaction trials or predicted interactions for the following drugs when coadministered with DOVATO:

(cont’d on next page)

BRIEF SUMMARY for DOVATO (dolutegravir and lamivudine) tablets (cont’d) % Antiarrhythmic: dofetilide – coadministration is contraindicated with DOVATO. % Anticonvulsant: carbamazepine – an additional dolutegravir 50-mg dose should be taken, separated by 12 hours from DOVATO. % Anticonvulsants: oxcarbazepine, phenytoin, phenobarbital – avoid coadministration with DOVATO because there are insufficient data to make dosing recommendations. % Antidiabetic: metformin – refer to the prescribing information for metformin for assessing the benefit and risk of concomitant use of DOVATO and metformin. % Antimycobacterial: rifampin – an additional 50-mg dose of dolutegravir should be taken, separated by 12 hours from DOVATO. % Herbal product: St. John’s wort (Hypericum perforatum) – avoid coadministration with DOVATO because there are insufficient data to make dosing recommendations. % Medications containing polyvalent cations (e.g., Mg or Al): cationcontaining antacids or laxatives, sucralfate, buffered medications – administer DOVATO 2 hours before or 6 hours after taking medications containing polyvalent cations. % Oral calcium and iron supplements, including multivitamins containing calcium or iron – when taken with food, DOVATO and supplements or multivitamins containing calcium or iron can be taken at the same time.

Under fasting conditions, DOVATO should be taken 2 hours before or 6 hours after taking supplements containing calcium or iron. % Potassium channel blocker: dalfampridine – elevated levels of dalfampridine increase the risk of seizures. The potential benefits of taking dalfampridine concurrently with DOVATO should be considered against the risk of seizures in these patients. % Sorbitol – when possible, avoid use of sorbitol-containing medicines with DOVATO. Consult the full Prescribing Information for potential drug interactions; this list is not all inclusive.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to DOVATO during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263.

Risk Summary: Data from a birth outcome surveillance study have identified a possible increased risk of neural tube defects when dolutegravir, a component of DOVATO, is administered at the time of conception compared with non-dolutegravir-containing antiretroviral regimens. As defects related to closure of the neural tube occur from conception through the first 6 weeks of gestation, embryos exposed to dolutegravir from the time of conception through the first 6 weeks of gestation are at potential risk. In addition, 2 of the 5 birth defects (encephalocele and iniencephaly) that have been observed with dolutegravir use, although often termed neural tube defects, may occur post-neural tube closure, the time period of which may be later than 6 weeks of gestation, but within the first trimester. Due to the limited understanding of the types of reported neural tube defects associated with dolutegravir use and because the date of conception may not be determined with precision, an alternative treatment to DOVATO should be considered at the time of conception through the first trimester of pregnancy. Initiation of DOVATO is not recommended in individuals actively trying to become pregnant unless there is no suitable alternative. In individuals of childbearing potential currently on DOVATO who are actively trying to become pregnant, or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing DOVATO versus switching to another antiretroviral regimen and consider switching to an alternative regimen. Advise pregnant individuals of the potential risk to the embryo exposed to DOVATO from the time of conception through the first trimester of pregnancy. A benefit-risk assessment should consider factors such as feasibility of switching, tolerability, ability to maintain viral suppression, and risk of transmission to the infant against the risk of neural tube defects (see Data). There are insufficient human data on the use of DOVATO during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. Lactation: 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. Lamivudine, a component of DOVATO, is present in human milk. It is not known whether dolutegravir, a component of DOVATO, is present in human milk. When administered to lactating rats, dolutegravir was present in milk. There is no information on the effects of DOVATO or the components of DOVATO on the breastfed infant or the

effects of the drugs on milk production. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving DOVATO. Females and Males of Reproductive Potential: Pregnancy Testing: Perform pregnancy testing in individuals of childbearing potential before initiation of DOVATO. Contraception: In individuals of childbearing potential currently on DOVATO who are actively trying to become pregnant, or if pregnancy is confirmed in the first trimester, assess the risks and benefits of continuing DOVATO versus switching to another antiretroviral regimen and consider switching to an alternative regimen. Counsel individuals of childbearing potential who are taking DOVATO to consistently use effective contraception. Pediatric Use: The safety and efficacy of DOVATO have not been established in pediatric patients. Geriatric Use: Clinical trials of DOVATO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. In general, caution should be exercised in the administration of DOVATO in elderly patients reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Renal Impairment: DOVATO is not recommended for patients with creatinine clearance <50 mL/min because DOVATO is a fixed-dose combination and the dosage of the individual components cannot be adjusted. If a dose reduction of lamivudine, a component of DOVATO, is required for patients with creatinine clearance <50 mL/min, then the individual components should be used. Hepatic Impairment: No dosage adjustment of DOVATO is necessary in patients with mild or moderate hepatic impairment (Child-Pugh Score A or B). Dolutegravir has not been studied in patients with severe hepatic impairment (Child-Pugh Score C); therefore, DOVATO is not recommended for patients with severe hepatic impairment.

OVERDOSAGE There is no known specific treatment for overdose with DOVATO. If overdose occurs, the patient should be monitored and standard supportive treatment applied as required. Dolutegravir: As dolutegravir is highly bound to plasma proteins, it is unlikely that it will be significantly removed by dialysis. Lamivudine: Because a negligible amount of lamivudine was removed via (4-hour) hemodialysis, continuous ambulatory peritoneal dialysis, and automated peritoneal dialysis, it is not known if continuous hemodialysis would provide clinical benefit in a lamivudine overdose event.

ViiV Healthcare Research Triangle Park, NC 27709

GlaxoSmithKline Research Triangle Park, NC 27709

DVT:4BRS August 2020

Trademarks owned or licensed theHealthcare ViiV Healthcare of companies.

Trademarks areare owned by orbylicensed to theto ViiV group of group companies. ©2020 ViiV or licensor. ©2020 ViiVHealthcare Healthcare or licensor.

[CODE] [Month] [Year] Produced DLLJRNA200007 August 2020in USA. Produced in USA.

IDSA Gives Bamlanivimab a Conditional ‘No-Go’ ommendations For Routine Use in COVID-19 Recommendations

BY MARIE ROSENTHAL, MS

T

he Infectious Diseases Society of America (IDSA) recommended against the routine use of bamlanivimab, but added a caveat that it could be considered if the patient understands the uncertainties regarding its benefits and risks.

The FDA recently granted emergency use authorizations (EUAs) to the monoclonal antibodies (mAbs)—bamlanivimab (Eli Lilly) and the cocktail casirivimab and imdevimab (Regeneron)—for use in patients with mild to moderate SARSCoV-2 infection, but who are at risk for serious disease.

The FDA considered the interim results of the BLAZE-1 (Blocking Viral Attachment and Cell Entry with SARSCoV-2 Neutralizing Antibodies) trial when granting the EUA for bamlanivimab. In the phase 2 randomized, double-blind, placebo-controlled clinical trial in 465 outpatient adults with mild to moderate COVID-19 symptoms, 101 received a 700-mg dose of bamlanivimab, 107 received a 2,800-mg dose, 101 received a 7,000-mg dose and 156 received placebo within three days of obtaining a positive SARS-CoV-2 viral test (N Engl J Med 2020 Oct 28. [Epub ahead of print]).

The prespecified primary end point was change in viral load from baseline to day 11 for bamlanivimab versus placebo. Most patients, including those receiving placebo, cleared the virus by day 11. However, the most important evidence that bamlanivimab may be effective came from the predefined secondary end point of COVID-19– related hospitalizations or emergency department (ED) visits within 28 days after treatment, according to the FDA. For patients at high risk for disease progression, hospitalizations and ED visits occurred in 3% of bamlanivimabtreated patients on average compared with 10% in placebo-treated patients.

The effects on viral load and reduction in hospitalizations and ER visits, and

ceiving safety, were similar in patients receiving oses. any of the three bamlanivimab doses.

IDSA’s Panel Deliberation Although the preliminary resultss demzations onstrated a reduction in hospitalizations ents, and ED visits among treated patients, the actual numbers of patientss o were quite small—too small to bout its make any clear conclusions about himraj, benefits, according to Adarsh Bhimraj, cian in MD, an associate staff physician the Department of Infectious Disease d. “The at Cleveland Clinic in Cleveland. ive out event rate was in single digits—five d about of 209 in the antibody group and nine out of 156 in the placebo group,” d by b he said, during a briefing sponsored IDSA. “The reason why that is important is even a small change in these numbers [as the study continues] can make the difference nonsignificant.

“There was also no report of any critical outcomes like severe disease or survival between these groups, and that’s part of the reason we gave a conditional against recommendation with remarks that it can be specifically used in high-risk patients if the patient values [the treatment],” said Bhimraj, a cochair of the guidelines committee.

Made in the laboratory, mAbs are proteins that mimic the immune system’s ability to fight off harmful antigens, such as viruses, and banlanivimab is directed against the spike protein of SARS-CoV-2, blocking the virus’ ability to attach and enter human cells.

“I think that these monoclonal antibodies show potential for benefit, but we just don’t know for sure—the evidence is not definitive,” added Rajesh T. Gandhi, MD, FIDSA, a professor of medicine at Harvard Medical School and the director of HIV clinical services at Massachusetts General Hospital, in Boston. The numbers in the trials are too small “to be certain that there is a benefit. If there is a benefit, we also do not know yet how big of an effect these

Why mAbs for COVID-19?

Animal studies found mAbs reduce viral load in the upper and lower airways reducing pathology.

Source: IDSA Guideline, https://bit.ly/2V6fcQ2

antibodies have, and which patients are most likely to benefit.”

Gandhi, also a member of the guidelines panel, said there are a number of challenges to using mAbs in clinical practice. The first is the sheer number of people with mild to moderate disease. (As of Dec. 14, more than 16 million people in the United States tested positive for COVID-19, and most have had mild to moderate disease.)

Administration might be another challenge in the outpatient setting.

Bamlanivimab is provided as a concentrated solution that must be diluted prior to administration and given as a single IV infusion over 60 minutes.

Although mAbs are not to be used for everyone—only those at high risk for serious disease—there are many people in the high-risk category because of age and comorbidities, such as obesity and heart disease. continued on page 21

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2020

19

Is One Quadrivalent Flu Vaccine Better Than Others for Seniors?

BY MARIE ROSENTHAL, MS

A

n adjuvanted trivalent seasonal influenza vaccination (aTIV; Fluad, Seqirus) appeared more effective than nonadjuvanted quadrivalent vaccines in reducing influenza-related encounters in older adults with at least one underlying condition, according to a presentation at IDWeek 2020.

In a retrospective study (abstract LB-2), researchers reviewed more than 3.8 million electronic health records from primary care and specialty clinics across the 2017-2018 and 2018-2019 seasons, which were linked to pharmacy and medical claims of U.S. adults aged 65 years and older. The adults had at least one comorbidity, such as chronic pulmonary disease, heart disease or diabetes, and had received either aTIV, a high-dose trivalent inactivated influenza vaccine (TIV-HD), or standard egg-based quadrivalent influenza vaccine (QIV).

They wanted to determine the relative vaccine effectiveness of aTIV compared with the other vaccines given to older adults (TIV-HD and QIV) in reducing influenza-related encounters with a medical professional.

“If they had a record of receiving either aTIV, TIV-HD or QIV between Aug. 1 and Feb. 28 of each influenza season, patients were considered fully protected against influenza 14 days following the recorded data vaccination to allow for the development of vaccine-specific immunity,” said lead author Constantina Boikos, MScPH, PhD, the senior manager, Center for Outcomes Research & Evaluation, at Seqirus in Canada, who presented the data.

The primary outcome was influenza-related medical encounters in both the primary care and hospital settings.

Odds ratios adjusted for age, sex, race, ethnicity, geographic region, comorbidities and weeks of vaccination were calculated for each health condition using inverse probability of treatment weighting. The relative vaccine efficacy (rVE) was determined using the formula (1-OR)*100.

Adjusted rVE indicated that older adults with underlying health conditions who received aTIV had statistically significant reductions in medical encounters compared with QIV for the 2017-2018 and 2018-2019 seasons. In the 2017-2018 season, the adjusted rVE for adults with at least one health condition who received aTIV versus QIV was 7.1 (95% CI, 3.3-10.8) for the 2017-2018 season and 20.4 (95% CI, 16.2-24.4) for the 2018-2019 season. Nonsignificant estimates precluded definitive conclusions for comparisons versus TIV-HD in reducing medical encounters for both seasons, Boikos said.

For the 2017-2018 season, the adjusted rVE of aTIV versus TIV-HD was –0.8 (95% CI, –8.9 to 6.6) and 2.7 (95% CI, –2.7 to 7.8) for the 2018-2019 season.

Boikos said differences between the two seasons were likely “related to the circulation of different influenza subtypes in these two seasons.”

20

IDSE.NET

Overall, the results indicate the use of aTIV may be more effective in reducing medical encounters than standard quadrivalent seasonal influenza vaccines among older adults with at least one chronic condition.

“The most important aspect from the present study is that flu vaccines work to reduce the incidence of flu, and that persons over 65 years benefit from the use of an adjuvant in the influenza vaccine formula,” said Steven J. Martin, PharmD, BCPS, FCCP, FCCM, the dean and a professor at the Rudolph H. Raabe College of Pharmacy, Ohio Northern University, in Ada. He added that the study emphasizes the importance of adjuvants producing good immunity, regardless of the vaccine. “Adjuvants increase the response to vaccines and may also direct the adaptive response to improve the effectiveness of immunity for specific pathogens,” said Martin, who was asked to comment, but did not participate in the study.

Older adults are susceptible to age-related immunologic decline, which can result in reduced immune response and in turn, reduced seasonal vaccine effectiveness of flu shots.

Source: Vaccine 2009;27[37]:5043-5053

“Although adjuvants are used with influenza vaccination to boost immune response in the elderly, adjuvants are also used for vaccinations in younger populations against other pathogens such as diphtheria, tetanus, hepatitis B and others. Adjuvants have been successfully used since the 1930s to boost immune response and improve the success of vaccination strategies,” he said.

A main limitation of this analysis is that the effectiveness outcome was not laboratory-confirmed influenza.

Furthermore, estimates from observational studies may be affected by residual confounding and bias, even after adjusting for confounding variables, the researchers said.

Influenza causes significant morbidity and mortality in adults 65 years and older, resulting in higher hospitalization and death rates, compared with young, healthy adults (https:// www.cdc.gov/flu/highrisk/65over.htm). Older adults are susceptible to age-related immunologic decline, which can result in reduced immune response and in turn, reduced seasonal vaccine effectiveness (Vaccine 2009;27[37]:5043-5053).

Related News As of Dec. 5, seasonal influenza activity in the United States remains low, according to the CDC. Because this flu season is occurring during the COVID-19 pandemic, experts are strongly recommending influenza vaccination. The CDC said 14.3% of deaths could be attributed to pneumonia, influenza or COVID19, which is above the epidemic threshold. However, most of these are due to COVID-19, not influenza.

In other flu news, the FDA granted a new indication to baloxavir marboxil (Xofluza, Genentech) for post-exposure prophylaxis in people 12 years of age and older after contact with someone with influenza.

In the phase 3 BLOCKSTONE study, a single dose of baloxavir was compared with placebo as prophylaxis for household members (adults and children) who were living with someone with influenza. The double-blind, multicenter, randomized, placebo-controlled, post-exposure prophylaxis study was conducted

by Shionogi & Co. Ltd. in Japan during the 2018-2019 influenza season.

Baloxavir is a first-in-class, single-dose oral medicine with an innovative proposed mechanism of action that has demonstrated efficacy in a wide range of influenza viruses, including in vitro activity against oseltamivir-resistant strains and avian strains (H7N9, H5N1) in nonclinical studies. Baloxavir inhibits the cap-dependent endonuclease protein, which is essential for viral replication.

In all, 607 people received treatment (303) or placebo (304).

Those diagnosed with influenza were required to have onset of symptoms for fewer than 48 hours, and participants were required to have lived with the influenza patient for more than 48 hours. The participants were randomized to receive a single dose of baloxavir or placebo for prophylaxis.

The trial’s primary end point was the proportion of people who were infected with influenza virus and presented with fever and at least one respiratory symptom from day 1 to 10. Baloxavir showed a statistically significant prophylactic effect on influenza after a single oral dose in people exposed to an infected household contact. The proportion of household members 12 years of age and older who developed influenza was 1% in participants treated with baloxavir and 13% in the placebo-treated group.

“This expanded indication for Xofluza will provide an important option to help prevent influenza just in time for a flu season that is anticipated to be unlike any other because it will coincide with the coronavirus pandemic,” said Debra Birnkrant, MD, the director of the Division of Antiviral Products in the FDA’s Center for Drug Evaluation and Research. “Americans will have to be more vigilant than ever as these viruses spread concurrently.”

Treating flu patients with antiviral drugs within 48 hours of their becoming sick can reduce symptoms and duration of the illness.

Baloxavir is already indicated for acute uncomplicated influenza in people 12 years of age, but must be prescribed within 48 hours of influenza symptom development.

The FDA said an annual seasonal flu vaccine is the best way n to protect against the flu.

The sources reported no relevant financial disclosures.

Bamlanivimab continued from page 19

It is also important, the panel said, to discuss the risks of mAbs with patients because they can make matters worse. Monoclonal antibodies may be associated with worse clinical outcomes when administered to hospitalized patients requiring high-flow oxygen or mechanical ventilation with COVID-19. They should not be used in patients hospitalized for COVID-19.

The panel reinforced its suggestion that remdesivir (Veklury, Gilead) be used for patients hospitalized with COVID-19, who require respiratory support, even though recent results from the SOLIDARITY trial led the World Health Organization to recommend against its use.

This was a decision, based on remdesivir’s effect on time to recovery rather than mortality, Gandhi admitted.

Results from ACTT-1 (Adaptive COVID-19 Treatment Trial) showed that remdesivir, an inhibitor of the viral RNA-dependent, RNA polymerase, significantly shortened patients’ hospital length of stay (N Engl J Med 2020;383[19]:1813-1826). In the study of more than 1,000 patients who received remdesivir or placebo, patients taking remdesivir tended to recover within 10 versus 15 days for patients taking placebo. The death rate was 11% in the remdesivir and 15% in the placebo group, which was not statistically significant. Gandhi suggested that as hospitals are again being inundated with COVID-19 cases, freeing up hospital beds is an important consideration.

“As hospitals around the United States fill up, the IDSA panel viewed the effect that remdesivir has on speeding up time to recovery to be an important benefit, and that is why we continue to suggest its use in hospitalized patients requiring respiratory support,” Gandhi said.

Published data on casirivimab and imdevimab are lacking, so the panel did not make a statement on these antibodies at this time.

The panel took another look at tocilizumab, but kept the recommendation against its routine use, according to Bhimraj. “When we looked at critical outcomes like mortality or clinical deterioration across five studies, we did not find a significant difference [in the tocilizumab group],” he said.

In addition, use of tocilizumab can reduce levels of C-reactive protein, an inflammatory marker used in many hospitals to monitor a patient’s course. Knowing that C-reactive protein has decreased essentially unblinds the study and opens the results up to clinician bias, he explained.

“Better medications that improve survival are clearly needed,” Gandhi said. “The only medicine thus far that’s been shown to improve survival is the steroid n dexamethasone.”

The sources reported no relevant financial disclosures.

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2020

21

Better Options Available For Multidrug-Resistant HIV

BY KAREN BLUM

P

atients with multidrug-resistant HIV currently make up a drugs designed to inhibit the maturation of the virus inside smaller but still challenging part of the population living cells or prevent its entry into immune system T cells. with HIV. With careful monitoring and new drugs coming, “The good thing about these new drugs is they don’t providers can still help their patients. show cross-resistance to the existing drugs, because their “It’s really great that we have a relatively low number of mechanisms of action are different,” Appelbaum said. “If patients with this issue,” said Milena Murray, PharmD, MSc, you’re resistant to the older drugs, you are not automatically BCIDP, AAHIVP, an associate professor of pharmacy prac- resistant to these.” tice at Midwestern University-Chicago College of Pharmacy, and an HIV/ID clinical pharmacist at Northwestern Memorial New Medication Help One of the newer medications is an attachment inhibitor, Hospital, in Chicago. “Patients can have one or two mutaibalizumab-uiyk (Trogarzo, Theratechnologies), approved by tions and still have plenty of options at this point.”

About 3% to 7% of the HIV population are considered the FDA in 2018. The drug has a novel mechanism of action. multidrug-resistant (MDR) and need additional new agents, A monoclonal antibody that binds to the surface of immune according to Michael Kozal, MD, a professor of medicine at cells, ibalizumab blocks the steps required for viral entry into the Yale School of Medicine in New Haven, Conn., and the cells. Multiple centers participated in the pivotal study the chief of staff at the VA Connecticut Healthcare System. He FDA considered for approval, enrolling 40 patients with MDR HIV. Patients received a dose of IV ibalizumab-uiyk in addition has studied HIV multidrug resistance since 1991.

People can develop resistance to multiple drugs for sev- to their failing regimen for one week. After that period, they received ibalizumab-uiyk with optimized treatment regimens eral reasons, experts said.

Children who acquire HIV perinatally often have problems for six months. After one week on ibalizumab-uiyk, most adhering to medication, and can burn through several drugs patients (83%) experienced a decrease in viral load (N Engl J g adulthood.

Med 2018;379[7]:645-654). After 25 weeks, by the time they reach adolescence and yyoung edication ne nearly half saw their viral load fall below the Some patients are less adherent to medication llevel of detection. The researchers also because they’re in and out of the criminall justice reported an increase in CD4 T cells, system, have substance use issues or forr which are a marker of immunity. other reasons, and develop viral muta“This is a great drug that has worked tions that render the drugs ineffective. well,” Appelbaum noted, but because Additionally, some patients experience it is given intravenously, it’s not used toxicities or cannot tolerate some of the early in HIV treatment. existing drug classes, or are long-term The FDA recently approved fostemsurvivors initially diagnosed in the late savir (Rukobia, ViiV Healthcare), which 1980s to early 1990s who have gone After one week on was developed specifically for patients through a myriad of drugs over time. with MDR HIV and works by a novel “We have had a number of great ibalizumab-uiyk, mechanism of action, said Kozal, the agents over six different drug classes, 83% of patients lead author on a recent article (N Engl but some people develop drug resisJ Med 2020;382:1232-1243) describtance,” Kozal said. “It sounds like a experienced a ing phase 3 trial results. lot—six classes—but as patients have Fostemsavir is a prodrug whose reactions, it limits the drugs they can decrease in viral load. take, and some patients are infected Source: N Engl J Med 2018;379[7]:645-654 active metabolite, temsavir, is an attachment inhibitor that prevents viral with drug-resistant virus. There is a need entry into host immune cells by binding to a glycoprotein for new agents that have different mechanisms of action.”

Until the past couple of years, there were a limited number on the surface of the virus. In the ongoing BRIGHTE trial in of targets on the human immunodeficiency virus that could 23 countries, 371 patients with MDR HIV-1 infection were be hit by available medications, said Jonathan Appelbaum, given fostemsavir along with their failing HIV regimen. After MD, FACP, AAHIVS, a professor and the chair of the 48 weeks of therapy, 54% of randomized and 38% of nonDepartment of Clinical Sciences at Florida State University randomized patients who took the drug had undetectable viral RNA levels. The most common side effects included College of Medicine, in Tallahassee continued on page 26 Recently, several new targets have emerged, including

22

IDSE.NET

Whatâ&#x20AC;&#x2122;s In Your Inbox?

Infectious Disease Special Edition prints four times a year.

But, you can keep up with the latest ID news through our website and digital offerings. Register online to start receiving our FREE, twice-weekly e-newsletter containing all the news from bench to bedside.

Go to idse.net/Registration

C. difficile: Old Disease,

New Changes In Management

BY DAVID WILD

D

ecades have passed since Clostridioides difficile infection (CDI) was first documented as the primary cause of antibiotic-associated diarrhea, but the optimal management of primary and recurrent CDI keeps evolving.

Changes in Testing For example, new data published in The New England Journal of Medicine underscore the shortcomings of advances in testing technology, suggested Sahil Khanna, MBBS, an associate professor of medicine at Mayo Clinic College of Medicine and Science, in Rochester, Minn.

(2020;382[14]:1320-1330).

At first glance, the study, which used data from 10 sites nationwide to derive a national estimate of the incidence of CDI, reported a relatively unchanged rate of the disease over a six-year period: 476,400 cases in 2011 and 462,100 cases in 2017. However, Dr. Khanna noted that after adjusting for the increasing use of nucleic acid amplification testing (NAAT), the researchers concluded that the incidence of CDI had actually decreased by 24% during the study period, including a 36% drop in health care–acquired CDI cases.

The study highlights a problem with NAAT, according to Khanna.

“NAAT is approximately 95% sensitive in detecting the C. difficile gene, but it cannot determine if the gene is active and toxin-producing, so it has the potential for overdiagnosis and for producing clinical false positives,” he explained.

“Because of this, it’s important that we interpret NAAT results in the context of patient symptoms.”

Clinicians must be selective when deciding which patients should be tested, he said, only using it in patients who have acute diarrhea with no obvious alternative explanation, and

24

IDSE.NET

who have the risk factors for CDI. These include older age, longer hospitalization, immunosuppression, use of antibiotics, gastric acid–suppressing agents, gastrointestinal surgery, manipulation of the gastrointestinal tract, and tube feeding.

“Patients not experiencing an active infection can be colonized with C. difficile, in which case there is a risk of a clinical false positives and unnecessary treatment,” Khanna emphasized.

An alternative testing approach now recommended by the Infectious Diseases Society of America (IDSA) and the Society for Healthcare Epidemiology of America (SHEA) is the use of a multistep algorithm including glutamate dehydrogenase (GDH) to identify pathogenic bacteria and enzyme immunoassay (EIA) to detect C. difficile toxin (Clin Infect Dis 2018;66[7]:e1-e48). NAAT should be reserved for instances in which results from GDH and EIA are inconclusive, the guidelines recommend.

“Unfortunately, NAAT remains the most commonly used test method,” Khanna said, adding that laboratories are increasingly adopting a two-step protocol of GDH and EIA.

Treatment Changes The treatment landscape for CDI also has changed over the past few years, noted Kim Ly, PharmD, a clinical pharmacy specialist in critical care and infectious diseases at Sunrise Hospital and Medical Center, in Las Vegas.

Bezlotoxumab (Zinplava, Merck), a monoclonal antibody, is now approved for combination treatment of toxin B–producing CDI, along with an established antibiotic. Additionally, metronidazole, while still approved for the treatment of CDI, is no longer recommended by IDSA/SHEA as a first-line agent for primary CDI in adults.

“For severe initial episodes of CDI, oral vancomycin and fidaxomicin [Dificid, Merck] are now the preferred agents, and metronidazole is only recommended for nonsevere initial episodes when patients are unable to be treated with oral vancomycin or fidaxomicin,” Kim explained.

For a first recurrence of CDI, the IDSA/SHEA guidelines recommend administering oral vancomycin as a tapered and pulsed regimen or fidaxomicin, rather than a standard 10-day course of vancomycin. For subsequent recurrences, clinicians can use the same regimen, with the addition of a standard course of oral vancomycin followed by rifaximin or fecal microbiota transplantation (FMT).

Metronidazole comes into play again in the management of fulminant CDI, Ly noted.

“The IDSA/SHEA guidelines recommend treating this with oral or rectal vancomycin 500 mg four times daily along with intravenous metronidazole,” she explained.

Recurrent CDI mostly occurs in people: • 65 and older who take antibiotics and receive medical care • staying in hospitals and nursing homes for a long time • with weakened immune systems

Microbiota Disruption Given that antibiotic-induced microbiota disruption “is far and away the number one precipitant for getting recurrent CDI,” selecting the CDI treatment with the least impact on the microbiota is important, said former IDSA president Cynthia Sears, MD, a professor in the Department of Medicine, Division of Infectious Diseases, at the Johns Hopkins University School of Medicine, in Baltimore.

“Vancomycin is the most commonly used therapy for CDI and its recurrences, but it decreases intestinal diversity and so impedes recovery of the normal microbiota after CDI, setting the stage for CDI recurrence,” Sears said. “We have learned that vancomycin hits the colon with full force when taken orally because it is not absorbed, and it has off-target effects on lots of anaerobic bacteria that are essential to intestinal resistance of CDI.” Fidaxomicin has less of an effect on the microbiota, and has been shown to sometimes decrease the risk for CDI recurrence when compared with vancomycin (N Engl J Med 2011;364[5]:422-431), but it can be expensive, she said.

Fecal Microbiota Transplantation FMT is a less expensive, highly effective treatment that has received increasingly widespread attention, specifically for the management of recurrent CDI. Despite the enthusiasm surrounding the treatment, Sears expressed significant reservations about employing it.

“While there’s no question that FMT benefits patients with recurrent CDI, I feel we don’t yet have a quality-controlled product that we know is safe as well as being effective,” she said.

Sears pointed to two recent FDA safety alerts that warned of the harm that FMT can cause. The first, from 2019, reported that stool from a single donor had not been thoroughly screened before FMT and contained extended-spectrum ß-lactamase–producing Escherichia coli. The specimen had been used in separate FMTs for two immunocompromised patients, leading to infection with the pathogen and death in

one case (bit.ly/3gKXZED-idse).

In another FDA safety alert from earlier this year, the organization said a stool bank specimen that had undergone comprehensive screening nevertheless contained enteropathogenic E. coli and Shiga toxin–producing E. coli. Transfer of the stool for the treatment of recurrent CDI resulted in one nonfatal infection and one death (bit.ly/2ZZC72e-IDSE).

“Stool banks try very hard to be sure their specimens are free of disease-causing microbes, but if you have very low-level colonization, molecular diagnostics can miss this,” Sears said. More recently, she noted, the FDA has also raised concerns about the possibility of transferring SARSCoV-2 through FMT, given that the virus can be present in the stool of infected individuals (bit.ly/2U0DUAb-IDSE).

What would a safer and equally effective microbiota-based treatment look like? According to Sears, while microbial diversity seems to be protective against recurrent CDI, there are suggestions that administration of specific strains may be able to treat CDI and can be produced under the same strict quality control manufacturing processes as other FDAapproved drugs. One study published in 2015 using human and mouse samples found that colonization with Clostridium scindens, a strain of Firmicutes, increased resistance to CDI (Nature 2015;517[7533]:205-208). Many microbiota-based therapeutics are in the research pipeline as well.

“I am optimistic that we will see something emerge that’s safer and still as effective as FMT for patients, whether it’s an n orally or rectally administered product,” Sears said.

The sources reported no relevant financial disclosures.

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2020

25

HIV Resistance

Not the Same Boat

continued from page 22

continued from page 12

diarrhea, nausea and upper respiratory tract infections.

“The data were very promising in that the viral load stayed nondetectable in a large number of patients out to week 48,” Kozal said. “There’s no cross-resistance to other classes, so we think it’s going to be helpful for people who have exhausted other drug classes or can’t take other drug classes because [of intolerance].”

Current management of patients still comes down to individual resistance profiles, Murray said. Protease inhibitors are good options for some patients with drug resistance.

Maraviroc can be helpful but requires a tropism assay.

Enfuvirtide (Fuzeon, Genentech) is an injectable that may cause painful injection site reactions and is usually used as a last resort. At times, adding an integrase inhibitor to the regimen will be enough if there are no mutations to this class.

“Sometimes we need to have patients on four to five medications, but that regimen is able to get them to an undetectable viral load,” Murray said, while other times medications are not enough to get to undetectable but can keep the viral load at a lower point. Ibalizumab can be a good option for patients who are extensively drug-resistant, she added.

“One of the caveats of HIV treatment is you never want to add on or substitute just one drug if patients have resistance to multiple drugs,” Appelbaum noted. “You want to have two, and ideally three, active medications.”

When monitoring patients, Murray said, always check the viral load. “If patients are undetectable, that’s the best case scenario,” she said. “But if we can’t get them to undetectable, we want to make sure their viral load isn’t continuing to increase.”

race/ethnic groups do not differ in mortality rates.

Although Del Rio noted that some of the effect is caused by a disproportionate burden of comorbidities on people of color, this does not fully explain the differences.

Due to economic discrimination, Black and Latin populations tend to live in more segregated, poorer neighborhoods. “Poor people in urban settings live in crowded conditions and are more likely to be employed in public-facing positions that prevent physical distancing,” Del Rio said.

“In fact, it is this racial segregation with COVID-19 that really drives a lot of what we are seeing,” Del Rio explained.

“Race, together with socioeconomic resources, social resources and health care resources, drives increased risk of exposure and increased risk of complications. Racism then drives the worse outcomes. You really have to break the cycle if you are going to impact the outcome.”

A recent study conducted by L. Silvia Munoz-Price, MD, PhD, a professor of medicine in the Department of Medicine—Division of Infectious Diseases at Froedtert and the Medical College of Wisconsin in Milwaukee, reinforced many of these findings (JAMA Netw Open 2020;3[9]:e2021892. doi: 10.1001/ jamanetworkopen.2020.21892).

Focusing on the effect of COVID-19 in Milwaukee, Munoz-Price found that people residing in urban counties rated by the CDC as socially susceptible—in terms of lower socioeconomic status, household composition, minority status or language, and housing and transportation—had a greater likelihood of COVID-19 cases and deaths than those living in less susceptible counties.

Further analysis revealed that poverty, more than any other factor, was to blame. “Seventy-nine percent of the COVID-19 positivity was explained by the ZIP code of residence,” Munoz-Price said. “However, after controlling for ZIP code of residence, only poverty was associated with poor outcomes. These and other studies suggest that factors related to structural racism, not race, are associated with the incidence and severity of COVID-19.”

The effect of these disparities has been grim during the pandemic, but Del Rio hopes that understanding this information will lead to changes that will improve health care for all Americans. “A silver lining of the COVID-19 pandemic is that this can finally be an opportunity to eliminate inequalities in health in the U.S.,” he said. “Health equity is the road to ending COVID-19.”

Schaffner agreed. “Among many other lessons, COVID has forcefully reminded us all that our country and its people need to continue to strive to achieve the goal of a more perfect union. Within ourselves, we must all work n toward that goal.”

Don’t Forget CD4 Counts In addition, monitor CD4 counts to make sure they’re not decreasing. Check for any signs or symptoms of opportunistic infections and make sure any comorbid conditions are being addressed. Follow all guideline recommendations for screenings.

T-cell count also is important, Appelbaum said, “because if you don’t have the virus under control, the immune system is being constantly attacked by the virus, and so the patient is at risk for opportunistic infections and malignancies.”

Be mindful that as patients get older and need to add statins or antihypertensives to their regimens, drug interactions can occur with their HIV medications, Murray said. Then you can run into the issue of not being able to change the antiretroviral therapy to mitigate drug interactions because there aren’t any other options to treat the drug-resistant HIV. Overall, have good encouragement and support for your patients, Kozal advised: “You’ve got to take the drugs in order n for them to work.”

Appelbaum reported a relationship with Merck and ViiV Healthcare.

Murray reported a relationship with Merck.

26

IDSE.NET

The sources reported no relevant financial disclosures.

FLU UAD® QUADRIV VALENT The first-and-only adjuvanted quadrivalent seasonal influenza vaccine approved for adults YEARS AND OLDER1 FLUAD QUADRIVALENT is formulated with MF59® adjuvant to boost the immune response to the 4 influenza strains represented in the vaccine.1

COVERE ED BY Y MEDICAR RE PA ART B CPT CODE 90694

For more information, please see Brief Summary on adjacent page.

Learn more at flu.seqirus.com

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

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

WARNINGS AND PRECAUTIONS

The immune response to FLUAD QUADRIVALENT in immunocompromised persons, including individuals receiving immunosuppressive therapy, may be lower than in immunocompetent individuals.

Syncope (fainting) may occur in association with administration of injectable vaccines including FLUAD QUADRIVALENT. Ensure procedures are in place to avoid injury from falling associated with syncope.

Vaccination with FLUAD QUADRIVALENT may not protect all vaccine recipients against influenza disease.

ADVERSE REACTIONS The most common (*10%) local and systemic reactions in elderly subjects 65 years of age and older were injection site pain (16.3%), headache (10.8%) and fatigue (10.5%).

If Guillain-Barré syndrome (GBS) has occurred within 6 weeks of receipt of prior influenza vaccine, the decision to give FLUAD QUADRIVALENT should be based on careful consideration of the potential benefits and risks.

To report SUSPECTED ADVERSE REACTIONS, contact Seqirus USA Inc. at 1-855-358-8966 or VAERS at 1-800-822-7967 or www.vaers.hhs.gov.

Appropriate medical treatment and supervision must be available to manage possible anaphylactic reactions following administration of the vaccine.

FLUAD® QUADRIVALENT is a registered trademark of Seqirus UK Limited or its affiliates.

Before administration, please see the full US Prescribing Information for FLUAD QUADRIVALENT.

REFERENCE: 1. FLUAD QUADRIVALENT [package insert]. Holly Springs, NC: Seqirus Inc; 2020.

FLUAD QUADRIVALENT and MF59 are registered trademarks of Seqirus UK Limited or its affiliates.

Manufactured by: Seqirus Inc., 475 Green Oaks Parkway, Holly Springs, NC 27540, USA Distributed by: Seqirus USA Inc., 25 Deforest Avenue, Summit, NJ 07901, USA ©2020 Seqirus USA Inc. November 2020 US/FQIV/1019/0015(1)

FLUAD QUADRIVALENT (Influenza Vaccine, Adjuvanted) Injectable Emulsion for Intramuscular Use 2020-2021 Formula Initial U.S. Approval: 2020 BRIEF SUMMARY These highlights do not include all the information needed to use FLUAD® QUADRIVALENT safely and effectively. See full prescribing information for FLUAD QUADRIVALENT. ------INDICATIONS AND USAGE------FLUAD QUADRIVALENT is an inactivated influenza vaccine indicated for active immunization against influenza disease caused by influenza virus subtypes A and types B contained in the vaccine. FLUAD QUADRIVALENT is approved for use in persons 65 years of age and older. (1) This indication is approved under accelerated approval based on the immune response elicited by FLUAD QUADRIVALENT (1). Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

---DOSAGE AND ADMINISTRATION--A single 0.5 mL dose for intramuscular injection. (2.1) --DOSAGE FORMS AND STRENGTHS-Injectable emulsion supplied in 0.5 mL single-dose pre-filled syringes. (3)

-----------CONTRAINDICATIONS----------Severe allergic reaction to any component of the vaccine, including egg protein, or after a previous dose of any influenza vaccine. (4, 11) -------WARNINGS AND PRECAUTIONS----If Guillain-Barré Syndrome (GBS) has occurred within six weeks of previous influenza vaccination, the decision to give FLUAD QUADRIVALENT should be based on careful consideration of the potential benefits and risks. (5.1) -----------ADVERSE REACTIONS----------The most common (* 10%) local and systemic reactions in elderly subjects 65 years of age and older were injection site pain (16.3%), headache (10.8%) and fatigue (10.5%). (6) To report SUSPECTED ADVERSE REACTIONS, contact Seqirus at 1-855-358-8966 or VAERS at 1-800-822-7967 and www.vaers.hhs.gov.

FLUAD QUADRIVALENT and MF59 are registered trademarks of Seqirus UK Limited or its affiliates.

Why Won’t Physicians Prescribe New Antibiotics?

BY GLENN TILLOTSON, PhD, FIDSA

A

roundtable that was convened in 1965 by Max Finland and his 7 colleagues emphatically endorsed the need for new antibiotics.1 The problem pathogens were predominantly gramnegative, such as Pseudomonas, Klebsiella, and Proteus species. The roundtable members also recognized the emerging problems associated with methicillin-resistant Staphylococcus aureus (MRSA). Approximately 50 years later, not a lot had changed when the Infectious Diseases Society of America (IDSA) established the “10 × ‘20” campaign to encourage the development of new antimicrobials.

In the ensuing years, this target was achieved, as the FDA approved 19 new antibiotics. Apart from bedaquiline (Sirturo, Janssen)—a drug for multidrugresistant (MDR) tuberculosis—no new pathways or novel agents were created, however.

Still, the cost of developing new antibiotics is approximately $1.2 billion.2 With this investment, companies want to price the drugs in a manner that allows them to recoup the research costs. However, this approach leads to some thorny issues that may contribute to the headline question: Why won’t physicians prescribe new antibiotics?

Too High a Cost?

It would be glib to simply say the higher costs of new agents preclude their use, but that is one big factor.

There are, however, other potential reasons, including concern over the safety of new drugs and clinical evidence that invariably shows noninferior outcomes between old and new drugs.

Health economics data also are generally lacking, which is essential for formulary decision making. These reasons slow the uptake of some of these drugs on formularies. Once on a formulary, they are typically controlled by antibiotic stewardship programs (ASPs), which require some form of preauthorization and/or prospective audit and feedback

The cost of developing a new antibiotic is about $1.2 billion. system. Restrictive preauthorization or prior authorization processes can effectively deter clinicians from prescribing new drugs. The implications of these strategies have been discussed elsewhere by Vickers et al.3 There are complex issues for health care administrators to conflate the cost of new antibiotics into the bigger hospital economics picture, as discussed by Spellberg et al,4 but the general outcome is to slow the uptake of new “more costly” antibiotics.

Two recent examples illustrate the balance of clinical need to treat epidemic or MDR pathogens in which new drugs were introduced to manage these infections.

Clostridioides difficile infections affect some half a million U.S. citizens annually, with treatment being either oral metronidazole or oral vancomycin as per the 2010 IDSA guidelines.5 However, these drugs are associated with high recurrence rates of more than 25%, which increase with each

subsequent recurrence. Physicians had no option but to prescribe these inadequate drugs. In 2012, a new antibiotic developed for C. difficile, fidaxomicin (Dificid, Merck), was introduced.6 The drug showed superiority over vancomycin in terms of sustained clinical response, but uptake was probably slow due to the cost, which was about $2,800 per course. On the other hand, metronidazole cost pennies, and oral vancomycin could be compounded or acquired commercially at lower prices. The impact of this pricing, which was selected to recoup the significant investment, was to slow the uptake of fidaxomicin. When the IDSA/SHEA (Society for Healthcare Epidemiology of America) C. difficile guidelines were updated in 2018, there was a clear shift in recommendation away from metronidazole to vancomycin and fidaxomicin based on strong clinical data.7 But does being in the guidelines change clinical practice?

Clancy and Nguyen8 examined the courses of vancomycin and fidaxomicin written after the release of the 2018 guidelines using IQVIA data. Treatment courses increased by 45% (n=126,729) and 44% (n=11,243), respectively, over 12 months after publication of the guidelines compared with the 12 months prior to publication (Figure 1). Indeed, increased use was observed in the first month after the guidelines were published. During the same period, metronidazole prescribing decreased by 3%.

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2020

29

The authors concluded that updated guidelines had a marked effect on antibiotic utilization. External validation by experts provides the evidence needed by formulary and ASP committees and subsequently broader physician base. IDSA guidelines authors have been tasked to update their publications every 2 to 3 years to avoid the 6-year gap with C. difficile and the

accidental prevention of fidaxomicin use.9 An update to these 2018 guidelines is imminent.

Carbapenem-Resistant Enterobacteriaceae Carbapenem-resistant Enterobacteriaceae (CRE), a group of pathogens that has been the focus of research efforts, are globally recognized as pathogens

40,000 35,000 30,000 25,000 20,000 15,000

Estimated Oral Vancomycin Courses

Jan 19

Jul 18

Oct 18

Jan 18

Apr 18

Jul 17

Oct 17

Apr 17

Jul 16

Oct 16 Jan 17

Jan 16

Apr 16

Jul 15

Oct 15

Apr 15

Jul 14

Oct 14 Jan 15

Jan 14

Apr 14

Jul 13

Oct 13

Jan 13

5,000 0

Apr 13

10,000

Estimated Oral Fidaxomicin Courses

Figure 1. When the IDSA/SHEA (Society for Healthcare Epidemiology of America) C. difficile guidelines were updated in 2018, there was a clear shift in recommendation away from metronidazole to vancomycin and fidaxomicin.

Based on reference 8.

1,600 1,400 1,200

CRE Infections, n

1,000 800 600 400

0

Jun 2011 Sep 2011 Dec 2011 Mar 2012 Jun 2012 Sep 2012 Dec 2012 Mar 2013 Jun 2013 Sep 2013 Dec 2013 Mar 2014 Jun 2014 Sep 2014 Dec 2014 Mar 2015 Jun 2015 Sep 2015 Dec 2015 Mar 2016 Jun 2016 Sep 2016 Dec 2016 Mar 2017 Jun 2017 Sep 2017 Dec 2017 Mar 2018 Jun 2018 Sep 2018 Dec 2018

200

COL+PB vs CRE

C-A vs CRE

M-V vs CRE

PLZ vs CRE

Figure 2. Estimated number of colistin, polymyxin B, ceftazidime-avibactam, meropenem-vaborbactam, and plazomicin treatment courses for carbapenem-resistant Enterobacteriaceae infections.

C-A, ceftazidime-avibactam; COL, colistin; CRE, carbapenem-resistant Enterobacteriaceae; M-V, meropenem-vaborbactam; PB, polymyxin B; PLZ, plazomicin Based on reference 3.

30

IDSE.NET

of critical importance in terms of the need for new agents.10 CRE causes between 19,000 and 49,000 infections annually in the United States.

Indeed, since 2015, the FDA has approved 7 drugs to treat these infections. These are ceftazidime-avibactam (Avycaz, Allergan), ceftolazane/tazobactam (Zerbaxa, Merck), meropenemvaborbactam (Vabomere, Melinta), plazomicin (Zemdri, Cipla), imipenem-cilastatin-relebactam (Recarbrio, Merck), eravacycline (Xerava, Tetraphase), and most recently cefiderocol (Fetroja, Shionogi).11 However, clinicians are still using polymyxin B or colistin despite data showing the newer drugs to be more effective clinically and less toxic.12 Vickers et al3 illustrate the challenging situation of new drug uptake against a group of pathogens for which they were specifically developed (Figure 2).

Although polymyxin use is declining, it is still prescribed almost as much as all the new agents combined.

Clancy and Nguyen8 used IQVIA data to estimate that the first 3 of these agents were used to treat 23% of CRE infections over the period between February 2018 and January 2019. The estimated annual sales of these agents were $92.4 million, $7.9 million, and $700,000 for ceftazidime-avibactam, meropenem-vaborbactam, and plazomicin, respectively. As a result of these sales, the 3 companies find it difficult to sustain these agents, with Achaogen (plazomicin) declaring bankruptcy after spending $450 million on the drugâ&#x20AC;&#x2122;s development. To be profitable and sustainable, it is estimated that a drug must earn about $300 million.8 It will be even more daunting as more anti-CRE drugs are approved. If one considers the case of ceftazidimeavibactam launched in April 2015, it has taken 5 years to achieve one-third of the amount needed for an antibiotic to become profitable.

It has been observed that it takes about 8 to 9 years for an antibiotic to reach peak sales, in which case ceftazidime-avibactam is still in the positive direction. Yet, polymyxin is still being used, most likely due to the lower price.

These observations are not unique to antibiotic use primarily in hospitals.

Recent introductions into the community setting have not shown the uptake needed to be regarded as successful.

Despite the continued emergence of antibiotic resistance among respiratory pathogens, such as Streptococcus pneumoniae, and urinary tract infections caused by Escherichia coli, new drugs—such as omadacycline (Nuzyra, Paratek) and lefamulin (Xenleta, Nabriva)—are having difficulty capturing market share.11 These 2 drugs were developed specifically to be active against S. pneumoniae, with clinical trials supporting the claims of efficacy in communityacquired pneumonia. Despite both drugs being active against an array of resistant pathogens, their adoption has been modest, at best. One could speculate as to why physicians are slow to prescribe these agents. It may be that most primary care prescribers “don’t see much resistance” in their practice and do not see the need to turn to the new agents, but pricing also probably plays a role. These companies invested millions of dollars to bring these drugs to the community setting, but revenue has been less than $20 million annually.

Thus, pricing is a key reason why physicians do not prescribe new antibiotics. This undoubtedly plays a role in ASP and formulary acceptance. Yet, pharmaceutical companies are heavily criticized for the pricing strategies.

Finally, an editorial written in 2019 asks a key question about need.13 This commentary focused on delafloxacin (Baxdela, Melinta), a novel anionic fluoroquinolone approved for skin and skin-structure infections. The drug was developed for MRSA and the emergence of quinolone-resistant strains.

The clinical data demonstrated noninferiority to vancomycin, and the tolerability was similar between the regimens.

Miller also noted that unlike other fluoroquinolones, delafloxacin lacks a QT prolongation, phototoxicity, and a range of drug–drug interactions. But he asks the question, “Do we even need a new antibiotic for skin infections?” However,

the currently available agents each have at least 1 flaw, whether it be safety, developing resistance, or a paucity of relevant clinical data. But they are inexpensive and are thus prescribed.

Miller states that infectious disease specialists are novel in the medical world. They call for much-needed new antibiotics, and when they are approved and released, they do everything possible to restrict the ability of colleagues to use them. Infectious disease physicians, and pharmacists, seem to want to save the drugs for “that one desperate patient” when all other options have been tried and failed due to MDR pathogens and other factors. This approach seems self-defeating in the long term. Admittedly, infectious disease physicians are the stewards of antibiotics, but a balance is required.

Little to no use will contribute to the downfall of small biotech firms, which are the main drivers in the antibiotic development field.

So back to the question, “Why do physicians not use new antibiotics?”

There are several possible factors influencing prescribing decisions. These include not being on a formulary or being heavily restricted in ASP algorithms, as well as a lack of real-world clinical efficacy, safety, and economics data. Price is not the only reason, but it is a big one, given the cost of new agents should be commensurate with the development costs.

5. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol.

2010;31(5):431-455.

6. Crawford T, Huesgen E, Danziger L. Fidaxomicin: a novel macrocyclic antibiotic for the treatment of Clostridium difficile infection. Am J Health Syst Pharm.

2012;69(11):933-943.

7. McDonald LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile Infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):987-994.

8. Clancy CJ, Nguyen MH. Estimating the size of the United States market for new antibiotics with activity against carbapenem-resistant Enterobacteriaceae.

Antimicrob Agents Chemother.

2019;63(12):e01733-19.

9. Clancy CJ, Buerhle D, Vu M, et al. Impact of revised Infectious Diseases Society of America and Society for Healthcare Epidemiology of America clinical practice guidelines on the treatment of Clostridium difficile infections in the United States. Clin Infect Dis. 2020 Apr 28. [Epub ahead of print]. doi: 10.1093/cid/ciaa484 10. WHO publishes list of bacteria for which new antibiotics are urgently needed [news release]. World Health Organization; February 27, 2017. Accessed November 3, 2020. https://bit.ly/3lUR9xm-IDSE

References

11. Andrei S, Droc G, Stefan G. FDA approved drugs: 2018-2019. Discoveries (Craiova).

2019;7(4):e102.

1. Finland M, Kirby WMM, Chabbert Y, et al. Round table: are new antibiotics needed? Antimicrob Agents Chemother (Bethesda). 1965;5:1107-1114.

12. LaPlante K, Cusumano J, Tillotson G. Colistin for the treatment of multidrugresistant infections. Lancet Infect Dis. 2018;18(11):1174-1175.

2. Gardner J. New estimate puts cost to develop a new drug at $1B, adding to longrunning debate. BioPharma Dive. March 3, 2020. Accessed November 3, 2020. https://bit.ly/3lU2myr-IDSE

13. Miller LG. Another new antibiotic for skin infections and why infectious disease specialists are hypocrites. Clin Infect Dis. 2019;68(7):1223-1224.

3. Vickers RJ, Bassetti M, Clancy CJ, et al.

Combating resistance while maintaining innovation: the future of antimicrobial stewardship. Future Microbiol.

2019;14:1331-1341.

4. Spellberg B, Bartlett JG, Gilbert DN. How to pitch an antibiotic stewardship program to the hospital C-suite. Open Forum Infect Dis. 2016;3(4):ofw210.

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

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2020

31

IDSE Review

Updated Evidence For Optimal Management of C. diff Infection

BY MARK H. WILCOX, MD, FRCPATH

E

vidence continues to accumulate on the increased relative efficacy of some therapies for Clostridioides difficile infection (CDI), especially with respect to the prevention of recurrent infection.

There are 4 agents approved for managing CDI: 2 older antibiotics, metronidazole and vancomycin, and 2 newer options, the antibiotic fidaxomicin (Dificid, Merck) and a newer monoclonal antibody against toxin B, 1 of the 2 major C. difficile toxins (bezlotoxumab [Zinplava, Merck]). Four additional agents are in phase 1 to 3 clinical trials.

Bezlotoxumab is given along with one of the standard-of-care antibiotics to reduce the risk for CDI recurrence by augmenting the host endogenous antibody response against C. difficile toxin B. The antibiotics aim to stop C. difficile growth and, thus, toxin production. However, the other crucial issues are whether C. difficile persists in the gut as spores, with the potential to germinate once antibiotic administration has

32

IDSE.NET

stopped, and the extent of microbiome disturbance that the CDI therapeutic causes on top of the existing dysbiosis. Together, these issues determine the effectiveness of the therapeutic to achieve clinical cure and prevent infection recrudescence (recurrent CDI).

We know that metronidazole, until recently the most common option for treating CDI, is inferior to vancomycin (and almost certainly to fidaxomicin).1-3 Thus, guidelines increasingly advocate the use of vancomycin (or fidaxomicin) rather than metronidazole, especially for the treatment of non-mild cases of CDI.4 Notably, however, fidaxomicin and bezlotoxumab have been shown convincingly to reduce the risk for recurrent CDI by 40% to 50% compared with vancomycin alone.5-7 This review

IDSE Review

particularly effective at reducing the risk for recurrent CDI. First, in both fecal samples from human volunteers and gut model contents, fidaxomicin can be detected well beyond the cessation of dosing (2-3 weeks), at levels well in excess of the minimum inhibitory concentration of fidaxomicin for C. difficile.11,12 So, extended dosage regimens likely result in persistence of fidaxomicin for longer periods Emerging Evidence on Fidaxomicin Efficacy than standard dosing regimens, suppressing recrudescence of C. difficile spores but allowing recovA recent randomized, controlled, open-label, ery of gut microbiota populations. Notably, no evisuperiority, phase 3b/4 clinical trial in hospitaldence of the emergence of reduced susceptibility of ized adults aged ≥60 years demonstrated that an C. difficile has been associated with extended extended-pulsed dosing regimen of fidaxomicin dosage regimens. Second, in vitro studies show (200 mg twice daily on days 1-5, then once every that fidaxomicin persists on C. difficile other day on days 7-25)—comprising the spores, whereas vancomycin does same total dose of antibiotic as a not.13 Furthermore, persistence conventional course—can further reduce the risk for recurof fidaxomicin prevented C. difrent CDI compared with a ficile growth and toxin producstandard course of vancotion. Thus, it is possible that the mycin (125 mg 4 times daily on days continued presence of fidaxomi1-10).8 The primary end point was cin in the gut after cessation of dosing, coupled with the assosustained clinical cure 30 days ciation of antibiotic with after the end of treatment (day 55 spores, explains why this antifor extended-pulsed fidaxomicin biotic reduced CDI recurrence. and day 40 for vancomycin); 70% Such effects may be exploited by (124/177) of the extended-pulsed extended dosing of fidaxomicin.8 fidaxomicin recipients versus 59% (106/179) of the vancomycin In a follow-up report to the patients achieved sustained cliniphase 3b/4 clinical trial, both precal cure 30 days after the end of specified and post hoc subgroup treatment (difference, 11%; 95% analyses were presented to deterCI, 1.0%-20.7%; P=0.030; odds mine whether particular patient Source: N Engl J Med. 2017;376:305-317. ratio, 1.62 [95% CI, 1.04-2.54]). groups showed more benefit from Studies in an in vitro model that the extended fidaxomicin dossimulates conditions found in the human colon, and age regimen.14 Prespecified subgroup categories notably the gut microbiome in the context of CDI, included patient age (60-74 vs ≥75 years); canprovided a rationale for the above-mentioned novel cer diagnosis (presence vs absence); CDI severity; 9 extended dosage of fidaxomicin. This gut model, and number of prior CDI episodes within 3 months before study participation. A post hoc subgroup which is primed with pooled fecal samples from efficacy analysis also was performed in relation to elderly volunteers, has proven to be predictive of presence of C. difficile ribotype 027 (vs other riboantibiotic behavior in patients—both whether antitypes). The primary end point was sustained clinibiotics have high or low propensity to induce CDI cal cure (initial cure and absence of recurrence) 30 and whether novel agents will treat CDI and predays after end of treatment. Sustained clinical cure vent recurrent infection successfully.10 Gut model rates did not differ significantly between extended experiments showed that pulsed or tapered fidaxdosage fidaxomicin (124/177; 70.1%) and vancoomicin regimens may enhance suppression of C. mycin (106/179; 59.2%) according to age, candifficile, while allowing microbiota recovery.9 Two cer diagnosis, CDI severity, or history of CDI. Howother key lines of evidence are pertinent to underever, in patients with CDI due to ribotype 027, the standing why an extended dosage of fidaxomicin is focuses primarily on emerging evidence that underscores the efficacy of the newer CDI treatment options, summarizes the new agents undergoing clinical trials (phase 2 or beyond), and highlights a new focused update of the recently published CDI guideline from the Infectious Diseases Society of America.

Bezlotoxumab reduced CDI recurrence risk in predefined groups.

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2020

33

IDSE Review

Table. Patients Needed to Treat With Bezlotoxumab and Standard-of-Care Antibiotic To Prevent One Recurrence of CDIa Subgroup

a

NNT to Prevent a Recurrence

Patients aged ≥65 y

3.8

Patients who are immunocompromised

4.7

Patients who present with severe CDI

5.1

Patients aged ≥65 y who have had ≥1 previous episode in prior 6 mo

2.5

Patients who are immunocompromised and have had ≥1 previous episode in prior 6 mo

3.0

Patients who present with severe CDI and have had ≥1 previous episode in prior 6 mo

2.5

Patients were stratified according to baseline risk factors for recurrence.

CDI, Clostridioides difficile infection; NNT, number needed to treat

sustained clinical cure rate was significantly higher in extended fidaxomicin (20/25; 80%) than vancomycin (9/22; 40.9%) recipients (treatment difference, 39.1%; 95% CI, 13.2%-64.9%; P=0.006).14 Such data for a C. difficile type that is associated with poor outcomes, albeit from a post hoc analysis, provide added confidence about the efficacy of fidaxomicin in treating CDI. In a prospective surveillance study spanning 5 years (2011-2016) across 28 European countries (40 sites) 3,499 isolates from cases of CDI were monitored for changes in antimicrobial susceptibility and ribotype distribution.15 Ribotype prevalence varied greatly among countries and among years, but the most common of the 264 ribotypes found was 027 (mean prevalence 11.4%). Metronidazole and vancomycin geometric mean MICs were 0.46 mg/L and 0.70 mg/L, respectively.

Fidaxomicin susceptibility, including in ribotype 027, was maintained post-introduction; geometric mean MIC for years 1 to 5 was 0.04 mg/L, with only 1 fidaxomicin-resistant isolate (RT344) detected (MIC ≥4 mg/L).

Emerging Evidence for Bezlotoxumab In phase 3 trials, bezlotoxumab significantly reduced the risk for CDI recurrence in predefined groups at high risk for recurrent disease and/or poor outcome (≥65 years, previous CDI, immunocompromised, or severe CDI, but not CDI due to ribotype 027).16 Bezlotoxumab also was associated with a significant reduction in the 30-day

34

IDSE.NET

CDI-associated readmission rate (4.0% vs 9.6%; difference, –5.7%; 95% CI, –8.8% to –2.7%).17 Recent reports have added to our understanding of the efficacy of bezlotoxumab in preventing recurrent CDI. Higher host antitoxin B, but not antitoxin A, antibody titers were associated with protection against recurrent CDI, which is consistent with the MODIFY trial outcomes (bezlotoxumab, but not actoxumab, was efficacious).18 In addition, a post hoc analysis of the efficacy rates of bezlotoxumab according to the method used to diagnose CDI in the MODIFY clinical trials found that the magnitude of reduction in recurrent CDI was substantially larger in participants diagnosed by toxin tests (relative difference, –46.6%) than in subjects recruited on the basis of a (toxin gene) PCR test or toxigenic culture (–29.1%).19 Hence, bezlotoxumab recipients diagnosed by toxin testing had a lower rate of CDI recurrence than those recruited by indirect toxin tests (17.6% vs 23.6%).

These data show the magnitude of reduction in recurrent CDI achieved by bezlotoxumab is probably greater than the headline rate reported in the primary publication of the MODIFY studies.6 A subsequent analysis of the modified intentto-treat population from the MODIFY studies who received bezlotoxumab or placebo (n=1,554) according to their baseline risk factors for recurrent CDI recently was published.20 These risk factors were prespecified in the statistical analysis plan: age ≥65 years, history of CDI, compromised immunity, severe CDI, and ribotype 027/078/244. The proportion of placebo recipients who experienced

IDSE Review

recurrent CDI exceeded 30% for each risk factor compared with 20.9% of those without a risk factor.

Also, the rate of recurrent CDI increased with the number of risk factors (1 risk factor, 31.3%; ≥3 risk factors, 46.1%). In a separate analysis, the number of subjects needed to treat (NNT) to prevent a CDI recurrence was calculated (Table). This shows a very low NNT of 2 to 3 patients in those who have 2 risk factors for recurrent CDI, and provide a good basis for selecting patients to consider for bezlotoxumab treatment.21 In a real-world study of 46 patients receiving bezlotoxumab in 5 hospitals in Finland, 71% remained recurrence-free at 3 months.22 Of particular note, 8 patients were awaiting fecal microbiota transplantation (FMT). After stopping the antibiotics that were continued to prevent CDI recurrence (and receiving bezlotoxumab), all 8 patients remained free of recurrence and did not require FMT. Given that FMT is an experimental procedure, whereas bezlotoxumab has regulatory approval for the prevention of CDI recurrence, this (uncontrolled) observation is revealing. Similarly, in the 2 registrational phase 3 (MODIFY) clinical trials, 11% of patients in the placebo group went on to receive FMT, whereas only 3% of those receiving active treatment had FMT.23 Thus, these data are consistent with the recommendation in the IDSA CDI guideline that appropriate antibiotic treatments for at least 2 recurrences (ie, 3 CDI episodes) should be tried prior to offering FMT.4 Using pooled data from MODIFY I/II, a post hoc analysis examined CDI-related outcomes in participants with inflammatory bowel disease (IBD) and CDI.24 A total of 44 participants had IBD (ulcerative colitis, 23; Crohn’s disease, 18; and non-characterized IBD, 3). Given that overall recurrent CDI results were similar for the bezlotoxumab and the actoxumab plus bezlotoxumab groups, these groups were pooled (bezlotoxumab group); similarly, the actoxumab and placebo groups were pooled (no bezlotoxumab group).

This meant that 28 IBD subjects received bezlotoxumab, while 16 were in the no-bezlotoxumab group (14 completed the study). There was a trend toward a reduced rate of initial clinical cure in IBD participants in the bezlotoxumab group versus the no-bezlotoxumab group (53.6% vs 81.3%). During a 12-week follow-up period, there was a trend toward less recurrent CDI in the bezlotoxumab

group (26.7% vs 53.8%), representing a 27.2% absolute reduction (95% CI, –57.9% to 9.6%) in the incidence of recurrent CDI in participants with IBD. These data show promise for a subgroup of CDI patients for whom more evidence is needed about the efficacy of treatment options and justify the need for a prospective randomized study in this cohort with an unmet need.

A post hoc analysis of pooled MODIFY I/II data examined recurrent CDI rates according to the type of C. difficile strain.25 A technique known as restriction endonuclease analysis was used to categorize strains. Using this method, BI strains can be distinguished, and these are similar to the more frequently used term ribotype 027. It was shown that the recurrent CDI rate for BI strains treated with bezlotoxumab was lower than for those in the no-bezlotoxumab group (23.6% vs 43.9%); by comparison, recurrent CDI rates for cases due to non-BI strains were 21.4% versus 36.1%, respectively.

In a real-world study, 71% of 46 patients remained recurrence-free for 3 months after bezolotoxumab.

Source: Eur J Clin Microbiol Infect Dis. 2019;38(10):1947-1952.

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2020

35

IDSE Review

Pipeline Antibiotics for CDI Noting the recent demise of surotomycin (Merck) and cadazolid (Actelion) after disappointing results in pivotal phase 3 clinical trials, there are now very few remaining novel agents in the investigational pipeline of CDI therapeutics.26-30 The only remaining late-stage (phase 3) antibiotic for CDI treatment is ridinilazole (SMT19969; Summit Therapeutics), a novel, nonabsorbable, very narrow-spectrum antimicrobial.31-35 The efficacy and safety of ridinilazole were established in healthy patients and in a recently reported phase 2, randomized, double-blind trial (CoDIFy) comparing 10 days of therapy with 200 mg of oral ridinilazole twice daily or 125 mg of oral vancomycin 4 times daily.33 Ridinilazole had a superior sustained clinical response rate (66.7%) compared with vancomycin (42.4%). The very narrow spectrum of activity and, therefore, relative avoidance of further gut microbiome dysbiosis associated with ridinilazole likely contributes significantly to its high efficacy.34,35 Phase 3 clinical trials of ridinilazole versus vancomycin have been in progress since early 2019.

Three other investigational agents to treat CDI have reached the phase 2 clinical trial stage: CRS3123 (Crestone) is a novel diaryldiamine that targets methionyl-tRNA synthetase. A phase 2 randomized, double-blind trial of this agent is due to start shortly.36 DNV383714/DNV3681 (also known as MCB383714/MCB3681; Deinove) is an oxazolidinoneâ&#x20AC;&#x201C;quinolone hybrid (similar to cadazolid).

This intravenous (IV) prodrug of DNV3681 has completed a phase 1 trial,37 and has started a 2-part, phase 2, open-label trial (NCT03824795). Ibezapolstat (Acurx; formerly known as ACX-362E) is a poorly absorbed oral antibiotic that inhibits DNA polymerase IIIC (pol IIIC) of C. difficile. The results of a phase 1 trial were published recently,38 and a phase 2, open-label study has commenced (NCT04247542). It remains too soon to know how effective these agents will be, but it is promising to have 3 candidate treatment options in the phase 2 stage, in addition to ridinilazole in phase 3.

In addition, it is likely that new options may soon become available for the management of patients with recurrent CDI that are based on FMT or substitute versions thereof. Notably, Seres recently announced very positive results from its phase 3 clinical trial of SER-109 (NCT03183128), an oral,

36

IDSE.NET

biologically derived microbiome therapeutic, which met its primary end point in the treatment of patients with recurrent CDI. There was a highly statistically significant 30.2% absolute reduction in the rate of (further) CDI recurrence relative to placebo.39 Also, Rebiotix and Ferring Pharmaceuticals recently announced positive preliminary findings from their ongoing pivotal phase 3 trial of an investigational microbiome-based treatment, RBX2660. 40 The ongoing RBX2660 pivotal phase 3 trial, PUNCH CD3, is a multicenter, randomized, double-blind, placebo-controlled study (NCT03244644). RBX2660 has been granted fast track, orphan drug, and breakthrough therapy designations from the FDA. Updating IDSA Guidelines on CDI Treatment A treatment-focused update of the 2017 IDSA CDI guideline is underway; the 2017 guideline (published in 2018) was limited to evidence published up to the end of 2016.4 Thus, evidence on CDI therapeutics published since 2016 will be reviewed for the update, which is hoped to be available in late 2020.

References 1. Johnson S, Louie TJ, Gerding DN, et al. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014;59(3):345-354.

2. Nelson RL, Suda KJ, Evans CT. Antibiotic treatment for Clostridium difficile-associated diarrhoea in adults. Cochrane Database Syst Rev. 2017;3:CD004610.

3. Vardakas KZ, Polyzos KA, Patouni K, et al. Treatment failure and recurrence of Clostridium difficile infection following treatment with vancomycin or metronidazole: a systematic review of the evidence. Int J Antimicrob Agents. 2012;40(1):1-8.

4. McDonald LC, Gerding DN, Johnson S, et al. Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clin Infect Dis. 2018;66(7):e1-e48.

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

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

7. Goldenberg SD, Brown S, Edwards L, et al. The impact of the introduction of fidaxomicin on the management of Clostridium difficile infection in seven NHS secondary care hospitals in England: a series of local service evaluations. Eur J Clin Microbiol Infect Dis. 2016;35(2):251-259.

8. Guery B, Menichetti F, Anttila VJ, et al. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection in patients 60 years and older (EXTEND): a randomised, controlled, open-label, phase 3b/4 trial.

Lancet Infect Dis. 2018;18(3):296-307.

9. Chilton CH, Crowther GS, Todhunter SL, et al. Efficacy of alternative fidaxomicin dosing regimens for treatment of simulated Clostridium difficile

10. Best EL, Freeman J, Wilcox MH. Models for the study of Clostridium difficile infection. Gut Microbes. 2012;3(2):145-167.

11. Chilton CH, Crowther GS, Freeman J, et al. Successful treatment of simulated Clostridium difficile infection in a human gut model by fidaxomicin first line and after vancomycin or metronidazole failure. J Antimicrob Chemother. 2014;69(2):451-462.

12. European Medicines Agency. DIFICLIR Public Assessment Report. 22 September 2011. https://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002087/ WC500119707.pdf

28. Chilton CH, Crowther GS, Baines SD, et al. In vitro activity of cadazolid against clinically relevant Clostridium difficile isolates and in an in vitro gut model of C. difficile infection. J Antimicrob Chemother.

2014;69(3):697-705.

29. Gehin M, Desnica B, Dingemanse J. Minimal systemic and high faecal exposure to cadazolid in patients with severe Clostridium difficile infection.

Int J Antimicrob Agents. 2015;46(5):576-581.

30. Baldoni D, Gutierrez M, Timmer W, et al. Cadazolid, a novel antibiotic with potent activity against Clostridium difficile: safety, tolerability and pharmacokinetics in healthy subjects following single and multiple oral doses.

J Antimicrob Chemother. 2014;69(3):706-714.

13. Chilton CH, Crowther GS, Ashwin H, et al. Association of fidaxomicin with C. difficile spores: effects of persistence on subsequent spore recovery, outgrowth and toxin production. PLoS One. 2016;11(8):e0161200.

31. Goldstein EJ, Citron DM, Tyrrell KL, et al. Comparative in vitro activities of SMT19969, a new antimicrobial agent, against Clostridium difficile and 350 gram-positive and gram-negative aerobic and anaerobic intestinal flora isolates. Antimicrob Agents Chemother. 2013;57(10):4872-4876.

14. Cornely OA, Vehreschild MJGT, Adomakoh N, et al. Extended-pulsed fidaxomicin versus vancomycin for Clostridium difficile infection: EXTEND study subgroup analyses. Eur J Clin Microbiol Infect Dis. 2019;38(6):1187-1194.

32. Vickers R, Robinson N, Best E, et al. A randomised phase 1 study to investigate safety, pharmacokinetics and impact on gut microbiota following single and multiple oral doses in healthy male subjects of SMT19969, a novel agent for Clostridium difficile infections. BMC Infect Dis. 2015;15:91.

15. Freeman J, Vernon J, Pilling S, et al. Five-year Pan-European, longitudinal surveillance of Clostridium difficile ribotype prevalence and antimicrobial resistance: the extended ClosER study. Eur J Clin Microbiol Infect Dis 2020;39(1):169-177.

33. Vickers RJ, Tillotson GS, Nathan R, et al. Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Lancet Infect Dis. 2017;17(7):735-744.

16. Wilcox MH, Gerding DN, Poxton IR, et al; MODIFY I and MODIFY II Investigators. Bezlotoxumab for prevention of recurrent Clostridium difficile infection. N Engl J Med. 2017;376:305-317.

34. Chang J, Kane A, McDermott L, et al. Ridinilazole preserves major components of the intestinal microbiota during treatment of Clostridium difficile infection. Presented at: ECCMID 2016; April 9-12, 2016; Amsterdam, Netherlands. Abstract LB-116.

17. Prabhu VS, Cornely OA, Golan Y, et al. Thirty-day readmissions in hospitalized patients who received bezlotoxumab with antibacterial drug treatment for Clostridium difficile infection.

Clin Infect Dis. 2017;65(7):1218-1221.

18. Kelly CP, Poxton IR, Shen J, et al. Effect of endogenous Clostridioides difficile toxin antibodies on recurrence of C. difficile infection.

Clin Infect Dis. 2019. pii: ciz809. doi: 10.1093/cid/ciz809 19. Wilcox MH, Rahav G, Dubberke ER, et al. Influence of diagnostic method on outcomes in phase 3 clinical trials of bezlotoxumab for the prevention of recurrent Clostridioides difficile infection: a post hoc analysis of MODIFY I/II. Open Forum Infect Dis. 2019;6. pii: ofz293.

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

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

22. Oksi J, Aalto A, Säilä P, et al. Real-world efficacy of bezlotoxumab for prevention of recurrent Clostridium difficile infection: a retrospective study of 46 patients in five university hospitals in Finland. Eur J Clin Microbiol Infect Dis. 2019;38(10):1947-1952.

23. FDA. Minutes of the Antimicrobial Drugs Advisory Committee, June 9, 2016. Acessed November 30, 2020. https://www.fda.gov/ media/99345/download 24. Kelly CP, Wilcox MH, Glerup H, et al. Bezlotoxumab for Clostridium difficile infection complicating inflammatory bowel disease. Gastroenterology.

2018;155(4):1270-1271.

25. Johnson S, Citron DM, Gerding DN, et al. Efficacy of bezlotoxumab in trial participants infected with Clostridioides difficile strain BI associated with poor outcomes. Clin Infect Dis. 2020. In press. doi: 10.1093/cid/ ciaa1035 26. Boix V, Fedorak RN, Mullane KM, et al. Primary outcomes from a phase 3, randomized, double-blind, active-controlled trial of surotomycin in subjects with Clostridium difficile infection. Open Forum Infect Dis. 2017;19(4):ofw275.

27. Deshpande A, Hurless K, Cadnum JL, et al. Effect of surotomycin, a novel cyclic lipopeptide antibiotic, on intestinal colonization with vancomycinresistant enterococci and Klebsiella pneumoniae in mice. Antimicrob Agents Chemother. 2016;60(6):3333-3339.

IDSE Review

infection in an in vitro human gut model. J Antimicrob Chemother.

2015;70(9):2598-2607.

35. Chang J, Kane A, Snydman D. Ridinilazole preserves major components of the intestinal microbiota during treatment of Clostridium difficile infection. Presented at: ASM Microbe 2016; June 16-20, 2016; Boston, MA. Abstract LB-116.

36. Business wire. Crestone, Inc. (Boulder) secures BIH Funding for phase 2 clinical rial of novel antibiotic candidate. September 12, 2019. Accessed November 30, 2020. http://www.businesswire.com/news/home/20190912005834/ en/Crestone-Boulder-Secures-NIH-Funding-Phase-2 37. Dalhoff A, Rashid M-U, Kapsner T, et al. Analysis of effects of MCB3681, the antibacterially active substance of prodrug MCB3837, on human resident microflora as proof of principle. Clin Microbiol Infect.

2015;21(8):767.e1-767.e4.

38. Garey KW, Begum K, Lancaster C, et al. A randomized, double blind, placebo controlled, single and multiple ascending dose phase 1 study to determine the safety, pharmacokinetics and food and faecal microbiome effects of ibezapolstat administered orally to healthy subjects.

J Antimicrob Chemother. 2020 Sep 6. [Epub ahead of print]. doi: 10.1093/jac/dkaa364 39. Businesswire. Seres Therapeutics announces positive topline results from SER-109 phase 3 ECOSPOR III study in recurrent C. difficile infection. August 10, 2020. Accessed September 21, 2020. http://www.businesswire.com/news/home/20200810005194/en/ Seres-Therapeutics-Announces-Positive-Topline-Results-from-SER109-Phase-3-ECOSPOR-III-Study-in Recurrent-C.-difficile-Infection 40. Rebiotix and Ferring announce world’s first with positive preliminary pivotal phase 3 data for investigational microbiome-based therapy RBX2660.

Accessed November 30, 2020. https://www.ferringusa.com/press/ rebiotix-and-ferring-announce-worlds-first-with-positive-preliminary-pivotalphase-3-data-for-investigational-microbiome-based-therapy-rbx2660/

About the Author Mark H. Wilcox, MD, FRCPath, is the lead on CDI for Public Health England, and an expert advisor to National Health Service Improvement on infection prevention and control in the United Kingdom.

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2020

37

The key to optimal therapy.

Unlock better antimicrobial stewardship with comprehensive results from BioFire.

Pneumonia is the leading cause of sepsis,1 and relying on slow and insensitive culture alone can shut the doors to effective antimicrobial stewardship. Unlock optimal therapy by using the BioFire® FilmArray® Pneumonia (PN) Panel and the BioFire® Blood Culture Identification 2 (BCID2) Panel to identify pathogens from lower respiratory specimens and positive blood cultures in about an hour. With rapid and reliable results from BioFire, you can open your stewardship program up to better patient outcomes.

BioFire PN Panel

1 Test. 33 Targets. ~1 Hour.

Overall 96.3% Sensitivity and 97.2% Specificity2

The BioFire PN Panel identifies the most common causes of lower respiratory tract infections by detecting 33 targets, including bacteria, viruses, and antimicrobial resistance genes.

BioFire BCID2 Panel

1 Test. 43 Targets. ~1 Hour.

Overall 99% Sensitivity and 99.8% Specificity3

The BioFire BCID2 Panel tests for 43 of the most common gram-positive bacteria, gramnegative bacteria, yeast, and antimicrobial resistance genes—all in a single test.

biofiredx.com

BFR0001-0713-01

1. Novosad SA, Sapiano MR, Grigg C, et al. Vital Signs: Epidemiology of Sepsis: Prevalence of Health Care Factors and Opportunities for Prevention. MMWR Morb Mortal Wkly Rep 2016;65:864–869.

2. The stated performance is the aggregate of the prospective data from the clinical study for the BioFire® Filmarray® Pneumonia (PN) Panel.

3. The stated performance is the aggregate of the prospective data from the clinical study for the BioFire® Blood Culture Identification 2 (BCID2) Panel.

IDSE Review

Rapid Diagnostics Revolutionize Management Of Hospital Infections

BY MAYA BEGANOVIC, PHARMD, MPH, BCIDP, AND SARAH M. WIECZORKIEWICZ, PHARMD, FIDSA, BCPS, BCIDP

A

ccurate and timely administration of antimicrobial agents in hospitalized patients, specifically critically ill patients with sepsis, is essential to prevent mortality.1-2 Rapid diagnostic tests (RDTs) have revolutionized the treatment of these patients, becoming one of the most powerful tools for antimicrobial stewardship programs (ASPs). Although routinely used laboratory methods, such as Gram stains, can provide helpful guidance in some clinical circumstances (eg, stopping gram-positive coverage when a gram-negative organism is identified for a generally monomicrobial infection), they do not predict antimicrobial susceptibility patterns, and often result in prolonged use of unnecessarily broad-spectrum antimicrobials or—even more concerning—ineffective therapy. RDTs provide actionable details, such as the ability to predict patterns through the use of local antibiograms, knowledge of intrinsic resistance, and genotypic resistance marker detection when available.

The impact of RDTs can be largely attributed to reduced duration of empiric antimicrobial therapy. Prolonged broadspectrum empiric therapy can lead to an increased burden of Clostridioides difficile infection, antimicrobial resistance, and adverse events (eg, acute kidney injury). In addition, erroneous empiric antimicrobial coverage can detrimentally delay effective therapy and lead to dramatic increases in mortality among critically ill patients.1-8 In fact, a recent study found delays in therapy as more important for mortality than multidrug resistance (MDR) among patients with carbapenemresistant and carbapenem-susceptible Enterobacteriaceae infections.7 However, MDR was identified previously as an independent predictor of delays in time to

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2020

39

IDSE Review

effective therapy (TTET), likely as a result of providing inadequate empiric coverage,9 highlighting the need for RDTs with either genotypic resistance marker detection or rapid antimicrobial susceptibility testing (AST) for geographic areas with problematic multidrug-resistant organisms (MDROs). When combined with ASPs, RDTs demonstrate substantial benefit on patient outcomes, including mortality10 and attributable cost.11 With many RDT options available, diagnostic stewardship is an essential component of ASPs enabling the teams to select the right test, for the right patient, at the right time.12 Furthermore, practical concerns for specific sites should be considered by the ASP, ideally comprising a multidisciplinary group that includes infectious disease physicians and pharmacists, microbiologists, nurses, infection preventionists, information technology specialists, and hospital epidemiologists.13 Global considerations to assess when choosing RDT platforms include, but are not limited to, institutional or regional problem pathogens, the patient population served (ie, pediatric, adult, and/or geriatric; immunocompromised vs general community), laboratory hours, location (ie, centralized or decentralized), operations and workflow, and leadership support. Specific practical considerations for FDAcleared RDTs are outlined in the Table.

Barriers to RDT implementation, and solutions that are justified by the CDC core elements of leadership commitment, accountability, pharmacy expertise (previously drug expertise), action, tracking, reporting, and education have been described.14 This article provides a clinically practical overview for selecting RDTs for infectious syndromes, including bloodstream infections (BSIs), respiratory tract infections (RTIs), central nervous system (CNS) infections, and gastrointestinal infections.

Blood Rapid blood culture identification technologies are one of the most commonly used RDTs, and are endorsed by the Infectious Diseases Society of America (IDSA) guidelines for implementing ASPs to optimize antimicrobial use.13 This endorsement is supported by a substantial number of studies that demonstrate ASPs combined with molecular RDTs have favorable clinical outcomes, including a significant reduction in mortality in a meta-analysis of 31 mostly quasi-experimental studies.10,15-23 Available

40

IDSE.NET

technologies identify organisms through genotypic (eg, nucleic acid amplification) and/or phenotypic (eg, biochemical assays, mass spectrometry, nuclear magnetic resonance [NMR] spectrometry) methods. FDA-cleared rapid assays from various manufacturers include peptic nucleic acid fluorescent in situ hybridization, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), polymerase chain reaction (PCR), multiplex PCR panels, nanoparticle probe technology, and NMR. Although most RDTs require organism isolation before identification, and previously included none or minimal genotypic resistance testing, this strategy is rapidly evolving with the need to further close the gap between broad-spectrum empiric and targeted therapy.

This evolution is exemplified by the T2 Magnetic Resonance (T2MR) technology by T2 Biosystems that can detect the presence of organisms directly from a whole blood specimen without prior isolation. T2Candida, T2Bacteria, and T2Resistance are rapid detection panels that use this strategy. Of note, T2Resistance is not available for clinical use in the United States but has been granted â&#x20AC;&#x153;breakthrough deviceâ&#x20AC;? designation by the FDA in response to combating resistant infections, and will be useful among immunocompromised patients, as well as patients or regions with a high burden of MDROs. It can identify gram-negative markers including KPC, OXA-48, NDM/VIM/IMP, CTX-M, and 14/15AmpC (CMY/DHA), as well as gram-positive markers including vanA/B and mecA/C. T2Bacteria and T2Candida are FDA-cleared, commercially available assays that use a miniaturized MR diagnostic technique that assesses the reaction of water molecules in the presence of magnetic fields, and can detect various targets in 3 to 5 hours.24 Candidemia mortality rates are as high as 30% to 40%, and increase by approximately 50% each day therapy is delayed.24 This is concerning, as prompt antifungal initiation can be inadvertently missed, given the overall sensitivity of blood cultures in diagnosing invasive candidiasis is around 50%.25 The T2Candida assay can be incredibly useful in facilities with high rates of fungal infections (eg, immunocompromised patient population), as it not only

RDTs can greatly reduce the duration of empiric antimicrobial therapy.

IDSE Review

detects organisms at densities of 1 colony-forming unit (CFU)/mL compared with 100 to 1,000 CFU/ mL required for PCR-based detection,24 but also has the ability to substantially reduce TTET once detected.26 In fact, patients with positive blood cultures identified by T2Candida noted a 27-hour reduction in time to appropriate antifungal therapy (P=0.01).27 Conversely, ASPs can use negative tests to shorten antifungal therapy. Previous data demonstrate this can be associated with a 4.3-day reduction in micafungin use resulting in cost savings of $48,440 on antifungals.27 The T2Bacteria assay uses multiplex detection to identify common ESKAPE organisms (ie, Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Escherichia coli) that pose particular problems due to their propensity for MDR.28,29 In a performance assessment study, the T2Bacteria assay identified organism species in 3.61±0.2 to 7.7±1.38 hours, with a per-patient sensitivity of 90% (95% CI, 76%-96%), specificity of 90% (95% CI, 88%91%), and negative predictive value of 99.7% for proven BSIs.29 Given previous benefit of RDTs including reductions in TTET, time to optimal therapy, mortality, and the observation of ASP intervention being an independent predictor of survival in MDR infections, 30 the T2Bacteria assay is expected to demonstrate favorable clinical outcomes.

While T2MR technology reduces time to organism identification by elimination of the need for prior organism isolation, other technologies target rapid phenotypic AST to prevent delays in therapy and avoid prolonged unnecessarily broad-spectrum therapy. One such technology is the Accelerate Pheno

system (Accelerate Diagnostics), which uses rapid phenotypic methods to provide AST within 7 hours.

Conventional identification with AST can take as long as 90 hours.31 This is particularly important when clinicians are concerned about prolonged exposure of insufficient antimicrobial concentrations (eg, patients with unpredictable pharmacokinetics/pharmacodynamics, augmented renal clearance, or pathogens with a high minimum inhibitory concentration), as inappropriate exposure can result in poor outcomes.32,33 A recent multicenter, randomized controlled trial comparing rapid identification plus phenotypic AST (RAPID; Accelerate Pheno) with standard of care (SOC; MALDI-TOF MS) plus AST using broth microdilution or agar dilution was conducted in patients with gram-negative BSIs.34 The primary outcome measured was time to first antimicrobial modification within 72 hours of randomization. First antimicrobial modification was 6.3 hours faster in the RAPID group compared with the SOC group for overall antimicrobials (median [interquartile range], 8.6 [2.6-27.6] hours vs 14.9 [3.3-41.1] hours; P=0.02), and 24.8 hours faster for antimicrobials targeted against gram-negative organisms (median [interquartile range], 17.3 [4.9-72] hours vs 42.1 [10.1-72] hours; P<0.001).

Among a subset of 40 patients in the RAPID group and 44 in the SOC group with resistant organisms, time to antimicrobial escalation was 43.3 hours faster in the RAPID group than the SOC group (P=0.01), while no difference was observed in deescalations. Although the study authors report no significant differences in clinical outcomes, such as length of stay (LOS) and mortality, the ability to escalate therapy more rapidly and reduce time to effective therapy is clinically meaningful nonetheless.34 One recent quasi-experimental study of 830 bacteremic cases, however, has demonstrated a shorter median LOS (6.3-6.6 days vs 8.1. days) when the Accelerate Pheno is used paired with or without real-time notification when compared with historical controls lacking rapid diagnostics or antimicrobial stewardship intervention.35 Overall, rapid blood culture identification systems demonstrate a substantial benefit when paired with ASPs for both clinical and economic outcomes.10,11 In fact, probabilistic analyses of RDTs combined with ASPs show an 80% chance of being cost-effective versus a 41% chance without ASPs.11 These data suggest RDTs should be the SOC across all hospitals INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2020

41

42

IDSE.NET

mPCR

PCR

PNA-FISH

Technology Type

C. albicans, C. glabrata, Candida krusei, Candida parapsilosis, Candida tropicalis None

Yeast Traffic Light (AdvanDx)

mecA XpressFISH

FilmArray BCID (BioFire Diagnostics)

A. baumannii, C. albicans, C. glabrata, C. krusei, C. parapsilosis, C. tropicalis, E. coli, Enterobacter cloacae complex, Enterobacteriaceae, Enterococcus species, Haemophilus influenzae, Klebsiella oxytoca, K. pneumoniae, Listeria monocytogenes, Proteus species, P. aeruginosa, Neisseria meningitidis, S. marcescens, Staphylococcus species, S. aureus, Streptococcus species, Streptococcus agalactiae, Streptococcus pneumoniae, Streptococcus pyogenes

S. aureus

E. coli, Klebsiella pneumoniae, P. aeruginosa

Gram-negative QuickFISH (AdvanDx)

StaphSR (BD GeneOhm)

E. faecalis, E. faecium, Enterococcus species

Enterococcus QuickFISH (AdvanDx)

S. aureus

CoNS

Staphylococcus QuickFISH (AdvanDx)

Xpert MRSA/SA BC (Cepheid)

Staphylococcus aureus, Staphylococcus lugdunensis, CoNS, Enterococcus faecalis, Enterococcus faecium, Streptococcus species, Escherichia coli, Klebsiella species, Enterobacter species, Proteus species, Citrobacter species, Serratia marcescens, Pseudomonas aeruginosa, Acinetobacter baumannii, Candida albicans, Candida glabrata

Organisms on Panel

Accelerate Pheno (Accelerate Diagnostics)

Example Systems (Manufacturer)

1h

2h

1h

20 min

90 min

20 min

20 min

20 min

~1.5 h to identify, and 7 h to antimicrobial susceptibility

Blood Cultures

Detection Time

mecA, vanA/B, KPC

mecA

SCCmec, mecA

mecA

None

None

None

None

MRSA and macrolide-lincosamidestreptogramin B phenotypically reported

Resistance Detection

Table. Selected FDA-Approved Rapid Diagnostic Tests and Clinical Practice Considerations62,a

• Identifies polymicrobial infections that may be missed by other technologies

• Multiple primers allow for identification of multiple organisms

• Comprehensive number of targets

• Limited number of targets

• Prompt differentiation between MRSA and MSSA can facilitate faster TTET

• May miss MRSA with non-mecA resistance

• Prompt identification of MRSA

• Useful for hospitals with high fungal infections (eg, immunocompromised)

• Useful among community hospitals with low resistance rate

• Limited number of targets per panel

• Limited number of targets per panel

• Previously associated with reduction in LOS in CoNSpositive cultures, and reduced TTET in enterococcal bacteremia

• Unreliable MIC for bacteria with multiple morphologies or polymicrobial infections

• Ability to rapidly detect resistance patterns

• Potential benefit for patients requiring rapid PK/PD dose adjustments (eg, augmented renal clearance)

Practical Considerations for Clinical Practice

IDSE Review

43

3-5 h 3-5 h

E. faecium, S. aureus, K. pneumoniae, P. aeruginosa, E. coli C. albicans, C. tropicalis, C. krusei, C. glabrata, C. parapsilosis

T2Bacteria

T2Candida

mecA/C, vanA/B

None

mecA, vanA/B

CTX-M, IMP, KPC, NDM, OXA, VIM

None

None

CTX-M, IMP, KPC, NDM, OXA (OXA-23 and OXA-48), VIM

mecA, mecC, vanA, vanB

Can reduce TTET and unnecessary antimicrobial utilization Unreliable for detection in polymicrobial bacteremia

continued on page 26

• Detects presence of organisms directly from blood specimen (ie, prior isolation not required) substantially expediting time to identification • Low limit of detection can detect positive blood cultures missed by standard testing • Limited targets detected with separate resistance panel that is not yet clinically available

•

•

• Ability to detect a vast array of bacterial and fungal microbes • Useful for facilities with patients at risk for uncommon infections (eg, immunocompromised population, transplant centers) • Lacks ability to detect resistance markers or provide susceptibility reports

• Identifies polymicrobial infections that may be missed by other technologies

• Gram-positive and gram-negative panels contain pan targets to ensure organism inclusivity

• Most comprehensive organism and resistance detection panels currently available on the market

ASP, antimicrobial stewardship program; CNS, central nervous system; CoNS, coagulase-negative staphylococci; GI, gastrointestinal; LOS, length of stay; MALDI-TOF, matrix-assisted laser desorption/ ionization time of flight; MIC, minimum inhibitory concentration; mPCR, multiplex polymerase chain reaction; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible S. aureus; NMR, nuclear magnetic resonance; PK/PD, pharmacokinetic/pharmacodynamic; PNA-FISH, peptic nucleic acid fluorescent in situ hybridization; TTET, time to effective therapy

Not an all-inclusive list. Table adapted and refined from ref 61.

a

2.5 h

S. aureus, S. epidermidis, S. lugdunensis, S. anginosus, S. agalactiae, S. pneumoniae, S. pyogenes, E. faecalis, E. faecium

Verigene BC-GP (Luminex)

NMR

2.5 h

Acinetobacter species, Citrobacter species, E. coli, Enterobacter species, K. oxytoca, K. pneumoniae, P. aeruginosa, Proteus species

Verigene BC-GN (Luminex)

30 min

Nanoparticle probe technology

All organisms

1.5 h

C. albicans, Candida auris, Candida dubliniensis, Candida famata, C. glabrata, Candida guilliermondii, Candida kefyr, C. krusei, Candida lusitaniae, C. parapsilosis, C. tropicalis, Cryptococcus gattii, Cryptococcus neoformans, Fusarium, Rhodotorula

ePlex BCID-FP panel (GenMark Diagnostics)

MALDI-TOF (bioMérieux and Brucker)

1.5 h

A. baumannii, Bacteroides fragilis, Citrobacter, Cronobacter sakazakii, Enterobacter (non-cloacae complex), E. cloacae complex, E. coli, Fusobacterium nucleatum, Fusobacterium necrophorum, H. influenzae, K. oxytoca, K. pneumoniae group, Morganella morganii, N. meningitidis, Proteus, Proteus mirabilis, P. aeruginosa, Salmonella, Serratia, S. marcescens, Stenotrophomonas maltophilia Pan targets: Pan gram-positive and Pan Candida

ePlex BCID-GN panel (GenMark Diagnostics)

MALDI-TOF

1.5 h

Bacillus cereus group, Bacillus subtilis group, Corynebacterium, Cutibacterium acnes, Enterococcus, E. faecalis, E. faecium, Lactobacillus, Listeria, L. monocytogenes, Micrococcus, Staphylococcus, S. aureus, Staphylococcus epidermidis, S. lugdunensis, Streptococcus, S. agalactiae (GBS), Streptococcus anginosus group, S. pneumoniae, S. pyogenes (GAS) Pan targets: Pan gram-negative and Pan Candida

ePlex BCID-GP panel (GenMark Diagnostics)

IDSE Review

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2020

44

IDSE.NET

Example Systems (Manufacturer)

mPCR

Gastrointestinal

mPCR

Detection Time

Campylobacter species (jejuni, coli, upsaliensis), Clostridioides difficile (toxin A/B), Plesiomonas shigelloides, Salmonella species, Yersinia enterocolitica, Vibrio species (parahaemolyticus, vulnificus), Vibrio cholerae, enteroaggregative E. coli, enteropathogenic E. coli, enterotoxigenic E. coli, Shigalike toxin–producing E. coli stx1/stx2, E. coli 0157, Shigella/enteroinvasive E. coli, adenovirus F 40/41, astrovirus, norovirus GI/GII, rotavirus A, Sapovirus (I, II, IV, V), Cryptosporidium, Cyclospora cayetanensis, Entamoeba histolytica, Giardia lamblia Campylobacter species ( jejuni, coli, lari), C. difficile toxin A/B, enterohemorrhagic E. coli, enterotoxigenic E. coli, E. coli O157, Salmonella species, Shigella species (boydii, sonnei, flexneri, dysenteriae), Vibrio species (cholerae), Y. enterocolitica (not in US), adenovirus F40/41, norovirus GI/GII, rotavirus A, Cryptosporidium species (parvum, hominis), E. histolytica, G. lamblia Campylobacter group, Salmonella species, Shigella species, Vibrio group, Yersinia enterocolitica, Shiga toxin 1 (stx1), Shiga toxin 2 (stx2), norovirus, rotavirus Rotavirus, astrovirus, adenovirus

xTAG GPP (Luminex Corporation)

VERIGENE Enteric Pathogens Test in the Gastro (Luminex)

InGenius Gastrointestinal Viral Elite Panel (ELITechGroup)

2.5 h

<2 h

5h

1h

1h

Blood Cultures

E. coli (K1 serotype only), H. influenzae, L. monocytogenes, N. meningitidis (encapsulated strains only), S. agalactiae, S. pneumoniae, C. neoformans/gattii, cytomegalovirus, enterovirus, herpes simplex viruses 1 and 2, human herpesvirus 6, human parechovirus, and varicella-zoster virus

Organisms on Panel

FilmArray GP (BioFire Diagnostics)

FilmArray ME (BioFire Diagnostics)

Central Nervous System

Technology Type

None

None

None

None

None

Resistance Detection

Table. Selected FDA-Approved Rapid Diagnostic Tests and Clinical Practice Considerations62,a (continued)

• Consider implementing in high-prevalence units (eg, pediatrics)

• Can detect multiple pathogens; however, the clinical significance to polymicrobial GI infections is unknown

• Should not be used as a test of cure

• Many GI pathogens may be shed asymptomatically for prolonged periods complicating positive results

• Infants and young children <3 y likely test positive for C. difficile due to high rates of colonization; pediatric centers may blind C. difficile results or include clinical decision support to interpret positives in this population with caution

• Cannot differentiate between live and dead organisms

• Not intended to replace traditional diagnostic testing for CNS infections

• Associated with a rapid time to diagnosis of viral infections

• Implementation may be most useful for hospitals with pediatric and neonatal patients

Practical Considerations for Clinical Practice

IDSE Review

45

Adenovirus, coronavirus HKU1, coronavirus NL63, coronavirus 229E, coronavirus OC43, human metapneumovirus, human rhinovirus/enterovirus, influenza A, influenza A/H1, influenza A/H3, influenza A/H1-2009, influenza B, parainfluenza virus 1, parainfluenza Virus 2, Parainfluenza virus 3, parainfluenza virus 4, respiratory syncytial virus, Bordetella pertussis, C. pneumoniae, M. pneumoniae; RP2 panel adds Bordetella parapertussis Adenovirus, coronavirus (229E, HKU1, NL63, OC43), human metapneumovirus, human rhinovirus/enterovirus, influenza A, influenza A H1, influenza A H1-2009, influenza A H3, influenza B, parainfluenza 1, parainfluenza 2, parainfluenza 3, parainfluenza 4, RSV A, RSV B, C. pneumoniae, M. pneumoniae Adenovirus, human metapneumovirus, influenza A, influenza A (subtype H1), influenza A (subtype H3), influenza B, parainfluenza 1, parainfluenza 2, parainfluenza 3, parainfluenza 4, rhinovirus, RSV A, RSV B, Bordetella pertussis, Bordetella parapertussis/B. bronchiseptica, Bordetella holmesii Influenza A, influenza A H1, influenza A H3, influenza B, respiratory syncytial virus A, RSV B, rhinovirus/enterovirus, parainfluenza virus 1, parainfluenza virus 2, parainfluenza virus 3, parainfluenza virus 4, human metapneumovirus, adenovirus, coronavirus HKU1, coronavirus NL63, coronavirus 229E, coronavirus OC43, human bocavirus, Chlamydophila pneumoniae, Mycoplasma pneumoniae

FilmArray RP and RP2 (BioFire Diagnostics)

ePlex Respiratory Pathogen Panel (GenMark Diagnostics)

VERIGENE Respiratory Pathogens Flex Test (Luminex)

NxTAG Respiratory Pathogens Panel (Luminex)

Not an all-inclusive list. Table adapted and refined from reference 61.

Adenovirus, coronavirus, human metapneumovirus, human rhinovirus/enterovirus, influenza A, influenza B, parainfluenza virus, respiratory syncytial virus, Acinetobacter calcoaceticus-baumannii complex, E. cloacae complex, E. coli, H. influenzae, Klebsiella aerogenes, K. oxytoca, K. pneumoniae group, Moraxella catarrhalis, Proteus species, P. aeruginosa, S. marcescens, S. aureus, S. agalactiae, S. pneumoniae, S. pyogenes, Chlamydia pneumoniae, Legionella pneumophila, Mycoplasma pneumoniae

BioFire FilmArray Pneumonia (PN) panel

<3 h

<2 h

90 min

1h

1h

None

None

None

None

mecA/C and MREJ KPC, NDM, Oxa48-like, VIM, IMP, CTX-M

• First pneumonia panel with 15 bacterial isolated and resistance detection capabilities

• In conjunction with procalcitonin, can assist ASP in reducing antimicrobial utilization

• Can rule viral etiologies in or out

• Implementation encouraged in institutions with high rates of inappropriate prescribing for respiratory tract infections

ASP, antimicrobial stewardship program; CNS, central nervous system; CoNS, coagulase-negative staphylococci; GI, gastrointestinal; LOS, length of stay; MALDI-TOF, matrix-assisted laser desorption/ ionization time of flight; MIC, minimum inhibitory concentration; mPCR, multiplex polymerase chain reaction; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible S. aureus; NMR, nuclear magnetic resonance; PK/PD, pharmacokinetic/pharmacodynamic; PNA-FISH, peptic nucleic acid fluorescent in situ hybridization; TTET, time to effective therapy

a

mPCR

Respiratory

IDSE Review

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2020

IDSE Review

and continue to evolve with public health needs to slow the progression of resistance and ensure antimicrobial therapy is optimized.

Karius testing is a blood test based on nextgeneration sequencing of microbial cell-free DNA, allowing it to quantify more than 1,000 clinically relevant pathogens that include viruses, bacteria, fungi, and parasites. It may be useful for patients with severe illness, those who are immunocompromised, and/or those with a lack of pathogen identification after standard attempts via other methodologies.36 Moreover, a prospective pilot study explored the utility of Karius testing as a BSI prediction tool among 47 pediatric patients with relapsed or refractory cancers. Sixteen BSI episodes (15 bacterial) were available for predictive sampling, and a predictive sensitivity of 80% (n= 12/15; 95% CI, 55%-93%) was identified for bacterial BSIs.36 These data suggest that Karius testing may have a future role in enabling prompt intitiation of antimicrobials prior to development of BSI in immunocompromised hosts.

Respiratory Acute RTIs are commonly caused by viral organisms. However, differentiating between viral and bacterial pneumonia is a significant challenge, and often results in unnecessary antimicrobial utilization for viral infections,37 especially when bacterial coinfection cannot be ruled out. To date, no single test exists to make this differentiation, but several RDTs together can assist ASPs in the clinical decision-making process. These tests can include respiratory pathogen (viral/bacterial) panels, methicillin-resistant S. aureus (MRSA) nasal PCR, and biomarker expression (eg, procalcitonin). Procalcitonin is a pro-inflammatory biomarker previously associated with a reduction in antimicrobial therapy for lower RTIs,38 and may be useful for ruling out bacterial coinfections.39 However, a clear cutoff between bacterial and viral pneumonia remains to be elucidated,40 and interpretation is limited among some patient populations (eg, hemodialysis).41 In the future, other promising biomarker approaches assessing host gene expression to categorize acute RTIs as either viral or bacterial may become more readily available for ASPs.42 Nonetheless, when ordering respiratory diagnostic assays, it is important to consider whether the test will affect clinical management. For example, influenza is the only

46

IDSE.NET

respiratory virus for which treatment is available, suggesting identification by nucleic acid amplification testing (NAAT) can facilitate prompt initiation or discontinuation of anti-influenza therapy during influenza season. However, ordering the same test for a mildly ill patient not expected to receive treatment, or during a period of low prevalence, does not provide value. Of note, NAAT is favored over traditional influenza antigenâ&#x20AC;&#x201C;based diagnostic tests, as they are significantly more sensitive, resulting in more accurate and usable results.42 More recently, multiplex PCR panels for respiratory viruses have become more common, and are able to optimize anti-influenza therapy.44 Clinical and economic outcomes vary across respiratory diagnostic studies, largely due to heterogeneity and variability in the quality of currently available data. Nonetheless, reduced antimicrobial utilization with rapid viral panels has been described among pediatric45 and adult patients.46 Overall, respiratory pathogen panels play an important role in RTI diagnostics. Novel bacterial panels have become available, but clinical outcomes have yet to be assessed. The IDSA Diagnostics Committee recently released clinical and diagnostic recommendations for management of acute RTIs.47 When bacterial pneumonia is diagnosed in patients with risk factors for resistance or at high risk for mortality, gram-positive coverage for MRSA is often empirically initiated. Because S. aureus is a pathogen routinely implicated in pneumonia, and a common colonizer of the nares, a MRSA nasal PCR can be used to help discontinue unnecessary vancomycin. A meta-analysis of 22 studies and 5,163 patients identified a positive predictive value of 44.8% and negative predictive value of 96.5% using 10% prevalence,48 indicating a negative result can be particularly useful to rule out MRSA pneumonia thereby decreasing days of vancomycin therapy, especially among patients who are not critically ill. ASPs can utilize a combination of these RDTs in conjunction with a patientâ&#x20AC;&#x2122;s clinical picture to help ensure that those who require antibiotics are treated effectively and those who have solely viral infections are spared unnecessary antimicrobials.

Central Nervous System CNS infections are medical emergencies that are associated with considerable mortality and rapid decline that requires prompt diagnostic identification and antimicrobial administration.49 Diagnostic

IDSE Review

testing for CNS infections is particularly challenging, as more than 20 diagnostic tests exist and various testing combinations are ordered in clinical practice.50 ASPs are incredibly important for such scenarios, as they can help guide medical teams, especially when a limited amount of cerebrospinal fluid (CSF) volume is obtained. Low-volume yield of CSF during lumbar puncture is commonly seen, especially among pediatric patients. Identifying viral etiologies by PCR can facilitate diagnostics, reduce hospital LOS, and reduce duration of unnecessary antimicrobial therapy.51 However, rapid bacterial identification expedites appropriate antimicrobial utilization and improves clinical outcomes.52,53

testing.51 Despite promising potential, the ME panel cannot replace traditional testing methods for ME diagnosis.53,55 It may be particularly helpful in hospitals with high CNS infection prevalence (eg, pediatric and neonatal patients).

Gastrointestinal Infection Cultures Acute gastroenteritis is a leading cause of morbidity and mortality and responsible for an estimated 47.8 million episodes annually in the United States.56,57 Gastroenteritis is characterized by acute onset of diarrhea with or without vomiting and caused by a wide variety of bacteria, viruses, and parasites as well as other noninfectious cases.

Identification of an infectious agent is critical for patient care and infection prevention practices; however, the etiologic pathogen goes unidentified in approximately 80% of cases.56,58,59 Conventional methods of identification (eg, antigen testing, microscopic examinations, and culture) are timeconsuming, expensive, and have limited sensitivity.60 Multiplex PCRâ&#x20AC;&#x201C;based gastrointestinal panels, such as the FilmArray, have emerged as a more rapid and accurate diagnostic tool to diagnose gastroenteritis, although clinical outcomes data are limited. The FilmSource: Emerg Infect Dis. 2011;17(1):16-22.

Array GI panel combines 22 enteric pathogens into a single cartridgebased test with a turnaround time of less than 2 The only clinically used, FDA-approved rapid hours. Assay performance was assessed and dempanel is the BioFire FilmArray meningitis/encephonstrated 100% and 94.5% or higher sensitivity for alitis (ME) panel (BioFire Diagnostics), with a 12/22 and 7/22 targets, respectively, and 97.1% or turnaround time of 1 hour and only 2 minutes of higher specificity for all targets.61 hands-on time. It is a nucleic acidâ&#x20AC;&#x201C;based panel that requires a small volume of CSF (0.2 mL), and Although symptoms are often self-limiting, some has 14 total targets, including E. coli (K1 serotype patients may benefit from antimicrobials and experionly), Haemophilus influenzae, Listeria monocyence delays in therapy due to lengthy testing methtogenes, Neisseria meningitidis (encapsulated ods. Hospitalization and further testing such as strains only), Streptococcus agalactiae, S. pneucolonoscopy or abdominal ultrasonography may moniae, Cryptococcus neoformans/gattii, cytobe required in patients with multiple comorbidities megalovirus, enterovirus, herpes simplex viruses or severe illness pending test results, leading to 1 and 2, human herpesvirus 6, human parechoviunnecessary patient isolation and more extensive rus, and varicella-zoster virus.54 In a study of 1,560 infection prevention practices. Beal et al evaluated the clinical and economic impact of the FilmArray CSF samples, the ME panel established an 84.4% GI panel compared with historical controls using positive and greater than 99% negative agreement traditional stool culture testing methodology.62 The to traditional testing methods.53,55 Additionally, the ME panel results in a faster time to diagnosis by positivity rate of the GI panel was 32.8% compared 10.3 hours compared with pathogen-specific PCR with 6.7% for the historical controls. The GI panel

The etiologic pathogen for gastrointestinal infections goes unidentified in about 80% of cases.

INFECTIOUS DISEASE SPECIAL EDITION â&#x20AC;˘ WINTER 2020

47

IDSE Review

resulted in faster results reported in the electronic health record (8.94 vs 54.75 hours), fewer additional stool tests ordered overall (0.58 vs 3.02 additional tests; P=0.0001), fewer antibiotic days per patient (1.73 [95% CI, 1.41-2.04] and 2.12 [95% CI, 1.89-2.35] days per patient; P=0.06), fewer imaging studies (0.18 vs 0.39 imaging studies per patient; P=0.0002), shorter LOS (5.2±3.2 vs 5.6±3.4 days; P=0.14), and a cost savings of approximately $294 per patient.

A similar rate of positivity was observed in another study comparing the FilmArray GI panel with historical stool culture controls (29.2% vs 4.1%, respectively). Clinical outcomes were also improved with the GI panel; patients were less likely to undergo endoscopy (8.4% vs 9.6%; P=0.008) or abdominal radiology (29.4% vs 31%; P=0.002) and less likely to receive antimicrobials (36.2% vs 40.9%; P<0.001).63 The prevalence of GI coinfection in the United States is not well known compared with developing countries; however, the FilmArray GI panel commonly detects coinfection in up to 32.9%.61-63 This may be because the PCR is not able to differentiate between asymptomatic colonization and infection.

Conclusion The development and implementation of RDTs have significantly augmented ASPs and improved the care for patients with suspected or confirmed infections. When paired with stewardship initiatives, RDTs improve the timeliness and effectiveness of antimicrobial optimization. Although outcomes data are most substantive for BSIs, RTIs, and CNS infections, GI panels are offering advances for patients suffering from these ailments. Awareness of the benefits they may provide, along with a critical assessment of institutional needs, can optimize patient care while minimizing harm associated with inappropriate antimicrobial utilization.

References 1. Rhodes A, Evans L, Alhazzani W, et al. Surviving Sepsis Campaign: International guidelines for the management of sepsis and septic shock: 2016.

Crit Care Med. 2017;45:486-552.

2. Ibrahim EH, Sherman G, Ward S, et al. The influence of inadequate antimicrobial treatment of bloodstream infections on patient outcomes in the ICU setting. Chest. 2000;118(1):146-155.

48

5. Paul M, Kariv G, Goldberg E, et al. Importance of appropriate empirical antibiotic therapy for methicillin-resistant Staphylococcus aureus bacteraemia. J Antimicrob Chemother. 2010;65(12):2658-2665.

6. Paul M, Shani V, Muchtar E, et al. Systematic review and meta-analysis of the efficacy of appropriate empiric antibiotic therapy for sepsis. Antimicrob Agents Chemother. 2010;54(11):4851-4863.

7. Lodise TP, Berger A, Altincatal A, et al. Antimicrobial resistance or delayed appropriate therapy—does one influence outcomes more than the other among patients with serious infections due to carbapenem-resistant versus carbapenem-susceptible Enterobacteriaceae? Open Forum Infect Dis. 2019;6(6):ofz194.

8. Zasowski EJ, Claeys KC, Lagnf AM, et al. Time is of the essence: the impact of delayed antibiotic therapy on patient outcomes in hospital-onset enterococcal bloodstream infections. Clin Infect Dis. 2016;62(10):1242-1250.

9. Beganovic M, Timbrook TT, Wieczorkiewicz SM. Predictors of time to effective and optimal antimicrobial therapy in patients with positive blood cultures identified via molecular rapid diagnostic testing. Open Forum Infect Dis. 2019;6(1):ofy350.

10. Timbrook TT, Morton JB, McConeghy KW, et al. The effect of molecular rapid diagnostic testing on clinical outcomes in bloodstream infections: a systematic review and meta-analysis. Clin Infect Dis. 2017;64(1):15-23.

11. Pliakos EE, Andreatos N, Shehadeh F, et al. The cost-effectiveness of rapid diagnostic testing for the diagnosis of bloodstream infections with or without antimicrobial stewardship. Clin Microbiol Rev. 2018;31(3):e00095-17.

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

13. Barlam TF, Cosgrove SE, Abbo LM, et al. Executive summary: implementing an antibiotic stewardship program: guidelines by the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America. Clin Infect Dis. 2016;62(10):1197-1202.

14. Wenzler E, Timbrook TT, Wong JR, et al. Implementation and optimization of molecular rapid diagnostics in bloodstream infections: a clinical review.

Am J Health Syst Pharm. 2018;75(16):1191-1202.

15. Aitken SL, Hemmige VS, Koo HL, et al. Real-world performance of a microarray-based rapid diagnostic for gram-positive bloodstream infections and potential utility for antimicrobial stewardship. Diagn Microbiol Infect Dis. 2015;81(1):4-8.

16. Wong JR, Bauer KA, Mangino JE, et al. Antimicrobial stewardship pharmacist interventions for coagulase-negative staphylococci positive blood cultures using rapid polymerase chain reaction. Ann Pharmacother.

2012;46(11):1484-1490.

17. Nagel JL, Huang AM, Kunapuli A, et al. Impact of antimicrobial stewardship intervention on coagulase-negative Staphylococcus blood cultures in conjunction with rapid diagnostic testing. J Clin Microbiol.

2014;52(8):2849-2854.

18. Wenzler E, Wang F, Goff DA, et al. An automated, pharmacist-driven initiative improves quality of care for Staphylococcus aureus bacteremia.

Clin Infect Dis. 2017;65(2):194-200.

19. 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):e00189-17.

20. Pogue JM, Heil EL, Lephart P, et al. An antibiotic stewardship program blueprint for optimizing Verigene BC-GN within an Institution: a tale of two cities. Antimicrob Agents Chemother. 2018;62(5):e02538-17.

21. Rivard KR, Athans V, Lam SW, et al. Impact of antimicrobial stewardship and rapid microarray testing on patients with gram-negative bacteremia.

Eur J Clin Microbiol Infect Dis. 2017;36(10):1879-1887.

22. Walker T, Dumadag S, Lee CJ, et al. Clinical impact of laboratory implementation of Verigene BC-GN Microarray-based assay for detection of gram-negative bacteria in positive blood cultures. J Clin Microbiol.

2016;54(7):1789-1796.

3. Kumar A, Ellis P, Arabi Y, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest.

2009;136(5):1237-1248.

23. Huang AM, Newton D, Kunapuli A, et al. Impact of rapid organism identification via matrix-assisted laser desorption/ionization time-of-flight combined with antimicrobial stewardship team intervention in adult patients with bacteremia and candidemia. Clin Infect Dis. 2013;57(9):1237-1245.

4. Kumar A, Roberts D, Wood KE, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med. 2006;34(6):1589-1596.

24. Pfaller MA, Wolk DM, Lowery TJ. T2MR and T2Candida: novel technology for the rapid diagnosis of candidemia and invasive candidiasis. Future Microbiol. 2016;11(1):103-117.

IDSE.NET

26. Wilson NM, Alangden G, Tibbetts RJ, et al. T2 Magnetic Resonance assay improves timely management of candidemia. J Antimicrob Stewardship.

2017;1(1):12-18.

27. Patch ME, Weisz E, Cubillos A, et al. Impact of rapid, culture-independent diagnosis of candidaemia and invasive candidiasis in a community health system. J Antimicrob Chemother. 2018;73(suppl 4):iv27-iv30.

28. De Angelis G, Posteraro B, De Carolis E, et al. T2Bacteria magnetic resonance assay for the rapid detection of ESKAPEc pathogens directly in whole blood. J Antimicrob Chemother. 2018;73(suppl 4):iv20-iv26.

29. Nguyen MH, Clancy CJ, Pasculle AW, et al. Performance of the T2Bacteria Panel for diagnosing bloodstream infections: a diagnostic accuracy study. Ann Intern Med. 2019;170(12):845-852.

30. Perez KK, Olsen RJ, Musick WL, et al. Integrating rapid diagnostics and antimicrobial stewardship improves outcomes in patients with antibioticresistant gram-negative bacteremia. J Infect. 2014;69(3):216-225.

31. Kerremans JJ, Verboom P, Stijnen T, et al. Rapid identification and antimicrobial susceptibility testing reduce antibiotic use and accelerate pathogen-directed antibiotic use. J Antimicrob Chemother.

2008;61(2):428-435.

32. Lodise TP Jr, Lomaestro B, Drusano GL. Piperacillin-tazobactam for Pseudomonas aeruginosa infection: clinical implications of an extendedinfusion dosing strategy. Clin Infect Dis. 2007;44(3):357-363.

33. Roberts JA, Paul SK, Akova M, et al. DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis. 2014;58(8):1072-1083.

34. Banerjee R, Komarow L, Virk A, et al. Randomized trial evaluating clinical impact of RAPid IDentification and susceptibility testing for gram negative bacteremia (RAPIDS-GN). Clin Infect Dis. 2020 May 7. [Epub ahead of print]. doi: 10.1093/cid/ciaa528 35. Dare RK, Lusardi K. Pearson C, et al. Clinical impact of Accelerate Pheno Rapid Blood Culture Detection System in bacteremic patients.

Clin Infect Dis. 2020; ciaa649. http://doi.or/10.1093/cid/ciaa649.

PMID:32463864 36. Goggin KP, Gonzalez-Pena V, Inaba Y, et al. Evaluation of plasma microbial cell-free DNA sequencing to predict bloodstream infection in pediatric patients with relapsed or refractory cancer. JAMA Oncol.

2019;6(4):552-556.

IDSA’s Diagnostics Committee. Clin Infect Dis. 2020 May 5. [Epub ahead of print] 48. Parente DM, Cunha CB, Mylonakis E, et al. The clinical utility of methicillin resistant Staphylococcus aureus (MRSA) nasal screening to rule out MRSA pneumonia: a diagnostic meta-analysis with antimicrobial stewardship implications. Clin Infect Dis. 2018;67(1):1-7.

49. Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis. 2004;39(9):1267-1284.

50. Wootton SH, Aguilera E, Salazar L, et al. Enhancing pathogen identification in patients with meningitis and a negative Gram stain using the BioFire FilmArray Meningitis/Encephalitis panel. Ann Clin Microbiol Antimicrob.

2016;15:26.

51. Messacar K, Breazeale G, Robinson CC, et al. Potential clinical impact of the film array meningitis encephalitis panel in children with suspected central nervous system infections. Diagn Microbiol Infect Dis. 2016;86(1):118-120.

52. Blaschke AJ, Holmberg KM, Daly JA, et al. Retrospective evaluation of infants aged 1-60 days with residual CSF tested using the FilmArray(R) Meningitis/Encephalitis (ME) panel. J Clin Microbiol.

2018;56(7):e00277-18.

53. Leber AL, Everhart K, Balada-Llasat JM, et al. Multicenter evaluation of BioFire FilmArray meningitis/encephalitis panel for detection of bacteria, viruses, and yeast in cerebrospinal fluid specimens. J Clin Microbiol.

2016;54(9):2251-2261.

54. He T, Kaplan S, Kamboj M, et al. Laboratory diagnosis of central nervous system infection. Curr Infect Dis Rep. 2016;18(11):35.

55. Hanson KE, Couturier MR. Multiplexed molecular diagnostics for respiratory, gastrointestinal, and central nervous system infections. Clin Infect Dis. 2016;63(10):1361-1367.

56. Scallan E, Griffin PM, Angulo FJ, et al. Foodborne illness acquired in the United States—unspecified agents. Emerg Infect Dis. 2011;17(1):16-22.

57. Scallan E, Hoekstra RM, Angulo FJ, et al. Foodborne illness acquired in the United States—major pathogens. Emerg Infect Dis. 2011;17(1):7-15.

58. Axelrad JE, Joelson A, Nobel Y, et al. The distribution of enteric infections utilizing stool microbial polymerase chain reaction testing in clinical practice. Dig Dis Sci. 2018;63(7):1900-1909.

59. Axelrad JE, Joelson A, Nobel YR, et al. Enteric infection in relapse of inflammatory bowel disease: the utility of stool microbial PCR testing.

Inflamm Bowel Dis. 2017;23(6):1034-1039.

37. Fleming-Dutra KE, Hersh AL, Shapiro DJ, et al. Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011.

JAMA. 2016;315(17):1864-1873.

60. Riddle MS, DuPont HL, Connor BA. ACG clinical guideline: diagnosis, treatment, and prevention of acute diarrheal infections in adults. Am J Gastroenterol. 2016;111(5):602-622.

38. Schuetz P, Wirz Y, Sager R, et al. Effect of procalcitonin-guided antibiotic treatment on mortality in acute respiratory infections: a patient level metaanalysis. Lancet Infect Dis. 2018;18(1):95-107.

61. Buss SN, Leber A, Chapin K, et al. Multicenter evaluation of the BioFire FilmArray gastrointestinal panel for etiologic diagnosis of infectious gastroenteritis. J Clin Microbiol. 2015;53(3):915-925.

39. Timbrook T, Maxam M, Bosso J. Antibiotic discontinuation rates associated with positive respiratory viral panel and low procalcitonin results in proven or suspected respiratory infections. Infect Dis Ther. 2015;4(3):297-306.

62. Beal SG, Tremblay EE, Toffel S, et al. A gastrointestinal PCR panel improves clinical management and lowers health care costs. J Clin Microbiol. 2017;56(1):e01457-17.

40. Self WH, Balk RA, Grijalva CG, et al. Procalcitonin as a marker of etiology in adults hospitalized with community-acquired pneumonia. Clin Infect Dis. 2017;65(2):183-190.

63. Axelrad JE, Freedberg DE, Whittier S, et al. Impact of gastrointestinal panel implementation on health care utilization and outcomes. J Clin Microbiol. 2019;57(1):e01775-18.

41. Grace E, Turner RM. Use of procalcitonin in patients with various degrees of chronic kidney disease including renal replacement therapy. Clin Infect Dis. 2014;59(12):1761-1767.

42. Tsalik EL, Henao R, Nichols M, et al. Host gene expression classifiers diagnose acute respiratory illness etiology. Sci Transl Med. 2016;8(322):322ra11.

43. Vemula SV, Zhao J, Liu J, et al. Current approaches for diagnosis of influenza virus infections in humans. Viruses. 2016;8(4):96.

44. Green DA, Hitoaliaj L, Kotansky B, et al. Clinical utility of on-demand multiplex respiratory pathogen testing among adult outpatients. J Clin Microbiol. 2016;54(12):2950-2955.

45. Doan Q, Enarson P, Kissoon N, et al. Rapid viral diagnosis for acute febrile respiratory illness in children in the emergency department. Cochrane Database Syst Rev. 2014;(9):CD006452.

46. Brendish NJ, Malachira AK, Armstrong L, et al. Routine molecular pointof-care testing for respiratory viruses in adults presenting to hospital with acute respiratory illness (ResPOC): a pragmatic, open-label, randomised controlled trial. Lancet Respir Med. 2017;5(5):401-411.

47. Hanson KE, Azar MM, Banerjee R, et al. Molecular testing for acute respiratory tract infections: clinical and diagnostic recommendations from the

IDSE Review

25. Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-e50.

64. Beganovic M, McCreary EK, Mahoney MV, et al. Interplay between rapid diagnostic tests and antimicrobial stewardship programs among patients with bloodstream and other severe infections. J Appl Lab Med. 2019;3(4):601-616.

About the Authors Maya Beganovic, PharmD, MPH, BCID, is an infectious diseases and antimicrobial stewardship clinical pharmacy specialist at Advocate Aurora Health and Advocate Children’s Hospital, in Park Ridge, Illinois.

Sarah M. Wieczorkiewicz, PharmD, FIDSA, BCPS, BCIDP, is an infectious diseases clinical specialist in Chicago, Illinois, and has 15 years of clinical experience.

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2020

49

TREATMENT FOR NOSOCOMIAL PNEUMONIA HAS ARRIVED

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

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

Fetroja—the world’s only siderophore cephalosporin—overcomes Gram-negative antibacterial resistance1 INDICATIONS Fetroja® (cefiderocol) is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex.

Fetroja is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens.

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

IMPORTANT SAFETY INFORMATION CONTRAINDICATIONS Fetroja is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of Fetroja.

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

Stable in vitro against all known classes of ϐ-lactamases, including serine-carbapenemases (such as KPC and OXA) and metallo-ϐ-lactamases (such as VIM, IMP, and NDM)1 Active against pathogens with porin channel deletions and efflux pump up-regulation1,3,4 The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with Fetroja than in patients treated with BAT [25/101 (24.8%) vs 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with Fetroja than in patients treated with BAT through Day 49 [34/101 (33.7%) vs 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including non-fermenters such as Acinetobacter baumannii complex, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established.

Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP. Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Hypersensitivity was observed in Fetroja-treated patients in clinical trials. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins.

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

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

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

• Study highlights:

In vitro activity does not necessarily correlate with clinical efficacy.

Enterobacteralesa Overall

Enterobacterales

a

carbapenem-non-susceptible

P aeruginosaa

(n=25,995)

100%

(n=814)

97%

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

98%

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

(n=6213)

Overall

P aeruginosaa

95%

(n=1416)

carbapenem-non-susceptible

A baumannii complexa A baumannii complexa

(n=2274)

S maltophilia b

(n=1565)

carbapenem-non-susceptible

Overall

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

90%

(n=4185)

Overall

85% 100%

(inherently carbapenem-resistant)5,7

0

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

20

40

PERCENT

60

80

100

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

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

IMPORTANT SAFETY INFORMATION (continued) WARNINGS AND PRECAUTIONS (continued) Hypersensitivity Reactions (continued) Before therapy with Fetroja is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactam antibacterial drugs. Discontinue Fetroja if an allergic reaction occurs.

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

Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.

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

• Fetroja exhibited comparable safety vs extended-infusion, high-dose meropenem in HABP/VABP1 Study Design Multicenter, double-blind, parallel-group, randomized, active-controlled Phase 3 study in approximately 300 adults with documented nosocomial pneumonia caused

by Gram-negative bacteria. Subjects were randomized (1:1) to either cefiderocol, 2 grams, administered IV over 3 hours every 8 hours (q8h) or extended-infusion, high-dose meropenem, 2 grams, administered IV over 3 hours q8h. Randomization was performed by the stratified randomization method using their infection diagnosis (HABP, VABP, and HCABP) and Acute Physiology And Chronic Health Evaluation II (APACHE II) score (≤15 and ≥16) as allocation factors. Linezolid was administered for at least 5 days to subjects in both arms to provide coverage for methicillin-resistant Staphylococcus aureus (MRSA), and to maintain the study blind.1,5 CI=confidence interval.

FOR MORE INFORMATION, VISIT

Fetroja.com Seizures and Other Central Nervous System (CNS) Adverse Reactions Cephalosporins, including Fetroja, have been implicated in triggering seizures. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust Fetroja dosing based on creatinine clearance. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether Fetroja should be discontinued.

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

ADVERSE REACTIONS The most common adverse reactions occurring in (≥2%) of patients receiving Fetroja compared to imipenem/cilastatin in the cUTI trial were: diarrhea (4% vs 6%), infusion site reactions (4% vs 5%), constipation (3% vs 4%), rash (3% vs <1%), candidiasis (2% vs 3%), cough (2% vs <1%), elevations in liver tests (2% vs <1%), headache (2% vs 5%), hypokalemia (2% vs 3%), nausea (2% vs 4%), and vomiting (2% vs 1%). The most common adverse reactions occurring in (≥4%) of patients receiving Fetroja compared to meropenem in the HABP/VABP trial were: elevations in liver tests (16% vs 16%), hypokalemia (11% vs 15%), diarrhea (9% vs 9%), hypomagnesemia (5% vs <1%), and atrial fibrillation (5% vs 3%).

Please see a Brief Summary of Prescribing Information on following page.

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

Fetroja is a registered trademark of Shionogi & Co., Ltd. Osaka, Japan. USFET-0209 09/20

FETROJA (cefiderocol) for injection, for intravenous use Initial U.S. Approval: 2019 BRIEF SUMMARY: Please see package insert for full prescribing information.

1

INDICATIONS AND USAGE

1.1 Complicated Urinary Tract Infections (cUTIs), Including Pyelonephritis FETROJA® is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex [see Clinical Studies (14.1) in the full prescribing information].

1.2 Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) FETROJA is indicated in patients 18 years of age or older for the treatment of hospitalacquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens [see Clinical Studies (14.2) in the full prescribing information].

1.3 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of FETROJA and other antibacterial drugs, FETROJA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

4 CONTRAINDICATIONS FETROJA is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of FETROJA [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

5 WARNINGS AND PRECAUTIONS 5.1 Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections An increase in all-cause mortality was observed in patients treated with FETROJA as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically ill patients with carbapenem-resistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin.

The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with FETROJA than in patients treated with BAT [25/101 (24.8%) vs. 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with FETROJA than in patients treated with BAT through Day 49 [34/101 (33.7%) vs. 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including non-fermenters such as Acinetobacter baumannii complex, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established.

Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP. 5.2 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs.

Hypersensitivity was observed in FETROJA-treated patients in clinical trials [see Adverse Reactions (6.1)]. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins.

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

5.4 Seizures and Other Central Nervous System (CNS) Adverse Reactions Cephalosporins, including FETROJA, have been implicated in triggering seizures [see Adverse Reactions (6.1)]. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment.

Adjust FETROJA dosing based on creatinine clearance [see Dosage and Administration (2.2) in the full prescribing information]. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether FETROJA should be discontinued.

5.5 Development of Drug-Resistant Bacteria Prescribing FETROJA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Indications and Usage (1.3)].

6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail in the Warnings and Precautions section: • Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections [see Warnings and Precautions (5.1)] • Hypersensitivity Reactions [see Warnings and Precautions (5.2)] • Clostridioides difficile-associated Diarrhea (CDAD) [see Warnings and Precautions (5.3)] • Seizures and Other Central Nervous System Adverse Reactions [see Warnings and Precautions (5.4)] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Complicated Urinary Tract Infections (cUTIs), Including Pyelonephritis FETROJA was evaluated in an active-controlled, randomized clinical trial in patients with cUTI, including pyelonephritis (Trial 1). In this trial, 300 patients received FETROJA 2 grams every 8 hours infused over 1 hour (or a renally-adjusted dose), and 148 patients were treated with imipenem/cilastatin 1gram/1gram every 8 hours infused over 1 hour (or a renally-adjusted dose). The median age of treated patients across treatment arms was 65 years (range 18 to 93 years), with approximately 53% of patients aged greater than or equal to 65. Approximately 96% of patients were White, most were from Europe, and 55% were female. Patients across treatment arms received treatment for a median duration of 9 days.

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 1, a total of 14/300 (4.7%) cUTI patients treated with FETROJA and 12/148 (8.1%) of cUTI patients treated with imipenem/cilastatin experienced serious adverse reactions. One death (0.3%) occurred in 300 patients treated with FETROJA as compared to none treated with imipenem/cilastatin. Discontinuation of treatment due to any adverse reaction occurred in 5/300 (1.7%) of patients treated with FETROJA and 3/148 (2.0%) of patients treated with imipenem/cilastatin. Specific adverse reactions leading to treatment discontinuation in patients who received FETROJA included diarrhea (0.3%), drug hypersensitivity (0.3%), and increased hepatic enzymes (0.3%).

Common Adverse Reactions Table 4 lists the most common selected adverse reactions occurring in ≥ 2% of cUTI patients receiving FETROJA in Trial 1.

Selected Adverse Reactions Occurring in ≥ 2% of cUTI Patients Receiving FETROJA in Trial 1 FETROJAa Imipenem/Cilastatinb Adverse Reaction (N = 300) (N = 148)

Table 4

Before therapy with FETROJA is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactam antibacterial drugs.

Discontinue FETROJA if an allergic reaction occurs.

Diarrhea

4%

6%

Infusion site reactionsc

4%

5%

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

Constipation

3%

4%

Rashd

3%

< 1%

Candidiasise

2%

3%

Cough

2%

< 1% < 1%

C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy.

CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents.

Elevations in liver testsf

2%

Headache

2%

5%

Hypokalemiag

2%

3% (continued)

Table 4

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

Imipenem/Cilastatinb (N = 148)

Nausea

2%

4%

Vomiting

2%

1%

Adverse Reaction

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

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

Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 2, serious adverse reactions occurred in 54/148 (36.5%) HABP/VABP patients treated with FETROJA and 45/150 (30%) of HABP/VABP patients treated with meropenem. Adverse reactions leading to death were reported in 39/148 (26.4%) patients treated with FETROJA and 35/150 (23.3%) patients treated with meropenem.

Adverse reactions leading to discontinuation of treatment occurred in 12/148 (8.1%) of patients treated with FETROJA and 14/150 (9.3%) of patients treated with meropenem.

The most common adverse reactions leading to discontinuation in both treatment groups were elevated liver tests.

Common Adverse Reactions Table 5 lists the most common selected adverse reactions occurring in ≥ 4% of patients receiving FETROJA in the HABP/VABP trial.

Table 5

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

Meropenemb N = 150

Elevations in liver testsc

16%

16%

Hypokalemiad

11%

15%

Diarrhea

9%

9%

Hypomagnesemia

5%

< 1%

Atrial fibrillation

5%

3%

Adverse Reaction

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

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

Blood and lymphatic disorders: thrombocytopenia, thrombocytosis Cardiac disorders: myocardial infarction, atrial flutter Gastrointestinal disorders: nausea, vomiting, abdominal pain Hepatobiliary disorders: cholecystitis, cholestasis Infections and infestations: C. difficile infection, oral candidiasis Laboratory investigations: prolonged prothrombin time (PT) and prothrombin time international normalized ratio (PT-INR), activated partial thromboplastin time (aPTT) Metabolism and nutrition disorders: hypocalcemia, hyperkalemia Nervous system disorders: seizure Renal and genitourinary disorders: acute interstitial nephritis Respiratory, thoracic, and mediastinal disorders: cough Skin and subcutaneous tissue disorders: rash including rash erythematous 7 DRUG INTERACTIONS 7.1 Drug/Laboratory Test Interactions Cefiderocol may result in false-positive results in dipstick tests (urine protein, ketones, or occult blood). Use alternate clinical laboratory methods of testing to confirm positive tests.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on FETROJA use in pregnant women to evaluate for a drugassociated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Available data from published prospective cohort studies, case series, and case reports over several decades with cephalosporin use in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).

Developmental toxicity studies with cefiderocol administered during organogenesis to rats and mice showed no evidence of embryo-fetal toxicity, including drug-induced fetal malformations, at doses providing exposure levels 0.9 times (rats) or 1.3 times (mice) higher than the average observed in patients receiving the maximum recommended daily dose.

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data Human Data While available studies cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified an association with cephalosporin use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups.

Animal Data Developmental toxicity was not observed in rats at intravenous doses of up to 1000 mg/kg/day or mice at subcutaneous doses of up to 2000 mg/kg/day given during the period of organogenesis (gestation days 6-17 in rats and 6-15 in mice). No treatment-related malformations or reductions in fetal viability were observed. Mean plasma exposure (AUC) at these doses was approximately 0.9 times (rats) and 1.3 times (mice) the daily mean plasma exposure in patients that received 2 grams of cefiderocol infused intravenously every 8 hours.

In a pre- and postnatal development study, cefiderocol was administered intravenously at doses up to 1000 mg/kg/day to rats from Day 6 of pregnancy until weaning. No adverse effects on parturition, maternal function, or pre- and postnatal development and viability of the pups were observed.

In pregnant rats, cefiderocol-derived radioactivity was shown to cross the placenta, but the amount detected in fetuses was a small percentage (< 0.5%) of the dose.

8.2 Lactation Risk Summary It is not known whether cefiderocol is excreted into human milk; however, cefiderocolderived radioactivity was detected in the milk of lactating rats that received the drug intravenously. When a drug is present in animal milk, it is likely that the drug will be present in human milk. No information is available on the effects of FETROJA on the breastfed infant or on milk production.

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

Data

Patients Receiving CRRT

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

8.5 Geriatric Use

A total of 16 patients treated with FETROJA received CRRT in clinical trials. Dosage adjustment of FETROJA is required in patients receiving CRRT including CVVH, CVVHD, and CVVHDF. Dosage of FETROJA should be based on the effluent flow rate in patients receiving CRRT [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. While on CRRT, a patientâ&#x20AC;&#x2122;s residual renal function may change. Improvements or reductions in residual renal function may warrant a change in FETROJA dosage.

cUTI

Patients with CLcr 120 mL/min or Greater

Of the 300 patients treated with FETROJA in the cUTI trial, 158 (52.7%) were 65 years of age and older, and 67 (22.3%) were 75 years of age and older. No overall differences in safety or efficacy were observed between these patients and younger patients.

CLcr 120 mL/min or greater may be seen in seriously ill patients, who are receiving intravenous fluid resuscitation. Dosage adjustment of FETROJA is required in patients with CLcr 120 mL/min or greater [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. Monitor renal function regularly and adjust the dosage of FETROJA accordingly as renal function may change during the course of therapy.

8.4 Pediatric Use Safety and effectiveness of FETROJA in pediatric patients younger than 18 years of age have not been established.

HABP/VABP Of the 148 patients treated with FETROJA in the HABP/VABP trial, 83 (56.1%) were 65 years of age and older, and 40 (27%) were 75 years of age and older.

The incidence of adverse reactions in patients treated with FETROJA was similar in patients under 65 years of age as compared to older patients (65 years of age and older and 75 years of age and older). The incidence of adverse reactions in older patients (65 years of age and older and 75 years of age and older) was also similar between treatment groups.

Clinical cure rates at the Test-of-Cure visit (TOC) in FETROJA-treated adult patients younger than 65 years of age, 65 years of age to younger than 75 years of age and 75 years of age and older were 60%, 77.5%, and 60%, respectively. In comparison, the clinical cure rates at the TOC visit in the meropenem-treated patients for each of these subgroups were 65.5%, 64.4%, and 70.5%, respectively. The observed all-cause mortality rates at Day 14 in the FETROJA-treated patients for each of these subgroups were 12.3%, 7.5%, and 17.5%, respectively. In comparison, in the meropenem-treated patients for each of these subgroups, they were 10.3%, 17.8%, and 9.1%, respectively.

8.7 Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of cefiderocol have not been evaluated. Hepatic impairment is not expected to alter the elimination of cefiderocol as hepatic metabolism/excretion represents a minor pathway of elimination for cefiderocol.

Dosage adjustments are not necessary in patients with impaired hepatic function.

10 OVERDOSAGE There is no information on clinical signs and symptoms associated with an overdose of FETROJA. Patients who receive doses greater than the recommended dose regimen and have unexpected adverse reactions possibly associated with FETROJA should be carefully observed and given supportive treatment, and discontinuation or interruption of treatment should be considered.

Approximately 60% of cefiderocol is removed by a 3- to 4-hour hemodialysis session [see Clinical Pharmacology (12.3) in the full prescribing information].

cUTI and HABP/VABP FETROJA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. No dosage adjustment is required based on age. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3) in the full prescribing information].

8.6 Renal Impairment Patients with CLcr 60 to 89 mL/min No dosage adjustment of FETROJA is recommended in patients with CLcr 60 to 89 mL/min.

Patients with CLcr Less Than 60 mL/min Including Patients Receiving Intermittent HD Dose adjustment is required in patients with CLcr less than 60 mL/min, and in patients who are receiving HD. In patients requiring HD, complete HD at the latest possible time before the start of cefiderocol dosing [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3) in the full prescribing information]. Monitor renal function regularly and adjust the dosage of FETROJA accordingly as renal function may change during the course of therapy.

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

SEAN M. STAINTON, PHARMD

MARY STAICU, PHARMD, BCIDP

MARYROSE LAGUIO-VILA, MD

Clinical Pharmacy Specialist Department of Infectious Diseases Rochester General Hospital Rochester, New York

Clinical Pharmacy Specialist

Internal Medicine, Infectious Diseases Department of Infectious Diseases Rochester General Hospital Rochester, New York

T

Department of Infectious Diseases Rochester General Hospital Rochester, New York

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 broadspectrum 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 institutionspecific and geographic factors, including various institutional sites (for example, outpatient vs inpatient, ICU vs ward). Therefore, an 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 â&#x20AC;˘ WINTER 2020

55

IDSE Review

Antimicrobial Efficacy

Monobactams

Carbapenems Penicillins

56 Amoxicillin-clavulanate

1 2

Ampicillin-sulbactam

1 2

Piperacillin-tazobactam

2

Ticarcillin-clavulanate

2 1 2 2 2 2 3 1

2 2 1 2 2 2 2 2 2ab 2

2 2 2 2 2 2 2 2 2 2 2 2 2 3 2 3 1 2

2 2 2 3 2 2 2 2 2 2 2 2 2 2 2 3 2 3 2 2

Doripenem

2 2 2 2 2 1 1 2 2 2 2 2 2 2 2 2 1

Ertapenem

2 2 1 1 2 2 2 2 2 2

Meropenem

2 2 2 2 2 1 1 2 2 2 2 2 2 2 2 2 2 1

Imipenem-cilastatin

2

2

2

2

2

1

1

2

2

2

2

2

2

2

2

2

2

1

Imipenem-cilastatin relebactam

2

2

2

2

Meropenemvaborbactam

3

2

2

3

3

2

2

2

2

Aztreonam

IDSE.NET

2

Ampicillin

Penicillin G

2

Amoxicillin

Penicillin V

2 3

3 1

Cloxacillin/ Dicloxacillin

Nafcillin/Oxacillin

1 3 3

1 3 2 3

2

3 3 2

3 2 3

2 2

3

2 3

2 2

Piperacillin

3 2 3 2 3 2

Ticarcillin

3 2 3 2 3 3 2

2 2

2

2

2 2

3

2

2

2 1

3

2

2

3

3

Pasteurella multocida

Stenotrophomonas maltophilia

Pseudomonas aeruginosa h

Burkholderia cepacia complex h

Ferment-Positive

Ferment-Negative

Enterobacteriaceaef

Acinetobacter spp.h

Shigella spp.

Serratia spp.

Salmonella typhi

Salmonella spp.

Providencia stuartii

Proteus vulgaris

Proteus mirabilis

Coccobacilli

Morganella morganii

Klebsiella spp.f,g,ad

Escherichia coli f,g

Enterobacter spp.e,f

Citrobacter spp.e

Legionella pneumophila

Haemophilus influenzae d

Haemophilus ducreyi

Helicobacter pylori c

Francisella tularensis

Campylobacter jejuni

Cocci

Brucella spp.b

Bordetella pertussis

Chlamydia trachomatis

Chlamydophila psittaci

Chlamydophila pneumoniae (TWAR)

Neisseria meningitidisag

Neisseria gonorrhoeae a

Moraxella catarrhalis

IDSE Review

Table 1.

Penicillins, Carbapenems, Monobactams Gram-Negative Aerobes

Other Bacilli (non-Enterobacteriaceae)

3 2 2

3 2 2

1 1

2 2 2 2 2 3 2 3 2 3 1 2

2 2 2 2 3 3 2 3 2 3 3 2

1 2

1 2

1

2

3 1

3 1 Streptococcus Group A (S. pyogenes)

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

Ferment-Positive

3

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 2 3 2 2 2 2

2 2 2 2 2 3 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

2 2 2

2 2 2

3 3 3 3

1 1 3 3 3 3 3 3 3

3 2

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 2 3 2 2 2 2 2

2 2 2 2 2 2 3 3 3 2 2 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 2

2 1

INFECTIOUS DISEASE SPECIAL EDITION â&#x20AC;˘ WINTER 2020

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

Enterococcus faecalis

Streptococcus Group B (S. agalactiae)

1

Anaerobes

IDSE Review

Vibrio cholerae

Gram-Positive Aerobes

2

2

1

2

57

Gram-Negative Aerobes Other Bacilli (non-Enterobacteriaceae)

Enterobacteriaceae

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

Stenotrophomonas maltophilia

3 3

2

Pseudomonas aeruginosa h

3

2 3

Burkholderia cepacia complex 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

Campylobacter jejuni

Brucella spp.b

Bordetella pertussis

Chlamydia trachomatis

Chlamydophila psittaci

Chlamydophila pneumoniae (TWAR)

Neisseria meningitidisag

Neisseria gonorrhoeae a

Moraxella catarrhalis

Cefadroxil 3

Pasteurella multocida

Coccobacilli

Ferment-Negative

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

4th

2

3 2

2

2

2 2

Ceftizoxime 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

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

2

2

3 1 2 2 2

3

2ae 2 3ae

1

Cefiderocol

58

2

2

AntiMRSA

Other

3 3

2af

2

3

3 1

3

2 2 3 2

2

2 2

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 2 2 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

3

2

3 2 2 2 3 2

2 2 2 3 2

INFECTIOUS DISEASE SPECIAL EDITION â&#x20AC;˘ WINTER 2020

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

Vibrio cholerae

Gram-Positive Aerobes

2

2 2

3

2 3 2

3 2 1

2 3 2 2 2

1 2

3

2

59

Gram-Negative Aerobes

Amikacin 3 Aminoglycosides

2

1

1

1

1 1 1 3 1

Clarithromycin 1

2

1

Dirithromycin 2

2

2 2

Erythromycin 2 3 3

2

1 2 1 3 2

Ciprofloxacin 2 2 2

2

2 2 2 2 3 3 3 3

2

1 1 1 1 1 1 1 2 1

3

1

2 3 1

Ferment Positive Pasteurella multocida

1 1

3

3 2

3 3

2 2 1 2 2 2 2 2 2 2 2 2 1 2 2 2 2 2 2 2 2

2

2 2 3

2

2 2 2 1 2 2 2 2 2 2 2 2 2

2 2 2

2

2 3

2

2 1 2 2 2 2 2 2 2

3 2 3

2

3 2

2

2

1

3

2

3

2

Moxifloxacin 2 2 2

3

2

3

Levofloxacin 2 2 2

2 2

Stenotrophomonas maltophilia

2

2

3

1

2 3 1

3 3 3 2 3

2

3

1

Delafloxacin

Clindamycin

Pseudomonas aeruginosa g

1

Gemifloxacin 2

Chloramphenicol 3

Burkholderia cepacia complex g

Shigella spp.

1

1 3 1

2 1 1

1 3 2

Acinetobacter spp.g

Serratia spp.

Salmonella typhi

Salmonella spp.

Providencia stuartii

Proteus vulgaris

Proteus mirabilis

Morganella morganii

Klebsiella spp. f,g,ad

Escherichia coli

Enterobacter spp.e

2 3 3

1 1 1 1 1 1 1 2 2

3 2

Citrobacter spp.e

Legionella pneumophila

2 2 2 2 2 2 2 2 2

3

2

Tobramycin 3 Azithromycin 1 2 2

Macrolides

3

ac

Streptomycin

Quinolonesr

Haemophilus influenzae d

Haemophilus ducreyi

Helicobacter pylori c

Francisella tularensis

Campylobacter jejuni

Brucella spp.b

Bordetella pertussis

Chlamydia trachomatis

Chlamydophila psittaci

Neisseria meningitidisag

Chlamydophila pneumoniae (TWAR)

Neisseria gonorrhoeae a

FermentNegative

Gentamicin 3 Plazomicin

Other Bacilli (non-Enterobacteriaceae)

Enterobacteriaceaef

Coccobacilli Chlamydiae

Cocci

Moraxella catarrhalis

IDSE Review

Table 3.

Aminoglycosides, Macrolides, Quinolones, Other Antibiotics

3

3

3 3

2

3 2 2 3 3

2 2 3

3 2 2 2

Colistin/Polymyxin B

2

2

Dalbavancinz Daptomycins

2 2 2 2 2

Eravacycline

2 2 2

Fidaxomicin Lefamulin

2

2 2

Other Antibiotics

Linezolid

2

Metronidazole Omadacycline 3

2

2 2 3 2

2

Oritavancin Quinupristin-dalfopristin 3

3

Rifampin 2 2 2

3 2

1

2 2

3

3 3

3

2 3 3

3

3

Tedizolid Telavancin Telithromycin 2 Tetracyclines (eg, Doxycycline, 3 3 3 Minocycline)t Tigecycline 2 Trimethoprim-sulfamethoxazole 1

2 2

2 2 2 1 2 1 3 2 1

2

2 3 2 1

2 2

2 2 2 2 2 2 2 1

1 2 2 2 3 2

3 3

2

2

2

2

2

1

1

2 2 2 2 2 2 2 2 2 2 2 2

UTI

Agentsu

Vancomycin Fosfomycin (oral formulation only)

60

Nitrofurantoin

IDSE.NET

3

3 3 2 2 3 3 3

3

3 3 1 3 3 2 3 3

3

3

Vancomycin-resistant Enterococcus faecalis Enterococcus faecium Vancomycin-resistant Enterococcus faecium

2 3 3 3

3 3 3 3

3

2 3

2

2 3 3 3 3 2 2 2 1 2 3 3

3 2 3 3 3 3 2 2 2 2 1 2 3 3 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

3 3

2

2

2

2

2 3

3y

1

3

2

3

1

2 2

2 1 2

2 2 2

1

2

2

3

2

2

2 2

3 3y 2 1 3 3 2 2 2 2

aa

2 2 2 2 2 2 2 2 2

2 2 2 2 2 2

1

2

1

2

3

1 3

2 3

3

2 2 1 3 2

3 3 3 3

2 2

3 3

Methicillin-resistant 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

1

2 2

1 1 3

3

1

2 2 2

3 3 2 1 3

2 1 2 2 2 2

2 2 3 2

3 2

2

2

3 3 2 2 2 2 3 3 2 2 2

2

3

2

2

2

1

2

2

2 2

2 2

2

2 2

2

1

3

2

3

3 3

2

2

3 2 2

2 2

3 3

2 2 2

2 2

2 2

2

2

2

1

2

2

2 2 2 2 2

2

1

3

3

3

3

3 2

2

2

1

1

2

1

2 3

2 2 2

2

2

1 2

3

2

2 2

2

l

3

2 1

1

3 3 1

3

2 1

2

1

2 2

3

3 3 2

3

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

2 2 2 3 3 2

2

1

3

3

2 3 2 2 2 2 2

2 2 2 2

2

2 2 2 2

2 2 3 2 2 2 3

2 2 2 2 2 2 3 3 3 2 2 3 2 3 3

2 2 2 3 2 2 2 3 3

2

3 3 3 3 3 2 2 2

2

2

3 3 2 2

2

2

1

1

1

1 3 3 3

2 2

INFECTIOUS DISEASE SPECIAL EDITION â&#x20AC;˘ WINTER 2020

61

Treponema pallidum

Mycoplasma

Leptospira spp.

Anaerobes GramGramNegative Positive

Borrelia recurrentis

Clostridium tetani

Clostridium perfringens

Clostridioides difficile p

Borrelia burgdorferi (Lyme disease) q

2

Ureaplasma urealyticum

2

Mycoplasma pneumoniae

3

Peptostreptococcus spp.

3

Prevotella melaninogenica

Fusobacterium spp.

Bacilli

Bacteroides fragilis

Listeria monocytogenes o

Gardnerella vaginalis n

Corynebacterium jeikeium

Actinomycetes

Cocci

Corynebacterium diphtheriae m

Bacillus anthracis

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

Gram-Positive Aerobes Spiral Organisms

3

3

2 2

2 3 2

1 2

1 1 1 2 2 2 2 2

2

3

2

2 2

IDSE Review

3 3 3 2

Methicillin-susceptible Staphylococcus epidermidis

2 Methicillin-susceptible Staphylococcus aureus

Enterococcus faecalis

Vibrio cholerae

Gram-Positive Aerobes

IDSE Review

Footnotes

r

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.

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.

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. 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. h Combination therapy is suggested, particularly during empiric treatment until susceptibility results are finalized. i

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.

62

IDSE.NET

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

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.

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.

y

Dalbavancin is not active against vancomycin-resistant enterococci (VRE) exhibiting vanA resistance.

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.

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 UTI, 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 reclasified 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.

IDSE Review

Suggested Reading Abdelraouf K, Linder KE, Nailor MD, et al. Predicting and preventing antimicrobial resistance utilizing pharmacodynamics: part II gram-negative bacteria. Expert Opin Drug Metab Toxicol.

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, Oâ&#x20AC;&#x2122;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 â&#x20AC;˘ WINTER 2020

63

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

INDICATION RUKOBIA, in combination with other antiretrovirals (ARVs), is indicated to treat HIV-1 infection in heavily treatment-experienced adults with multidrug-resistant HIV-1 infection failing their current ARV regimen due to resistance, intolerance, or safety considerations.

IMPORTANT SAFETY INFORMATION Contraindications • Do not use in patients with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA. • Do not use RUKOBIA in patients receiving strong cytochrome P450 (CYP)3A inducers, including but not limited to enzalutamide, carbamazepine, phenytoin, rifampin, mitotane, and St John’s wort (Hypericum perforatum).

Warnings and precautions Immune Reconstitution Syndrome, including the occurrence of autoimmune disorders with variable time to onset, has been reported with the use of RUKOBIA.

QTc Prolongation with Higher than Recommended Dosages: RUKOBIA at 2,400 mg twice daily has been shown to significantly prolong the QTc interval of the electrocardiogram. Use RUKOBIA with caution in patients with a history of QTc interval prolongation or in patients with relevant pre-existing cardiac disease or who are taking drugs with a known risk of Torsade de Pointes. Elderly patients may be more susceptible to drug-induced QT interval prolongation.

Elevations in Hepatic Transaminases in Patients with Hepatitis B or C Virus Co-infection: • Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection.

• Diligence should be applied in initiating or maintaining effective hepatitis B therapy when starting RUKOBIA in patients co-infected with hepatitis B. Adverse Reactions or Loss of Virologic Response Due to Drug Interactions with concomitant use of RUKOBIA and other drugs may occur (see Contraindications and Drug Interactions).

Trademarks are owned by or licensed to the ViiV Healthcare group of companies. ©2020 ViiV Healthcare or licensor. FSTJRNA200003 November 2020 Produced in USA.

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

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

Visit RUKOBIAhcp.com to learn more

Adverse reactions

Use in specific populations

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

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

• 81% of adverse reactions reported with RUKOBIA were mild or moderate in severity.

Drug interactions • See the full Prescribing Information for RUKOBIA for a complete list of significant drug interactions.

• Temsavir may increase plasma concentrations of grazoprevir and voxilaprevir. Use an alternative hepatitis C virus regimen if possible.

• Use the lowest possible starting dose for statins and monitor for statin-associated adverse events.

• Patients receiving RUKOBIA should not take doses of estrogen-based therapies, including oral contraceptives, that contain more than 30 mcg/day of ethinyl estradiol. Caution is advised particularly in patients with additional risk factors for thromboembolic events.

• Lactation: Breastfeeding is not recommended due to the potential for HIV-1 transmission, developing viral resistance, and adverse reactions in a breastfed infant.

Please see Brief Summary of Prescribing Information for RUKOBIA on the following pages.

ARV=antiretroviral; BID=twice daily; CI=confidence interval; HIV-1=human immunodeficiency virus type 1.

References: 1. Data on file, ViiV Healthcare. 2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in adults and adolescents with HIV. Department of Health and Human Services. https://clinicalinfo. hiv.gov/sites/default/files/guidelines/documents/AdultandAdolescentGL.pdf.

Updated December 18, 2019. Accessed September 18, 2020.

BRIEF SUMMARY

RUKOBIA (fostemsavir) extended-release tablets, for oral use The following is a brief summary only; see full prescribing information for complete product information.

CONTRAINDICATIONS RUKOBIA is contraindicated in patients: with previous hypersensitivity to fostemsavir or any of the components of RUKOBIA; coadministered strong F\WRFKURPH 3 &<3 $ LQGXFHUV DV VLJQLÂżFDQW GHFUHDVHV LQ WHPVDYLU (the active moiety of fostemsavir) plasma concentrations may occur which may result in loss of virologic response. These drugs include, but are not limited to: Androgen receptor inhibitor: Enzalutamide; Anticonvulsants: Carbamazepine, phenytoin; Antimycobacterial: Rifampin; Antineoplastic: Mitotane; Herbal product: St Johnâ&#x20AC;&#x2122;s wort (Hypericum perforatum).

WARNINGS AND PRECAUTIONS Immune Reconstitution Syndrome: Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including RUKOBIA. During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may GHYHORS DQ LQĂ&#x20AC;DPPDWRU\ UHVSRQVH WR LQGROHQW RU UHVLGXDO RSSRUWXQLVWLF infections (such as Mycobacterium avium infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis), which may necessitate further evaluation and treatment. Autoimmune disorders (such as Gravesâ&#x20AC;&#x2122; disease, polymyositis, Guillain-BarrĂŠ syndrome, and autoimmune hepatitis) have also been reported to occur in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment. QTc Prolongation with Higher than Recommended Dosages: RUKOBIA at 2,400 mg twice daily, WLPHV WKH UHFRPPHQGHG GDLO\ GRVH KDV EHHQ VKRZQ WR VLJQLÂżFDQWO\ prolong the QTc interval of the electrocardiogram. RUKOBIA should be used with caution in patients with a history of QTc interval prolongation, when coadministered with a drug with a known risk of Torsade de Pointes, or in patients with relevant pre-existing cardiac disease.

Elderly patients may be more susceptible to drug-induced QT interval prolongation. Elevations in Hepatic Transaminases in Patients with Hepatitis B or C Virus Co-infection: Monitoring of liver chemistries is recommended in patients with hepatitis B and/or C co-infection. Elevations in hepatic transaminases were observed in a greater proportion of subjects with HBV and/or HCV co-infection compared with those with HIV mono-infection. Some of these elevations in transaminases were consistent with hepatitis B reactivation, particularly in the setting where anti-hepatitis therapy was withdrawn. Particular diligence should be applied in initiating or maintaining effective hepatitis B therapy (referring to treatment guidelines) when starting RUKOBIA in patients co-infected with hepatitis B. Risk of Adverse Reactions or Loss of Virologic Response Due to Drug Interactions: The concomitant use of RUKOBIA and certain other drugs PD\ UHVXOW LQ NQRZQ RU SRWHQWLDOO\ VLJQLÂżFDQW GUXJ LQWHUDFWLRQV VRPH RI which may lead to: Loss of therapeutic effect of RUKOBIA and possible development of resistance due to reduced exposure of temsavir; possible prolongation of QTc interval from increased exposure to temsavir. See Drug Interactions for steps to prevent or manage these possible and known VLJQLÂżFDQW GUXJ LQWHUDFWLRQV LQFOXGLQJ GRVLQJ UHFRPPHQGDWLRQV &RQVLGHU the potential for drug interactions prior to and during therapy with RUKOBIA, review concomitant medications during therapy with RUKOBIA, and monitor for the adverse reactions associated with the concomitant drugs.

ADVERSE REACTIONS Clinical Trials Experience: A total of 620 subjects with HIV-1 infection received at least one dose of RUKOBIA as part of a controlled clinical trial.

The primary safety assessment of RUKOBIA is based on 96 weeks of data from a Phase 3 partially randomized, international, multicenter, double-blind, placebo-controlled trial (BRIGHTE) conducted in 371 heavily treatmentexperienced adult subjects. A total of 370 subjects (271 randomized and 99 nonrandomized) received at least 1 dose of RUKOBIA 600 mg twice daily in the BRIGHTE trial. Overall, most (81%) of the adverse reactions reported with RUKOBIA were mild or moderate in severity. The proportion of subjects who discontinued treatment with RUKOBIA due to an adverse event was 7% at Week 96 (randomized: 5% and nonrandomized: 12%). The most common adverse events leading to discontinuation were related to infections (3% of subjects receiving RUKOBIA). Serious drug reactions occurred in 3% of VXEMHFWV DQG LQFOXGHG FDVHV RI VHYHUH LPPXQH UHFRQVWLWXWLRQ LQĂ&#x20AC;DPPDWRU\ syndrome. Data from the randomized cohort form the basis of the safety DVVHVVPHQW RI 58.2%,$ EHFDXVH WKH SUHVHQFH RI VLJQLÂżFDQW FRPRUELG illness in the nonrandomized cohort (associated with advanced HIV infection) may confound the assessment of causality. Adverse reactions (all JUDGHV UHSRUWHG LQ Â&#x2022; RI VXEMHFWV LQ WKH UDQGRPL]HG FRKRUW LQ WKH :HHN 96 analysis are listed in Table 1.

Table 1. Adverse Reactionsa *UDGHV WR 5HSRUWHG LQ Â&#x2022; RI 6XEMHFWV Receiving RUKOBIA plus OBT in the BRIGHTE Trial, Randomized Cohort (Week 96 Analysis) Adverse Reaction Nausea Diarrhea Headache Abdominal painc Dyspepsia Fatigued Rashe Sleep disturbancef Immune Reconstitution ,QĂ&#x20AC;DPPDWRU\ 6\QGURPH Somnolence Vomiting

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

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

Adverse reactions in the nonrandomized cohort were similar to those observed in the randomized cohort. The most common adverse reactions reported in nonrandomized subjects were fatigue (7%), nausea (6%), and diarrhea (6%). Less Common Adverse Reactions: The following adverse reactions occurred in <2% of subjects receiving RUKOBIA in the randomized cohort of the BRIGHTE trial. These events have been included based on the assessment of potential causal relationship and were also reported in the nonrandomized cohort. â&#x20AC;&#x201C; Cardiac Disorders: Electrocardiogram QT prolonged. All reports were asymptomatic. â&#x20AC;&#x201C; Musculoskeletal Disorders: Myalgia. â&#x20AC;&#x201C; Nervous System Disorders: Dizziness, dysgeusia, neuropathy peripheral (includes pooled terms: neuropathy peripheral and peripheral sensory neuropathy). â&#x20AC;&#x201C; Skin and Subcutaneous Tissue Disorders: Pruritus.

Laboratory Abnormalities: Selected laboratory abnormalities (Grades 3 to 4) with a worsening grade from baseline and representing the worst-grade WR[LFLW\ LQ Â&#x2022; RI VXEMHFWV LQ WKH UDQGRPL]HG FRKRUW RI WKH %5,*+7( WULDO DUH presented in Table 2.

7DEOH 6HOHFWHG /DERUDWRU\ $EQRUPDOLWLHV *UDGHV WR 5HSRUWHG LQ Â&#x2022; RI 6XEMHFWV LQ WKH 5DQGRPL]HG &RKRUW 5HFHLYLQJ 58.2%,$ SOXV OBT in the BRIGHTE Trial (Week 96 Analysis) Laboratory Parameter Preferred Term ALT (>5.0 x ULN) AST (>5.0 x ULN) Direct bilirubin (>ULN)b %LOLUXELQ Â&#x2022; [ 8/1

&KROHVWHURO Â&#x2022; PJ G/ b Creatinine (>1.8 x ULN or 1.5 x baseline) &UHDWLQH NLQDVH Â&#x2022; [ 8/1

Hemoglobin (<9.0 g/dL) Hyperglycemia (>250 mg/dL) Lipase (>3.0 x ULN) /'/ &KROHVWHURO Â&#x2022; PJ G/

1HXWURSKLOV Â&#x201D; FHOOV PP3) Triglycerides (>500 mg/dL) Urate (>12 mg/dL)

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

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

The incidence of selected laboratory abnormalities (Grades 3 to 4) in the nonrandomized cohort were overall consistent with those of the randomized cohort, with the exception of direct bilirubin (14% versus 7%), bilirubin (6% (contâ&#x20AC;&#x2122;d on next page)

BRIEF SUMMARY

RUKOBIA (fostemsavir) extended-release tablets, for oral use (contâ&#x20AC;&#x2122;d) versus 3%), lipase (10% versus 5%), triglycerides (10% versus 5%), neutrophils (7% versus 4%), and leukocytes (6% versus 1%), respectively.

Changes in Serum Creatinine: Clinically relevant increases in serum FUHDWLQLQH KDYH SULPDULO\ RFFXUUHG LQ SDWLHQWV ZLWK LGHQWLÂżDEOH ULVN IDFWRUV for reduced renal function, including pre-existing medical history of renal disease and/or concomitant medications known to cause increases in creatinine. A causal association between RUKOBIA and elevation in serum creatinine has not been established. Changes in Direct Bilirubin: Increases in direct (conjugated) bilirubin have been observed following treatment with 58.2%,$ 7DEOH &DVHV RI FOLQLFDO VLJQLÂżFDQFH ZHUH XQFRPPRQ DQG were confounded by the presence of intercurrent serious comorbid events (e.g., sepsis, cholangiocarcinoma, or other complications of viral hepatitis co-infection). In the remaining cases, elevations in direct bilirubin (without clinical jaundice) were typically transient, occurred without increases in liver transaminases, and resolved on continued RUKOBIA. Changes in ALT and AST in Subjects with Hepatitis B and/or Hepatitis C Virus Co-infection: A total of 29 subjects with Hepatitis B and/or Hepatitis C co-infection were enrolled in the BRIGHTE trial (randomized and nonrandomized cohorts combined). Grade 3 and 4 elevations in ALT and AST occurred in 14% of these subjects compared with 3% (ALT) and 2% (AST) of subjects without viral hepatitis co-infection. Some of these elevations in transaminases were consistent with hepatitis B reactivation particularly in the setting where antihepatitis therapy was withdrawn.

DRUG INTERACTIONS Potential for RUKOBIA to Affect Other Drugs: Temsavir may increase plasma concentrations of grazoprevir or voxilaprevir to a clinically relevant extent due to organic anion transporting polypeptide (OATP)1B1/3 inhibition.

When RUKOBIA was coadministered with oral contraceptives, temsavir increased concentrations of ethinyl estradiol. Potential for Other Drugs to Affect RUKOBIA: Coadministration of RUKOBIA with rifampin, a strong &<3 $ LQGXFHU VLJQLÂżFDQWO\ GHFUHDVHV WHPVDYLU SODVPD FRQFHQWUDWLRQV The use of RUKOBIA with drugs that are strong inducers of CYP3A4 can VLJQLÂżFDQWO\ GHFUHDVH WHPVDYLU SODVPD FRQFHQWUDWLRQV ZKLFK PD\ OHDG WR loss of virologic response. (VWDEOLVKHG DQG 2WKHU 3RWHQWLDOO\ 6LJQLĂ&#x20AC;FDQW Drug Interactions: Information regarding potential drug interactions with RUKOBIA is provided below. These recommendations are based on either drug interaction trials or predicted interactions due to the expected magnitude of interaction and potential for serious adverse events or loss RI HIÂżFDF\ â&#x20AC;˘ Androgen receptor inhibitor: Enzalutamideâ&#x20AC;&#x201D;Coadministration is contraindicated due to potential for loss of therapeutic effect to RUKOBIA. â&#x20AC;˘ Anticonvulsants: Carbamazepine, Phenytoinâ&#x20AC;&#x201D;Coadministration is contraindicated due to potential for loss of therapeutic effect to RUKOBIA. â&#x20AC;˘ Antimycobacterial: Rifampinâ&#x20AC;&#x201D;Coadministration is contraindicated due to potential for loss of therapeutic effect to RUKOBIA. â&#x20AC;˘ Antineoplastic: Mitotaneâ&#x20AC;&#x201D;Coadministration is contraindicated due to potential for loss of therapeutic effect to RUKOBIA. â&#x20AC;˘ Herbal product: St Johnâ&#x20AC;&#x2122;s wort (Hypericum perforatum)â&#x20AC;&#x201D; Coadministration is contraindicated due to potential for loss of therapeutic effect to RUKOBIA. â&#x20AC;˘ Hepatitis C virus direct-acting antivirals: Grazoprevir, Voxilaprevirâ&#x20AC;&#x201D; Coadministration may increase exposures of grazoprevir or voxilaprevir; however, the magnitude of increase in exposure is unknown. Increased exposures of grazoprevir may increase the risk of ALT elevations. Use an alternative HCV regimen if possible. â&#x20AC;˘ Oral contraceptive: Ethinyl estradiolâ&#x20AC;&#x201D;Ethinyl estradiol daily dose VKRXOG QRW H[FHHG PFJ Caution is advised particularly in patients with additional risk factors for thromboembolic events. â&#x20AC;˘ Statins: Rosuvastatin, Atorvastatin, Fluvastatin, Pitavastatin, Simvastatinâ&#x20AC;&#x201D;Use the lowest possible starting dose for statins and monitor for statin-associated adverse events.

Consult the full Prescribing Information for potential drug interactions; this list is not all-inclusive.

Drugs that Prolong QT Interval: Coadministration of RUKOBIA with a drug with a known risk of Torsade de Pointes may increase the risk of Torsade de Pointes. Use RUKOBIA with caution when coadministered with drugs with a known risk of Torsade de Pointes. Drugs without Clinically 6LJQLĂ&#x20AC;FDQW ,QWHUDFWLRQV ZLWK 58.2%,$ Based on drug interaction study results, the following drugs can be coadministered with RUKOBIA without a dose adjustment: atazanavir/ritonavir, buprenorphine/naloxone, cobicistat, darunavir/cobicistat, darunavir/ritonavir with and without etravirine, etravirine,

famotidine, maraviroc, methadone, norethindrone, raltegravir, ritonavir, rifabutin with and without ritonavir, tenofovir disoproxil fumarate.

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Exposure Registry: There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to RUKOBIA during pregnancy. Healthcare providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry (APR) at 1-800-258-4263. Risk Summary: 7KHUH DUH LQVXIÂżFLHQW KXPDQ GDWD RQ WKH use of RUKOBIA during pregnancy to adequately assess a drug-associated risk of birth defects and miscarriage. In animal reproduction studies, oral administration of fostemsavir to pregnant rats and rabbits during organogenesis resulted in no adverse developmental effects at clinically relevant temsavir exposures (see Data). Lactation: Risk Summary: The Centers for Disease Control and Prevention recommends that HIV-1â&#x20AC;&#x201C; infected mothers in the United States not breastfeed their infants to avoid risking postnatal transmission of HIV-1 infection. It is not known whether RUKOBIA is present in human breast milk, affects human milk production, or has effects on the breastfed infant. When administered to lactating rats, fostemsavir-related drug was present in rat milk. Because of the potential for (1) HIV-1 transmission (in HIV-negative infants), (2) developing viral resistance (in HIV-positive infants), and (3) adverse reactions in a breastfed infant similar to those seen in adults, instruct mothers not to breastfeed if they are receiving RUKOBIA. Pediatric Use: The safety and effectiveness of RUKOBIA have not been established in pediatric patients. Geriatric Use: &OLQLFDO WULDOV RI 58.2%,$ GLG QRW LQFOXGH VXIÂżFLHQW QXPEHUV RI VXEMHFWV aged 65 and older to determine whether they respond differently from younger subjects. In general, caution should be exercised in administration RI 58.2%,$ LQ HOGHUO\ SDWLHQWV UHĂ&#x20AC;HFWLQJ JUHDWHU IUHTXHQF\ RI GHFUHDVHG hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Elderly patients may be more susceptible to drug-induced QT interval prolongation. Renal Impairment: No dosage adjustment is required for patients with renal impairment or those on hemodialysis.

Hepatic Impairment: No dosage adjustment is required in patients with mild to severe hepatic impairment (Child-Pugh Score A, B, or C).

OVERDOSAGE 7KHUH LV QR NQRZQ VSHFLÂżF WUHDWPHQW IRU RYHUGRVH ZLWK 58.2%,$ ,I overdose occurs, the patient should be monitored and standard supportive treatment applied as required, including monitoring of vital signs and ECG (QT interval), as well as observation of the clinical status of the patient. As fostemsavir is highly bound to plasma proteins, it is unlikely that it will be VLJQLÂżFDQWO\ UHPRYHG E\ GLDO\VLV

ViiV Healthcare Research Triangle Park, NC 27709

GlaxoSmithKline Research Triangle Park, NC 27709

RKB:1PIL July 2020 Trademarks are owned by or licensed to the ViiV Healthcare group of companies. Š2020 ViiV Healthcare or licensor. FSTJRNA200003 November 2020 Produced in USA.

IDSE Review

What’s New in HIV Therapy?

BY HIND ALROWAIS, MD, AMY K. FEEHAN, PHD, AND JULIA GARCIA-DIAZ, MD

I

n the United States, an estimated 1.2 million people are living with HIV infection and many remain undiagnosed.1 HIV testing is recommended at least once for individuals aged 13 to 64 years, including all pregnant women, and more frequently for high-risk individuals.2,3 Initiation of antiretroviral therapy (ART) at the time of diagnosis has been shown to suppress viral load and prevent HIV transmission, rapidly improving individual and public health outcomes.4,5 Delaying treatment in patients with AIDS-defining illness, acute HIV infection, or pregnant women is associated with increased risk for HIV transmission, morbidity, and mortality.6 However, there are some instances when delaying treatment is appropriate: if a patient is not ready to commit to starting medications or is experiencing certain opportunistic infections, such as cryptococcal infection or tuberculosis meningitis.7,8 People with nonmeningeal tuberculosis can initiate ART immediately,9 as well as those with many other opportunistic infections or malignancies.6

68

IDSE.NET

New therapies for HIV continue to be developed; a private–public partnership was announced to accelerate the development of broadly neutralizing antibodies that can block the virus from invading cells.10 The FDA has just designated an experimental long-acting injectable, cabotegravir, as a breakthrough therapy for pre-exposure prophylaxis (PrEP).11 Several studies including GEMINI-1 and -2 have shown that sometimes less is more; 2-drug regimens are noninferior to 3-drug regimens and often have fewer side effects. New treatment options are beginning to be used clinically for experienced patients—the CD4 attachment inhibitors fostemsavir (Rukobia, ViiV Healthcare) and ibalizumab-uiyk (Trogarzo, Thera technologies). This article will discuss recent advancements in treatment and changing ideas on how to manage HIV.

2- Versus 3-Drug Regimens Strategies that minimize burden increase patient adherence, and nowhere is this truer than in the case of single-tablet regimens (STRs) for 3-drug treatment. The first STR was approved in 2006, efavirenz-emtricitabine-tenofovir disoproxil (EFV/FTC/ TDF; Atripla, Gilead), but this EFV-based regimen is known to cause neurologic and neuropsychiatric side effects, including nightmares, depression, suicidal ideation, dizziness, and lack of concentration.12

IDSE Review

Seven classes of ART are FDA-approved for the treatment of HIV infection. They include the nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), a fusion inhibitor (FI), a CCR5 antagonist, and CD4 T lymphocyte (CD4) postattachment inhibitors. In addition, 2 drugs, ritonavir (RTV) and cobicistat (COBI), are used as pharmacokinetic (PK) enhancers to improve the PK profiles of PIs and the INSTI elvitegravir (EVG).6 Selected agents within these drug classes are summarized in Table 1. Additionally, islatravir (ISL) is the first in a new class of drugs called nucleoside reverse transcriptase translocation inhibitors (NRTTI), but this compound is still in phase 3 clinical trials.

Studies have repeatedly shown the benefits of initiating treatment as soon as possible after diagnosis,4,5 and official guidelines support rapid treatment initiation.3 (A table showing the most up-to-date guidelines on initiating therapy is available with the online version at https://www.idse. net/Review-Articles/Article/12-20/Whats-New-inHIV-Therapy/61408.) Early initiation of treatment offers many benefits, including breaking the chain of transmission, lowering barriers to entry, establishing a pattern of treatment, and preparing the patient for a lifetime of care. Health care practitioners should select therapy that is the most potent while minimizing short- and long-term side effects, and reducing the chances of drug resistance. Initial therapy should include a 3-drug regimen with an integrase inhibitor as backbone (dolutegravir or bictegravir) and 2 NRTIs. Generally, abacavir is less desirable than tenofovir because it requires HLA B*5701 testing to avoid serious side effects and is associated with increased risk for cardiovascular disease. After initial treatment, there are many options for maintenance therapy.

The first 2-drug regimen was approved in 2017, dolutegravir-rilpivirine (DTG/RPV; Juluca, ViiV Healthcare), after SWORD-1/2 trials showed virologic suppression and a favorable safety profile.

DTG/RPV is indicated as a replacement only in patients with levels of HIV-1 less than 50 copies/ mL for at least 6 months on their current HIV treatment.13 DTG with lamivudine (DTG/3TC; Dovato, ViiV Healthcare) was approved in 2019, and is recommended for initial treatment of naive patients with a viral load less than 500,000 copies/mL, without active hepatitis B infection, and a CD4 count more than 200 cells/mm3.

There is growing interest in 2-drug regimens with DTG and 3TC. Two parallel, phase 3 randomized clinical trials, GEMINI-1 and GEMINI-2, showed the 2-drug regimen with DTG/3TC was noninferior to a 3-drug regimen with DTG plus TDF/FTC in terms of virologic efficacy. The primary end point was the proportion of participants with HIV-1 RNA plasma less than 50 copies/mL at week 48; a secondary end point included the proportion of participants with HIV-1 RNA plasma less than 50 copies/mL at week 144, which was recently presented at the HIV Glasgow 2020 Congress.14 A pooled analysis of the 2 studies showed that DTG/3TC demonstrated noninferiority, with 82% (584/716) of participants having HIV-1 RNA less than 50 copies/mL at week 144, compared with 84% (599/717) receiving a 3-drug regimen of DTG plus TDF/FTC (adjusted difference, –1.8%; 95% CI, –5.8% to 2.1%). Cholesterol measurements at 144 weeks were better in the 3-drug regimen, but renal and bone measurements were better in the 2-drug regimen. Inclusion criteria were limited to patients with a viral load less than 500,000 copies/mL and without active hepatitis B infection or any pre-existing major viral resistance mutations.

Thus, efficacy at higher viral loads is unknown.

Patients with a CD4 count less than 200 cells/ mm3 had lower treatment response with DTG/3TC (67% [42/63] vs 76% [42/55]).14,15 The TANGO trial assessed whether switching virologically suppressed patients to DTG/3TC would maintain virologic suppression.16 At 96 weeks, DTG/3TC was noninferior to baseline treatments; in this cohort, 66% had been given COBIboosted EVG with TAF. The study population was 92% male and 79% white, and had no history of virologic failure, limiting the extrapolation of results INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2020

69

IDSE Review

Table 1. Selected ART Agents by Drug Class Generic Name (Abbreviation) Trade Name

Dosing Recommendations

Adverse Events

Nucleoside Reverse Transcriptase Inhibitors • Patients who test positive for HLA-B*5701 are at the highest risk for experiencing HSRs. HLA screening should be done before initiating ABC. • For patients with a history of HSRs, rechallenge is not recommended.

Abacavir (ABC) Ziagen

600 mg once daily, or 300 mg twice daily

• Symptoms of HSRs may include fever, rash, nausea, vomiting, diarrhea, abdominal pain, malaise, fatigue, or respiratory symptoms (eg, sore throat, cough, or shortness of breath).

• Some cohort studies suggest an increased risk for MI with recent or current use of ABC, but this risk is not substantiated in other studies.

• Minimal toxicity

Emtricitabine (FTC) Emtriva

Capsule: 200 mg once daily Oral solution: 240 mg (24 mL) once daily

Lamivudine (3TC) Epivir

300 mg once daily, or 150 mg twice daily

• Hyperpigmentation/skin discoloration • Severe acute exacerbation of hepatitis may occur in patients with HBV/HIV coinfection who discontinue FTC. • Minimal toxicity • Severe acute exacerbation of hepatitis may occur in patients with HBV/HIV coinfection who discontinue 3TC. • Renal insufficiency, Fanconi syndrome, and proximal renal tubulopathy are less likely to occur with TAF than TDF.

Tenofovir alafenamide (TAF) Vemlidy

1 tablet once daily in combination with other drugs

• Osteomalacia and decreases in bone mineral density are less likely to occur with TAF than TDF. • Severe acute exacerbation of hepatitis may occur in patients with HBV/HIV coinfection who discontinue TAF. • Diarrhea, nausea, headache • Renal insufficiency, Fanconi syndrome, proximal renal tubulopathy

Tenofovir disoproxil fumarate (TDF) Viread

300 mg once daily, or 7.5 level scoops of oral powder once daily (one level scoop contains 1 g of oral powder)

• Osteomalacia, decrease in BMD • Severe acute exacerbation of hepatitis may occur in patients with HBV/HIV coinfection who discontinue TDF. • Asthenia, headache, diarrhea, nausea, vomiting, flatulence

Non-Nucleoside Reverse Transcriptase Inhibitors Doravirine (DOR) Pifeltro

• Nausea 1 tablet once daily

• Dizziness • Abnormal dreams • Rash • Neuropsychiatric symptoms • Serum transaminase elevations

Efavirenz (EFV) Sustiva

600 mg once daily, at or before bedtime

• Hyperlipidemia • Use of EFV may lead to false-positive results with some cannabinoid and benzodiazepine screening assays.

• QT interval prolongation • Rash, including Stevens-Johnson syndrome

Etravirine (ETR) Intelence

200 mg twice daily following a meal

• HSRs, characterized by rash, constitutional findings, and sometimes organ dysfunction (including hepatic failure), have been reported.

• Nausea • Rash

Rilpivirine (RPV) Edurant

25 mg once daily with a meal

• Depression, insomnia, headache • Hepatotoxicity • QT interval prolongation

70

IDSE.NET

Atazanavir (ATV) Reyataz (ATV/c) Evotaz

All with food Reyataz In ARV-naive patients: rATV 300 mg once daily, or ATV 400 mg once daily In ARV-naive patients with EFV: rATV 400 mg once daily In ARV-experienced patients with TDF: rATV 300 mg once daily with food Unboosted ATV is not recommended Evotaz 1 tablet once daily

• Indirect hyperbilirubinemia • PR interval prolongation. First-degree symptomatic AV block has been reported. Use with caution in patients who have underlying conduction defects or who are on concomitant medications that can cause PR prolongation.

• Cholelithiasis • Nephrolithiasis • Renal insufficiency • Serum transaminase elevations • Hyperlipidemia (especially with RTV boosting) • Skin rash • Hyperglycemia • Fat maldistribution • An increase in serum creatinine may occur when ATV is administered with COBI.

Darunavir (DRV) Prezista

In ARV-naive patients or ARV-experienced patients with no DRV mutations: rDRV 800 mg once daily with food

(DRV/c) Prezcobix

In ARV-experienced patients with one or more DRV resistance mutations: rDRV 600 mg twice daily with food Unboosted DRV is not recommended.

Prezcobix: 1 tablet once daily with food Not recommended for patients with one or more DRV resistance-associated mutations

• Skin rash: DRV has a sulfonamide moiety; however, incidence and severity of rash are similar in patients with or without a sulfonamide allergy; Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and erythema multiforme have been reported.

• Hepatotoxicity • Diarrhea, nausea • Headache • Hyperlipidemia • Serum transaminase elevation • Hyperglycemia • Fat maldistribution • An increase in serum creatinine may occur when DRV is administered with COBI.

Ritonavir (RTV) Norvir RTV is currently used at a lower dose of 100-200 mg once or twice daily as a PK enhancer to increase the concentrations of other PIs.

As a PK booster (or enhancer) for other PIs: 100-400 mg per day in 1 or 2 divided doses (refer to other PIs for specific dosing recommendations) Food Restrictions Tablet: Take with food Capsule and oral solution: to improve tolerability, take with food if possible

• • • • • • • • •

GI intolerance, nausea, vomiting, diarrhea Paresthesia (circumoral and extremities) Hyperlipidemia (especially hypertriglyceridemia) Hepatitis Asthenia Taste perversion Hyperglycemia Fat maldistribution Possible increase in frequency of bleeding episodes in patients with hemophilia

Integrase Strand Transfer Inhibitors Bictegravir (BIC)

Biktarvy: 1 tablet PO once daily

• Diarrhea • Nausea • Headache • Weight gain

Dolutegravir (DTG) Tivicay

Elvitegravir (EVG)

In ARV-naive or ARV-experienced, INSTInaive patients: 50 mg PO once daily

• Insomnia

In ARV-naive or ARV-experienced, INSTInaive patients when coadministered with EFV, FPV/r, TPV/r, or rifampin: 50 mg PO twice daily

• Depression and suicidal ideation (rare; usually occurs in patients with pre-existing psychiatric conditions)

INSTI-experienced patients with certain INSTI mutations (see product label) or with clinically suspected INSTI resistance: 50 mg PO twice daily

• HSRs, including rash, constitutional symptoms, and organ dysfunction (including liver injury), have been reported.

Genvoya: 1 tablet PO once daily with food

• Headache

• Weight gain

• Hepatotoxicity

• Nausea • Diarrhea • Depression and suicidal ideation (rare; usually occurs in patients with pre-existing psychiatric conditions)

INFECTIOUS DISEASE SPECIAL EDITION • WINTER 2020

71

IDSE Review

Protease Inhibitors

IDSE Review

Fusion Inhibitor Enfuvirtide (T-20) Fuzeon

90 mg/1 mL SQ twice daily

• Local injection site reactions (eg, pain, erythema, induration, nodules and cysts, pruritus, ecchymosis) in almost 100% of patients • Increased incidence of bacterial pneumonia • HSR occurs in less than 1% of patients. Symptoms may include rash, fever, nausea, vomiting, chills, rigors, hypotension, or elevated serum transaminases. Rechallenge is not recommended.

CCR5 Antagonist Maraviroc (MVC) Selzentry

150 mg PO twice daily when given with drugs that are strong CYP3A inhibitors (with or without CYP3A inducers), including PIs (except TPV/r) 300 mg PO twice daily when given with NRTIs, T-20, TPV/r, NVP, RAL, and other drugs that are not strong CYP3A inhibitors or inducers 600 mg PO twice daily when given with drugs that are CYP3A inducers, including EFV, ETR, etc (without a CYP3A inhibitor)

• Abdominal pain • Orthostatic hypotension, especially in patients with severe renal insufficiency • Hepatotoxicity, which may be preceded by severe rash or other signs of systemic allergic reactions • Cough • Dizziness • Musculoskeletal symptoms • Pyrexia • Rash • Upper respiratory tract infections

CD4 Post-Attachment Inhibitor Ibalizumab (IBA) Trogarzo

Single loading dose of 2,000 mg IV infusion • Diarrhea over 30 min, followed by a maintenance dose • Dizziness of 800 mg IV infusion over 15 min every 2 wk • Nausea • Rash

to other groups. Adverse events (AEs) were more common in the group that switched to new treatment, which is not surprising given that the control group was stable on their medication. However, AEs commonly associated with DTG were listed as reasons for withdrawal from the trial: depression, anxiety, insomnia, fatigue, and increased weight, but no confirmed virologic withdrawals were seen in the DTG/3TC group, nor resistance development.

A phase 3 trial (DRIVE-FORWARD) of doravirine (DOR) with 3TC/TDF (Delstrigo, Merck) included only treatment-naive HIV patients. Patients were randomized to receive either DOR or darunavir/ ritonavir. The primary end point was the proportion of participants who had a plasma HIV-1 RNA less than 50 copies/mL at 48 weeks. At week 96, a higher proportion of the DOR group (277/383 [73%]) achieved this end point than the DRV group (248/383 [66%]; difference, 7.1%; 95% CI, 0.5%-13.7%).17,18 Selecting an appropriate regimen should be based on patients’ characteristics, including comorbidities, pregnancy status, pill burden, drug–drug interaction, cost, and potential side effects. Table 2 summarizes clinical scenarios that warrant special consideration in initiating therapy.

72

IDSE.NET

Treatment-Experienced HIV Patients The proportion of people in the United States with extensive resistance to ART and limited treatment options has declined markedly since 2012, in large part made possible by the availability of potent new drugs. Bajema et al19 examined data from 27,133 experienced HIV patients, of whom 916 were classified as having limited treatment options (LTO). The prevalence of patients with LTO was 5.2% to 7.5% in 2000-2006, decreased to 1.8% in 2007, and has remained less than 1% after 2012.

Ibalizumab, a humanized IgG4 antibody postattachment inhibitor, was approved in 2018 as an IV infusion every 2 weeks for the treatment of adults with multidrug-resistant (MDR) HIV-1 combined with other antiretroviral medications in patients with limited treatment options. At 48 weeks of the phase 3 trial, significant antiviral activity was found.20 Fostemsavir is an attachment inhibitor in an oral formulation targeting HIV-1 gp120 and preventing viral attachment to CD4 cells, and was recently approved in July 2020.21 The BRIGHTE trial enrolled participants with a viral load of 400 copies/mL or more and at least 2 classes of antiretroviral medications remaining at baseline due to resistance. In the randomized cohort, HIV-1 RNA less than 40 copies/mL was achieved in 53% and 60% of subjects

Investigational ART Strategies Albuvirtide (Frontier Biologics) is a fusion inhibitor that binds to gp41, which is given as a once-weekly subcutaneous injection. In patients with firstline treatment failure, the TALENT study showed albuvirtide with RTV-boosted lopinavir resulted in 80.4% viral suppression when compared with an NRTI group at 66% at 48 weeks.23 There is another ongoing phase 2 multicenter study to evaluate dosage and safety as a long-acting maintenance therapy in virologically suppressed patients.24 Islatravir (ISL, Merck) is a first-in-class NRTTI being investigated as a monotherapy in ART-naive patients. This once-weekly tablet is a long-acting formulation that could increase patient compliance and be used for PrEP in patients who are unwilling or unable to receive a long-acting injection of cabotegravir. In a phase 2b trial (DRIVE2Simplify) of ARTnaive adults with HIV RNA more than 1,000 copies/ mL and a CD4+ count more than 200 cells/mm3, 3 doses of ISL+DOR+3TC were compared with DOR/3TC/TDF at 24 weeks.25 For weeks 24 to 96, patients receiving ISL+DOR+3TC were switched to ISL+DOR. At week 96, 5.5% of the ISL+DOR treatment groups had protocol-defined virologic failure compared with 3.2% in the DOR/3TC/TDF group.

However, all these individuals had fewer than 80 copies/mL HIV-1 RNA levels, and 5 out of 7 had baseline HIV-1 RNA more than 100,000 copies/ mL. In the ISL+DOR groups, 82.2% had more than 1 adverse event compared with 87.1% in the DOR/3TC/TDF groups; drug-related AEs occurred in 7.8% and 22.6%, and serious AEs were noted in 5.6% and 9.7%, respectively. No participant in any treatment group met criteria for resistance testing (all confirmed HIV RNA for protocol-defined virologic failure, <80 copies/mL). Given how promising these early results are, drug-eluting implant devices are being studied for prolonged ISL release in rodents, and studies have shown maintenance

IDSE Review

at weeks 24 and 96, respectively (ITT-E, Snapshot algorithm). Mean changes in CD4+ cell count from baseline continued to increase over time (ie, 90 cells/mm3 at week 24 and 205 cells/mm3 at week 96). In an ongoing phase 3 trial targeting MDR HIV patients, higher viral suppression has been shown in patients on fostemsavir versus placebo.22 These agents provide treatment options for heavily treatment-experienced people living with HIV.

Until an HIV vaccine is available, testing and early ART are crucial. plasma levels of ISL for more than 6 months resulting in a 1.6-log decrease of viral load.26,27 A monthly long-acting, intramuscular injection of a 2-drug regimen of cabotegravir and RPV (ViiV Healthcare and Janssen) was compared with standard oral regimens in several studies (ATLAS, FLAIR, and LATTE-2). In FLAIR,28 ART-naive adults with HIV-1 RNA more than 1,000 copies/mL were started on DTG/ABC/3TC and a subset switched to CAB plus oral RPV prior to initiating a long-acting IM injection of the same combination. Half of those who remained on DTG/ABC/3TC were directly switched to an IM injection of long-acting CAB+RPV and half were given CAB+RPV orally for 4 weeks prior to initiating the long-acting injection. Whether patients elected to initiate the long-acting injection or an oral regimen lead-in, 99.1% and 93.4% had less than 50 copies/mL at 24 weeks after the switch, respectively. There were no fatal AEs and roughly equal percentages of AEs in the direct-toinjection and oral lead-in groups.28 Switching to an injection of this long-acting regimen may significantly help to maintain patients who have difficulty with daily medication, and this study suggests that an oral lead-in of CAB+RPV may not be necessary.

CAB was submitted to the FDA in August 2020, and is currently awaiting a decision. However, the FDA did grant a breakthrough therapy designation for CAB for HIV PrEP on November 18, 2020.11 Conclusion Until an effective vaccine is available, identification and prompt initial treatment of HIV infection are of utmost importance. Our goals for the treatmentnaive patient are to begin therapy as soon as possible; an integrase is the backbone of therapy; strive for a single-pill combination daily regimen; and always INFECTIOUS DISEASE SPECIAL EDITION â&#x20AC;˘ WINTER 2020

73

IDSE Review

Table 2. Recommended Initial Regimens for Certain Clinical Situations These regimens are effective and tolerable but have some disadvantages when compared with the most common initial regimens or have less supporting data from randomized clinical trials.

INSTI Plus 2 NRTIs: • EVG/c/(TAF or TDF)a/FTC (BI)

Boosted PI Plus 2 NRTIs: • In general, boosted DRV is preferred over boosted ATV

emphasize the importance of adherence. Soon, long-acting injectables and pills will likely be available.

References 1.

CDC. HIV Surveillance. Accessed December 1, 2020. https://www. cdc.gov/hiv/library/reports/hiv-surveillance/vol-31/index.html

2.

US Preventive Services Task Force, Owens DK, et al. JAMA. 2019;321(23):2326-2336.

3.

Thompson MA, et al. Clin Infect Dis. 2020. doi: 10.1093/cid/ciaa1391

4.

Labhardt ND, et al. JAMA. 2018;319(11):1103-1112.

5.

Coffey S, et al. AIDS. 2019;33(5):825-832.

6.

US Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and Adolescents. 2019. Accessed December 1, 2020. https://bit.ly/3oAt4xN-idse

7.

Torok ME, et al. Clin Infect Dis. 2011;52(11):1374-1383.

• (DRV/c or DRV/r) plus (TAF or TDF)a plus (FTC or 3TC) (AI) • (ATV/c or ATV/r) plus (TAF or TDF)a plus (FTC or 3TC) (BI) • (DRV/c or DRV/r) plus ABC/3TC—if HLA-B*5701 negative (BII)

NNRTI Plus 2 NRTIs:

8.

Boulware DR, et al. N Engl J Med. 2014;370(26):2487-2498.

9.

Abdool Karim SS, et al. N Engl J Med. 2010;362(8):697-706.

10.

IAVI and Scripps Research join efforts with NIH to expedite development of globally accessible and affordable HIV antibody combination products. July 9, 2020. Accessed October 23, 2020. https://bit. ly/3fVVIWS-IDSE

11.

ViiV Healthcare receives FDA breakthrough therapy designation for investigational, long-acting cabotegravir for HIV prevention; November 17, 2020. https://bit.ly/3luONVM-IDSE

12.

Apostolova N, et al. J Antimicrob Chemother.

2015;70(10):2693-2708.

13.

Llibre JM, et al. Lancet. 2018;391(10123):839-849.

14.

Cahn P, et al. Lancet. 2019;393(10167):143-155.

15.

Cahn P, et al. J Acquir Immune Defic Syndr. 2020;83(3):310-318.

16.

van Wyk J, et al. Clin Infect Dis. 2020;71(8):1920-1929.

17.

Molina JM, et al. Lancet HIV. 2020;7(1):e16-e26.

18.

Molina JM, et al. Lancet HIV. 2018;5(5):e211-e220.

19.

Bajema KL, et al. AIDS. 2020;34(14):2051-2059.

• DOR/TDFa/3TC (BI) or DOR plus TAFa/FTC (BIII) • EFV plus (TAF or TDF)a plus (FTC or 3TC) • EFV 600 mg plus TDF plus (FTC or 3TC) (BI) • EFV 400 mg/TDF/3TC (BI) • EFV 600 mg plus TAF/FTC (BII) • RPV/(TAF or TDF)/FTC (BI)—if HIV RNA <100,000 copies/mL and CD4 count >200 cells/mm3

Regimens to Consider When ABC, TAF, And TDF Cannot Be Used or Are Not Optimal: • DTG/3TC (AI), except for individuals with HIV RNA >500,000 copies/mL, HBV coinfection, or in whom ART is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available • DRV/r plus RAL twice a day (CI)—if HIV RNA <100,000 copies/mL and CD4 count >200 cells/mm3 • DRV/r once daily plus 3TCa (CI)

20.

Emu B, et al. N Engl J Med. 2018;379(7):645-654.

21.

Nowicka-Sans B, et al. Antimicrob Agents Chemother.

2012;56(7):3498-3507.

22.

Kozal M, et al. N Engl J Med. 2020;382(13):1232-1243.

23.

Wu HY, et al. SSRN. 2018. doi: dx.doi.org/10.2139/ssrn.3309414

Rating of Recommendations: A = Strong; B = Moderate; C = Optional

24.

Rating of Evidence: I = Data from randomized controlled trials; II = Data from well-designed nonrandomized trials, observational cohort studies with long-term clinical outcomes, relative bioavailability/bioequivalence studies, or regimen comparisons from randomized switch studies; III = Expert opinion

Albuvirtide and 3BNC117 as long-acting maintenance therapy in virologically suppressed subjects. Accessed October 23, 2020. https://clinicaltrials.gov/ct2/show/NCT03719664

25.

Molina J, et al. 2020 International Congress on Drug Therapy in HIV Infection; October 5-8, 2020; Glasgow, United Kingdom. Abstract O415.

26.

Barrett SE, et al. Antimicrob Agents Chemother. 2018;62(10).

27.

Schurmann D, et al. Lancet HIV. 2020;7(3):e164-e172.

28.

D’Amico R, et al. 2020 International Congress on Drug Therapy in HIV Infection; October 5-8, 2020; Glasgow, United Kingdom. Abstract O414.

a

TAF and TDF are two forms of TFV approved by FDA. TAF has fewer bone and kidney toxicities than TDF, while TDF is associated with lower lipid levels. Safety, cost, and access are among the factors to consider when choosing between these drugs.

Note: The following are available as coformulated drugs: ABC/3TC, ATV/c, BIC/ TAF/FTC, DOR/TDF/3TC, DRV/c, DRV/c/TAF/FTC, DTG/3TC, DTG/ABC/3TC, EFV (400 mg or 600 mg)/TDF/3TC, EFV/TDF/FTC, EVG/c/TAF/FTC, EVG/c/ TDF/FTC, RPV/TAF/FTC, RPV/TDF/FTC, TAF/FTC, TDF/3TC, and TDF/FTC. 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; ARV, antiretroviral; ATV, atazanavir; ATV/c, atazanavir/cobicistat; ATV/r, atazanavir/ritonavir; BIC, bictegravir; CD4, CD4 T lymphocyte; DOR, doravirine; DRV, darunavir; DRV/c, darunavir/cobicistat; DRV/r, darunavir/ritonavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; EVG/c, elvitegravir/cobicistat; FDA, Food and Drug Administration; FTC, emtricitabine; HLA, human leukocyte antigen; INSTI, integrase strand transfer inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; RAL, raltegravir; RPV, rilpivirine; STR, single-tablet regimen; TAF, tenofovir alafenamide; TFV, tenofovir; TDF, tenofovir disoproxil fumarate

Reproduced from Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Adult and Adolescent Panel on Antiretroviral Guidelines for Adults and Adolescents. Department of Health and Human Services.

Accessed November 20, 2020. https://clinicalinfo.hiv.gov/en/guidelines/ adult-and-adolescent-arv/what-start-initial-combination-regimens-antiretroviral-naive

74

IDSE.NET

About the Authors Hind Alrowais, MD, is an infectious diseases fellow at Ochsner Medical Center in New Orleans, Louisiana.

Amy K. Feehan, PhD, is a clinical infectious disease research scientist at Ochsner Health.

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

WINTER 2020

JUNE 2019

CLASSIFIEDS

3HQQ 6WDWH +HDOWK 0LOWRQ 6 +HUVKH\ 0HGLFDO &HQWHU LV VHHNLQJ D 0HGLFDO 'LUHFWRU RI WKH +,9 $,'6 $GXOW ,QIHFWLRXV 'LVHDVH SURJUDP LQ VFHQLF +HUVKH\ 3HQQV\OYDQLD What Weâ&#x20AC;&#x2122;re Offering: â&#x20AC;˘ Competitive salary with comprehensive beneďŹ t and retirement package â&#x20AC;˘ Rank will be commensurate with experience â&#x20AC;˘ Join a high quality program with a national reputation for teaching, research, and patient care â&#x20AC;˘ Participation in Resident and Medical Student education â&#x20AC;˘ Relocation Assistance â&#x20AC;˘ No J1 visa waiver opportunities

FOR MORE INFORMATION PLEASE CONTACT:

Heather PefďŹ&#x201A;ey, PHR FASPR Physician Recruiter Penn State Health Email: hpefďŹ&#x201A;ey@pennstatehealth.psu.edu Website: careers.pennstatehealth.org

What Weâ&#x20AC;&#x2122;re Seeking: â&#x20AC;˘ MD, DO, or foreign equivalent â&#x20AC;˘ Completion of accredited training program â&#x20AC;˘ Ability to acquire a medical license in the Commonwealth of Pennsylvania â&#x20AC;˘ BE/BC by ABIM

What the Area Offers: Located in a safe family-friendly setting, Hershey, PA, our local neighborhoods boast a reasonable cost of living whether you prefer a more suburban setting or thriving city rich in theater, arts, and culture. Known as the home of the Hershey chocolate bar, Hersheyâ&#x20AC;&#x2122;s community is rich in history and offers an abundant range of outdoor activities, arts, and diverse experiences. Weâ&#x20AC;&#x2122;re conveniently located within a short distance to major cities such as Philadelphia, Pittsburgh, NYC, Baltimore, and Washington DC.

Penn State Health is fundamentally committed to the diversity of our faculty and staff. We believe diversity is unapologetically expressing itself through every personâ&#x20AC;&#x2122;s perspectives and lived experiences. We are an equal opportunity and afďŹ rmative action employer. All qualiďŹ ed applicants will receive consideration for employment without regard to age, color, disability, gender identity or expression, marital status, national or ethnic origin, political afďŹ liation, race, religion, sex (including pregnancy), sexual orientation, veteran status, and family medical or genetic information.

For classified advertising, contact Craig Wilson 212-957-5300 x235 â&#x20AC;˘ cwilson@mcmahonmed.com

75

What is the power of the microbiome?

...and how can it be unlocked to treat disease?

UNLOCK THE POTENTIAL AT POWEROFMICROBIOME.COM Ferring is committed to exploring the crucial link between the gut microbiome and the threat of recurrent Clostridioides difficile infections. With the 2018 acquisition of Rebiotix and several other alliances, Ferring is rapidly advancing its microbiome research, Š2020 Ferring B.V. US-MBIO-2000020

developing novel therapies to address significant unmet needs in deadly and debilitating diseases, and helping people live better lives.