Let’s face it, delivering the news to a patient that they’re HIV positive is still incredibly hard. The stigma and misinformation around HIV are overwhelming and their life is forever changed. But, thanks to treatment advances, I can tell my patients with conviction that advancing in their career, growing old with their loved ones, having children–these things all remain possible. 

We’ve come a long way since the first antiretroviral drug (ARV) was approved. Since then, many different powerful classes of drugs have been approved, and we evolved from taking many drugs, multiple times a day, to taking one pill a day for many patients. The evolution prompted researchers to challenge the belief that HIV needed to be managed by three or more medicines. They were onto something, and the hypothesis for two-drug regimens was then validated by numerous peer-reviewed and pivotal studies in both treatment-naïve and virologically suppressed patients.

DOVATO (dolutegravir [DTG] 50 mg, and lamivudine [3TC] 300 mg) was the first complete, two-drug regimen approved by the U.S. Food and Drug Administration for adults starting and switching ARV regimens with no known resistance to its two components. DOVATO is indicated for treatment-naïve and virologically suppressed adults with HIV-1. See full indication below.

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. 

Please see full Important Safety Information below.

In addition, DOVATO is strongly recommended as an 

initial regimen for most people living with HIV

 and as a regimen for most virologically suppressed adults by the DHHS Antiretroviral Treatment Guidelines, marking the first time a complete, two-drug regimen has been recommended by the DHHS in the treatment-naïve setting. The AI* rating DOVATO received is the highest rating, meaning it is backed by the highest level of evidence. There are three exceptions in these guidelines, reflective of the exclusion criteria in the pivotal GEMINI 1 & 2 trials which supported the approval of DOVATO. Specifically, DOVATO is not recommended for use in individuals with HBV co-infection, those who will start antiretroviral therapy before results of HIV genotypic resistance testing for RT or HBV testing are available, or those who have HIV RNA >500,000 copies/mL. 

So why does this matter? Many living with HIV will be on treatment for decades. To deliver on my commitment that everything is possible, I focus on long-term treatment goals like reducing the number of ARVs taken per day. These considerations often point me toward a two-drug regimen, like DOVATO.

The most incredible realization is that HIV treatment research is now centered around the patient. Whether that’s examining regimens or removing medicines, we’re helping to navigate the HIV treatment journey. Recently, I prescribed DOVATO for a young man who was just about to start college. It was important for me to anticipate both short-term and long-term side effects and toxicities as he moves into the future.

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.

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.

Do not use DOVATO in patients with previous hypersensitivity reaction to dolutegravir or lamivudine

Do not use DOVATO in patients receiving dofetilide

Hypersensitivity reactions have been reported with dolutegravir and were characterized by rash, constitutional findings, and sometimes organ dysfunction, including liver injury

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

Hepatic adverse events have been reported, including cases of hepatic toxicity (elevated serum liver biochemistries, hepatitis, and acute liver failure), in patients receiving a dolutegravir-containing regimen without pre-existing hepatic disease or other identifiable risk factors

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

Monitoring for hepatotoxicity is recommended

Alternative treatments to DOVATO should be considered at the time of conception through the first trimester of pregnancy due to the risk of neural tube defects

Perform pregnancy testing before use of DOVATO and counsel that consistent use of effective contraception is recommended while using 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 findings suggestive of lactic acidosis or pronounced hepatotoxicity develop, including hepatomegaly and steatosis in the absence of marked transaminase elevations.

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).

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

The most common adverse reactions (incidence ≥2%, all grades) with DOVATO were headache (3%), nausea (2%), diarrhea (2%), insomnia (2%), fatigue (2%), and anxiety (2%).

Consult full Prescribing Information for DOVATO for more information on potentially significant drug interactions

DOVATO is a complete regimen. Coadministration with other antiretroviral medications for the treatment of HIV-1 infection is not recommended

Drugs that induce or inhibit CYP3A or UGT1A1 may affect the plasma concentrations of dolutegravir

Administer DOVATO 2 hours before or 6 hours after taking polyvalent cation-containing antacids or laxatives, sucralfate, oral supplements containing iron or calcium, or buffered medications. Alternatively, DOVATO and supplements containing calcium or iron can be taken with food

There are insufficient human data on the use of DOVATO during pregnancy to definitively assess a drug-associated risk for birth defects and miscarriage. An Antiretroviral Pregnancy Registry has been established. If planning a pregnancy or if pregnancy is confirmed while taking DOVATO during the first trimester, assess the risks and benefits of continuing DOVATO versus switching to another antiretroviral regimen. For individuals actively trying to become pregnant, initiation of DOVATO is not recommended unless there is no suitable alternative

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

Females and Males of Reproductive Potential: 

Perform pregnancy testing before initiation of DOVATO. Advise individuals of childbearing potential to consistently use effective contraception while taking DOVATO

DOVATO is not recommended for patients with creatinine clearance <50 mL/min

DOVATO is not recommended in patients with severe hepatic impairment (Child-Pugh Score C)

* “A” standing for strongly recommended by an expert panel and “I” for having undergone one or more randomized trials with positive clinical outcomes and/or validated laboratory end points.

For US HCPs only.
Trademarks are owned by or licensed to the ViiV Healthcare group of companies.
©2020 ViiV Healthcare or licensor.
DLLOGM200008 December 2020
Produced in USA.

Opinion: HIV Management Is Ready for A Long-Term View

Anthony Mills, MD

Immunocompromised patients are at elevated risk of complications from primary and reactivation infections with herpesviruses, including varicella zoster virus (VZV) and human papillomavirus (HPV). In the past several decades, vaccines have been become available to prevent primary VZV infection (chickenpox), reactivation VZV infection (herpes zoster, or shingles), and primary HPV infection, and all are routinely recommended for distinct age groups in the general population.

The presence of immunocompromise requires special attention to several aspects of vaccination. The first is safety: Live attenuated vaccines are “weakened” but potentially have viable virus. This may cause disseminated infection in severely immunocompromised patients, and live vaccines are therefore generally avoided. Inactivated vaccines do not contain live virus and cannot cause disseminated infection; therefore, they are safer. However, many inactivated vaccines contain adjuvants, which might theoretically increase the risk of rejection and/or graft-versus-host disease (GVHD) in solid organ transplant (SOT)

 and allogeneic hematopoietic stem cell transplant (HSCT) recipients, respectively.

 The second consideration is efficacy: Immunocompromised patients may not mount the expected immune response to a vaccine and may therefore derive less benefit.

As a general principle, vaccines should be administered prior to initiation of immunosuppression whenever feasible (eg, patients being listed for SOT should be vaccinated prior to transplant). Live vaccines should be administered 4 weeks or more prior to initiation of immunosuppression, and they should especially be avoided within 2 weeks prior to immunosuppression given the risk of developing disseminated disease. Inactivated vaccines should be given at least 2 weeks prior to immunosuppression to allow time for an adequate immune response.

In this article, we will discuss the specifics of VZV and HPV in immunocompromised patients, with a specific focus on vaccine safety and efficacy in this population. The 

 gives a summary of recommendations by type of immunosuppression.

Immunocompromised patients who contract primary varicella infection are at risk for disseminated disease, and they have a several-fold increased risk of death compared with their immunocompetent counterparts.

 The first varicella vaccine was approved in 1995 for the prevention of primary VZV infection in susceptible children and adults. It is available in 2 formulations, both of which are live attenuated: a single-antigen formulation (VAR; Varivax), licensed for use in patients 12 months or older, and a combination formulation with measles, mumps, and rubella (MMRV; ProQuad), licensed only for use in patients aged 12 months to 12 years. MMRV contains a 7-fold higher dose of varicella antigen than the single-antigen formulation,

 and it is not recommended for use in any immunocompromised population. VAR is given as 2 doses at at ages 12-15 months and age 4-6 years for children, and 2 doses at least 4 weeks apart for patients 13 years and older.

VAR is recommended prior to immunosuppression for patients without evidence of varicella immunity, as long as it can be given 3-4 weeks prior to starting immunosuppression. It is also recommended for patients with HIV and CD4 greater than 200 cells/mm3, and for patients with primary immune deficiencies without defects in T-cell–mediated immunity. It can be considered for patients on long-term low-level immunosuppression (ie, patients receiving steroids equivalent to £ 20 mg of prednisone daily; patients on low-dose methotrexate or azathioprine). As a live vaccine, it is contraindicated in patients who are highly immunosuppressed, including SOT and HSCT recipients.

 There have been reports of disseminated varicella due to the vaccine in this population.

VAR has been shown to be safe, effective, and immunogenic in children with HIV and CD4 percentages of at least 15%.

 Data on the immunogenicity of the vaccine in the other immunocompromised populations who can safely receive it are lacking.

Immunosuppressed patients are similarly at increased risk of disseminated infection and complications of herpes zoster. Two zoster vaccines exist but only 1 remains available in the United States.

 No longer available is the older of these, known as zoster vaccine live (ZVL; Zostavax), which was approved in 2006. A live attenuated vaccine, ZVL contains 13 to 44 times as much VZV antigen as VAR. The newer zoster vaccine, available since 2017, is called recombinant zoster vaccine (RZV; Shingrix) and is a recombinant glycoprotein E vaccine. Systematic reviews suggested that RZV is more effective than ZVL in reducing the incidence of herpes zoster

 and RZV is now preferred in most clinical contexts.

Zoster vaccination is indicated for immunocompetent patients 50 years and older. There is no evidence for earlier vaccination in immunocompromised populations, with the exception of patients who have undergone autologous HSCT; autologous HSCT recipients 18 years and older may receive the RZV series starting 50 to 70 days post transplant, on the strength of a 2019 randomized controlled trial (RCT) showing RZV vaccination to be both safe and effective in reducing the incidence of herpes zoster in this population.

 Like other live vaccines, ZVL is contraindicated in many immunocompromised patients; it can be considered for patients with anticipated or low-level immunosuppression and for patients with HIV and CD4200 cells/mm3or greater. In the latter group, it has been shown to be safe and immunogenic.

For patients with higher-level immunosuppression, RZV is generally considered relatively safe, although for SOT and allogeneic HSCT recipients, there is a theoretical risk that the immune activation generated by the vaccine adjuvant could increase the risk of organ rejection or GVHD. A recent RCT enrolling renal transplant recipients 4 to 18 months post transplant found that RZV induced an immunologic response without increasing the incidence of adverse events, including rejection

; a similar study in lung transplant recipients is ongoing.

 For now, the current recommendation of the American Society of Transplantation and Infectious Diseases Community of Practice is that RZV use for posttransplant patients be determined on an individual basis using clinical judgment.

 Data for RZV use in allogeneic HSCT recipients are lacking. RZV has been shown to be safe and immunogenic in patients with HIV,

 and it is the preferred zoster vaccine for this population (although an official recommendation from the US Department of Health & Human Services is pending).

The HPV vaccine has been available since 2006 for the prevention of HPV-related cancers (eg, cervical, anal, vulvar, vaginal, and oropharyngeal cancers) and genital warts. Previous iterations have included a quadrivalent and a bivalent formulation; the formulation currently available in the United States is a 9-valent vaccine (Gardasil 9) and is recommended for unvaccinated immunocompetent females and males starting when aged 11 to 12 years, through 26 years. The vaccine is FDA approved for use through 45 years, and the Advisory Committee on Immunization Practices recommends shared decision-making for patients aged 26 to 45 years.

 For immunocompetent patients 11 years or older, and for all immunocompromised patients, it is given as a 3-dose series, at 0, 1 to 2, and 6 months.

Immunocompromised patients are at significantly elevated risk of HPV-related cancers,

 and because the vaccine is considered safe, immunocompromised patients should be vaccinated according to the usual age guidelines. In patients with HIV, the quadrivalent vaccine is well tolerated and produces high rates of seroconversion in patients both on and off antiretroviral therapy.

 Although immunogenicity is lower in patients with CD4 less than 200 cells/mm3, seroconversion rates are still in the 70% to 90% range, depending on the serotype.

 Data for immunogenicity in patients with immunocompromising conditions other than HIV are more limited. A study of the quadrivalent HPV vaccine in 50 SOT recipients found that the vaccine series produced seroconversion in 53% to 68% of subjects, in contrast to 97% to 99% of immunocompetent patients in prior studies.

Immunocompromised patients have a higher burden of VZV- and HPV-associated disease. As such, immunization becomes a key strategy to prevent the occurrence of disease. Guiding principles for the administration of vaccines include as follows:

Administer vaccines 2 to 4 weeks before solid organ transplantation.

If this is not possible, give vaccines (or missed doses) 3 to 6 months following solid organ transplantation to maximize productive antibody response.

In general, do not use live vaccines (such as ZVL) in immunocompromised patients.

For VZV, we recommend RZV whenever possible as it is safe (inactivated virus) and effective. For autologous HSCT patients, we recommend RZV for recipients 18 years and older. For all other immunocompromised patients, we recommend RZV for those 50 years or older, administered prior to solid organ transplantation if possible. Fewer data exist for patients who have received solid organ transplants and for allogeneic HSCT recipients, so we recommend RZV vaccination on an individual basis (Table). For HPV, we recommend offering the nine-valent vaccine to all immunocompromised patients aged 11 to 26 years.

Catherine DeVoe, MD, is a second-year fellow in Infectious Diseases at the University of California, San Francisco. Her research and clinical interests focus on immunocompromised hosts, with a particular emphasis on patients with hematologic malignancies.

Peter Chin-Hong, MD, is Professor of Medicine and director of the immunocompromised host infectious diseases program at the University of California, San Francisco. His primary research interests include donor derived infections in solid organ transplant recipients and molecular diagnostics for infectious diseases in immunosuppressed patients.

Vaccination for VZV and HPV requires special consideration in immunocompromised patients. They are at risk for more severe viral illnesses if not immune, but they may also have decreased response to, and increased adverse effects from, vaccines.

Varicella Zoster Virus and Human Papillomavirus Vaccination in Immunocompromised Patients

Catherine DeVoe, MD, and Peter Chin-Hong, MD

Winter, riding in on the coattails of autumn, is just starting to make its appearance. The leaves have tumbled gracefully from the trees, and the bite in the air and the possibility of snow on the ground has forced some of us to don our insulated clothing and cozy up indoors with the fireplace crackling in the background. Despite the familiarity and comfort during this time of year, there is also uncertainty––a foreign, unknown, obscure landscape that we are still learning to navigate: coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has upended our lives this year. Despite the continued threat of this pandemic, there are large family gatherings, holiday traveling, and crowding together in celebration for sporting events (read: Chiefs or in Nebraska, Huskers). Although SARS-CoV-2 has become the elephant in the room during such gatherings, it isn’t alone at this party; there are also the frequent sniffles, sneezes, and coughs from the variety of seasonal respiratory viruses that arrive as unwanted party guests.

Typically, it is at this time of year that we tend to see many respiratory viruses surface. Influenza has been of most concern, historically, with its ability to cause life-threatening disease and its tendency to mutate and spread rapidly, which has resulted in past pandemics. But now we have a new guest––SARS-CoV-2––and we realize that we are unsure how it will play with the others. Will it start to peak in a similar fashion? What about its impact on coinfections that are known to occur with the other seasonal respiratory viruses? Let’s first take a look at how SARS-CoV-2 compares with our standard seasonal viruses.

COVID-19 and other respiratory viruses have similar clinical presentations, creating difficulty in differentiating them without a diagnostic test. Although asymptomatic infections do occur, these infections, including COVID-19, generally exhibit an overlapping influenza-like illness: cough, shortness of breath, muscle aches, fatigue, sore throat and runny nose, headaches, and fever are among the more common symptoms.

 There are some less common, though notable symptoms, such as loss of taste and smell or gastrointestinal complaints such as nausea and diarrhea, that are more specific to COVID-19 and thus may help differentiate it.

 However, this all becomes even more difficult to distinguish based on symptoms alone with coinfections of 2 or more pathogens.

Overall, most respiratory viruses cause a relatively mild illness, though there are several viruses (Respiratory syncytial virus (RSV) and influenza) that can have a more severe course. Whereas many people recover without complications, there are certain groups of people who are at higher risk for developing more severe disease or complications from infection, especially with SARS-CoV-2 and influenza: older adults and those with certain underlying medical conditions are among the highest-risk populations.

All the above can be summarized thusly: although there are some differences between COVID-19 and other common seasonal respiratory viruses, there are plenty of similarities with significant overlap, and the courses of such viruses are relatively well understood. But there is one aspect in which we still don’t have much experience and that we may start to encounter shortly: what happens when a person becomes infected with COVID-19 and another respiratory virus (especially influenza), a phenomenon we refer to as coinfection?

We know that infection with different, yet simultaneous, respiratory viruses does occur.

 Virus-specific interactions play a key role in the morbidity and mortality of respiratory viral coinfections, but our understanding of this concerning even our typical pathogens is limited; the introduction of SARS-CoV-2 raises even more questions.

 Early in the COVID-19 pandemic, there were reports of coinfection in various parts of the world. One particular study in northern California revealed that of 116 patients with COVID-19, 21% exhibited coinfections, with the most common being rhinovirus, RSV, and other types of coronaviruses.

 Additionally, there were some reports of coinfection with influenza in particular that demonstrated a subset of patients progressing to severe disease.

 Although the data are far from definitive due to the limited number of patients and the varying treatment modalities employed for them, there were suggestions in these cases that persons who were coinfected with SARS-CoV-2 and another respiratory virus had severe disease and poor outcomes.

Ultimately, it is unclear if influenza and COVID-19 will peak at the same time this season, nor do we fully understand the interactions between the 2 viruses within an individual. Yet reason for concern remains as both viruses cause life-threatening illness in certain populations and have very different ways in which clinicians approach their treatment, potentially impacting those who do develop coinfection with influenza and COVID-19. Due to the differences in treatment, rapid, easily accessible, and reliable testing for a broad variety of respiratory viruses has been a focus of diagnostics, leading to both the development of a combination SARS-CoV-2/influenza multiplex PCR assay and the inclusion of SARS-CoV-2 on a revised respiratory pathogen panel that detects nearly 2 dozen viral and bacterial pathogens.

Prevention and Management of Coinfection with COVID-19

Most seasonal respiratory viruses are self-limited (that is, people tend to recover without the assistance of medication that targets the virus). Influenza and SARS-CoV-2 can be exceptions, as there are certain circumstances and specific populations in which treatment is recommended. For influenza, this is typically with the antiviral oseltamivir (Tamiflu), which is given to patients who require hospitalization, especially those with severe disease, or to high-risk populations. For COVID-19, on the other hand, although there are many ongoing trials to determine what works best, the most recent National Institutes of Health guidelines recommend the use of the antiviral remdesivir, often with dexamethasone, in hospitalized patients.

 The effects of administering oseltamavir and remdesivir to those who are simultaneously infected with both viruses are unknown, but clinicians have found that steroids, which have become important in the treatment of COVID-19, worsen outcomes with influenza. This makes treatment decisions in coinfection more convoluted, as the optimal treatment is currently unknown.

Most important, however, as we move into this season, will be our efforts to mitigate the spread of infection. Social distancing, hand hygiene, and wearing masks remain crucial to preventing the spread of COVID-19, with similar effects on seasonal respiratory viruses. Vaccinations, similarly, have an important role in mitigation efforts; we do have a safe and reasonably effective influenza vaccine, which will become that much more important to receive this year, particularly while we await the completion of COVID-19 vaccination trials.

We have witnessed the severity and intensity with which both influenza and COVID-19 can strike, and we are uncomfortably aware of how quickly and efficiently both can permeate a population.

 Therefore, as we enter the season when influenza and other respiratory viruses are most prominent, while remaining very much in the midst of the COVID-19 pandemic, we must become more vigilant in our public health and research efforts to prepare for a rise in such coinfections.

Clayton Mowrer, DO, MBA, is a PGY2 ID fellow in internal medicine/pediatrics infectious diseases at the University of Nebraska Medical Center in Omaha.

Kelly Cawcutt, MD, MS, is Assistant Professor, Divisions of Infectious Diseases and Pulmonary and Critical Care Medicine, Associate Director of Infection Control and Hospital Epidemiology, Co-Director of Digital Innovation & Social Media Strategy for the Division of Infectious Diseases at the University of Nebraska Medical Center.

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Antony SJ, Almaghlouth NK, Heydemann EL. Are coinfections with COVID‐19 and influenza low or underreported? An observational study examining current published literature including three new unpublished cases. 

. 2020;92(11):2489-2497. doi:10.1002/jmv.26167

Ashley H. COVID-19 and the Flu. American Society for Microbiology. Published August 1, 2020. Accessed October 22, 2020. 

Huang C, Wang Y, Li X, et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. 

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Chen N, Zhou M, Dong X, et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study. 

. 2020;395(10223):507-513. doi:10.1016/s0140-6736(20)30211-7

Hu B, Guo H, Zhou P, Shi ZL. Characteristics of SARS-CoV-2 and COVID-19. 

. Published October 6, 2020. doi:10.1038/s41579-020-00459-7

Coronavirus disease 2019 (COVID-19): people with certain medical conditions. Centers for Disease Control and Prevention (CDC). Updated October 16, 2020. Accessed October 30, 2020. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html?CDC_AA_refVal=https%3A%2F%2Fwww.cdc.gov%2Fcoronavirus%2F2019-ncov%2Fneed-extra-precautions%2Fgroups-at-higher-risk.html

Coronavirus disease 2019 (COVID-19): older adults. CDC. Updated September 11, 2020. Accessed October 1, 2020. 

https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/older-adults.html

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Holiday Guest List—When the Uninvited Arrive: COVID-19 and Coinfections

Clayton Mowrer, DO, MBA; and Kelly Cawcutt, MD, MS, FACP

Regulatory requirements have underscored the role of 

 programs (ASPs), leading to their increased presence in hospitals.

 Although ASPs have demonstrated the ability to improve antimicrobial use and patient outcomes, concerns have been described regarding task-shifting away from infectious diseases consultation (IDC) because it purportedly antagonizes colleagues in other specialties; an overall reduction in IDCs has occurred as a result.

 In contrast, published data suggest that ASPs can actually increase the number of IDCs, since ASPs typically delineate roles separate from those of IDCs.

 IDC services are patient-focused and include direct communication with patients and making patient-specific plans, whereas ASPs are typically focused on activities that are more administrative in nature, such as developing institutional guidelines, updating antibiograms, and evaluating antimicrobial metrics.

 However, in hospitals with robust ASPs there may be overlapping patient care activities, because members of the ASP often perform prospective audits and provide patient-specific recommendations. So what is the impact of IDC in the presence of a well-established ASP?

Bork and colleagues sought to evaluate antibiotic use among patients with and without IDC in a hospital with robust ASP services.

 This was a cross-sectional retrospective analysis of inpatients at the University of Maryland Medical Center (UMMC), a large tertiary care center with a comprehensive IDC program consisting of 6 inpatient adult IDC services and primary ID service. Institutional policies promote pervasive influence by IDC, as IDC is required within 24 hours of ordering a restricted antimicrobial and is also required upon starting any antimicrobial for the treatment of infection among patients in the oncology ward, medical intensive care unit (ICU), or trauma services.

UMMC also has an established ASP with 2 ID physicians and 3 ID pharmacists. Prospective audit and feedback are the mainstay of the ASP, which is performed on all active antimicrobial orders started for treatment within 3-5 days of starting therapy for patients without IDC, and within 4-6 days for patients being seen by the IDC service. Antimicrobial appropriateness, along with the indication and any interventions, are documented in the electronic medical record for each antimicrobial reviewed.

The study included all antimicrobial prescriptions active for more than 2 days that were reviewed by the ASP over an 18-month time period. The primary outcome was antimicrobial appropriateness defined as (1) having an indication for antimicrobial treatment, and (2) using an antimicrobial consistent with institutional guidelines or using an antimicrobial that was otherwise justified by ASP review. Appropriate antimicrobial therapies were further categorized as either “guideline-concordant” or “guideline-discordant but justified.” The investigators performed several statistical analyses to mitigate limitations of the retrospective analysis, including multivariable logistic regression, stratification by primary service, and propensity score matching.

A total of 10,507 (6615 unique patient encounters) antimicrobial prescriptions met inclusion criteria. IDC was present in most (72%) of the antibiotics reviewed. Antimicrobial prescriptions with IDC were more likely to be a restricted antimicrobial and written for patients in the ICU. Patients with IDC were also more likely to have positive cultures and be colonized with organisms that were multidrug resistant.

Appropriate therapy was greater among antimicrobials with IDC compared with those without IDC (94% vs 84%; 

<.0001). Unsurprisingly, “guideline-discordant but justified” antimicrobials occurred more frequently with IDC than without IDC (9% vs 5%; 

 <.0001). After propensity score matching, the sample size decreased to 3566 with relatively improved distribution of baseline characteristics. In the propensity score matched sample, IDC was positively associated with antimicrobial appropriateness (OR, 2.5; 95% CI, 2.1-3.0) and the difference in appropriate therapy remained (93% with IDC vs 85% without IDC; 

<.0001). When stratified by primary service, IDC improved antimicrobial appropriateness among both the medical and surgical specialties, with the greatest benefit among surgical specialties. The authors conclude that IDC and ASPs may be synergistic.

Several considerations potentially limit the reproducibility of these results in other hospitals. The intensive and pervasive IDC and ASP services at the study site are one important reason. At UMMC, the ASP and IDC services appear well-established and appropriately resourced, allowing the evaluation of a large proportion of patients receiving antibiotics. Institutions with an imbalance of resources for the ASP and/or IDC services may not observe such high rates of antimicrobial appropriateness and the results may skew in favor of the service, with its improved ability to provide direct patient care services to a great proportion of patients. For example, in hospitals with ASPs that are unable to perform prospective audit and feedback on all antimicrobials, the baseline rate of appropriateness may be lower, potentially leading to a larger improvement with IDC. In this study, most patients were seen by IDC and all patients were prospectively evaluated by the ASP. Additionally, reviewer bias may have skewed the results, as only antimicrobials reviewed by the ASP were included in the analysis and appropriateness was determined by an unblinded ASP team member. Reviews were also performed later in the course of therapy for antimicrobials with IDC, which may have allotted more time for diagnostic tests and antimicrobial adjustments.

Overall, well-resourced centers with robust IDC services are best able to relate to these findings, which demonstrate the benefits of IDC even in the presence of a well-established ASP. Some centers, particularly those with other strong subspecialties, may have providers who are reluctant to consult ID. These findings underscore the benefits of bedside IDC services and add to the current body of published literature that supports the relationship between IDC and ASPs. ASPs can also use these data to quell fears of an ASP overtaking. Working together, IDC and ASPs can optimize antimicrobial use, particularly for more nuanced cases that fall outside of ASP guideline recommendations.

Highlighted Study: Bork JT, Claeys KC, Heil EL, et al. A propensity score matched study of the positive impact of infectious diseases consultation on antimicrobial appropriateness in hospitalized patients with antimicrobial stewardship oversight. 

. 2020;64(8):e00307-20. doi:10.1128/AAC.00307-20

Cynthia Nguyen, PharmD, is an infectious diseases clinical pharmacy specialist at the University of Chicago Medicine. She is an active member of the Society of Infectious Diseases Pharmacists, Society for Healthcare Epidemiology of America, and American College of Clinical Pharmacy.

1. The Joint Commission. 2020 Comprehensive Accreditation Manual for Hospitals. Joint Commission Resources, 2019.

2. Sunenshine RH, Liedtke LA, Jernigan DB, Strausbaugh LJ; Infectious Diseases Society of America Emerging Infections Network. Role of infectious diseases consultants in management of antimicrobial use in hospitals. 

3. Morrill HJ, Gaitanis MM, LaPlante KL. Antimicrobial stewardship program prompts increased and earlier infectious diseases consultation. 

4. Beach JE, Ramsey TD, Gorman SK, Lau TTY. Roles of infectious diseases consultant pharmacists and antimicrobial stewardship pharmacists: a survey of Canadian tertiary care academic hospitals. 

. 2017;70(6):415-422. doi:10.4212/cjhp.v70i6.1709

5. Bork JT, Claeys KC, Heil EL, et al. A propensity score matched study of the positive impact of infectious diseases consultation on antimicrobial appropriateness in hospitalized patients with antimicrobial stewardship oversight. 

Benefits of ID Consultation and ASP Collaboration

Cynthia Nguyen, PhD

The alarming rise in bacterial resistance has led to a growing need for new antibacterial drug targets. According to the World Health Organization, approximately 60% of hospital infections are resistant to at least 1 first-line therapy, leading to longer hospital stays and increased mortality and morbidity.

 Designated a “serious threat” in the CDC’s 2019 report Antibiotic Resistance Threats in the United States, methicillin-resistant 

(MRSA) accounts for more than 323,000 cases annually and causes over 10,000 deaths in the United States.

 The extensive resistance of MRSA to several antibacterial classes, along with less than ideal dosing of and therapeutic monitoring requirements for the first-line agent, vancomycin, has led to significant interest in the discovery of new antistaphylococcal agents with novel bacterial targets.

Wittke et al reported the phase 2 clinical trial results of afabicin for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) caused by 

Afabicin (AFN-1720, Debio-1450) is a first-in-class antistaphylococcal agent that works by inhibiting a key enzyme––enoyl-acyl carrier protein (ACP) reductase, or FabI––in the bacterial fatty acid synthesis pathway (FAS-II). This enzyme is responsible for producing the essential fatty acids needed for a functional cell membrane. Because the bacterial FAS-II pathway is distinct from eukaryotic fatty acid synthesis (FAS-I), enzymes in this pathway have held considerable interest for investigators as selective antibacterial drug targets.

 The FabI enzyme is a critical, rate-limiting enzyme in the FAS-II pathway. Importantly, FabI is one of several known enoyl-ACP reductase isozymes that are both species-specific and mechanistically distinct. This, coupled with the ability of some organisms to bypass FAS-II inhibition using fatty acids from the host, makes FabI a narrow-spectrum antibacterial target. Afabicin is a phosphate prodrug that is converted to the active dephosphono moiety in vivo after oral or intravenous (IV) administration (

The investigators reported results from a randomized, double-blind, double-dummy study consisting of 330 participants across 15 study centers for the treatment of ABSSSIs. A microbiological intent-to-treat (mITT) population included 284 patients with baseline 

 or pathogenic coagulase-negative staphylococcus isolated from blood or primary lesion. Participants were divided into 1 of 3 cohorts and treated for 7 to 10 days. Cohort 1 received 80 mg IV afabicin followed by 120 mg oral afabicin twice daily. Cohort 2 received 160 mg IV afabicin followed by 280 mg oral afabicin twice daily. Cohort 3 received 15 mg/kg IV vancomycin followed by 600 mg oral linezolid twice daily. There was no separate cohort for patients with polymicrobial infections with staphylococcal and nonstaphylococcal species (21.1% of the mITT population), although the investigators tracked and reported the data. The primary efficacy end point in this study was early clinical response, defined as a reduction in lesion area, erythema, and edema at 2 to 3 days post initiation. Of note, MRSA was the primary causative agent for approximately half the population in each group. Investigators reported that the early clinical response in the afabicin cohorts 1 and 2 was noninferior to that of the vancomycin/linezolid cohort 3 (94.6% and 90.1% vs 91.1%). Commonly reported adverse events in both the high-dose and low-dose afabicin groups were headache, nausea, vomiting, and diarrhea. Interestingly, the diarrhea rate in the afabicin cohorts was 50% less than that in the vancomycin/linezolid cohort.

The results of this clinical trial suggest that afabicin has the potential to be an antistaphylococcal drug of similar efficacy to vancomycin. The availability of oral and IV formulations, as with linezolid, would alleviate the complexities associated with switching from IV to oral antibiotics for severe infections. However, although linezolid has broad gram-positive activity, afabicin possesses narrow-spectrum activity, which will limit the use of the drug to confirmed staphylococcal infections, including MRSA. Additionally, this drug is unlikely to be effective against gram-negative bacteria due to difficulties with cell penetration.

 With limited potential as an empiric treatment, it is likely that rapid diagnostic tests would be needed with afabicin, although this could result in quicker time to targeted therapy. Anticipated advantages of afabicin’s narrow-spectrum activity include a limited microbiome impact, mitigation of antibiotic resistance, and decreased prevalence of infections from opportunists such as 

. Afabicin, if approved, would certainly have a place in the clinic as a 

-targeted, narrow-spectrum antibacterial agent. However, additional clinical trials with larger sample sizes are needed to further assess the drug’s safety and long-term effects.

 Wittke F, Vincent C, Chen J, et al. Afabicin, a first-in-class antistaphylococcal antibiotic, in the treatment of acute bacterial skin and skin structure infections: clinical noninferiority to vancomycin/linezolid. 

 2020;64(10):e00250-20. doi:10.1128/AAC.00250-20

Humna N. Meer is a 2nd-year professional pharmacy student at the University of Tennessee College of Pharmacy in Memphis. She previously received a bachelor of arts degree in chemistry from Hendrix College in Conway, Arkansas.

Kirk E. Hevener, PharmD, PhD, is an assistant professor of pharmaceutical sciences at the University of Tennessee College of Pharmacy in Memphis. His research focuses on the characterization and validation of narrow-spectrum antibacterial drug targets.

Ventola CL. The antibiotic resistance crisis: part 1: causes and threats. 

Antibiotic resistance threats in the United States, 2019. CDC. Updated December 2019. Accessed October 6, 2020. https://www.cdc.gov/drugresistance/pdf/threats-report/2019-ar-threats-report-508.pdf

Wittke F, Vincent C, Chen J, et al. Afabicin, a first-in-class antistaphylococcal antibiotic, in the treatment of acute bacterial skin and skin structure infections: clinical noninferiority to vancomycin/linezolid. 

. 2020; 64(10):e00250-20. doi:10.1128/AAC.00250-20

Campbell JW, Cronan JE Jr. Bacterial fatty acid biosynthesis: targets for antibacterial drug discovery. 

. 2001;55:305-332. doi:10.1146/annurev.micro.55.1.305

Hafkin B, Shinabarger D, Sweeney D, et al. Specific spectrum activity of AFN-1252 against aerobic and anaerobic bacterial pathogens. Paper presented at: 48th Annual International Conference on Antimicrobial Agents and Chemotherapy; October 25-28, 2008; Washington, DC. Abstract F1-341.

Afabicin: A Novel, Narrow-Spectrum, Antistaphylococcal Agent

Humna N. Meer, PharmD Candidate; and Kirk E. Hevener, PharmD, PhD

H1 2009 influenza with multiple organ involvement.

An African American man, aged 22 years, was admitted to the hospital with complaints of progressive weakness and hematuria. One week prior to admission, he had begun developing upper respiratory tract symptoms, including rhinorrhea and sore throat, as well as fever and chills. Four days before admission, he started experiencing muscle pain, mainly over his cervical and paraspinal muscles, as well as pain in bilateral legs. He did not take any medications, including over-the-counter pain relievers, for these symptoms.

He reported that his 4 children (aged 1, 2, 4, and 7 years) experienced similar symptoms preceding the onset of his illness. He denied alcohol or drug use, but he was an active smoker before this illness with 1.5 pack-year smoking history. He worked in a tire shop.

Upon admission to the hospital he was found to be afebrile, with blood pressure of 140/88 mm Hg. He was in no distress, with a clear lung exam, but he was tachycardic, with a heart rate of 105 beats per minute.

Laboratory studies demonstrated white blood cell count 5.9, creatinine (Cr) 1.59 mg/dL (normal range, 0.6-1.3 mg/dL; all subsequent figures in parentheses are normal ranges), calcium ionized 3.3 mg/dL (4.5-5.3 mg/dL), creatine phosphokinase (CPK) 407,176 U/L (24-195 U/L), myoglobin 33,673 ng/mL (17.4-105.7 ng/mL), C-reactive protein (CRP) 7 mg/dL (<0.9 mg/dL). Urinalysis showed zero red blood cells with large hemoglobin and protein of 300 mg/dL. Rapid strep testing of the throat was negative. However, streptozyme was positive. Throat culture collected on the day of admission was negative for group A streptococcal infection. Chest x-ray did not show any infiltrate or acute abnormality, and abdominal CT scan done in the emergency department for hematuria did not demonstrate nephrolithiasis or other abnormalities.

Liver function tests (LFTs) done 6 hours after admission showed aspartate aminotransferase (AST) 1540 U/L (0-41 U/L),alanine aminotransferase (ALT) 286 U/L (0-40 U/L), alkaline phosphatase (ALP) 50 U/L (39-130 U/L), albumin 3.3 g/dL (3.2-5.3 g/dL), and total bilirubin 0.6 mg/dL (0.3-1.2 mg/dL). As part of the workup for acute kidney injury (AKI) by nephrology, all of the following were checked and were negative: thyroid panel, antinuclear antibody, HIV, C and P ANCA, anti–JO-1, complement, and anti-GBM antibody. Uric acid was 10.1 mg/dL (2.6-7.2 mg/dL), and random urine protein was 6260 mg/L with protein (Pr)/Cr ratio of 9.2. Serum protein electrophoresis (SPEP) and urine protein electrophoresis both were negative. Blood cultures and urine culture remained negative. Kidney ultrasound showed normal kidney size and no signs of hydronephrosis. Respiratory culture from the date of admission turned positive for 

. Due to abnormal LFTs, with AST/ALT ratio more than 2, hepatitis panel was obtained; it reported negative other than positive immunoglobulin G for hepatitis A.

, he noticed red discoloration of the urine along with worsening weakness and muscle pain. He was admitted to the general medical floor with the diagnosis of rhabdomyolysis.

On day 1 of admission, Cr was 2.05 and CPK was 670,516.Both values continued to rise, with hemodialysis initiated when levels were 4.89 (Figure) and 1,271,160 (Table 2), respectively. AST peak was 4100 and ALT peak was 1043, with highest total bilirubin of 0.8 and lowest albumin level of 2.9; ALP stayed within the range of 44 to 51 and gamma-glutamyl transferase was 15 U/L (9-64 U/L). CRP also increased to 17.1 mg/dL.

A respiratory pathogen panel showed positivity for influenza H1 2009, and infectious diseases consultation was obtained. The patient was started on oseltamivir, dose-adjusted based on kidney function. For the positive streptozyme, he received 1 dose of intramuscular benzathine penicillin to prevent complications of probable recent strep infection. The patient received 2 days of intravenous (IV) ceftriaxone for positive 

Authors