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.

Articles

In the Literature

Afabicin: A Novel, Narrow-Spectrum, Antistaphylococcal Agent

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.

Stewardship & Prevention

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

The CDC reports that adherence to preexposure prophylaxis (PrEP) reduces the risk of acquiring HIV from sex by about 99% and from injection drug use by at least 74%.

 Currently, only 2 medications are approved for use as PrEP: TDF /FTC (Truvada™) and TAF/FTC (Descovy™).

Although tenofovir disoproxil fumarate/emtricitabine is currently approved for all adults in the prevention of sexually acquired HIV, tenofovir alafenamide/emtricitabine is approved only for prevention in men who have sex with men and in transgender women.

Most importantly, efficacy of these oral products relies on strict adherence, which poses a challenge for many at-risk populations.

To address this disparity, several investigational products are under development that incorporate a diverse armamentarium of options, analogous to contraceptives including but not limited to on-demand PrEP, non-oral formulations, and longer-acting agents.

Cabotegravir is an investigational integrase strand transfer inhibitor with potent antiviral activity.

 In combination with rilpivirine, its efficacy in the management of HIV has been documented.

 However, despite being well tolerated and acceptable as a long-acting injectable formulation, rilpivirine for PrEP has not moved forward into phase 3 studies because of storage and transportation limitations, and a low barrier to resistance.

 Conversely, cabotegravir is under investigation for long-acting PrEP.

 Interim analysis from HPTN 083 showed that cabotegravir 600-mg injection given every 8 weeks was statistically superior to daily tenofovir disoproxil fumarate/emtricitabine, with a 66% relative risk reduction in HIV acquisition.

 Both agents were well tolerated, and safe though injection-related adverse events were more common with cabotegravir and resistance testing data is in progress. But, the long pharmacokinetic (PK) tail of cabotegravir might complicate the management of drug adverse events in clinical practice. Secondary analysis from the HPTN 077 trial revealed that cabotegravir may remain detectable after discontinuation for nearly 3 years in males, 4 years in females, and longer exposureswere detected in higher body-mass index individuals; irrespective of sex.

Nonetheless, if approved, cabotegravir could address adherence issues. Yet, optimizing an implementation strategy for gluteal injection administration to suit patient needs will be critical component associated with this formulation of PrEP.

Dapivirineis an investigational nonnucleoside reverse transcriptase inhibitor (NNRTI) that has been studied in various formulations for the prevention of HIV.

 In two phase 3 trials (the Ring Study and ASPIRE), the monthly intravaginal ring was effective and safe with no difference in safety concerns between the dapivirine ring arm and the placebo arm.

 Effectiveness and tolerability of the monthly vaginal ring containing 25 mg dapivirine was further demonstrated in an extension study, DREAM, which estimated a 63% reduction in HIV-1 risk.

Minimal safety concerns related to dapivirine occurred in participants (7% experienced vulvovaginitis and 2% experienced severe adverse effects). However, the study lacked a contemporaneous placebo group and findings exposed a lower risk reduction in adolescent women due to poor adherence.

Currently, the monthly ring is under regulatory review by the European Medicines Agency; a 90-day vaginal ring containing 100 mg or 200 mg of dapivirine is also under investigation. The International Partnership for Microbicides (IPM) is planning to submit applications to the South African Health Products Regulatory Authority later this year, which may make the dapivirine ring available sometime in 2021 in Africa; the IPM also plans to submit an application to the FDA later this year.

 A three-month ring with 200 mg of dapivirine and 320mg of levonorgestrel is also being investigated to simultaneously offer PrEP and contraception.

Islatravir is a first-in-class long-acting nucleoside reverse transcriptase translocation inhibitor that is under investigation for use in prevention and treatment of HIV.

 Islatravir’s unique mechanism of action and pharmacokinetic profile provides flexibility in therapy formulations. In preclinical studies, islatravir dosed orally once weekly for PrEP protected against simian–human immunodeficiency virus infection.

A phase 2a trial, MK-8591-016, is currently enrolling to investigate the safety and PK of 60-mg and 120-mg islatravir doses administered orally in capsule form once monthly.

Studies have also demonstrated the safety and feasibility of islatravir triphosphateimplant.

 Modeling predicted that the levels of intracellular islatravir triphosphatewere consistent with the potential for once-yearly implantable administration. Other antiretrovirals with encouraging preclinical results for subdermal implantable PrEP include tenofovir alafenamide and cabotegravir.

Multipurpose Technologies for PrEP and Microbicides

Numerous technologies are in development to address multiple health concerns like HIV prevention and contraception in a single agent and are referred to as multipurpose prevention technology (MPT) products.

 The Population Council is working on coformulating a dual-purpose pill composed of the active pharmaceutical ingredients (APIs) in tenofovir disoproxil fumarate/emtricitabine and the combined APIs in the oral contraceptives levonorgestrel and ethinyl estradiol.

Many organizations are developing several other innovative MPTs including vaginal gel, vaginal ring, vaginal insert, diaphragm, microarray patch, rectal gel, rectal insert, long-acting injectable, an implant, and an intrauterine device. However, it will be several years before one is available.

Also underway is investigation of PC-1005 gel, a combination of an investigational NNRTI (MIV-150) plus zinc acetate and carrageenan. This is the only product designed for vaginal and rectal use targeting HIV, human papillomavirus, and herpes simplex virus simultaneously that has undergone a phase 1 study to date.

 Other early-phase explorations of MPTs include a microarray patch using cabotegravir and norelgestromin41 and a vaginal insert containing elvitegravir and tenofovir alafenamide.

An MPT that prevents HIV and sexually transmitted infections and simultaneously prevents unintended pregnancy would significantly help overcome barriers to negotiating condom use as well as adherence issues related to stigma and gender dynamics that have been seen in microbicide and PrEP trials.

Numerous microbicide products have been or will be investigated, including vaginal dosage forms (gel, film, tablet, ring, and insert) and rectal dosage forms (gel, douche, enema, suppository, and insert).

 Tenofovir 1% vaginal gel is furthest along in development, with a completed phase 3 study (FACTS 001). However, results revealed that the gel didn’t protect from HIV and adherence was a crucial factor in the unfavorable trial results.

Darunavir, maraviroc, raltegravir, and rilpivirine are also being investigated preclinically for utilization in HIV prevention as various microbicide topical products. Even though microbicides would fill an important HIV prevention need, it is imperative that any such product is safe and effective.

Immunologic approaches have been studied, include active immunization with vaccines and passive immunization with broadly neutralizing antibodies (bNAbs).

 VRC01 is the first of the bNAbs to be found safe and to advance to efficacy trials for HIV-1 prevention, with final results expected by 2021.

 Additionally, five sizeable clinical efficacy trials are underway to evaluate vaccination strategies for PrEP.

 Even with high manufacturing costs, bNAbs are expected to have favorable safety and PK profiles, potentially allowing for longer intervals between administrations. However, these immuno-prophylaxis products require intravenous administration, which may not be widely acceptable for patients.

A number of other delivery methods are in preclinical trials. Products using microneedles, fibers, enemas, mucoadhesive intravaginal tablets, thin-film polymer devices, foams, sponges, diaphragms, and nanotechnology are being investigated for PrEP.

 Early-phase studies of PK and tolerability are encouraging, but few additional data are available.

HIV prevention does not happen in isolation and there is not an ideal PrEP formulation as one size does not fit all. However, the investigational products described above address some challenges in HIV prevention by employing a mix of delivery systems that account for different transmission circumstances, discreet on-demand methods, and offer a consistent use routine that's available at every high-risk encounter or lack of adherence situation. On the contrary, these investigation therapies will not address the need for improved provider and public health education to ultimately employ positive attitudes related to HIV prevention strategies. Nonetheless, cost and overall feasibility will be additional considerations upon implementing these technologies.

Mikayla S. Johnson is in the postgraduate year 2 HIV clinical pharmacy resident at the University of Illinois at Chicago, College of Pharmacy in Chicago, Illinois.

Renata O. Smith is a clinical assistant professor at University of Illinois at Chicago College of Pharmacy and clinical pharmacy specialist in HIV/HCV/Gender affirming care at UI Health. She is the director of the PGY2 residency in HIV.

Melissa E. Badowski is a clinical associate professor at the University of Illinois at Chicago, College of Pharmacy. She provides clinical pharmacy services through telehealth to patients living with HIV in the Illinois Department of Corrections.

1. CDC. HIV prevention pill not reaching most Americans who could benefit – especially people of color. Published April 25, 2019. Accessed August 2, 2020. https://www.cdc.gov/nchhstp/newsroom/2018/croi-2018-PrEP-press-release.html

2. FDA approves second drug to prevent HIV infection as part of ongoing efforts to end the HIV epidemic. FDA. Published October 3, 2019. Accessed August 8, 2020. https://www.fda.gov/news-events/press-announcements/fda-approves-second-drug-prevent-hiv-infection-part-ongoing-efforts-end-hiv-epidemic

3. Mayer KH, Molina J-M, Thompson MA, et al. Emtricitabine and tenofovir alafenamide vs emtricitabine and tenofovir disoproxil fumarate for HIV pre-exposure prophylaxis (DISCOVER): primary results from a randomised, double-blind, multicentre, active-controlled, phase 3, non-inferiority trial. 

. 2020;396(10246):239-254. doi:10.1016/S0140-6736(20)31065-5

4. Centers for Disease Control and Prevention, US Public Health. Preexposure prophylaxis for the prevention of HIV infection in the United States—2017 update: a clinical practice guideline. 

5. Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. 

. 2012;367(5):399-410. doi:10.1056/NEJMoa1108524

6. Spreen W, Min S, Ford SL, et al. Pharmacokinetics, Safety, and Monotherapy Antiviral Activity of GSK1265744, an HIV Integrase Strand Transfer Inhibitor. 

. 2013;14(5):192-203. doi:10.1310/hct1405-192

7. Swindells S, Andrade-Villanueva J F. LONG-ACTING CABOTEGRAVIR + RILPIVIRINE AS MAINTENANCE THERAPY: ATLAS WEEK 48 RESULTS. In: 

. Accessed August 8, 2020. https://www.croiconference.org/abstract/long-acting-cabotegravir-rilpivirine-maintenance-therapy-atlas-week-48-results/

8. Tolley EE, Li S, Atujuna M, et al. Acceptability of rilpivirine LA (RPV LA): Long-acting injectable pre-exposure prophylaxis (PrEP) in HPTN 076. In: 

IXth International AIDS Society Conference on HIV Science Paris, France

9. Penrose KJ, Parikh UM, Hamanishi KA, et al. Selection of Rilpivirine-Resistant HIV-1 in a Seroconverter From the SSAT 040 Trial Who Received the 300-mg Dose of Long-Acting Rilpivirine (TMC278LA). 

. 2016;213(6):1013-1017. doi:10.1093/infdis/jiv528

10. Markowitz M, Frank I, Grant RM, et al. Safety and tolerability of long-acting cabotegravir injections in HIV-uninfected men (ECLAIR): a multicentre, double-blind, randomised, placebo-controlled, phase 2a trial. 

. 2017;4(8):e331-e340. doi:10.1016/S2352-3018(17)30068-1

11. Landovitz RJ. HPTN 083 FINAL RESULTS:Pre-exposure Prophylaxis containing long-acting injectable cabotegravir is safe and highly effective for cisgender men and transgender women who have sex with men. Presented at the: 23rd International AIDS Conference; July 7, 2020; Virtual.

12. Landovitz RJ, Li S, Eron JJ, et al. Tail-phase safety, tolerability, and pharmacokinetics of long-acting injectable cabotegravir in HIV-uninfected adults: a secondary analysis of the HPTN 077 trial. 

. 2020;7(7):e472-e481. doi:10.1016/S2352-3018(20)30106-5

13. McConville C, Major I, Devlin B, Brimer A. Development of a multi-layered vaginal tablet containing dapivirine, levonorgestrel and acyclovir for use as a multipurpose prevention technology. 

European Journal of Pharmaceutics and Biopharmaceutics

. 2016;104:171-179. doi:10.1016/j.ejpb.2016.05.003

14. Cazorla-Luna R, Martín-Illana A, Notario-Pérez F, et al. Dapivirine Bioadhesive Vaginal Tablets Based on Natural Polymers for the Prevention of Sexual Transmission of HIV. 

. 2019;11(3):483. doi:10.3390/polym11030483

15. Nel A, van Niekerk N, Kapiga S, et al. Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women. 

16. Brown E, Palanee-Philips T, Marzinke M, et al. Residual dapivirine ring levels indicate higher adherence to vaginal ring is associated with HIV-1 protection. In: 

Journal of the International Aids Society

. Vol 19. JOHN WILEY & SONS LTD THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W …; 2016.

17. Nel A, Malherbe M, Mans W, Van Baelen B, Van Niekerk N, Louw C. Safety, adherence and HIV-1 seroconversion in DREAM—an open-label dapivirine vaginal ring trial. In: 

18. Baeten JM, Palanee-Phillips T, Mgodi N, et al. High adherence and sustained impact on HIV-1 incidence: Final results of an open-label extension trial of the dapivirine vaginal ring. In: 

JOURNAL OF THE INTERNATIONAL AIDS SOCIETY

. Vol 22. JOHN WILEY & SONS LTD THE ATRIUM, SOUTHERN GATE, CHICHESTER PO19 8SQ, W …; 2019:29-29.

19. International Partnership for Microbicides (IPM). Final Results of Open-label Study of IPM’s Dapivirine Vaginal Ring Show Increased Use and Suggest Lower Infection Rates Compared to Earlier Phase III Study. Published June 12, 2019. Accessed August 9, 2020. https://www.ipmglobal.org/content/final-results-open-label-study-ipm%E2%80%99s-dapivirine-vaginal-ring-show-increased-use-and-suggest

20. Dallal Bashi YH, McCoy CF, Murphy DJ, et al. Towards a dapivirine and levonorgestrel multipurpose vaginal ring: Investigations into the reaction between levonorgestrel and addition-cure silicone elastomers. 

. 2019;569:118574. doi:10.1016/j.ijpharm.2019.118574

21. MTN-030/IPM 041. Microbicide Trials Network (MTN). Accessed August 13, 2020. https://mtnstopshiv.org/research/studies/mtn-044

22. Molina J, Yazdanpanah, Afani Saud A. Tolerability, Safety, and Efficacy of Islatravir (MK-8591) at Doses of 0.25 to 2.25 mg QD, in Combination With Doravirine and Lamivudine Through 24 Weeks in Treatment-Naïve AdultsWith HIV-1 Infection. In: ; 2019. Accessed August 8, 2020. https://www.natap.org/2019/IAS/IAS_15.htm

23. Markowitz M, Gettie A, St. Bernard L, et al. Once-weekly oral dosing of MK-8591 protects male rhesus macaques from intrarectal challenge with SHIV109CP3. 

24. Safety and Pharmacokinetics of Oral Islatravir (MK-8591) Once Monthly in Participants at Low Risk of Human Immunodeficiency Virus 1 (HIV-1) Infection (MK-8591-016) - Full Text View - ClinicalTrials.gov. Accessed August 8, 2020. https://clinicaltrials.gov/ct2/show/NCT04003103

25. Barrett SE, Teller RS, Forster SP, et al. Extended-Duration MK-8591-Eluting Implant as a Candidate for HIV Treatment and Prevention. 

. 2018;62(10):e01058-18, /aac/62/10/e01058-18.atom. doi:10.1128/AAC.01058-18

26. Gunawardana M, Remedios-Chan M, Miller CS, et al. Pharmacokinetics of long-acting tenofovir alafenamide (GS-7340) subdermal implant for HIV prophylaxis. 

. 2015;59(7):3913-3919. doi:10.1128/AAC.00656-15

27. Pons-Faudoa FP, Sizovs A, Di Trani N, et al. 2-Hydroxypropyl-β-cyclodextrin-enhanced pharmacokinetics of cabotegravir from a nanofluidic implant for HIV pre-exposure prophylaxis. 

28. The Dual Prevention Pill. PrEPWatch. Accessed August 9, 2020. https://www.prepwatch.org/nextgen-prep/dual-prevention-pill/

29. Friedland B. FROM THE PIPELINE | Fast track to an MPT: Development of a dual-purpose pill containing oral PrEP and an oral contraceptive. IMPT for Reproductive Health. Published July 22, 2019. Accessed August 9, 2020. https://www.theimpt.org/blog-impt/item/from-the-pipeline-fast-track-to-an-mpt-development-of-a-dual-purpose-pill-containing-oral-prep-and-an-oral-contraceptive

30. AIDS Vaccine Advisory Council (AVAC)). HIV Prevention Trials. AVAC Global Advocacy for HIV Prevention. Accessed August 9, 2020. https://www.avac.org/trial-search

31. Rein-Weston A, Tekko I, Vora L, et al. LB8. Microarray Patch Delivery of Long-Acting HIV PrEP and Contraception. In: 

32. Mc Crudden MT, Larrañeta E, Clark A, et al. Design, formulation, and evaluation of novel dissolving microarray patches containing Rilpivirine for Intravaginal delivery. 

33. ClinicalTrials.gov. Evaluating the Safety and Pharmacokinetics of PC-1005 Administered Rectally to HIV-1 Seronegative Adults - Full Text View - ClinicalTrials.gov. Accessed August 9, 2020. https://clinicaltrials.gov/ct2/show/NCT03408899

34. MPT Microarray Patch (MAP). The Initiative for Multipurpose Prevention Technologies (IMPT). Accessed August 11, 2020. http://mpts101.org/mpt-database/product-page/37-mpts/140-mpt-map

35. CONRAD. Safety, PK, and PD Study of a Vaginal Insert Containing TAF and EVG - Full Text View - ClinicalTrials.gov. Accessed August 11, 2020. https://clinicaltrials.gov/ct2/show/NCT03762772

36. Delany-Moretlwe S, Lombard C, Baron D, et al. Tenofovir 1% vaginal gel for prevention of HIV-1 infection in women in South Africa (FACTS-001): a phase 3, randomised, double-blind, placebo-controlled trial. 

. 2018;18(11):1241-1250. doi:10.1016/S1473-3099(18)30428-6

37. Stephenson KE, Wagh K, Korber B, Barouch DH. Vaccines and Broadly Neutralizing Antibodies for HIV-1 Prevention. 

. 2020;38(1):673-703. doi:10.1146/annurev-immunol-080219-023629

38. National Institute of Allergy and Infectious Diseases (NIAID). Evaluating the Safety and Efficacy of the VRC01 Antibody in Reducing Acquisition of HIV-1 Infection Among Men and Transgender Persons Who Have Sex With Men - Full Text View - ClinicalTrials.gov. Accessed August 10, 2020. https://clinicaltrials.gov/ct2/show/NCT02716675

39. Stieh DJ. ASCENT: Phase 2a, randomized, double-blind, placebo controlled study evaluating safety and immunogenicity of two HIV-1 prophylactic vaccine regimens comprising Ad26.Mos4.HIV and either clade C gp140 or bivalent gp140. In: 

Hot off the Press: What’s New in HIV Prevention

. Janssen Vaccines & Prevention B.V, Netherlands; 2020. Accessed August 10, 2020. http://programme.ias2019.org/Abstract/Abstract/4979

40. Janssen Vaccines & Prevention B.V. A Study of Heterologous Vaccine Regimen of Adenovirus Serotype 26 Mosaic4 Human Immunodeficiency Virus(Ad26.Mos4.HIV), Adjuvanted Clade C gp140 and Mosaic gp140 to Prevent HIV-1 Infection Among Cis-gender Men and Transgender Individuals Who Have Sex With Cis-gender Men and/or Transgender Individuals - Full Text View - ClinicalTrials.gov. Accessed August 10, 2020. https://clinicaltrials.gov/ct2/show/NCT03964415

41. Janssen Vaccines & Prevention B.V. A Study to Assess the Efficacy of a Heterologous Prime/Boost Vaccine Regimen of Ad26.Mos4.HIV and Aluminum Phosphate-Adjuvanted Clade C gp140 in Preventing Human Immunodeficiency Virus (HIV) -1 Infection in Women in Sub-Saharan Africa - Full Text View - ClinicalTrials.gov. Accessed August 10, 2020. https://clinicaltrials.gov/ct2/show/NCT03060629

42. Tyo KM, Vuong HR, Malik DA, et al. Multipurpose tenofovir disoproxil fumarate electrospun fibers for the prevention of HIV-1 and HSV-2 infections in vitro. 

. 2017;531(1):118-133. doi:10.1016/j.ijpharm.2017.08.061

43. Ball C, Woodrow KA. Electrospun solid dispersions of Maraviroc for rapid intravaginal preexposure prophylaxis of HIV. 

. 2014;58(8):4855-4865. doi:10.1128/AAC.02564-14

44. Xiao P, Gumber S, Marzinke MA, et al. Hypo-osmolar Formulation of Tenofovir (TFV) Enema Promotes Uptake and Metabolism of TFV in Tissues, Leading to Prevention of SHIV/SIV Infection. 

45. Cunha-Reis C, Machado A, Barreiros L, et al. Nanoparticles-in-film for the combined vaginal delivery of anti-HIV microbicide drugs. 

. 2016;243:43-53. doi:10.1016/j.jconrel.2016.09.020

46. Bunge KE, Dezzutti CS, Hendrix CW, et al. FAME-04: A Phase 1 trial to assess the safety, acceptability, pharmacokinetics and pharmacodynamics of film and gel formulations of tenofovir. 

. 2018;21(8):e25156. doi:10.1002/jia2.25156

HIV / AIDS

The Preexposure Prophylaxis Pipeline

The past decade has seen the introduction and increased use of multiplex polymerase chain reaction (PCR) panels by clinical microbiology laboratories for rapid detection of pathogens in blood cultures, cerebrospinal fluid (CSF), stool, and respiratory tract specimens. Adoption of rapid PCR panels for positive blood cultures has been particularly widespread, and antimicrobial stewardship programs at many institutions perform audit and feedback based upon the results of such panels as a basis for interventions with providers.

 In addition to blood culture and meningitis/encephalitis panels, the Nebraska Medicine Antimicrobial Stewardship Program now reviews results of a new Pneumonia Panel produced by BioFire Diagnostics.

Unlike previously available respiratory panels, which detect almost exclusively viral pathogens, the Pneumonia Panel tests specimens from the lower respiratory tract (sputum, endotracheal aspirate, and bronchoalveolar lavage) and detects a number of bacterial targets and associated antibiotic resistance genes in addition to viral pathogens (

). As such, it provides additional opportunities for stewardship interventions but also poses some unique challenges. Many of these challenges stem from the fact that the respiratory tract, unlike the blood and CSF, is not a sterile site, meaning that not every organism detected is clinically significant, and the relative abundance of different species is an important part of the microbiological work-up. Results for the bacterial targets on the Pneumonia Panel are semiquantitative; copy number is reported as being not detected, 10

 This imitates the semiquantitative reporting used by most laboratories for cultures, but the results are not generally concordant, and copies of DNA detected are not well correlated with bacterial colonies per mL. In polymicrobial specimens, the relative abundance does seem to correlate, with the highest copy numbers usually corresponding to the most common organism found. In our experience, organisms for which fewer than 10

 copies are detected are often not found by culture. Results with low copy numbers may represent colonization rather than infection, or the presence of nonviable organisms after exposure to antimicrobial therapy. We recommend that the panel only be performed once on each type of sample, so we have little experience with interpreting results from subsequent tests while on or off therapy.

The increased sensitivity of this PCR diagnostic tool over standard culture creates several difficulties related to interpretation, which have been noted in the literature.

 These difficulties include increased likelihood of identifying colonizing organisms present in low numbers that are not causing infection; detection of multiple organisms or organisms that are not identified on culture; and semiquantitative results that are higher than what would be detected on culture and therefore difficult to interpret. Despite these difficulties, the Pneumonia Panel has shown potential for facilitating rapid identification of organisms and resistance genes, providing results in approximately 75 minutes.

 This may lead to earlier initiation of appropriate therapy, prompt discontinuation of broad-spectrum empiric therapy, or rapid deescalation to targeted therapy.

 Our experience thus far with the Pneumonia Panel is discussed here.

The Pneumonia Panel was implemented at Nebraska Medicine in May 2020, in the midst of the coronavirus disease 2019 (COVID-19) pandemic. It does not currently have SARS-CoV-2 as a target, although the respiratory pathogen panel does now include it. Ordering has been restricted to the intensive care unit and the pulmonary/critical care or infectious diseases teams. An 

 with information regarding the panel’s use and interpretation, as well as empiric therapeutic recommendations based on panel results and the institutional antibiogram (

), was published on the Nebraska Medicine Antimicrobial Stewardship website (www.unmc.edu/asp). The Antimicrobial Stewardship Program reviews Pneumonia Panel results during business hours 5 days per week and makes treatment recommendations in order to optimize therapy. Most often, we communicate recommendations to deescalate to therapy that targets the detected organism, or to discontinue antibiotics on the basis of a negative panel result; these recommendations are communicated to providers or pharmacists rounding with the primary team.

In our experience, community-acquired pathogens are commonly identified, likely due to the relatively large proportion of Pneumonia Panels ordered for patients with COVID-19 near the time of admission. Similar to the staffs of other facilities that have studied the panel, we have found that 

are the most commonly identified organisms, followed by 

 Given the timing of our implementation and potentially ongoing COVID-19 prevention efforts, few respiratory viruses have been identified to date, with positive results consisting exclusively of rhinovirus/enterovirus. Several positive panels have detected 3 to 5 bacterial targets; however, in these situations, most organisms are detected at low quantities with 1 species predominating. A handful of exceptions have occurred, with 1 notable case in which 5 organisms (

 copies/mL in a patient previously treated with steroids. All of these organisms were subsequently isolated on culture and the patient was treated with antimicrobial therapy active against all identified organisms.

A balance between antimicrobial stewardship and the search for multidrug-resistant organisms.

Contagion, October 2020 (Vol. 05 No. 05)

Afabicin: A Novel, Narrow-Spectrum, Antistaphylococcal Agent

Varicella Zoster Virus and Human Papillomavirus Vaccination in Immunocompromised Patients

The Preexposure Prophylaxis Pipeline

Early Experience With the BioFire Pneumonia Panel

It doesn’t get much beta than this: Novel beta-lactam antibiotics for multidrug-resistant gram-negative organisms

A Case of Influenza H1 2009 With Severe Rhabdomyolysis and Secondary Acute Renal Failure With Liver Involvement

Staphylococcus aureus Bloodstream Infection Originating From the Urinary Tract: Characteristics and 30-day Mortality

What’s New in 2020 From the CLSI Subcommittee on Antimicrobial Susceptibility Testing

Benefits of ID Consultation and ASP Collaboration

When Shorter May Not Be Better: Pseudomonas Infection in Hematopoietic Stem Cell Transplant Recipients

COVID-19 Vaccination: Prepare to Engage

Partners in antimicrobial crime: Vancomycin and daptomycin in combination with β-lactams for serious MRSA infections

COVID-19 and Understanding Immunity

Making Lemonade Out of Lemons: The Effect of Mandatory Infectious Diseases Consultation on Carbapenem Use after Drug Shortages