Journal Club
In this feature, a panel of IDSA members identifies and critiques important new studies in the current literature that have a significant impact on the practice of infectious diseases medicine.
- De-escalation of Anti-MRSA Antimicrobial Therapy for Culture-Negative Pneumonia
- A Single-Tablet Antiretroviral Therapy Option in People Living with HIV and End-Stage Renal Disease
- Short-Course, High-Dose Liposomal Amphotericin B for Cryptococcal Meningoencephalitis: A Novel Induction Therapy Strategy?
Click here for the previous edition of Journal Club. For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, MD, FIDSA, in each issue of Clinical Infectious Diseases.
De-escalation of Anti-MRSA Antimicrobial Therapy for Culture-Negative Pneumonia
Reviewed by Kelly Cawcutt, MD, MS
Nosocomial pneumonia is a leading cause of health care-acquired infections resulting in increased patient morbidity, mortality, and health care costs. Many of these pneumonias are secondary to multidrug-resistant organisms, including methicillin-resistant Staphylococcus aureus (MRSA). Broad empiric antimicrobial coverage for such pneumonias is therefore within guideline recommendations, with the intent to de-escalate therapy based on culture results. However, this leaves culture-negative pneumonias in a gray area regarding when, and how, to de-escalate.
In a retrospective study published in Chest by Cowley et al, de-escalation of anti-MRSA antimicrobial therapy in culture-negative pneumonia was evaluated with primary outcomes of 28-day mortality, hospital mortality, intensive care unit (ICU) and hospital length of stay (LOS), incidence of treatment failure, and incidence of acute kidney injury (AKI). De-escalation was defined as transition to a narrower spectrum antibiotic (without MRSA coverage) within 4 days of the respective culture. Two hundred seventy-nine patients were included, and of these, 92 met the de-escalation criteria. Vancomycin was the most common anti-MRSA agent (78 percent), and the vast majority also received antipseudomonal coverage (92 percent).
A significantly higher number of patients undergoing de-escalation had chronic kidney disease (43 percent vs 32 percent), and most with de-escalation with anti-MRSA therapy also had antipseudomonal therapy de-escalated (73 percent vs 22 percent). The de-escalation group also had 5 fewer days of anti-MRSA therapy, decreased ICU and hospital LOS, and lower rates of AKI. There was no noted difference in mortality.
De-escalation in culture-negative pneumonia may result in lower AKI (although notably, the use of piperacillin/tazobactam or other nephrotoxic antipseudomonal agents was not described) and lower ICU and hospital LOS. There is clear potential benefit for patients and overall health care systems in advocating for earlier de-escalation, regardless of whether or not nares swabs were completed.
(Cowley et al. Chest. 2019;155(1):53-59.)
A Single-Tablet Antiretroviral Therapy Option in People Living with HIV and End-Stage Renal Disease
Reviewed by Lauren Richey, MD, MPH, FIDSA
Antiretroviral therapy options are limited for people living with HIV who also have end-stage renal disease (ESRD). Current guidelines recommend initial treatment with a combination of two nucleoside reverse transcriptase inhibitors (NRTIs) and a drug from another class. Because NRTIs are often renally eliminated, they often require dose adjustment in ESRD, making single-tablet options impossible. Complete regimens for these patients can be complex and include multiple tablets at multiple times. A co-formulated tablet of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide is a recommended initial treatment regimen for HIV; it has been shown to have a favorable safety profile in people with mild to moderate renal dysfunction. A recent Lancet HIV study assessed the safety and efficacy of this regimen in people living with HIV and ESRD at 48 weeks.
The single-arm, multicenter, open-label, phase 3B trial included 26 outpatient clinics and enrolled 55 total patients with HIV who were also on hemodialysis. The patients were virologically suppressed and had a CD4 count of at least 200. The medicine was given daily and after hemodialysis on dialysis days. Primary outcomes included incidence of treatment-emergent adverse events in the first 48 weeks. Grade 3 or higher adverse events were reported for 33 percent of the patients, although none were determined to be treatment related. Treatment-related adverse events were reported for 11 percent (n = 6), mostly nausea (n = 4); none led to study drug discontinuation.
A subset of individuals (n = 12) participated in an intensive pharmacokinetic substudy. Plasma concentrations were drawn when expected to be the highest (on the day before dialysis after three doses between sessions). Levels of emtricitabine were increased as expected but the authors felt the safety profile was not substantially affected. Most participants (82 percent) were virally suppressed at 48 weeks, and 82 percent were more satisfied with the convenience of a single-tablet regimen.
This study provides evidence supporting the safety and tolerability of a single-tablet regimen of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in people living with HIV on hemodialysis, although it remains limited by its small size and lack of a control group.
(Eron et al. Lancet HIV. 2019;6(1):E15-E24.)
Short-Course, High-Dose Liposomal Amphotericin B for Cryptococcal Meningoencephalitis: A Novel Induction Therapy Strategy?
Reviewed by Jennifer Brown, MD
Currently, the preferred induction therapy for cryptococcal meningoencephalitis (CM) in patients with HIV is amphotericin B plus flucytosine for at least 2 weeks. This treatment can be challenging, especially in resource-limited settings, and alternative strategies are needed.
In the February 1 issue of Clinical Infectious Diseases, Jarvis et al reported the results of their phase 2, noninferiority trial that evaluated short-course, high-dose liposomal amphotericin B (L-AmB) induction therapy in HIV-infected adults with a first episode of CM in Tanzania and Botswana. Patients were randomized to one of four arms: L-AmB 10 mg/kg on day 1; L-AmB 10 mg/kg on day 1 and 5 mg/kg on day 3; L-AmB 10 mg/kg on day 1 and 5 mg/kg on days 3 and 7; and L-AmB 3 mg/kg/day for 14 days (control). All patients also received fluconazole 1,200 mg/day for the first 2 weeks, then 800 mg/day until 10 weeks, and 200 mg/day thereafter. Lumbar punctures were performed at baseline and on treatment days 3, 7, and 14; patients with raised intracranial pressures had daily lumbar punctures.
The primary outcome measure of early fungicidal activity—the mean rate of decrease in cerebral spinal fluid cryptococcal colony forming units (CFU)—was calculated for 69/79 patients who completed the study. At the predefined noninferiority margin of 0.2 log10 CFU/ml/day, all short-course, high-dose L-AmB arms were deemed noninferior to the control arm. Maximal fungicidal activity was achieved with the first 10 mg/kg L-AmB dose, and a dose-response effect was not observed with additional doses. The trial was stopped early when the primary objective was achieved and no safety concerns were identified.
Although a phase 2 trial, its findings may provide hope for a new approach to HIV-associated CM induction therapy, particularly for those in resource-limited settings. The forthcoming phase 3 trial should provide further clinical endpoint information.
(Jarvis et al. Clin Infect Dis. 2019;68(3):393–401.)
| For a review of other recent research in the infectious diseases literature, see “In the Literature,” by Stanley Deresinski, MD, FIDSA, in each issue of Clinical Infectious Diseases: March 15
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