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.

• New Life for Atripla? Three-Times-Weekly Dosing Maintains Viral Suppression at 24 Weeks
• Checking Drug Levels – Not Just for Vanco
• Piperacillin-Tazobactam “Not Non-Inferior” to Meropenem for Ceftriaxone-Resistant E. coli and K. pneumoniae Bacteremia

New Life for Atripla? Three-Times-Weekly Dosing Maintains Viral Suppression at 24 Weeks

Reviewed by Erica Kaufman West, MD

While viral suppression is possible for almost every HIV-infected patient, the side effects and long-term toxicity of the medications cannot be denied. In developed countries, integrase inhibitors have overtaken efavirenz-based regimens; however, the World Health Organization and many developing countries still recommend and use efavirenz-based regimens as first-line therapy. A recent study published in AIDS looked at three-times-weekly efavirenz/emtricitabine/tenofovir disoproxil fumarate (Atripla) versus daily dosing and the effect on viral load, CD4 count, and several other parameters as surrogates of subclinical diseases.

Enrolled patients had been virologically suppressed on Atripla for at least 2 years with a CD4 cell count of at least 350 cells/µL. The primary end-point was treatment failure at 24 weeks. Secondary end-points were Pittsburgh Sleep Quality Index (PSQI), body mass index, bone mineral density, CD4+ and CD8+ cells, ultrasensitive HIV-1 RNA (2 copies/mL), plasma 25-OH vitamin D levels, estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, fasting blood lipids, and protein/creatinine, albumin/creatinine, and beta-2-microglobulin in urine. Thirty patients were assigned to the three-times-weekly group and 31 to the standard dose group.

All 61 patients remained virologically suppressed at 24 weeks. Total cholesterol was increased in the three-times-weekly group, likely due to tenofovir’s cholesterol-lowering properties. PSQI scores, femur T-scores, urine albumin/creatinine, and urine beta-2-microglobulin were significantly improved in the three-times-weekly group. The investigators have invited patients in the daily dosing group to change to three-times-weekly dosing with follow up for at least 3 years. 

While no economic evaluation was done, dropping to three-times-weekly dosing would lead to a significant cost savings. It remains to be seen if the small improvements seen in subclinical disease—such as osteoporosis, renal disease, and sleep disturbances—remain with prolonged monitoring.

(Rojas at al. AIDS. 2018;32(12):1633-1641.)

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Checking Drug Levels – Not Just for Vanco

Reviewed by Nirav Patel, MD

Antibiotic dosing has typically been established in studies involving healthy volunteers, but clinical use is frequently in patients with significant physiologic derangement. β-lactam antibiotics are the mainstay of therapy and provide empirically reliable, broad-spectrum activity. The activity of β-lactams is associated with the time that the free drug is greater than the organism’s minimum inhibitory concentration as a percentage of the dosing interval (%fT_>MIC). However, monitoring of drug levels in routine clinical practice is not utilized, thus clinicians are dependent on dosing schemes to ensure adequate drug levels.

In a prospective, observational study in the Journal of Antimicrobial Therapy, Wong and collaborators assessed achievement of unbound β-lactam antibiotic concentrations in critically ill patients. The study was performed at a single intensive care unit in Australia where therapeutic drug monitoring was routine, with protocolized dose adjustments based on a percentage of free drug concentration above the MIC of the causative organism. Drug concentrations were measured using high performance liquid chromatography after achieving steady state. The drugs included were: ceftriaxone, cefazolin, meropenem, ampicillin, benzylpenicillin, flucloxacillin, and piperacillin.

Three hundred sixty-nine infection episodes were included. Dose increases were needed in 33 percent of the episodes to achieve 100%fT_>MIC and 63 percent of episodes to achieve a more comfortable threshold of 100%fT_>4xMIC. On the other hand, 17 percent of cases required dose reduction as they were at levels 100%fT_>10xMIC. Failure to achieve target threshold was related to augmented renal clearance, whereas higher protein binding in antibiotics was associated with better target drug level attainment.

While many clinicians do not have access to drug monitoring for β-lactam antibiotics, this study highlights the challenges in obtaining potentially therapeutic drug levels in critically ill patients. Patients with severe sepsis/shock who apparently fail therapy may not be achieving appropriate drug levels to actually provide clinical benefit. As β-lactams are typically well tolerated, without significant dose-dependent toxicities, this study adds to the data suggesting that an aggressive initial dosing scheme may be important in this difficult to study patient cohort.

(Wong et al. J Antimicrob Chemother. Published online: August 17, 2018.)

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Piperacillin-Tazobactam “Not Non-Inferior” to Meropenem for Ceftriaxone-Resistant E. coli and K. pneumoniae Bacteremia

Reviewed by Christopher J. Graber, MD, MPH, FIDSA

The role of piperacillin-tazobactam in the management of infections caused by Enterobacteriaceae with extended-spectrum β-lactamase (ESBL) activity has been hotly debated, particularly after the Clinical Laboratory Standards Institute (CLSI) recommendation in 2010 to no longer specifically test for ESBL activity. Data on the clinical effectiveness of piperacillin-tazobactam (when deemed susceptible by CLSI breakpoints) versus carbapenems in bacteremia from ESBL-producing Enterobacteriaceae have been mixed in retrospective cohort studies.

A randomized clinical trial recently published in JAMA tested the non-inferiority of piperacillin-tazobactam versus meropenem among patients with Escherichia coli and Klebsiella pneumoniae bacteremia that were resistant to ceftriaxone but susceptible to piperacillin-tazobactam according to local laboratory standards. Patients from 29 countries (mostly in Singapore and Australia) were randomized within 72 hours of initial positive blood culture to either agent for 4 to 14 days (piperacillin-tazobactam 4.5 g every 6 hours versus meropenem 1 g every 8 hours) after being stratified by infecting species, urinary versus non-urinary source, and Pitt bacteremia score. 

Twenty-three of 187 (12.3 percent) patients in the piperacillin-tazobactam arm versus 7 of 191 (3.7 percent) in the meropenem arm met the primary outcome of 30-day all-cause mortality, a finding that did not meet statistical noninferiority (the implications of which are discussed well elsewhere). Findings appeared to be consistent across strata, and no clear relationship was seen between mortality and piperacillin-tazobactam minimum inhibitory concentration among patients in the piperacillin-tazobactam arm. Phenotypic ESBL production was seen in 86 percent and ESBL genes were confirmed in 85.3 percent of isolates, mostly bla_CTX-M (83.5 percent).

This trial suggests that carbapenems may be preferred over piperacillin-tazobactam for infections caused by ceftriaxone-resistant Enterobacteriaceae that are associated with bacteremia, though piperacillin-tazobactam may still have a role in non-bacteremic infections. Of note, the authors established a Twitter feed to address questions they have received regarding the trial.

(Harris et al. JAMA 2018;320(10):984-94.)

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