Daptomycin Plus β-Lactam Combination Therapy for Methicillin-resistant Staphylococcus aureus Bloodstream Infections: A Retrospective, Comparative Cohort Study

Abstract

Background Mounting evidence suggests the addition of a β-lactam (BL) to daptomycin (DAP) results in synergistic in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA) and bolsters the innate immune response to infection. This study’s objective was to provide clinical translation to these experimental data and determine if DAP+BL combination therapy results in improved clinical outcomes compared with treatment with DAP alone in patients with MRSA bloodstream infections (BSIs). Methods This was a retrospective, comparative cohort study conducted at 2 academic medical centers between 2008 and 2018. Adults with MRSA BSI treated with DAP for ≥72 hours and initiated ≤5 days of culture collection were included. Patients who received a BL for ≥24 hours and initiated ≤24 hours of DAP comprised the DAP+BL group. The primary outcome was composite clinical failure (60-day all-cause mortality and/or 60-day recurrence). Analyses were adjusted for confounding using inverse probability of treatment weighting (IPTW). Results A total of 229 patients were included (72 DAP+BL and 157 DAP). In unadjusted and IPTW-adjusted analyses, DAP+BL was associated with significantly reduced odds of clinical failure (odds ratio [OR], 0.362; 95% confidence interval [CI], .164–.801; adjusted OR, 0.386; 95% CI, .175–.853). Adjusted analyses restricted to prespecified subgroups based on infection complexity and baseline health status were consistent with the main analysis. Conclusions The addition of a BL to DAP was associated with improved clinical outcomes in patients with MRSA BSI. This study provides support to ongoing and future studies evaluating the impact of combination therapy for invasive MRSA infections. Patients treated with daptomycin plus a β-lactam for MRSA bloodstream infection had lower odds of composite clinical failure defined as 60-day all-cause mortality and/or 60-day recurrence compared with patients treated with daptomycin monotherapy after adjusting for confounding variables using inverse probability of treatment weighting.

Monotherapy with Vancomycin or Daptomycin versus Combination Therapy with β-Lactams in the Treatment of Methicillin-Resistant Staphylococcus Aureus Bloodstream Infections: A Retrospective Cohort Analysis

“…To our knowledge, this is the largest realworld study to date comparing clinical outcomes in MRSA BSI patients receiving VAN/DAP MT to VAN/DAP CT with BL. Strengths of this study include a specific definition of BL exposure with regards to VAN/DAP timing, exclusion of patients who have not had a follow-up blood culture, robust sample size captured in over 12 years duration, and findings that are confirmatory of previously published data in CT for MRSA BSI [8,25,26].…”

“…BL addition to VAN/DAP has been shown to have a significant impact on BSI duration compared with MT, with some influence on the rate of composite clinical outcomes such as mortality, relapse, and/or change in antibiotic therapy during treatment [8,16,26,[36][37][38]. Specifically, median duration of bacteremia had been reduced from 4 to 3 days when BL were used with VAN, and from 2.8 to 2.3 days when BL were used with DAP [8,26]. Notably, our definition for PB at a 5-day cut-off has prevented us from comparing our results to other studies that have used other definitions such as 3 days and 7 days.…”

“…Prior Presentation. This study has been presented, in part, at American Society for Microbiology (ASM); October 3 -7, 2018 San Francisco, CA (abstract 2379) and the following publications Zasowski et al and Jorgensen et al [25,26].…”

Adjuvant β-Lactam Therapy Combined with Vancomycin or Daptomycin for Methicillin-Resistant Staphylococcus aureus Bacteremia: a Systematic Review and Meta-analysis

“…1 ). After applying the inclusion/exclusion criteria, a total of 15 studies ( 6 , 18 – 31 ) comprising a total of 2,594 patients were included (1,189 patients in the standard therapy [STAN] group and 1,405 patients in the STAN therapy combined with β-lactams [COMBO] group), including 7 studies ( 21 – 27 ) based on the combination of VAN, 5 studies ( 6 , 28 – 31 ) based on the combination of DAP, and 3 studies ( 18 – 20 ) based on the combination of daptomycin or vancomycin. Among the included studies, the β-lactam of choice was ceftaroline in four studies ( 20 , 29 – 31 ), cefazolin in three studies ( 19 , 23 , 25 ), flucloxacillin in two studies ( 19 , 22 ), cloxacillin in one study ( 19 ), and cefepime in one study ( 27 ).…”

Ability of Bicarbonate Supplementation to Sensitize Selected Methicillin-ResistantStaphylococcus aureus(MRSA) Strains to β-Lactam Antibiotics in anEx VivoSimulated Endocardial Vegetation Model

“…The mecA gene is primarily responsible for mediating S. aureus resistance to traditional β-lactams, encoding for penicillin-binding protein 2A (PBP2A), which has low affinity to most standard-of-care antistaphylococcal β-lactam antibiotics (6). Despite this, combination therapy featuring β-lactams plus anti-MRSA agents such as vancomycin and daptomycin have proven to be effective in selected patients with recalcitrant MRSA infections (19, 28-30). In addition, many MRSA strains which exhibit reduced susceptibility to vancomycin and daptomycin often demonstrate a paradoxical increase in susceptibility to β-lactams, a phenomenon known as the “see-saw effect”; this provides an additional scenario in which β-lactam agents may provide synergistic efficacy for MRSA killing (19).…”