Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal β-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial

Abstract

Importance: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a β-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted.

Objective: To determine whether combining an antistaphylococcal β-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia.

Design, setting, and participants: Open-label, randomized clinical trial conducted at 27 hospital sites in 4 countries from August 2015 to July 2018 among 352 hospitalized adults with MRSA bacteremia. Follow-up was complete on October 23, 2018.

Interventions: Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal β-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) (n = 174) or standard therapy alone (n = 178). Total duration of therapy was determined by treating clinicians and the β-lactam was administered for 7 days.

Main outcomes and measures: The primary end point was a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse, and microbiological treatment failure. Secondary outcomes included mortality at days 14, 42, and 90; persistent bacteremia at days 2 and 5; acute kidney injury (AKI); microbiological relapse; microbiological treatment failure; and duration of intravenous antibiotics.

Results: The data and safety monitoring board recommended early termination of the study prior to enrollment of 440 patients because of safety. Among 352 patients randomized (mean age, 62.2 [SD, 17.7] years; 121 women [34.4%]), 345 (98%) completed the trial. The primary end point was met by 59 (35%) with combination therapy and 68 (39%) with standard therapy (absolute difference, -4.2%; 95% CI, -14.3% to 6.0%). Seven of 9 prespecified secondary end points showed no significant difference. For the combination therapy vs standard therapy groups, all-cause 90-day mortality occurred in 35 (21%) vs 28 (16%) (difference, 4.5%; 95% CI, -3.7% to 12.7%); persistent bacteremia at day 5 was observed in 19 of 166 (11%) vs 35 of 172 (20%) (difference, -8.9%; 95% CI, -16.6% to -1.2%); and, excluding patients receiving dialysis at baseline, AKI occurred in 34 of 145 (23%) vs 9 of 145 (6%) (difference, 17.2%; 95% CI, 9.3%-25.2%).

Conclusions and relevance: Among patients with MRSA bacteremia, addition of an antistaphylococcal β-lactam to standard antibiotic therapy with vancomycin or daptomycin did not result in significant improvement in the primary composite end point of mortality, persistent bacteremia, relapse, or treatment failure. Early trial termination for safety concerns and the possibility that the study was underpowered to detect clinically important differences in favor of the intervention should be considered when interpreting the findings.

Trial registration: ClinicalTrials.gov Identifier: NCT02365493.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Robinson reported receipt of grants from Royal Perth Hospital MRF. Dr Cass reported receipt of grants from Astellas and Novartis. Dr Paterson reported receipt of grants and personal fees from Merck and Shionogi and personal fees from Pfizer, Entasis, Venatorx, QPex, Wockhardt, and Accelerate Diagnostics. Dr Rogers reported receipt of personal fees from Mayne Pharma and Pfizer and grants and personal fees from Merck Sharp & Dohme Australia. Dr Young reported receipt of personal fees from Sanofi Pasteur and personal fees from Roche. Dr Fowler reported receipt of grants from Cerexa/Forest/Actavis/Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist/Merck, the National Institutes of Health, MedImmune, Basilea Pharmaceutica, Karius, ContraFect, Regeneron Pharmaceuticals, and Genentech and grants pending from the National Institutes of Health STTR/SBIR with Affinergy, Locus, and Medical Surface Inc; receipt of personal fees from Cubist, Cerexa, Durata, Debiopharm, and UpToDate; serving as consultant for Pfizer, Novartis, Galderma, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, the Medicines Company, Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Cubist, Basilea, Affinergy, Janssen, xBiotech, ContraFect, Regeneron, Basilea, Destiny, Amphliphi Biosciences; Integrated Biotherapeutics, and C3J; and receipt of honoraria from Theravance and Green Cross. Dr Fowler also reports a patent pending in sepsis diagnostics and serving as chair of the V710 Scientific Advisory Committee (Merck). Dr van Hal reported receipt of grants from Mayne Health and serving on advisory committees for Merck Sharp & Dohme Australia and Pfizer Australia. No other disclosures were reported.

Figures

Figure 1.. Patient Recruitment, Randomization, and Flow Through the CAMERA2 Trial

aPatients could have more than 1 reason for exclusion. bIncludes when a patient’s surrogate decision maker was unavailable, site was not approved for surrogate consent, or interpreters and/or investigators were unavailable. cInitial rapid test result was called methicillin-resistant Staphylococcus aureus (MRSA) but final laboratory antimicrobial susceptibility test result was methicillin-susceptible S aureus.

Figure 2.. Fold Change in Creatinine Levels vs Baseline Measurements

Fold change in creatinine levels up to postrandomization day 30 for all patients except those undergoing dialysis or with missing creatinine at baseline with a log2 scale for the y-axis. The horizontal lines depict a fold change of 1 (solid) and 1.5 (dashed). Acute kidney injury was defined as a 1.5-fold or greater increase in serum creatinine any time in the first 7 days. Participants contributing data at baseline, day 2, 5, 7, 14 (±3) and 28 (±7) in each treatment group are shown. After excluding patients undergoing dialysis at baseline, there were 5 participants in the combination therapy and 11 participants in the standard therapy group with missing baseline creatinine measurements. Each individual contributed only 1 measurement to each of the time points (days 2, 5, and 7) or intervals (days 14 [±3] and 28 [±7]). If individuals had multiple measurements in either of the last 2 intervals, the measurements closest to day 14 and day 28 were used. Solid lines for combination and standard therapy are the loess-smoothed mean creatinine in each group over time.