• Tong Steven Y C SYC Victorian Infectious Disease Service, Royal Melbourne Hospital, and University of Melbourne at the Peter Doherty Institute for Infection and Immunity,, David C Lye, Dafna Yahav, Archana Sud, J Owen Robinson, Jane Nelson, Sophia Archuleta, Matthew A Roberts, Alan Cass, David L Paterson, Hong Foo, Mical Paul, Stephen D Guy, Adrian R Tramontana, Genevieve B Walls, Stephen McBride, Narin Bak, Niladri Ghosh, Benjamin A Rogers, Anna P Ralph, Jane Davies, Patricia E Ferguson, Ravindra Dotel, Genevieve L McKew, Timothy J Gray, Natasha E Holmes, Simon Smith, Morgyn S Warner, Shirin Kalimuddin, Barnaby E Young, Naomi Runnegar, David N Andresen, Nicholas A Anagnostou, Sandra A Johnson, Mark D Chatfield, Allen C Cheng, Vance G Fowler, Benjamin P Howden, Niamh Meagher, David J Price, van Hal Sebastiaan J SJ Department of Microbiology and Infectious Disease, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia., O'Sullivan Matthew V N MVN Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia. , Joshua S Davis, and Australasian Society for Infectious Diseases Clinical Research Network.
• Victorian Infectious Disease Service, Royal Melbourne Hospital, and University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.
• JAMA. 2020 Feb 11; 323 (6): 527-537.

ImportanceMethicillin-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.ObjectiveTo 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 ParticipantsOpen-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.InterventionsParticipants 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 MeasuresThe 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.ResultsThe 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 RelevanceAmong 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 RegistrationClinicalTrials.gov Identifier: NCT02365493.

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