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Title: Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal beta-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia A Randomized Clinical Trial
Authors: Tong, Steven YC
Lye, David C 
Yahav, Dafna
Sud, Archana
Robinson, J Owen
Nelson, Jane
Archuleta, Sophia 
Roberts, Matthew A
Cass, Alan
Paterson, David L
Foo, Hong
Paul, Mical
Guy, Stephen D
Tramontana, Adrian R
Walls, Genevieve B
McBride, Stephen
Bak, Narin
Ghosh, Niladri
Rogers, Benjamin A
Ralph, Anna P
Davies, Jane
Ferguson, Patricia E
Dotel, Ravindra
McKew, Genevieve L
Gray, Timothy J
Holmes, Natasha E
Smith, Simon
Warner, Morgyn S
Kalimuddin, Shirin 
Young, Barnaby E
Runnegar, Naomi
Andresen, David N
Anagnostou, Nicholas A
Johnson, Sandra A
Chatfield, Mark D
Cheng, Allen C
Fowler, Vance G
Howden, Benjamin P
Meagher, Niamh
Price, David J
van Hal, Sebastiaan J
O'Sullivan, Matthew VN
Davis, Joshua S
Keywords: Science & Technology
Life Sciences & Biomedicine
Medicine, General & Internal
General & Internal Medicine
Issue Date: 11-Feb-2020
Citation: Tong, Steven YC, Lye, David C, Yahav, Dafna, Sud, Archana, Robinson, J Owen, Nelson, Jane, Archuleta, Sophia, Roberts, Matthew A, Cass, Alan, Paterson, David L, Foo, Hong, Paul, Mical, Guy, Stephen D, Tramontana, Adrian R, Walls, Genevieve B, McBride, Stephen, Bak, Narin, Ghosh, Niladri, Rogers, Benjamin A, Ralph, Anna P, Davies, Jane, Ferguson, Patricia E, Dotel, Ravindra, McKew, Genevieve L, Gray, Timothy J, Holmes, Natasha E, Smith, Simon, Warner, Morgyn S, Kalimuddin, Shirin, Young, Barnaby E, Runnegar, Naomi, Andresen, David N, Anagnostou, Nicholas A, Johnson, Sandra A, Chatfield, Mark D, Cheng, Allen C, Fowler, Vance G, Howden, Benjamin P, Meagher, Niamh, Price, David J, van Hal, Sebastiaan J, O'Sullivan, Matthew VN, Davis, Joshua S (2020-02-11). Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal beta-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia A Randomized Clinical Trial. JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION 323 (6) : 527-537. ScholarBank@NUS Repository.
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: Identifier: NCT02365493.
ISSN: 0098-7484
DOI: 10.1001/jama.2020.0103
Appears in Collections:Staff Publications

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