Tong SYC; Lye DC; Yahav D; Sud A; Robinson JO; Nelson J; Archuleta S; Roberts MA; Cass A; Paterson DL; Foo H; Paul M; Guy SD; Tramontana AR; Walls GB; McBride S; Bak N; Ghosh N; Rogers BA; Ralph, Anna; Davies, Jane; Ferguson PE; Dotel R; McKew GL; Gray TJ; Holmes NE; Smith S; Warner MS; Kalimuddin S; Young BE; Runnegar N; Andresen DN; Anagnostou NA; Johnson SA; Chatfield MD; Cheng AC; Fowler VG; Howden BP; Meagher N; Price DJ; van Hal SJ; O'Sullivan MVN; Davis JS

Author(s)

Tong SYC

Lye DC

Yahav D

Sud A

Robinson JO

Nelson J

Archuleta S

Roberts MA

Cass A

Paterson DL

Foo H

Paul M

Guy SD

Tramontana AR

Walls GB

McBride S

Bak N

Ghosh N

Rogers BA

Ralph, Anna

Davies, Jane

Ferguson PE

Dotel R

McKew GL

Gray TJ

Holmes NE

Smith S

Warner MS

Kalimuddin S

Young BE

Runnegar N

Andresen DN

Anagnostou NA

Johnson SA

Chatfield MD

Cheng AC

Fowler VG

Howden BP

Meagher N

Price DJ

van Hal SJ

O'Sullivan MVN

Davis JS

Publication Date

2020-02-11

Abstract

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. To determine whether combining an antistaphylococcal β-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia. 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. 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. 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. 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%). 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. ClinicalTrials.gov Identifier: NCT02365493.

Affiliation

Victorian Infectious Disease Service, Royal Melbourne Hospital, and University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.. Menzies School of Health Research, Charles Darwin University, Casuarina, Northern Territory, Australia..

National Centre for Infectious Diseases, Singapore.. Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore.. Yong Loo Lin School of Medicine, National University of Singapore, Singapore.. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore..

Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel..

Nepean Clinical School, University of Sydney, Sydney, New South Wales, Australia.. Nepean Hospital, Kingswood, New South Wales, Australia..

Royal Perth Hospital, Perth, Western Australia, Australia.. Fiona Stanley Hospital, Murdoch, Western Australia, Australia.. Pathwest Laboratory Medicine WA, Murdoch, Western Australia, Australia.. Antimicrobial Resistance and Infectious Diseases Research Laboratory, School of Veterinary and Life Sciences, Murdoch University, Murdoch, Western Australia, Australia..

Menzies School of Health Research, Charles Darwin University, Casuarina, Northern Territory, Australia..

Division of Infectious Diseases, National University Hospital, Singapore.. Department of Medicine, National University of Singapore, Singapore..

Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.. Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia..

Menzies School of Health Research, Charles Darwin University, Casuarina, Northern Territory, Australia..

Centre for Clinical Research, University of Queensland, Herston, Australia..

Department of Microbiology and Infectious Diseases, NSW Health Pathology, Liverpool, New South Wales, Australia..

Rambam Health Care Campus, Haifa, Israel.. Technion-Israel Institute of Technology, Haifa, Israel..

Footscray Hospital, Western Health, Footscray, Victoria, Australia..

Department of Infectious Diseases, Middlemore Hospital, Auckland, New Zealand..

Royal Adelaide Hospital, Adelaide, South Australia, Australia..

Wollongong Public Hospital, Wollongong, New South Wales, Australia..

School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.. Monash Infectious Diseases, Monash Medical Centre, Clayton, Victoria, Australia..

Menzies School of Health Research, Charles Darwin University, Casuarina, Northern Territory, Australia.. Division of Medicine, Royal Darwin Hospital, Tiwi, Northern Territory, Australia..

Department of Infectious Diseases, Blacktown Hospital, Blacktown, New South Wales, Australia..

Department of Infectious Diseases, Blacktown Hospital, Blacktown, New South Wales, Australia.. Centre for Infectious Diseases and Microbiology, Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia..

Department of Microbiology and Infectious Diseases, Concord Repatriation General Hospital, Concord, New South Wales, Australia.. Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia..

Department of Infectious Diseases, Austin Health, Austin Centre for Infection Research, Heidelberg, Victoria, Australia..

Cairns Hospital, Cairns, Queensland, Australia..

The Queen Elizabeth Hospital, Woodville, South Australia, Australia.. University of Adelaide, Adelaide, South Australia, Australia..

Department of Infectious Diseases, Singapore General Hospital, Singapore.. Duke-NUS Medical School, Singapore..

National Centre for Infectious Diseases, Singapore.. Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore..

Infection Management Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia.. Southern Clinical School, Faculty of Medicine, University of Queensland, Brisbane, Australia..

St Vincent's Public Hospital Sydney, Darlinghurst, New South Wales, Australia.. School of Medicine, University of Notre Dame, Darlinghurst, New South Wales, Australia..

Flinders Medical Centre, Adelaide, South Australia, Australia..

Victorian Infectious Disease Service, Royal Melbourne Hospital, and University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia..

Menzies School of Health Research, Charles Darwin University, Casuarina, Northern Territory, Australia.. Centre for Clinical Research, University of Queensland, Herston, Australia..

School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.. Infection Prevention and Healthcare Epidemiology Unit, Alfred Health, Melbourne, Victoria, Australia..

Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, North Carolina.. Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina..

Department of Infectious Diseases, Austin Health, Austin Centre for Infection Research, Heidelberg, Victoria, Australia.. Microbiological Diagnostic Unit Public Health Laboratory, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia..

Victorian Infectious Diseases Reference Laboratory Epidemiology Unit, Royal Melbourne Hospital, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia..

Victorian Infectious Diseases Reference Laboratory Epidemiology Unit, Royal Melbourne Hospital, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.. Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria, Australia..

Department of Microbiology and Infectious Disease, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia..

Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.. New South Wales Health Pathology, Westmead Hospital, Westmead, Australia..

Menzies School of Health Research, Charles Darwin University, Casuarina, Northern Territory, Australia.. Department of Infectious Diseases, John Hunter Hospital, Newcastle, New South Wales, Australia..

Citation

JAMA . 2020 Feb 11;323(6):527-537. doi: 10.1001/jama.2020.0103.

Pubmed ID

https://pubmed.ncbi.nlm.nih.gov/32044943/?otool=iaurydwlib

Link

https://hdl.handle.net/10137/8178

Title

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.

Type of document

Journal Article

Entity Type

Publication

Author(s)	Tong SYC Lye DC Yahav D Sud A Robinson JO Nelson J Archuleta S Roberts MA Cass A Paterson DL Foo H Paul M Guy SD Tramontana AR Walls GB McBride S Bak N Ghosh N Rogers BA Ralph, Anna Davies, Jane Ferguson PE Dotel R McKew GL Gray TJ Holmes NE Smith S Warner MS Kalimuddin S Young BE Runnegar N Andresen DN Anagnostou NA Johnson SA Chatfield MD Cheng AC Fowler VG Howden BP Meagher N Price DJ van Hal SJ O'Sullivan MVN Davis JS
Publication Date	2020-02-11
Abstract	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. To determine whether combining an antistaphylococcal β-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia. 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. 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. 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. 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%). 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. ClinicalTrials.gov Identifier: NCT02365493.
Affiliation	Victorian Infectious Disease Service, Royal Melbourne Hospital, and University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.. Menzies School of Health Research, Charles Darwin University, Casuarina, Northern Territory, Australia.. National Centre for Infectious Diseases, Singapore.. Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore.. Yong Loo Lin School of Medicine, National University of Singapore, Singapore.. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.. Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel.. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.. Nepean Clinical School, University of Sydney, Sydney, New South Wales, Australia.. Nepean Hospital, Kingswood, New South Wales, Australia.. Royal Perth Hospital, Perth, Western Australia, Australia.. Fiona Stanley Hospital, Murdoch, Western Australia, Australia.. Pathwest Laboratory Medicine WA, Murdoch, Western Australia, Australia.. Antimicrobial Resistance and Infectious Diseases Research Laboratory, School of Veterinary and Life Sciences, Murdoch University, Murdoch, Western Australia, Australia.. Menzies School of Health Research, Charles Darwin University, Casuarina, Northern Territory, Australia.. Division of Infectious Diseases, National University Hospital, Singapore.. Department of Medicine, National University of Singapore, Singapore.. Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia.. Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia.. Menzies School of Health Research, Charles Darwin University, Casuarina, Northern Territory, Australia.. Centre for Clinical Research, University of Queensland, Herston, Australia.. Department of Microbiology and Infectious Diseases, NSW Health Pathology, Liverpool, New South Wales, Australia.. Rambam Health Care Campus, Haifa, Israel.. Technion-Israel Institute of Technology, Haifa, Israel.. Footscray Hospital, Western Health, Footscray, Victoria, Australia.. Footscray Hospital, Western Health, Footscray, Victoria, Australia.. Department of Infectious Diseases, Middlemore Hospital, Auckland, New Zealand.. Department of Infectious Diseases, Middlemore Hospital, Auckland, New Zealand.. Royal Adelaide Hospital, Adelaide, South Australia, Australia.. Wollongong Public Hospital, Wollongong, New South Wales, Australia.. School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.. Monash Infectious Diseases, Monash Medical Centre, Clayton, Victoria, Australia.. Menzies School of Health Research, Charles Darwin University, Casuarina, Northern Territory, Australia.. Division of Medicine, Royal Darwin Hospital, Tiwi, Northern Territory, Australia.. Menzies School of Health Research, Charles Darwin University, Casuarina, Northern Territory, Australia.. Division of Medicine, Royal Darwin Hospital, Tiwi, Northern Territory, Australia.. Department of Infectious Diseases, Blacktown Hospital, Blacktown, New South Wales, Australia.. Department of Infectious Diseases, Blacktown Hospital, Blacktown, New South Wales, Australia.. Centre for Infectious Diseases and Microbiology, Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia.. Department of Microbiology and Infectious Diseases, Concord Repatriation General Hospital, Concord, New South Wales, Australia.. Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.. Department of Microbiology and Infectious Diseases, Concord Repatriation General Hospital, Concord, New South Wales, Australia.. Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.. Department of Infectious Diseases, Austin Health, Austin Centre for Infection Research, Heidelberg, Victoria, Australia.. Cairns Hospital, Cairns, Queensland, Australia.. The Queen Elizabeth Hospital, Woodville, South Australia, Australia.. University of Adelaide, Adelaide, South Australia, Australia.. Department of Infectious Diseases, Singapore General Hospital, Singapore.. Duke-NUS Medical School, Singapore.. National Centre for Infectious Diseases, Singapore.. Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore.. Infection Management Services, Princess Alexandra Hospital, Brisbane, Queensland, Australia.. Southern Clinical School, Faculty of Medicine, University of Queensland, Brisbane, Australia.. St Vincent's Public Hospital Sydney, Darlinghurst, New South Wales, Australia.. School of Medicine, University of Notre Dame, Darlinghurst, New South Wales, Australia.. Flinders Medical Centre, Adelaide, South Australia, Australia.. Victorian Infectious Disease Service, Royal Melbourne Hospital, and University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.. Menzies School of Health Research, Charles Darwin University, Casuarina, Northern Territory, Australia.. Centre for Clinical Research, University of Queensland, Herston, Australia.. School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.. Infection Prevention and Healthcare Epidemiology Unit, Alfred Health, Melbourne, Victoria, Australia.. Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, North Carolina.. Duke Clinical Research Institute, Duke University Medical Center, Durham, North Carolina.. Department of Infectious Diseases, Austin Health, Austin Centre for Infection Research, Heidelberg, Victoria, Australia.. Microbiological Diagnostic Unit Public Health Laboratory, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.. Victorian Infectious Diseases Reference Laboratory Epidemiology Unit, Royal Melbourne Hospital, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.. Victorian Infectious Diseases Reference Laboratory Epidemiology Unit, Royal Melbourne Hospital, University of Melbourne at the Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.. Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, Victoria, Australia.. Department of Microbiology and Infectious Disease, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia.. Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.. New South Wales Health Pathology, Westmead Hospital, Westmead, Australia.. Menzies School of Health Research, Charles Darwin University, Casuarina, Northern Territory, Australia.. Department of Infectious Diseases, John Hunter Hospital, Newcastle, New South Wales, Australia..
Citation	JAMA . 2020 Feb 11;323(6):527-537. doi: 10.1001/jama.2020.0103.
Pubmed ID	https://pubmed.ncbi.nlm.nih.gov/32044943/?otool=iaurydwlib
Link	https://hdl.handle.net/10137/8178
Title	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.
Type of document	Journal Article
Entity Type	Publication

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.

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