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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: | Tramontana A.R.;Tong S.Y.C.;Lye D.C.;Yahav D.;Sud A.;Robinson J.O.;Nelson J.;Archuleta S.;Roberts M.A.;Cass A.;Paterson D.L.;Foo H.;Paul M.;Guy S.D.;Runnegar N.;Andresen D.N.;Anagnostou N.A.;Johnson S.A.;Chatfield M.D.;Cheng A.C. ;Fowler V.G.;Howden B.P.;Meagher N.;Price D.J.;Van Hal S.J.;O'Sullivan M.V.N.;Davis J.S.;Walls G.B.;McBride S.;Bak N.;Ghosh N.;Rogers B.A.;Ralph A.P.;Davies J.;Ferguson P.E.;Dotel R.;McKew G.L.;Gray T.J.;Holmes N.E.;Smith S.;Warner M.S.;Kalimuddin S.;Young B.E. | Monash Health Department(s): | Infectious Diseases and Clinical Microbiology | Institution: | (Tong, Johnson) Victorian Infectious Disease Service, Royal Melbourne Hospital, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (Tong, Nelson, Cass, Ralph, Davies, Chatfield, Davis) Menzies School of Health Research, Charles Darwin University, Rocklands Drive, Tiwi, Darwin, NT 0811, Australia (Lye, Young) National Centre for Infectious Diseases, Singapore, Singapore (Lye, Young) Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore, Singapore (Lye) Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore (Lye) Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore (Yahav) Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel (Yahav) Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel (Sud) Nepean Clinical School, University of Sydney, Sydney, NSW, Australia (Sud) Nepean Hospital, Kingswood, NSW, Australia (Robinson) Royal Perth Hospital, Perth, WA, Australia (Robinson) Fiona Stanley Hospital, Murdoch, WA, Australia (Robinson) Pathwest Laboratory Medicine WA, Murdoch, WA, Australia (Robinson) Antimicrobial Resistance and Infectious Diseases Research Laboratory, School of Veterinary and Life Sciences, Murdoch University, Murdoch, WA, Australia (Archuleta) Division of Infectious Diseases, National University Hospital, Singapore, Singapore (Archuleta) Department of Medicine, National University of Singapore, Singapore, Singapore (Roberts) Australasian Kidney Trials Network, University of Queensland, Brisbane, Australia (Roberts) Eastern Health Clinical School, Monash University, Box Hill, VIC, Australia (Paterson) Centre for Clinical Research, University of Queensland, Herston, Australia (Foo) Department of Microbiology and Infectious Diseases, NSW Health Pathology, Liverpool, NSW, Australia (Paul) Rambam Health Care Campus, Haifa, Israel (Paul) Technion-Israel Institute of Technology, Haifa, Israel (Guy, Tramontana) Footscray Hospital, Western Health, Footscray, VIC, Australia (Walls, McBride) Department of Infectious Diseases, Middlemore Hospital, Auckland, New Zealand (Bak) Royal Adelaide Hospital, Adelaide, SA, Australia (Ghosh) Wollongong Public Hospital, Wollongong, NSW, Australia (Rogers) School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia (Rogers) Monash Infectious Diseases, Monash Medical Centre, Clayton, VIC, Australia (Ralph, Davies) Division of Medicine, Royal Darwin Hospital, Tiwi, NT, Australia (Ferguson, Dotel) Department of Infectious Diseases, Blacktown Hospital, Blacktown, NSW, Australia (Dotel) Centre for Infectious Diseases and Microbiology, Westmead Hospital, University of Sydney, Sydney, NSW, Australia (McKew, Gray) Department of Microbiology and Infectious Diseases, Concord Repatriation General Hospital, Concord, NSW, Australia (McKew, Gray, O'Sullivan) Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia (Holmes, Howden) Department of Infectious Diseases, Austin Health, Austin Centre for Infection Research, Heidelberg, VIC, Australia (Smith) Cairns Hospital, Cairns, QLD, Australia (Warner) Queen Elizabeth Hospital, Woodville, SA, Australia (Warner) University of Adelaide, Adelaide, SA, Australia (Kalimuddin) Department of Infectious Diseases, Singapore General Hospital, Singapore, Singapore (Kalimuddin) Duke-NUS Medical School, Singapore, Singapore (Runnegar) Infection Management Services, Princess Alexandra Hospital, Brisbane, QLD, Australia (Runnegar) Southern Clinical School, Faculty of Medicine, University of Queensland, Brisbane, Australia (Andresen) St Vincent's Public Hospital Sydney, Darlinghurst, NSW, Australia (Andresen) School of Medicine, University of Notre Dame, Darlinghurst, NSW, Australia (Anagnostou) Flinders Medical Centre, Adelaide, SA, Australia (Chatfield) Centre for Clinical-Research, University-Queensland, Herston, Australia (Cheng) School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia (Cheng) Infection Prevention and Healthcare Epidemiology Unit, Alfred Health, Melbourne, VIC, Australia (Fowler) Division of Infectious Diseases, Department of Medicine, Duke University Medical Center, Durham, NC, United States (Fowler) Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, United States (Howden) Microbiological Diagnostic Unit Public Health Laboratory, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (Meagher, Price) Victorian Infectious Diseases Reference Laboratory Epidemiology Unit, Royal Melbourne Hospital, University of Melbourne, Peter Doherty Institute for Infection and Immunity, Melbourne, VIC, Australia (Price) Centre for Epidemiology and Biostatistics, University of Melbourne, Melbourne, VIC, Australia (Van Hal) Department of Microbiology and Infectious Disease, Royal Prince Alfred Hospital, Sydney, NSW, Australia (O'Sullivan) New South Wales Health Pathology, Westmead Hospital, Westmead, Australia (Davis) Department of Infectious Diseases, John Hunter Hospital, Newcastle, NSW, Australia | Issue Date: | 21-Feb-2020 | Copyright year: | 2020 | Publisher: | American Medical Association (E-mail: smcleod@itsa.ucsf.edu) | Place of publication: | United States | Publication information: | JAMA - Journal of the American Medical Association. 323 (6) (pp 527-537), 2020. Date of Publication: 11 Feb 2020. | Journal: | JAMA - Journal of the American Medical Association | Abstract: | Importance: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a beta-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted. Objective(s): To determine whether combining an antistaphylococcal beta-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia. Design, Setting, and Participant(s): 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. Intervention(s): Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal beta-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 beta-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. Result(s): 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 beta-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.Copyright © 2020 American Medical Association. All rights reserved. | DOI: | http://monash.idm.oclc.org/login?url=http://acs.hcn.com.au/?acc=36265&url=http://dx.doi.org/10.1001/jama.2020.0103 | PubMed URL: | 32044943 [http://www.ncbi.nlm.nih.gov/pubmed/?term=32044943] | ISSN: | 0098-7484 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/29372 | Type: | Article | Subjects: | *vancomycin/iv [Intravenous Drug Administration] *vancomycin/pv [Special Situation for Pharmacovigilance] *daptomycin/iv [Intravenous Drug Administration] acute kidney failure/si [Side Effect] adult aged all cause mortality article clinical outcome controlled study diarrhea/si [Side Effect] *drug efficacy drug fever/si [Side Effect] drug monitoring drug safety female follow up general practitioner hospitalization human hypertransaminasemia/si [Side Effect] major clinical study male *methicillin resistant Staphylococcus aureus infection/dt [Drug Therapy] monotherapy *mortality rate pilot study priority journal randomized controlled trial rash/si [Side Effect] *recurrent disease therapy effect thrombocytopenia/si [Side Effect] thrombophlebitis/si [Side Effect] treatment duration *treatment failure *cefazolin/ae [Adverse Drug Reaction] *cefazolin/cb [Drug Combination] *cefazolin/dt [Drug Therapy] *cefazolin/iv [Intravenous Drug Administration] *cefazolin/pv [Special Situation for Pharmacovigilance] *cloxacillin/ae [Adverse Drug Reaction] *cloxacillin/cb [Drug Combination] *cloxacillin/dt [Drug Therapy] *cloxacillin/iv [Intravenous Drug Administration] *cloxacillin/pv [Special Situation for Pharmacovigilance] *daptomycin/ae [Adverse Drug Reaction] *daptomycin/cb [Drug Combination] *daptomycin/dt [Drug Therapy] *daptomycin/pv [Special Situation for Pharmacovigilance] *flucloxacillin/ae [Adverse Drug Reaction] *flucloxacillin/cb [Drug Combination] *flucloxacillin/dt [Drug Therapy] *flucloxacillin/iv [Intravenous Drug Administration] *flucloxacillin/pv [Special Situation for Pharmacovigilance] *vancomycin/ae [Adverse Drug Reaction] *vancomycin/cb [Drug Combination] *vancomycin/dt [Drug Therapy] vancomycin daptomycin acute kidney failure aged diarrhea drug efficacy drug fever drug monitoring drug safety general practitioner hospitalization hypertransaminasemia methicillin resistant Staphylococcus aureus infection monotherapy pilot study rash recurrent disease therapy effect thrombocytopenia thrombophlebitis cefazolin cloxacillin daptomycin flucloxacillin vancomycin drug safety female follow up general practitioner hospitalization human hypertransaminasemia / side effect major clinical study male *methicillin resistant Staphylococcus aureus infection / *drug therapy monotherapy *mortality rate pilot study priority journal randomized controlled trial rash / side effect *recurrent disease therapy effect thrombocytopenia / side effect aged treatment duration *treatment failure adult acute kidney failure / side effect thrombophlebitis / side effect all cause mortality Article clinical outcome controlled study diarrhea / side effect *drug efficacy drug fever / side effect drug monitoring |
Type of Clinical Study or Trial: | Randomised controlled trial |
Appears in Collections: | Articles |
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