Combination of Vancomycin and β-Lactam Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia: A Pilot Multicenter Randomized Controlled Trial.
BACKGROUND
In vitro laboratory and animal studies demonstrate a synergistic role for the combination of vancomycin and antistaphylococcal β-lactams for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. Prospective clinical data are lacking.


METHODS
In this open-label, multicenter, clinical trial, adults with MRSA bacteremia received vancomycin 1.5 g intravenously twice daily and were randomly assigned (1:1) to receive intravenous flucloxacillin 2 g every 6 hours for 7 days (combination group) or no additional therapy (standard therapy group). Participants were stratified by hospital and randomized in permuted blocks of variable size. Randomization codes were kept in sealed, sequentially numbered, opaque envelopes. The primary outcome was the duration of MRSA bacteremia in days.


RESULTS
We randomly assigned 60 patients to receive vancomycin (n = 29), or vancomycin plus flucloxacillin (n = 31). The mean duration of bacteremia was 3.00 days in the standard therapy group and 1.94 days in the combination group. According to a negative binomial model, the mean time to resolution of bacteremia in the combination group was 65% (95% confidence interval, 41%-102%; P = .06) that in the standard therapy group. There was no difference in the secondary end points of 28- and 90-day mortality, metastatic infection, nephrotoxicity, or hepatotoxicity.


CONCLUSIONS
Combining an antistaphylococcal β-lactam with vancomycin may shorten the duration of MRSA bacteremia. Further trials with a larger sample size and objective clinically relevant end points are warranted. Australian New Zealand Clinical Trials Registry: ACTRN12610000940077 (www.anzctr.org.au).
Global and Tropical Health Division, Menzies School of Health Research.|Department of Infectious Diseases, John Hunter Hospital, Newcastle.
Joshua S
JS
Davis
Department of Infectious Diseases, Nepean Hospital and University of Sydney.|Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney.
Archana
A
Sud
Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney.|Centre for Infectious Diseases and Microbiology, Westmead Hospital.
Matthew V N
MVN
O'Sullivan
Department of Microbiology and Infectious Diseases, PathWest Laboratory Medicine WA, Royal Perth Hospital and Fiona Stanley Hospital.|Australian Collaborating Centre for Enterococcus and Staphylococcus Species (ACCESS) Typing and Research, School of Veterinary and Life Sciences, Murdoch University and School of Biomedical Sciences, Curtin University, Perth, Western Australia.
James O
JO
Robinson
Marie Bashir Institute for Infectious Diseases and Biosecurity, University of Sydney.|Department of Infectious Diseases, Blacktown Hospital.
Patricia E
PE
Ferguson
Department of Microbiology and Infectious Diseases, Liverpool Hospital.
Hong
H
Foo
Department Microbiology and Infectious Diseases, Royal Prince Alfred Hospital, Sydney, New South Wales.
Sebastiaan J
SJ
van Hal
Global and Tropical Health Division, Menzies School of Health Research.|Department of Infectious Diseases, Royal Darwin Hospital, Darwin, Northern Territory.
Anna P
AP
Ralph
Department of Microbiology and Immunology, Microbiological Diagnostic Unit, The University of Melbourne at the Doherty Institute for Infection and Immunity.|Departments of Microbiology and Infectious Diseases, Austin Health.|Department of Microbiology, Monash University, Melbourne, Victoria, Australia.
Benjamin P
BP
Howden
Global and Tropical Health Division, Menzies School of Health Research.
Paula M
PM
Binks
National Health and Medical Research Council Clinical Trials Centre, University of Sydney.
Adrienne
A
Kirby
Global and Tropical Health Division, Menzies School of Health Research.|Department of Infectious Diseases, Royal Darwin Hospital, Darwin, Northern Territory.
Steven Y C
SYC
Tong
Steven
S
Tong
Joshua
J
Davis
Paula
P
Binks
Suman
S
Majumdar
Anna
A
Ralph
Rob
R
Baird
Claire
C
Gordon
Cameron
C
Jeremiah
Grace
G
Leung
Anna
A
Brischetto
Amy
A
Crowe
Farshid
F
Dakh
Kelly
K
Whykes
Maria
M
Kirkwood
Archana
A
Sud
Mahesh
M
Menon
Lucy
L
Somerville
Shrada
S
Subedi
Shirley
S
Owen
Matthew
M
O'Sullivan
Eunice
E
Liu
Fei
F
Zhou
Owen
O
Robinson
Geoffrey
G
Coombs
Patrician
P
Ferguson
Anna
A
Ralph
Eunice
E
Liu
Simon
S
Pollet
Sebastian
S
Van Hal
Hong
H
Foo
Sebastian
S
Van Hal
Rebecca
R
Davis
D061605:Administration, Intravenous; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016470:Bacteremia / Q000188:drug therapy* / Q000382:microbiology; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D005436:Floxacillin / Q000494:pharmacology*; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000302:isolation & purification*; D008875:Middle Aged; D009520:New Zealand; D011446:Prospective Studies; D013203:Staphylococcal Infections / Q000188:drug therapy* / Q000382:microbiology; D013997:Time Factors; D016896:Treatment Outcome; D014640:Vancomycin / Q000494:pharmacology*; D055815:Young Adult
D000900:Anti-Bacterial Agents; D005436:Floxacillin; D014640:Vancomycin
MRSA; Staphylococcus aureus; bacteremia; clinical trial; vancomycin; β-lactam