Combination of Vancomycin and β-Lactam Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia: A Pilot Multicenter Randomized Controlled Trial

Joshua S. Davis; Archana Sud; Matthew V N O'Sullivan; James O. Robinson; Patricia E. Ferguson; Hong Foo; Sebastiaan J. Van Hal; Anna P. Ralph; Benjamin P. Howden; Paula M. Binks; Adrienne Kirby; Steven Y C Tong; Suman Majumdar; Rob Baird; Claire Gordon; Cameron Jeremiah; Grace Leung; Anna Brischetto; Amy Crowe; Farshid Dakh; Kelly Whykes; Maria Kirkwood; Mahesh Menon; Lucy Somerville; Shrada Subedi; Shirley Owen; Eunice Liu; Fei Zhou; Owen Robinson; Geoffrey Coombs; Simon Pollet; Rebecca Davis; CAMERA Study Group

doi:10.1093/cid/civ808

Combination of Vancomycin and β-Lactam Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia: A Pilot Multicenter Randomized Controlled Trial

Joshua S. Davis, Archana Sud, Matthew V N O'Sullivan, James O. Robinson, Patricia E. Ferguson, Hong Foo, Sebastiaan J. Van Hal, Anna P. Ralph, Benjamin P. Howden, Paula M. Binks, Adrienne Kirby, Steven Y C Tong, Suman Majumdar, Rob Baird, Claire Gordon, Cameron Jeremiah, Grace Leung, Anna Brischetto, Amy Crowe, Farshid DakhKelly Whykes, Maria Kirkwood, Mahesh Menon, Lucy Somerville, Shrada Subedi, Shirley Owen, Eunice Liu, Fei Zhou, Owen Robinson, Geoffrey Coombs, Simon Pollet, Rebecca Davis, CAMERA Study Group

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Abstract

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).

Original language	English
Pages (from-to)	173-180
Number of pages	8
Journal	Clinical Infectious Diseases
Volume	62
Issue number	2
DOIs	https://doi.org/10.1093/cid/civ808
Publication status	Published - 15 Jan 2016

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Davis, J. S., Sud, A., O'Sullivan, M. V. N., Robinson, J. O., Ferguson, P. E., Foo, H., Van Hal, S. J., Ralph, A. P., Howden, B. P., Binks, P. M., Kirby, A., Tong, S. Y. C., Majumdar, S., Baird, R., Gordon, C., Jeremiah, C., Leung, G., Brischetto, A., Crowe, A., ... CAMERA Study Group (2016). Combination of Vancomycin and β-Lactam Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia: A Pilot Multicenter Randomized Controlled Trial. Clinical Infectious Diseases, 62(2), 173-180. https://doi.org/10.1093/cid/civ808

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title = "Combination of Vancomycin and β-Lactam Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia: A Pilot Multicenter Randomized Controlled Trial",

abstract = "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).",

keywords = "-lactam, bacteremia, clinical trial, MRSA, Staphylococcus aureus, vancomycin, β",

author = "Davis, {Joshua S.} and Archana Sud and O'Sullivan, {Matthew V N} and Robinson, {James O.} and Ferguson, {Patricia E.} and Hong Foo and {Van Hal}, {Sebastiaan J.} and Ralph, {Anna P.} and Howden, {Benjamin P.} and Binks, {Paula M.} and Adrienne Kirby and Tong, {Steven Y C} and Suman Majumdar and Rob Baird and Claire Gordon and Cameron Jeremiah and Grace Leung and Anna Brischetto and Amy Crowe and Farshid Dakh and Kelly Whykes and Maria Kirkwood and Mahesh Menon and Lucy Somerville and Shrada Subedi and Shirley Owen and Eunice Liu and Fei Zhou and Owen Robinson and Geoffrey Coombs and Simon Pollet and Rebecca Davis and {CAMERA Study Group}",

year = "2016",

month = jan,

day = "15",

doi = "10.1093/cid/civ808",

language = "English",

volume = "62",

pages = "173--180",

journal = "Clinical Infectious Diseases",

issn = "1058-4838",

publisher = "Oxford University Press",

number = "2",

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Davis, JS, Sud, A, O'Sullivan, MVN, Robinson, JO, Ferguson, PE, Foo, H, Van Hal, SJ, Ralph, AP, Howden, BP, Binks, PM, Kirby, A, Tong, SYC, Majumdar, S, Baird, R, Gordon, C, Jeremiah, C, Leung, G, Brischetto, A, Crowe, A, Dakh, F, Whykes, K, Kirkwood, M, Menon, M, Somerville, L, Subedi, S, Owen, S, Liu, E, Zhou, F, Robinson, O, Coombs, G, Pollet, S, Davis, R & CAMERA Study Group 2016, 'Combination of Vancomycin and β-Lactam Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia: A Pilot Multicenter Randomized Controlled Trial', Clinical Infectious Diseases, vol. 62, no. 2, pp. 173-180. https://doi.org/10.1093/cid/civ808

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T1 - Combination of Vancomycin and β-Lactam Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia

T2 - A Pilot Multicenter Randomized Controlled Trial

AU - Davis, Joshua S.

AU - Sud, Archana

AU - O'Sullivan, Matthew V N

AU - Robinson, James O.

AU - Ferguson, Patricia E.

AU - Foo, Hong

AU - Van Hal, Sebastiaan J.

AU - Ralph, Anna P.

AU - Howden, Benjamin P.

AU - Binks, Paula M.

AU - Kirby, Adrienne

AU - Tong, Steven Y C

AU - Majumdar, Suman

AU - Baird, Rob

AU - Gordon, Claire

AU - Jeremiah, Cameron

AU - Leung, Grace

AU - Brischetto, Anna

AU - Crowe, Amy

AU - Dakh, Farshid

AU - Whykes, Kelly

AU - Kirkwood, Maria

AU - Menon, Mahesh

AU - Somerville, Lucy

AU - Subedi, Shrada

AU - Owen, Shirley

AU - Liu, Eunice

AU - Zhou, Fei

AU - Robinson, Owen

AU - Coombs, Geoffrey

AU - Pollet, Simon

AU - Davis, Rebecca

AU - CAMERA Study Group

PY - 2016/1/15

Y1 - 2016/1/15

N2 - 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).

AB - 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).

KW - -lactam

KW - bacteremia

KW - clinical trial

KW - MRSA

KW - Staphylococcus aureus

KW - vancomycin

KW - β

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DO - 10.1093/cid/civ808

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Combination of Vancomycin and β-Lactam Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia: A Pilot Multicenter Randomized Controlled Trial

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