CAMERA2 - combination antibiotic therapy for methicillin-resistant Staphylococcus aureus infection

Study protocol for a randomised controlled trial

Steven Y C Tong, Jane Nelson, David L. Paterson, Vance G. Fowler, Benjamin P. Howden, Allen C. Cheng, Mark Chatfield, Jeffrey Lipman, Sebastian Van Hal, Matthew O'Sullivan, James O. Robinson, Dafna Yahav, David Lye, Joshua S. Davis, CAMERA2 study group and the Australasian Society for Infectious Diseases Clinical Research Network

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    Abstract

    Background: Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is a serious infection resulting in 20-50 % 90-day mortality. The limitations of vancomycin, the current standard therapy for MRSA, make treatment difficult. The only other approved drug for treatment of MRSA bacteraemia, daptomycin, has not been shown to be superior to vancomycin. Surprisingly, there has been consistent in-vitro and in-vivo laboratory data demonstrating synergy between vancomycin or daptomycin and an anti-staphylococcal β-lactam antibiotic. There is also growing clinical data to support such combinations, including a recent pilot randomised controlled trial (RCT) that demonstrated a trend towards a reduction in the duration of bacteraemia in patients treated with vancomycin plus flucloxacillin compared to vancomycin alone. Our aim is to determine whether the addition of an anti-staphylococcal penicillin to standard therapy results in improved clinical outcomes in MRSA bacteraemia.

    Methods/Design: We will perform an open-label, parallel-group, randomised (1:1) controlled trial at 29 sites in Australia, New Zealand, Singapore, and Israel. Adults (aged 18 years or older) with MRSA grown from at least one blood culture and able to be randomised within 72 hours of the index blood culture collection will be eligible for inclusion. Participants will be randomised to vancomycin or daptomycin (standard therapy) given intravenously or to standard therapy plus 7 days of an anti-staphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin). The primary endpoint will be a composite outcome at 90 days of (1) all-cause mortality, (2) persistent bacteraemia at day 5 or beyond, (3) microbiological relapse, or (4) microbiological treatment failure. The recruitment target of 440 patients is based on an expected failure rate for the primary outcome of 30 % in the control arm and the ability to detect a clinically meaningful absolute decrease of 12.5 %, with a two-sided alpha of 0.05, a power of 80 %, and assuming 10 % of patients will not be evaluable for the primary endpoint.

    Discussion: Key potential advantages of adding anti-staphylococcal β-lactams to standard therapy for MRSA bacteraemia include their safety profile, low cost, and wide availability.

    Original languageEnglish
    Article number170
    Pages (from-to)1-15
    Number of pages15
    JournalTrials
    Volume17
    Issue number1
    DOIs
    Publication statusPublished - 2016

    Fingerprint

    Methicillin-Resistant Staphylococcus aureus
    Vancomycin
    Bacteremia
    Randomized Controlled Trials
    Anti-Bacterial Agents
    Daptomycin
    Lactams
    Infection
    Floxacillin
    Therapeutics
    Cloxacillin
    Cefazolin
    Mortality
    Singapore
    Israel
    Treatment Failure
    New Zealand
    Penicillins
    Safety
    Costs and Cost Analysis

    Cite this

    Tong, S. Y. C., Nelson, J., Paterson, D. L., Fowler, V. G., Howden, B. P., Cheng, A. C., ... CAMERA2 study group and the Australasian Society for Infectious Diseases Clinical Research Network (2016). CAMERA2 - combination antibiotic therapy for methicillin-resistant Staphylococcus aureus infection: Study protocol for a randomised controlled trial. Trials, 17(1), 1-15. [170]. https://doi.org/10.1186/S13063-016-1295-3
    Tong, Steven Y C ; Nelson, Jane ; Paterson, David L. ; Fowler, Vance G. ; Howden, Benjamin P. ; Cheng, Allen C. ; Chatfield, Mark ; Lipman, Jeffrey ; Van Hal, Sebastian ; O'Sullivan, Matthew ; Robinson, James O. ; Yahav, Dafna ; Lye, David ; Davis, Joshua S. ; CAMERA2 study group and the Australasian Society for Infectious Diseases Clinical Research Network. / CAMERA2 - combination antibiotic therapy for methicillin-resistant Staphylococcus aureus infection : Study protocol for a randomised controlled trial. In: Trials. 2016 ; Vol. 17, No. 1. pp. 1-15.
    @article{aa43f17ad9b24bd8b87364673a6e7839,
    title = "CAMERA2 - combination antibiotic therapy for methicillin-resistant Staphylococcus aureus infection: Study protocol for a randomised controlled trial",
    abstract = "Background: Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is a serious infection resulting in 20-50 {\%} 90-day mortality. The limitations of vancomycin, the current standard therapy for MRSA, make treatment difficult. The only other approved drug for treatment of MRSA bacteraemia, daptomycin, has not been shown to be superior to vancomycin. Surprisingly, there has been consistent in-vitro and in-vivo laboratory data demonstrating synergy between vancomycin or daptomycin and an anti-staphylococcal β-lactam antibiotic. There is also growing clinical data to support such combinations, including a recent pilot randomised controlled trial (RCT) that demonstrated a trend towards a reduction in the duration of bacteraemia in patients treated with vancomycin plus flucloxacillin compared to vancomycin alone. Our aim is to determine whether the addition of an anti-staphylococcal penicillin to standard therapy results in improved clinical outcomes in MRSA bacteraemia. Methods/Design: We will perform an open-label, parallel-group, randomised (1:1) controlled trial at 29 sites in Australia, New Zealand, Singapore, and Israel. Adults (aged 18 years or older) with MRSA grown from at least one blood culture and able to be randomised within 72 hours of the index blood culture collection will be eligible for inclusion. Participants will be randomised to vancomycin or daptomycin (standard therapy) given intravenously or to standard therapy plus 7 days of an anti-staphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin). The primary endpoint will be a composite outcome at 90 days of (1) all-cause mortality, (2) persistent bacteraemia at day 5 or beyond, (3) microbiological relapse, or (4) microbiological treatment failure. The recruitment target of 440 patients is based on an expected failure rate for the primary outcome of 30 {\%} in the control arm and the ability to detect a clinically meaningful absolute decrease of 12.5 {\%}, with a two-sided alpha of 0.05, a power of 80 {\%}, and assuming 10 {\%} of patients will not be evaluable for the primary endpoint. Discussion: Key potential advantages of adding anti-staphylococcal β-lactams to standard therapy for MRSA bacteraemia include their safety profile, low cost, and wide availability.",
    keywords = "Cefazolin, Cloxacillin, Combination, Daptomycin, Flucloxacillin, Methicillin-resistant, MRSA, Nafcillin, Randomised controlled trial, Staphylococcus aureus, Vancomycin",
    author = "Tong, {Steven Y C} and Jane Nelson and Paterson, {David L.} and Fowler, {Vance G.} and Howden, {Benjamin P.} and Cheng, {Allen C.} and Mark Chatfield and Jeffrey Lipman and {Van Hal}, Sebastian and Matthew O'Sullivan and Robinson, {James O.} and Dafna Yahav and David Lye and Davis, {Joshua S.} and {CAMERA2 study group and the Australasian Society for Infectious Diseases Clinical Research Network}",
    year = "2016",
    doi = "10.1186/S13063-016-1295-3",
    language = "English",
    volume = "17",
    pages = "1--15",
    journal = "Trials",
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    Tong, SYC, Nelson, J, Paterson, DL, Fowler, VG, Howden, BP, Cheng, AC, Chatfield, M, Lipman, J, Van Hal, S, O'Sullivan, M, Robinson, JO, Yahav, D, Lye, D, Davis, JS & CAMERA2 study group and the Australasian Society for Infectious Diseases Clinical Research Network 2016, 'CAMERA2 - combination antibiotic therapy for methicillin-resistant Staphylococcus aureus infection: Study protocol for a randomised controlled trial', Trials, vol. 17, no. 1, 170, pp. 1-15. https://doi.org/10.1186/S13063-016-1295-3

    CAMERA2 - combination antibiotic therapy for methicillin-resistant Staphylococcus aureus infection : Study protocol for a randomised controlled trial. / Tong, Steven Y C; Nelson, Jane; Paterson, David L.; Fowler, Vance G.; Howden, Benjamin P.; Cheng, Allen C.; Chatfield, Mark; Lipman, Jeffrey; Van Hal, Sebastian; O'Sullivan, Matthew; Robinson, James O.; Yahav, Dafna; Lye, David; Davis, Joshua S.; CAMERA2 study group and the Australasian Society for Infectious Diseases Clinical Research Network.

    In: Trials, Vol. 17, No. 1, 170, 2016, p. 1-15.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - CAMERA2 - combination antibiotic therapy for methicillin-resistant Staphylococcus aureus infection

    T2 - Study protocol for a randomised controlled trial

    AU - Tong, Steven Y C

    AU - Nelson, Jane

    AU - Paterson, David L.

    AU - Fowler, Vance G.

    AU - Howden, Benjamin P.

    AU - Cheng, Allen C.

    AU - Chatfield, Mark

    AU - Lipman, Jeffrey

    AU - Van Hal, Sebastian

    AU - O'Sullivan, Matthew

    AU - Robinson, James O.

    AU - Yahav, Dafna

    AU - Lye, David

    AU - Davis, Joshua S.

    AU - CAMERA2 study group and the Australasian Society for Infectious Diseases Clinical Research Network

    PY - 2016

    Y1 - 2016

    N2 - Background: Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is a serious infection resulting in 20-50 % 90-day mortality. The limitations of vancomycin, the current standard therapy for MRSA, make treatment difficult. The only other approved drug for treatment of MRSA bacteraemia, daptomycin, has not been shown to be superior to vancomycin. Surprisingly, there has been consistent in-vitro and in-vivo laboratory data demonstrating synergy between vancomycin or daptomycin and an anti-staphylococcal β-lactam antibiotic. There is also growing clinical data to support such combinations, including a recent pilot randomised controlled trial (RCT) that demonstrated a trend towards a reduction in the duration of bacteraemia in patients treated with vancomycin plus flucloxacillin compared to vancomycin alone. Our aim is to determine whether the addition of an anti-staphylococcal penicillin to standard therapy results in improved clinical outcomes in MRSA bacteraemia. Methods/Design: We will perform an open-label, parallel-group, randomised (1:1) controlled trial at 29 sites in Australia, New Zealand, Singapore, and Israel. Adults (aged 18 years or older) with MRSA grown from at least one blood culture and able to be randomised within 72 hours of the index blood culture collection will be eligible for inclusion. Participants will be randomised to vancomycin or daptomycin (standard therapy) given intravenously or to standard therapy plus 7 days of an anti-staphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin). The primary endpoint will be a composite outcome at 90 days of (1) all-cause mortality, (2) persistent bacteraemia at day 5 or beyond, (3) microbiological relapse, or (4) microbiological treatment failure. The recruitment target of 440 patients is based on an expected failure rate for the primary outcome of 30 % in the control arm and the ability to detect a clinically meaningful absolute decrease of 12.5 %, with a two-sided alpha of 0.05, a power of 80 %, and assuming 10 % of patients will not be evaluable for the primary endpoint. Discussion: Key potential advantages of adding anti-staphylococcal β-lactams to standard therapy for MRSA bacteraemia include their safety profile, low cost, and wide availability.

    AB - Background: Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is a serious infection resulting in 20-50 % 90-day mortality. The limitations of vancomycin, the current standard therapy for MRSA, make treatment difficult. The only other approved drug for treatment of MRSA bacteraemia, daptomycin, has not been shown to be superior to vancomycin. Surprisingly, there has been consistent in-vitro and in-vivo laboratory data demonstrating synergy between vancomycin or daptomycin and an anti-staphylococcal β-lactam antibiotic. There is also growing clinical data to support such combinations, including a recent pilot randomised controlled trial (RCT) that demonstrated a trend towards a reduction in the duration of bacteraemia in patients treated with vancomycin plus flucloxacillin compared to vancomycin alone. Our aim is to determine whether the addition of an anti-staphylococcal penicillin to standard therapy results in improved clinical outcomes in MRSA bacteraemia. Methods/Design: We will perform an open-label, parallel-group, randomised (1:1) controlled trial at 29 sites in Australia, New Zealand, Singapore, and Israel. Adults (aged 18 years or older) with MRSA grown from at least one blood culture and able to be randomised within 72 hours of the index blood culture collection will be eligible for inclusion. Participants will be randomised to vancomycin or daptomycin (standard therapy) given intravenously or to standard therapy plus 7 days of an anti-staphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin). The primary endpoint will be a composite outcome at 90 days of (1) all-cause mortality, (2) persistent bacteraemia at day 5 or beyond, (3) microbiological relapse, or (4) microbiological treatment failure. The recruitment target of 440 patients is based on an expected failure rate for the primary outcome of 30 % in the control arm and the ability to detect a clinically meaningful absolute decrease of 12.5 %, with a two-sided alpha of 0.05, a power of 80 %, and assuming 10 % of patients will not be evaluable for the primary endpoint. Discussion: Key potential advantages of adding anti-staphylococcal β-lactams to standard therapy for MRSA bacteraemia include their safety profile, low cost, and wide availability.

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    KW - Daptomycin

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    KW - Methicillin-resistant

    KW - MRSA

    KW - Nafcillin

    KW - Randomised controlled trial

    KW - Staphylococcus aureus

    KW - Vancomycin

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