Abstract
BackgroundMethicillin-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/DesignWe 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.DiscussionKey potential advantages of adding anti-staphylococcal β-lactams to standard therapy for MRSA bacteraemia include their safety profile, low cost, and wide availability.Trial registrationClinicalTrials.gov Identifier: NCT02365493. Registered 24 February 2015.
Highlights
Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is a serious infection resulting in 20–50 % 90-day mortality
Invasive MRSA infection causes a substantial burden of disease The Australian and New Zealand Co-operative Outcomes of Staphylococcal Sepsis (ANZCOSS) study included data from 33 hospitals and found that of 10,085 Staphylococcus aureus bacteraemia (SAB) cases in 6 years (2007–2012), 2881 (22 %) were MRSA with an average of 480 MRSA bacteraemia (MRSA-B) cases per year [2]
In a single-centre retrospective cohort study, Dilworth and colleagues described the outcomes of 50 participants with MRSA-B who received combination therapy with vancomycin and at least 24 hours of β-lactam, and compared them with 30 participants treated at the same hospital, during the same time period with vancomycin alone [35]
Summary
Methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is a serious infection resulting in 20–50 % 90-day mortality. Invasive MRSA infection causes a substantial burden of disease The Australian and New Zealand Co-operative Outcomes of Staphylococcal Sepsis (ANZCOSS) study included data from 33 hospitals and found that of 10,085 Staphylococcus aureus bacteraemia (SAB) cases in 6 years (2007–2012), 2881 (22 %) were MRSA with an average of 480 MRSA bacteraemia (MRSA-B) cases per year [2]. Hospitalacquired MRSA infections have decreased in the US, UK and Australia with improved infection control practices, community-associated strains of MRSA have emerged in the past 10–15 years and the majority of invasive MRSA infections are community-onset rather than nosocomial [3] This is reflected in ANZCOSS data, where community-onset cases of MRSA-B (index blood culture taken earlier than 72 hours following admission) increased from 51 % in 2007 to 69 % in 2012. Attempts to prevent MRSA infections outside the hospital system are unlikely to be effective, and further reductions in the incidence of MRSA infections are not expected
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