https://nova.newcastle.edu.au/vital/access/ /manager/Index en-au 5 https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:24771 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. Trial registration: ClinicalTrials.gov Identifier: NCT02365493. Registered 24 February 2015.]]> Wed 11 Apr 2018 11:47:34 AEST ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:47712 HLA ‐B*57:01 is an established genetic risk factor for flucloxacillin DILI . To consolidate this finding, identify additional genetic factors, and assess relevance of risk factors for flucloxacillin DILI in relation to DILI due to other penicillins, we performed a genomewide association study involving 197 flucloxacillin DILI cases and 6,835 controls. We imputed single‐nucleotide polymorphism and human leukocyte antigen (HLA) genotypes. HLA ‐B*57:01 was the major risk factor (allelic odds ratio (OR ) = 36.62; P = 2.67 x 10⁻⁹⁷). HLA ‐B*57:03 also showed an association (OR = 79.21; P = 1.2 x 10⁻⁶). Within the HLA ‐B protein sequence, imputation showed valine⁹⁷, common to HLA ‐B*57:01 and HLA ‐B*57:03, had the largest effect (OR = 38.1; P = 9.7 x 10⁻⁹⁷). We found no HLA ‐B*57 association with DILI due to other isoxazolyl penicillins (n = 6) or amoxicillin (n = 15) and no significant non‐HLA signals for any penicillin‐related DILI.]]> Tue 21 Mar 2023 18:39:29 AEDT ]]> https://nova.newcastle.edu.au/vital/access/ /manager/Repository/uon:54577 Sat 02 Mar 2024 10:02:38 AEDT ]]>