Cefazolin versus flucloxacillin in bloodstream infections caused by methicillin-susceptible Staphylococcus aureus (MSSA): a quasi-randomized, prospective, observational study (CASABI)

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Methicillin-susceptible Staphylococcus aureus (MSSA) is a leading cause of serious invasive infections often complicated by bacteraemia. For decades antistaphylococcal penicillins (ASPs) have been the unquestioned first line therapeutic agents. Cefazolin has been degraded to an alternative mainly due to concerns about a reduced efficacy in high inoculum infections - derived from an in-vitro phenomenon with unclear clinical significance. Newer, mainly retrospective studies demonstrated a similar clinical efficacy of ASPs and cefazolin in the treatment of both uncomplicated MSSA blood stream infections (BSI) and blood stream infections from a deep-seated source. They concluded equally that adequate source control and severity of disease may better predict clinical outcome than the choice of the antibiotic agent. Surprisingly there was a consistent trend towards a lower mortality in patients treated with Cefazolin which was highly significant in a large retrospective analysis of more than 3000 patients. However, substantial selection bias with a preferential choice of ASPs for more severe infections cannot be excluded despite vigorous efforts of authors for statistical adjusting for confounding factors. Another consistent finding was a relevant better tolerability of Cefazolin compared to various ASPs. Along with a more convenient dosing scheme and lower costs of cefazolin, it might be the time to rethink the role of ASPs in the management of invasive MSSA infections. However, prospective controlled studies evaluating the clinical efficacy and tolerability of cefazolin versus ASPs are missing. The ultimate goal of this proposal is to conduct such a trial. For a solid sample size calculation and evaluation of feasibility a prospective, observational pilot study is needed. We propose a quasi-randomised, propensity score matched comparison of current therapy standards at the university hospitals of Cologne (primary use of an ASP) and Frankfurt (primary use of cefazolin). An established, well-accepted infectious disease consultation service at both hospitals with routine consultation for all patients with MSSA-BSI represent ideal research conditions. The type, grade and frequency of adverse events will be captured precisely while clinical and microbiological efficacy will be analysed exploratory to assess formal progression criteria. If a better tolerability of cefazolin as compared to ASPs with a similar or better efficacy can be shown in this pilot trial, its results will be used to design a definite randomised trial to compare the efficacy of both regimens, i.e. presumably on the non-inferiority of cefazolin to flucloxacillin. At the time of submission no other prospective trial answering this question could be identified in applicable databases.