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

甲氧西林敏感金黄色葡萄球菌（MSSA）是严重侵袭性感染的主要原因，通常并发菌血症。几十年来，抗葡萄球菌青霉素（ASP）一直是毋庸置疑的一线治疗药物。头孢唑林已被降解为替代品，主要是由于担心在高接种量感染中疗效降低-源自临床意义不明确的体外现象。较新的，主要是回顾性研究表明，ASP和头孢唑林在治疗简单的MSSA血流感染（BSI）和深部来源的血流感染方面具有相似的临床疗效。他们同样得出结论，充分的源头控制和疾病的严重程度可能比抗生素的选择更好地预测临床结果。令人惊讶的是，头孢唑林治疗患者的死亡率有降低的趋势，这在一项超过3000例患者的大型回顾性分析中非常显着。然而，尽管作者积极努力对混杂因素进行统计学调整，但无法排除更严重感染优先选择ASP的实质性选择偏倚。另一个一致的发现是与各种ASP相比，头孢唑林的耐受性更好。沿着更方便的给药方案和更低的头孢唑林成本，可能是时候重新考虑ASP在侵袭性MSSA感染管理中的作用了。然而，评价头孢唑林与ASP的临床疗效和耐受性的前瞻性对照研究缺失。这项建议的最终目标是进行这样的审判。对于可靠的样本量计算和可行性评价，需要进行前瞻性、观察性初步研究。我们提出了一个准随机，倾向评分匹配的比较目前的治疗标准在大学医院的科隆（主要使用ASP）和法兰克福（主要使用头孢唑林）。在两家医院建立的、被广泛接受的传染病咨询服务，为所有MSSA-BSI患者提供常规咨询，代表了理想的研究条件。将精确采集不良事件的类型、等级和频率，同时探索性分析临床和微生物学疗效，以评估正式的进展标准。如果在该初步试验中，头孢唑林的耐受性优于疗效相似或更好的ASP，则其结果将用于设计一项明确的随机试验，以比较两种治疗方案的疗效，即，假定头孢唑林非劣效于氟氯西林。在提交时，在适用的数据库中未发现回答该问题的其他前瞻性试验。

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.