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）一直是无可争议的一线治疗药物。头孢唑林已被降级为一种替代品，主要是由于担心对高接种率感染的疗效降低，这源于一种临床意义不明确的体外现象。较新的，主要是回顾性的研究表明，asp和头孢唑林在治疗无并发症的MSSA血流感染（BSI）和深层血流感染方面的临床疗效相似。他们同样得出结论，充分的传染源控制和疾病严重程度可能比选择抗生素更能预测临床结果。令人惊讶的是，在接受头孢唑林治疗的患者中，有一种死亡率较低的一致趋势，这在对3000多名患者进行的大型回顾性分析中非常显著。然而，尽管作者对混杂因素进行了积极的统计调整，但仍不能排除在更严重的感染中优先选择asp的实质性选择偏差。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。随着头孢唑林更方便的给药方案和更低的成本，可能是时候重新考虑asp在侵袭性msa感染管理中的作用了。然而，评估头孢唑林与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试验。为了可靠的样本量计算和可行性评估，需要进行前瞻性、观察性的试点研究。我们提出了一种准随机的倾向评分匹配比较科隆大学医院（主要使用ASP）和法兰克福大学医院（主要使用头孢唑林）的当前治疗标准。两家医院都建立了广泛接受的传染病咨询服务，为所有msa - bsi患者提供常规咨询，这代表了理想的研究条件。不良事件的类型、等级和频率将被精确地捕获，同时临床和微生物疗效将进行探索性分析，以评估正式的进展标准。如果在这个试点试验中可以显示头孢唑林的耐受性比具有相似或更好疗效的asp更好，其结果将用于设计一个明确的随机试验来比较两种方案的疗效，即可能是头孢唑林对氟氯西林的非劣效性。在提交时，在适用的数据库中无法确定其他回答此问题的前瞻性试验。

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.