Clinical Impact of the Cefazolin Inoculum Effect

摘要 金黄色葡萄球菌是一种主要的人类病原体，可导致多种危及生命的感染。 其中许多感染是由甲氧西林敏感的金黄色葡萄球菌(MSSA)引起的。MSSA代表着一个主要的 在金黄色葡萄球菌感染中造成负担，是造成死亡率的重要因素。几十年来，第一行 对严重MSSA感染的治疗一直是异恶唑基青霉素类药物(isp，如奈福西林)。然而，最近 数据表明，头孢唑林(VS)治疗的MSSA菌血症患者的临床结果相似 纳福西林)，一种头孢菌素，具有抗MSSA的活性，似乎毒性较低。事实上，纳福西林的治疗 似乎与费用增加、药物反应(包括肝毒性、间质性肾炎)有关 和中性粒细胞减少症)，而且可能会有更高的死亡率。由于这些担忧，治疗的一个重要转变是 临床医生正在使用头孢唑林作为治疗重症MSSA的一线药物。 感染。使用头孢唑林和其他头孢菌素作为治疗这些严重疾病的主要药物值得注意的问题 感染是头孢唑林的接种效应(CHIE)，定义为头孢唑林的最小抑菌浓度&GT； 当使用高接种量(107cfu/ml)时，为16微克/毫升。捷克IE一直与治疗失败有关 与深层次的MSSA感染和某些葡萄球菌β-内酰胺酶的产生有关。 然而，这种现象对深层次MSSA感染的临床影响的表征 是有限的。此外，目前还不可能在标准的临床微生物学实验室中检测到CHIE。 鉴于检测它的黄金标准测试的繁琐和昂贵的性质。我们出版的和 初步临床数据表明，CHIE是导致重型肝炎临床转归较差的重要因素。 MSSA感染。此外，我们还开发并发表了一种新的基于硝基呋喃的比色快速检测方法。 (~3h)具有高灵敏度和高特异度的检测，可纳入常规临床 微生物学实验室。我们假设，i)CHIE对MSSA菌血症的临床结局有负面影响 用头孢唑林治疗，以及，ii)可以很容易地实施快速试验来鉴定沙门氏菌。 金黄色葡萄球菌菌血症，可以检测出预后不良风险较高的患者。为了解决这些假设， 我们将利用金黄色葡萄球菌网络适应平台(SNAP)试验，一个多中心， 务实、多臂、开放标签的适应性平台试验，解决慢性阻塞性肺疾病患者的多种治疗问题 金黄色葡萄球菌菌血症。我们将重点关注评估MSSA的有效性和安全性的领域 头孢唑林与互联网服务提供商随机对照，目前在澳大利亚、新加坡、加拿大、以色列、纽约注册 新西兰、联合王国、美国、哥伦比亚和智利。我们建议的具体目标是：i)界定 CHIE对MSSA菌血症的临床影响和，ii)确定一种 快速检测捷克脑炎。我们的发现可能会改变MSSA感染的治疗方法， 将为开发新的诊断工具来管理MSSA感染提供基础。

ABSTRACT Staphylococcus aureus is a major human pathogen responsible for a wide range of life-threatening infections. Many of these infections are caused by methicillin-susceptible S. aureus (MSSA). MSSA represent a major burden among S. aureus infections and are important contributors to mortality. For decades, the first line of therapy for severe MSSA infections have been the isoxazolyl-penicillins (ISP, e.g., nafcillin). However, recent data suggest that clinical outcomes in MSSA bacteremia are similar in patients treated with cefazolin (vs nafcillin), a cephalosporin with activity against MSSA that appears to be less toxic. Indeed, treatment with nafcillin seems to be associated with increased costs, more drug reactions (including hepatotoxicity, interstitial nephritis and neutropenia) and, possibly, higher mortality. Due to these concerns, an important shift in the treatment of MSSA is occurring whereby clinicians are now using cefazolin as first line of therapy for severe MSSA infections. An important concern of using cefazolin and other cephalosporins as primary therapy for these serious infections is the cefazolin inoculum effect (CzIE), defined as a cefazolin minimal inhibitory concentration of > 16 µg/ml when a high inoculum (107 CFU/ml) is used. The CzIE has been associated with failures in the treatment of deep-seated MSSA infections and with the production of certain isotypes of the staphylococcal β-lactamase. However, the characterization of the clinical impact of this phenomenon in deep-seated MSSA infections is limited. In addition, it is currently not possible to detect the CzIE in a standard clinical microbiology laboratory given the cumbersome and expensive nature of the gold standard test for its detection. Our published and preliminary clinical data suggest that the CzIE is an important contributor to worse clinical outcomes of severe MSSA infections. Furthermore, we have developed and published a novel colorimetric nitrocefin-based rapid test (~3 h) that detects the CzIE with high sensitivity and specificity that can be incorporated in the routine clinical microbiology laboratory. We postulate that, i) the CzIE negatively impacts clinical outcomes in MSSA bacteremia treated with cefazolin and, ii) a rapid test can be readily implemented for the identification of the CzIE in S. aureus bacteremia and can detect patients at higher risk of poor outcomes. In order to address these hypotheses, we will take advantage of the Staphylococcus aureus Network Adaptive Platform (SNAP) trial, a multicenter, pragmatic, multi-arm, open-label adaptive platform trial addressing multiple therapeutic questions in patients with S. aureus bacteremia. We will focus in the MSSA “domain” that evaluates the effectiveness and safety of cefazolin vs ISP in a randomized fashion, currently enrolling in Australia, Singapore, Canada, Israel, New Zealand, United Kingdom, United States, Colombia and Chile. The specific aims of our proposal are: i) to define the clinical impact of the CzIE in MSSA bacteremia and, ii) to determine the clinical value and feasibility of a rapid test to detect the CzIE. Our findings are likely to transform the treatment approach for MSSA infections and will provide the basis to develop novel diagnostic tools to the management of MSSA infections.