Clinical Impact of the Cefazolin Inoculum Effect

头孢唑啉接种效果的临床影响

• 批准号: 10735541
• 负责人: Cesar Augusto Arias
• 金额: $ 68.77万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-05 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10735541
• 关键词: Address; Adverse reactions; Affect; Antibiotics; Attention; Australia; Bacteremia; Biological; Blood Circulation; Canada; Cefazolin; Cephalosporins; Child; Chile; Clinical; Clinical Data; Clinical Microbiology; Colombia; Data; Detection; Early Diagnosis; Effectiveness; Enrollment; Failure; Floxacillin; Generations; Genomics; Genus staphylococcus; Geographic Locations; Goals; Hepatotoxicity; Infection; Interstitial Nephritis; Israel; Laboratories; Latin America; Life; Mediator; Methicillin; Methodist Church; Minimum Inhibitory Concentration measurement; Nafcillin; Nature; Neutropenia; New Zealand; Osteomyelitis; Outcome; Oxacillin; Patient-Focused Outcomes; Patients; Penicillins; Performance; Pharmaceutical Preparations; Phenotype; Predisposition; Prevalence; Production; Publishing; Randomized; Reaction; Rest; Retrospective Studies; Risk; Risk Factors; Safety; Sample Size; Sensitivity and Specificity; Sepsis; Singapore; Specific qualifier value; Staphylococcus aureus; Staphylococcus aureus infection; Test Result; Testing; Therapeutic; United Kingdom; United States; arm; beta-Lactamase; beta-Lactams; clinically relevant; cost; diagnostic tool; effectiveness evaluation; high risk; human pathogen; insight; methicillin resistant Staphylococcus aureus; minimal inhibitory concentration; mortality; nitrocefin; novel; novel diagnostics; open label; participant enrollment; pathogen; primary outcome; public health relevance; rapid detection; rapid test; recruit; secondary outcome; success; treatment optimization

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.

摘要 金黄色葡萄球菌是一种主要的人类病原体，可引起多种危及生命的感染。 许多感染是由甲氧西林敏感的沙门氏菌引起的。金黄色葡萄球菌（MSSA）。MSSA代表一个主要的 S.的负担。金黄色葡萄球菌感染，并且是死亡率的重要贡献者。几十年来， 严重MSSA感染的治疗是异恶唑基青霉素（ISP，例如，萘夫西林）。但最近的 数据表明，MSSA菌血症的临床结局与头孢唑林治疗的患者相似（vs 萘夫西林），一种具有抗MSSA活性的头孢菌素，其毒性似乎较低。事实上，用萘夫西林治疗 似乎与费用增加、更多的药物反应（包括肝毒性、间质性肾炎）有关 和中性粒细胞减少症）以及可能的更高的死亡率。由于这些问题，治疗的一个重要转变 MSSA正在发生，临床医生现在使用头孢唑林作为严重MSSA的一线治疗 感染.使用头孢唑啉和其他头孢菌素作为这些严重的主要治疗的一个重要问题是， 感染的最小抑制浓度是头孢唑林接种物效应（CzIE），定义为头孢唑林最小抑制浓度> 当使用高接种量（107 CFU/ml）时，为16 µg/ml。CzIE与治疗失败有关 深部MSSA感染和葡萄球菌β-内酰胺酶某些同种型的产生。 然而，这种现象在深层MSSA感染中的临床影响的表征 是有限的。此外，目前还无法在标准的临床微生物实验室中检测CzIE 鉴于用于其检测的金标准测试的繁琐和昂贵的性质。我们的出版和 初步的临床数据表明，CzIE是导致严重急性胰腺炎临床结局恶化的重要因素。 MSSA感染。此外，我们还开发并发表了一种新的基于比色法的硝头孢菌素快速检测方法 （~3小时），其以高灵敏度和特异性检测CzIE，可并入常规临床试验中。 微生物实验室我们假设，i）CzIE对MSSA菌血症的临床结局产生负面影响 用头孢唑啉处理，和ii）快速测试可以很容易地实现用于鉴定的CzIE在S。 金黄色葡萄球菌菌血症，并可以检测出患者在高风险的不良后果。为了解决这些假设， 我们将利用金黄色葡萄球菌网络自适应平台（SNAP）试验，一个多中心， 一项务实、多组、开放标签的适应性平台试验，旨在解决 S.金黄色菌血症我们将重点关注MSSA“领域”，评估以下药物的有效性和安全性： 头孢唑林与ISP的随机对照研究，目前正在澳大利亚、新加坡、加拿大、以色列、新西兰 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 CzIE在MSSA菌血症中的临床影响，ii）确定CzIE的临床价值和可行性， 快速检测CzIE。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以管理MSSA感染提供基础。