Clinical Impact of the Cefazolin Inoculum Effect

头孢唑啉接种效果的临床影响

基本信息

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
项目类别：
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

项目摘要

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.

抽象的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金黄色葡萄球菌 (MSSA) 引起的，其中 MSSA 是主要感染。几十年来，金黄色葡萄球菌感染是导致死亡的重要因素。严重 MSSA 感染的治疗方法是异恶唑青霉素（ISP，例如萘夫西林）。数据表明，接受头孢唑林治疗的 MSSA 菌血症患者的临床结果相似（与萘夫西林），一种具有抗 MSSA 活性的头孢菌素，实际上，用萘夫西林治疗毒性较小。似乎与成本增加、更多药物反应（包括肝毒性、间质性肾炎和中性粒细胞减少症），并且可能导致更高的死亡率，因此治疗方法发生了重大转变。 MSSA 正在发生，上级现在使用头孢唑林作为严重 MSSA 的一线治疗使用头孢唑啉和其他头孢菌素作为这些严重感染的主要治疗方法的一个重要问题。感染是头孢唑林接种效应（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，CzIE 为 16 µg/ml，与治疗失败有关。深层 MSSA 感染并产生葡萄球菌 β-内酰胺酶的某些同种型。然而，这种现象对深部 MSSA 感染的临床影响的表征此外，目前无法在标准临床微生物实验室中检测 CzIE。考虑到我们发布和检测的金标准测试的繁琐和昂贵的性质。初步临床数据表明，CzIE 是导致重症患者临床结果较差的一个重要因素。此外，我们还开发并发布了一种基于头孢硝基的新型比色快速检测方法。 (~3 小时)，以高灵敏度和特异性检测 CzIE，可纳入常规临床我们假设，i) CzIE 对 MSSA 菌血症的临床结果产生负面影响。用头孢唑啉处理，并且，ii) 可以很容易地进行快速测试来鉴定链球菌中的 CzIE。金黄色葡萄球菌菌血症，并可以检测出不良结果风险较高的患者。我们将利用金黄色葡萄球菌网络自适应平台 (SNAP) 试验，这是一个多中心、务实、多臂、开放标签的适应性平台试验，解决了患者的多种治疗问题我们将重点关注评估金黄色葡萄球菌菌血症的有效性和安全性的 MSSA“领域”。头孢唑啉与 ISP 以随机方式进行比较，目前在澳大利亚、新加坡、加拿大、以色列、新注册新西兰、英国、美国、哥伦比亚和智利我们提案的具体目标是： i) 定义。 CzIE 对 MSSA 菌血症的临床影响，以及，ii) 确定临床价值和可行性检测 CzIE 的快速测试我们的发现可能会改变 MSSA 感染的治疗方法和将为开发新的诊断工具来管理 MSSA 感染提供基础。