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负责广泛威胁生命的感染的主要人类病原体。这些感染中的许多是由甲氧西林的金黄色葡萄球菌（MSSA）引起的。 MSSA代表一个主要金黄色葡萄球菌感染之间的负担是死亡率的重要促进者。几十年来，第一行严重的MSSA感染的治疗一直是异恶唑基苯甲林（ISP，例如Nafcillin）。但是，最近数据表明，在用头孢唑素治疗的患者中，MSSA细菌的临床结果相似（VS Nafcillin），一种针对MSSA活性的头孢菌素，似乎毒性较小。确实，用纳菲林治疗似乎与成本增加，更多的药物反应有关（包括肝毒性，间质性肾炎和中酸）以及可能更高的死亡率。由于这些担忧，对待的重要转变 MSSA正在发生，临床医生现在使用头孢唑素作为严重MSSA的第一线治疗感染。使用头孢唑蛋白和其他头孢菌素作为这些严重的主要疗法的重要问题感染是头孢曲唑素接种作用（CZIE），被定义为头孢唑素最小的抑制浓度> 当使用高接种物（107 CFU/mL）时，16 µg/ml。 Czie与治疗失败有关深处的MSSA感染以及葡萄球菌β-内酰胺酶的某些同种型的产生。但是，这种现象在深座的MSSA感染中的临床影响的表征有限。此外，目前无法在标准临床微生物实验室中检测CZIE 鉴于黄金标准测试的检测繁琐且昂贵的性质。我们出版的初步临床数据表明，CZIE是严重临床结果的重要原因 MSSA感染。此外，我们已经开发并发表了一种新型的基于硝基的比色快速测试（〜3 h）以高灵敏度和特异性检测CZIE，可以纳入常规临床微生物学实验室。我们假设，i）Czie对MSSA细菌血症的临床结果负面影响用头孢唑素治疗，ii）可以轻松实施快速测试以识别S. 金黄色黄细菌，可以检测出较高预后风险的患者。为了解决这些假设，我们将利用金黄色葡萄球菌网络自适应平台（SNAP）试验，多中心，务实的多臂，开放标签自适应平台试验，该试验涉及患者的多种治疗问题 S.金黄色葡萄球菌。我们将专注于MSSA“域”，以评估 Cefazolin vs ISP以随机方式，目前在澳大利亚，新加坡，加拿大，以色列，新的招募西兰，英国，美国，哥伦比亚和智利。我们提案的具体目的是：i）定义 CZIE在MSSA细菌血症中的临床影响和ii）确定A的临床价值和可行性快速测试以检测CZIE。我们的发现可能会改变MSSA感染的治疗方法将为MSSA感染管理开发新型诊断工具的基础。