FDA对折点认可决定的理由：米诺环素用于嗜麦芽窄食单胞菌
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FDA对折点认可决定的理由：米诺环素用于嗜麦芽窄食单胞菌 开发资源 推进真实世界证据项目 抗菌药物开发工作组 BEST资源分类法 临床结局评估汇编 复杂创新试验设计会议项目 FDA认可的抗微生物药物敏感性试验解释标准 医学影像与药物开发 模型引导的药物开发配对会议项目 新药办公室定制医学查询（OCMQs） 儿科与孕产妇健康 罕见病终点推进试点项目 拆分实时申请审评（STAR） 标准安全性表格和图形（ST&Fs） 药物和生物制品开发替代终点资源 药物相互作用与标签 标签信息 | 药品 FDA认可由临床和实验室标准协会（CLSI）针对嗜麦芽窄食单胞菌建立的米诺环素中介和耐药折点，但不认可敏感折点。FDA此前未认可任何针对嗜麦芽窄食单胞菌的米诺环素折点。 所审查的材料包括临床和实验室标准协会（CLSI）用于建立嗜麦芽窄食单胞菌米诺环素MIC和DD折点的数据[1]。 米诺环素是一种四环素类抗菌药物，有口服和静脉注射两种剂型。它获批用于多种革兰阴性菌和革兰阳性菌感染。在成人中，注射用米诺环素的说明书标注24小时内最高可达400 mg。米诺环素胶囊的说明书最大剂量为初始200 mg，随后每12小时100 mg。 2024年2月，临床和实验室标准协会（CLSI）在CLSI M100第34版中发布了针对嗜麦芽窄食单胞菌的修订米诺环素MIC和纸片扩散（DD）折点，见下表。 当前CLSI米诺环素对嗜麦芽窄食单胞菌的折点 最低抑菌浓度（mcg/mL） 抑菌圈直径（mm） S I R S I R ≤ 1 2 ≥ 4 ≥ 26 21-25 ≤ 20 S：敏感；I：中介；R：耐药。 折点基于每12小时静脉注射/口服200 mg的剂量。 来源：CLSI M100补充文件第36版；2026（折点首次发布于M100第34版；2024）。 在审查现有数据后，FDA发现了接受米诺环素对嗜麦芽窄食单胞菌敏感折点为1 mcg/mL的几个问题。 首先，近期MIC分布数据提示嗜麦芽窄食单胞菌的米诺环素流行病学折点值为2 mcg/mL [2]。因此，1 mcg/mL的敏感折点会将野生型群体一分为二，由于野生型分布内的标准技术变异，使抗菌药物敏感性试验（AST）的可重复性降低。 此外，嗜麦芽窄食单胞菌通常引起严重的呼吸道和血流感染，在这些临床情形中通常采用细菌载量降低≥1-log10的药代动力学-药效学（PK-PD）目标。然而，现有数据显示，使用1-log10杀灭PK-PD目标时，仅在MIC≤0.5 mcg/mL时才达到≥90%的目标达成概率（PTA）。0.5 mcg/mL的敏感折点会将野生型群体进一步分割。 关于临床数据，虽然研究结果提示由MIC为4 mcg/mL的分离株所致感染结局较差，但这些数据不支持特定的敏感折点。尽管如此，FDA得出结论，现有数据支持米诺环素对嗜麦芽窄食单胞菌的 intermediary 折点为2 mcg/mL（相应的DD折点为21-25 mm）以及耐药折点为≥4 mcg/mL（相应的DD折点为≤20 mm）。 CLSI抗菌药物敏感性检测（AST）小组委员会2023年1月（MIC折点）和2023年6月（DD折点）会议纪要。https://clsi.org/resources/ast-meeting-files-and-resources/ EUCAST MIC和抑菌圈直径分布网站（https://mic.eucast.org），最后访问日期2026年9月23日。 内容截至日期： 2026年10月30日 受监管产品 药物
正文 · 英文原文
FDA Rationale for Breakpoints Recognition Decision: Minocycline for Stenotrophomonas maltophilia Development Resources Advancing Real-World Evidence Program Antibacterial Drug Development Task Force BEST Resource Taxonomy Clinical Outcome Assessment Compendium Complex Innovative Trial Design Meeting Program FDA-Recognized Antimicrobial Susceptibility Test Interpretive Criteria Medical Imaging and Drug Development Model-Informed Drug Development Paired Meeting Program Office of New Drugs Custom Medical Queries (OCMQs) Pediatrics and Maternal Health Rare Disease Endpoint Advancement Pilot Program Split Real Time Application Review (STAR) Standard Safety Tables and Figures (ST&Fs) Surrogate Endpoint Resources for Drug and Biologic Development Drug Interactions & Labeling Labeling Information | Drug Products The FDA recognizes the minocycline intermediate and resistant breakpoints established by the Clinical and Laboratory Standards Institute (CLSI) for Stenotrophomonas maltophilia, but it does not recognize the susceptible breakpoints. The FDA has not previously recognized any minocycline breakpoints for S. maltophilia. The reviewed materials included data used by the Clinical and Laboratory Standards Institute (CLSI) for establishing minocycline MIC and DD breakpoints for S. maltophilia [1]. Minocycline is a tetracycline class antibacterial drug available in oral and intravenous forms. It is approved for various gram-negative and gram-positive infections. In adults, minocycline for injection is labeled up to 400 mg in 24 hours. The maximum labeled dosage for minocycline capsules is 200 mg initially, followed by 100 mg every 12 hours. In February 2024, the Clinical and Laboratory Standards Institute (CLSI) published revised minocycline MIC and disk diffusion (DD) breakpoints for S. maltophilia in the 34th edition of CLSI M100, see the table below. Current CLSI Minocycline Breakpoints against S. maltophilia Minimum Inhibitory Concentration (mcg/mL) Zone Diameter (mm) S I R S I R ≤ 1 2 ≥ 4 ≥ 26 21-25 ≤ 20 S: susceptible; I: intermediate; R: resistant. Breakpoints are based on a dosage of 200 mg intravenously/orally every 12 hours. Source: 36th ed. CLSI supplement M100; 2026 (breakpoints were first published in the 34 ed. M100; 2024). After reviewing the available data, the FDA identified several concerns with accepting the susceptible minocycline breakpoint against S. maltophilia of 1 mcg/mL. First, recent MIC distribution data suggest a minocycline epidemiological cutoff value of 2 mcg/mL for S. maltophilia [2]. Consequently, a susceptible breakpoint of 1 mcg/mL would bisect the wild-type population, making antimicrobial susceptibility testing (AST) less reproducible due to standard technical variation within the wild-type distribution. Furthermore, S. maltophilia commonly causes severe respiratory and bloodstream infections, clinical scenarios where a pharmacokinetic-pharmacodynamic (PK-PD) target of a ≥1-log10 bacterial burden reduction is typically used. However, available data show that ≥90% probability of target attainment (PTA) was only achieved at MICs ≤0.5 mcg/mL using the 1-log10 kill PK-PD target. A susceptible breakpoint of 0.5 mcg/mL would split the wild-type population even further. Regarding clinical data, while the findings indicate worse outcomes for infections caused by isolates with an MIC of 4 mcg/mL, they do not support a specific susceptible breakpoint. Nonetheless, the FDA concludes that available data support an intermediate breakpoint of 2 mcg/mL (a corresponding DD breakpoint of 21-25 mm) and a resistant breakpoint of ≥ 4 mcg/mL (a corresponding DD breakpoint of ≤ 20 mm) for minocycline against S. maltophilia. The CLSI Subcommittee on Antimicrobial Susceptibility Testing (AST) January 2023 (MIC breakpoints) and June 2023 (DD breakpoints) minutes. https://clsi.org/resources/ast-meeting-files-and-resources/ The EUCAST MIC and Zone diameter distribution website (https://mic.eucast.org), last accessed 23 September 2026. Content current as of: 10/30/2026 Regulated Product(s) Drugs