FDA公布米诺环素对嗜麦芽窄食单胞菌折点承认决定的理由

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

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.

1. 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/
2. The EUCAST MIC and Zone diameter distribution website (https://mic.eucast.org), last accessed 23 September 2026.