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FDA Rationale for Recognition Decision: Cefiderocol

FDA has reevaluated data supporting cefiderocol breakpoints against Stenotrophomonas maltophilia. The review included data submitted to FDA under the cefiderocol new drug application, published literature, and materials presented at a Clinical and Laboratory Standards Institute (CLSI) Subcommittee on Antimicrobial Susceptibility Testing meeting in February 2021.1

Cefiderocol for injection is approved for the treatment of complicated urinary tract infections including pyelonephritis (November 2019), and hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (September 2020). FDA has identified cefiderocol breakpoints for Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii complex.2 No cefiderocol breakpoints against S. maltophilia have been recognized by FDA.

CLSI set cefiderocol breakpoints against S. maltophilia in 2019 with a susceptible minimal inhibitory concentration (MIC) breakpoint of ≤ 4 mcg/mL, an intermediate breakpoint of 8 mcg/mL, and a resistant breakpoint of ≥ 16 mcg/mL. In 2022 CLSI updated the cefiderocol breakpoints against S. maltophilia by setting only a susceptible breakpoint at an MIC of ≤ 1 mcg/mL with a corresponding zone diameter breakpoint of ≥ 15 mm.3 The breakpoints were revised because the cefiderocol MIC for S. maltophilia clinical isolates remained < 0.5 mcg/mL and there were no clinical data to support the original breakpoints.1

FDA recognizes that there are limited treatment options for S. maltophilia infections, and that susceptibility test interpretive criteria are important in informing the selection of antimicrobial drugs. Consequently, FDA reevaluated the data supporting the cefiderocol breakpoints against S. maltophilia. The assessment relies on MIC distributions, pharmacokinetic/pharmacodynamic (PK/PD) data, and limited clinical data.

Microbiological data indicate that the cefiderocol MIC90 for S. maltophilia is 0.5 mcg/mL4 with the epidemiological cutoff value (ECV) of 1 mcg/mL.1

Pharmacokinetic/pharmacodynamic data in plasma and epithelial lining fluid (ELF) lacked cefiderocol PK/PD target or activity information against S. maltophilia isolates with MICs ≥ 1 mcg/mL; however, other bacterial organisms (i.e., K. pneumoniae, E.coli, P. aeruginosa, A. baumannii) did include strains with MICs > 1 mcg/mL (up to 16 mcg/mL) and the PK/PD target did not appear to be substantially different. Therefore, the probability of target attainment (PTA) analyses based on a PK/PD target of 75% fT > MIC associated with 1-log10 bacterial reduction in a murine lung infection model (caused by multiple bacterial species) and a target of 100% fT>MIC as part of a sensitivity analysis was used. In all tested scenarios, PTAs are > 90% for the cefiderocol dosage of 2g q8h infused over 3 hours at MICs of up to 2 mcg/mL in plasma and ELF regardless of renal function, supporting the CLSI established MIC susceptible breakpoint of 1 mcg/mL.

Clinical data on the use of cefiderocol in S. maltophilia infections are limited to a small number of patients enrolled in the cefiderocol clinical trials and several case reports in the published literature, making analysis of clinical outcomes by MIC difficult.

FDA concludes that available PK/PD data coupled with the MIC distribution data and the ECV value of 1 mcg/mL support the recognition of the current CLSI MIC breakpoint for cefiderocol against S. maltophilia, i.e., a susceptible only breakpoint at an MIC of ≤ 1 mcg/mL. As for a susceptible disk diffusion breakpoint (DD BP), FDA concluded that the diameter of a zone of inhibition of ≥ 17 mm provides a more optimal fit using a model-based approach as compared to the DD BP of ≥ 15 mm (the current CLSI disk diffusion susceptible breakpoint). In addition, given variability in test media, the susceptible DD BP of ≥ 17 mm would mitigate the risk of overcalling susceptibility as compared to ≥ 15 mm, while providing acceptable error rates.

1 Summary of the CLSI Subcommittee on Antimicrobial Susceptibility Testing Meeting Minutes, February 2021 https://clsi.org/umbraco/api/astfiles/download/?id=43239
2 Cefiderocol Injection, FDA Susceptibility Test Interpretive Criteria website, accessed on July 31, 2024. https://www.fda.gov/drugs/development-resources/cefiderocol-injection
3 Performance Standards for Antimicrobial Susceptibility Testing, 32nd ed. CLSI supplement M100; 2022.
4 Shortridge D, Streit JM, Mendes R, Castanheira M. In Vitro Activity of Cefiderocol against U.S. and European Gram-Negative Clinical Isolates Collected in 2020 as Part of the SENTRY Antimicrobial Surveillance Program. Microbiol Spectr. 2022 Apr 27;10(2):e0271221.

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