In Vitro Activity of the Siderophore Cephalosporin, Cefiderocol, against a Recent Collection of Clinically Relevant Gram-Negative Bacilli from North America and Europe, Including Carbapenem-Nonsusceptible Isolates (SIDERO-WT-2014 Study)

Abstract

Cefiderocol (formerly S-649266) is an investigational siderophore cephalosporin. Iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) was prepared according to the Clinical and Laboratory Standards Institute (CLSI) protocol and used to perform broth microdilution testing of cefiderocol against a 2014-2015 collection of clinical isolates of Gram-negative bacilli from North America (n = 4,239) and Europe (n = 4,966). The concentrations of cefiderocol inhibiting 90% of isolates tested (MIC90s) were 0.5 μg/ml (North America; n = 3,007) and 1 μg/ml (Europe; n = 3,080) for all isolates of Enterobacteriaceae; 1 μg/ml (North America; n = 30) and 4 μg/ml (Europe; n = 139) for meropenem-nonsusceptible (MIC ≥ 2 μg/ml) isolates of Enterobacteriaceae; 0.5 μg/ml for both North American (n = 765) and European (n = 765) isolates of Pseudomonas aeruginosa; 0.5 μg/ml (North America; n = 151) and 1 μg/ml (Europe; n = 202) for meropenem-nonsusceptible (MIC ≥ 4 μg/ml) isolates of P. aeruginosa; 1 μg/ml for both North American (n = 309) and European (n = 839) isolates of all Acinetobacter baumannii strains as well as for both North American (n = 173) and European (n = 595) isolates of meropenem-nonsusceptible A. baumannii; and 0.5μg/ml (North America; n = 152) and 0.25 μg/ml (Europe; n = 276) for isolates of Stenotrophomonas maltophilia. MICs of cefiderocol were ≤4 μg/ml for 99.9% (6,078/6,087) of all Enterobacteriaceae, 97.0% (164/169) of meropenem-nonsusceptible Enterobacteriaceae, 99.9% (1,529/1,530) of all P. aeruginosa isolates, 100% (353/353) of meropenem-nonsusceptible P. aeruginosa isolates, 97.6% (1,120/1,148) of all A. baumannii isolates, 96.9% (744/768) of meropenem-nonsusceptible A. baumannii isolates, 100% of isolates of S. maltophilia (428/428) and 93.8% of isolates of Burkholderia cepecia (11/12). We conclude that cefiderocol demonstrated potent in vitro activity against a recent collection of clinical isolates of commonly encountered Gram-negative bacilli, including carbapenem-nonsusceptible isolates.

Efficacy of Humanized Exposures of Cefiderocol (S-649266) against a Diverse Population of Gram-Negative Bacteria in a Murine Thigh Infection Model

“…Bacterial isolates. A total of 140 Gram-negative isolates comprising P. aeruginosa (23 isolates), A. baumannii (74 isolates), and Enterobacteriaceae (43 isolates) with cefiderocol MICs ranging from low to high (i.e., 0.12, 0.25, 0.5, 1, 2, 4, 8, 16, 32, 64, 128, and Ͼ256 g/ml) were provided by the Shionogi & Co., Ltd., or IHMA, Inc., collection (13). The isolates were screened for MICs of cefiderocol in triplicate using iron-depleted cation-adjusted Mueller-Hinton broth (ID-CAMHB) as recommended by CLSI for this class of compounds (22).…”

Treatment of Infections Caused by Extended-Spectrum-Beta-Lactamase-, AmpC-, and Carbapenemase-Producing Enterobacteriaceae

“…Cefiderocol is a new siderophore cephalosporin that is active against MDR Gramnegative organisms, including carbapenemase-producing Enterobacteriaceae (370)(371)(372)(373)(374)(375). At a dose of 2 g every 8 h, it reaches Ͼ50% time above the MIC for MICs of up to 8 mg/liter (376).…”

Difficult-to-Treat Antibiotic-Resistant Gram-Negative Pathogens in the Intensive Care Unit: Epidemiology, Outcomes, and Treatment

“…FDA, but like eravacycline, evidence of clinical effectiveness in serious A. baumannii infections is currently lacking. 126,127 Stenotrophomonas maltophilia and Burkholderia species Stenotrophomonas maltophilia is intrinsically resistant to many first-line antibiotics in the cephalosporin and carbapenem family. The first-line therapy for infections due to S. maltophilia is trimethoprim-sulfamethoxazole with other treatment options including levofloxacin and ceftazidime, although the utility of trimethoprim-sulfamethoxazole for treatment of Stenotrophomonas bacteremia has been questioned in light of its bacteriostatic property.…”