Cefiderocol Treatment for Patients with Multidrug- and Carbapenem-Resistant Pseudomonas aeruginosa Infections in the Compassionate Use Program

Abstract

Cefiderocol is an option for infections caused by multidrug-resistant Pseudomonas aeruginosa, but its in vitro activity against these isolates and its clinical effectiveness for isolates with MICs of >1 μg/mL is unclear. We investigated the in vitro activity of cefiderocol against P. aeruginosa isolates collected from patients treated with cefiderocol through the compassionate use program and assessed physician-reported clinical response and 28-day all-cause mortality by cefiderocol MIC values. P. aeruginosa isolates underwent susceptibility testing to cefiderocol and comparator agents by using reference broth microdilution. U.S. Food and Drug Administration (FDA; susceptible, ≤1 μg/mL) and Clinical and Laboratory Standards Institute (CLSI; susceptible, ≤4 μg/mL) cefiderocol breakpoints were applied. Additionally, molecular characterization of β-lactamase genes was performed. Clinical response and vital status were reported by treating physicians. Forty-six patients with P. aeruginosa infections were evaluated. Twenty-nine (63%) and 42 (91%) isolates were susceptible to cefiderocol using FDA and CLSI breakpoints, respectively. Thirty-seven (80%) and 32 (70%) isolates were not susceptible to ceftolozane-tazobactam and ceftazidime-avibactam, respectively. The clinical response rate was 69% (20/29) with a cefiderocol MIC of ≤1 μg/mL, 69% (9/13) with a cefiderocol MIC of 2 to 4 μg/mL, and 100% (4/4) with an MIC of ≥8 μg/mL, while day 28 all-cause mortality rates were 23% (6/26; MIC ≤ 1 μg/mL), 33% (4/12; MIC, 2 to 4 μg/mL), and 0% (0/4; MIC ≥8 μg/mL), respectively. Cefiderocol was active in vitro against most P. aeruginosa isolated from patients with limited or no alternative therapies. Patients with cefiderocol MICs of 2 to 4 μg/mL did not have significantly worse outcomes than those with MICs of ≤1 μg/mL.

Keywords: carbapenem-resistant Pseudomonas aeruginosa; cefiderocol; clinical response; compassionate use; susceptibility breakpoint.

FIG 1

Patient flow diagram and study eligibility of cases with Pseudomonas aeruginosa infections under compassionate use of cefiderocol.

FIG 2

Cefiderocol MIC distribution of 46 multidrug- or carbapenem-resistant Pseudomonas aeruginosa isolates treated with cefiderocol under the compassionate use program. CLSI, Clinical and Laboratory Standards Institute; FDA, U.S. Food and Drug Administration.

FIG 3

Physician-reported clinical response to cefiderocol therapy in the compassionate use program by cefiderocol MIC category. Ninety-five percent confidence intervals determined by the Clopper-Pearson method as follows: MIC of ≤1 μg/mL, 49.17 to 84.72%; MIC of >1 μg/mL, 50.10 to 93.19%; MIC of 2 to 4 μg/mL, 38.57 to 90.91%; and MIC of ≥8 μg/mL, 39.76 to 100%.