Activity of Cefiderocol and Comparators against Isolates from Cancer Patients.

Cefiderocol inhibited 97.5% of 478 Gram-negative isolates from cancer patients at ≤ 4 mg/L. It had potent activity against ESBL positive Enterobacteriaceae, carbapenem resistant Enterobacteriaceae, and non-fermenting Gram-negative bacilli including Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Acinetobacter spp. Amikacin, ceftazidime/avibactam and meropenem had appreciable activity against non-CRE Enterobacteriaceae No comparators were active against MDR P. aeruginosa. Only trimethoprim/sulfamethoxazole had appreciable activity against S. maltophilia Overall, cefiderocol was associated with the lowest level of resistance.

(data not shown). Among comparator agents, amikacin, ceftazidime-avibactam, ceftolozane-tazobactam, meropenem, and tigecycline were active against these isolates. Most agents were less active against E. cloacae than they were against Citrobacter spp. While CFDC inhibited 34 (89%) of 38 Enterobacter species isolates at Յ4.0 mg/liter, 2 isolates had MICs of 8.0 mg/liter and 2 had MICs of Ͼ64.0 mg/liter. All agents except colistin had good activity against Serratia spp.
Activity against nonfermenting Gram-negative bacilli. CFDC was the most active agent tested against S. maltophilia isolates, with an MIC 90 of 0.25 mg/liter and a range of Ͻ0.03 to 4.0 mg/liter. Among comparators, only trimethoprim-sulfamethoxazole was   active against S. maltophilia isolates, CFDC was active against Acinetobacter spp. isolates (MIC 90 , 4.0 mg/liter). Two of 20 isolates tested were resistant to CFDC, with MICs of 16.0 and Ͼ64.0 mg/liter, respectively. Among comparator agents, amikacin, colistin, and tigecycline inhibited Ն90% of isolates. The MIC 90 of CFDC against 15 isolates of Achromobacter spp. was 0.125 mg/liter. Among comparator agents, imipenem had the best activity.
CFDC inhibited all 38 P. aeruginosa isolates that did not exhibit multidrug resistance (MDR) at Յ1.0 mg/liter. Comparator agents with activity against these isolates included ceftolozane-tazobactam, ceftazidime-avibactam, amikacin, colistin, and ceftazidime. Against 32 MDR P. aeruginosa isolates, CFDC was the most active agent tested, with an MIC 90 of 1.0 mg/liter. Only 1 isolate was resistant to CFDC, with an MIC of Ͼ64.0 mg/ liter. The activity of comparator agents against these isolates was uniformly poor.
Nonsusceptible isolates. CFDC was associated with the lowest level of nonsusceptibility ( Table 1). The highest level of nonsusceptibility to CFDC was seen among non-CRE Enterobacter spp. isolates, with 2 (5.3%) of 38 isolates being nonsusceptible. Many comparators had nonsusceptibility percentages of Ͻ2%. Of note, MDR P. aeruginosa nonsusceptibility to CFDC was 3.1%, whereas the nonsusceptible range for comparator agents was 25% to 91%. The MIC distributions for individual organisms and antimicrobial agents are presented in Table 2. Distributions for CFDC showed lower MICs for nonsusceptible organisms, including CRE, MDR P. aeruginosa, and S. maltophilia, than those of all other agents tested.
Illumina MiSeq short-read whole-genome sequencing was performed for the CFDC-resistant isolates, followed by an analysis focused on the presence of ␤lactamase-encoding genes and the composition of major porins known to contribute to ␤-lactam resistance. (9) Klebsiella spp. isolates demonstrated outer membrane porin OmpK36, OmpK37, and OmpK35 disruption and the presence of various ␤-lactamases. The Enterobacter spp. isolates had alterations in OmpC and OmpF and the presence of AmpC and ESBLs. Finally, Acinetobacter spp. isolates had carbapenemases and various ␤-lactamases. No clear mechanisms for CFDC resistance were found.
The standard of care for the treatment of febrile episodes in cancer patients is prompt administration of empirical antibiotic therapy (10). GNOs are now the predominant bacterial pathogens in this setting, and resistance among many GNOs is increasing. CFDC has potent in vitro activity against various GNOs isolated from patients with cancer, including carbapenem-resistant organisms and MDR nonlactose fermenting organisms, including S. maltophilia. Based on these in vitro findings and the general exclusion of patients with cancer from registration studies, we believe future study of the clinical utility of CFDC in patients with cancer is warranted.