Prevalence and genetics of cefepime resistance among the AmpC-producing organisms Citrobacter freundii complex, Enterobacter cloacae complex, and Klebsiella aerogenes.

Cefepime is generally recommended for treatment of clinically significant AmpC producers, including Citrobacter freundii complex (Cfre), Enterobacter cloacae complex (Eclo), and Klebsiella aerogenes (Kaer). Clinicians increasingly use the results of multiplex PCR panels to make early treatment decisions, with cefepime often chosen when an AmpC producer is detected without a blaCTX-M extended-spectrum beta-lactamase (ESBL) or carbapenemase. To understand the safety of this approach, we evaluated the prevalence of cefepime resistance among 4,687 Cfre; 9,878 Eclo; and 4,800 Kaer clinical isolates collected in our hospital network in New England, USA, from 2015 to 2024. We additionally reviewed Blood Culture Identification 2 (BCID2) (bioMérieux) results for 136 blood cultures and the sequenced genomes of 184 isolates (14 cefepime-susceptible dose-dependent [SDD], 34 cefepime-resistant). Cefepime-SDD and cefepime-resistant isolates made up 0.4% (18/4,687) and 1.3% (59/4,687) of Cfre, 2.0% (194/9,879) and 3.0% (299/9,879) of Eclo, and 0.3% (16/4,800) and 0.6% (28/4,800) of Kaer. Of 117 Eclo and Kaer identified in blood cultures on the BCID2, 4.3% (5/117) were cefepime-SDD or cefepime-resistant and negative for an ESBL or carbapenemase target. Among sequenced cefepime-SDD isolates, 21% (3/14) carried an ESBL. Cefepime-resistant isolates carried diverse beta-lactamase genes, including ESBL genes, carbapenemase genes, and plasmid-borne ampC. While reduced cefepime susceptibility was generally associated with carriage of more beta-lactamase genes, 57% of cefepime-SDD and 35% of cefepime-resistant isolates encoded only chromosomal ampC. Our results highlight variable cefepime susceptibility rates for AmpC producers across clinical settings and demonstrate diverse mechanisms underlying reduced cefepime susceptibility.