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

Cefepime is generally recommended for treatment of clinically significant AmpC producers, including <i>Citrobacter freundii</i> complex (<i>Cfre</i>), <i>Enterobacter cloacae</i> complex (<i>Eclo</i>), and <i>Klebsiella aerogenes</i> (<i>Kaer</i>). 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 <i>bla</i>_CTX-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 <i>Cfre</i>; 9,878 <i>Eclo</i>; and 4,800 <i>Kaer</i> 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 <i>Cfre</i>, 2.0% (194/9,879) and 3.0% (299/9,879) of <i>Eclo</i>, and 0.3% (16/4,800) and 0.6% (28/4,800) of <i>Kaer</i>. Of 117 <i>Eclo</i> and <i>Kaer</i> 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 <i>ampC</i>. 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 <i>ampC</i>. Our results highlight variable cefepime susceptibility rates for AmpC producers across clinical settings and demonstrate diverse mechanisms underlying reduced cefepime susceptibility.