Extended-spectrum beta-lactamase (ESBL) coproduction among moderate-risk inducible AmpC Enterobacterales with third-generation cephalosporin or cefoxitin resistance is uncommon. Incorporating ESBL genotyping into clinical practice could help patients avoid unnecessary antibiotic use and strengthen antimicrobial stewardship, according to a new study.
Finding the Prevalence of Resistance
The overlap between inducible AmpC beta-lactamase production and ESBL coproduction presents an ongoing diagnostic and therapeutic challenge. Moderate-risk AmpC Enterobacterales—particularly Enterobacter cloacae complex, Klebsiella aerogenes and Citrobacter freundii complex—may exhibit third-generation cephalosporin resistance that mimics ESBL activity, often prompting escalation to carbapenems. Clarifying the true prevalence of ESBL genes in these organisms is essential for guiding stewardship practices.
“My colleagues and I noticed that our physicians felt more comfortable using carbapenems for infections caused by moderate-risk inducible AmpC pathogens that displayed third-generation cephalosporin-resistant with cefepime-susceptible phenotypes,” said Nicholas Piccicacco, PharmD, an infectious diseases pharmacotherapy specialist and the residency program director at Tampa General Hospital, in Florida. “When we’d discuss that this antibiotic-susceptibility phenotype was most likely depicting AmpC enzyme expression, we were met with hesitation and the fact that we were unable to 100% rule out ESBL coproduction.
“With collaboration from our hospital esoteric lab, we were able to bring in a research-use–only test that could detect common ESBL genes and start to obtain data on ESBL genotypes for our AmpC isolates,” Dr. Piccicacco continued. “Our hypothesis was that ESBL rates would be low for these AmpC pathogens, which could then in turn allow for more cefepime usage and spare carbapenems.”
ESBL Gene Detection Low
The retrospective study, presented at MAD-ID 2025, in Orlando, Fla. (abstract 84 OR), was conducted at Tampa General Hospital from Aug. 1, 2023, to March 15, 2025. The prevalence of ESBL genes was evaluated in 129 moderate-risk inducible AmpC isolates. Real-time polymerase chain reaction (PCR; Streck ARM-D Kit) was used to detect common ESBL markers (blaCTX-M-14, blaCTX-M-15, blaTEM, blaSHV, blaGES). Isolates included E. cloacae complex (77%), K. aerogenes (17%) and C. freundii complex (6%).
ESBL gene detection was low (15%) for moderate-risk inducible AmpC Enterobacterales isolates that displayed third-generation cephalosporin-resistant phenotypes.
“This data aligns with epidemiological data out of Johns Hopkins University that showed similar ESBL gene detection (14%) for their AmpC isolates [Open Forum Infect Dis 2023;10(4):ofad175],” Dr. Piccicacco said. “Therefore, clinicians should feel more comfortable recommending cefepime for AmpC infections, which is in alignment with the IDSA’s [Infectious Diseases Society of America] resistant gram-negative guidance document for these pathogens.”
Further Testing Needed
Dr. Piccicacco noted that certain questions still exist regarding these findings, which may be clarified via future research.
“First, not all TEM and SHV gene variants are ESBL genotypes,” he said. “Unfortunately, our ESBL PCR test detected multiple variants of TEM and SHV without differentiating penicillinase, cephalosporinase and ESBL variants. Therefore, our rate of ESBL might actually be lower than 15%. To parse this out, we’d need to find a different ESBL test that could differentiate these variants or perform whole-genome sequencing.
“Also, a randomized clinical trial [RCT] comparing cefepime versus a carbapenem for invasive, moderate-risk inducible AmpC infections is still needed,” Dr. Piccicacco said. “In my opinion, this RCT must be able to test isolates for ESBL genotypes in order to completely paint the picture of cefepime’s effectiveness against these AmpC pathogens.”
Dr. Piccicacco reported no relevant financial disclosures.