avoid beta lactam antibiotics for enterobacter because of ampC

This patient has developed catheter-related urinary tract infection due to E cloacae, a gram-negative bacterium with known potential for inducible AmpC production. AmpC is a β-lactamase enzyme able to hydrolyze penicillins, cephamycins, monobactams, and secondand third-generation cephalosporins. In the presence of β-lactam antibiotics that induce AmpC expression, there is increased transcription of the ampC gene.

Multiple pathways lead to AmpC expression. Some organisms (“SPICE” or “ESKAPE” organisms, including E cloacae, Citrobacter freundii, Serratia marcescens, Providencia stuartii, Pseudomonas aeruginosa, Hafnia alvei, and Morganella morganii) have inducible resistance through chromosomally encoded ampC genes. Other organisms do not have chromosomally encoded ampC but acquire resistance through plasmid-medicated ampC genes. A third pathway leading to resistance is a mutation in the transcriptional regulator of ampC, which allows for overexpression of the ampC gene.

The commonly implicated antibiotics that induce ampC gene expression are aminopenicillins, cephamycins, amoxicillin-clavulanic acid, and first-, second-, and third-generation cephalosporins (choice B is incorrect). Resistance often emerges owing to selection, meaning isolates with resistance to the administered antibiotic will proliferate while cells that are susceptible to the antibiotic will not.

Clinically, the risk for emergent AmpC-mediated resistance is greatest for Enterobacter species. Multiple studies of patients with Enterobacter species (which classification now includes Klebsiella aerogenes) infections initially susceptible to penicillins and cephalosporins found that up to 19% of isolates developed resistance after treatment with third-generation cephalosporins. Some of these studies noted that isolates from bloodstream infections were more likely to develop resistance. There are few widely available methods for routine detection of inducible plasmid-encoded AmpC β-lactamases in clinical microbiology laboratories. Phenotypic susceptibility testing is often unhelpful because the organism may appear susceptible to penicillins and cephalosporins in vitro, and only after exposure to these drugs will phenotypic resistance appear. Therefore, the Infectious Diseases Society of America 2023 guidance on treatment of antimicrobial resistant gram-negative infections, as well as other consensus statements, recommends initial treatment of serious Enterobacter species infections with cefepime even in the presence of in vitro susceptibility to third-generation cephalosporins (choice A is correct; choice C is incorrect).

Some studies suggested that continuous infusion of β-lactam drugs may result in higher clinical cure rates, while others found no difference in clinical outcomes. Continuous infusion of the appropriate drug could be considered, but in this case, ceftriaxone should first be replaced with optimal therapy (choice D is incorrect). Of note, when indwelling urinary catheters are placed, they should be evaluated for removal as soon as possible given the risk of catheter-associated urinary tract infections.123456

Footnotes

  1. SEEK Questionnaires ↩

  2. Harris PN, Ferguson JK. Antibiotic therapy for inducible AmpC β-lactamase-producing gram-negative bacilli: what are the alternatives to carbapenems, quinolones and aminoglycosides? Int J Antimicrob Agents. 2012;40(4):297-305. PubMed ↩

  3. Maillard A, Delory T, Bernier J, et al; Treatment of AmpC-Producing Enterobacterales Study Group. Effectiveness of third-generation cephalosporins or piperacillin compared with cefepime or carbapenems for severe infections caused by wild-type AmpC β-lactamase-producing Enterobacterales: a multi-centre retrospective propensity-weighted study. Int J Antimicrob Agents. 2023;62(1):106809. PubMed ↩

  4. Tamma PD, Aitken SL, Bonomo RA, Mathers AJ, van Duin D, Clancy CJ. Infectious Diseases Society of America 2023 guidance on the treatment of antimicrobial resistant gram-negative infections. Clin Infect Dis. Published online July 18, 2023. PubMed ↩

  5. Tamma PD, Doi Y, Bonomo RA, Johnson JK, Simner PJ; Antibacterial Resistance Leadership Group. A primer on AmpC β-lactamases: necessary knowledge for an increasingly multidrug-resistant world. Clin Infect Dis. 2019;69(8):1446-1455. PubMed ↩

  6. Tamma PD, Girdwood SC, Gopaul R, et al. The use of cefepime for treating AmpC β-lactamase-producing Enterobacteriaceae. Clin Infect Dis. 2013;57(6):781-788. PubMed ↩