Carbapenem Use in US Hospitals Diverges from Current Guidance

The current use of carbapenem for extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales was found consistent with 2020 guidance from the Infectious Diseases Society of America (IDSA) but in excess and in variance with the 2023 update,¹ in the largest multicenter study² of carbapenem prescribing over time and in relation to evolving guidance and the pivotal MERINO 3 trial.

"Our findings highlight an actionable stewardship gap between prevailing real-world use of carbapenems in US hospitals and updated and recent practice recommendations from both the American and European infectious disease societies," declare Morgan Walker, MD, and colleagues of the National Institutes of Health Antimicrobial Resistance Outcomes Research Initiative (NIH-ARORI).

The 2020 guidance had suggested carbapenems as first-line for complicated cystitis and all non-urinary tract infections (UTI) from ESBL-producing Enterobacterales, largely following the MERINO trial finding that piperacillin-tazobactam did not meet non-inferiority to meropenem.Walker and colleagues note, however, that the 2023 IDSA update prioritizes stewardship, narrowing the indications for carbapenems.

"A 2023 update to IDSA guidance no longer recommends carbapenems as first-line therapy for complicated UTI or pyelonephritis caused by ESBL-producing Enterobacterales unless resistance, toxicities, or critical illness preclude the use of trimethoprim-sulfamethoxazole or fluroquinolones," Walker and colleagues point out.

They also point out that the 2023 IDSA update is more in line with the 2021 guidance from the European Society of Clinical Microbiology and Infectious Diseases, which reserves carbapenems for severe infections such as bacteremia with ESBL-producing Enterobacterales.

In contrast to the current guidance, however, the investigators found high use of carbapenems for non-severe extended-spectrum cephalosporin-resistant (ECR) Enterobacterales infections that predates the 2020 IDSA guidance and has persisted since, and despite the 2023 update.

Their retrospective cohort study from January 2018 though December 2023 drew upon the PINC AI (formerly Premier Healthcare) database of approximately 25% of all US hospital admissions. Microbiology, laboratory, and vital signs data were available from a subset of the hospitals.The study cohort comprised over 30,000 adults admitted at 168 US hospitals with microbiological evidence of ECR Esherichia coli or Klebsiella pneumoniae.

Although few patients (17.7% of 30,041) received carbapenems empirically, as initiated on or before day of culture collection, the investigators found many (58.3% of 30,041) received carbapenems as targeted treatment, so defined if initiated after first day of antimicrobial susceptibility test result. These included subgroups of patients without septic shock (45.6% of 6651); as well as patients with UTI without septic shock (46.8% of 3943) for whom specific narrower-spectrum alternatives were active.³

Carbapenems were the most frequent choice to treat ECR Enterbacterales over time (adjusted odds ratio 1.00 [95% CI 1.00-1.00]). The investigators note that there was no additional immediate change (1.07 [0.95-1.2]) or sustained change (0.99 [0.98-1.00]) after IDSA guidance release.

In accompanying commentary, Erika Ernst, PharmD, College of Pharmacy, University of Iowa, Iowa City, IA, found it "perhaps unsurprisingly" that there was no impact from the IDSA guidance on the rate of carbapenem use. "Future priorities to improve treatment of ECR Enterobacterales must include dissemination of current guidance," she declared.⁴

Ernst also noted, however, that "education alone will not be enough to change practice." She called for additional measures such as prospective audits and feedback, and modifying susceptibility results to help guide appropriate treatment.

Walker and colleagues also acknowledge that translating updated guidance to clinical practice is a formidable challenge. "Despite 97% of acute care hospitals in the USA having implemented the core elements of an antimicrobial stewardship program (ASP), the quality and impact of each ASP varies across institutions," they observe.

"Expedited delivery of updated expert guidance recommendations and an improved understanding of the best strategy for guidance implementation and dissemination of information could improve the effectiveness of existing ASP infrastructures," Walker and colleagues of the NIH-ARORI recommend.

References
1.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 2023; published online July 18. https://doi. org/10.1093/cid/ciad428. Accessed May 2, 2024.

2.Walker MK, Diao G, Warner S, et al. Carbapenem use in extended-spectrum cephalosporin-resistant Enterobacterales infections in US hospitals and influence of IDSA guidance: A retrospective cohort study. Lancet Infect Dis 2024; Apr 25:S1473-3099(24)00149-X. doi: 10.1016/S1473-3099(24)00149-X. Accessed May 2, 2024.

3.Harris PNA, Tambyah PA, Lye DC, et al. Effect of piperacillin-tazobactam vs meropenem on 30-day mortality for patients with E coli or Klebsiella pneumoniae bloodstream infection and ceftriaxone resistance: a randomized clinical trial. JAMA 2018; 320: 984–94.

4.Ernest EJ. Carbapenem use in US hospitals; guidance and stewardship. Comment. Lancet Infect Dis 2024; Apr 25:S1473-3099(24)00231-7. doi: 10.1016/S1473-3099(24)00231-7. Accessed May 2, 2024.