Carbapenems Sometimes Overused for Drug-Resistant Enterobacterales Infections

Broad spectrum carbapenems were the most commonly used therapy for targeted treatment of extended-spectrum cephalosporin-resistant (ECR) Enterobacterales infections in U.S. hospitals, according to a retrospective cohort study.

Among over 30,000 inpatient encounters involving ECR Enterobacterales infections, 58.3% of patients received targeted treatment with carbapenems, Sameer Kadri, MD, of the NIH in Bethesda, Maryland, and colleagues reported in Lancet Infectious Diseases.

Prescribers also chose carbapenems in 45.6% of ECR Enterobacterales infections without septic shock and in 46.8% of genitourinary infections without septic shock — situations where narrower-spectrum antibiotic alternatives were potential therapeutic choices.

“Results showed a marked prescriber preference for carbapenems in microbiologically confirmed ECR Enterobacterales infections,” the authors wrote. “These findings highlight several opportunities to improve carbapenem stewardship, including for patients with mild disease manifestations and with pathogens for which other narrower-spectrum agents retain in-vitro activity.”

Among all encounters, the most frequently prescribed empirical treatments were piperacillin-tazobactam and cefepime, each prescribed in approximately 22% of encounters with patients who had ECR Enterobacterales infections.

However, carbapenems were less likely to be used as an initial empirical treatment before antimicrobial susceptibility test (AST) results were available. Carbapenems were prescribed empirically in just 17.7% of all encounters and in 19.4% of encounters involving septic shock.

“Carbapenems were used infrequently as empirical therapy in our study, and, concerningly, a proportion of patients with septic shock received empirical therapy without activity against ECR Enterobacterales,” Kadri and colleagues pointed out. “Clinicians globally still rely on probabilistic approaches for empirical antibiotic prescription.”

Of note, the transition from a non-carbapenem antibiotic to a carbapenem occurred most frequently on the date that the AST results became available, indicating that susceptibility testing drove carbapenem prescribing.

Frequent carbapenem use in U.S. hospitals predated a 2020 Infectious Diseases Society of America (IDSA) guidance document that recommended carbapenems for complicated urinary tract infections (UTIs) and pyelonephritis, as well as all other extended-spectrum ß-lactamase-producing (ESBL) infections, regardless of illness severity, Kadri and colleagues explained.

The study found no change in carbapenem use over the course of the 4-year period (adjusted OR 1.00, 95% CI 1.00-1.00), regardless of changes in IDSA recommendations, indicating that carbapenems were already in widespread use.

“This finding probably reflects the profound impact of the landmark MERINO trial, viewed from a clinical point of view, which often favors overtreating versus undertreating infections to maximize individual outcomes,” the authors wrote.

Published in 2018, the MERINO trial established that piperacillin-tazobactam was not superior to the carbapenem antibiotic meropenem for the treatment of ECR Enterobacterales infections. This finding led to the 2020 IDSA guidance update. However, in 2023, the organization issued another updated guidance document. Based on evidence from a systematic review, the guidance document dropped the recommendation of carbapenems as first-line treatment for complicated UTIs, ostensibly to reserve carbapenems for more severe infections, such as bloodstream infections or septic shock. The 2023 IDSA guidance document update now recommends the use of fluoroquinolones and trimethoprim-sulfamethoxazole for complicated UTIs.

“Rapidly changing guidance could lead to uncertainty and inertia,” commented Erika Ernst, PharmD, of the University of Iowa College of Pharmacy in Iowa City, in an accompanying editorial. “Additional efforts will be needed to increase awareness of the most recent guidance and guide implementation.”

Ernst posited that new implementation strategies “should also include principles of diagnostic stewardship, such as modifying susceptibility results by laboratories or as agreed upon by the antimicrobial stewardship team to help guide appropriate treatment.”

“Elective and cascade reporting, in which the preferred antibiotic options are shown and less desirable options are hidden or suppressed, has been shown to improve prescribing,” Ernst noted, pointing out that in the study, AST results led to changes in therapy.

The study analyzed data from the PINC AI database from 2018 to 2021 at 168 U.S. hospitals. Researchers found that over this time period, 30,041 encounters were associated with ECR Enterobacterales infection. Of these, 53.3% were in women, and patients had a mean age of 67 years.

Among patients included in the study, 54.4% had an ICD-10 diagnosis of sepsis and 34.4% required admission to the ICU. Approximately 20% required mechanical ventilation and 27% required vasopressors. Infections of the genitourinary tract accounted for approximately 54% of all infections, with bloodstream infections (17.6%) as the next most common. Escherichia coli and Klebsiella species were the most frequently isolated pathogens.

The authors noted several limitations of their analysis. Researchers relied on charge codes since laboratory data were not consistently available. COVID-19 pandemic-related factors may have altered rates of mechanical ventilation and vasopressor use, as well as selection of antibiotic therapies. Also, researchers could not discern the effect of selective reporting of susceptibility testing on prescribers’ choice of antibiotic.

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