High-dose Cefepime vs Carbapenems for Bacteremia Caused by Enterobacterales With Moderate to High Risk of Clinically Significant AmpC β-lactamase Production

Abstract

Background Limited data suggest that serious infections caused by Enterobacterales with a moderate to high risk of clinically significant AmpC production can be successfully treated with cefepime if the cefepime minimum inhibitory concentration (MIC) is ≤2 µg/mL. However, isolates with a cefepime susceptible dose-dependent (SDD) MIC of 4-8 µg/mL should receive a carbapenem due to target attainment and extended-spectrum β-lactamase (ESBL) concerns. Methods Retrospective cohort study of hospitalized patients with E. cloacae, K. aerogenes or C. freundii bacteremia from January 2015 to March 2022 receiving high dose cefepime or a carbapenem. Cox regression models were used with incorporation of inverse probability of treatment weighting (IPTW) and time-varying covariates. Results Of the 315 patients included, 169 received cefepime and 146 received a carbapenem (ertapenem n = 90, meropenem n = 56). Cefepime was not associated with an increased risk of 30-day mortality compared to carbapenem therapy (adjusted hazard ratio [aHR] 1.45; 95% confidence interval [CI] 0.79-2.14), which was consistent for patients with cefepime SDD isolates (aHR 1.19; 95% CI 0.52-1.77). Multivariable weighted Cox models identified Pitt Bacteremia score >4 (aHR 1.41; 95% CI 1.04-1.92), deep infection (aHR 2.27; 95% CI 1.21-4.32), and ceftriaxone-resistant AmpC-E (aHR 1.32; 95% CI 1.03-1.59) to be independent predictors associated with increased mortality risk, while receipt of prolonged infusion β-lactam was protective (aHR 0.67; 95% CI 0.40-0.89). Conclusion Among patients with bacteremia caused by Enterobacterales with moderate to high risk of clinically significant AmpC production, these data demonstrate similar risk of 30-day mortality for high dose cefepime or a carbapenem as definitive β-lactam therapy.

Extended-Infusion β-Lactam Therapy, Mortality, and Subsequent Antibiotic Resistance Among Hospitalized Adults With Gram-Negative Bloodstream Infections

“…The median (IQR) duration of EI-BL therapy was 4 (3-9) days. The median (IQR) duration of antibiotic therapy in the PSM cohort was 11 (9)(10)(11)(12)(13)(14) days, similar between both treatment groups.…”

“… 1 , 2 , 3 , 4 Pharmacokinetic and pharmacodynamic studies indicate that extending the infusion of a β-lactam agent may be particularly beneficial for gram-negative organisms with elevated antibiotic MICs. 1 Several observational studies 5 , 6 , 7 , 8 , 9 , 10 , 11 and clinical trials 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 have investigated the effect of EI-BL therapy on patient outcomes. Clinical trials, however, have shown conflicting results with some suggesting no benefit 12 , 13 , 14 , 17 , 18 , 20 , 21 and others indicating improved patient outcomes 11 , 15 , 16 , 19 with EI-BL therapy.…”