Category: Professional Posters
Purpose: Cefepime-enmetazobactam (FPE) is a novel β-lactam-β-lactamase inhibitor combination in phase III trials for the treatment of complicated urinary tract infections caused by Gram-negative pathogens. Novel combination β-lactam-β-lactamase inhibitors such as FPE are currently being developed to combat increasing resistance patterns observed in a variety of clinically challenging Gram-negative infections. The following Monte-Carlo analysis was conducted to in order to simulate the efficacy of FPE against a selection of Enterobacteriaceae clinical isolates. FPE was compared to piperacillin-tazobactam (TZP), one of the most commonly prescribed empiric regimens for serious Gram-negative infections including bacteremia and sepsis.
Methods: MIC values were collected for three different subsets of Enterobacteriaceae including wild-type Enterobacteriaceae (WTE), carbapenem-resistant Enterobacteriaceae (CRE), and Enterobacteriaceae expressing non-β-lactamase resistance mechanisms (ENBL). Pharmacokinetic (PK) variables included two different volumes of distribution, representing a population of healthy volunteers and septic patients, and four different weights (60, 70, 80, and 90 kg). Drug clearance (Cl) was calculated from a CrCl vs. Cl regression equation using CrCl distributions from our institution. Protein binding was estimated for each drug using the average of reported estimates in the literature. Pharmacodynamic (PD) targets, expressed as the percent of time the free plasma concentration of drug remains above the MIC (% fT > MIC), were chosen based on parameters required to achieve bacterial stasis (no net killing or growth) and near maximal bactericidal killing (2-logs killing). PD targets were specific for cephalosporins (40% fT > MIC and 70% fT> MIC) and for penicillin antibiotics (30% fT > MIC and 60% fT > MIC) in Gram negative organisms. Dosing regimens were chosen based on TZP dosing regimens used clinically for the treatment of sepsis and FPE phase III clinical trial dosing, which closely mirrors cefepime dosing regimens used clinically for the treatment of sepsis. Monte-Carlo analysis (n=10,000) was used to determine percent target attainment (%TA), representing the percent of simulated patients achieving selected PD parameters.
Results: FPE achieved 99% TA and 100% TA for the high PD target and the low PD target, respectively, across all PK parameters and body weights for WTE and ENBL. In comparison, TZP achieved 86% TA across all parameters for both the low PD and high PD targets against WTE. TZP attained lower %TA against ENBL achieving 65% TA for the low target and a range of 62-64% TA for the high target. The most significant difference in %TA was seen in regard to CRE, with FPE achieving 96-98% TA for the low PD target and 80-88% TA for the high PD target compared to TZP, which achieved only 4% TA across all parameters. Although slight differences in %TA were seen with variations in body weight and volume, these differences were not substantial (less than 8% change in %TA across all organisms). As a general trend, higher volumes and higher weights were correlated with slightly higher %TA. This is likely due to increased drug half-lives in patients with higher volumes of distribution, which can serve to prolong the time above the minimum inhibitory concentration.
Conclusion: FPE showed superior results to TZP against all organisms studied, a result that was particularly apparent in the subset of CRE and ENBL isolates. However, it is important to note that TZP maintained relatively high target attainment in the WTE subset. Given the increasing prevalence of resistant pathogens in clinical practice, it is reasonable to conclude that FPE would be a promising antimicrobial combination in the treatment of serious Enterobacteriaceae infections, especially in isolates demonstrating antimicrobial resistance and as empiric therapy in patients with life-threatening infections such as sepsis and septic shock.