1422. Comparative Monte-Carlo Analysis of Aztreonam-Avibactam vs. Ceftazidime–Avibactam Against Carbapenem-Resistant Gram-Negative Pathogens

Abstract

Background. The new β-lactamase inhibitor, avibactam (AVI), has recently been combined with ceftazidime (CAZ) as CAZ-AVI. AVI is also in Phase 3 clinical trials combined with aztreonam as ATM-AVI. Both drug combinations have similar in vitro activity against some organisms, but ATM-AVI is more potent against metallo-β-lactamase (MBL) producing organisms. However, against P. aeruginosa (PA), CAZ-AVI is more potent. Since these compounds have similar pharmacokinetic (PK)/pharmacodynamic (PD) profiles, and there is a need for drugs for the treatment of resistant microorganisms, a Monte-Carlo analysis (MCA) was used to assess their potential efficacy against carbapenem-resistant pathogens. Methods. MCA (n = 10,000) was performed for ATM-AVI and CAZ-AVI using PK parameters, CrCl vs. Cl regression, PD targets, and recent MICs from peer-reviewed literature against five carbapenem-resistant (CR) organisms: P. aeruginosa (CR-PA), E. cloacae (CR-EC), K. pneumoniae (CR-KP), Enterobacteriaceae (CR-ENT), and MBL producing Enterobacteriaceae (MBL-ENT). Only MIC studies that directly evaluated both combinations were utilized. Our institution's inpatient CrCl distribution (range: 10-120 mL/minute) was used to assess drug clearance. The ATM-AVI regimen was 1.5 g q6h with a 3 hours infusion and adjusted for renal function) and the CAZ-AVI regimen was 2 g q8h with a 2-hour infusion and adjusted for renal function). PD targets (%fT>MIC) for ATM-AVI were 40 and 60% and for CAZ-AVI were 40 and 70%. Results. Target attainment (TA%) for each regimen and organism was: Conclusion. Both ATM-AVI and CAZ-AVI displayed very high TA% (>95%) for CR-EC, CR-KP, and CR-ENT at both PD targets. However, TA% for MBL-ENT was very low for CAZ-AVI and ≥99% for ATM-AVI. Against CR-PA, CAZ-AVI was had much higher TA% than ATM-AVI (87-93% vs. 43-48%). These differences suggest different roles for each drug combination in clinical practice.