Co-Administration Dosing of Ceftazidime-Avibactam and Aztreonam in Patients with Varying Renal Function for Carbapenem-Resistant Enterobacterales Infections via Monte Carlo Simulation.

Abstract

Background: For infections caused by metallo-β-lactamase (MBL)-producing carbapenem-resistant Enterobacterales (CRE), ceftazidime-avibactam (CZA) alone is inactive because avibactam does not inhibit MBLs. Co-administration with aztreonam can restore activity but requires simultaneous delivery and harmonization of non-aligned renal dose adjustments. Pharmacodynamic (PD) targets for MBL producers may also differ from those for serine β-lactamase producers. This study aimed to define practical CZA plus aztreonam dosing regimens across renal function strata using Monte Carlo simulation.

Materials and methods: Pharmacokinetic (PK) parameters from infected patients receiving concomitant CZA plus aztreonam were modeled using a one-compartment structure with Chronic Kidney Disease Epidemiology Collaboration renal function as the key covariate. Monte Carlo simulations (n=5,000) evaluated concentration-time profiles during the first 24 hours and at steady state across renal strata. Both conventional and stringent PK/PD targets were assessed. Probability of target attainment (PTA) was estimated at clinically relevant minimal inhibitory concentrations (MICs) for ceftazidime and aztreonam and threshold concentrations (CT 2.5 and 4 mg/L) for avibactam. Joint PTA was defined as the probability of simultaneous attainment of aztreonam and avibactam targets. A ceftazidime C_min >80 mg/L was applied as a neurotoxicity risk threshold.

Results: Across simulations, aztreonam and ceftazidime achieved ≥90% PTA at MIC breakpoints under conventional targets. Avibactam achieved ≥90% PTA only at steady-state CT 2.5 mg/L and failed at 4 mg/L or under stringent targets, reflecting limited avibactam exposure relative to higher PD thresholds. In preserved renal function, q6h regimens provided higher joint PTA than q8h dosing, though neither achieved ≥90% joint PTA under stringent targets. Most regimens in reduced renal function (eGFR ≤90 mL/min) maintained ≥90% joint PTA under conventional targets, while attainment under stringent targets was limited. Neurotoxicity risk (C_min >80 mg/L) remained low across renal strata.

Conclusion: Co-administration of CZA and aztreonam using renal-adjusted doses provides a practical and effective strategy for MBL-CRE infections. This approach ensures high joint PTA attainment while maintaining a low neurotoxicity risk across all renal function strata.