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

backgroundFor 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

methodsPharmacokinetic (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

resultsAcross 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

conclusionCo-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.