Dosing Regimen Optimization of Aztreonam/Avibactam According to Renal Function Stratification: A Population Pharmacokinetic-Guided Simulation Study

Background/Objectives: Aztreonam/avibactam is a promising treatment option for serious infections caused by metallo-β-lactamase-producing carbapenem-resistant Enterobacterales (MBL-CRE). However, the labeled regimen is operationally demanding because it requires frequent, prolonged infusions, and the recommended loading dose does not match the commercially available vial strength. This population pharmacokinetic (PopPK)-based Monte Carlo simulation study aimed to optimize aztreonam/avibactam dosing across renal function strata while maintaining pharmacokinetic/pharmacodynamic (PK/PD) target attainment. Methods: Published PopPK models for aztreonam and avibactam were reconstructed and applied in Monte Carlo simulations. Virtual adult patients (body weight 70 kg) were stratified into five renal function groups according to creatinine clearance (CrCL): 101–120, 81–100, 51–80, 31–50, and 15–30 mL/min. Simulated scenarios varied infusion duration, dosing interval, maintenance dose, and loading strategy. Prespecified PK/PD targets were 60% fT > MIC (the percentage of dosing interval that free drug concentration remains above the minimum inhibitory concentration) for aztreonam (MIC 8 mg/L) and 50% fT > CT (the percentage of dosing interval that free drug concentration remains above the critical threshold concentration) for avibactam (CT 2.5 mg/L). A joint probability of target attainment (PTA) ≥ 90% was considered acceptable. Results: Regimen performance differed across renal function strata. For patients with CrCL > 80 mL/min, the labeled q6h regimen infused over 3 h remained the most robust option, whereas shortening the infusion to 1 h or 2 h reduced target attainment. In the CrCL 51–80 and 31–50 mL/min subgroups, both q6h/3 h and q6h/2 h regimens generally achieved acceptable PTA. However, in the CrCL 31–50 mL/min subgroup receiving q6h/2 h administration, omitting a loading dose was associated with reduced early avibactam exposure. In the CrCL 15–30 mL/min subgroup, a simplified half-vial regimen (0.75/0.25 g q8h/2 h) provided PTA comparable to that of the complex labeled reduced-dose regimen. Across loading dose scenarios, omission of the loading dose was best supported in the CrCL 51–80 mL/min subgroup, whereas retaining the labeled loading dose remained the more prudent approach in the CrCL 31–50 mL/min subgroup when a 2 h infusion was used. Conclusions: PopPK-guided, renal function-stratified simplification of aztreonam/avibactam dosing may improve clinical practicality without materially compromising PK/PD target attainment in selected patient subgroups. A 2 h infusion appears a reasonable alternative for patients with CrCL 31–80 mL/min, and a 0.75/0.25 g q8h/2 h half-vial regimen may be considered a plausible exploratory option for patients with CrCL 15–30 mL/min. These findings support more feasible administration strategies, but prospective clinical validation remains necessary.