Pragmatic options for dose optimization of ceftazidime/avibactam with aztreonam in complex patients

Background: Avibactam is a beta-Lactamase inhibitor that is combined with aztreonam against Enterobacterales co-expressing serine- and metallo-beta-Lactamases (MBL). Optimal dosing of aztreonam with avibactam is not well-defined in critically ill patients and contingent on ceftazidime/avibactam product labelling. Objectives: To identify a pragmatic dosing strategy for aztreonam with avibactam to maximize the probability of target attainment (PTA). Methods: We conducted a prospective observational pharmacokinetic study. Five blood samples were collected around the fourth dose of aztreonam or ceftazidime/avibactam and assayed for all three drugs. Population pharmacokinetic (PK) analysis coupled with Monte Carlo simulations were used to create a dosing nomogram for aztreonam and ceftazidime/avibactam based on drug-specific pharmacodynamic (PD) targets. Results: A total of 41 participants (59% male) median age of 75 years (IQR 63-79 years) were enrolled. They were critically ill (46%) with multiple comorbidities and complications including burns (20%). Population PK analysis identified higher volume of distribution and Lower clearance (CL) compared with typical value expectations for aztreonam and ceftazidime/avibactam. Estimated glomerular filtration (eGFR) rate using the CKD-EPI equation predicted CL for all three drugs. The need for high doses of aztreonam and ceftazidime/avibactam above those in the existing product Labels are not predicted by this analysis with the exception of ceftazidime/avibactam for patients with eGFR of 6-15 mL/min, in whom suboptimal PTA of <= 71% is predicted. Conclusions: Pragmatic and Lower daily-dose options are predicted for aztreonam and ceftazidime/avibactam when the eGFR is <90 mL/min. These options should be tested prospectively.

Automated summary

This study investigated dosing strategies for aztreonam with avibactam in critically ill patients, finding that pragmatic and lower daily dose options are predicted for aztreonam and ceftazidime/avibactam when the eGFR is <90 mL/min.