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

J Antimicrob Chemother. 2021 Mar 12;76(4):1025-1031. doi: 10.1093/jac/dkaa549.

Abstract

Background: Avibactam is a β-lactamase inhibitor that is combined with aztreonam against Enterobacterales co-expressing serine- and metallo-β-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.

Publication types

  • Observational Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Anti-Bacterial Agents / therapeutic use
  • Azabicyclo Compounds
  • Aztreonam*
  • Ceftazidime*
  • Drug Combinations
  • Female
  • Humans
  • Male
  • Microbial Sensitivity Tests
  • Middle Aged
  • beta-Lactamases

Substances

  • Anti-Bacterial Agents
  • Azabicyclo Compounds
  • Drug Combinations
  • avibactam
  • Ceftazidime
  • beta-Lactamases
  • Aztreonam