Pharmacokinetics and target attainment of aztreonam/avibactam in plasma and tissue: A human microdialysis study

Background This study investigated the pharmacokinetics (PK) and target attainment of the novel β-lactam/β-lactamase inhibitor combination aztreonam/avibactam in tissue and plasma. Methods Ten healthy volunteers received a single intravenous 3-hour infusion of aztreonam/avibactam 2000/670 mg. Unbound concentrations in plasma (ultrafiltration) and in subcutaneous and intramuscular interstitial fluid (microdialysis, calibrated by retrodialysis) were quantified over 12 h by liquid chromatography–tandem mass spectrometry. We performed a non-compartmental analysis and assessed the number of participants attaining the joint PK/pharmacodynamic (PD) target of aztreonam 60% f T >MIC and avibactam 50% f T >CT of 2.5 mg/L during the first 6-hour dosing interval. Results The geometric mean (geometric coefficient of variation) f AUC 0–12 of aztreonam was 208.9 (17.3%), 100.5 (39.4%), and 115.3 (36.2%) h·mg/L in plasma, subcutis, and muscle, respectively, and that of avibactam was 63.2 (22.1%), 37.3 (37.6%), and 40.2 (36.7%) h·mg/L. Geometric mean tissue-to-plasma f AUC 0–12 ratios were 0.48–0.64. At an aztreonam minimum inhibitory concentration (MIC) of 8 mg/L, the joint target was attained in 10/10 participants in plasma and in 9/10 participants in subcutis and muscle (95% confidence interval 55–100%). Conclusion In healthy volunteers, unbound subcutaneous and muscle exposure of aztreonam/avibactam was approximately half to two-thirds of unbound plasma exposure. Under the conditions studied, most participants attained the joint target up to an MIC of 8 mg/L in all compartments. Studies in patients with skin and soft tissue infections are needed to confirm these findings.