The primary pharmacology of ceftazidime/avibactam: in vivo translational biology and pharmacokinetics/pharmacodynamics (PK/PD)

This review describes the translational in vivo and non-clinical pharmacokinetics/pharmacodynamics (PK/PD) research that supported clinical trialling and subsequently licensing approval of ceftazidime/avibactam, a new beta-lactam/beta-lactamase inhibitor combination aimed at the treatment of infections by Enterobacterales and Pseudomonas aeruginosa. The review thematically follows on from the co-published article, Nichols et al. (J Antimicrob Chemother 2022; dkac171). Avibactam protected ceftazidime in animal models of infection with ceftazidime-resistant, beta-lactamase-producing bacteria. For example, a single subcutaneous dose of ceftazidime at 1024 mg/kg yielded little effect on the growth of ceftazidime-resistant, bla(KPC-2)-carrying Klebsiella pneumoniae in the thighs of neutropenic mice (final counts of 4 x 10(8) to 8 x 10(8) cfu/thigh). In contrast, co-administration of avibactam in a 4:1 ratio (ceftazidime:avibactam) was bactericidal in the same model (final counts of 2 x 10(4) to 3 x 10(4) cfu/thigh). In a rat abdominal abscess model, therapy with ceftazidime or ceftazidime/avibactam (4:1 w/w) against bla(KPC-2)-positive K. pneumoniae resulted in 9.3 versus 3.3 log cfu/abscess, respectively, after 52 h. With respect to PK/PD, in Monte Carlo simulations, attainment of unbound drug exposure targets (ceftazidime fT(>8 mg/L) and avibactam fT(>1 mg/L), each for 50% of the dosing interval) for the labelled dose of ceftazidime/avibactam (2 and 0.5 g, respectively, q8h by 2 h IV infusion), including dose adjustments for patients with impaired renal function, ranged between 94.8% and 99.6% of patients, depending on the infection modelled.

Automated summary

This review discusses the preclinical pharmacokinetics/pharmacodynamics (PK/PD) research and clinical translation of ceftazidime/avibactam for the treatment of infections by Enterobacterales and Pseudomonas aeruginosa. Animal models and Monte Carlo simulations show that avibactam protects ceftazidime and achieves the desired drug exposure levels.