The postantibiotic effect and post‐β‐lactamase‐inhibitor effect of ceftazidime, ceftaroline and aztreonam in combination with avibactam against target Gram‐negative bacteria

• Published in: Letters in applied microbiology Vol. 63; no. 2; pp. 96 - 102
• Main Authors: Pillar, C.M., Stoneburner, A., Shinabarger, D.L., Krause, K.M., Nichols, W.W.
• Format: Journal Article
• Language: English
• Published: England 01.08.2016
• Subjects: Anti-Bacterial Agents - pharmacology; antibacterial agents; Azabicyclo Compounds - pharmacology; Aztreonam - pharmacology; Bacterial Proteins - genetics; beta-Lactamase Inhibitors - pharmacology; beta-Lactamases - genetics; Ceftaroline; Ceftazidime - pharmacology; Cephalosporins; Drug Combinations; Humans; Klebsiella pneumoniae - drug effects; Klebsiella pneumoniae - genetics; Microbial Sensitivity Tests; postantibiotic effect; post‐β‐lactamase‐inhibitor effect; primary pharmacodynamics; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - genetics; Sulbactam - pharmacology; β‐lactamase inhibitors; β‐lactams; primary pharmacodynamics; β-lactamase inhibitors; β-lactams; post-β-lactamase-inhibitor effect; postantibiotic effect; antibacterial agents
• ISSN: 0266-8254; 1472-765X
• DOI: 10.1111/lam.12592

The magnitudes of the postantibiotic effect (PAE) and post‐β‐lactamase‐inhibitory effect (PLIE) of ceftazidime‐avibactam, ceftaroline‐avibactam, and aztreonam‐avibactam were determined against isolates of Enterobacteriaceae and Pseudomonas aeruginosa that either harboured genes encoding serine and/or metallo‐β‐lactamases, or did not harbour bla genes. The bla genes included ones that encoded extended spectrum β‐lactamases, AmpC and KPC β‐lactamases, and one metallo‐β‐lactamase, NDM‐1. No substantial PAE was observed for any combination against any isolate. One substantial PLIE was found: a value of 1·9 h for ceftazidime‐avibactam against Klebsiella pneumoniae (blaKPC‐2). From comparison with results in the literature, we propose that the existence of a substantial PLIE depends on the bacterial isolate and on the specific β‐lactamase inhibitor and β‐lactam combination. Significance and Impact of the Study A wave of new β‐lactamase inhibitors is entering either therapeutic use or clinical trials. The present work characterizes the postantibiotic effect (PAE) and post‐β‐lactamase‐inhibitory effect (PLIE) of the clinically most advanced of these compounds, avibactam. We show that the existence of a measurable PLIE is strain‐ (and possibly compound‐) dependent, and cannot be relied upon as a standard component of the primary pharmacology of a new β‐lactamase inhibitor. This variability was not reported in earlier studies of clavulanic acid or sulbactam. Significance and Impact of the Study: A wave of new β‐lactamase inhibitors is entering either therapeutic use or clinical trials. The present work characterizes the postantibiotic effect (PAE) and post‐β‐lactamase‐inhibitory effect (PLIE) of the clinically most advanced of these compounds, avibactam. We show that the existence of a measurable PLIE is strain‐ (and possibly compound‐) dependent, and cannot be relied upon as a standard component of the primary pharmacology of a new β‐lactamase inhibitor. This variability was not reported in earlier studies of clavulanic acid or sulbactam.