Antibacterial activity of human simulated epithelial lining fluid concentrations of ceftazidime-avibactam alone or in combination with Amikacin Inhale (BAY41-6551) against carbapenem-resistant pseudomonas aeruginosa and Klebsiella pneumoniae

Abstract

The role of inhalational combination therapy when treating carbapenem-resistant Pseudomonas aeruginosa and Klebsiella pneumoniae with newer beta-lactam/ beta-lactamase inhibitors has not been established. Using a 72-h in vitro pharmacodynamic chemostat model, we simulated the human exposures achieved in epithelial lining fluid (ELF) following intravenous treatment with ceftazidime-avibactam (CZA) 2.5 g every 8 h (q8h) alone and in combination with inhaled amikacin (AMK-I) 400 mg q12h, a reformulated aminoglycoside designed for inhalational administration, against three P. aeruginosa isolates (CZA [ceftazidime/avibactam] MICs, 4/4 to 8/4 g/ml; AMK-I MICs, 8 to 64 g/ml) and three K. pneumoniae isolates (CZA MICs, 1/4 to 8/4 g/ml; AMK-I MICs, 32 to 64 g/ml). Combination therapy resulted in a significant reduction in 72-h CFU compared with that of CZA monotherapy against two of three P. aeruginosa isolates (4.14 log10 CFU/ml, P 0.027; 1.42 log10 CFU/ml, P 0.020; and 0.4 log10 CFU/ ml, P 0.298) and two of three K. pneumoniae isolates (0.04 log10 CFU/ml, P 0.963; 4.34 log10 CFU/ml, P 0.001; and 2.34 log10 CFU/ml, P 0.021). When measured by the area under the bacterial growth curve (AUBC) over 72 h, significant reductions were observed in favor of the combination regimen against all six isolates tested. AMK-I combination therapy successfully suppressed CZA resistance development in one K. pneumoniae isolate harboring blaKPC-3 that was observed during CZA monotherapy. These studies suggest a beneficial role for combination therapy with intravenous CZA and inhaled AMK when treating pneumonia caused by carbapenem-resistant Gram-negative bacteria.