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

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 mu g/ml; AMK-I MICs, 8 to 64 mu g/ml) and three K. pneurnoniae isolates (CZA MICs, 1/4 to 8/4 mu g/ml; AMK-1 MICs, 32 to 64 mu 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 log(10) , CFU/ml, P = 0.027; -1.42 log(10) CFU/ml, P = 0.020; and -0.4 log(10) , CFU/ ml, P = 0.298) and two of three K. pneurnoniae isolates (0.04 log(10) , CFU/ml, P = 0.963; -4.34 log(10) CFU/ml, P < 0.001; and -2.34 log(10) , 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 bla(KPC-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 carbapenemresistant Gram-negative bacteria.