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 hour in vitro pharmacodynamic chemostat model, we simulated the human exposures achieved in epithelial lining fluid (ELF) following intravenous ceftazidime-avibactam (CZA) 2.5g q8h alone and in combination with inhaled amikacin (AMK) 400mg q12h, a reformulated aminoglycoside designed for inhalational administration, against 3 P. aeruginosa (CZA MICs: 4/4-8/4 μg/ml; AMK-I MICs: 8-64 μg/ml) and 3 K. pneumoniae (CZA: 1/4-8/4 μg/ml; AMK-I: 32-64 μg/ml). Combination therapy resulted in a significant reduction in 72 hour colony forming units (CFU) compared with CZA monotherapy against 2 of 3 P. aeruginosa (-4.14 log₁₀CFU/ml, P= 0.027; -1.42 log₁₀CFU/ml, P=0.020; and -0.4 log₁₀CFU/ml, P= 0.298) and 2 of 3 K. pneumoniae (0.04 log₁₀CFU/ml, P=0.963; -4.34 log₁₀CFU/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 hours, significant reductions were observed in favor of the combination regimen against all 6 isolates tested. AMK-I combination therapy successfully suppressed CZA resistance development in one K. pneumoniae harboring bla_kpc3 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.