Antibacterial activity of achievable epithelial lining fluid exposures of Amikacin Inhale with or without meropenem

Abstract

Objectives: While Amikacin Inhale (BAY41-6551), an integrated drug-device combination under development, achieves an estimated amikacin epithelial lining fluid (ELF) concentration of ∼ 5000 mg/L, its target site pharmacodynamics are unknown. We evaluated the pharmacodynamics of ELF exposure of inhaled amikacin ± meropenem.

Methods: ELF exposures of inhaled amikacin (400 mg every 12 h), intravenous meropenem (2 g every 8 h) and a combination of both were studied in an in vitro pharmacodynamic model. Seven Klebsiella pneumoniae and 10 Pseudomonas aeruginosa with amikacin/meropenem MICs of 1 to 32,768/≤ 0.125 to >128 mg/L were included. Efficacy was assessed over 24-72 h.

Results: The mean ± SD 0 h bacterial density was 6.5 ± 0.1 log10 cfu/mL. Controls grew to 8.0 ± 0.5 log10 cfu/mL by the end of the experiments. Simulation of inhaled amikacin monotherapy rapidly achieved and sustained bactericidal activity near the limit of detection over 24 h for all 13 isolates with amikacin MIC ≤ 256 mg/L except only ∼ 2 log10 cfu/mL reduction was observed in K. pneumoniae 375 (amikacin/meropenem MIC 64/32 mg/L) and P. aeruginosa 1544 (amikacin/meropenem MIC 64/128 mg/L). No activity was seen against the three isolates with amikacin MIC ≥ 2048 mg/L. Among the six isolates tested with meropenem monotherapy, five (meropenem MIC ≥ 16 mg/L) grew similarly to the controls while one (meropenem MIC 2 mg/L) achieved ∼ 2.5 log10 cfu/mL decrease. Among seven isolates tested in combination, four (amikacin/meropenem MIC ≤ 64/32 mg/L), including K. pneumoniae 375, maintained limit of detection until 72 h, whereas P. aeruginosa 1544 sustained a 1 log reduction. Combination therapy had no activity against the two isolates with amikacin MIC ≥ 2048 mg/L.

Conclusions: Inhaled amikacin monotherapy showed bactericidal activity against most isolates tested with amikacin MICs ≤ 256 mg/L. Adjunct inhaled amikacin plus meropenem sustained this activity for 72 h for the tested isolates with amikacin/meropenem MIC ≤ 64/32 mg/L.