Efficacy of meropenem and amikacin combination therapy against carbapenemase-producing Klebsiella pneumoniae mouse model of pneumonia

Background: The emergence and spread of carbapenem-resistant Enterobacteriaceae (CRE) is a global health problem due to its high mortality and limited treatment options. Combination antimicrobial therapy is reported to be effective against CRE in vitro; however, its efficacy in vivo has not been thoroughly evaluated. Thus, this study assessed the efficacy of combination therapy of meropenem (MEPM) and amikacin (AMK) in a carbapenem-resistant Klebsiella pneumoniae (CR-Kp) mouse model of pneumonia. Materials and methods: Agar-based bacterial suspension of CR-Kp clinical isolates was inoculated into the trachea of BALB/c mice. Treatment was initiated 6 h post infection, with 100 mg/kg MEPM every 6 h, 100 mg/kg AMK every 12 h, or in combination; survival was evaluated for 7 days. The number of viable bacteria in the lungs, lung histopathology, and neutrophil counts in broncho-alveolar lavage fluid (BALF) were evaluated 42 h after infection. Results: All mice in the untreated control group died in 48 h, while all the mice in treatment groups survived past 7 days following infection. The bacterial count in the lungs (log(10) CFU/mL, mean +/- SEM) in the combination group (2.00 +/- 0.00) decreased significantly compared to that in control (10.19 +/- 0.11, p < 0.0001), MEPM (6.38 +/- 0.17, p < 0.0001), and AMK (6.17 +/- 0.16, p < 0.0001) groups. BALF neutrophil count reduced only in the combination therapy group. Combination therapy prevented the progression of lung inflammation, including alveolar neutrophil infiltration and hemorrhage. Conclusions: This study demonstrates in vivo efficacy of MEPM and AMK combination therapy against CR-Kp pneumonia. (C) 2020 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.