In Vitro and in Vivo Evaluation of Antibiotic Combination against Multidrug Resistant Enterobacter Species Isolated From Patients of a Tertiary Care Hospital, Bangladesh

The emergence of multidrug-resistant (MDR) Enterobacter as a worrying resistant pathogen is an important health concern, especially when there is scarcity of new antibiotics active against Gram-negative bacteria. However, currently no defined therapies available for MDR Enterobacter infections. In this study, in vitro and in vivo efficacy of different antimicrobial combinations were assessed. This cross-sectional study was carried out in the department of Microbiology of Dhaka medical college hospital, Bangladesh from July, 2018 to June, 2019. Multidrug resistance among isolated Enterobacter species were detected phenotypically by disk diffusion method. PCR and sequencing of fosfomycin resistance genes were done. In vitro activity of fosfomycin, amikacin, imipenem, piperacillin-tazobactam and their combinations were evaluated using agar dilution method and synergy was assessed by Fractional inhibitory concentration index. Mice models were made by using the MDR Enterobacter strain. We evaluate the efficacy of fosfomycin, amikacin, imipenem and their combination against multi-drug resistant Enterobacter infection in experimental mice models. Among 28 isolated Enterobacter spp. 53.33% were multidrug-resistant. Among the fosfomycin resistant Enterobacter spp. 70% , 50%, 40% were positive for fosA. foA5 and fosB2 respectively. The fractional inhibitory concentration index indicated that combining antibiotics resulted 2 to 8 fold reduction of MIC compared to single therapy. The ratio of synergy observed in imipenem-amikacin, fosfomycin-amikacin, fosfomycin-imipenem 16.67%, 87.33%, 50.0% respectively in vitro. No synergy observed in imipenem-piperacillin tazobactam combination. In mice model, compared to single antibiotic therapy, fosfomycin-amikacin, imipenem-amikacin, fosfomycin-imipenem showed increased sterile blood culture (100%, 60%, 80%). Fosfomycin plus amikacin or fosfomycin plus imipenem may be alternative treatment option against multidrug-resistant Enterobacter infection.