Disulfiram enhances meropenem activity against NDM- and IMP-producing carbapenem-resistantAcinetobacter baumanniiinfections

美罗培南 鲍曼不动杆菌 微生物学 二硫仑 抗生素 佩内多林 药理学 碳青霉烯 不动杆菌 医学 生物 抗生素耐药性 细菌 铜绿假单胞菌 遗传学
作者
Vineet Dubey,Kuldip Devnath,Vivek Gupta,Gazal Kalyan,Mangal Singh,Ashish Kothari,Balram Ji Omar,Ranjana Pathania
出处
期刊:Journal of Antimicrobial Chemotherapy [Oxford University Press]
卷期号:77 (5): 1313-1323 被引量:3
标识
DOI:10.1093/jac/dkac057
摘要

To evaluate the in vitro and in vivo efficacy of the FDA-approved drug disulfiram in combination with meropenem against MBL-expressing carbapenem-resistant Acinetobacter baumannii.Chequerboard and antibiotic resistance reversal analysis were performed using 25 clinical isolates producing different MBLs. Three representative strains harbouring NDM, IMP or non-MBL genes were subjected to a time-kill assay to further evaluate this synergistic interaction. Dose-dependent inhibition by disulfiram was assessed to determine IC50 for NDM-1, IMP-7, VIM-2 and KPC-2. Further, to test the efficacy of meropenem monotherapy and meropenem in combination with disulfiram against NDM- and IMP-harbouring A. baumannii, an experimental model of systemic infection and pneumonia was developed using BALB/c female mice.Chequerboard and antibiotic reversal assay displayed a synergistic interaction against MBL-expressing A. baumannii strains with 4- to 32-fold reduction in MICs of meropenem. In time-kill analysis, meropenem and disulfiram exhibited synergy against NDM- and IMP-producing carbapenem-resistant A. baumannii (CRAb) isolates. In vitro dose-dependent inhibition analysis showed that disulfiram inhibits NDM-1 and IMP-7 with IC50 values of 1.5 ± 0.6 and 16.25 ± 1.6 μM, respectively, with slight or no inhibition of VIM-2 (<20%) and KPC-2. The combination performed better in the clearance of bacterial load from the liver and spleen of mice infected with IMP-expressing CRAb. In the pneumonia model, the combination significantly decreased the bacterial burden of NDM producers compared with monotherapy.These results strongly suggest that the combination of disulfiram and meropenem represents an effective treatment option for NDM- and IMP-associated CRAb infections.
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