Journal article

Synergy of the Polymyxin-Chloramphenicol Combination against New Delhi Metallo-beta-Lactamase-Producing Klebsiella pneumoniae Is Predominately Driven by Chloramphenicol

Nusaibah Abdul Rahim, Yan Zhu, Soon-Ee Cheah, Matthew D Johnson, Heidi H Yu, Hanna E Sidjabat, Mark S Butler, Matthew A Cooper, Jing Fu, David L Paterson, Roger L Nation, John D Boyce, Darren J Creek, Phillip J Bergen, Tony Velkov, Jian Li

ACS INFECTIOUS DISEASES | AMER CHEMICAL SOC | Published : 2021

Abstract

Carbapenem-resistant Klebsiella pneumoniae has been classified as an Urgent Threat by the Centers for Disease Control and Prevention (CDC). The combination of two "old" antibiotics, polymyxin and chloramphenicol, displays synergistic killing against New Delhi metallo-β-lactamase (NDM)-producing K. pneumoniae. However, the mechanism(s) underpinning their synergistic killing are not well studied. We employed an in vitro pharmacokinetic/pharmacodynamic model to mimic the pharmacokinetics of the antibiotics in patients and examined bacterial killing against NDM-producing K. pneumoniae using a metabolomic approach. Metabolomic analysis was integrated with an isolate-specific genome-scale metaboli..

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Grants

Awarded by Australian National Health and Medical Research Council (NHMRC)


Awarded by National Institute of Allergy and Infectious Diseases of the National Institutes of Health


Funding Acknowledgements

This study is partially funded by the Australian National Health and Medical Research Council (NHMRC, APP1046561). J.L., T.V., and D.J.C. are supported by a research grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (R01 AI111965). J.L. and M.A.C. are Australian NHMRC Principal Research Fellows. T.V. and D.J.C. are Australian NHMRC Career Development Research Fellows. Part of this study was presented at the 26th European Congress of Clinical Microbiology and Infectious Diseases (Abstract EV0651).