Activity of polymyxin B combinations against genetically well-characterised Klebsiella pneumoniae producing NDM-1 and OXA-48-like carbapenemases.

Autor: Olsson A; Department of Medical Sciences, Uppsala University, Uppsala, Sweden., Allander L; Department of Medical Sciences, Uppsala University, Uppsala, Sweden., Shams A; Department of Medical Sciences, Uppsala University, Uppsala, Sweden., Al-Farsi H; Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institute, Stockholm, Sweden., Lagerbäck P; Department of Medical Sciences, Uppsala University, Uppsala, Sweden., Tängdén T; Department of Medical Sciences, Uppsala University, Uppsala, Sweden. Electronic address: thomas.tangden@medsci.uu.se.
Jazyk: angličtina
Zdroj: International journal of antimicrobial agents [Int J Antimicrob Agents] 2023 Nov; Vol. 62 (5), pp. 106967. Date of Electronic Publication: 2023 Sep 15.
DOI: 10.1016/j.ijantimicag.2023.106967
Abstrakt: Background: Combination therapy can enhance the activity of available antibiotics against multidrug-resistant Gram-negative bacteria. This study assessed the effects of polymyxin B combinations against carbapenemase-producing Klebsiella pneumoniae (K. pneumoniae).
Methods: Twenty clinical K. pneumoniae strains producing NDM-1 (n = 8), OXA-48-like (n = 10), or both NDM-1 and OXA-48-like (n = 2) carbapenemases were used. Whole-genome sequencing was applied to detect resistance genes (e.g. encoding antibiotic-degrading enzymes) and sequence alterations influencing permeability or efflux. The activity of polymyxin B in combination with aztreonam, fosfomycin, meropenem, minocycline, or rifampicin was investigated in 24-hour time-lapse microscopy experiments. Endpoint samples were spotted on plates with and without polymyxin B at 4 x MIC to assess resistance development. Finally, associations between synergy and bacterial genetic traits were explored.
Results: Synergistic and bactericidal effects were observed with polymyxin B in combination with all other antibiotics: aztreonam (11 of 20 strains), fosfomycin (16 of 20), meropenem (10 of 20), minocycline (18 of 20), and rifampicin (15 of 20). Synergy was found with polymyxin B in combination with fosfomycin, minocycline, or rifampicin against all nine polymyxin-resistant strains. Wildtype mgrB was associated with polymyxin B and aztreonam synergy (P = 0.0499). An absence of arr-2 and arr-3 was associated with synergy of polymyxin B and rifampicin (P = 0.0260). Emergence of populations with reduced polymyxin B susceptibility was most frequently observed with aztreonam and meropenem.
Conclusion: Combinations of polymyxin B and minocycline or rifampicin were most active against the tested NDM-1 and OXA-48-like-producing K. pneumoniae. Biologically plausible genotype-phenotype associations were found. Such information might accelerate the search for promising combinations and guide individualised treatment.
Competing Interests: Conflict of Interest All authors declare no conflicts of interest.
(Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
Databáze: MEDLINE
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