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Synergy of polymyxin B and minocycline against KPC-3- and OXA-48-producing Klebsiella pneumoniae in dynamic time–kill experiments: agreement with in silico predictions.
- Source :
- Journal of Antimicrobial Chemotherapy (JAC); Feb2024, Vol. 79 Issue 2, p391-402, 12p
- Publication Year :
- 2024
-
Abstract
- Objectives Combination therapy is often used for carbapenem-resistant Gram-negative bacteria. We previously demonstrated synergy of polymyxin B and minocycline against carbapenem-resistant Klebsiella pneumoniae in static time–kill experiments and developed an in silico pharmacokinetic/pharmacodynamic (PK/PD) model. The present study assessed the synergistic potential of this antibiotic combination in dynamic experiments. Methods Two clinical K. pneumoniae isolates producing KPC-3 and OXA-48 (polymyxin B MICs 0.5 and 8 mg/L, and minocycline MICs 1 and 8 mg/L, respectively) were included. Activities of the single drugs and the combination were assessed in 72 h dynamic time–kill experiments mimicking patient pharmacokinetics. Population analysis was performed every 12 h using plates containing antibiotics at 4× and 8× MIC. WGS was applied to reveal resistance genes and mutations. Results The combination showed synergistic and bactericidal effects against the KPC-3-producing strain from 12 h onwards. Subpopulations with decreased susceptibility to polymyxin B were frequently detected after single-drug exposures but not with the combination. Against the OXA-48-producing strain, synergy was observed between 4 and 8 h and was followed by regrowth. Subpopulations with decreased susceptibility to polymyxin B and minocycline were detected throughout experiments. For both strains, the observed antibacterial activities showed overall agreement with the in silico predictions. Conclusions Polymyxin B and minocycline in combination showed synergistic effects, mainly against the KPC-3-producing K. pneumoniae. The agreement between the experimental results and in silico predictions supports the use of PK/PD models based on static time–kill data to predict the activity of antibiotic combinations at dynamic drug concentrations. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 03057453
- Volume :
- 79
- Issue :
- 2
- Database :
- Complementary Index
- Journal :
- Journal of Antimicrobial Chemotherapy (JAC)
- Publication Type :
- Academic Journal
- Accession number :
- 175158087
- Full Text :
- https://doi.org/10.1093/jac/dkad394