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- Title
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.
- Authors
Olsson, Anna; Malmberg, Christer; Zhao, Chenyan; Friberg, Lena E; Nielsen, Elisabet I; Lagerbäck, Pernilla; Tängdén, Thomas
- 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.
- Subjects
POLYMYXIN B; KLEBSIELLA pneumoniae; MINOCYCLINE; CARBAPENEM-resistant bacteria; BACTERICIDAL action; GRAM-negative bacteria
- Publication
Journal of Antimicrobial Chemotherapy (JAC), 2024, Vol 79, Issue 2, p391
- ISSN
0305-7453
- Publication type
Article
- DOI
10.1093/jac/dkad394