Evaluation of In Vitro Synergistic Activities of Some Antibiotic Combinations Containing Colistin, Meropenem, Vancomycin, and Minocycline Against Oxacillinase-48 Carbapenemase-producing Klebsiella pneumoniae

Abstract

Introduction: Infection with carbapenem-resistant bacteria, such as Klebsiella pneumoniae, is a major issue due to a global shortage of antibiotic options. Moreover, due to concerns about emerging resistance and toxicity, as well as the potential synergistic effects, antibiotic combinations are preferred for carbapenem-resistant bacteria. In comparison with other carbapenemases, data on synergy tests for oxacillinase-48 (OXA-48) carbapenemase-producing K. pneumoniae are scarce. We aimed to evaluate the synergistic effects of colistin–meropenem, colistin–vancomycin, colistin–minocycline, and meropenem–minocycline combinations on OXA-48 carbapenemase-producing K. pneumoniae. Materials and Methods: In a previous study, clonal analysis of ertapenem-resistant K. pneumoniae strains collected between May 2012 and April 2013 was performed using the repetitive element palindromic-polymerase chain reaction (Rep-PCR), and a multiplex PCR was applied to detect carbapenemase genes. From each clone, a representative isolate containing only OXA-48 carbapenemase genes was selected. Further, the broth microdilution method was used to determine the minimum inhibitor concentrations of the antimicrobials under study. Between October 2018 and March 2019, the antibiotic synergism of colistin–meropenem, colistin–vancomycin, colistin–minocycline, and meropenem–minocycline combinations was investigated using the checkerboard method against the selected strains. Results: Oxacillinase-48-carbapenemase-producing 14 K. pneumoniae strains from various clones were all resistant to colistin. Three of the strains were intermediate, whereas the others were meropenem-resistant. Five strains were found to be susceptible to minocycline, whereas the remaining strains were found to be intermediate. Moreover, the highest synergy was between meropenem and minocycline, which was seen in seven (50%) of the strains. Colistin–minocycline, colistin–meropenem, and colistin-vancomycin combinations were found to have a synergistic interaction in five (35.7%), four (28.6%), and three (21.4%) strains, respectively. Further, there was no evidence of antagonistic interaction. Conclusion: Although all antibiotic combinations studied had a synergistic interaction, minocycline-based combinations had a more promising outcome in clinical trials.

Keywords

• checkerboard
• synergy testing
• polymyxin e
• oxacillinase-48
• carbapenemase
• in vitro