Synergy between Mecillinam and Ceftazidime/Avibactam or Avibactam against Multi-Drug-Resistant Carbapenemase-Producing <i>Escherichia coli</i> and <i>Klebsiella pneumoniae</i>
Background: Carbapenemase-producing <i>Klebsiella pneumoniae</i> and <i>Escherichia coli</i> have become a significant global health challenge. This has created an urgent need for new treatment modalities. We evaluated the efficacy of mecillinam in combination with either avi...
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| Main Authors: | , , , , , , , , |
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| Format: | Book |
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MDPI AG,
2022-09-01T00:00:00Z.
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| Summary: | Background: Carbapenemase-producing <i>Klebsiella pneumoniae</i> and <i>Escherichia coli</i> have become a significant global health challenge. This has created an urgent need for new treatment modalities. We evaluated the efficacy of mecillinam in combination with either avibactam or ceftazidime/avibactam against carbapenemase-producing clinical isolates. Materials and methods: Nineteen MDR clinical isolates of <i>K. pneumoniae</i> and <i>E. coli</i> were selected for the presence of <i>bla</i>KPC, <i>bla</i>NDM, <i>bla</i>OXA or <i>bla</i>IMP based on whole-genome sequencing and phenotypic susceptibility testing. We tested the synergy between mecillinam and avibactam or ceftazidime/avibactam. We used time-kill studies in vitro and a mouse peritonitis/sepsis model to confirm the synergistic effect. We investigated avibactam's impact on mecillinam´s affinity for penicillin-binding proteins with a Bocillin assay, and cell changes with phase-contrast and confocal laser scanning microscopy. Results: Mecillinam combined with ceftazidime/avibactam or avibactam substantially reduced MICs (from up to >256 µg/mL to <0.0016 µg/mL) for 17/18 strains. Significant log-CFU reductions were confirmed in time-kill and in vivo experiments. The Bocillin assay did not reveal changes. Conclusion: Mecillinam in combination with avibactam or ceftazidime/avibactam has a notable effect on most types of CPEs, both in vitro and in vivo. The mecillinam/avibactam combination treatment could be a new efficient antibiotic treatment against multi-drug-resistant carbapenemase-producing Gram-negative pathogens. |
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| Item Description: | 10.3390/antibiotics11101280 2079-6382 |