TY - JOUR

T1 - Synergy between Mecillinam and Ceftazidime/Avibactam or Avibactam against Multi-Drug-Resistant Carbapenemase-Producing Escherichia coli and Klebsiella pneumoniae

AU - List, Karoline Knudsen

AU - Kolpen, Mette

AU - Kragh, Kasper Nørskov

AU - Charbon, Godefroid

AU - Radmer, Stine

AU - Hansen, Frank

AU - Løbner-Olesen, Anders

AU - Frimodt-Møller, Niels

AU - Hertz, Frederik Boetius

PY - 2022

Y1 - 2022

N2 - Background: Carbapenemase-producing Klebsiella pneumoniae and Escherichia coli 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 K. pneumoniae and E. coli were selected for the presence of blaKPC, blaNDM, blaOXA or blaIMP 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.

AB - Background: Carbapenemase-producing Klebsiella pneumoniae and Escherichia coli 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 K. pneumoniae and E. coli were selected for the presence of blaKPC, blaNDM, blaOXA or blaIMP 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.

U2 - 10.3390/antibiotics11101280

DO - 10.3390/antibiotics11101280

M3 - Journal article

C2 - 36289937

VL - 11

JO - Antibiotics

JF - Antibiotics

SN - 2079-6382

IS - 10

M1 - 1280

ER -