Meropenem-Vaborbactam Resistance Selection, Resistance Prevention, and Molecular Mechanisms in Mutants of KPC-Producing Klebsiella pneumoniae

Autor: Debora Rubio-Aparicio, Olga Lomovskaya, Dongxu Sun, Kirk Nelson, Michael N. Dudley
Rok vydání: 2017
Předmět:
0301 basic medicine
Klebsiella pneumoniae carbapenemases
Klebsiella
Klebsiella pneumoniae
030106 microbiology
Mutant
Gene Dosage
Porins
Microbial Sensitivity Tests
Drug resistance
Meropenem
beta-Lactamases
Microbiology
Heterocyclic Compounds
1-Ring
03 medical and health sciences
Bacterial Proteins
Mechanisms of Resistance
Drug Resistance
Bacterial
polycyclic compounds
medicine
Humans
Pharmacology (medical)
Mutation frequency
Pharmacology
Vaborbactam
single-step mutants
biology
Gene Expression Regulation
Bacterial
biochemical phenomena
metabolism
and nutrition
bacterial infections and mycoses
biology.organism_classification
Boronic Acids
Anti-Bacterial Agents
Klebsiella Infections
Isoenzymes
KPC
Drug Combinations
Infectious Diseases
Mutation
Thienamycins
Pharmacophore
vaborbactam
resistance development
Plasmids
medicine.drug
Zdroj: Antimicrobial Agents and Chemotherapy
ISSN: 1098-6596
0066-4804
DOI: 10.1128/aac.01694-17
Popis: Vaborbactam (formerly RPX7009) is a new β-lactamase inhibitor based on a cyclic boronic acid pharmacophore with potent inhibitory activity against K lebsiella p neumoniae c arbapenemases (KPC). It has been developed in combination with meropenem. The objective of these studies was to identify the concentrations of both agents associated with the selection or prevention of single-step mutations leading to reduced sensitivity to the combination and to characterize the selected mutations. Eighteen strains of KPC-producing Klebsiella pneumoniae with various degrees of sensitivity to meropenem (MICs, 8 to 512 μg/ml) and meropenem-vaborbactam (MICs, ≤0.06 to 32 μg/ml) and preexisting resistance mechanisms were selected from a worldwide collection of isolates recovered from surveillance studies, emphasizing strains for which MICs were in the upper range of the meropenem-vaborbactam MIC distribution. Meropenem and vaborbactam at 8 μg/ml each suppressed the drug resistance mutation frequency to −8 in 77.8% (14/18) of strains, and all strains were inhibited when the meropenem concentration was increased to 16 μg/ml. Mutants selected at lower drug concentrations showed phenotypes associated with previously described carbapenem resistance mechanisms, including ompK36 inactivation in mutants selected from OmpK36-proficient strains and an increased bla KPC gene copy number in strains with partially functional ompK36 . No mutations in the coding region of bla KPC were identified. These data indicate that the selection of mutants with reduced sensitivity to meropenem-vaborbactam from KPC-producing Klebsiella pneumoniae strains is associated with previously described mechanisms involving porin mutations and the increase in the bla KPC gene copy number and not changes in the KPC enzyme and can be prevented by the drug concentrations achieved with optimal dosing of the combination.
Databáze: OpenAIRE
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