Mutations in ompK36 differentially impact in vitro synergy of meropenem/vaborbactam and ceftazidime/avibactam in combination with other antibiotics against KPC-producing Klebsiella pneumoniae.
JAC Antimicrob Resist
; 5(5): dlad113, 2023 Oct.
Article
em En
| MEDLINE
| ID: mdl-37901589
ABSTRACT
Objectives:
Ceftazidime/avibactam and meropenem/vaborbactam are preferred agents for Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp) infections and are often used in combination with other agents. We aimed to characterize the synergy of combinations against KPC-Kp with varying ompK36 genotypes.Methods:
KPC-Kp that harboured ompK36 WT, IS5 or glycine-aspartic acid duplication (GD) genotypes were selected. MICs were determined in triplicate. Synergy was assessed by time-kill assays for ceftazidime/avibactam and meropenem/vaborbactam in combination with colistin, gentamicin, tigecycline, meropenem or fosfomycin against 1â×â108â cfu/mL KPC-Kp.Results:
KPC-Kp harboured ompK36 WT (nâ=â5), IS5 (nâ=â5) or GD (nâ=â5); 11 were KPC-2 and 4 were KPC-3. All were susceptible to ceftazidime/avibactam and meropenem/vaborbactam. In time-kill analysis, ceftazidime/avibactam and meropenem/vaborbactam 1â×âMIC exhibited mean 24â h log-kills of -2.01 and -0.84, respectively. Ceftazidime/avibactam was synergistic in combination with colistin independent of ompK36 genotype. Ceftazidime/avibactam combinations impacted by porin mutations (compared to WT) were meropenem (-5.18 versus -6.62 mean log-kill, Pâ<â0.001) and fosfomycin (-3.98 versus -6.58, Pâ=â0.058). Mean log-kills with meropenem/vaborbactam were greatest in combination with gentamicin (-5.36). In the presence of porin mutations, meropenem/vaborbactam killing activity was potentiated by the addition of colistin (-6.65 versus -0.70, Pâ=â0.03) and fosfomycin (-3.12 versus 1.54, Pâ=â0.003).Conclusions:
Our results shed new light on the synergy of ceftazidime/avibactam and meropenem/vaborbactam combinations against KPC-Kp with or without porin mutations. Killing activity of ceftazidime/avibactam with other cell wall active agents was decreased against isolates with porin mutations. On the other hand, some meropenem/vaborbactam combinations demonstrated enhanced killing in the presence of porin mutations.
Texto completo:
1
Base de dados:
MEDLINE
Idioma:
En
Revista:
JAC Antimicrob Resist
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
Estados Unidos