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Mutations in differentially impact synergy of meropenem/vaborbactam and ceftazidime/avibactam in combination with other antibiotics against KPC-producing . | LitMetric
Department of Medicine, University of Pittsburgh, 3601 Fifth Avenue, Falk Medical Building, Suite 5B, Pittsburgh, PA, USA.
Published: October 2023
AI Article Synopsis
Article Abstract
Objectives: Ceftazidime/avibactam and meropenem/vaborbactam are preferred agents for carbapenemase (KPC)-producing (KPC-) infections and are often used in combination with other agents. We aimed to characterize the synergy of combinations against KPC- with varying genotypes.
Methods: KPC- that harboured WT, IS 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 1 × 10 cfu/mL KPC-.
Results: KPC- harboured WT ( = 5), IS ( = 5) or GD ( = 5); 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 1 × MIC exhibited mean 24 h log-kills of -2.01 and -0.84, respectively. Ceftazidime/avibactam was synergistic in combination with colistin independent of genotype. Ceftazidime/avibactam combinations impacted by porin mutations (compared to WT) were meropenem (-5.18 versus -6.62 mean log-kill, < 0.001) and fosfomycin (-3.98 versus -6.58, = 0.058). 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, = 0.03) and fosfomycin (-3.12 versus 1.54, = 0.003).
Conclusions: Our results shed new light on the synergy of ceftazidime/avibactam and meropenem/vaborbactam combinations against KPC- 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.
