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. 2023 Oct 26;5(5):dlad113.
doi: 10.1093/jacamr/dlad113. eCollection 2023 Oct.

Mutations in ompK36 differentially impact in vitro synergy of meropenem/vaborbactam and ceftazidime/avibactam in combination with other antibiotics against KPC-producing Klebsiella pneumoniae

Tara M Rogers  1   2 , Ellen G Kline  2 , Marissa P Griffith  2 , Chelsea E Jones  2 , Abigail M Rubio  2 , Kevin M Squires  2 , Ryan K Shields  2   3   4
Affiliations

Mutations in ompK36 differentially impact in vitro synergy of meropenem/vaborbactam and ceftazidime/avibactam in combination with other antibiotics against KPC-producing Klebsiella pneumoniae

Tara M Rogers et al. JAC Antimicrob Resist. .

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 1 × 108 cfu/mL KPC-Kp.

Results: KPC-Kp harboured ompK36 WT (n = 5), IS5 (n = 5) or GD (n = 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 ompK36 genotype. Ceftazidime/avibactam combinations impacted by porin mutations (compared to WT) were meropenem (-5.18 versus -6.62 mean log-kill, P < 0.001) and fosfomycin (-3.98 versus -6.58, P = 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, P = 0.03) and fosfomycin (-3.12 versus 1.54, P = 0.003).

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.

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Figures

Figure 1.
Figure 1.
Proportion of bactericidal, synergistic and antagonistic interactions for isolates tested against ceftazidime/avibactam (CZA) or meropenem/vaborbactam (MVB) at 1× and 4×MIC as single agents, and at 1×MIC in combination with colistin (CST), gentamicin (GEN), tigecycline (TGC), meropenem (MEM) or fosfomycin (FOS). Bactericidal activity was defined as ≥3 log-kill from time 0 at 24 h; synergy was defined as ≥2 log-kill in combination compared with most active single agent. Antagonism was defined as at least 2 log less killing in combination compared with the most active single agent.
Figure 2.
Figure 2.
Mean ± SE 24 h time-kill curves for ompK36 WT (n = 5), GD (n = 5) and IS5 (n = 5) isolates tested against ceftazidime/avibactam (CZA, left) or meropenem/vaborbactam (MVB, right) at 1×MIC plus colistin (CST), gentamicin (GEN), tigecycline (TGC), fosfomycin (FOS) or meropenem (MEM). Bactericidal activity was defined as ≥3 log-kill from time 0 at 24 h and is represented by the horizontal dotted line. Significant change in log-kill (P < 0.05) compared with WT denoted by *.
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