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<p>To investigate the antibacterial activity of ceftazidime/avibactam (CZA) combined with auranofin (AUR) against Carbapenem-resistant <i>Klebsiella pneumoniae</i> (CRKP) in vitro and in vivo. The minimum inhibitory concentrations (MICs) of CZA and AUR in 40 non-redundant CRKP isolates were determined by broth microdilution method. Drug resistance genes were detected by polymerase chain reaction (PCR). Checkerboard assays, time-kill assays and <i>Galleria mellonella</i> infection models were employed to assess the effect of CZA plus AUR in vitro and in vivo. Additionally, serial subculture experiments were used to evaluate resistance progression. 75.0% (30/40) of clinical isolates exhibited resistance to CZA. The addition of AUR resulted in a remarkable 16-fold reduction in MIC<sub>50</sub> (from 128 to 8&#xa0;mg/L) and MIC<sub>90</sub> &gt; 64-fold (from &gt; 2048 to 32&#xa0;mg/L). Fractional inhibitory concentration index (FICI) analysis demonstrated synergistic activity in 67.5% (27/40) of isolates, including 80.0% (24/30) CZA-resistant strains.At sub-inhibitory concentrations, CZA monotherapy increased the MIC 256-fold, in contrast to CZA combined with AUR treatment which significantly reduced the level of resistance. Monotherapy with either agent showed limited bactericidal effects in vivo, whereas combination therapy achieved complete bacterial eradication within 72–96&#xa0;h. AUR synergizes with CZA on killing a broad spectrum of carbapenem or CZA resistant <i>Klebsiella pneumoniae</i> both in vitro and in vivo, and slows down the development of CZA resistance. The combination of CZA and AUR might be a potential therapeutic strategy for combating superbugs CZA resistant CRKP.</p>

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Synergistic Antibacterial Effects of Ceftazidime/Avibactam and Auranofin Combination against Carbapenem-Resistant Klebsiella pneumoniae: In Vitro and in Vivo Evaluation

  • 期刊论文

  • 发表日期：

    2025年12月10日

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  • Lingfei Wang,
  • Yunge Wang,
  • Huijie Yue,
  • Weiping Wang,
  • Yunlong Liu,
  • Guohua Zhou,
  • Ying Wang,
  • Xuejiao Liu,
  • Haiping Wu

摘要

To investigate the antibacterial activity of ceftazidime/avibactam (CZA) combined with auranofin (AUR) against Carbapenem-resistant Klebsiella pneumoniae (CRKP) in vitro and in vivo. The minimum inhibitory concentrations (MICs) of CZA and AUR in 40 non-redundant CRKP isolates were determined by broth microdilution method. Drug resistance genes were detected by polymerase chain reaction (PCR). Checkerboard assays, time-kill assays and Galleria mellonella infection models were employed to assess the effect of CZA plus AUR in vitro and in vivo. Additionally, serial subculture experiments were used to evaluate resistance progression. 75.0% (30/40) of clinical isolates exhibited resistance to CZA. The addition of AUR resulted in a remarkable 16-fold reduction in MIC50 (from 128 to 8 mg/L) and MIC90 > 64-fold (from > 2048 to 32 mg/L). Fractional inhibitory concentration index (FICI) analysis demonstrated synergistic activity in 67.5% (27/40) of isolates, including 80.0% (24/30) CZA-resistant strains.At sub-inhibitory concentrations, CZA monotherapy increased the MIC 256-fold, in contrast to CZA combined with AUR treatment which significantly reduced the level of resistance. Monotherapy with either agent showed limited bactericidal effects in vivo, whereas combination therapy achieved complete bacterial eradication within 72–96 h. AUR synergizes with CZA on killing a broad spectrum of carbapenem or CZA resistant Klebsiella pneumoniae both in vitro and in vivo, and slows down the development of CZA resistance. The combination of CZA and AUR might be a potential therapeutic strategy for combating superbugs CZA resistant CRKP.