In Vitro and In Vivo Evaluations of β-Lactam/β-Lactamase Mono- and Combined Therapies against Carbapenem-Nonsusceptible Enterobacteriaceae in Taiwan

• Main Authors: Tsung-Ying Yang, Ya-Ju Hsieh, Li-Ting Kao, Guan-Hong Liu, Shao-Hsuan Lian, Liang-Chun Wang, I-Ling Lin, Yu-Tzu Lin, Sheng-Fan Wang, Sung-Pin Tseng, Po-Liang Lu
• Format: Article
• Language: English
• Published: MDPI AG 2020-12-01
• Series: Microorganisms
• Subjects: CR Enterobacteriaceae; combination therapy; molecular epidemiology of antimicrobial resistance
• Online Access: https://www.mdpi.com/2076-2607/8/12/1981

Increasing carbapenem resistance rates worldwide underscored the urgent need of novel antimicrobials. Ceftazidime–avibactam and aztreonam–avibactam combinations are developed to combat carbapenem resistance, but biological and geographic variations must be considered for antibiotic susceptibility patterns varied. Thus, we sought to assess the susceptibilities of ceftazidime–avibactam and aztreonam–avibactam against 660 carbapenem-nonsusceptible Enterobacteriaceae<i> </i>isolates (472 <i>Klebsiella</i><i> </i><i>pneumoniae</i> and 188 <i>Escherichia coli</i>) collected during an earlier Taiwan surveillance study. Agar dilution method was used to determine ceftazidime–avibactam and aztreonam–avibactam susceptibility. Metallo-carbapenemase’s contribution to resistance were investigated with EDTA addition. The in vivo efficacies were evaluated using a <i>Caenorhabditis</i><i> </i><i>elegans</i> model. High susceptibility rates were observed for ceftazidime–avibactam and aztreonam–avibactam against the 472 carbapenem-nonsusceptible<i> K. </i><i>pneumoniae</i> (CnsKP) (85.2% and 95.3%, respectively) and 188 carbapenem-nonsusceptible <i>E. coli</i> (CnsEC) isolates (91.5% and 94.1%, respectively). For non-metallo-carbapenemase producers, the susceptibility rates for ceftazidime–avibactam were 93.6% for CnsKP and 97.7% for CnsEC, whereas only 7.1% CnsKP and 11.1% CnsEC in metallo-carbapenemase producers were susceptible to ceftazidime–avibactam. Of all isolates, 95.3% CnsKP and 94.1% CnsEC were susceptible to aztreonam–avibactam. In <i>C. </i><i>elegans</i> model, ceftazidime–avibactam and aztreonam–avibactam revealed effective against a <i>bla</i>_KPC-producing <i>K. </i><i>pneumoniae</i> isolate in vivo. Our results propose a positive therapeutic approach for both combinations against carbapenem-nonsusceptible Enterobacteriaceae in Taiwan.