Global susceptibility profiles and potential resistance mechanisms of ceftazidime–avibactam-resistant, non-carbapenemase-producing carbapenem-resistant Enterobacterales: 2020–23 data from the Antimicrobial Testing Leadership and Surveillance

Abstract Objectives A total of 2361 ceftazidime–avibactam-resistant non-carbapenemase-producing (CP) carbapenem-resistant Enterobacterales (CRE) isolates were identified, accounting for 45.8% of global non-CP-CRE (n = 5156) and 3.0% of all Enterobacterales isolates (n = 78 371) during 2020–23. The high prevalence of non-CP-CRE resistant to ceftazidime–avibactam prompted investigations into alternative antibiotics for the effective management of ceftazidime–avibactam-resistant non-CP-CRE infections. Methods Using the susceptibility breakpoints for Enterobacterales recommended by CLSI 2025 (for ceftazidime–avibactam, amikacin and meropenem–vaborbactam), EUCAST 2025 (for aztreonam–avibactam, colistin) and the US FDA (for tigecycline), susceptibility data of key antibiotics against global ceftazidime–avibactam-resistant non-CP-CRE isolates were extracted from the 2020–23 Antimicrobial Testing Leadership and Surveillance database. Additionally, data on genes encoding ESBL and plasmid-mediated AmpC enzymes were also analysed. Results In vitro susceptibility rates of global ceftazidime–avibactam-resistant non-CP-CRE isolates to aztreonam–avibactam, colistin and tigecycline all exceeded 86%. In contrast, non-susceptibility rates to amikacin and meropenem–vaborbactam were 78.7% and 94.8%, respectively. These high non-susceptibility rates for amikacin and meropenem–vaborbactam persisted regardless of region, infection source or species [Klebsiella pneumoniae (n = 1576), Escherichia coli (n = 388) and potentially chromosomal AmpC hyperproducers (n = 337)]. The prevalence of blaCTX-M-15 (the predominant ESBL) was closely correlated with amikacin non-susceptibilities across all three species groups (r = 0.901; P = 0.286). Conclusion Based on the data from this study, poor in vitro susceptibility rates for amikacin and meropenem–vaborbactam against contemporary ceftazidime–avibactam-resistant non-CP-CRE were observed. In contrast, aztreonam–avibactam, colistin and tigecycline appear to be reasonable options for the management of infections caused by ceftazidime–avibactam-resistant non-CP-CRE.