Ceftazidime-avibactam: are we safe from class A carbapenemase producers' infections?

Recently, new combinations of β-lactams and β-lactamase inhibitors became available, including ceftazidime-avibactam, and increased the ability to treat infections caused by carbapenem-resistant Enterobacterales (CRE). Despite the reduced time of clinical use, isolates expressing resistance to ceftazidime-avibactam have been reported, even during treatment or in patients with no previous contact with this drug. Here, we detailed review data on global ceftazidime-avibactam susceptibility, the mechanisms involved in resistance, and the molecular epidemiology of resistant isolates. Ceftazidime-avibactam susceptibility remains high (≥ 98.4%) among Enterobacterales worldwide, being lower among extended-spectrum β-lactamase (ESBL) producers and CRE. Alterations in class A β-lactamases are the major mechanism involved in ceftazidime-avibactam resistance, and mutations are mainly, but not exclusively, located in the Ω loop of these enzymes. Modifications in Klebsiella pneumoniae carbapenemase (KPC) 3 and KPC-2 have been observed by many authors, generating variants with different mutations, insertions, and/or deletions. Among these, the most commonly described is Asp179Tyr, both in KPC-3 (KPC-31 variant) and in KPC-2 (KPC-33 variant). Changes in membrane permeability and overexpression of efflux systems may also be associated with ceftazidime-avibactam resistance. Although several clones have been reported, ST258 with Asp179Tyr deserves special attention. Surveillance studies and rationale use are essential to retaining the activity of this and other antimicrobials against class A CRE.