Klebsiella pneumoniae Carbapenemase Variants Resistant to Ceftazidime-Avibactam: an Evolutionary Overview

• Published in: Antimicrobial agents and chemotherapy Vol. 66; no. 9; p. e0044722
• Main Authors: Hobson, Claire Amaris, Pierrat, Gautier, Tenaillon, Olivier, Bonacorsi, Stéphane, Bercot, Béatrice, Jaouen, Ella, Jacquier, Hervé, Birgy, André
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 20.09.2022
• Subjects: Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antimicrobial Chemotherapy; Azabicyclo Compounds - pharmacology; Azabicyclo Compounds - therapeutic use; Bacterial Proteins - genetics; beta-Lactamase Inhibitors - pharmacology; beta-Lactamases - genetics; Carbapenems - pharmacology; Ceftazidime - pharmacology; Ceftazidime - therapeutic use; Drug Combinations; Drug Resistance, Multiple, Bacterial; Humans; Klebsiella Infections - drug therapy; Klebsiella Infections - microbiology; Klebsiella pneumoniae - drug effects; Life Sciences; Microbial Sensitivity Tests; Minireview; KPC-3; insertions; KPC-2; deletions; trade-off; ceftazidime-avibactam; omega loop; KPC beta-lactamase; epidemiology; ceftazidime-avibactam resistance; spectrum; stability; KPC
• ISSN: 0066-4804; 1098-6596; 1098-6596
• DOI: 10.1128/aac.00447-22

First variants of the Klebsiella pneumoniae carbapenemase (KPC), KPC-2 and KPC-3, have encountered a worldwide success, particularly in K. pneumoniae isolates. These beta-lactamases conferred resistance to most beta-lactams including carbapenems but remained susceptible to new beta-lactam/beta-lactamase inhibitors, such as ceftazidime-avibactam. First variants of the Klebsiella pneumoniae carbapenemase (KPC), KPC-2 and KPC-3, have encountered a worldwide success, particularly in K. pneumoniae isolates. These beta-lactamases conferred resistance to most beta-lactams including carbapenems but remained susceptible to new beta-lactam/beta-lactamase inhibitors, such as ceftazidime-avibactam. After the marketing of ceftazidime-avibactam, numerous variants of KPC resistant to this association have been described among isolates recovered from clinical samples or derived from experimental studies. In KPC variants resistant to ceftazidime-avibactam, point mutations, insertions and/or deletions have been described in various hot spots. Deciphering the impact of these mutations is crucial, not only from a therapeutic point of view, but also to follow the evolution in time and space of KPC variants resistant to ceftazidime-avibactam. In this review, we describe the mutational landscape of the KPC beta-lactamase toward ceftazidime-avibactam resistance based on a multidisciplinary approach including epidemiology, microbiology, enzymology, and thermodynamics. We show that resistance is associated with three hot spots, with a high representation of insertions and deletions compared with other class A beta-lactamases. Moreover, extension of resistance to ceftazidime-avibactam is associated with a trade-off in the resistance to other beta-lactams and a decrease in enzyme stability. Nevertheless, the high natural stability of KPC could underlay the propensity of this enzyme to acquire in vivo mutations conferring resistance to ceftazidime-avibactam (CAZavi), particularly via insertions and deletions.