In vivo evolution of resistant subpopulations of KPC-producing Klebsiella pneumoniae during ceftazidime/avibactam treatment

Abstract

Our analysis indicates that mixed subpopulations of ceftazidime/avibactam-resistant KPC-Kp emerge after ceftazidime/avibactam treatment. The evolution of different subpopulations that are highly resistant to ceftazidime/avibactam likely contributes to treatment failure, thereby highlighting the need for combination treatment strategies to limit selection of ceftazidime/avibactam-resistant KPC-Kp subpopulations.

Detection in two hospitals of transferable ceftazidime-avibactam resistance in Klebsiella pneumoniae due to a novel VEB β-lactamase variant with a Lys234Arg substitution, Greece, 2019

“…Ceftazidime-avibactam (CAZ-AVI) is a combination medication, which is active against various multidrugresistant Gram-negative bacteria including Klebsiella pneumoniae carbapenemase (KPC)-K. pneumoniae (Kp) [1]. CAZ-AVI resistance among KPC-Kp strains is still rare and commonly associated with selection of KPC-2/3-derived mutant β-lactamases, resisting inhibition by avibactam [2][3][4][5]. In 2019, in view of the rapid risk assessment raising awareness on the emergence of resistance to ceftazidime-avibactam in carbapenemresistant Enterobacteriaceae in Europe issued by the European Centre for Disease Control and Prevention (ECDC) [6], KPC-Kp isolates referred to Hellenic Pasteur Institute from Greek hospitals were further investigated.…”

Meropenem-Vaborbactam as Salvage Therapy for Ceftazidime-Avibactam-Resistant Klebsiella pneumoniae Bacteremia and Abscess in a Liver Transplant Recipient

“…The U.S. Food and Drug Administration (FDA) approvals of ceftazidimeavibactam and meropenem-vaborbactam in 2015 and 2017, respectively, alleviated many of the concerns with traditional treatment options for KPC-mediated CRE infections. However, treatment-emergent ceftazidime-avibactam resistance has recently been described in multiple centers (9)(10)(11)(12), highlighting the need for additional treatment options. We report the use of meropenem-vaborbactam as salvage therapy for ceftazidime-avibactam-resistant KPC-producing K. pneumoniae infection in a liver transplant recipient.…”

Beware of broad-spectrum generalizations: ceftazidime-avibactam compared to meropenem for the treatment of gram-negative pneumonia

“…Because CA use will largely be used in infections from CRE as opposed to MERO-susceptible isolates, this paper provides important and relevant data when considering its use in a real life manner. Lastly, de novo resistance (11) and evolution of resistance during CA treatment (including for pneumonia) have also been reported from other centers (3,12). This raises the possibility of a relatively low barrier to resistance for CA and has important implications for antibiotic stewardship programs.…”