Ceftazidime-avibactam resistance in Klebsiella pneumoniae: A growing public health concern across diverse sublineages, 2019-2024

Abstract

Objectives: Strains resistant to last-line β-lactam antibiotics pose a global public health threat, requiring close monitoring and action. This study investigated ceftazidime-avibactam (CAZ-AVI) resistance rates among Klebsiella pneumoniae infection isolates from northern Portugal in a 6-year period.

Methods: A total of 539 carbapenem-resistant or KPC-positive K. pneumoniae isolates identified between May 2019 and February 2024 were screened for CAZ-AVI resistance by gradient diffusion. Species identification and antimicrobial susceptibility testing were performed using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and VITEK 2 automated systems, respectively. CAZ-AVI resistance and extended susceptibility profiles were confirmed by disk diffusion. Isolates exhibiting resistance or reduced susceptibility to CAZ-AVI were further characterized by Fourier-transform infrared spectroscopy and whole genome sequencing or polymerase chain reaction and sequencing.

Results: We observed an average CAZ-AVI resistance rate of 1.7%, which increased post-COVID19 (1.1% in 2021 to 2.7% in 2022) alongside rising CAZ-AVI usage. Notably, CAZ-AVI-resistant isolates also exhibited resistance to last-line β-lactams not yet introduced in routine clinical practice (89% cefiderocol, 33% imipenem-relebactam and 22% meropenem-vaborbactam). Resistance to CAZ-AVI was associated with production of diverse KPC-3 variants (KPC-31, KPC-46, KPC-66), IMP-22 or DHA-1 often in combination with porin deficiencies. A multiclonal population was identified, including high-risk sublineages commonly linked to KPC-3 production (ST147-KL64 and ST323-KL21). All patients had prior exposure to different β-lactams, including CAZ-AVI in five cases.

Conclusions: Our findings highlight a concerning scenario for managing carbapenem-resistant K. pneumoniae and underscore the need for routine laboratory testing of last-line antibiotics and the implementation of effective antimicrobial stewardship guidelines.

Keywords: Carbapenemase-producing Klebsiella pneumoniae; Ceftazidime-avibactam; High-risk sublineages; Infection control; KPC-3 variants; Multidrug resistance.