Impact of ompk36 genotype and KPC subtype on the in vitro activity of ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam against KPC-producing K. pneumoniae clinical isolates

Tara M Rogers; Ellen G Kline; Marissa P Griffith; Chelsea E Jones; Abigail M Rubio; Kevin M Squires; Ryan K Shields

doi:10.1093/jacamr/dlad022

Impact of ompk36 genotype and KPC subtype on the in vitro activity of ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam against KPC-producing K. pneumoniae clinical isolates

JAC Antimicrob Resist. 2023 Mar 23;5(2):dlad022. doi: 10.1093/jacamr/dlad022. eCollection 2023 Apr.

Authors

Tara M Rogers¹, Ellen G Kline², Marissa P Griffith², Chelsea E Jones², Abigail M Rubio², Kevin M Squires², Ryan K Shields^{2

3

4}

Affiliations

¹ School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
² Department of Medicine, University of Pittsburgh, 3601 Fifth Avenue, Falk Medical Building, Suite 5B, Pittsburgh, PA 15213, USA.
³ Center for Innovative Antimicrobial Therapy, University of Pittsburgh, Pittsburgh, PA, USA.
⁴ Antibiotic Management Program, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Abstract

Objectives: The availability of new β-lactam/β-lactamase inhibitors ceftazidime/avibactam, meropenem/vaborbactam and imipenem/relebactam have redefined contemporary treatment of Klebsiella pneumoniae carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) infections. We aimed to characterize and contrast the in vitro activity of these agents against genetically diverse KPC-Kp clinical isolates.

Methods: We analysed genomes of 104 non-consecutive KPC-Kp isolates and compared the in vitro antibiotic activity by KPC subtype and ompK36 genotype. MICs were determined in triplicate by CLSI methods. Twenty representative isolates were selected for time-kill analyses against physiological steady-state and trough concentrations, as well as 4× MIC for each agent.

Results: Fifty-eight percent and 42% of isolates harboured KPC-2 and KPC-3, respectively. OmpK36 mutations were more common among KPC-2- compared with KPC-3-producing Kp (P < 0.0001); mutations were classified as IS5 insertion, glycine-aspartic acid insertion at position 134 (GD duplication) and other mutations. Compared to isolates with WT ompK36, ceftazidime/avibactam, imipenem/relebactam and meropenem/vaborbactam MICs were elevated for isolates with IS5 by 2-, 4- and 16-fold, respectively (P < 0.05 for each). Against isolates with GD duplication, imipenem/relebactam and meropenem/vaborbactam MICs were increased, but ceftazidime/avibactam MICs were not. In time-kill studies, ceftazidime/avibactam-mediated killing correlated with ceftazidime/avibactam MICs, and did not vary across ompK36 genotypes. Imipenem/relebactam was not bactericidal against any isolate at trough concentrations. At steady-state imipenem/relebactam concentrations, regrowth occurred more commonly for isolates with IS5 mutations. Log-kills were lower in the presence of meropenem/vaborbactam for isolates with GD duplication compared with IS5 mutations.

Conclusions: Our investigation identified key genotypes that attenuate, to varying degrees, the in vitro activity for each of the new β-lactam/β-lactamase inhibitors. Additional studies are needed to translate the importance of these observations into clinical practice.