Pre-existing antibiotic tolerance facilitates plasmid-mediated carbapenem resistance evolution in clinical Klebsiella pneumoniae

A long-term study examining more than 800 clinical Klebsiella pneumoniae isolates from 1997 to 2020 has revealed a key mechanism behind the evolution of carbapenem resistance in these bacteria. Among the isolates, 17.6% displayed hidden ertapenem tolerance, a phenomenon where bacteria survive exposure to 30 times their specific ertapenem MIC.

This tolerance was mostly undetected and did not delay bacterial growth, yet it was more common in ertapenem-resistant strains. The presence of tolerance was noted even before the introduction of local ertapenem use and was more prevalent in strains with carbapenem resistance. Crucially, tolerant bacteria with pre-existing resistance plasmids were better able to acquire resistance plasmids, survive antibiotic exposure, and had an accelerated evolution of resistance to ceftazidime-avibactam.

Genetic analysis identified the uhpABC regulatory operon as a potential candidate linked to tolerance, and its coordinated expression enhanced ertapenem survival. In summary, the findings suggest that antibiotic tolerance, a hidden phenotype, can play a significant role in the evolution of carbapenem resistance in K. pneumoniae, highlighting the importance of understanding pre-existing bacterial characteristics in the context of antibiotic use and resistance evolution.