Loss and resurgence of carbapenem resistance

A clinical Escherichia coli isolate (CDC AR Isolate Bank 0118) was found to be resistant to all beta-lactam antibiotics, including DOR, IPM, MER, and ERT, aztreonam-avibactam excluded. Isolate 0118 was subjected to continual antibiotic-free broth culture for 294 days. Susceptibility to doripenem gradually returned. Aminoglycoside and tetracycline resistance increased over time, while ciprofloxacin resistance remained stable. Whole genome sequencing revealed structural mutations and large genomic deletions associated with these phenotypic shifts, including full deletions of envelope- and stress-associated genes (nlpD, rpoS, mutS) and truncations in key outer membrane and peptidoglycan biosynthesis genes (murein transglycosylase, UDP-galactose LPS alpha 1,2-galactosyltransferase). The findings presented here underscore the complexity and adaptability of clinical CRE isolates in the face of antibiotic pressure at even sub-inhibitory levels. The reemergence of high-level carbapenem resistance in the absence of known carbapenemase genes highlights the potential for non-canonical, structural, and physiologically based resistance mechanisms that can easily be missed by standard molecular diagnostics.