The role of bla C̳T̳X̳-̳M̳ and porins in mediating ertapenem resistance among carbapenem resistant enterobacterales



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This study investigates the emergence of an ertapenem-resistant, meropenem-susceptible (ErMs) phenotype among non-carbapenemase producing (NCP) and carbapenemase producing (CP) Escherichia coli and Klebsiella pneumoniae. ErMs strains are of particular interest as they seem to develop from persistent strains among vulnerable patients after Β-lactam or hospital exposure. Whole genome sequencing was conducted on 76 carbapenem-resistant isolates across 5 hospitals in San Antonio, U.S. Among these, NCP isolates accounted for the majority of carbapenem resistant Enterobacterales (CRE) (41/76). bla [subscript CTX-M] was found to be most prevalent among NCP isolates (NCP v. CP; p = 0.02). LC-MS/MS analyses revealed that bla [subscript CTX-M] mediated carbapenem hydrolysis, indicating the need to reappraise the term “non-carbapenemase (NCP)” for quantitatively uncharacterized CRE strains harboring bla [subscript CTX-M]. Antimicrobial susceptibility results showed that 56% of all NCPE isolates had an ErMs phenotype (NCPE v. CPE; p < 0.001), with E. coli driving the phenotype (E. coli v. K. pneumoniae; p < 0.001). ErMs strains carrying bla [subscript CTX-M] had approximately 4-fold more copies of bla [subscript CTX-M] than ceftriaxone-resistant but ertapenem-susceptible isolates (3.7 v. 0.9, p < 0.001). Immunoblot analysis demonstrated the absence of OmpC expression in all NCP-ErMs E. coli, with 92% of strains lacking full contig coverage of ompC, features not shared among CP E. coli. Overall, this work provides evidence of a collaborative effort between bla [subscript CTX-M] and OmpC in NCP strains that confer resistance to ertapenem but not meropenem resistance. To thwart potential mismanagement of CRE infected patients, future efforts should focus on understanding the mechanism(s) underlying OmpC loss, developing rapid methods to detecting bla [subscript CTX-M] copy number variants, and targeted antimicrobials for NCPE and ErMs strains.


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