Identification of A Novel CG307 Sub-clade in Third Generation Cephalosporin ResistantKlebsiella pneumoniaeCausing Invasive Infections in the United States

Abstract

Despite the notable clinical impact, recent molecular epidemiology regarding third-generation cephalosporin-resistantKlebsiella pneumoniae(3GC-RKp) in the United States remains limited. We performed whole genome sequencing of 3GC-RKpbacteremia isolates collected from March 2016 to May 2022 at a tertiary care cancer center in Houston, TX using Illumina and Oxford Nanopore Technologies platforms. A comprehensive comparative genomic analysis was performed to dissect population structure, transmission dynamics, and pan-genomic signatures of our 3GC-RKppopulation. Of the 194 3GC-RKpbacteremias that occurred during our study timeframe, we were able to analyze 153 (79%) bacteremia isolates, 126 initial and 27 recurrent isolates respectively. While isolates belonging to the widely prevalent clonal group (CG) 258 were rarely observed, the predominant clonal group, CG307, accounted for 37 (29%) index isolates and displayed a significant correlation (Pearson correlation testP-value = 0.03) with the annual frequency of 3GC-RKpbacteremia. Within our CG307 cohort, 89% (33/37) of our isolates belong to the global rather than previously described Texas-specific clade. Strikingly, we identified a new CG307 sub-clade (i.e.,cluster 1 isolates) comprised of 18 isolates characterized by the chromosomally-encodedblaSHV-205and unique accessory genome content. This CG307 sub-clade was detected in various United States regions, with genome sequences from 24 additional strains becoming recently available in the NCBI SRA database. Collectively, this study underscores the emergence and dissemination of a distinct CG307 sub-clade that is a prevalent cause of 3GC-RKpbacteremia among cancer patients seen in Houston, TX and has recently been isolated throughout the United States.DATA SUMMARYWGS data sequenced during this study period was submitted to NCBI and can be accessed within BioProject PRJNA648389. WGS data from previous study of carbapenem non-susceptibleEnterobacteralescan be accessed from BioProject PRJNA836696. Assembly information and BioAccession numbers are provided in Table S1.IMPACT STATEMENTInfections due to 3rdgeneration cephalosporin resistantKlebsiella pneumoniae(3GC-RKp) are considered among the most urgent public health threats. However, molecular epidemiology studies on 3GC-RKpin the United States are limited. Our analysis indicates a preponderance of genetically diverse 3GC-RKpisolates harboring the key antimicrobial resistance determinantblaCTX-M-15at our institution. Importantly, however, we detected evidence of long duration transmission of highly genetically related CG307 and CG29 specific clusters at our institution. Interestingly, we rarely detected the pandemic CG258 lineage in our cohort and did not detect more than two genetically related CG258 isolates from this lineage. We found that 90% of our isolates from the most prevalent clonal group, CG307, belonged to a novel, nested-population of a “global” CG307 clade in contrast to the more commonly detected “Texas-specific” clade that has circulated in our region. We searched the NCBI SRA database using genomic markers of the novel CG307 clade and found evidence of this clade causing recent invasive infections in other locations across the United States. Our study highlights the shifting population dynamics ofK. pneumoniaecausing invasive infections and the necessity to continue AMR surveillance in order to identify emerging high-risk populations.