Clinical and genomic epidemiology ofmcr-9-carrying carbapenem-resistant Enterobacterales isolates in Metropolitan Atlanta, 2012-2017

Colistin is a last-resort antibiotic for multidrug-resistant gram-negative infections. Recently, the ninth allele of the mobile colistin resistance ( mcr ) gene family, designated mcr-9 , was reported. However, its clinical and public health significance remains unclear. We queried genomes of carbapenem-resistant Enterobacterales (CRE) for mcr-9 from a convenience sample of clinical isolates collected between 2012-2017 through the Georgia Emerging Infections Program, a population- and laboratory-based surveillance program. Isolates underwent phenotypic characterization and whole genome sequencing. Phenotypic characteristics, genomic features, and clinical outcomes of mcr-9 positive and negative CRE cases were then compared. Among 235 sequenced CRE genomes, thirteen (6%) were found to harbor mcr-9 , all of which were Enterobacter cloacae complex. The median MIC, rates of heteroresistance and inducible resistance to colistin were similar between mcr-9 positive and negative isolates. However, rates of resistance were higher among mcr-9 positive isolates across most antibiotic classes. All cases had significant healthcare exposures. The 90-day mortality was similarly high in both mcr-9 positive (31%) and negative (7%) CRE cases. Nucleotide identity and phylogenetic analysis did not reveal geo-temporal clustering. mcr-9 positive isolates had a significantly higher number of median [range] AMR genes (16 [4-22] vs. 6 [2-15]; p <0.001) compared to mcr-9 negative isolates. Pan genome tests confirmed a significant association of mcr-9 detection with mobile genetic element and heavy metal resistance genes. Overall, the presence of mcr-9 was not associated with significant changes in colistin resistance or clinical outcomes but continued genomic surveillance to monitor for emergence of AMR genes is warranted.