Fitness barriers to spread of colistin resistance overcome by first establishing niche in patients with enhanced colistin exposure

Abstract

To combat antibiotic resistance, it is critical to improve our understanding of how new resistant strains emerge and spread. An antibiotic resistance threat of critical priority is the epidemic ST258 strain of carbapenem-resistant Klebsiella pneumoniae (CRKP). Here, we studied the spread of resistance among ST258 to an antibiotic of last resort, colistin, by tracking its evolution across 21 U.S. long-term acute care hospitals over the course of a year. Phylogenetic analysis suggested that a significant cost was associated with colistin resistance in most cases, as resistance emergence was common but resistance variants were rarely transmitted. The high cost of resistance was further supported by the observation that several of the resistance variants that were transmitted had acquired secondary variants that reverted the strain to colistin susceptibility. The exceptions to the general pattern of instability associated with colistin resistance were two large clusters of resistant strains in one ST258 clade II sublineage (clade IIB) present across 11 of the 12 sampled Southern California hospitals. Quantification of transmission fitness in the healthcare environment using time-scaled haplotypic density indicated that while resistant isolates from other clades were less fit than their susceptible counterparts, clade IIB resistant isolates were more fit. Overlaying patient clinical data suggested that the increased fitness of colistin-resistant clade IIB isolates is in part driven by a lineage defining variant that increased clade IIB’s association with patient subpopulations who were more likely to be treated with colistin. These results show that a favorable genetic background and sustained selective pressure led to the emergence and spread of a colistin-resistant ST258 sublineage across a regional healthcare network. More broadly, these findings highlight the utility of integrating pathogen genomic and corresponding clinical data from regional healthcare networks to detect and understand the origin and dissemination of antibiotic resistance threats.

MgrB-Dependent Colistin Resistance in Klebsiella pneumoniae Is Associated with an Increase in Host-to-Host Transmission

“…Furthermore, a recent molecular epidemiological study by Lapp et al . suggests that certain colistin-resistant K. pneumoniae isolates of the ST258 lineage have enhanced transmissibility attributed to point mutations in either mgrB or phoQ that abrogates their function, as well as the disruption of the putative O-antigen glycosyltransferase kfoC ( 56 ), suggestive of a role of the O-antigen and acquisition of colistin resistance in transmissibility. K. pneumoniae isolates are genetically diverse ( 57 ), and both KPPR1S and ST1322 are genetically distinct from ST258 and do not contain kfoC .…”