Whole-Genome Sequencing To Identify Drivers of Carbapenem-Resistant Klebsiella pneumoniae Transmission within and between Regional Long-Term Acute-Care Hospitals

Abstract

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an antibiotic resistance threat of the highest priority. Given the limited treatment options for this multidrug-resistant organism (MDRO), there is an urgent need for targeted strategies to prevent transmission. Here, we applied whole-genome sequencing to a comprehensive collection of clinical isolates to reconstruct regional transmission pathways and analyzed this transmission network in the context of statewide patient transfer data and patient-level clinical data to identify drivers of regional transmission. We found that high regional CRKP burdens were due to a small number of regional introductions, with subsequent regional proliferation occurring via patient transfers among health care facilities. While CRKP was predicted to have been imported into each facility multiple times, there was substantial variation in the ratio of intrafacility transmission events per importation, indicating that amplification occurs unevenly across regional facilities. While myriad factors likely influence intrafacility transmission rates, an understudied one is the potential for clinical characteristics of colonized and infected patients to influence their propensity for transmission. Supporting the contribution of high-risk patients to elevated transmission rates, we observed that patients colonized and infected with CRKP in high-transmission facilities had higher rates of carbapenem use, malnutrition, and dialysis and were older. This report highlights the potential for regional infection prevention efforts that are grounded in genomic epidemiology to identify the patients and facilities that make the greatest contribution to regional MDRO prevalence, thereby facilitating the design of precision interventions of maximal impact.

Keywords: carbapenem resistance; epidemiology; genomic epidemiology; long-term acute-care hospitals; regional transmission.

FIG 1

Phylogeographic reconstruction of ST258 Klebsiella pneumoniae. A phylogeographic analysis was performed on ST258 isolates from the current study, along with previously sequenced ST258 genomes that had documented locations and dates of isolation (see Table S3). The x axis corresponds to predicted dates of ancestral strains and the colors of internal branches correspond to the predicted locations of ancestral strains. Abbreviations: EUR, Europe; LA, Los Angeles; SA, South America; US-MA, Massachusetts; US-MW, Midwest; US-NC, North Carolina; US-NE, Northeast; US-NY, New York; US-S, South; US-W, West.

FIG 2

Regional transmission map for carbapenem-resistant K. pneumoniae (CRKP) among 11 Los Angeles area LTACHs. (A) Each gray circle represents a single LTACH, with the size of the circle corresponding to the CRKP colonization/infection rate in that facility. The relative positions of the different circles on the graph are based on the longitude and latitude of each facility. Arrows between different LTACHs indicate that there was at least one predicted transmission between the pair of facilities, with the thicker lines corresponding to larger numbers of predicted transmissions. To highlight interfacility transmissions between facilities with more linkages than would be expected by chance, only links between facilities whose isolates cluster on the whole-genome phylogeny more than in randomly permuted phylogenies are shown (P < 0.1; see Materials and Methods). (B) Paths of maximum patient flow between the facilities in each pair of LTACHs were extracted from the statewide patient transfer network and categorized into path motifs based on the types of facilities on the paths (LT, long-term acute-care hospital; ST, short-stay hospital; SNF, skilled-nursing facility). The fraction of LTACH pairs (y axis) whose maximum flow paths were assigned to each path motif (x axis) was determined for LTACH pairs with and without genomic transmission linkages. (C) Levels of patient flow between LTACHs were compared for pairs of LTACHs with and without genomic transmission linkages. Pairs of LTACHs were binned into groups based upon the number of intervening facilities on the maximal patient flow path between those LTACHs (e.g., 0, direct transfer between LTACHs; 1, one intervening facility; etc.).

FIG 3

Facility colonization/infection rate associated with ratio of intrafacility transmissions per importation. Each diamond represents 1 of the 11 Los Angeles area LTACHs, with the x axis showing the colonization/infection rate within the LTACH and the y axis showing the number of intrafacility transmissions per importation, as inferred from the genomic transmission network (see Fig. S3). The CRKP colonization/infection rate for a facility was calculated as the total number of colonization/infection episodes divided by the number of beds.