Distinct Origins and Transmission Pathways of blaKPC Enterobacterales across Three U.S. States

Abstract

Carbapenem-resistant Enterobacterales (CRE) are among the most concerning antibiotic resistance threats due to high rates of multidrug resistance, transmissibility in health care settings, and high mortality rates. We evaluated the potential for regional genomic surveillance to track the spread of bla_KPC-carrying CRE (KPC-CRE) by using isolate collections from health care facilities in three U.S. states. Clinical isolates were collected from Connecticut (2017 to 2018), Minnesota (2012 to 2018), and Tennessee (2016 to 2017) through the U.S. Centers for Disease Control and Prevention's Multi-site Gram-negative Surveillance Initiative (MuGSI) and additional surveillance. KPC-CRE isolates were whole-genome sequenced, yielding 255 isolates from 214 patients across 96 facilities. Case report data on patient comorbidities, facility exposures, and interfacility patient transfer were extracted. We observed that in Connecticut, most KPC-CRE isolates showed evidence of importation from outside the state, with limited local transmission. In Minnesota, cases were mainly from sporadic importation and transmission of bla_KPC-carrying Klebsiella pneumoniae ST258, and clonal expansion of bla_KPC-carrying Enterobacter hormaechei ST171, primarily at a single focal facility and its satellite facilities. In Tennessee, we observed transmission of diverse strains of bla_KPC-carrying Enterobacter and Klesbiella, with evidence that most derived from the local acquisition of bla_KPC plasmids circulating in an interconnected regional health care network. Thus, the underlying processes driving KPC-CRE burden can differ substantially across regions and can be discerned through regional genomic surveillance. This study provides proof of concept that integrating genomic data with information on interfacility patient transfers can provide insights into locations and drivers of regional KPC-CRE burden that can enable targeted interventions.

Keywords: carbapenem-resistant Enterobacterales (CRE); importation; patient transfer; transmission.

FIG 1

Evidence of importation and clonal dissemination differs across states and sequence types (STs). Phylogenetic clusters containing isolates from each state were identified using publicly available genomes to provide genetic and geographic context and extracting subclades that were monophyletic for a single state. MOB-suite and blastn were used to predict bla_KPC plasmids carried by isolates in each region. (A) Bipartite graphs show which plasmids (black circles) are predicted to be harbored by isolates in each phylogenetic cluster (colored/gray circles). Most phylogenetic clusters are associated with a single plasmid, with the exception being 5 clusters in Tennessee, which were presumed to derive from multiple plasmid acquisition events into common strain backgrounds. (B) Phylogenetic clusters are separated by white lines between the colored bars, where the bar height of a given cluster is the cluster size. Importation events were considered those where genetic neighbors of a phylogenetic cluster from other states were already associated with bla_KPC (see Materials and Methods). We observed events with limited onward transmission in all states. We also see a large cluster of E. hormaechei ST171 in Minnesota that arose from a putative importation event, indicating importation followed by sustained dissemination. Additionally, we observed large clusters of E. hormaechei ST114 and K. pneumoniae ST307 in Tennessee with no evidence of importation from another state. ST, sequence type; Eh, E. hormaechei; Kp, K. pneumoniae.

FIG 2

Small pairwise single nucleotide variant (SNV) distances between isolates suggest that local transmission was captured. (A) For each isolate with at least one intrafacility isolate pair and at least one interfacility isolate pair, pairwise SNV distance to the most closely related isolates from the same or different facilities is shown. (B) Pairwise SNV distance of interfacility isolate pairs from patients with a shared facility exposure compared to those not linked by a shared facility exposure. A shared facility exposure is when individuals with isolates from different facilities both spent time in the same facility at some point in the last year. Only STs with >10 isolate pairs with a pairwise SNV distance of ≤15 SNVs are shown. One-sided Wilcox P values compare pairwise SNV distances of isolates with a shared facility exposure (n ranges from 14 to 35) to isolates without a shared facility exposure (n ranges from 67 to 376). SNV, single nucleotide variant; ST, sequence type; Eh, E. hormaechei; Kp, K. pneumoniae.

FIG 3

Transmission of KPC-Eh ST171 in Minnesota. (A) The number of years separating ST171 and ST258 isolate pairs, stratified by the genetic distance between strains, shows that closely related ST171 isolates are observed years apart. (B) Grouping of intrafacility ST171 isolate pairs by facility show that most pairs are from facility F38. (C) Grouping of interfacility isolate pairs by facility again shows facility F38 being overrepresented in interfacility pairs with small genetic distances. (D) Facilities sharing ST171 isolates within 5 SNVs of isolates from facility F38 show many connections with a small number of satellite facilities. (E) Degree centrality of all facilities, with F38 highlighted as among the most connected facilities in Minnesota. Degree centrality of a given facility is defined as the number of facilities connected to that facility by at least one patient transfer in the past year. The in- and out-degree values were summed (patient transfers from and to a facility). The values to and from each facility were summed. SNV, single nucleotide variant; ST, sequence type; Eh, E. hormaechei; Kp, K. pneumoniae.

FIG 4

Distinct facility subnetworks in Tennessee harbor different lineages. (A) The number of patient exposures in the prior year to each facility is shown for each ST and plasmid. Each patient may be represented more than once if they have more than one facility exposure. A cluster of facilities identified using the complete linkage clustering method (left of the solid black line) are common in patients with ST114, ST307, and other isolates and often contain plasmid cluster AA739 or AB978. (B) Patient transfer network of facilities with at least one whole-genome-sequenced isolate plotted using the Kamada-Kawai algorithm. Facilities where ST114 or ST307 are most common are clustered in the network. (C) The numbers of patient transfers for facility pairs where 0, 1, or 2 of the facilities are ones where ST114 or ST307 are most common. Facility pairs where ST114 or ST307 are most common in both have more patient sharing than facility pairs where ST114 or ST307 is most common in 0 or 1 of the facilities. ST, sequence type; Eh, E. hormaechei; Kp, K. pneumoniae.