Application of Combined Genomic and Transfer Analyses to Identify Factors Mediating Regional Spread of Antibiotic-resistant Bacterial Lineages

Abstract

Background: Patients entering nursing facilities (NFs) are frequently colonized with antibiotic-resistant organisms (AROs). To understand the determinants of ARO colonization on NF admission, we applied whole-genome sequencing to track the spread of 4 ARO species across regional NFs and evaluated patient-level characteristics and transfer acute care hospitals (ACHs) as risk factors for colonization.

Methods: Patients from 6 NFs (n = 584) were surveyed for methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis/faecium (VREfc/VREfm), and ciprofloxacin-resistant Escherichia coli (CipREc) colonization. Genomic analysis was performed to quantify ARO spread between NFs and compared to patient-transfer networks. The association between admission colonization and patient-level variables and recent ACH exposures was examined.

Results: The majority of ARO isolates belonged to major healthcare-associated lineages: MRSA (sequence type [ST] 5); VREfc (ST6); CipREc (ST131), and VREfm (clade A). While the genomic similarity of strains between NF pairs was positively associated with overlap in their feeder ACHs (P < .05 for MRSA, VREfc, and CipREc), limited phylogenetic clustering by either ACH or NF supported regional endemicity. Significant predictors for ARO colonization on NF admission included lower functional status and recent exposure to glycopeptides (adjusted odds ratio [aOR], > 2 for MRSA and VREfc/VREfm) or third-/fourth-generation cephalosporins (aOR, > 2 for MRSA and VREfm). Transfer from specific ACHs was an independent risk factor for only 1 ARO/ACH pair (VREfm/ACH19: aOR, 2.48).

Conclusions: In this region, healthcare-associated ARO lineages are endemic among connected NFs and ACHs, making patient characteristics more informative of NF admission colonization risk than exposure to specific ACHs.

Keywords: antibiotic-resistant organisms; genomic epidemiology; nursing facilities; surveillance; transmission.

Figure 1.

High prevalence of antibiotic-resistant organisms (AROs) in regional nursing facilities due to endemic spread of epidemic lineages. A, Percentage of patients colonized with prevalent AROs within major healthcare lineages (methicillin-resistant Staphylococcus aureus [MRSA]: sequence type [ST] 5 and ST5-like; vancomycin-resistant Enterococcus faecalis [VREfc]: ST6; ciprofloxacin-resistant Escherichia coli [CipREc]: ST43/131 and ST43/131-like, and clade A vancomycin-resistant Enterococcus faecium [VREfm] isolates) at the time of enrollment or during nursing facility stay, by nursing facility. Each color corresponds to the colonization prevalence of a specific ARO. B and C, Phylogenetic tree of VREfc isolates labeled by patient’s most recent acute care hospital (ACH) exposure (B) and patient’s nursing facility (NF) residence (C) at the time of isolate detection. Isolates collected at the time of admission are shown as solid circles, and those collected during follow-up visits are shown as filled circles. Follow-up isolates pruned from analysis due to close genetic distance with an admission or earlier isolate within the same NF are shown as solid black circles. Sequence type of each isolate is shown on the right. The tree was inferred from maximum likelihood (RAxML) analysis with midpoint rooting. Scale bar represents substitutions per nucleotide site.

Figure 2.

Patient-sharing network between regional acute care hospitals (ACHs) and study nursing facilities (NFs). Visualization of patient sharing network involving 6 NFs (blue nodes) and 11 ACHs (pink nodes) in southeast Michigan, 2013–2016. Directed arrows represent patient flow from an ACH to an NF, with the number of patients transferred shown in red. Only ACH/NF pairs with ≥5 patients transferred are shown.

Figure 3.

Genomic relatedness among antibiotic-resistant organisms (AROs) isolates from different nursing facilities (NFs) associated with patient sharing and geographic proximity. Relationship between the genomic similarity of isolates between each pair of nursing facilities (NFs) and overlap in feeder acute care hospitals (ACHs) between the NF pair (A), and geographical distance between NF pair (B). Patient sharing between NFs (x-axis, A) indicates the extent of divergence in the proportion of patients from feeder ACHs between 2 NFs. Lower values indicate higher similarity. Isolate similarity (y-axis, A and B) indicates the divergence of the population structure of each ARO. Lower values indicate more genomic homogeneity between 2 NFs. Spearman rank correlation coefficients are shown on the right. The colors of the data points and regression lines correspond to different AROs. Closed circles denote NF pairs excluding facility 1; open circles denote NF pairs including facility 1. Abbreviations: CipREc, ciprofloxacin-resistant Escherichia coli; MRSA, methicillin-resistant Staphylococcus aureus; NF, nursing facility; VREfc, vancomycin-resistant Enterococcus faecalis; VREfm, vancomycin-resistant Enterococcus faecium.