Molecular Epidemiology, Natural History, and Long-Term Outcomes of Multidrug-Resistant Enterobacterales Colonization and Infections Among Solid Organ Transplant Recipients

Abstract

Background: Multidrug-resistant Enterobacterales (MDR-E), including carbapenem-resistant and third-generation cephalosporin-resistant Enterobacterales (CRE, CefR-E), are major pathogens following solid organ transplantation (SOT).

Methods: We prospectively studied patients who underwent lung, liver, and small bowel transplant from February 2015 through March 2017. Weekly perirectal swabs (up to 100 days post-transplant) were cultured for MDR-E. Whole-genome sequencing (WGS) was performed on gastrointestinal (GI) tract-colonizing and disease-causing isolates.

Results: Twenty-five percent (40 of 162) of patients were MDR-E GI-colonized. Klebsiella pneumoniae was the most common CRE and CefR-E. Klebsiella pneumoniae carbapenemases and CTX-M were leading causes of CR and CefR, respectively. Thirty-five percent of GI colonizers developed MDR-E infection vs 2% of noncolonizers (P < .0001). The attack rate was higher among CRE colonizers than CefR-E colonizers (53% vs 21%, P = .049). GI colonization and high body mass index were independent risk factors for MDR-E infection (P ≤ .004). Thirty-day mortality among infected patients was 6%. However, 44% of survivors developed recurrent infections; 43% of recurrences were late (285 days to 3.9 years after the initial infection). Long-term survival (median, 4.3 years post-transplant) did not differ significantly between MDR-E-infected and MDR-E-noninfected patients (71% vs 77%, P = .56). WGS phylogenetic analyses revealed that infections were caused by GI-colonizing strains and suggested unrecognized transmission of novel clonal group-258 sublineage CR-K. pneumoniae and horizontal transfer of resistance genes.

Conclusions: MDR-E GI colonization was common following SOT and predisposed patients to infections by colonizing strains. MDR-E infections were associated with low short- and long-term mortality, but recurrences were frequent and often occurred years after initial infections. Findings provide support for MDR-E surveillance in our SOT program.

Keywords: CRE colonization and infection; MDR-E colonization; MDR-E infection; molecular epidemiology; solid organ transplant.

Figure 1.

MDR-E GI colonization-free survival after SOT. The Kaplan-Meier curve was stratified by CefR-E and CRE. The median times from transplant to detection of CefR-E and CRE colonization were 14 days (range, 1 to 83) and 17 days (range, 3 to 59), respectively (P = .96). Abbreviations: CefR-E, third-generation cephalosporin-resistant Enterobacterales; CRE, carbapenem-resistant Enterobacterales; GI, gastrointestinal; MDR-E, multidrug-resistant Enterobacterales; SOT, solid organ transplantation.

Figure 2.

MDR-E infection-free survival after solid organ transplantation. The Kaplan-Meier curve was stratified by MDR-E GI colonization status. Abbreviations: GI, gastrointestinal; MDR-E, multidrug-resistant Enterobacterales.

Figure 3.

Long-term survival of solid organ transplantation patients stratified by the presence or absence of MDR-E infections encountered within 6 months of transplant. Median follow-up of patients was 4.3 years (0.04 to 5.3 years) post-transplant. At the last follow-up, the mortality rate of patients with MDR-E infections was 29% (5 of 17) vs 23% (34 of 145) among patients without MDR-E infections (P = .56). Abbreviation: MDR-E, multidrug-resistant Enterobacterales.

Figure 4.

Core genome phylogeny of CG258 Klebsiella pneumoniae. Comparisons of core genome phylogeny enabled us to put CG258 K. pneumoniae isolates from our solid organ transplantation recipients into the context of broader institutional epidemiology. Isolates recovered at our center during the study period clustered within a novel clade II sublineage (blue oval), which differed from clade II (orange circles) and clade I (green circles) lineages from previous years.

Figure 5.

Klebsiella pneumoniae carbapenemase (KPC) plasmids derived from Nanopore and Illumina hybrid assembly of Klebsiella oxytoca and Enterobacter hormaechei strains from patient CR-001. The strains shared 2 KPC-3 plasmids belonging to the IncC and IncM replicon groups. IncC plasmids were 169.0 kb and 179.7 kb in length, with >99.9% nucleotide identity. The extra 10.7 kb of the E. hormaechei IncC plasmid harbored additional genes encoding macrolide (ereA) and aminoglycoside (aac (3)-IIg and aac(6’)-IIc) resistance determinants. IncM KPC-3 plasmids were virtually identical.