Molecular Surveillance of Carbapenem-Resistant Gram-Negative Bacteria in Liver Transplant Candidates

Tilman G Schultze; Philip G Ferstl; David Villinger; Michael Hogardt; Wolf O Bechstein; Stephan Göttig; Thomas A Wichelhaus; Stefan Zeuzem; Jonel Trebicka; Oliver Waidmann; Martin-Walter Welker; Volkhard A J Kempf

doi:10.3389/fmicb.2021.791574

Molecular Surveillance of Carbapenem-Resistant Gram-Negative Bacteria in Liver Transplant Candidates

Front Microbiol. 2021 Nov 22:12:791574. doi: 10.3389/fmicb.2021.791574. eCollection 2021.

Authors

Tilman G Schultze^{1

2

3}, Philip G Ferstl^{2

4}, David Villinger^{1

2

3}, Michael Hogardt^{1

2

3}, Wolf O Bechstein⁵, Stephan Göttig^{1

2

3}, Thomas A Wichelhaus^{1

2

3}, Stefan Zeuzem^{2

4}, Jonel Trebicka^{2

4}, Oliver Waidmann^{2

4}, Martin-Walter Welker^{2

4}, Volkhard A J Kempf^{1

2

3}

Affiliations

¹ Institute of Medical Microbiology and Infection Control, University Hospital Frankfurt, Frankfurt, Germany.
² University Center for Infectious Diseases, University Hospital Frankfurt, Frankfurt, Germany.
³ University Center of Competence for Infection Control of the State of Hesse, Frankfurt, Germany.
⁴ Division of Gastroenterology and Hepatology, Department for Internal Medicine, Goethe University Frankfurt, Frankfurt, Germany.
⁵ Department of General and Visceral Surgery, Goethe University Frankfurt, Frankfurt, Germany.

Abstract

Background: Carbapenem-resistant Gram-negative bacteria (CRGN) cause life-threatening infections due to limited antimicrobial treatment options. The occurrence of CRGN is often linked to hospitalization and antimicrobial treatment but remains incompletely understood. CRGN are common in patients with severe illness (e.g., liver transplantation patients). Using whole-genome sequencing (WGS), we aimed to elucidate the evolution of CRGN in this vulnerable cohort and to reconstruct potential transmission routes. Methods: From 351 patients evaluated for liver transplantation, 18 CRGN isolates (from 17 patients) were analyzed. Using WGS and bioinformatic analysis, genotypes and phylogenetic relationships were explored. Potential epidemiological links were assessed by analysis of patient charts. Results: Carbapenem-resistant (CR) Klebsiella pneumoniae (n=9) and CR Pseudomonas aeruginosa (n=7) were the predominating pathogens. In silico analysis revealed that 14/18 CRGN did not harbor carbapenemase-coding genes, whereas in 4/18 CRGN, carbapenemases (VIM-1, VIM-2, OXA-232, and OXA-72) were detected. Among all isolates, there was no evidence of plasmid transfer-mediated carbapenem resistance. A close phylogenetic relatedness was found for three K. pneumoniae isolates. Although no epidemiological context was comprehensible for the CRGN isolates, evidence was found that the isolates resulted of a transmission of a carbapenem-susceptible ancestor before individual radiation into CRGN. Conclusion: The integrative epidemiological study reveals a high diversity of CRGN in liver cirrhosis patients. Mutation of carbapenem-susceptible ancestors appears to be the dominant way of CR acquisition rather than in-hospital transmission of CRGN or carbapenemase-encoding genetic elements. This study underlines the need to avoid transmission of carbapenem-susceptible ancestors in vulnerable patient cohorts.

Keywords: antimicrobial stewardship; carbapenem resistance; infection control; liver transplantation; transmission; whole-genome sequencing.