Abstract
Background: Clostridium difficile strain DH/NAP11/106, a relatively antibiotic-susceptible strain, is now the most common cause of C. difficile infection (CDI) among adults in the USA. Objectives: To identify mechanisms underlying the evolution and transmission of an MDR DH/NAP11/106 clone. Methods: WGS (Illumina MiSeq), restriction endonuclease analysis (REA) and antibiotic susceptibility testing were performed on 134 C. difficile isolates collected from paediatric patients with CDI over a 2 year period. Results: Thirty-one of 134 (23%) isolates were REA group DH. Pairwise single-nucleotide variant (SNV) analyses identified a DH clone causing seven instances of CDI in two patients. During the 337 days between the first and second CDI, Patient 1 (P1) received 313 days of antibiotic therapy. Clindamycin and rifaximin resistance, and reduced vancomycin susceptibility (MIC 0.5-2 mg/L), were newly identified in the relapsed isolate. This MDR clone was transmitted to Patient 2 (P2) while P1 and P2 received care in adjacent private rooms. P1 and P2 each developed two additional CDI relapses. Comparative genomics analyses demonstrated SNVs in multiple antibiotic resistance genes, including rpoB (rifaximin resistance), gyrB and a gene encoding PBP; gyrB and PBP mutations did not consistently confer a resistance phenotype. The clone also acquired a 46000 bp genomic element, likely a conjugative plasmid, which contained ermB (clindamycin resistance). The element shared 99% identity with the genomic sequence of Faecalibacterium prausnitzii, an enteric commensal. Conclusions: These data highlight the emergence of MDR in C. difficile strain DH/NAP11/106 through multiple independent mechanisms probably as a consequence of profound antibiotic pressure.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1222-1229 |
| Number of pages | 8 |
| Journal | Journal of antimicrobial chemotherapy |
| Volume | 73 |
| Issue number | 5 |
| DOIs | |
| State | Published - May 1 2018 |
Funding
L. K. K. is a scientific advisor for Actelion, has received research supplies from Alere, and received research grants from Merck and Cubist. D. N. G. holds patents for the prevention of Clostridium difficile infection, is a consultant for Sanofi Pasteur, DaVolterra, MGB, and Pfizer and is an advisory board member for Merck, Rebiotix, Summit and Actelion. S. J. P. has received research grants from Merck. All other authors: none to declare. This work was supported by grants from the Thrasher Research Fund (Early Career Award grant number 11854 to L. K. K.); the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (grant numbers K23 AI123525 to L. K. K., K24 AI104831 and R01 AI118257 to A. R. H.); and the American Cancer Society (MRSG-13-220-01 to E. A. O.). Research reported in this publication was supported, in part, by the National Institutes of Health’s National Center for Advancing Translational Sciences, Grant Number UL1TR001422. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. These data were previously presented as an oral presentation at ClostPath: The 10th International Conference on the Molecular Biology and Pathogenesis of the Clostridia, 7-10 August 2017, Ann Arbor, MI, USA (Session 9, Abstract 2). We acknowledge James Osmolski at Loyola University Chicago Stritch School of Medicine and Bill Kabat at Lurie Children's for their assistance with performance of antibiotic susceptibility testing on bacterial isolates, and Katherine Murphy and the NUSeq Core at Northwestern University Feinberg School of Medicine (NUFSM) for their assistance with performance of WGS. We acknowledge Lennel Reynolds, Jr. and the NUFSM Center for Advanced Microscopy for their assistance with bacterial cell imaging.This work was supported by grants from the Thrasher Research Fund (Early Career Award grant number 11854 to L. K. K.); the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (grant numbers K23 AI123525 to L. K. K., K24 AI104831 and R01 AI118257 to A. R. H.); and the American Cancer Society (MRSG-13-220-01 to E. A. O.). Research reported in this publication was supported, in part, by the National Institutes of Health's National Center for Advancing Translational Sciences, Grant Number UL1TR001422. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
ASJC Scopus subject areas
- Microbiology (medical)
- Pharmacology (medical)
- Infectious Diseases
- Pharmacology
