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Genome-Based Infection Tracking Reveals Dynamics of Clostridium difficile Transmission and Disease Recurrence.

ABSTRACT: Accurate tracking of Clostridium difficile transmission within healthcare settings is key to its containment but is hindered by the lack of discriminatory power of standard genotyping methods. We describe a whole-genome phylogenetic-based method to track the transmission of individual clones in infected hospital patients from the epidemic C. difficile 027/ST1 lineage, and to distinguish between the 2 causes of recurrent disease, relapse (same strain), or reinfection (different strain).We monitored patients with C. difficile infection in a UK hospital over a 2-year period. We performed whole-genome sequencing and phylogenetic analysis of 108 strains isolated from symptomatic patients. High-resolution phylogeny was integrated with in-hospital transfers and contact data to create an infection network linking individual patients and specific hospital wards.Epidemic C. difficile 027/ST1 caused the majority of infections during our sampling period. Integration of whole-genome single nucleotide polymorphism (SNP) phylogenetic analysis, which accurately discriminated between 27 distinct SNP genotypes, with patient movement and contact data identified 32 plausible transmission events, including ward-based contamination (66%) or direct donor-recipient contact (34%). Highly contagious donors were identified who contributed to the persistence of clones within distinct hospital wards and the spread of clones between wards, especially in areas of intense turnover. Recurrent cases were identified between 4 and 26 weeks, highlighting the limitation of the standard <8-week cutoff used for patient diagnosis and management.Genome-based infection tracking to monitor the persistence and spread of C. difficile within healthcare facilities could inform infection control and patient management.

SUBMITTER: Kumar N

PROVIDER: S-EPMC4772841 | biostudies-other | 2016 Mar

REPOSITORIES: biostudies-other

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Genome-Based Infection Tracking Reveals Dynamics of Clostridium difficile Transmission and Disease Recurrence.

Kumar Nitin N Miyajima Fabio F He Miao M Roberts Paul P Swale Andrew A Ellison Louise L Pickard Derek D Smith Godfrey G Molyneux Rebecca R Dougan Gordon G Parkhill Julian J Wren Brendan W BW Parry Christopher M CM Pirmohamed Munir M Lawley Trevor D TD

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20151218 6

<h4>Background</h4>Accurate tracking of Clostridium difficile transmission within healthcare settings is key to its containment but is hindered by the lack of discriminatory power of standard genotyping methods. We describe a whole-genome phylogenetic-based method to track the transmission of individual clones in infected hospital patients from the epidemic C. difficile 027/ST1 lineage, and to distinguish between the 2 causes of recurrent disease, relapse (same strain), or reinfection (different ...[more]

PMID: 26683317

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Project description:Bezlotoxumab is a human monoclonal antibody against Clostridium difficile toxin B, indicated to prevent recurrence of C. difficile infection (rCDI) in high-risk adults receiving antibacterial treatment for CDI. An exploratory genome-wide association study investigated whether human genetic variation influences bezlotoxumab response. DNA from 704 participants who achieved initial clinical cure in the phase 3 MODIFY I/II trials was genotyped. Single nucleotide polymorphisms (SNPs) and human leukocyte antigen (HLA) imputation were performed using IMPUTE2 and HIBAG, respectively. A joint test of genotype and genotype-by-treatment interaction in a logistic regression model was used to screen genetic variants associated with response to bezlotoxumab. The SNP rs2516513 and the HLA alleles HLA-DRB1*07:01 and HLA-DQA1*02:01, located in the extended major histocompatibility complex on chromosome 6, were associated with the reduction of rCDI in bezlotoxumab-treated participants. Carriage of a minor allele (homozygous or heterozygous) at any of the identified loci was related to a larger difference in the proportion of participants experiencing rCDI versus placebo; the effect was most prominent in the subgroup at high baseline risk for rCDI. Genotypes associated with an improved bezlotoxumab response showed no association with rCDI in the placebo cohort. These data suggest that a host-driven, immunological mechanism may impact bezlotoxumab response. Trial registration numbers are as follows: NCT01241552 (MODIFY I) and NCT01513239 (MODIFY II).IMPORTANCE Clostridium difficile infection is associated with significant clinical morbidity and mortality; antibacterial treatments are effective, but recurrence of C. difficile infection is common. In this genome-wide association study, we explored whether host genetic variability affected treatment responses to bezlotoxumab, a human monoclonal antibody that binds C. difficile toxin B and is indicated for the prevention of recurrent C. difficile infection. Using data from the MODIFY I/II phase 3 clinical trials, we identified three genetic variants associated with reduced rates of C. difficile infection recurrence in bezlotoxumab-treated participants. The effects were most pronounced in participants at high risk of C. difficile infection recurrence. All three variants are located in the extended major histocompatibility complex on chromosome 6, suggesting the involvement of a host-driven immunological mechanism in the prevention of C. difficile infection recurrence.

Project description:BACKGROUND:Fecal microbiota transplantation (FMT) is an effective treatment for recurrent Clostridium difficile infection (rCDI). The use of freeze-dried, encapsulated donor material for FMT (cap-FMT) allows for an easy route of administration and remains clinically effective in the majority of rCDI patients. We hypothesized that specific shifts in the microbiota in response to cap-FMT could predict clinical outcome. We further evaluated the degree of donor microbiota engraftment to determine the extent that donor transfer contributed to recovery. RESULTS:In total, 89 patients were treated with 100 separate cap-FMTs, with a success rate (no rCDI 60 days post cap-FMT) of 80%. Among responders, the lower alpha diversity (ANOVA P?<?0.05) observed among patient's pre-FMT samples was restored following cap-FMT. At 1 week post-FMT, community composition varied by clinical outcome (ANOSIM P?<?0.001), with similar abundances among families (Lachnospiraceae, Ruminococcaceae, and Bacteroidaceae) in responder and donor samples. Families that showed differential abundances by outcome (response vs. recurrence) from samples collected 7 days following cap-FMT were used to construct a regression tree-based model to predict recurrence. Results showed a training accuracy of 100% to predict recurrence and the model was 97% accurate against a test data set of samples collected 8-20 days following cap-FMT. Evaluation of the extent of engraftment using the Bayesian algorithm SourceTracker revealed that approximately 50% of the post-FMT communities of responders were attributable to donor microbiota, while an additional 20-30% of the communities were similar to a composite healthy microbiota consisting of all donor samples. CONCLUSIONS:Regression tree-based analyses of microbial communities identified taxa significantly related to clinical response after 7 days, which can be targeted to improve microbial therapeutics. Furthermore, reinstatement of a healthy assemblage following cap-FMT was only partially attributable to explicit donor engraftment and continued to develop towards an overall healthy assemblage, independent of donor.

Project description:Abstract Background Bezlotoxumab (BEZ) and actoxumab (ACT) are monoclonal antibodies against C. difficile toxins B and A, respectively. Patients receiving a single infusion of BEZ alone or with ACT in the MODIFY I/II trials showed a consistent reduction in the rate of rCDI over a 12-week period compared with a placebo (PBO) infusion. Exploratory genome wide analyses were conducted to determine whether genetic variants across the genome were associated with treatment response (rCDI). Methods DNA was extracted from blood obtained from patients who consented to genetic analysis (PGx population). Genetic data were generated on a commercial Axiom array platform (Affymetrix). Genotype imputation was performed using the 1000 Genomes Phase 3 reference data and Impute2 software after genetic quality control. Data from BEZ and ACT+BEZ arms were combined to provide increased power. The logistic regression with likelihood ratio test was used to search for single nucleotide polymorphisms (SNPs) that were strongly associated with a treatment effect on rCDI. Results An SNP rs2516513 located in the extended major histocompatibility complex (xMHC), region with a minor allele frequency of 25% in the general population, was associated with rCDI (P = 3.04E-08) (Figure 1). rCDI rates for the PGx population and in subgroups at high/low risk for rCDI stratified by SNP rs2516513 are shown in Table 1. Carriers of the T allele of SNP rs2516513 were associated with a statistically significant reduction in rCDI in BEZ-treated patients but not in PBO-treated patients (DrCDI = -21.5%). The magnitude of the effect of the T allele on rCDI is most prominent in patients who have ?1 risk factor for rCDI (DrCDI = -24.6%), but is also present in patients without risk factors (DrCDI = -10.6%). In CC homozygous patients, rCDI rates are similar in both treatment groups and in patients at high and low risk of rCDI. Conclusion An SNP variant rs2516513 is associated with a lower rate of rCDI recurrence in patients treated with BEZ. The location of the associated genetic variant on chromosome 6 within xMHC, suggests that a host driven, immunological mechanism may play a role in rCDI and may predict patients most likely to respond to BEZ. As this is an exploratory finding, the results should be replicated in an independent validation study. Disclosures P. Shaw, Merck & Co., Inc.: Employee, May own stock/hold stock options in Company; J. Shen, Merck & Co., Inc.: Employee, may hold stock/hold stock options in the Company; M. B. Dorr, Merck & Co., Inc.: Employee and Shareholder, may own stock/hold stock options in the Company; J. Li, BGI-Shenzhen: Employee, Salary; R. Mogg, Merck & Co., Inc.: Employee, May hold stock/stock options in the Company; D. V. Mehrotra, Merck & Co., Inc.: Employee, may own stock/hold stock options in the Company; R. L. Blanchard, Merck & Co., Inc.: Employee, may own stock/hold stock options in the Company

Project description:OBJECTIVE: To examine the rate of Clostridium difficile infection (CDI) and hospital-associated outcomes in a national cohort of hospitalized patients with chronic kidney disease (CKD) and assess the impact of long-term dialysis on outcome in these patients. PATIENTS AND METHODS: Data for January 1, 2005, through December 31, 2009 were obtained from the National Hospital Discharge Survey, which includes information on patient demographics, diagnoses, procedures, and discharge types. Data collected and analyzed for this study included age, sex, race, admission type (urgent or emergent combined vs elective), any colectomy diagnosis, length of stay, type of discharge, and mortality. International Classification of Diseases, Ninth Revision, Clinical Modification codes were utilized to identify CKD patients and CDI events. Weighted analysis was performed using JMP version 9. RESULTS: An estimated 162 million adults were hospitalized during 2005-2009, and 8.03 million (5%) had CKD (median age, 71 years). The CDI rate in CKD patients was 1.49% (0.119 million) compared with 0.70% (1.14 million) in patients without CKD (P<.001). Patients with CKD who were undergoing long-term dialysis were more than 2 times as likely to develop CDI than non-CKD patients and 1.33 times more likely than CKD patients not undergoing dialysis (all P<.001). In a weighted multivariate analysis adjusting for sex and comorbidities, patients with CKD and CDI had longer hospitalization, higher colectomy rate (adjusted odds ratio [aOR], 2.30; 95% confidence interval [CI], 2.14-2.47), dismissal to a health care facility (aOR, 2.22; 95% CI, 2.19-2.25), and increased in-hospital mortality (aOR, 1.55; 95% CI, 1.52-1.59; all P<.001) as compared with CKD patients without CDI. Patients with CKD who were undergoing long-term dialysis did not have worse outcomes as compared with CKD patients who were not undergoing long-term dialysis. CONCLUSION: These data suggest that patients with CKD have a higher risk of CDI and increased hospital-associated morbidity and mortality. Future prospective studies are needed to confirm these findings and to identify effective CDI prevention in CKD patients, who appear to have an increased risk of CDI acquisition.

Dataset Information

Genome-Based Infection Tracking Reveals Dynamics of Clostridium difficile Transmission and Disease Recurrence.

Publications

Genome-Based Infection Tracking Reveals Dynamics of Clostridium difficile Transmission and Disease Recurrence.

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