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Microevolutionary analysis of Clostridium difficile genomes to investigate transmission.

ABSTRACT: The control of Clostridium difficile infection is a major international healthcare priority, hindered by a limited understanding of transmission epidemiology for these bacteria. However, transmission studies of bacterial pathogens are rapidly being transformed by the advent of next generation sequencing.Here we sequence whole C. difficile genomes from 486 cases arising over four years in Oxfordshire. We show that we can estimate the times back to common ancestors of bacterial lineages with sufficient resolution to distinguish whether direct transmission is plausible or not. Time depths were inferred using a within-host evolutionary rate that we estimated at 1.4 mutations per genome per year based on serially isolated genomes. The subset of plausible transmissions was found to be highly associated with pairs of patients sharing time and space in hospital. Conversely, the large majority of pairs of genomes matched by conventional typing and isolated from patients within a month of each other were too distantly related to be direct transmissions.Our results confirm that nosocomial transmission between symptomatic C. difficile cases contributes far less to current rates of infection than has been widely assumed, which clarifies the importance of future research into other transmission routes, such as from asymptomatic carriers. With the costs of DNA sequencing rapidly falling and its use becoming more and more widespread, genomics will revolutionize our understanding of the transmission of bacterial pathogens.

SUBMITTER: Didelot X

PROVIDER: S-EPMC4056369 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Microevolutionary analysis of Clostridium difficile genomes to investigate transmission.

Didelot Xavier X Eyre David W DW Cule Madeleine M Ip Camilla L C CL Ansari M Azim MA Griffiths David D Vaughan Alison A O'Connor Lily L Golubchik Tanya T Batty Elizabeth M EM Piazza Paolo P Wilson Daniel J DJ Bowden Rory R Donnelly Peter J PJ Dingle Kate E KE Wilcox Mark M Walker A Sarah AS Crook Derrick W DW Peto Tim E A TE Harding Rosalind M RM

Genome biology 20121221 12

<h4>Background</h4>The control of Clostridium difficile infection is a major international healthcare priority, hindered by a limited understanding of transmission epidemiology for these bacteria. However, transmission studies of bacterial pathogens are rapidly being transformed by the advent of next generation sequencing.<h4>Results</h4>Here we sequence whole C. difficile genomes from 486 cases arising over four years in Oxfordshire. We show that we can estimate the times back to common ancesto ...[more]

PMID: 23259504

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Project description:IntroductionCombined genotyping/whole genome sequencing and epidemiological data suggest that in endemic settings only a minority of Clostridium difficile infection, CDI, is acquired from other cases. Asymptomatic patients are a potential source for many unexplained cases.MethodsWe prospectively screened a cohort of medical inpatients in a UK teaching hospital for asymptomatic C. difficile carriage using stool culture. Electronic and questionnaire data were used to determine risk factors for asymptomatic carriage by logistic regression. Carriage isolates were compared with all hospital/community CDI cases from the same geographic region, from 12 months before the study to 3 months after, using whole genome sequencing and hospital admission data, assessing particularly for evidence of onward transmission from asymptomatic cases.ResultsOf 227 participants recruited, 132 provided ?1 stool samples for testing. 18 participants were culture-positive for C. difficile, 14/132(11%) on their first sample. Independent risk factors for asymptomatic carriage were patient reported loose/frequent stool (but not meeting CDI criteria of ?3 unformed stools in 24 hours), previous overnight hospital stay within 6 months, and steroid/immunosuppressant medication in the last 6 months (all p?0.02). Surprisingly antibiotic exposure in the last 6 months was independently associated with decreased risk of carriage (p?=?0.005). The same risk factors were identified excluding participants reporting frequent/loose stool. 13/18(72%) asymptomatically colonised patients carried toxigenic strains from common disease-causing lineages found in cases. Several plausible transmission events to asymptomatic carriers were identified, but in this relatively small study no clear evidence of onward transmission from an asymptomatic case was seen.ConclusionsTransmission events from any one asymptomatic carrier are likely to be relatively rare, but as asymptomatic carriage is common, it may still be an important source of CDI, which could be quantified in larger studies. Risk factors established for asymptomatic carriage may help identify patients for inclusion in such studies.

Project description:BackgroundClostridium difficile is one of the most common and important nosocomial pathogens, causing severe gastrointestinal disease in hospitalized patients. Although "bundled" interventions have been proposed and promoted, optimal control strategies remain unknown.MethodsWe designed an agent-based computer simulation of nosocomial C. difficile transmission and infection, which included components such as: patients and health care workers, and their interactions; room contamination via C. difficile shedding; C. difficile hand carriage and removal via hand hygiene; patient acquisition of C. difficile via contact with contaminated rooms or health care workers; and patient antimicrobial use. We then introduced six interventions, alone and "bundled" together: aggressive C. difficile testing; empiric isolation and treatment of symptomatic patients; improved adherence to hand hygiene and contact precautions; improved use of soap and water for hand hygiene; and improved environmental cleaning. All interventions were tested using values representing base-case, typical intervention, and optimal intervention scenarios.FindingsIn the base-case scenario, C. difficile infection rates ranged from 8-21 cases/10,000 patient-days, with a case detection fraction between 32%-50%. Implementing the "bundle" at typical intervention levels had a large impact on C. difficile acquisition and infection rates, although intensifying the intervention to optimal levels had much less additional impact. Most of the impact came from improved hand hygiene and empiric isolation and treatment of suspected C. difficile cases.ConclusionA "bundled" intervention is likely to reduce nosocomial C. difficile infection rates, even under typical implementation conditions. Real-world implementation of the "bundle" should focus on those components of the intervention that are likely to produce the greatest impact on C. difficile infection rates, such as hand hygiene and empiric isolation and treatment of suspected cases.

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Microevolutionary analysis of Clostridium difficile genomes to investigate transmission.

Publications

Microevolutionary analysis of Clostridium difficile genomes to investigate transmission.

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