Characterisation of Clostridium difficile hospital ward-based transmission using extensive epidemiological data and molecular typing

Abstract

Background: Clostridium difficile infection (CDI) is a leading cause of antibiotic-associated diarrhoea and is endemic in hospitals, hindering the identification of sources and routes of transmission based on shared time and space alone. This may compromise rational control despite costly prevention strategies. This study aimed to investigate ward-based transmission of C. difficile, by subdividing outbreaks into distinct lineages defined by multi-locus sequence typing (MLST).

Methods and findings: All C. difficile toxin enzyme-immunoassay-positive and culture-positive samples over 2.5 y from a geographically defined population of ~600,000 persons underwent MLST. Sequence types (STs) were combined with admission and ward movement data from an integrated comprehensive healthcare system incorporating three hospitals (1,700 beds) providing all acute care for the defined geographical population. Networks of cases and potential transmission events were constructed for each ST. Potential infection sources for each case and transmission timescales were defined by prior ward-based contact with other cases sharing the same ST. From 1 September 2007 to 31 March 2010, there were means of 102 tests and 9.4 CDIs per 10,000 overnight stays in inpatients, and 238 tests and 15.7 CDIs per month in outpatients/primary care. In total, 1,276 C. difficile isolates of 69 STs were studied. From MLST, no more than 25% of cases could be linked to a potential ward-based inpatient source, ranging from 37% in renal/transplant, 29% in haematology/oncology, and 28% in acute/elderly medicine to 6% in specialist surgery. Most of the putative transmissions identified occurred shortly (≤ 1 wk) after the onset of symptoms (141/218, 65%), with few >8 wk (21/218, 10%). Most incubation periods were ≤ 4 wk (132/218, 61%), with few >12 wk (28/218, 13%). Allowing for persistent ward contamination following ward discharge of a CDI case did not increase the proportion of linked cases after allowing for random meeting of matched controls.

Conclusions: In an endemic setting with well-implemented infection control measures, ward-based contact with symptomatic enzyme-immunoassay-positive patients cannot account for most new CDI cases.

Figure 1. Ward-based links.

(A) Ward-based links between cases of an example ST, ST-2. Cases from the first part of the study, 1 September 2007–29 February 2008 (the run-in period, where the source of the cases may plausibly be before 1 September 2007), are shown as white circles, and cases from the remainder of the study, 1 March 2008–31 March 2010 (the test period) are shown in grey. Where patients with CDI shared time on a common ward before either or both patients' CDI, links are indicated with solid or broken lines, representing possible transmission events for maximum allowable infectious and incubation periods of 8 and 12 wk, respectively. All potential ward-based transmission links are included; the single most plausible link to each recipient based on minimising infectious period is shown in solid lines. Links arising from ward contamination persisting after discharge of the donor patients are not shown. Letters indicate wards on which contact events occurred; wards that are related by specialty have the same letter but different numbers. Links of known direction (ward contact after potential donor CDI and before recipient CDI) are indicated with an arrowhead. Cases are approximately evenly spaced, with linked cases adjacent for the purpose of illustration (i.e., the distance between circles does not generally correspond to any physical quantity). (B) Schema showing different types of ward-based contact.

Figure 2. Samples and patients, 1 September 2007–31 March 2010.

* The number of unique patients with whom the index patient shared a ward during the study period. ** 55 patients had multiple ST infections during the study period: 54 patients had two STs, and one had four STs. Six isolates were not successfully typed (either because of ambiguous sequences despite repeated testing or because of loss of sample). Note: 55 cases had no record of ORH inpatient admission during the study. Some patients had different ST infections in the test and run-in periods and are therefore counted in both.

Figure 3. Time distribution of C. difficile cases, by sequence type.

The first EIA-positive sample per ST per patient is plotted as a point for STs other than ST-1 (PCR-ribotype-027), where the 207 cases are instead shown as a histogram per week. Secondary cases are those with an identified credible donor based on incubation periods up to 12 wk and infectious periods up to 8 wk.

Figure 4. Distribution of infectious and incubation periods for putative transmissions within 69 STs and 705 “test” CDI cases.

Only the most plausible transmission links, where the direction of transmission is known (ward contact after potential donor CDI and before recipient CDI), are plotted, assuming maximum allowable infection and incubation periods of 26 wk and no ward contamination persisting after donor discharge (see Figure B in Text S1 for distributions from all potential links). Times are plotted rounded up to the nearest week, e.g., intervals of 0–6 d are plotted as 1 wk.

Figure 5. Percentage of cases explained by ward-based contact with a C. difficile toxin EIA-positive donor.

The circled dots indicate a potential upper bound for the proportion of linked CDI cases. Controls are drawn at random 1,000 times from hospital-exposure-matched EIA-negative patients; linked ward-based contacts for controls therefore represent the proportion of ward-based contacts that would likely arise in the CDI cases merely from chance movements around the hospitals. Net linked cases correct the overall total linked CDI cases for these chance ward meetings estimated from controls. (A) Maximum allowable incubation period of 12 wk, no ward contamination. (B) Maximum allowable infectious period of 8 wk and incubation period of 12 wk. (C) Missing data analysis with maximum allowable infectious period of 8 wk and incubation period of 12 wk.