1. To screen or not to screen – Clostridium difficile Simon Goldenberg, Consultant Microbiologist Guy’s & St Thomas’ NHS Foundation Trust

2. To screen or not to screen – C. difficile ‘Screening’ in this context suggests detection of asymptomatic carriage or colonisation C. difficile is a toxin mediated disease: presence of toxigenic C. difficile without expression of toxin

3. 87% of organisations have an attributable CDI rate (FY2014/15) that is within 2 SDs of the national mean Large reductions in Trust attributable CDI numbers PHE Mandatory Surveillance Scheme for Clostridium difficile

4. Most major Infection Prevention & Control Interventions have already been introduced, although there is still much to be achieved in antimicrobial stewardship There is evidence that patient to patient transmission within hospitals is now limited ~20% in a study in Oxford in 2012 Didelot et al Genome Biol 13:12, R118

5. What is the prevalence of colonisation? Hung et al J Microbiol Immunol Infect. 2015 Jun;48(3):241-8

6. How to screen? Not with toxin EIA / cytotoxin assay – detects disease Not with GDH – does not differentiate between toxigenic and non-toxigenic strains Toxigenic culture – anerobic culture on selective agar followed by demonstration of toxin (or toxin gene) PCR – detection of toxin gene (B usually)

7. Why screen? Isolation / cohorting and Personal Protective Equipment Enhanced environmental decontamination (eg with Vaporized Hydrogen Peroxide etc.) What is the risk of transmission from an asymptomatic patient?

8. 3-month study in LTCF with 73 residents Five (7%) patients had CDI 35 (51%) were asymptomatic carriers (nine had a prior history of CDI) Asymptomatic carriers associated with significantly higher rates of skin (61% vs. 19%) and environmental contamination (59% vs. 24%) than non-carriers Asymptomatic carriers are a potential source for transmission of Clostridium difficile Riggs et al Clin Infect Dis 2007 45:8, 992-8

9. Estimating Risk of C. difficile Transmission from PCR Positive but Cytotoxin Negative Cases Kamboj et al PLoS One 2014 9:2, e88262. MLVA undertaken on 43 PCR positive stool samples at Memorial Sloan Kettering Cancer Hospital Cases detected by PCR only (assumed to be colonised) contribute towards hospital based transmission Transmission from PCR- /Cytotoxin negative cases

10. Asymptomatic Clostridium difficile Colonisation and Onward Transmission 132 asymptomatic patients stool samples cultured for C. difficile 18/132 (14%) positive WGS applied to cultured isolates and ward movements tracked Risk factor for carriage (multivariate analysis)OR95%CIP value Overnight hospital stay in last 6 months5.19(0.58, 46.0)0.14 Antibiotics in last 6 months0.04(0.002, 0.51)0.01 Steroids/immunosupressants in last 6 months16.5(1.25, 215)0.03 Eyre et al PLoS One 2013 8:11, e78445 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

11. Is isolation of colonised patients feasible? Number of asymptomatically colonised patients probably outweighs that of infected patients Competing priorities – CROs’ MRSA, Norovrus, respiratory viruses etc

12. Why screen? Avoid / select less risky antibiotics (if required)

13. Slimings & Riley, 2014Brown, 2013Desphande, 2013 ClindamycinOR 2.86 95% CI 2.04 to 4.02 OR 16.80 95% CI 7.48 to 37.76 OR 20.43 95% CI 8.50 to 49.09 CephalosporinsOR 1.97 95% CI 1.21 to 3.23 OR 5.68 95% CI 2.12 to 15.23 OR 4.47 95% CI 1.60 to 12.50 QuinolonesOR 1.66 95% CI 1.17 to 2.35 OR 5.50 95% CI 4.26 to 7.11 OR 5.65 95% CI 4.38 to 7.28

14. Why screen? Prophylaxis/decolonisation? NO CDI rate 1.4% (n = 11) among patients receiving metronidazole for non-CDI indications and 6.5% (n = 728) among those who did not (OR= 0.21; 95% CI 0.11-0.38; P<.001), adjusted for age, sex, and comorbidities Rodriguez et al. Clin Gastroenterol Hepatol. 2014 Nov;12(11):1856-61

15. Decreased Diversity of the Faecal Microbiome in Recurrent C.difficile -Patients with recurrent C.difficile have decreased phylogenetic richness Chang JY, et al. J Infect Dis 2008:197;435-8 -After antibiotics some bacteria remain disrupted for long periods: -Up to 2 years following treatment with clindamycin -Up to 4 years after H. pylori eradication therapy Sadowsky et al. The Fecal Bacteria, 2011 Zaura et al. mBio 2015 vol. 6 no. 6 e01693-15

16. Is colonisation a risk or protective factor for subsequent infection?

17. Predominant thinking was that while C. difficile was a necessary step towards infection, prolonged colonization was ultimately protective against active disease Mechanism unclear but boosting of serum antibody levels over long periods of time thought to play a role

18. Protection of hamsters against C. difficile ileocaecitis by prior colonisation with non-pathogenic strains Borriello et al J Med Microbiol 1985 19:3, 339-50 Prior colonisation of clindamycin-treated hamsters with non-toxigenic strains of C. difficile protected them from subsequent colonisation with a toxigenic pathogenic strain. In total, 13 of 18 'protected' hamsters survived up to 27 days vs. all 27 animals challenged with the toxigenic strain alone died within 48 h

19. Nosocomial C. difficile colonisation and disease Johnson et al Lancet 1990 336:8707, 97-100 Risk of CDI assessed in patients colonised with C. difficile Rectal swabs taken weekly for 9 weeks from patients with long- term (at least 7 days) hospital stays and cultured for C. difficile 60 (21%) of 282 patients were culture-positive for C. difficile during their hospital stay, of whom 51 were symptom-free faecal excretors. The symptom-free excretors were not at increased risk of subsequent clinical illness.

20. Primary symptomless colonisation by C. difficile and decreased risk of subsequent diarrhoea Shim et al Lancet 1998; 351: 633-6

21. Elevated levels of serum immunoglobulins in asymptomatic carriers of C. difficile Mulligan et al Clin Infect Dis 1993 16 Suppl 4, S239-44

22. Asymptomatic carriage of C. difficile and serum levels of IgG antibody against toxin A Kyne et al Infect N Engl J Med 2000 342:6, 390-7

23. However, more recent studies suggest that colonisation is actually a significant risk factor for progression to disease

24. Impact of Toxigenic C. difficile Colonization on the Risk of Subsequent CDI in Intensive Care Unit Patients Tschudin-Sutter et al Infect Control Hosp Epidemiol 2015 1-6 Colonization with toxigenic C. difficile on admission, Length of ICU stay prior to CDI, Exposure to penicillins during hospitalization all identified as significant risk for development of CDI

25. Colonization with toxinogenic C. difficile upon hospital admission, and risk of infection: a systematic review and meta-analysis Zacharioudakis et al Am J Gastroenterol 2015; 110: 381-90. 19 out of 26,081 studies on 8,725 patients included Pooled prevalence of colonization = 8.1% (95% CI 5.7-11.1%) Patients colonized on admission had a 5.9 times higher risk of subsequent CDIs compared with noncolonized patients (relative risk (RR) 5.86; 95% CI 4.21-8.16) Risk of CDI for colonized patients was 21.8% (95% CI 7.9-40.1%), vs. noncolonized patients (3.4%; 95% CI 1.5-6.0%; P =0.03), with an attributable risk of 18.4% RFs for colonisation: Hospitalization in previous 3 months, Previous antibiotic, PPI use, History of CDI

26. Why screen? Better epidemiology, more accurate picture of whether cases are truly community or hospital associated….

27. Why screen? Better epidemiology, more accurate picture of whether cases are truly community or hospital associated…. ….or more cynically, avoid attribution to organisation

28. Trust apportioning of cases: Specimen date is on, or after, the fourth day of admission, where the day of admission is day 1

29. Relationship among CDI epidemiological definitions Clinical Microbiol Infect 2006 12; 2-18 pages 2-18.

30. Can we afford it?

31. The potential economic value of screening hospital admissions for C. difficile Bartsch et al Eur J Clin Microbiol Infect Dis 2012 31:11, 3163-71 Assuming screening for CDI using peri-rectal swab PCR (USD 7.66)

32. The potential economic value of screening hospital admissions for C. difficile Bartsch et al Eur J Clin Microbiol Infect Dis 2012 31:11, 3163-71

33. Effectiveness of Screening Hospital Admissions to Detect Asymptomatic Carriers of C. difficile: A Modeling Evaluation Lanzas et al Infect Control Hosp Epidemiol 2014 35:8, 1043-50 Testing for asymptomatic carriers coupled with isolation and PPE reduced the number of new colonizations and HO-CDI cases by 40%-50% and 10%-25% Simulations indicated that tests with a sensitivity greater than 90% and turnaround times less than 2.5 days could reduce the number of secondary new colonizations (and subsequent CDIs) caused by asymptomatic carriers.

34. Summary Prevalence of colonisation is highly variable and dependent on the population screened There is conflicting evidence to suggest that colonisation is a protective or a risk factor for infection Decolonisation with metronidazole or vancomycin is ineffective and probably increases risk of subsequent infection Asymptomatic carriers may be an underappreciated source of transmission There are several infection control interventions that have potential in limiting transmission from carriers Modelling suggests widespread screening programmes could be cost effective but implementation studies are lacking