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1 ECDIS-NET: Update on Clostridium difficile epidemiology in Europe 1 E d J. K u i j p e r, S o f i e v a n D o r p a n d D a a n N o t e r m a n s. D e p a r t m e n t o f M e d i c a l M i c r o b i o l o g y, L e i d e n U n i v e r s i t y M e d i c a l C e n t r e ; C e n t e r f o r I n f e c t i o n C o n t r o l a n d P r e v e n t i o n o f N a t i o n a l I n s t i t u t e o f H e a l t h, B i l t h o v e n, T h e N e t h e r l a n d s.

2 Topics of the presentation Update of CDI as hospital-acquired disease in Europe. National Reference Laboratory Is CDI also a zoonotically acquired disease? 2

3 Pathogenesis of CDI 3 Factor Mechanism Effect TcdA TcdB Binary toxin Enterotoxin; glycosylates small GTP-ases Cytotoxin; glycosylates small GTP-ases ADPribosylates G- actin Inflammation and destruction of epithelial cell wall Inducing microtubule protrusion formation on host cells> increased adherence and colonization

4 Binding of bile salt germinants to pseudoprotease CspC triggers a signaling cascade, allowing the spore to resume metabolism and growth.

5 Early microbiota regulates Type 2 immunity though induction of Tregg cells and Th17 cells Tregg cells are stimulated by bacterial species all belonging to Clostrida, including C. scindens Stimulated Tregg cells result in anti-inflammatory uch as Il-10 Administration of Tregg cells inducing bacteria results in prevention of allergic colitis in mice (Atarashi et al, Nature 2013) Human patients with inflammatory bowel disease have less Clostridia clusters.

6 Clostridium difficile infection watch?v=qrjyimseoqm 6 Antibiotics as risk factor 77% used antibiotics in prior month OR Cephalosporins 1e-3e gen; OR Carbapenems OR 5.4 Penicillinen OR 2.3 Metronidazol OR 2.4 Jin; JAMA Hensgens; J Antimicrob Chemother

7 Clostridium difficile in animals Numerous different species Pets, calves, horses, poultry and pigs most frequently investigated

8 Exponential increase of CDI 8 PCR Ribotype 027: *Increased mortality and complications rate *FQR resistance *Related to healthcare facilities Le monnier, Med Mal Infect Miao He, Nat Genet 2013.

9 Clin Infect Dis. 2013;56: Mortality is high, even in an endemic situation CDI is associated with a 2.5 fold increase in 30-day mortality

10 Almost half a million infections with 29,000 deaths in 2011 Underestimation of communityacquired CDI; per 100,000 populations Netherlands: per 100,000 populations, 1700 admission of patients with CDI and 1600 deaths. :

11 ECDC estimated burden of HCAI Clostridium difficile infections in Europe: 123,997 (at least 6,000 deaths) 11

12 65 PCR-ribotypes (6 new) other 001 (9.3%) 002 (4.6%) 012 (4.3%) 014/020 (15.7%) 015 (3.3%) 017 (3.5%) 018 (5.8%) 023 (2.5%) 027 (4.8%) 078 (7.8%) 106 (5.1%) 126 (3.0%) Bauer MP et al. Clostridium difficile infection in Europe: a hospital-based survey. Lancet. 2011;377:

13 ECDC ACTIONS

14 ECDIS-net I. Standardize laboratory diagnostics II. III. Enhance typing capacity 14 Standardised surveillance protocol, applicable in routine practice for European countries with or without ongoing surveillance Thursday, September 3, 2015

15 Towards a Europe-wide C. difficile infection surveillance a minimal module for aggregated numerator and denominator data, a light module for basic epidemiological data on each CDI case an enhanced module for additional risk factors and detailed microbiological data on the first ten cases per hospital. 15

16 Collected information Surveillance periods Standardised surveillance protocol Minimal Protocol Light Protocol Enhanced Protocol Form Minimum CDI Minimum CDI Minimum CDI Form H surveillance surveillance surveillance (aggregated (aggregated numerator (aggregated numerator (aggregated numerator numerator data) data) data) data) Aggregated hospital Aggregated hospital Aggregated hospital data for each hospital data for each hospital data for each hospital (denominator data) (denominator data) (denominator data) Information on each Information on each CDI Form C CDI case case (aggregated (numerator data) (numerator data) numerator data) Additional cases data Form E (enhanced numerator (one form for data) each case and C. difficile strain) Microbiological data Form M (strain typing, (one form for characterisation and each strain) susceptibility testing) Recommended: continuous surveillance Minimum requirement: continuous surveillance from 1 January to 31 March. Note that on average, a 300-bed European hospital can expect 7 CDI cases every 3 months, or 26 cases per year. The pilot study demonstrated that completion of Form H is made much easier by starting surveillance on the 1st day of a month. 2 hospitals 3 hospitals 4 hospitals

17 ECDIS pilot surveillance 17 2 hospitals 3 hospitals 4 hospitals ECDIS network; 14 countries with of without CDI surveillance (Estonia, Norway, Poland, Romania, Republic of Serbia) 37 hospitals (57% tertiary care) May-October 2013 N=787 (limited data) N=1078 cases N=291 (enhanced data and typing)

18 Ribotyping results 18 Type 027 was the predominant type (28%), found in 9/14 countries!

19 Conclusions on European-wide C. difficile infection surveillance Local laboratory diagnostics improved in Capacity for (capillary) PCR ribotyping expanded Standardised surveillance protocol feasible for 14 EU countries with or without ongoing surveillance; Median time needed for the minimal, light and enhanced modules was 1.1, 2.0 and 2.9 person days per 10, 000 discharges, respectively 19

20 Rapid spread of type 027 Lack of clinical recognition and late diagnostics Change of attack-rate, alteration of the strain of sporulation, toxin production Antibiotic misusage: role of fluoroquinolones and resistance of 027 Change of cleaning of hospital environment Handwashing with ethanol Combatting CDI has insufficient priority in hospital management Lack of facilities for isolation and cohort isolation Transfer of patients with non-diagnosed CDAD between hospitals/countries

21 21

22 Czech Republic; emerging Type 176 ECCMID

23 Czech Republic; emerging Type Thursday, September 3, 2015

24 Clostridium difficile infections in the Netherlands: re-emergence of PCR ribotype 027 S. van Dorp, MD 24 C C. Harmanus, I. Sanders, E.J. Kuijper (LUMC) D. Notermans, S. de Greeff (RIVM)

25 Risk factors, Prediction models Clostridium difficile Reference laboratorium 25 Surveillance and outbreaks

26 20 hospitals Hospital surveillance All hospitalized patients >2 years old with a positive toxin test for C. difficile Patient data linked to PCR ribotypes Surveillance methods Incidence rates, clinical characteristics, circulating ribotypes and clusters Outbreak investigation All Dutch health-care facilities n>155 PCR ribotyping for outbreaks/severe cases Support with epidemiological and molecular (MLVA) analysis Outbreaks and transmission routes Surveillance hospitals All Dutch hospitals

27 5-year overview 27 N=4,399 patients, 51% female, 70% on antibiotics before infection 33% onset at home, 61% inhospital 18% recurrent infection (lab confirmed; 24% incl. unconfirmed cases) 24% severe infection N=465 overall mortality (13.3%)

28 Outbreak investigation n=547 n=274 n=330 n=296 N=174 Prevalence of PCR ribotype 027 4% 26% 15% 20% 31.7% Number of 027/all outbreaks 2/8 2/5* 1/3 2/2* 5 * Including an ongoing outbreak from previous year Increase of number of PCR ribotype 027 outbreaks in the prior year By MLVA, three distinct 027 clusters were found (n=98): Cluster 1 n=42 in 6 HCF Cluster 2 n=13 in 1 HCF Cluster 3 n=36 in >10 HCF n=7 unrelated cases

29 Conclusions National Reference Laboratory Re-emergence of C. difficile type 027 Most frequent types are Type 014/020 and C.difficile types 078 as third most frequently found C. difficile Type 078 associated with complicated course Thursday, September 3, 2015

30 C. difficile Type 078 similar severe CDI as type 027 younger population associated with community acquired CDI

31 31 pig farms, 30 farms with Type 078 and 1 farm 045 Of 56 farmers and employees, 14 (25%) were positive for fecal carriership of C. difficile Of 32 partners, 4 (13%) were positive Of 41 children, none was positive Typing revealed all Type 078, except for 1 farm (type 045) 31 Thursday, September 3, 2015

32 Wellcome Trust Sanger Institute 32 32

33 LUMC studies of C. difficile using NGS To study spread of epidemic strains (Type 027) To study evolution He et al., Nature genetics To study zoonotic potential Knetsch et al., Eurosurveillance To study antimicrobial resistance resistance Knetsch et al., Infect Genet & evol. Knetsch et al., Eurosurveillance

34 Knetsch et al; Eurosurveillance, Volume 19, Issue 45, 13 November 2014 Jun;19(6): >Knetsch et al, submitted. Spread of Clostridium difficile between humans and farm animals in the Netherlands revealed by whole genome sequencing 34 Keessen et al. Emerg Infect Dis. 2013

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36 Summary The number of reported cases of CDI-027 has increased in the year in many European countries, except UK The concept of CDI as a nosocomially acquired disease needs to be reconsidered 36 The burden of CA-CDI in Europe may be underestimated due to a lack of clinical suspicion and testing Many possible genetically diverse sources outside hospitals -animals, food, environment, carriers (infants), symptomatic patients- but no epidemiological evidence

37 Web portal support team Michael Behnke Axel Kola Petra Gastmeier Jeroen Alblas Daan Notermans Jaap van Dissel Acknowledgements 37 Pete Kinross Carl Suetens Warren Fawley Mark Wilcox All participants of ECDIS-Net!