Epidemiology of Epidemiology of Clostridium Clostridium

difficiledifficile infection (CDI)infection (CDI)Lyn Gilbert,Lyn Gilbert,

Sydney Institute for Emerging Sydney Institute for Emerging

Infectious Disease & CIDMInfectious Disease & CIDM-- Public Public

Health Health

Hospital Week 2010Hospital Week 2010

Clostridium difficile

- background

• 1st described 1935 – Bacillus difficilis

• 1978 - cause of: – (10-20%) antibiotic-associated diarrhoea

– pseudomembranous colitis

• Gram positive; spore-forming anae anaerobe

• Toxin-mediated disease

Distribution & acquisition

• Ubiquitous – environment (water), domestic animals

• Asymptomatic faecal carriage– 3% adults (~50% in LTCF) ; 66% infants

• Acquisition – ingestion– Spores widely disseminated

• Resistant to antiseptics

– Hand/skin contamination; fomites

• Major risks:– Hospital admission; prolonged stay

Acquisition

Imprint of a health care worker's gloved hand after

examining a patient with Clostridium difficile infection

Pathogenesis

• Acquisition of toxigenic strain– Reduced colonisation resistance

• e.g. ?gastric acid suppressants

• Altered bowel flora• Antibiotics – broad spectrum; prolonged;

polypharmacy

• GI surgery; procedures; co-morbidities; age

• Neonates resistant to disease

• Elderly most at risk

C. difficile toxins

• 19.6 kb pathogenicity locus (PaLoc)

– tcdA, tcdB – encode toxins A & B

– tcdR, tcdE – toxin regulation/secretion

• Produced during stationary phase

– tcdC – -ve regulator of toxin synthesis

• Produced during log phase

• Binary toxin - ?role; uncommon

– ?enhances bacteria adherence

• Most common:

– A+B+binary-ve; A-B+binary-ve

Risks for nosocomial CDIRisk factor Odds ratio P value

No acid suppression 1

H2RA only 1.53 .008

Daily protein pump

inhibitor (PPI)

1.74

<.001

>Daily PPI 2.36

Age, per year 1.01

No antibiotics 1

Low risk a/b 1.82 .008

High risk a/b 3.57

<.001Other co-morbidities 1.5-2.3

Howell et al. Arch Intern Med 2010; 170:784-90

Risk factors for nosocomial

CDI

Howell et al. Arch Intern Med 2010; 170:784-90

Acid suppression

& antibiotics

Hospital length of stay

CDI in Canada

• 2003-4: CDI outbreaks

– Montreal (& other Quebec) hospitalsEggerston & Sibbald: CMAJ 2004;171:19-21

• Hypotheses Loo et al: CMAJ 2004;171:47-8

– Emergence of hypervirulent strain?

• 85% strains - clonal (by PFGE)

– More susceptible hosts?

• Older, sicker, immunocompromised; PPIs

– High risk antibiotics (fluoroquinolones)

– Poor housekeeping/infection control

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CDI in Estrie region of Quebec

1991-2 2003

Rate/100,000

– All 35.6 156.3

- >65yrs 102.0 866.5

Complications (%) 7.1 18.2

Deaths – 30d (%) 4.7 13.8

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• Review of cases: 680-bed hospital - defined population base

• 1721 cases – sharp increase, 2003

Pepin et al. CMAJ 2004;171:466-72

Age-related incidence of CDI

Quebec 1991-2003

--

Pepin et al. CMAJ 2004;171:466-72

Epidemic C. difficile strain

• PFGE type NAP1; PCR ribotype 027

• Increased/prolonged toxin production

– tcdC - 18 bp deletion

• Most produce binary toxin

• Quinolone resistant

• Increased sporulation

• Spread widely in USA, Canada & UK

Risks for CDI (mainly 027)

Cohort study; inpatients 2003-4

• 7421 episodes of care; 5619 patients

• 293 CDI episodes

Risk factors: (adjusted hazards ratio; AHR)

• Increasing age (1.04 per year)

• Prolonged hospital stay (3-5)

• Quinolone Rx, incl. cipro. (3.44)

• BS β lactams; azithro, clinda (1.6-1.9)

• Longer duration of antibiotic Rx

Not significant: Use of PPIs; recent surgery

Pepin et al. CID 2005;41:1254-60

Is C. difficile 027 controllable?

• 2003-5 UK - serious hospital outbreaks

• 2004: mandatory hospital reporting

• 2004-7 steady increase in rates – x4 incr. in “CDI” on death certificate

• 2007: enhanced surveillance; ribotyping

• 2008: 29% decr. “CDI” deaths

• 2008-9: CDI rates falling – 19% fall in 027 (from 36% in 2007-8)

Freeman et al Clin Microbiol Rev 2010;23:529-49

Is C. difficile 027 controllable?

UK mandatory CDI reporting (www.hpa.org.uk

Is C. difficile 027 inevitable?

• European CDI hospital surveys:

– 2005: 2.45 (0.13-7.1)/10,000 patient days

– 2008: 5.5 (0-36) per 10,000 pd

• (106 hospitals; 34 countries)

• 395 isolates: 62 PCR ribotypes

– 014 (15%), 001 (10%), 078 (8%) 027 (5%)

• 80% hospital acquired; 79% antibiotics

• 7% ICU; ~9% attributable mortality

*Freeman et al Clin Microbiol Rev 2010;23:529-49

C. difficile in Australia • No evidence of increased incidence

– BUT - minimal surveillance;

– Variable diagnostic testing

• Various genotypes

– BUT – limited culture/typing of isolates

– 1 case of 027 in 2008 (imported)

– At least 7 027 cases in 2010 in Victoria

• Epworth Hospital & LTCF

• Fluoroquinolone res. rare (1-2%)

• Mandatory reporting – coming soon

Community-acquired (CA) CDI

• Not well recognised but not new:

• 1990s - CA CDI = 11-28% of CDI cases

• UK – GP-based study 1994-2004– CA-CDI– increased from 0 to 18/100,000

• Risk factors: hospital admission 2-6m ago

– 50% no antibiotics;

– 1/3 no antibiotics or hospital admission

– Younger patients (vs HA CDI)

• ?Recent increase (with 027) ?recognition

CDI in animals

• Various studies:– 10% dogs; 2-20% cats

– 40% calves with diarrhoea; 21% controls

• Various ribotypes – rarely 027– 078 found in piglets & calves (& humans)

• C. difficile isolates from meat (esp. 078)– no evidence of food-borne disease

• 078 – virulent– tcdC deletion & mutation; binary toxin +ve

Antibiotic use as risk factor

• Most frequently

– Broad spectrum (cephs; clindamycin - any)

– Fluoroquinolone use – esp. 027 (OR ~13)

– Prolonged use; combinations

• CDI rates reduced by restricting:– Use of high risk antibiotics

– (Duration of antibiotic Rx & combinations)

• e.g. IV penicillin for pneumonia;• Especially in the elderly

– Single dose/ <24 hr surgical prophylaxis

Summary

• Limited penetration of virulent strains in Australia so far (probably)

• Need to be prepared– Laboratory testing; typing; surveillance

• Can be prevented/controlled by– Continued improvement in

• Hand hygiene

• Patient isolation; contact precautions

• Environmental cleaning

• Antibiotic stewardship

C. difficile diagnosis in NSW*

• 13 labs surveyed - private and public

• 5 - GDH (+toxin tests) +/or PCR

• 7 toxin A/B EIA; 1 toxin A only

• 7 culture C. difficile

– 2 submit cultures for typing

• Of all stools submitted:

– 31% (11-61%) tested for C. difficile

– Of tested stools, 6.2% (3.3-10%) +ve

*John Ferguson, personal communication

Risks for complicated CDI (027)

• Definition:

– Megacolon, perforation, colectomy, shock

requiring vasopressors, +/or death within 30d

• Significant risk factors (adj. OR; p value)

– Age >65 yrs (3.4; <0.05)

– Hospital acquisition (4.6; <0.001)

– Tube feeding, 2 m (2.4; <0.001)

– Immunosuppression (2.3; <0.001)

– Leucocytosis – wcc >20 (3.8; <0.001);

– Renal failure - creat >200 (4.1; <0.001)

– Rx vanc vs metr (0.2; p=0.02)

Pepin et al. CMAJ 2004;171:466-72

Prevalence of CDI

• Limited, inconsistent surveillance

• Varied testing indications & methods

• Varied case definitions, denominators

• Europe 2004:

– Hospital incidence: 2.45 (0.13-7.1) per

10,000 patient days

• USA, Canada, UK: 2000-2005:

– increased rates/complications/deaths

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Freeman et al Clin Microbiol Rev 2010;23:529-49