Clostridium difficile

David B. Blossom, MD MSDivision of Healthcare Quality Promotion

Coordinating Center for Infectious DiseasesCenters for Disease Control and Prevention

Objectives

• Review of Clostridium difficile• Discuss the transmission and virulence of C.

difficile • Describe briefly the clinical manifestations,

evaluation and treatment of C. difficile-associated disease (CDAD)

• Identify the changing epidemiology of CDAD • Define surveillance strategies• Clarify preventive measures

Clostridium difficile

• Anaerobic spore-forming bacillus• Ubiquitous in nature

– Prevalent in soil– Isolated also from river, lake, sea, and swimming pool water

as well as from farm animals, dogs, and cats1

• 1935 - First described by Hall and O'Toole2 – Known colonizer of neonates (50% to 60%)

• 1978 - recognized as cause of antimicrobial-

associated pseudomembranous colitis3 • Now regarded as most common cause of

antimicrobial-associated diarrhea (20-30% of cases)

1. Brazier JS, al Saif. J Med Microbiol 1996; 45: 133-72. Hall I; O'Toole E. Am J Dis Child 1935; 49: 3903. Larson HE et al. Lancet 1978; 8073: 1063–1066.

Clostridium difficile : Pathogenesis

• Fecal oral transmission

• Survive gastric acidity

• Small intestine – spores germinate into vegetative forms

• Large intestine – normal flora disrupted by antibiotics

Diagram: Sunenshine et al Clev Clin J Med 2006 73(2) 187-197

C. difficile : Pathogenesis (cont)

• C. difficile can produce 3 toxins– Toxin A – enterotoxin– Toxin B – cytotoxin– (Binary toxin)

• Toxins cause the disease– Some strains only

produce one toxin• (A-, B+) 1% in a recent

study from Chicago1

Diagram: Sunenshine, et al. Clev Clin J Med 2006 73: 187-197

1.Geric B, et al. J Med Micro 2004;53:887-94

C. difficile-Associated Disease (CDAD)

• Incubation period – not known

• Diarrhea• Pseudomembranous colitis

- Has become the hallmark of

CDAD1

- Bloody diarrhea

- Raised whitish-yellow plaques

- Unexplained leukocytosis

(>10,000/cubic mm )

Pseudo-membranous

colitis

Healthy colon

1. Bartlett JG, et al. Gastroenterology 1978; 75:778-82

Toxic megacolon• Life-threatening acute dilation

• Characterized by - a dilated colon (megacolon) - Diameter : ≥ 5.5 cm - Fever, abdominal pain, abdominal distension - Radiograph: apparent edema of bowel wall • Complications - Perforation of colon - Sepsis, Shock - Death

Diagram: http://www.nlm.nih.gov/medlineplus/ency/imagepages/17189.htm

Summary: Pathogenesis of C. difficile

Exposed to C. difficile

Antibiotic therapy

Disturbed colonic microflora

Toxin A & Toxin B

Diarrhea & colitis

C. difficile : Risk Factors

• Increasing age1

• Exposure to antimicrobials• Length of stay in hospital2

• Infected patients/CDAD pressure• Immune response – IgG or local IgA against

toxin A3

• Severe underlying gastrointestinal diseases– GI procedures or GI surgery

• PPI/H2 blockers?

1.Brown E et al. Infect Control Hosp Epi 1990;11: 283-90 2. Johnson S, et al Lancet 1990;336:97-100 3. M. Delmee Clin Microbiol Infect 2001; 7: 411-416

Biggest Risks

Increasing Age

• Population based study in Sweden– Rate in those over 65 y.o = 20 times higher than

those under 20 y.o

• Quebec 2002 to 2003– Rates in >65 y.o increased from 120 to 800 per

100,000– Rates in under 65 y.o stayed stable (<100 per

100,0001.Karlstrom et al. Clin Infect Dis 1998;26:141-5 2.Pepin et al. CMAJ 2004;171:466-72

Antimicrobial Exposure

• Major risk factor for disease - Acquisition and growth of C. difficile- Suppression of normal flora of the colon- The risk doubles with longer than three days of antibiotic

therapy (risk ratio: 2.28) 1

• Clindamycin, penicillins, cephalosporins

• Fluroquinolones2

1.Wistrom J et al. J Antimicrob Chemother 2001;47:43-50 2. Pepin J. Clin Infect Dis. 2005 Nov 1;41(9):1254-60

Flouroquinolones• Quebec1

– 12 hospitals in 2004, OR for quinolones was 3.9 (95%CI 2.3-6.6)

– Ciprofloxacin, gatifloxacin and moxifloxacin associated, levofloxacin was not

• Pittsburgh2

– Formulary change: ciprofloxacin to levofloxacin

– C. diff rate = 2.7/1000 d/c increased to 6.8/1000 d/c

• OR 2.0 (95% CI 1.2-3.3)

1 Loo VG, et al. NEJM 2005; 353:2442-92 Muto CA et al. Infect Control Hosp Epidemiol 1005; 26:273-80

Length of Hospitalization

• Related to rates of colonization1,2

• Rates increase from <5% at admission to 26% after hospitalization

1.McFarland et al. N Engl J Med 1989;320:204-102. Clabots et al. JID 1992;166:561-67

Other Risk Factors:CDAD Pressure

• Number of concurrent inpatients with CDAD on the same ward increases a patient’s risk of developing CDAD

= daily exposure to CDAD patients

Length of stay at risk

CDAD Pressure

Dubberke et al. Arch Int Med 2007; 167: 1092-7

Variable Rel. Risk 95% CI

Sum CDAD pressure

1 or less Ref. Ref.

2-8 3.9 2.8-5.5

More than 8 9.7 7.1-13.1

Mean CDAD pressure

Less than 0.3 Ref. Ref.

0.3-1.4 6.4 4.6-8.9

More than 1.4 8.7 6.3-12.0

C. difficile : Laboratory Tests

• Stool culture: Most sensitive - Requiring 2-3 days for growth - Unable to distinguish between the

presence of toxin positive strains or toxin negative strains

• Cell cytotoxin test – most specific - Cytotoxin B• Direct Enzyme immunoassay (EIA) – most

common - May detect Toxin A only or Toxin A and B

C difficile colonies on agar plate: http://en.wikipedia.org/wiki/Clostridium_difficile

C. difficile: Resolution and Recurrence

• Resolution: 15 to 23% of patients - Within 2 to 3 days after discontinuation

- But most patients require specific

treatment

• C. difficile diarrhea recurs after treatment in ~20% of cases

• Historically mortality rate was 1 to 2.5 percent

Treatment• Initial Course of Antibiotics

– At least 10 days– Metronidazole (mild/moderate disease)– Oral vancomycin (severe disease)1

• Treatment of Recurrence– Longer course of metronidazole– Vancomycin with a taper– Rifaximin – Nitazoxanide – Vancomycin and rifaximin2

1. Zar FA, et al. CID 2007; 45: 302-7 2. Johnson S, et al. CID 2007; 44: 846-8

Costs

• Responsible for more than $1 billion annually in excess healthcare costs*

- Average of $3,600 excess costs per case

- Average of 3.6 extra hospital days

* Kyne L, et al. Clin Infect Dis. 2002;34:346-353

Increasing Rates of C. difficile-associated Disease

(CDAD) in US Hospitals

McDonald et al. 14th Annual Scientific Meeting of the Society for Healthcare Epidemiology of America, Philadelphia, PA. 2004

McDonald LC, et al. Emerg Infect Dis. 2006;12(3):409-15

National Estimates of US Short-Stay Hospital Discharges with C. difficile as First-Listed

or Any Diagnosis

McDonald LC, et al. Emerg Infect Dis. 2006;12(3):409-15

Rates of US Short-Stay Hospital Discharges with C. difficile Listed as Any Diagnosis by Age

United Kingdom, 1994-5 1

- Comparing well-matched C difficile patients and controls – no difference in mortality at d/c, 3 mos. and 6 mos.

Pittsburgh, 2000 2

– “Life-threatening disease” from 1.6% to 3.2% from 1989 to 2000– Colectomies increased from 0.48% to 2.6%– In hospital deaths (attr. to C. difficile) increased from 0.21-1.4%

Quebec, Canada, 2004 3

– Attributable mortality of 16.7% in 2005 epidemic in Quebec (in one hospital)

– Attributable 30 day mortality 6.9% in 12 Quebec hospital prospective study

Increasing Severity of CDAD

1. MacGowan AP, et al. J Antimicrob Chemother 1997;39:537-412. Dallal RM, et al. Ann Surg. 2002;235:363-372. Loo VG, et al. NEJM 2005;353:2442-24493. Pepin J et al. CMAJ. 2005;173(23):1037-42.

Potential reasons for increased CDAD incidence and severity

• Changes in underlying host susceptibility

• Changes in antimicrobial prescribing

• Changes in infection control practice

• New strain with increased virulence

Hypothesis: Change in underlying host susceptibility

• Increase in the average age of the population

- Increase in exposure to healthcare facilities

- Increase exposure to antimicrobials

• Possible, but probably not the whole story

Hypothesis: Use of alcohol-based hand rubs

• Hand hygiene

- Important prevention strategy

- HCWs can transmit C. difficile

• Traditional: Soap and water hand washing

• Increased use of alcohol-based hand rub over the last several years

Boyce et al. Infect Control Hosp Epidemiol 2006; 27:479-483

No relationship between alcohol-based hand rubs and increasing rates of CDAD

Hypothesis: Change in antimicrobial prescribing

• Quinolones– Popular for the management of CAP 1

– Most common treatment for uncomplicated UTI in women4

– Increased use by >50% from 2000– 2002 (p<0.001) 2

• Multiple antimicrobials and longer course of therapy

- Increases risk for C. difficile3

1. Jones RN, Mandell LA. Diagn Microbiol Infect Dis. 2002;44:69–76 2. MacDougall C et al Emerg Infect Dis . 2005 ; 11(3):380-4

3. Bignardi GE. J Hosp Infect 1998; 40:1–15.4. Kallen et al. Arch Int Med. 2005

Fact: Epidemic C. difficile Strain • Characteristics

– North American Pulsed Field Type 1 (NAP1) by PFGE– PCR ribotype 027– Toxinotype III or “BI” by REA

• Distinct from “J” strain of 1989-19921

– Binary toxin as a possible virulence factor• In addition to Toxin A&B containing

– 18 bp deletion in tcdC gene• May allow increased toxin production2

– Increased resistance to fluoroquinolones– No resistance to metronidazole

1 Johnson S, et al. N Engl J Med 1999;341:1645-512 Warny M, et al. Lancet 2005; 366: 1079-84

Acute Care Hospitals with CDAD Outbreaks* Between 2001-2004

*Detected by increases in the number of positive routine clinical laboratory tests for C. difficile.

McDonald LC, et al. N Engl J Med. 2005;353:2433-2441.

2

12

1

1

1

Common (Epidemic) Strain by PFGEDice (Opt:0.50%) (Tol 1.3%-1.3%) (H>0.0% S>0.0%) [0.0%-100.0%]

100

959085

Maine, Hospital APennsylvaniaPennsylvaniaMaine, Hospital B

Maine, Hospital BIllinoisIllinoisGeorgia

Maine, Hospital ANew JerseyNew JerseyOregonHistoric, 1988-1991Historic, 1993

Historic, 1990-1991Historic, 1984-1991

Historic, 1993-2000Oregon

Toxinotype and Potential Virulence Factors of Isolates

Characteristic:

1 Epidemic strain

n=62 (%)

Non-epidemic strain n=36 (%)

Toxinotype III 62 (100) 02

Binary toxin positive 62 (100) 2 (6)

18 bp tcdC deletion 62 (100) 1 (3)

1 Includes 5 historic “BI” isolates2 32 (89%) were toxinotype 0 or wild type

Increased Toxin A Production in vitro

Warny M, et al. Lancet. 2005;366:1079-1084.

In vitro production of toxins A and B by C. difficile isolates. Median concentration and IQRs are shown. C. difficile strains included 25 toxinotype 0 and 15 NAP1/027 strains (toxinotype III) from various locations.

Increased Toxin B Production in vitro

Warny M, et al. Lancet. 2005;366:1079-1084.

In vitro production of toxins A and B by C. difficile isolates. Median concentration and IQRs are shown. C. difficile strains included 25 toxinotype 0 and 15 NAP1/027 strains (toxinotype III) from various locations.

Increased Resistance in Epidemic Strain Isolates (After 2000)

No. (%) Intermediate or Resistant:

Epidemic strain (n=18)

Non-epidemic strains

(n=18) P

Clindamycin 16 (89) 10 (56) 0.06

Fluoroquinolones 18 (100) 8 (44) <0.001

States with the Epidemic Strain of C. difficile Confirmed by CDC and Hines VA labs (N=27),

Updated 4/3/2007

DC

PRAK

HI

Lethal hospital bug cases rocket, United Kingdom

• Potentially lethal cases of C. difficile “rocketed” from 1990s to 2004

• Cases had increased from 1,000 in 1990 to over 35,000 in 2003

• 44,488 cases of C. difficile in > 65 year olds in 2004.

BBC News. http://news.bbc.co.uk/2/hi/health/4186834.stm

NAP1/BI/027 in the Netherlands, 2006

1.Kuiper EJ et al. Emerg Infect Dis 2006;12(5):827-830.2. Goorhuis A et al. CID 2007; 45: 695-703

Other Places…

• Canada

• France

• Poland

• Austria

• Japan

Eurosurveillance Weekly Release. http://www.eurosurveillance.org/index.asp

Community-associated CDAD: Sentinel Cases of Severe Disease

•23 cases of severe community-associated CDAD (CA-CDAD)•Generally young and healthy•Approximately 1/3 without precedent antimicrobial use

Severe CDAD in Populations Previously at Low Risk—Four States, 2005 (1)

• Recent reports to the Pennsylvania Department of Health and CDC– Young patients without serious underlying disease– C. difficile toxin-positive by routine diagnostic testing– Responded to CDAD-specific therapy

• Peripartum – Within 4 weeks of delivery– Reports from PA, NJ, OH, and NH

• Community-associated– No hospital exposure in prior 3 months– Reports from Philadelphia and 4 surrounding counties

CDC. MMWR. 2005;54:1201-1205.

Severe CDAD in Populations Previously at Low Risk—Four States, 2005 (2)

CDC. MMWR. 2005;54:1201-1205.

Characteristic,

No. (%)

Community

(N=23)

Peripartum

(N=10)

Total

(N=33)

Aged < 18 years 11 (48) 0 (0) 11 (33)

Female 15 (65) 10 (100) 25 (76)

Antimicrobial exposure 15 (65) 9 (90) 24 (73)

Bloody diarrhea 6 (26) 2 (20) 8 (24)

Hospitalization necessary

6 (26) 4 (40) 10 (24)

ER visit necessary 3 (13) 2 (20) 5 (15)

Relapse 8 (35) 5 (50) 13 (39)

• Recent onset dates– February 26, 2003 – June 28, 2005– Only 1 case in 2003

• Transmission to close contacts in 4 cases• 8 cases without antimicrobial exposure

– 5 children; 3 required hospitalization– 3 had close contact with diarrheal illness

• Another 3 cases with < 3 doses of antimicrobials

• Clindamycin most common exposure (10 cases)

Severe CDAD in Populations Previously at Low Risk—Four States, 2005 (3)

CDC. MMWR. 2005;54:1201-1205.

Community-associated CDAD may be Increasing, Atlanta VA Hospital

0%

5%

10%

15%

20%

25%

30%

35%

2003 2004 2005 2006

Year

Pro

po

rtio

n o

f a

ll c

as

es

73 totalcases

93 total cases

99 total cases

67 total cases*

•Through July 31, 2006•Chi-square for trend: P<0.05

Gaynes, R et al. ICAAC 2006, San Francisco

Gaynes, R et al. ICAAC 2006, San Francisco

Many Patients Develop CDAD without Recent Hospital or Antimicrobial Exposure, Atlanta

VA Hospital, 2003-2006

Gaynes, R et al. ICAAC 2006, San Francisco

What is the Source?• Is it in the food supply?

– Pathogen of food animals1

– C. difficile has been found in retail meat (beef and veal)2

• 20% of Canadian convenience sample• Only 3 of the 12 isolates found had corresponding isolated that had caused

disease in humans• C difficile reported to live after being exposed to 71 degrees Celsius for 120

min.

– Potential for interspecies transmission3

• Turkey fed to dogs

1Songer JG, et al. Anaerobe 2006; 12: 1-42Rodriguez-Palacios A, et al. EID 2007; 13: 485-73Arroyo LG, et al. J Med Microbiol 2005; 54: 163-6

Defining CDAD Below the Waterline

Diarrhea in older ambulatory patients +/-

chronic conditions

Antibiotics? NSAIDS? PPIs?H2 blockers?

Dramatic, Severe Disease In Healthy,

Young Persons

Source: Human-to-Human and ?

Antibiotic-associated Inpatient Disease

?

C. difficile Surveillance

• Potential Role– Detect disease trends– Detect outbreaks– Compare CDAD rates between institutions– Guide interventions to control CDAD– Monitor the impact of these interventions

CDAD Definitions

• CDAD – Diarrhea in a patient with a

1. Positive C. difficile laboratory assay or

2. Pseudomembranous colitis on endoscopy or surgeryor

3. Pseudomembranous colitis seen on histopathology

• Recurrent CDAD– An episode of CDAD that occurs 8 weeks or less after the onset

of a previous episode• As long as the earlier episode resolved

Community vs. Hospital

HospitalizationAdmission Discharge

48 h

CA HO CO-HCFA CAIndeterminate

4 weeks 8 weeks

McDonald LC, et al. ICHE 2007; 28: 140-45

3 months after Discharge

• Inpatient rates– Case patients per 10,000 patient-days

• Community-associated rates– Case patients per 100,000 person-years

Expression of Rates

McDonald LC, et al. ICHE 2007; 28: 140-45

• Hospitals should be encouraged to conduct surveillance for CDAD – Track positive lab results (e.g. toxin A or A/B assays)– Consider measures to track outcomes

• Early diagnosis and treatment is important for reducing severe outcomes and should be emphasized

• Strict infection control: CDC fact sheet* – Contact precautions for CDAD patients– An environmental cleaning and disinfection strategy– Hand washing with CDAD patients in outbreak

Recommendations for Hospitals

*See C. difficile fact sheets: http://www.cdc.gov/ncidod/dhqp/

Hand Hygiene Measures • Alcohol-based hand rubs are now widely used

for routinely cleaning hands before/after patient care

• Alcohol-based hand rubs may not be effective against spore-forming organisms1

– Several studies ongoing

• If an institution is experiencing an outbreak of C. difficile disease, it is prudent to wash hands with soap and water after caring for patients with CDAD

1 Weber DJ et al. JAMA 2003;289:1274

Impact of Hydrogen Peroxide Vapor Room Impact of Hydrogen Peroxide Vapor Room Bio-Decontamination on Environmental Bio-Decontamination on Environmental

Contamination and Nosocomial Transmission Contamination and Nosocomial Transmission by by Clostridium difficileClostridium difficile

John M. Boyce1, MD, Nancy L. Havill1, MT,

Jonathan A. Otter2, BSc, L. Clifford McDonald3, MD

Nicholas M.T. Adams2, BSc, Angela Thompson3, MSc,

Lois Wiggs3, Judith Noble-Wang3, PhD

Hospital of Saint Raphael1, New Haven, CT

Bioquell PLC2, Andover, England

Centers for Disease Control & Prevention3, Atlanta, GA

Recommendations for CDAD in Previously Low-Risk Populations

• Further investigation and surveillance in these populations are warranted

– Strains responsible for severe CDAD in previously low-risk populations are unknown but under study

– May be other toxin variants and/or hospital epidemic strain

• Clinicians should consider the diagnosis - CDAD in patients without traditional risk factors

• Antimicrobial exposure is not benign– Continue to emphasize judicious antimicrobial use

Recommendations for Clinicians

• Vaccinate• Get the catheters out• Target the pathogen• Access the experts• Practice antimicrobial control• Use local data• Treat infection, not contamination• Treat infection, not colonization• Know when to say “no” to vanco• Stop treatment when infection is cured or unlikely• Isolate the pathogen• Break the chain of contagion

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Recommendations for Clinicians

• Vaccinate• Get the catheters out• Target the pathogen• Access the experts• Practice antimicrobial control• Use local data• Treat infection, not contamination• Treat infection, not colonization• Know when to say “no” to vanco• Stop treatment when infection is cured or unlikely• Isolate the pathogen• Break the chain of contagion

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Use Antimicrobials

Wisely

Some CDC References

• Campaign to Prevent Antimicrobial Resistance: 12 Steps for Healthcare Settings

• Management of Multidrug-Resistant Organisms in Healthcare Settings, 2006

http//:www.cdc.gov/ncidod/dhqp/index.html

dblossom@cdc.govhttp//:www.cdc.gov/ncidod/dhqp/index.html

Thank You!

The information presented here represents the opinion of the presenter and does not necessarily represent the opinion of the US Public Health Service, the Centers for Disease Control and Prevention or the Department of Health and Human Services