Clostridium difficile : Biology, Diagnosis and Infection Control Clostridium difficile Disease.

Clostridium Clostridium difficiledifficile::

Biology, Diagnosis Biology, Diagnosis and Infection Controland Infection Control

Clostridium Clostridium difficiledifficile Disease Disease

Clostridium difficile

Microbiology and Clinical diseaseMicrobiology and Clinical disease

Laboratory detectionLaboratory detection

Infection Control considerationsInfection Control considerations

Treatment Treatment

MicrobiologyMicrobiology

Clostridium spp. - Characteristics

Gram-positive bacillus - Usually Gram-positive bacillus - Usually largelarge

Produce endosporesProduce endosporesMay appear terminal or centralMay appear terminal or centralexcellent survival in environmentexcellent survival in environment

Strictly anaerobic metabolismStrictly anaerobic metabolism

Produce variety of potent toxinsProduce variety of potent toxins

Clostridium perfringens Gas gangrene Food poisoning

Clostridium tetani Tetanus

Clostridium botulinum Botulism

Clostridium difficile Antibiotic associated diarrhea and colitis

Clostridium spp. of clinical importance


Normal flora in 1-3% normal adultNormal flora in 1-3% normal adult

~ 70% of children less than 12 months ~ 70% of children less than 12 months GI floraGI flora

50% of individuals with exposure to 50% of individuals with exposure to inpatient health care facilities may be inpatient health care facilities may be asymptomatic carriers of asymptomatic carriers of C. difficileC. difficile

Accounts for 15-25% of all antimicrobial-Accounts for 15-25% of all antimicrobial-associated diarrheaassociated diarrhea

Accounts for 95-100% of antibiotic Accounts for 95-100% of antibiotic associated pseudomembranous colitisassociated pseudomembranous colitis

Fecal-oral transmissionFecal-oral transmissioncontaminated environment contaminated environment hands of healthcare personnelhands of healthcare personnel

Produce 2 exotoxinsProduce 2 exotoxins A enterotoxin, B cytotoxinA enterotoxin, B cytotoxin


Toxin A

Binds to specific CHO receptors on Binds to specific CHO receptors on intestinal epitheliumintestinal epithelium

Toxin induced inflammatory processToxin induced inflammatory processneutrophilsneutrophils inflammatory mediatorsinflammatory mediatorsfluid secretionfluid secretionaltered membrane permeabilityaltered membrane permeabilityhaemorrhagic necrosishaemorrhagic necrosis

Toxin B

Binding site not yet identifiedBinding site not yet identified

Depolymerization of filamentous actinDepolymerization of filamentous actindestruction of cell cytoskeletondestruction of cell cytoskeletonrounding of cellsrounding of cells

Clinical Manifestations

Asymptomatic carriage (neonates)Asymptomatic carriage (neonates)

Diarrhea - Diarrhea - 5-10 days after starting antibiotics5-10 days after starting antibiotics maybe be 1 day after startingmaybe be 1 day after starting may be up to 10 weeks after stoppingmay be up to 10 weeks after stopping may be after single dosemay be after single dose

Spectrum of diseaseSpectrum of disease brief, self limitingbrief, self limiting cholera-like - 20X/day, watery stoolcholera-like - 20X/day, watery stool

Clinical Manifestations

Additional symptomsAdditional symptomsabdominal pain, fever, nausea, malaise, abdominal pain, fever, nausea, malaise,

anorexia, hypoalbuminaemia, colonic bleeding, anorexia, hypoalbuminaemia, colonic bleeding, dehydrationdehydration

Acute toxic megacolonAcute toxic megacolonacute dilatation of colonacute dilatation of colonsystemic toxicitysystemic toxicityobstructionobstructionhigh mortality (64%)high mortality (64%)

Colonic perforationColonic perforation

Pathogenesis

Microflora of gutMicroflora of gut10101212 bacteria/gram bacteria/gram400-500 species400-500 speciescolonisation resistancecolonisation resistance

Acquisition of spores by faecal/oral Acquisition of spores by faecal/oral

Disruption of normal colonic floraDisruption of normal colonic flora

Pathogenesis

Colonisation with Colonisation with C. difficileC. difficile

Late log / early stationary phase - toxin Late log / early stationary phase - toxin productionproduction

Production of toxin A +/- BProduction of toxin A +/- B

Mucosal injuryMucosal injury

Pathogenesis

Colonic mucosa - raised yellow / white Colonic mucosa - raised yellow / white plaquesplaques initially smallinitially smallenlarge and coalesceenlarge and coalesce

Inflamed mucosaInflamed mucosa

Epidemiology - Current epidemic strain

BI/NAP1/027, toxinotype IIIBI/NAP1/027, toxinotype III Historically uncommon – epidemic since 2000Historically uncommon – epidemic since 2000

More resistant to fluoroquinolonesMore resistant to fluoroquinolonesHigher MICs compared to historic strains and Higher MICs compared to historic strains and

current strainscurrent strains

More virulentMore virulent Increased toxin A and B productionIncreased toxin A and B productionPolymorphisms in binding domain of toxin BPolymorphisms in binding domain of toxin B Increased sporulationIncreased sporulation

Stabler et al. J Med Micro. 2008;57:771–5.Akerlund et al. J Clin Microbiol. 2008;46:1530–3.

Epidemiology -Risk Factors for Disease

Antimicrobial exposureAntimicrobial exposure

Acquisition of Acquisition of C. difficileC. difficile

Advanced ageAdvanced age

Underlying illnessUnderlying illness

ImmunosuppressionImmunosuppression

Tube feedsTube feeds

? Gastric acid suppression? Gastric acid suppression

Antibiotic Risk

High Risk AntibioticsHigh Risk Antibiotics

Cefotaxime/CeftriaxoneCefotaxime/Ceftriaxone

CefalexinCefalexin

CefuroximeCefuroxime

CeftazidimeCeftazidime

CiprofloxacinCiprofloxacin

MoxifloxacinMoxifloxacin

Clindamycin (low dose)Clindamycin (low dose)

Medium Risk Medium Risk AntibioticsAntibiotics

MeropenemMeropenem

ErtapenemErtapenem

Clindamycin (high dose)Clindamycin (high dose)

Amox/clavAmox/clav

Piperacillin/TazoPiperacillin/Tazo

ErythromycinErythromycin

ClarithromycinClarithromycin

Antibiotic Risk

Low Risk Antibimobial agentsLow Risk Antibimobial agents

Benzyl penicillinBenzyl penicillin GentamicinGentamicin

AmoxicillinAmoxicillinMetronidazoleMetronidazole

CloxacillinCloxacillin VancomycinVancomycin

TetracyclinesTetracyclines TeicoplaninTeicoplanin

TrimethoprimTrimethoprim Quin/DalfoQuin/Dalfo

NitrofurantoinNitrofurantoin Linezolid Linezolid

Fusidic acidFusidic acid TigecyclineTigecycline

RifampicinRifampicin DaptomycinDaptomycin

Disease ImpactDisease Impact

Disease ImpactDisease Impact

Hospital-acquired, hospital-onset: 165,000 Hospital-acquired, hospital-onset: 165,000 cases, $1.3 billion in excess costs, and cases, $1.3 billion in excess costs, and 9,000 deaths annually9,000 deaths annually

Hospital-acquired, post-discharge (up to 4 Hospital-acquired, post-discharge (up to 4 weeks): 50,000 cases, $0.3 billion in weeks): 50,000 cases, $0.3 billion in excess costs, and 3,000 deaths annuallyexcess costs, and 3,000 deaths annually

Nursing home-onset: 263,000 cases, $2.2 Nursing home-onset: 263,000 cases, $2.2 billion in excess costs, and 16,500 deaths billion in excess costs, and 16,500 deaths annuallyannually

Age-Adjusted Death Rate* for Enterocolitis Due to C. difficile, 1999–

2006

*Per 100,000 US standard population

0

0.5

1.0

1.5

2.0

2.5

1999 2003

Rat

e

2000 20042001 20052002 2006Year

MaleFemaleWhiteBlackEntire US population

Laboratory Laboratory TestingTesting

Current Testing Options

CytotoxinCytotoxin Neutralization Assay*Neutralization Assay*

Toxigenic Culture Toxigenic Culture

Microwell EIA*Microwell EIA*

Rapid Cartridge EIA*Rapid Cartridge EIA*

Glutamate Dehydrogenase Based Glutamate Dehydrogenase Based Combination Procedures*Combination Procedures*

Molecule Procedures*Molecule Procedures*

* DIDTL Research Lab published or presented

History of testing at CCHMC

Antigen testing followed by cell culture Antigen testing followed by cell culture based cytotoxin assay - 48 hour TATbased cytotoxin assay - 48 hour TAT

Cell culture cytotoxin assay only – 48 hour Cell culture cytotoxin assay only – 48 hour TATTAT

Plate based EIA for toxin A and B - 24 hour Plate based EIA for toxin A and B - 24 hour TATTAT

Lateral flow EIA - Same day TATLateral flow EIA - Same day TAT

NAAT Testing – Same day TATNAAT Testing – Same day TAT

Molecular Based Tests

BD GeneOhm Cdiff AssayBD GeneOhm Cdiff Assay

Gen-Probe Prodesse® ProGastro Gen-Probe Prodesse® ProGastro CdCd

Cepheid® Xpert Cepheid® Xpert C. difficileC. difficile

Meridian Meridian illumiillumigenegene C. difficileC. difficile


Peterson L R , Robicsek A Ann Intern Med 2009;151:176-179

Quinn, et.al. 2010. JCM, 48:603-605

Noren, et.al. 2010 JCM, 49:710-711


The Key =Good Specimens

Only diarrheal stools (≥ 3/day) should be Only diarrheal stools (≥ 3/day) should be submitted for testing submitted for testing no asymptomatic patient stoolsno asymptomatic patient stools

Only a single specimen should be testedOnly a single specimen should be tested

Test should be used for diagnosis only and Test should be used for diagnosis only and not “test-of-cure”not “test-of-cure”

One specimen per 7 daysOne specimen per 7 days

Children < 1 year old?Children < 1 year old?

Value of Repeat Testing

Peterson L R , Robicsek A Ann Intern Med 2009;151:176-179

Aichinger et.al. J Clin Microbiol 2008;46:3795-3797

Conclusion: “..little value of repeat testing for C. difficle by EIA or PCR.”

Value of Repeat Testing

Luo and Banaei, J Clin Microbiol, 2010;48:3738-3741

Conclusion: “Repeat PCR within 7 days appears rarely useful, except for patients with evidence of a new infection.”

Studies

Peterson L R , Robicsek A Ann Intern Med Peterson L R , Robicsek A Ann Intern Med 2009; 151: 1762009; 151: 176 ““Diagnoses of CDI will be more accurate if clinicians Diagnoses of CDI will be more accurate if clinicians

use tests with a higher sensitivity, reduce the use tests with a higher sensitivity, reduce the frequency of testing for a single episode of diarrhea, frequency of testing for a single episode of diarrhea, and give more attention to key elements of the and give more attention to key elements of the patient's history.” patient's history.”

Aichinger et.al. J Clin Microbiol 2008;46:3795-Aichinger et.al. J Clin Microbiol 2008;46:3795-37973797 ““..little value of repeat testing for ..little value of repeat testing for C. difficle C. difficle by EIA or by EIA or

PCR.” PCR.”

C. difficle testing conclusions

Many Many C. difficile C. difficile toxin testing optionstoxin testing options

Molecular assays perform very wellMolecular assays perform very well

Test only patients with diarrheaTest only patients with diarrhea

Repeat testing for toxin within 7 days of Repeat testing for toxin within 7 days of little valuelittle value

Infection ControlInfection Control

Clostridium difficile Clostridium difficile (CDI)(CDI) Infections Infections ToolkitToolkit

Carolyn Gould, MD MSCR

Cliff McDonald, MD, FACP

Division of Healthcare Quality Promotion

Centers for Disease Control and Prevention

Prevention Strategies: Core

Contact Precautions for duration of diarrheaContact Precautions for duration of diarrhea

Hand hygiene in compliance with CDC/WHOHand hygiene in compliance with CDC/WHO

Cleaning and disinfection of equipment and Cleaning and disinfection of equipment and environmentenvironment

Laboratory-based alert system for Laboratory-based alert system for immediate notification of positive test immediate notification of positive test resultsresults

Educate about CDI: HCP, housekeeping, Educate about CDI: HCP, housekeeping, administration, patients, familiesadministration, patients, families

Prevention Strategies: Supplemental

Extend use of Contact Precautions beyond Extend use of Contact Precautions beyond duration of diarrhea (e.g., 48 hours)*duration of diarrhea (e.g., 48 hours)*

Presumptive isolation for symptomatic Presumptive isolation for symptomatic patients pending confirmation of CDIpatients pending confirmation of CDI

Evaluate and optimize testing for CDIEvaluate and optimize testing for CDI

Implement soap and water for hand Implement soap and water for hand hygiene before exiting room of a patient hygiene before exiting room of a patient with CDIwith CDI

* Not included in CDC/HICPAC 2007 Guideline for Isolation Precautions

Prevention Strategies: Supplemental

Implement universal glove use on units Implement universal glove use on units with high CDI rates*with high CDI rates*

Use sodium hypochlorite–containing agents Use sodium hypochlorite–containing agents for environmental cleaningfor environmental cleaning

Implement an antimicrobial stewardship Implement an antimicrobial stewardship programprogram


Rationale for considering extending isolation beyond duration of diarrhea

Bobulsky et al. Clin Infect Dis 2008;46:447-50.

Consider presumptive isolation for patients with > 3 unformed stools within

24 hours

Patients with CDI may contaminate environment Patients with CDI may contaminate environment and hands of healthcare personnel pending results and hands of healthcare personnel pending results of diagnostic testingof diagnostic testing

CDI responsible for only ~30-40% of hospital-onset CDI responsible for only ~30-40% of hospital-onset diarrheadiarrhea

However, CDI more likely among patients with However, CDI more likely among patients with >>3 3 unformed stools within 24 hoursunformed stools within 24 hours Send specimen for testing and presumptively isolate Send specimen for testing and presumptively isolate

patient pending resultspatient pending results Positive predictive value of testing will also be optimized if Positive predictive value of testing will also be optimized if

focused on patients with focused on patients with >>3 unformed stools within 24 3 unformed stools within 24 hourshours

Exception: patient with possible recurrent CDI (isolate and Exception: patient with possible recurrent CDI (isolate and test following first unformed stool)test following first unformed stool)

Evaluate and optimize test-ordering practices and diagnostic methods

Most laboratories have relied on Toxin A/B Most laboratories have relied on Toxin A/B enzyme immunoassaysenzyme immunoassaysLow sensitivities (70-80%) lead to low negative Low sensitivities (70-80%) lead to low negative

predictive valuepredictive value

Despite high specificity, poor test ordering Despite high specificity, poor test ordering practices (i.e. testing formed stool or repeat practices (i.e. testing formed stool or repeat testing in negative patients) may lead to testing in negative patients) may lead to many false positivesmany false positives

Peterson et al. Ann Intern Med 2009;15:176-9.

Evaluate and optimize test-ordering practices and diagnostic methods

Consider more sensitive diagnostic Consider more sensitive diagnostic paradigms but apply these more judiciously paradigms but apply these more judiciously across the patient population across the patient population Employ a highly sensitive screen with Employ a highly sensitive screen with

confirmatory test or a PCR-based molecular confirmatory test or a PCR-based molecular assayassay

Restrict testing to unformed stool onlyRestrict testing to unformed stool onlyFocus testing on patients with Focus testing on patients with >> 3 unformed 3 unformed

stools within 24 hoursstools within 24 hoursRequire expert consultation for repeat testing Require expert consultation for repeat testing

within 5 dayswithin 5 days

Peterson et al. Ann Intern Med 2009;15:176-9.

Hand Hygiene – Soap vs. Alcohol gel

Alcohol not effective in eradicating Alcohol not effective in eradicating C. C. difficiledifficile spores spores

Discouraging alcohol gel use may Discouraging alcohol gel use may undermine overall hand hygiene program undermine overall hand hygiene program with untoward consequences for HAIs in with untoward consequences for HAIs in generalgeneral

Boyce et al. Infect Control Hosp Epidemiol 2006;27:479-83.

Lack of efficacy of alcohol-based handrub against C. difficile

Oughton et al. Infect Control Hosp Epidemiol 2009;30:939-44.

Hand Washing: Product Comparison

Product Log10 Reduction

Tap Water 0.76

4% CHG antimicrobial hand wash 0.77

Non-antimicrobial hand wash 0.78

Non-antimicrobial body wash 0.86

0.3% triclosan antimicrobial hand wash 0.99

Heavy duty hand cleaner used in manufacturing environments

1.21*

* Only value that was statistically better than others

Edmonds, et al. Presented at: SHEA 2009; Abstract 43.

Hand Hygiene Methods

Conclusion: Spores may be difficult to Conclusion: Spores may be difficult to eradicate even with hand washing.eradicate even with hand washing.

Since spores may be difficult to remove Since spores may be difficult to remove from hands even with hand washing, from hands even with hand washing, adherence to glove use, and Contact adherence to glove use, and Contact Precautions in general, should be Precautions in general, should be emphasized for preventing emphasized for preventing C. difficile C. difficile transmission via the hands of transmission via the hands of healthcare personnelhealthcare personnelJohnson et al. Am J Med 1990;88:137-40.

Glove Use

Rationale for considering universal Rationale for considering universal glove on units with high CDI ratesglove on units with high CDI rates

Although the magnitude of their Although the magnitude of their contribution is uncertain, asymptomatic contribution is uncertain, asymptomatic carriers have a role in transmissioncarriers have a role in transmission

There may be a role for universal glove use There may be a role for universal glove use as a special approach to reducing as a special approach to reducing transmission on units with longer lengths of transmission on units with longer lengths of stay and high endemic CDI rates stay and high endemic CDI rates

Universal Glove Use

Riggs et al. Clin Infect Dis 2007;45:992–8.

Role of asymptomatic carriers?

Environmental Cleaning

Bleach kills spores, other standard Bleach kills spores, other standard disinfectants much less sodisinfectants much less so

Limited data suggest cleaning with bleach Limited data suggest cleaning with bleach reduces reduces C. difficileC. difficile transmission transmission

Two before-after intervention studies Two before-after intervention studies demonstrated benefit of bleach cleaning in demonstrated benefit of bleach cleaning in units with high endemic CDI ratesunits with high endemic CDI rates

Bleach may be most effective in reducing Bleach may be most effective in reducing burden where CDI is highly endemicburden where CDI is highly endemic

Mayfield et al. Clin Infect Dis 2000;31:995-1000.Wilcox et al. J Hosp Infect 2003;54:109-14.

Environmental Cleaning

Assess adequacy of cleaning before Assess adequacy of cleaning before changing to new cleaning product changing to new cleaning product such as bleachsuch as bleach

Ensure that environmental cleaning is adequate Ensure that environmental cleaning is adequate and high-touch surfaces are not being overlookedand high-touch surfaces are not being overlooked

One study using a fluorescent environmental One study using a fluorescent environmental marker to asses cleaning showed:marker to asses cleaning showed: only 47% of high-touch surfaces in 3 hospitals were only 47% of high-touch surfaces in 3 hospitals were

cleaned cleaned sustained improvement in cleaning of all objects, sustained improvement in cleaning of all objects,

especially in previously poorly cleaned objects, following especially in previously poorly cleaned objects, following educational interventions with the environmental services educational interventions with the environmental services staffstaff

Antibiotic Stewardship

A prospective, controlled interrupted time-A prospective, controlled interrupted time-series analysis in 3 acute medical wards series analysis in 3 acute medical wards for the elderly in the UK demonstrated the for the elderly in the UK demonstrated the impact of antimicrobial management on impact of antimicrobial management on reducing CDI. reducing CDI. Introduced a narrow-spectrum antibiotic policyIntroduced a narrow-spectrum antibiotic policy Reinforced using feedbackReinforced using feedback Associated with significant changes in targeted Associated with significant changes in targeted

antibiotics and a significant reduction in CDIantibiotics and a significant reduction in CDI

Fowler et al. J Antimicrob Chemother 2007;59:990-5.

Contact Precautions for Contact Precautions for duration of illnessduration of illness

Hand hygiene in Hand hygiene in compliance with compliance with CDC/WHOCDC/WHO

Cleaning and Cleaning and disinfection of disinfection of equipment and equipment and environmentenvironment

Laboratory-based alert Laboratory-based alert system system

CDI surveillanceCDI surveillance

EducationEducation

Prolonged duration of Prolonged duration of Contact Precautions* Contact Precautions*

Presumptive isolation Presumptive isolation

Evaluate and optimize Evaluate and optimize testingtesting

Soap and water for HH Soap and water for HH upon exiting CDI roomupon exiting CDI room

Universal glove use on Universal glove use on units with high CDI units with high CDI rates*rates*

Bleach for environmental Bleach for environmental disinfectiondisinfection

Antimicrobial Antimicrobial stewardship programstewardship program

Core Measures Supplemental Measures


TreatmentTreatment

Treatment regimens

MetronidazoleMetronidazole

VancomycinVancomycin

CholestyramineCholestyramine

Yeast supplement – Yeast supplement – Saccharomyces (boulardii) Saccharomyces (boulardii) cerevisiaecerevisiae

Fresh stool instilationFresh stool instilation

Broth cultured bacteriaBroth cultured bacteria

ProbioticsProbiotics

References

Dubberke ER, Butler AM, Reske KA, et al. attributable Dubberke ER, Butler AM, Reske KA, et al. attributable outcomes of endemic outcomes of endemic Clostridium difficileClostridium difficile-associated -associated disease in nonsurgical patients. Emerg Infect Dis disease in nonsurgical patients. Emerg Infect Dis 2008;14:1031-8.2008;14:1031-8.

Dubberke ER, Reske KA, Olssen MA, et al. Short- and long Dubberke ER, Reske KA, Olssen MA, et al. Short- and long term attributable costs of term attributable costs of Clostridium difficileClostridium difficile-associated -associated disease in nonsurgical inpatients. Clin Infect Dis disease in nonsurgical inpatients. Clin Infect Dis 2008:46:497-504. 2008:46:497-504.

Edmonds S, Kasper D, Zepka C, et al. Edmonds S, Kasper D, Zepka C, et al. Clostridium difficileClostridium difficile and hand hygiene: spore removal effectiveness of and hand hygiene: spore removal effectiveness of handwash products. Presented at: SHEA 2009; Abstract handwash products. Presented at: SHEA 2009; Abstract 43.43.

References

Elixhauser, A. (AHRQ), and Jhung, MA. (Centers for Disease Elixhauser, A. (AHRQ), and Jhung, MA. (Centers for Disease Control and Prevention). Control and Prevention). Clostridium Difficile-Associated Disease Clostridium Difficile-Associated Disease in U.S. Hospitals, 1993–2005in U.S. Hospitals, 1993–2005. HCUP Statistical Brief #50. April . HCUP Statistical Brief #50. April 2008. Agency for Healthcare Research and Quality, Rockville, 2008. Agency for Healthcare Research and Quality, Rockville, MD. MD. http://www.hcup-us.ahrq.gov/reports/statbriefs/sb50.pdf http://www.hcup-us.ahrq.gov/reports/statbriefs/sb50.pdf

Fowler S, Webber A, Cooper BS, et al. Successful use of Fowler S, Webber A, Cooper BS, et al. Successful use of feedback to improve antibiotic prescribing and reduce feedback to improve antibiotic prescribing and reduce Clostridium difficile Clostridium difficile infection: a controlled interrupted time infection: a controlled interrupted time series. J Antimicrob Chemother 2007;59:990-5.series. J Antimicrob Chemother 2007;59:990-5.

Heron MP, Hoyert DLm Murphy SL, et al. Heron MP, Hoyert DLm Murphy SL, et al. Natl Vital Stat Rep Natl Vital Stat Rep 2009;57(14). US Dept of Health and Human Services, CDC; 2009;57(14). US Dept of Health and Human Services, CDC; 2009. Available at 2009. Available at http://www.cdc.gov/nchs/data/nvsr/nvsr57/nvsr57_14.pdf

http://www.cdc.gov/nchs/data/nvsr/nvsr57/nvsr57_14.pdf

References

Johnson S, Gerding DN, Olson MM, et al. Prospective, Johnson S, Gerding DN, Olson MM, et al. Prospective, controlled study of vinyl glove use to interrupt controlled study of vinyl glove use to interrupt Clostridium difficile Clostridium difficile nosocomial transmission. nosocomial transmission. Am J Med Am J Med 1990;88:137-40.1990;88:137-40.

Mayfield JL, Leet T, Miller J, et al. Mayfield JL, Leet T, Miller J, et al. Environmental Environmental control to reduce transmission of control to reduce transmission of Clostridium difficileClostridium difficile. . Clin Infect DisClin Infect Dis 2000;31:995–1000. 2000;31:995–1000.

McDonald LC, Killgore GE, Thompson A, et al. An McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene–variant strain of epidemic, toxin gene–variant strain of Clostridium Clostridium difficiledifficile. N Engl J Med. 2005;353:2433-41.. N Engl J Med. 2005;353:2433-41.

References

McDonald LC, Coignard B, Dubberke E, et al. Ad Hoc CDAD McDonald LC, Coignard B, Dubberke E, et al. Ad Hoc CDAD Surveillance Working Group. Recommendations for Surveillance Working Group. Recommendations for surveillance of surveillance of Clostridium difficileClostridium difficile-associated disease.-associated disease. Infect Control Hosp Epidemiol 2007; 28:140-5.Infect Control Hosp Epidemiol 2007; 28:140-5.

Oughton MT, Loo VG, Dendukuri N, et al.Oughton MT, Loo VG, Dendukuri N, et al. Hand hygiene with Hand hygiene with soap and water is superior to alcohol rum and antiseptic soap and water is superior to alcohol rum and antiseptic wipes for removal of wipes for removal of Clostridium difficileClostridium difficile. Infect Control . Infect Control Hosp EpidemiolHosp Epidemiol 2009; 30:939-44.2009; 30:939-44.

Peterson LR, Robicsek A. Does my patient have Peterson LR, Robicsek A. Does my patient have Clostridium Clostridium difficile difficile infection? infection? Ann Intern Med 2009;15:176-9Ann Intern Med 2009;15:176-9

Riggs MM, Sethi AK, Zabarsky TF, et al. Asymptomatic Riggs MM, Sethi AK, Zabarsky TF, et al. Asymptomatic carriers are a potential source for transmission of epidemic carriers are a potential source for transmission of epidemic and nonepidemic and nonepidemic Clostridium difficile Clostridium difficile strains among long-strains among long-term care facility residents. Clin Infect Dis 2007; 45:992–8.term care facility residents. Clin Infect Dis 2007; 45:992–8.

References

SHEA/IDSA Compendium of Recommendations. Infect SHEA/IDSA Compendium of Recommendations. Infect Control Hosp Epidemiol 2008;29:S81–S92. Control Hosp Epidemiol 2008;29:S81–S92. http://www.journals.uchicago.edu/doi/full/10.1086/591065

Stabler RA, Dawson LF, Phua LT, et al. Comparitive analysis Stabler RA, Dawson LF, Phua LT, et al. Comparitive analysis of BI/NAP1/027 hypervirulent strains reveals novel toxin B-of BI/NAP1/027 hypervirulent strains reveals novel toxin B-encoding gene (tcdB) sequences. J Med Micro. encoding gene (tcdB) sequences. J Med Micro. 2008;57:771–5.2008;57:771–5.

Sunenshine RH, McDonald LC. Sunenshine RH, McDonald LC. Clostridium difficileClostridium difficile--associated disease: new challenges from and established associated disease: new challenges from and established pathogen. Cleve Clin J Medpathogen. Cleve Clin J Med.. 2006;73:187-97. 2006;73:187-97.

http://www.journals.uchicago.edu/doi/full/10.1086/591065

References

Warny M, Pepin J, Fang A, Killgore G, et alWarny M, Pepin J, Fang A, Killgore G, et al.. Toxin Toxin production by and emerging strain of production by and emerging strain of Clostridium Clostridium difficile difficile associated with outbreaks of severe disease in associated with outbreaks of severe disease in North America and Europe. North America and Europe. Lancet.Lancet. 2005;366:1079-84. 2005;366:1079-84.

Wilcox MF, Fawley WN, Wigglesworth N, et al. Wilcox MF, Fawley WN, Wigglesworth N, et al. Comparison of the effect of detergent versus Comparison of the effect of detergent versus hypochlorite cleaning on environmental contamination hypochlorite cleaning on environmental contamination and incidence of and incidence of Clostridium difficile Clostridium difficile infection. J Hosp infection. J Hosp Infect 2003:54:109-14.Infect 2003:54:109-14.

Clostridium difficile : Biology, Diagnosis and Infection Control Clostridium difficile Disease.

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