Infectious Infectious DiarrheaDiarrhea

ID Fellows CourseID Fellows Course

July 2, 2010July 2, 2010

Frederick S. Buckner, MDFrederick S. Buckner, MD

Global mortality from selected Global mortality from selected infectious diseasesinfectious diseases

RankRank DiseaseDisease No. of deaths*No. of deaths*

11 Acute lower respiratory Acute lower respiratory infectionsinfections

3.9 million3.9 million

22 HIV/AIDSHIV/AIDS 2.9 million2.9 million

33 Diarrheal diseaseDiarrheal disease 2.0 million2.0 million

44 TuberculosisTuberculosis 1.6 million1.6 million

55 MalariaMalaria 1.1 million1.1 million

*WHO 2002*WHO 2002

Intestinal Fluid Balance:Intestinal Fluid Balance:

SiteSite L In / L OutL In / L Out EfficiencyEfficiency

Jejunum Jejunum 9-10/4-59-10/4-5 50% 50%

IleumIleum 4-5/3-4 4-5/3-4 80% 80%

ColonColon 1.5/1.4 1.5/1.4 95% 95%

StoolStool 100-200 ml 100-200 ml 98-99%98-99%

Diarrhea occurs when reabsorption decreases to around Diarrhea occurs when reabsorption decreases to around 95-96%; minor changes result in major fluid losses95-96%; minor changes result in major fluid losses

FIC-NIH

Pathogenic mechanismsPathogenic mechanisms

• Toxins:Toxins:– Preformed: Preformed: Staphylococcus aureus, Clostridium perfringens, Staphylococcus aureus, Clostridium perfringens,

Bacillus cereusBacillus cereus – Formed in the intestine by ingested bacteria:Formed in the intestine by ingested bacteria:

• Stimulate intestinal secretion: Stimulate intestinal secretion: Vibrio cholerae, Vibrio cholerae, enterotoxigenic enterotoxigenic E. coliE. coli

• Cytotoxins: Cytotoxins: Clostridium difficile, Shigella, Clostridium difficile, Shigella, enterohemorrhagic enterohemorrhagic E. coliE. coli

• Invasion: Invasion: Shigella, Salmonella, Campylobacter, YersiniaShigella, Salmonella, Campylobacter, Yersinia • Disruption of enterocytes leading to decreased Disruption of enterocytes leading to decreased

absorption: absorption: Giardia, CryptosporidiumGiardia, Cryptosporidium

Is the pathology in the small bowel or colon?

Small Bowel Colon

Symptoms Nausea, bloating, cramping, gas, weight loss

Fever, rectal pain, frequent painful stools

Physical signs Dehydration, orthostasis, decreased skin tugor

Fever, abdominal pain

Diarrhea Large volume, watery Small volume, pasty, and/or blood, mucous

Microscopic exam of stool

Without inflammatory cells or blood, with/without mucous

Inflammatory cells, blood, mucous

Agents of diarrhea based on localization within the intestine

Small Bowel Colon

Bacteria E. coli (ETEC, EPEC), Staphylococcus aureus, Clostridium perfringens, Bacillus cereus, Vibrio cholera, Salmonella sp.

Campylobacter sp., Shigella sp., Salmonella sp., Clostridium difficile, Yersinia sp., EHEC (0157:H7),Vibrio parahemolyticus, Plesiomonas shigelloides,Aeromonas hydrophila

Viruses RotavirusNorwalk agentAstrovirusesCaliciviruses

CytomegalovirusAdenovirus

Parasites Giardia lamblia, Cyclospora cayatenensis, Cryptosporidium parvum, Microsporidium sp., Dientamoeba fragilis, Isospora belli

Entamoeba histolytica,Balantidium coli

Group Etiology Situation RxViruses Norovirus Community Supportive

Rotavirus Children, global SupportiveBacteria Enterotoxigenic E. coli Travelers, community Supportive, Cipro

Shigella Travelers CiproCampylobacter Travelers AzithromycinSalmonella Foodborne ControversialC. difficile Hospital MTZ or PO VancoEnterohemorrhagic E. coli Foodborne Rx contraindicated

Parasites Giardia Travel, person-to-person MTZE. histolytica Travel MTZ

Important agents of infectious diarrheaImportant agents of infectious diarrhea

www.staceysstuff.com/ images/diarrhea.jpg

Case 1Case 1 A 72 y/o man with Alzheimer’s A 72 y/o man with Alzheimer’s

disease is sent to the Emergency disease is sent to the Emergency Room from his nursing home for Room from his nursing home for evaluation of lethargy and fever. He evaluation of lethargy and fever. He has been incontinent of stool for 2-3 has been incontinent of stool for 2-3 days and his attendants have started days and his attendants have started using diapers on him. The patient using diapers on him. The patient has a history of recurrent UTIs. has a history of recurrent UTIs. Exam: T102Exam: T102°, BP 100/60, HR 120, °, BP 100/60, HR 120, RR24. Abd: moderate tenderness. RR24. Abd: moderate tenderness. Rectal: no masses, heme +Rectal: no masses, heme +

Clostridium difficileClostridium difficile

Anaerobic spore forming bacillus

Coloured transmission electron micrograph of Clostridium difficle forming an endospore (red)

Dr Kari Lounatmaa/Science Photo Library

Clostridium difficile Clostridium difficile colitiscolitis

Pseudomembranous colitisPseudomembranous colitisNormal colonNormal colon

OverviewOverview

Epidemiology of Epidemiology of C. difficile C. difficile infectionsinfections Emergence of more virulent strainsEmergence of more virulent strains

PathogenesisPathogenesis Clinical spectrumClinical spectrum Diagnostic testsDiagnostic tests ManagementManagement

Fulminant casesFulminant cases RecurrencesRecurrences New treatmentsNew treatments

Infection controlInfection control

Frequency Frequency of CDAD.of CDAD.

Mortality Mortality from CDAD.from CDAD.

Annual Incidence (per 100,000 Population) of C. difficile Infection in Sherbrooke, Quebec, 1991–2003

Kelly C, LaMont J. N Engl J Med 2008;359:1932-1940

University of WashingtonUniversity of WashingtonC. difficileC. difficile cases 2008-2010 cases 2008-2010

YearYear New New casecase

ss

# # hospitahospital daysl days

CasesCases/1000 /1000 hosp. hosp. daysdays

2008*2008* 116116 119,99119,9900

0.970.97

2009**2009** 179179 116,98116,9899

1.531.53

2010** 2010** (May)(May)

7171 49,47149,471 1.441.44

YearYear New New casecase

ss

# # hospitahospital daysl days

CasesCases/1000 /1000 hosp. hosp. daysdays

2008*2008* 7474 119,99119,9900

0.620.62

2009**2009** 8989 116,98116,9899

0.760.76

2010** 2010** (May)(May)

3737 49,47149,471 0.750.75

Health Care + Community acquiredHealth Care + Community acquired Health Care acquiredHealth Care acquired

*2008: includes pts with + results after 48 hours*2008: includes pts with + results after 48 hours**After 2008: Includes pts with + results after 72 hours**After 2008: Includes pts with + results after 72 hours

C. difficile-C. difficile-associated associated disease:disease:

what’s changing?what’s changing? Geographic spread of “epidemic” strainsGeographic spread of “epidemic” strains Appearance of strains with increased Appearance of strains with increased

virulence (?)virulence (?) Spread of disease into “low risk” Spread of disease into “low risk”

populationspopulations Emergence of fluoroquinolones as a major Emergence of fluoroquinolones as a major

risk factor for CDADrisk factor for CDAD Increasing failure rate with metronidazole Increasing failure rate with metronidazole

therapytherapy

Recent reports

Fulminant CDADFulminant CDAD(Pittsburgh Hospital)(Pittsburgh Hospital)

1989-991989-99 20002000 CDAD rateCDAD rate 6.86.8 11.611.6

(rate/1,000 admissions)(rate/1,000 admissions)

Fulminant cases Fulminant cases 1.6%1.6% 3.2%3.2%

Colectomies*Colectomies* 2.7/year2.7/year17/year17/year*Recent surgery, immunosupression, and prior CDAD were common predisposing conditions

Dallal RM, et al. Ann Surg 2002;235:363

Epidemic strainEpidemic strain Emerged 2000-2003Emerged 2000-2003 NAP1/027, REA Group BI / Toxinotype IIINAP1/027, REA Group BI / Toxinotype III Previously an uncommon strainPreviously an uncommon strain

First recognized in the 1980’sFirst recognized in the 1980’s Increased toxin production:Increased toxin production:

Toxin A: 16XToxin A: 16X Toxin B: 23XToxin B: 23X

Binary toxin: unknown significanceBinary toxin: unknown significance Uniformly quinolone resistant Uniformly quinolone resistant in vitroin vitro

Recent review on B1/NAP1/027 strain: Gastroenterology 136:1913, 2009Recent review on B1/NAP1/027 strain: Gastroenterology 136:1913, 2009

States that have had States that have had >> 1 hospital that has reported CDI caused by the 1 hospital that has reported CDI caused by the B1/NAP1/027 epidemic strain as of October, 2008 (red).B1/NAP1/027 epidemic strain as of October, 2008 (red).

Clostridium difficileClostridium difficileReservoirs (asymptomatic Reservoirs (asymptomatic

carriage)carriage) 15-70% of healthy neonates (15-70% of healthy neonates (C. diffC. diff

was discovered in 1933 during a study was discovered in 1933 during a study of the intestinal biota of newborns)of the intestinal biota of newborns)

3-8% of healthy adults3-8% of healthy adults 7-14% of elderly hospital patients7-14% of elderly hospital patients Up to 18% of pregnant women have Up to 18% of pregnant women have

vaginal colonization vaginal colonization

Asymptomatic C. difficile colonization

PathogenesisPathogenesis

C. difficile exposure

Antimicrobial

C. difficile-associated diarrhea

Hospitalization

Modified from: Johnson S, Gerding DN. Clin Infect Dis. 1998;26:1027-1036

432100

10

20

30

40

50

Length of hospital stay (wks)

Per

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. dif

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<1 1-2 2-3 3-4 >4

Clostridium difficile acquisition is correlated to duration of hospitalization

Johnson and Gerding J Infect Dis 1998; 26:1027

Clostridium difficile diarrhea istoxin-mediated

• Large clostridial toxins (LCTs): Large (>250 kDa), single-unit proteins which glycosylate small GTP-binding proteins (Rho, Ras) involved in cell cytoskeleton organization

Toxin A ‘enterotoxin’Toxin B ‘cytotoxin’

Both toxins are pathogenic*

*Lyras D et al. Nature 458:1176, 2009*Lyras D et al. Nature 458:1176, 2009

Normal Cytotoxic Effect

Histopathology of CDADHistopathology of CDAD

Normal colon brush border Necrotic colon brush border (CDAD)

Clinical Spectrum ofClinical Spectrum ofClostridium difficileClostridium difficile Infections Infections

SyndromeSyndrome FrequencyFrequency

Asymptomatic colonizationAsymptomatic colonization ++++++ ++++++++++++

Diarrhea (Diarrhea (++ PMC) PMC) ++ ++ Pseudomembranous colitisPseudomembranous colitis + + Severe ileus/ Fulminant colitis <+Severe ileus/ Fulminant colitis <+

Antimicrobial agents that may induce CDAD

• Antineoplastic agents have also been associated with CDAD:• Doxorubicin, cisplatin, cyclophosphamide, methotrexate, chlorambucilDoxorubicin, cisplatin, cyclophosphamide, methotrexate, chlorambucil

Clostridium difficileClostridium difficileRisk FactorsRisk Factors

Additional risk factors in hospitalized pts.Additional risk factors in hospitalized pts. Advanced ageAdvanced age Severity of underlying illnessSeverity of underlying illness Disruption of normal intestinal motility: Disruption of normal intestinal motility:

enemas, stool softeners, pro-motility agentsenemas, stool softeners, pro-motility agents PPIs (although spores are acid resistant. May PPIs (although spores are acid resistant. May

be a marker of co-morbidity).be a marker of co-morbidity). Adverse prognostic factorsAdverse prognostic factors

Peak WBC > 20,000 (RR 4.8)Peak WBC > 20,000 (RR 4.8) Peak creatinine > 2 (RR 3.1)Peak creatinine > 2 (RR 3.1)

Clostridium difficileClostridium difficileClinicalClinical

Usually occurs after 5-10d of antibiotic Rx, but Usually occurs after 5-10d of antibiotic Rx, but range from 1-70+ daysrange from 1-70+ days

Diarrhea may range up to “cholera-like”Diarrhea may range up to “cholera-like” Fever: 30-50%Fever: 30-50% Mean peripheral WBC 15-16,000; 25% may have Mean peripheral WBC 15-16,000; 25% may have

WBC > 35,000WBC > 35,000 May present w/ toxic megacolon or acute May present w/ toxic megacolon or acute

abdomen without diarrhea, particularly in patients abdomen without diarrhea, particularly in patients on opiates, anti-motility agents, or post GI-on opiates, anti-motility agents, or post GI-surgerysurgery

Case fatality rate ~2-3%Case fatality rate ~2-3%

Antibiotic associated diarrhea DDX

Only 10-20% of AAD is due to Only 10-20% of AAD is due to C. difficileC. difficile

C. difficile C. difficile disease diagnosisdisease diagnosis

Toxic megacolon

Pseudomembranous colitis “Accordion Sign”

The d-zone, vol 37, 2008http://uw.prnrx.org/therapyTopics.asp

C. difficile testing at UWMC + HMCOrder: “Stool for “Stool for C.difficileC.difficile testing.” testing.”

Formed stool samples will be rejected

C. difficile disease

PCR for Toxin B gene*

#1#1

++

#2#2

*Sensitivity: 98.8%, Specificity: 90.8%*Sensitivity: 98.8%, Specificity: 90.8%

Previous C. difficile testing at UWMC + HMC

C. difficile antigen assay (EIA)• Very sensitive (97%), not specific for disease• >95% negative predictive value

Combo-tox (A/B) testing (EIA)• >95% specificity

C. difficile disease

PCR for Toxin B gene

+

Negative for C. difficile

++

#1#1

#2#2

++

-- --

--

#3#3

CDAD:CDAD: Appropriate TestingAppropriate Testing

Only re-test after negative PCR if pre-test Only re-test after negative PCR if pre-test suspicion is VERY highsuspicion is VERY high

No need to order stool tests in triplicate!No need to order stool tests in triplicate!

No need to test for cure… pt comes out of No need to test for cure… pt comes out of precautions if diarrhea is gone and 7 days precautions if diarrhea is gone and 7 days of treatment under his / her belt!of treatment under his / her belt!

CDAD:CDAD: Treatment BasicsTreatment Basics

STOPSTOP the offending abx (if possible) the offending abx (if possible)

STARTSTART anti-C.diff therapy as soon as anti-C.diff therapy as soon as you start to rule out CDAD (unless pt you start to rule out CDAD (unless pt looks clinically great, in which case you looks clinically great, in which case you could consider waiting for testing to come could consider waiting for testing to come back).back).

AVOIDAVOID anti-motility drugs. anti-motility drugs.

Clostridium difficileClostridium difficileTreatment (circa 2005)Treatment (circa 2005)

MetronidazoleMetronidazole VancomycinVancomycin

RouteRoute Oral or Oral or IVIV Oral onlyOral only

DoseDose 500mg TID500mg TID 125mg QID125mg QID

ResponseResponse 94%94% 94%94%

DurationDuration 10-14 days10-14 days 10-14 days10-14 days

CostCost $20$20 $200-800$200-800

RecurrenRecurrencece

20%20% 19%19%

Response Rates to Vancomycin and Metronidazole Therapy, According to the Severity of C. difficile Infection

Kelly C, LaMont J. N Engl J Med 2008;359:1932-1940

≥ ≥ 2 points = Severe2 points = Severe

1 point:1 point: AgeAge > 60> 60 TempTemp >101 F>101 F AlbuminAlbumin < 2.5 mg/dL< 2.5 mg/dL WBCWBC >15K>15K

2 points:2 points: PMC at colonoscopyPMC at colonoscopy ICU patientICU patient

Cohen SH et al. Infection Control and Hospital Epidemiology. May, 2010Cohen SH et al. Infection Control and Hospital Epidemiology. May, 2010

Request imaging (Abd CT) and obtain surgery consult if Request imaging (Abd CT) and obtain surgery consult if evidence for toxic megacolonevidence for toxic megacolon

Clostridium difficileClostridium difficileTreatment: Special Treatment: Special

SituationsSituations When to operate??When to operate??

Strong indications:Strong indications: MegacolonMegacolon Prolonged and (?) irreversible ileusProlonged and (?) irreversible ileus PerforationPerforation

Mortality rates (in reported series) of Mortality rates (in reported series) of cases requiring surgery range from 30 cases requiring surgery range from 30 to > 50%. Are we waiting too long??to > 50%. Are we waiting too long??

Equivalent response rates of low dose Equivalent response rates of low dose and high-dose vancomycinand high-dose vancomycin

Lefler DA and Lamont JT. Gastroenterology 136:1899, 2009Lefler DA and Lamont JT. Gastroenterology 136:1899, 2009

CDAD:CDAD: Treatment PearlsTreatment Pearls

Switch from metro to PO vanco if pt Switch from metro to PO vanco if pt deteriorates, or if no improvement in first deteriorates, or if no improvement in first 3 days of therapy.3 days of therapy.

No role for IV vanco.No role for IV vanco.

In SEVERE, COMPLICATED disease, In SEVERE, COMPLICATED disease, you may combine IV metro with PO you may combine IV metro with PO vanco (PR if ileus).vanco (PR if ileus).

No tapering No tapering for first episode.for first episode.

Recurrent Recurrent C. difficile C. difficile DiarrheaDiarrhea

Occurs 6-25% Occurs 6-25%

Retreat first-time recurrences with the Retreat first-time recurrences with the same regimen used to treat the initial same regimen used to treat the initial episode (usually MTZ)episode (usually MTZ)

Risk of subsequent episode in patients who Risk of subsequent episode in patients who already have had a recurrence: 45%already have had a recurrence: 45%

Antibiotic resistance not a factor in relapse Antibiotic resistance not a factor in relapse   

Multiple Recurrent Multiple Recurrent C. difficile C. difficile DiarrheaDiarrhea

Treatment Options:Treatment Options:

Vancomycin regimensVancomycin regimens Tapering or pulsed (see Sanford guide)Tapering or pulsed (see Sanford guide)

Metronidazole not recommendedMetronidazole not recommended risk of neurotoxicityrisk of neurotoxicity

Vanco + Rifaximin chaser? (CID 44:846, Vanco + Rifaximin chaser? (CID 44:846, 2007) Needs more study.2007) Needs more study.

Nitazoxanide: Needs more study.Nitazoxanide: Needs more study. Saccharomyces boulardii Saccharomyces boulardii (not FDA (not FDA

approved)approved) ID consultID consult

Prevention of Prevention of C. diff.C. diff.

““Administration of currently available Administration of currently available probiotics is not recommended to prevent probiotics is not recommended to prevent primary CDI, as there are limited data to primary CDI, as there are limited data to support this approach and there is a support this approach and there is a potential risk of bloodstream infection (C-potential risk of bloodstream infection (C-III)”III)”

Clinical Practice Guidelines for Clinical Practice Guidelines for Clostridium difficile Clostridium difficile Infections in Adults: 2010 Infections in Adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Inf. Control and Hosp. the Infectious Diseases Society of America (IDSA). Inf. Control and Hosp. Epid. 31: 431, 2010.Epid. 31: 431, 2010.

Control Measures (1)Control Measures (1) Barrier protection:Barrier protection:

GlovesGloves GownsGowns

Alcohol hand-gel products Alcohol hand-gel products are not sporicidalare not sporicidal

Hand washing with Hand washing with chlorhexidine gluconate chlorhexidine gluconate containing soapcontaining soap

Patient isolation until Patient isolation until diarrhea resolveddiarrhea resolved

Cleaning and disinfection Cleaning and disinfection of environmental surfaces of environmental surfaces after pt dischargeafter pt discharge

Control Measures (2)Control Measures (2)

Judicious use of antibioticsJudicious use of antibiotics Targeted antibiotic restriction of high-Targeted antibiotic restriction of high-

risk agentsrisk agents Antibiotic stewardship program Antibiotic stewardship program

associated with decrease in CDAD up by associated with decrease in CDAD up by 60%*60%*

*Clin. Inf. Dis. 45(Suppl 2):S112, 2007*Clin. Inf. Dis. 45(Suppl 2):S112, 2007

Case 2Case 2

36 y/o man with sinusitis treated with 36 y/o man with sinusitis treated with Amox-Clav. Seven days into treatment Amox-Clav. Seven days into treatment he develops abdominal cramps and he develops abdominal cramps and bloody diarrheabloody diarrhea

Stool w/u:Stool w/u: C. diff toxin –C. diff toxin – Culture: negative for Campylobacter, Culture: negative for Campylobacter,

Yersinia, Shigella, Salmonella, and E. coli Yersinia, Shigella, Salmonella, and E. coli O157O157

NEJM 355:2418, 2006NEJM 355:2418, 2006

Clin. Inf. Dis. 47:e74, 2008Clin. Inf. Dis. 47:e74, 2008

Case 3

You are working in a clinic in Pakistan.

A woman brings a 6 month boy with watery diarrhea of 2 days duration. The child has stopped breastfeed and is difficult to arouse.

FluidsFluids

Center for Vaccine DevelopmentCenter for Vaccine DevelopmentUniv. of Maryland Sch. of Med.Univ. of Maryland Sch. of Med.

Diarrhea in children Diarrhea in children in developing countriesin developing countries

2000: 2000: 2.5 million 2.5 million deaths/yeardeaths/year

1 billion episodes/year 1 billion episodes/year in childrenin children 6-7 episodes/child/year in 6-7 episodes/child/year in

developing countriesdeveloping countries 1-2 episodes/child/year in 1-2 episodes/child/year in

developed countriesdeveloped countries

Darfur orphanage (Sudan)http://www.thewe.cc/contents/more/archive/darfur_sudan.html

Death rate from diarrheaDeath rate from diarrheais decliningis declining

1980’s: 4-6 million deaths/year1980’s: 4-6 million deaths/year 2000: 2000: 2.5 million deaths/year2.5 million deaths/year

“ORT was probably the greatest medical innovation of the 20th century”

Lancet

Composition of various Composition of various solutionssolutions

ORS (WHO)ORS (WHO) PedialytePedialyte GatoradeGatorade

SodiumSodium 75 mEq/L75 mEq/L 45 mEq/L45 mEq/L 20 mEq/L20 mEq/L

PotassiumPotassium 20 mEq/L20 mEq/L 20 mEq/L20 mEq/L 3.2 mEq/L3.2 mEq/L

SugarSugar 20 g/L20 g/L 25 g/L25 g/L 59 g/L59 g/L

See referencesWHO and UNICEF

IMCI

Adjunctive therapy in Adjunctive therapy in children?children?

Anti-motility agents? NoAnti-motility agents? No Anti-emetics? NoAnti-emetics? No Zinc supplements? Yes, in malnourished Zinc supplements? Yes, in malnourished

populations. Zinc given during an episode of populations. Zinc given during an episode of diarrhea and for 10-14 days after reduces the diarrhea and for 10-14 days after reduces the severity of the episode and the incidence of severity of the episode and the incidence of diarrhea for the following 4 to 6 months.diarrhea for the following 4 to 6 months. Administer 10-20 mg per day x 10-14 daysAdminister 10-20 mg per day x 10-14 days Syrup (20 mg/5 mL) or Tablets (20 mg)Syrup (20 mg/5 mL) or Tablets (20 mg)

http://centre.icddrb.org/news/index.jsp?idDetails=194

Administration of zinc

Use of zinc was found to be safe, with few side effects reported, and did not affect the use of traditional treatments for diarrhea (oral rehydration solution).

Center for Vaccine DevelopmentM. Levine, Univ. Maryland

Center for Vaccine DevelopmentM. Levine, Univ. Maryland

Center for Vaccine DevelopmentM. Levine, Univ. Maryland

ERI = Excess Rate of Isolation

Center for Vaccine DevelopmentM. Levine, Univ. Maryland

ERI = Excess Rate of Isolation

NepalNepal

P. BucknerP. Buckner

TheTheendend

AcknowledgementsAcknowledgements

Ciarán P. Kelly, MDCiarán P. Kelly, MD Harvard Medical SchoolHarvard Medical School

Paul Pottinger, MDPaul Pottinger, MD University of Washington Med CtrUniversity of Washington Med Ctr

Stuart Johnson, MDStuart Johnson, MD Loyola University Med CtrLoyola University Med Ctr

Richard Miller, MDRichard Miller, MD VA Puget Sound Health Care SystemVA Puget Sound Health Care System

Manuel Mah, MD, MPHManuel Mah, MD, MPH University of CalgaryUniversity of Calgary

[1] Cohen S.H. (2010). Clinical Practice Guidelines for Clostridium difficile Infections in Adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Inf. Control and Hosp. Epid. 31: 431, 2010.

[2] Leffler D.A. and Lamont J.T. Treatment of Clostridium difficile-Associated Disease. Gastroenterology 136:1899, 2009.

[3] Bartlett, J. G. (2006). Narrative review: the new epidemic of Clostridium difficile-associated enteric disease. Ann. Intern. Med. 758-764.

[4] Severe Clostridium difficile-Associated Disease in Populations Previously at Low Risk - Four States, 2005. Morbidity and Mortality Weekly Report 1201-1205, 2007.

[5] Muto, C. A., Pokrywka, M., Shutt, K., Mendelsohn, A. B., Nouri, K., Posey, K., Roberts, T., Croyle, K., Krystofiak, S., Patel-Brown, S., Pasculle, A. W., Paterson, D. L., Saul, M. and Harrison, L. H. (2005). A large outbreak of Clostridium difficile-associated disease with an unexpected proportion of deaths and colectomies at a teaching hospital following increased fluoroquinolone use. Infect. Control Hosp. Epidemiol. 273-280.

References

[6] McDonald, L. C., Owings, M. and Jernigan, D. B. (2006). Clostridium difficile infection in patients discharged from US short-stay hospitals, 1996-2003. Emerg. Infect. Dis. 409-415.

[7] McDonald, L. C., Killgore, G. E., Thompson, A., Owens, R. C., Jr., Kazakova, S. V., Sambol, S. P., Johnson, S. and Gerding, D. N. (2005). An epidemic, toxin gene-variant strain of Clostridium difficile. N. Engl. J. Med. 2433-2441.

[8] Rupnik M., Wilcox MK, and Gerding DN. Clostridium difficile infection: new developments in epidemiology and pathogenesis. Nature Reviews Microbiology 7:526-536, 2009[9] O’Connor JR, Johnson S, Gerding DN. Clostridium difficile infection caused by the Epidemic B1/NAP1/027 strain. Gastroenterology 136:1913, 2009[10] Pawloski SW, Warren CA, and Guerrant R. Diagnosis and treatment of

acute or persistent diarrhea. Gastroenterology 136:1874, 2009.