Clostridium difficile Associated Diarrhea (CDAD)Whats going on?

New IssuesPPIs appear to be a risk factor for CDADCDAD rates are increasingAn epidemic C. difficile strain has been found in the US, Canada, and EuropeCDAD-associated mortality/morbidity is increasingAlcohol hand cleaning inadequate for C. difficile

Background

ClostridiaGram +, spore forming, obligate anaerobesWorldwide distributionInfections range from localized wound infection to overwhelming systemic disease

C. difficile Pathogenesis2 major toxinsA: mediates alteration in fluid secretion, enhances inflammation, induces postcapillary venules to leak albuminB: more active in causing damage to and exfoliation of superficial epthelial cellsBoth cause electrophysiologic alterations of colonic tissue

C. difficile Pathogenesis

Gastric Acid Suppression and CDADCase-control study1672 cases with CDAD16720 controlsAdjusted risk ratio (95% CI)PPI = 2.9 (2.4-3.4)H2 antagonist = 2.0 (1.6-2.7)NSAIDs = 1.3 (1.2-1.5)Dial S et al. JAMA 2005; 294:2989

Clinical Manifestations20-30% of antibiotic-associated diarrheaToxins detectable in stoolOnset during or within 10 weeks antibiotic useAssociated with all antibiotics4 categories based on colon appearanceNormal colonic mucosaMild erythema with some edemaGranular, friable, or hemorrhagic mucosaPseudomembrane formation - mucosa shows raised plaques with skip areas

DiagnosisDiverse clinical spectrumDiarrhea may be profuse/wateryBlood or mucus may be presentAbdominal crampsFever & leukocytosisLarge numbers of RBCs and WBCs in stool 95% have positive stool toxin assaysC. difficile toxin is very unstableToxin degrades at room temperature and may be undetectable within 2 hours after collection of a stool specimenFalse-negative results occur when specimens are not promptly tested or kept refrigerated until testing can be done

Epidemiology

Archibald LK, et. al. J Infect Dis 2004; 189:15859

Annual CDAD rates, hospitals >500 beds, ICU surveillance component, NNIS

Figure 1. Annual Clostridium difficile-associated diarrhea rates, hospitals >500 beds, intensive care unit surveillance component, National Nosocomial Infections Surveillance system, 1987-2001

r = 0.61P

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

Chart1

30.72961390688.79891638844.38281978784.38281978781.88376704871.8837670487

40.749530743810.90189262516.99421522736.99421522732.40384595612.4038459561

36.727875080910.28283843226.41451309916.41451309912.85992431052.8599243105

36.94989036549.15735660884.97132101754.97132101752.19300962142.1930096214

34.79920936989.00282656655.00512574075.00512574072.10652457362.1065245736

49.064331584712.729559961810.456812118110.45681211812.85691754632.8569175463

58.725411293914.812481421112.13276628312.1327662833.25346496683.2534649668

61.390059581118.58071549049.35908156419.35908156414.46312353584.4631235358

Any Diagnosis

Primary

Year

Discharges per 100,000 population

National Estimates of U.S. Short stay Hospital Discharges with C. difficile Listed as First-listed or Any Diagnosis

Figure 1

Figure 1

30.72961390688.79891638844.38281978784.38281978781.88376704871.8837670487

40.749530743810.90189262516.99421522736.99421522732.40384595612.4038459561

36.727875080910.28283843226.41451309916.41451309912.85992431052.8599243105

36.94989036549.15735660884.97132101754.97132101752.19300962142.1930096214

34.79920936989.00282656655.00512574075.00512574072.10652457362.1065245736

49.064331584712.729559961810.456812118110.45681211812.85691754632.8569175463

58.725411293914.812481421112.13276628312.1327662833.25346496683.2534649668

61.390059581118.58071549049.35908156419.35908156414.46312353584.4631235358

Any Diagnosis

Primary

Year

Discharges per 100,000 population

Figure 1

Figure 2

Figure 2

7.064050535332.8080472842154.703904224326.719715758926.71971575898.70306550548.70306550542.36044287932.3604428793

12.473606110936.3901104523208.78776258239.416047868139.41604786819.30957424239.30957424235.11193724795.1119372479

8.66847594537.8554422454184.366857613130.079526566330.079526566311.318478930511.31847893053.52434781283.5243478128

9.718999867133.1990959665188.715438847633.393340327833.393340327810.362173543110.36217354313.01315159433.0131515943

11.99612178727.1706443286175.012516979629.097742084529.09774208456.50551193146.50551193144.78644251634.7864425163

11.560988541443.2997896772254.822284311764.475215919764.47521591979.49591926299.49591926294.39230209754.3923020975

16.830907067452.3493339114305.980766032575.622583320375.622583320316.311786512216.31178651224.42030448934.4203044893

11.497211857748.9613139354340.322413872965.175689996765.175689996710.083339756910.08333975693.03621314023.0362131402

15-45

46-64

>64

Year

Discharges per 100,000 population

Figure 2

Figure 3

Figure 3

51.536919549535.226039442221.810302206121.962826923211.061964809711.061964809711.946378659111.94637865915.08019517585.08019517588.65665086738.6566508673

69.111980516447.128237975926.927109279331.523595320820.833261924320.833261924318.714527158618.71452715867.70039498657.700394986511.08568840611.085688406

48.893406424340.991471568733.823812962526.554496796413.022964153413.022964153412.842632961412.842632961412.577823206712.577823206711.29259717311.292597173

62.098338540539.030703293327.999736003127.750673005715.497440209415.497440209412.122906779612.12290677965.52866883275.52866883279.69672119369.6967211936

53.699913603537.508144349527.821950569827.017238259516.630105000216.630105000211.161267007211.16126700726.52261926816.52261926817.87041545257.8704154525

82.083053073245.067344393843.384266785934.341032964531.905308430831.905308430814.32647793914.32647793920.418673274620.418673274613.33453930813.334539308

82.407269945768.001714779154.539807387936.41945089328.787882090728.787882090721.058904316121.058904316126.548979067126.54897906719.77157030239.7715703023

90.142799244374.864758879949.920403624842.445038819630.805374973730.805374973724.178834602824.178834602812.008490872312.008490872310.643287033410.6432870334

Northeast

Midwest

South

West

Year

Discharges per 100,000 population

Figure 3

Figure 4

Figure 4

0.002050.002710.003020.000550760.000550760.000537040.000537040.000537040.00053704

0.00280.003860.003630.000776160.000776160.0007350.0007350.0007350.000735

0.002860.003390.003020.000540960.000540960.000556640.000556640.000556640.00055664

0.002280.003530.003260.000595840.000595840.000791840.000791840.000791840.00079184

0.002360.003410.003160.000711480.000711480.000517440.000517440.000517440.00051744

0.003090.004940.004140.001272040.001272040.000834960.000834960.000834960.00083496

0.003320.006220.004510.00172480.00172480.000782040.000782040.000782040.00078204

0.004660.005210.00530.000948640.000948640.000782040.000782040.000782040.00078204

300

Year

Proportion of discharges

Figure 4

Overall rates of any listed CDAD discharge diagnosis by various demographic factors, 1996-2003*Per 100,000 populationMcDonald et al. 14th Annual Scientific Meeting of the Society for Healthcare Epidemiology of America, Philadelphia, PA. 2004

PFGE: Epidemic StrainMaine, Hospital APennsylvaniaPennsylvaniaMaine, Hospital BMaine, Hospital BIllinoisIllinoisGeorgiaMaine, Hospital ANew JerseyNew Jersey

OregonHistoric, 1988-1991Historic, 1993Historic, 1990-1991Historic, 1984-1991Historic, 1993-2000OregonBI strain by REABI strain by REA80%McDonald et al. 42nd Annual Meeting of the Infectious Diseases Society of America, Boston, Massachusetts. 2004

US Map

Distribution of isolates by healthcare facility outbreak and proportion attributed to the BI/NAP1 strainMcDonald et al. 42nd Annual Meeting of the Infectious Diseases Society of America, Boston, Massachusetts. 2004

Fluoroquinolones as a risk factor in outbreaks involving the epidemic strain, 2001-2004FluoroquinoloneNRatio95% CIAny15703.42.7-4.4Moxifloxacin272.00.5-8.3Levofloxacin3682.51.7-3.8Ciprofloxacin11533.72.8-5.0Gatifloxacin226.12.2-16.7Pepin et al. CID Nov 1, 2005;41

CDAD Rate in Relation to Fluoroquinolone Use in a LTCFp < 0.002Gaynes et al. CID 2004;38:640

Increasing severity of CDADPittsburgh, PA 20001Life threatening disease from 1.6% to 3.2%44 colectomies and 20 deathsRecent reports from Quebec, CanadaSevere outcomesDeaths1Dallal RM et al. Ann Surg 2002; 235 : 363-70

Emerging Infections Network Survey525 ID Physicians responded38% reported increasing caseload40% reported increased severity of cases435 cases of toxic megacolon 181 requiring colectomy94 colonic perforations198 patient deathsLayton BA et al. 15th Annual Scientific Meeting of the Society for Healthcare Epidemiology of America, Los Angeles, CA. 2005

Changes in EpidemiologyEmergence of a new epidemic strain Toxinotype III or BI by READistinct from J strain of 1989-199218 bp deletion in tcdCCould lead to increased toxin productionIncreased resistance to fluoroquinolonesAppears responsible for increase in cases16- and 23- fold increase in toxins A & B production, respectively, may be responsible for increased disease severityJohnson S, et al. N Engl J Med 1999;341:1645-51

Treatment

CDAD Treatment PrinciplesStop offending antibiotic if possible 25% respond without further therapyOral therapy preferredMean time for diarrhea to stop: 2 - 4 daysTreat for 10 daysTreat for ~7 days before declaring failure if the patient is not worseningAvoid antiperistaltic agentsDo not perform test of cure toxin assays

Primary CDAD (First Episode)Metronidazole (first-line treatment)Dose: 250 mg qid or 500 mg tid x 10 daysNot FDA approved for CDADInexpensiveSystemic absorptionNo drug in stool in absence of diarrhea

Oral dose: 125 mg QID x 10 daysMore expensive than metronidazole - approximately $400-$600No systemic absorptionStool levels in the range of 1000-3000 g/gm stoolUse discouraged in hospitals because of risk of resistance in enterococci and staphylococci (HICPAC recommendations, 1995)Primary CDAD: Vancomycin

Response Time for Treatment of CDAD with Metronidazole or VancomycinWilcox MH, Howe R. J Antimicrob Chemother 1995; 36: 673-9

CDAD RecurrencesRecurrence rate following treatment of the initial episode 15%-25%Genetic typing studies show a new strain for a recurrence 50% of the timeFailure to develop serum antibodies against toxin A has been correlated with recurrenceTreatment for first recurrence is repeat treatment with metronidazole for 10 daysNo consensus for treatment beyond first recurrence

Response to treatment ofClostridium difficile associated diarrheaAslam et al. Lancet, 2005Vancomycin19% Recurrence 4% Failure% treated subjectsYear of publication

Multiple Recurrences of CDADRisk of subsequent episode in patients who already have had a recurrence is 45%*Many empiric treatments advocatedVancomycin regimens : tapering, pulsed dosing, combination treatment with rifampinProbiotics using S. boulardii or Lactobacillus sp.Passive treatment with immunoglobulinToxin binding agents (cholestyramine, cholestipol or newer agents)Fecal reconstitution using spousal donors *McFarland LV, et al. Am J Gastro 2002:97:1769

Saccharomyces boulardiiSaccharomyces boulardiiSpecific strain of Saccharomyces cervesiaeSurvives passage through human GI tractCaution: fungemia in immunosuppressed patients

S. boulardii plus High Dose Vancomycin for Recurrent C. difficile Disease 50%16.7%*Surawicz CM et al Clin Infect Dis 2000;31:1012-7.S. boulardii + VancomycinVancomycin 2 g/d*p=0.05Vancomycin (500 mg/d) or metronidazole (1g/d) plus S. boulardii no more effective than placebo

Is metronidazole still effective therapy for CDAD?Is metronidazole-resistance clinically important?What, if any, are the alternative therapiesCurrent Treatment Controversies

Musher et al. CID. 2005;40:1586-1590207 CDAD patients at Houston VAMCHistorical controlsReduced response rates and higher recurrence rates with metronidazolePepin et al. CID. 2005;40:1591-1597438 Quebec patients treated in 2003-2004688 Quebec patients treated from 1991-2002Reduced response rates and higher recurrence rates with metronidazole Recent Reports of Poor CDAD Responses to Metronidazole

Reports of C. difficile with Reduced Susceptibility to Metronidazole 20/105 (19%) equine isolates (U.S.) Jang 199719/20 resistant isolates were identical by AP-PCR typing

6/198 (3%) human isolates (France) Barbut 19995/6 resistant isolates were non-toxigenic strains

1/100 (1%) human isolates (China) Wong 1999Resistant isolate (MIC: 64 g/ml) was recovered from 65 year old patient with diarrhea

26/415 (6%) human isolates (Spain) Pelez 2002Clinical significance not reported

Metronidazole Failure Not Associated with Metronidazole Resistance10-year prospective surveillance: 14/632 (2%) episodes of CDAD did not respond to metronidazole (MTR)Susceptibility of 10 isolates from MTR failures compared to 20 isolates from MTR successesMTR Failure MTR successMIC (g/ml)0.23 0.29

Sanchez J, et al. Anaerobe 1999

Prospective Randomized Trials for CDADJohnson S, Gerding DN. In: Antimicrobial Therapy & Vaccines, 2nd Ed.

Management of CDAD in the Presence of Severe IleusVancomycin orally or via nasogastric tube 500 mg q 6h (DC suction for 45-60 min post dose)Metronidazole 500 mg q 6h intravenouslyVancomycin enemas 500 mg q 6h in 100 cc NS; clamp catheter for 60 min post doseInf Cont Hosp Epidemiol 1994;15:371-381

Vancomycin EnemasAdjunct treatment for severe C. difficile Non-randomized open trials Inf Cont Hosp Epidemiol 1994;15:371-381 6/8 patients with ileus responded in 4-17 days 2 patients died, one following colectomyApisarnthanarak et al Clin Inf Dis 2002;35:690-96 8/9 cases resolved

Investigational Rx for CDAD

Prevention of C. difficileUse antibiotics judiciouslyUse Contact Precautions for patients with known or suspected C. difficile-associated disease: Place these patients in private roomsIf private rooms are not available, patients can be cohortedUse soap and water for hand hygiene when caring for patients with C. difficile-associated diseaseUse gloves when entering patients rooms and during patient care Use gowns if soiling of clothes is likely Dedicate equipment whenever possibleContinue precautions until diarrhea ceases

Alcohol vs Chlorhexidine

C. difficile Transferred by HandshakingDonor Post-Recipient Pre-Recipient Post-Pair Alcohol Rub*Handshake*Handshake*1406012826650369318003348850317515471151* Colony forming units

Environmental Cleaning and Disinfection Ensure adequate cleaning and disinfection of environmental surfaces and reusable devicesUse an EPA-registered hypochlorite-based disinfectantAlcohol-based disinfectants are not effective against C. difficile and should not be used to disinfect environmental surfaces Follow the manufacturers instructions for disinfection of endoscopes and other devices

CDC RecommendationsHospitals should conduct surveillance for CDAD Track positive lab results (e.g. toxin A or A/B assays)Consider measures to track outcomesEarly diagnosis and treatment important for reducing severe outcomes and should be emphasizedSubset of epidemic isolates tested for metronidazole susceptibilityStrict infection controlContact precautions for CDAD patientsAn environmental cleaning and disinfection strategyHand washing with CDAD outbreak Further research needed

Reasons for New RequirementsThe emergence of a new strain of C. difficile-associated disease associated with hospital outbreaks in several states has been reported by the Centers for Disease Control and Prevention (CDC) at scientific meetingsThe new strain appears to be more virulent, with ability to produce greater quantities of toxins A and BIn addition, it is more resistant to the antibiotic group known as fluoroquinolones

New Reporting RequirementsODH Directors Journal Entry December 28, 2005In effect January 1 through June 30, 2006Aggregate numbers of confirmed cases of C. difficile reported by hospitals and long term care facilities to the local health departmentReport by the close of each work weekOnly health care-associated infections reportedCommunity onset infections are not reportable

Case DefinitionsDiagnostic test for Clostridium difficile EIACytotoxinAntigenCulture (not a recommended test)Pseudomembranes seen on endoscopyPositive histology from surgical or autopsy specimen

Case DefinitionsHealth Care-Associated (Initial)Positive result > 48 hours after admission to a health care facilityNo CDAD in past 6 monthsHealth Care-Associated (Recurrent)Positive resultPrevious healthcare-associated positive within prior 6 monthsClinical resolution after previous treatmentCommunity-Onset: Positive result as outpatient (or < 48 after admission) No healthcare-associated episodes in past 6 monthsRegardless of recent hospitalizations

January Local Reporting9 acute care hospitals reported 23 initial and 8 recurrent cases8 initial cases and 1 recurrent case not included in the ODH report (facilities not on the current ODH report) Thirty-seven nursing homes reported 6 initial cases and 1 recurrent case

SummaryCDAD rates are increasingAn epidemic C. difficile strain has been found in the US, Canada, and EuropeCDAD-associated mortality/morbidity is increasingNew reporting requirementsBetter define the problem in OhioAllow for design of ongoing surveillance

Questions

Sandra Dial, MD, MSc; J. A. C. Delaney, MSc; Alan N. Barkun, MD, MSc; Samy Suissa, PhD JAMA.2005;294:2989-2995. Context Recent reports suggest an increasing occurrence and severity of Clostridium difficileassociated disease. We assessed whether the use of gastric acidsuppressive agents is associated with an increased risk in the community. Objective To determine whether the use of gastric acidsuppressive agents increases the risk of C difficileassociated disease in a community population. Design, Setting, and Patients We conducted 2 population-based case-control studies using the United Kingdom General Practice Research Database (GPRD). In the first study, we identified all 1672 cases of C difficile recorded between 1994 and 2004 among all patients registered for at least 2 years in each practice. Each case was matched to 10 controls on calendar time and the general practice. In the second study, a subset of these cases defined as community-acquired, that is, not hospitalized in the prior year, were matched on practice and age with controls also not hospitalized in the prior year. Main Outcome Measures The incidence of C difficile and risk associated with gastric acidsuppressive agent use. Results The incidence of C difficile in patients diagnosed by their general practitioners in the General Practice Research Database increased from less than 1 case per 100000 in 1994 to 22 per 100000 in 2004. The adjusted rate ratio of C difficileassociated disease with current use of proton pump inhibitors was 2.9 (95% confidence interval [CI], 2.4-3.4) and with H2-receptor antagonists the rate ratio was 2.0 (95% CI, 1.6-2.7). An elevated rate was also found with the use of nonsteroidal anti-inflammatory drugs (rate ratio, 1.3; 95% CI, 1.2-1.5). Five related isolates were found in the historic database; these isolates have been cataloged BI strains using REA typing and are here labeled in yellow. The five historical isolates shown here represent infections in 14 patients dating back to as early as 1984. In addition there is evidence to suggest increasing severity of CDAD. Dallal reported an increase in the rate of life threatening disease from 1.6% to 3.2% with a total of 44 colectomies and 20 deaths attributed to CDAD. Morris noted a five-fold increase in the rate of overall mortality in CDAD patients. Finally, recent reports from Quebec, Canada, point to alarming increases severe outcomes and deaths. The 201 (38%) IDCs who perceived an increase in caseload over the six months preceding the first and/or second survey collectively saw an estimated 3292 cases. The 210 (40%) IDCs who saw an apparent increase in disease severity encountered an estimated 435 patients with toxic megacolon (181 requiring colectomy), 94 patients with colonic perforations, and 198 patients who died.Moreover, the emergence of this strain may be responsible for an increase in disease severity observed in some settings. One last major area for potential public health intervention is one where further research is perhaps most needed. This is in determining the role for antimicrobial controls in stemming this epidemic.