Clostridium difficile Associated Diarrhea (CDAD) What’s going on?

New Issues PPIs appear to be a risk factor for CDAD CDAD rates are increasing An epidemic C. difficile strain has been found in the US, Canada, and Europe CDAD-associated mortality/morbidity is increasing Alcohol hand cleaning inadequate for C. difficile

Background

Clostridia Gram +, spore forming, obligate anaerobes Worldwide distribution Infections range from localized wound infection to overwhelming systemic disease

C. difficile Pathogenesis 2 major toxins –A: mediates alteration in fluid secretion, enhances inflammation, induces postcapillary venules to leak albumin –B: more active in causing damage to and exfoliation of superficial epthelial cells Both cause electrophysiologic alterations of colonic tissue

C. difficile Pathogenesis

Gastric Acid Suppression and CDAD Case-control study –1672 cases with CDAD –16720 controls Adjusted risk ratio (95% CI) –PPI = 2.9 ( ) –H2 antagonist = 2.0 ( ) –NSAIDs = 1.3 ( ) Dial S et al. JAMA 2005; 294:2989

Clinical Manifestations 20-30% of antibiotic-associated diarrhea –Toxins detectable in stool –Onset during or within 10 weeks antibiotic use –Associated with all antibiotics 4 categories based on colon appearance –Normal colonic mucosa –Mild erythema with some edema –Granular, friable, or hemorrhagic mucosa –Pseudomembrane formation - mucosa shows raised plaques with skip areas

Diagnosis Diverse clinical spectrum –Diarrhea may be profuse/watery –Blood or mucus may be present –Abdominal cramps –Fever & leukocytosis Large numbers of RBCs and WBCs in stool 95% have positive stool toxin assays –C. difficile toxin is very unstable –Toxin degrades at room temperature and may be undetectable within 2 hours after collection of a stool specimen –False-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; 189:1585–9 Annual CDAD rates, hospitals >500 beds, ICU surveillance component, NNIS

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

Overall rates of any listed CDAD discharge diagnosis by various demographic factors, *Per 100,000 population Demographics:CategoryEstimated rate*95% CI*P value Geographic regionNortheast Midwest Southern <0.001 Western <0.001 Hospital size by number of beds< % % % %0.004 > % %0.03 McDonald et al. 14th Annual Scientific Meeting of the Society for Healthcare Epidemiology of America, Philadelphia, PA. 2004

PFGE: Epidemic Strain Maine, Hospital A Pennsylvania Maine, Hospital B Illinois Georgia Maine, Hospital A New Jersey Oregon Historic, Historic, 1993 Historic, Historic, Historic, Oregon “BI” strain by REA 80% 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 strain LocationDate of outbreak onset No. of isolates tested No. (%) epidemic strain GeorgiaOctober, (63) IllinoisJuly, (43) Maine, Facility AMarch, (69) Maine, Facility BJuly, (63) New JerseyJune, (75) OregonApril, (10) Pennsylvania, Facility A (40) Pennsylvania, Facility BOctober, (50) Total18796 (51%) McDonald 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, FluoroquinoloneNRatio95% CI Any Moxifloxacin Levofloxacin Ciprofloxacin Gatifloxacin Pepin et al. CID Nov 1, 2005;41

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

Pittsburgh, PA –Life threatening disease from 1.6% to 3.2% –44 colectomies and 20 deaths Recent reports from Quebec, Canada –Severe outcomes –Deaths 1 Dallal RM et al. Ann Surg 2002; 235 : Increasing severity of CDAD

Emerging Infections Network Survey 525 ID Physicians responded 38% reported increasing caseload 40% reported increased severity of cases –435 cases of toxic megacolon 181 requiring colectomy 94 colonic perforations 198 patient deaths Layton BA et al. 15th Annual Scientific Meeting of the Society for Healthcare Epidemiology of America, Los Angeles, CA. 2005

Changes in Epidemiology Emergence of a new epidemic strain –Toxinotype III or “BI” by REA Distinct from “J” strain of –18 bp deletion in tcdC Could lead to increased toxin production –Increased resistance to fluoroquinolones Appears responsible for increase in cases 16- and 23- fold increase in toxins A & B production, respectively, may be responsible for increased disease severity Johnson S, et al. N Engl J Med 1999;341:

Treatment

CDAD Treatment Principles Stop offending antibiotic if possible – 25% respond without further therapy Oral therapy preferred Mean time for diarrhea to stop: days Treat for 10 days Treat for ~7 days before declaring failure if the patient is not worsening Avoid antiperistaltic agents Do not perform ‘test of cure’ toxin assays

Metronidazole (first-line treatment) Dose: 250 mg qid or 500 mg tid x 10 days Not FDA approved for CDAD Inexpensive Systemic absorption No drug in stool in absence of diarrhea Primary CDAD (First Episode)

Oral dose: 125 mg QID x 10 days More expensive than metronidazole - approximately $400-$600 No systemic absorption Stool levels in the range of µg/gm stool Use 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 Vancomycin Wilcox MH, Howe R. J Antimicrob Chemother 1995; 36: 673-9

CDAD Recurrences Recurrence rate following treatment of the initial episode 15%-25% Genetic typing studies show a new strain for a recurrence 50% of the time Failure to develop serum antibodies against toxin A has been correlated with recurrence Treatment for first recurrence is repeat treatment with metronidazole for 10 days No consensus for treatment beyond first recurrence

Aslam et al. Lancet, 2005 Vancomycin 19% Recurrence 4% Failure % treated subjects Metronidazole 20% Recurrence 13% Failure Year of publication Response to treatment of Clostridium difficile associated diarrhea

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

Saccharomyces boulardii Specific strain of Saccharomyces cervesiae Survives passage through human GI tract Caution: 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: S. boulardii + Vancomycin Vancomycin 2 g/d *p=0.05 Vancomycin (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 therapies Current Treatment Controversies

Musher et al. CID. 2005;40: CDAD patients at Houston VAMC Historical controls Reduced response rates and higher recurrence rates with metronidazole Pepin et al. CID. 2005;40: Quebec patients treated in Quebec patients treated from Reduced 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 /20 resistant isolates were identical by AP-PCR typing 6/198 (3%) human isolates (France) Barbut /6 resistant isolates were non-toxigenic strains 1/100 (1%) human isolates (China) Wong 1999 Resistant isolate (MIC: 64  g/ml) was recovered from 65 year old patient with diarrhea 26/415 (6%) human isolates (Spain) Peláez 2002 Clinical significance not reported

Metronidazole Failure Not Associated with Metronidazole Resistance 10-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 successes MTR Failure MTR success MIC (  g/ml) Sanchez J, et al. Anaerobe 1999

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

Management of CDAD in the Presence of Severe Ileus Vancomycin orally or via nasogastric tube 500 mg q 6h (DC suction for min post dose) Metronidazole 500 mg q 6h intravenously Vancomycin enemas 500 mg q 6h in 100 cc NS; clamp catheter for 60 min post dose Inf Cont Hosp Epidemiol 1994;15:

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

Investigational Rx for CDAD Product (type)Pt. ResultsStage Tolevamer (poly)58/70 PtsPhase III Ramoplanin (abx)25/29 PtsPhase III OPT-80 (abx)NonePhase II Rifalazil (abx)NonePhase II Rifaximin (abx)9/10 PtsPhase III Tinidazole (abx)NoneUnknown Nitazoxanide (abx)14/19 PtsPhase II Monoclonal AbNonePhase II CD VaccineUnknownPhase I

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

Alcohol vs Chlorhexidine

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

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

Hospitals should 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 important for reducing severe outcomes and should be emphasized –Subset of epidemic isolates tested for metronidazole susceptibility Strict infection control –Contact precautions for CDAD patients –An environmental cleaning and disinfection strategy –Hand washing with CDAD outbreak Further research needed CDC Recommendations

Reasons for New Requirements The 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 meetings The new strain appears to be more virulent, with ability to produce greater quantities of toxins A and B In addition, it is more resistant to the antibiotic group known as fluoroquinolones

New Reporting Requirements ODH Director’s Journal Entry December 28, 2005 In effect January 1 through June 30, 2006 Aggregate numbers of confirmed cases of C. difficile reported by hospitals and long term care facilities to the local health department Report by the close of each work week Only health care-associated infections reported Community onset infections are not reportable

Case Definitions Diagnostic test for Clostridium difficile –EIA –Cytotoxin –Antigen –Culture (not a recommended test) Pseudomembranes seen on endoscopy Positive histology from surgical or autopsy specimen

Case Definitions Health Care-Associated (Initial) –Positive result > 48 hours after admission to a health care facility –No CDAD in past 6 months Health Care-Associated (Recurrent) –Positive result –Previous healthcare-associated positive within prior 6 months –Clinical resolution after previous treatment Community-Onset: Positive result as outpatient (or < 48 after admission) –No healthcare-associated episodes in past 6 months –Regardless of recent hospitalizations

January Local Reporting 9 acute care hospitals reported 23 initial and 8 recurrent cases 8 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

Summary CDAD rates are increasing An epidemic C. difficile strain has been found in the US, Canada, and Europe CDAD-associated mortality/morbidity is increasing New reporting requirements –Better define the problem in Ohio –Allow for design of ongoing surveillance

Questions