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Clostridium difficile Associated Disease: The New Epidemic Walter J. Coyle, MD, FACP, FACG Lecture Outline History and background Emerging epidemic Pathophysiology Risk factors and Clinical Presentation Diagnosis Treatment New horizons C. diff on microvilli History Entity described in 1935 by Hall and O’Toole C. diff associated with disease in 1978 with clindamycin- associated diarrhea Larson et al described toxin in stool of affected individuals Difficult to define disease because of problems with culture techniques and description as a commensal organism (found in healthy neonates) Discovery of stool toxins defined pathophysiology NEJM 1978;298 Ann Intern Med 2006;145 History Well known entity for years Easily diagnosed Responsive to treatment Known relapse rate Essentially a “nuisance” infection with known risk factors Epidemiology has now changed… The New Epidemic First reported increased frequency and severity in Quebec, Canada From 1991-2003, 4 fold rise in incidence (10 fold for > 65 yo) Increased hospitalizations (from 3-43 per 1000) More complications: megacolon, need for colectomy, shock and death Increased mortality (16%) NEJM 2005;353 CMAJ 2004;171 The New Epidemic Similar increases noted in US From 1996-2003, >2 fold rise in reports (82,000 cases to 178,000 cases; by ICD codes ) Most reports from 6 Northeast states Increase severity also noted: including megacolon, need for surgery, shock and death NEJM 2005;353 Ann Intern Med 2006;145 The New Epidemic Most severe disease associated with a new strain of C. difficile Issues of resistance and recurrence noted. Risk factors expanding from “classic” teaching NEJM 2005;353 Ann Intern Med 2006;145 Pathophysiology Colonization, alteration of flora, organism growth and toxin elaboration Toxin A – enterotoxin-causes tissue damage and fluid secretion, inflammation Not necessary for virulence Less potent than B Cytotoxin B 1000X more potent than A Activate release of cytotoxins from monocytes Histology Type I-patchy epithelial necrosis with fibrin/polys exudate Type II-prominent exudate as “summit lesion” from ulcer Type III-diffuse necrosis/ulceration with pseudomembranes composed of neutrophils, fibrin, mucin, cellular debris Risk Factors Classic factors were exposure to antibiotics, advanced age, hospitalization, and GI surgery or procedures. Initially, clindamycin, ampicillin or amoxacillin Then cephalosporins, Augmentin, quinolones 20 fold rise in risk with aging 20-40% colonization in inpatients (vs 2-3%) Clin Infec Dis 1998;26 NEJM 1989;320 New Risk Factors Inflammatory bowel disease (3.6 X, ARR) Acid suppressive agents H2-blockers (2.0 X, ARR) PPIs (2.9 X, ARR) Exposure to antibiotics not seen as frequently 3.1 X , ARR Immunosuppression/chemotherapy Age >65, ARR 16.3 ; CRF: 3.7X, ARR JAMA 2005; 294:2989-2995 Clinical presentation: Traditional Almost always diarrhea Rarely hematochezia Cramps, fever, malaise, anorexia Ileus Advanced disease has pseudomembranes Nearly pathonogmonic of CDAD Clinical presentation: Epidemic Similar to old cases but more severe More toxic megacolon (less diarrhea) Profound leukemoid reactions Severe hypoalbuminemia (PLE) Septic shock Need for colectomy Increased mortality Ann Intern Med 2006;245 The New Strain: Epidemic New strain identified from Quebec and Northeast US outbreaks BI / NAP1 : 5 unique features High levels of both A and B toxin A is Toxinotype III (most strains are 0) Deletion of gene tcdA Binary toxin produced (seen in C perfringens) Resistance to quinolones Lancet 2005;366 Ann Intern Med 2006;245 Diagnosis: Lab Elevated serum WBC and usually fecal WBC Culture (with strain identification) Difficult, not routine for most labs Detection of toxin remains the mainstay of dx Tissue culture assay (only B toxin) Spec 99-100% Sens 80-90% Enzyme immunoassay (can detect A and B) Spec 95-100% Sens 65-85% Most widely available test PCR detection of toxin (not well standardized) Spec 100% Sens 92-97% Need multiple samples to adjust for instability/poor samples J Clin Micro 2005;43 J Clin Micro 2006;44 Diagnostic tests J Clin Micro 2005;43 J Clin Micro 2006;44 Diagnostic Tests: Rads Do not forget the KUB Not everyone who has belly pain needs a CT of abdomen KUB ileus vs toxic megacolon Perforation, thumbprinting Toxic Megacolon Radiologic Findings: CT CT-nonspecific ”thumbprinting” of mucosa suggesting edema Wall thickening Fat stranding Severe cases: ascites Perforation CT Appearance “Thumbprinting” Diagnosis: Endoscopic Normal to patchy, nonspecific colitis to inflamed mucosa studded with adherent raised white and yellow plaques 2-10mm May be confined to proximal colon Caution: Avoid endoscopy in patients with fulminant colitis due to risk of megacolon and perforation Endoscopic Appearance More endoscopic images Treatment DC offending antibiotic (s) if possible Avoid antiperistaltic agents (incl narcs) Supportive care (hydrate, electrolytes) Antimicrobial therapy: Oral metronidazole: 250 mg qid or 500 mg TID for 10 days; low cost, effective Oral Vancomycin: 125-250 mg QID for 10 days High cost Ann Intern Med 2006;145 Treatment Oral metronidazole vs Vancomycin: Vanc is the only FDA approved Rx Metro preferred by IDSA, CDC, SHEA Metro cheaper than Vanco Vanc more effective in some studies Vanc active against all strain; some metro resistance seen in vitro now Sicker patients should get vancomycin Ann Intern Med 2006;145 The New Strain: Treatment Cannot identify new strain at this time Only research labs Suspect if epidemic or severe case Usual Rx as outlined above except: Early diagnosis more critical Vancomycin may have an advantage Preferred drug in any patient with severe C diff or slow response to therapy Lancet 2005;366 Ann Intern Med 2006;245 Treatment: Surgery Indications: medical non-responders (decreased motility impairs delivery of medication) with severe disease colonic perforation toxic megacolon refractory shock due to abdominal source (surgical abdomen) Subtotal or total colectomy with temporary diverting ileostomy: procedure of choice Mortality in one study: 45% Int Care Med. 2003;29 Ann Intern Med 2006;145 C diff megacolon Treatment If not tolerating PO IV metronidazole (500 mg q6) Vancomycin by NG or retention enema (500 mg q6) NO IV VANC-not excreted into the colon Consider IVIG: Retrospective review of 10 (of 228) pts tx with IVIG since Nov 2003; 8 were severe, 2 recurrent (4 with megacolon) 8 responded to IVIG with normal BM in median 8 days Dis Colon Rectum 2006;49 Ann Intern Med 2006;145 Infection Control Single room with bathroom Barrier precautions Hand hygiene with soap and water No rectal temps Room cleaning with 1:10 bleach solution Prevention Hand wash with soap (resist ETOH/antiseptics) Contact/enteric precautions Probiotics given with abx tx Vaccines? Tx of asx carriers with vanc or flagyl does NOT reduce rate of carriage Recurrence 15-30% of patients (20% average) Usu by 1 wk (1-8 wks) Same symptoms recur 50% due to re-infection (new strain) 50% due to relapse Abx resistance is rare Residual spores Gastro 2006;130 Ann Intern Med 2006; 145 Recurrence Risk factors: age>65, comorbidities, extra abx after tx, poor immune response to toxin A Low serum IgG to toxin A may be most important risk factor May be related to lack of exposure to C diff in childhood Gastro 2006;130 Ann Intern Med 2006; 145 C diff spores Recurrence: Treatment Repeat same dose of same antibiotic: Can use same agent; not resistance Rare reported cases of added rifampin Taper and pulse metronidazole or vancomycin Add Anion-binding resins: Cholestyramine 4g tid Colestipol 5g q 12 hours Best evidence for use with pulse therapy. Gastro 2006;130 Ann Intern Med 2006; 145 Recurrence: Treatment Probiotics Saccharomyces boulardii: 500 mg bid for 4-6 weeks Best evidence of all probiotics Several DB / PC trials show good efficacy Lactobacilli: 1 g qid for 4-6 weeks Evidence not as convincing PO nontoxicogenic C Diff: experimental Effective but only case reports to date Gastro 2006;130 Ann Intern Med 2006; 145 Recurrence: Treatment Stool transplants: “prepared” feces by NGT or enema Usually family member; 30-50 g fresh stool Case series of 18 refractory C diff patients Stool via NG from healthy family member 15 of 18 became recurrence-free Gastro 2006;130 Clin Infect Dis 2003;36 Coyle’s Corollary It is better to be a stool donor than a recipient. Stool donor cards will be made available after this lecture. New Horizons Tolevamer: Toxin receptor decoy, mimics a part of the toxin receptor Binds both A and B toxins Large human trial underway Vaccination: toxoid vaccine Good serum response in normal subjects Few open label studies; large trial pending Gastro 2004;126 Gastro 2005;128 Gastro 2006;130 New Horizons Rifaximin-In vitro; ideal in theory Not absorbed by GI tract or inactivated by gastric juices Active entirely in intestinal lumen; broad-spectrum, GPR/GNR, anaerobes and aerobes MIC superior to metronidazole and vancomycin Low incidence of resistant strains Actively being studied in severe C diff and recurrent C diff Chemotherapy 2000;46 Ann Intern Med 2006; 145 Summary CDAD is increasing; mostly due to a new strain The disease is more severe and mortality is increased Surgery more often required. Prevention and suspicion are the keys to controlling the disease Vancomycin most effective for severe diseases but early detection and treatment are key. Summary Recurrence of CDAD can be treated with pulsed therapy, toxin binders, and probiotics. Role of stool transplants being “explored”. IVIG may a role in the critically ill patients. Rifaxamin will be used more frequently now Tolevamer and vaccination are promising new therapies on the horizon.
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