Clostridium difficile Ricardo A. Caicedo, M.D. Pediatric Gastroenterology UPDATED JULY 2006

OBJECTIVES Introduction Epidemiology Clinical spectrum Diagnosis Treatment Prevention

INTRODUCTION Historically…. Gram + bacillus Slow growing Anaerobic Spore-forming Slow growing Difficult to culture Historically…. 1935: first described in fecal flora healthy neonates 1970s: toxins implicated in antibiotic-associated diarrhea and colitis JA Hobot University of Wales College of Medicine UK

FREQUENCY Age-dependent Neonates Infants (1-24 m) Children 3-18 y High colonization rate (60-65%) Usually asymptomatic carriers Infants (1-24 m) More symptomatic Peak: 6-12 m Children 3-18 y Prevalence 5-8% as in adults Outbreaks Nosocomial Daycare centers McFarland LV et al (2000). JPGN 31(3):220-31.

C. difficile in the neonate Susceptible to colonization Immature intestinal microflora Exposure to spores in the nursery Rarely symptomatic Immature mucosal inflammatory response Gut epithelial toxin receptor defect Maternal Ab Absence of complex dietary substrates

PATHOGENESIS Toxin-mediated Toxins bind to villus enterocyte receptors Toxin A (enterotoxin) More biologically active Toxin B (cytotoxin) Diagnostic marker Toxins bind to villus enterocyte receptors Inflammation Increased permeability Increased secretion Fibrin deposition Activation of enteric NS Poutanen SM, Simor AE (2004) CMAJ 171(1):51-8. G

RISK FACTORS Disruption of normal microflora Altered mucin layer ANTIBIOTICS Altered mucin layer Prematurity Immunosuppression GI problems Short bowel Colonic stricture Hirschsprung’s IBD Co-infection

CLINICAL PRESENTATION Asymptomatic carrier Acute/protracted diarrhea Colitis Recurrent disease

Acute/protracted diarrhea > 3 watery stools/d for > 2 days Fluid content > 10 ml/kg/d Typical duration: 2-9 days Chronic diarrhea (>14 d) 7 wks-19 m (Cooperstock M, 1990) Other possible GI sx Colicky abdominal pain Abdominal distention Vomiting May or may not be associated with antibiotic use

Antibiotic-associated diarrhea McFarland LV et al (2000). JPGN 31(3):220-31. 4-18 days after first antibiotic dose (Ferroni A et al, 1997) Almost any antimicrobial Abx exposure not prerequisite for C. diff. disease 78% symptomatic outpts had no abx for at least 1 m (Buenning DA et al, 1982)

C. difficile COLITIS TYPES Pseudomembranous (PMC) Non-PMC Toxic megacolon SIGNS/Sx Profuse diarrhea Blood in stool Abdominal pain Crampy LQ tenderness Fever Leukocytosis/L shift

Pseudomembranous colitis From G. Ginsberg MD, Univ. Penn. www.endoatlas.com/ Composition: Fibrin WBCs and cell debris Mucus Adherent Raised 0.2-2 cm diameter

COMPLICATIONS Dehydration Protein-losing enteropathy Colon perforation Hypoalbuminemia Ascites/edema Colon perforation Shock (fulminant colitis) Undernutrition Recurrent infection

DIAGNOSIS Detection + clinical Stool assays NEJM (1994) 330:256. Detection + clinical Detection of organism or its toxin is not diagnostic by itself If sx suggest C. diff. disease, but stool is negative, repeat stool assays Stool assays Gold standard = cytotoxin cell culture assay Drawback: results can take up to 72 h Culture on CCFA agar EIA (rapid enzyme immunoassay) Results within 24 h PPV 100% when both toxins A and B tested (Kader H et al, Gastro., 1998) Endoscopy – reserve for ill patients Pseudomembranes specific for C. diff. CT scan – less specific

TREATMENT D/C inciting antibiotic if feasible Antibiotic therapy Metronidazole Vancomycin (PO) Bacitracin Biotherapeutics Probiotics Cholestyramine IVIG Whole bowel irrigation Avoid anti-motility agents

Treatment METRONIDAZOLE VANCOMYCIN PO Pros: effective, less expensive Cons: taste, side effects, emerging resistance Dosing: 20-40 mg/kg/d div. BID-QID VANCOMYCIN PO Pros: better colonic absorption, few side effects Cons: expensive, resistance, recurrence Indications: severe PMC, recurrence, immunocompromised Dosing: 40 mg/kg/d div. QID

Treatment PROBIOTICS Cholestyramine IVIG LGG Saccharomyces boulardii N= 19 infants C. diff. + diarrhea PO yeast X 15 d, no abx Sx resolved in 95% within 1 wk Rectal infusion of stool from healthy donor Broth culture bacteria Cholestyramine Binds both C. diff. toxins Also binds vancomycin Tastes like sand/seawater Primary tx failure, but better at preventing relapse IVIG Successful in uncontrolled trials in adults Very limited data in children Colon irrigation N = 2 children (Liacouras C, Piccoli D, J Clin Gastro 1996) McFarland LV et al (2000). JPGN 31(3):220-31.

RECURRENCE 15-57% after standard tx Mechanisms Management options Typically 2-8 wks after completion of tx Mechanisms Re-acquisition Persistence of spores in colon Resistant strains Management options PO Vanc Probiotics Cholestyramine IVIG Solution of fresh stool from healthy donor McFarland LV et al (2000). JPGN 31(3):220-31.

PREVENTION Exclusion from daycare for duration of diarrhea Avoid abx in 1st 2 m after PMC Probiotics in pts with hx recurrent disease Inpatients Narrow spectrum and use of abx when possible Strict handwashing and enteric or contact precautions Alcohol based hand sanitizer is not sporicidal Decontaminate colonoscopes Sporicides = glutaraldehyde or sodium hypochlorite Brook I (2005). J Gastroenterol Hepatol. 20(2):182-6.

Rising rate and severity of C. difficile disease in U.S. Emergence of new strain Increased virulence Increased resistance Associated with use of fluoroquinolone antibiotics