C Diff Colitis

Clostridium Difficile 
 
Clostridium difficile is the causative organism of antibiotic-associated colitis. The organism is capable of elaborating exotoxins that bind to receptors on intestinal epithelial cells, leading to inflammation and diarrhea. 
 
 C difficile is highly transmissible via fomites and can be cultured readily from nearly any surface, including items in patient rooms as well as the hands, clothing, and stethoscopes of healthcare workers. 
 
The antibiotics most frequently implicated in predisposition to CDAD include fluoroquinolones, Clindamycin, and broad-spectrum penicillins and cephalosporins. However, any antibiotic can predispose to colonization by C. difficile, including metronidazole and vancomycin, which are the major antibiotics used to treat C. difficile infection. 
 
Toxins - C. difficile releases two potent exotoxins that mediate colitis and diarrhea: toxin A ("enterotoxin") and toxin B ("cytotoxin"). A minority of C. difficile strains are non-toxigenic and do not produce toxins in vivo or in vitro; these strains can colonize the gastrointestinal tract and grow normally in culture media but are not pathogenic. 
 
Clinical Features –Watery diarrhea is the cardinal clinical symptom of C. difficile infection, although it can cause a spectrum of manifestations ranging from the asymptomatic carrier state to severe fulminant disease with toxic megacolon.  
  1. Carrier state — About 20% of hospitalized adults are C. difficile carriers who shed C. difficile in their stools but do not have diarrhea; Although asymptomatic, these individuals serve as a reservoir for environmental contamination. 
  2. Diarrhea with colitis — Manifestations of C. difficile-associated diarrhea with colitis include watery diarrhea up to 10 or 15 times daily with lower abdominal pain and cramping, low grade fever, and leukocytosis . These symptoms generally occur in the setting of antibiotic administration; they may begin during antibiotic therapy or 5 to 10 days following antibiotic administration. Infrequently, symptoms present as late as 10 weeks after cessation of therapy. 
Sigmoidoscopic or colonoscopic examination may demonstrate a spectrum of findings, from patchy mild erythema and friability to severe pseudomembranous colitis.  
 
Pseudomembranous colitis — Patients with pseudomembranous colitis usually present with clinical manifestations of CDAD with colitis. In addition, sigmoidoscopic examination in these patients demonstrates the presence of pseudomembranes, which is sufficient to make a presumptive diagnosis of C. difficile infection. CT scan in patients with pseudomembranous colitis demonstrates pronounced thickening of the colonic wall. 
  1. Recurrent disease: relapse vs. reinfection - Recurrence of symptoms after successful initial therapy for C. difficile, due to relapse of the initial infecting strain or due to reinfection with a new strain, develops in 10 to 25 percent of cases;  
  1. Fulminant colitis - The manifestations of fulminant colitis typically include severe lower quadrant or diffuse abdominal pain, diarrhea, abdominal distention, fever, hypovolemia, lactic acidosis, hypoalbuminemia, and marked leukocytosis (up to 40,000). Diarrhea may be less prominent in patients with prolonged ileus due to pooling of secretions in the dilated, atonic colon. Other potential complications of fulminant colitis include toxic megacolon and bowel perforation. 
Toxic megacolon is a clinical diagnosis based upon the finding of colonic dilatation (>7 cm in its greatest diameter) accompanied by severe systemic toxicity. Abdominal plain films may also demonstrate small bowel dilatation, air-fluid levels (mimicking an intestinal obstruction or ischemia), and "thumb printing" (scalloping of the bowel wall) due to submucosal edema.  
 
Aggressive diagnostic and therapeutic interventions are warranted in the setting of fulminant C. difficile infection. Bedside sigmoidoscopy or colonoscopy may be performed to make a presumptive diagnosis of C. difficile infection by evaluating for presence of pseudomembranes. Given the risk of perforation, care should be taken to introduce minimal amounts of air to avoid exacerbating ileus or distention. Prompt surgical consultation is warranted to assess the requirement for colectomy. 
  1. Other Presentations -  other manifestations of C. difficile include protein-losing enteropathy with ascites, C. difficile infection in the setting of chronic inflammatory bowel disease, and extra colonic involvement. 
 
Diagnosis — the diagnosis of C. difficile infection requires the presence of moderate to severe diarrhea or ileus, and either a stool test positive for C. difficile toxins or endoscopic or histologic findings of pseudomembranous colitis. Only watery or semi-formed stool should be tested for C.Diff toxin. 
 
Laboratory diagnosis — Laboratory diagnosis of C. difficile infection requires demonstration of C. difficile toxin(s) or detection of toxigenic C. difficile organism(s). A number of tests are available, including: 
  • Polymerase chain reaction (PCR): Real-time PCR tests that detect toxin A and B genes are highly sensitive and specific. The sensitivity of PCR is greater than enzyme immunoassay and comparable to cytotoxicity assay. In addition, PCR results can be available within as little as one hour.  
  • Enzyme immunoassay (EIA) for C. difficile glutamate dehydrogenase (GDH): GDH antigen is an essential enzyme produced constitutively by all C. difficile isolates; its detection cannot distinguish between toxigenic and nontoxigenic strains. Therefore, testing for GDH antigen is useful as an initial screening test, and is further confirmed with PCR on specimens that are GDH antigen positive. GDH results are available in less than one hour. 
  • Enzyme immunoassay (EIA) for C. difficile toxins A and B: Most C. difficile strains produce both toxins A and B, although some strains produce toxin A or B only. There is a relatively high false negative rate since 100 to 1000 pg of toxin must be present for the test to be positive.  
  • Cell culture cytotoxicity assay: The cell culture cytotoxicity assay is the ‘gold standard’ test for diagnosis of C. difficile, and is the standard against which other tests should be compared. The cytotoxicity assay is more sensitive than enzyme immunoassays, but is labor intensive and takes approximately two days. 
  • Selective anaerobic culture: Culture is useful for epidemiologic studies, but is generally too slow and labor-intensive for clinical use. 
 
Nucleic acid amplification tests (NAAT) for C. difficile toxin genes such as PCR are superior to toxins A + B EIA testing as a standard diagnostic test for CDI. 
 
Repeat stool assays are NOT warranted during or following treatment in patients who are recovering or are symptom free. Up to 50 percent of patients have positive stool assays for as long as six weeks after the completion of therapy. 
 
Treatment:   
 
Mild to Moderate (Non Severe) Disease 
Described as WBC<15000, creatinine<1.5 times baseline and no abdominal pain.  
  1. Initial episode 
    • Mild disease: metronidazole 500 mg orally three times daily or 250 mg four times daily for 10 to 14 days. Failure to respond to metronidazole therapy within 5 – 7 days should prompt consideration of a change in therapy to vancomycin at standard dosing.  
    • Severe disease: vancomycin 125 mg orally four times daily for 10 to 14 days 
  2. First relapse 
    • If antibiotics are needed, repeat treatment as in initial episode above.  
    • Alternative: fidaxomicin 200 mg orally twice daily for 10 days. 
  3. Second relapse 
Tapering and pulsed oral vancomycin, with or without probiotics. The probiotics may be overlapped with the final week of the taper and continued for two additional weeks in the absence of antibiotics. 
  • 125 mg orally four times daily for 7 to 14 days 
  • 125 mg orally twice daily for 7 days 
  • 125 mg orally once daily for 7 days 
  • 125 mg orally every other day for 7 days 
  • 125 mg orally every 3 days for 14 days 
  • Alternative: fidaxomicin 200 mg orally twice daily for 10 days 
  1. Subsequent relapse 
    • Fidaxomicin 200 mg orally twice daily for 10 days. Fidaxomicin is a bactericidal antibiotic against C. difficile, in contrast to metronidazole and vancomycin, which are bacteriostatic.  
    • Alternative: Vancomycin 125 mg orally four times daily for 14 days, followed by rifaximin 400 mg twice daily for 14 days 
    • Fecal Transplant 
Limitations of metronidazole include dose-dependent peripheral neuropathy and side effects of nausea and metallic taste.  
 
Severe Disease 
Described as WBC>15000, creatinine>1.5 times baseline and abdominal tenderness.  
 
 Oral vancomycin (125 mg four times daily) should be initiated promptly for severely ill patients. Some data suggest that levels achieved with higher dosing of vancomycin (500 mg four times daily) may be equivalent to levels with standard dosing. Nevertheless, many clinicians favor higher dosing for severe disease although there is no supportive evidence. 
 
Severely ill patients with ileus may have markedly delayed passage of oral antibiotics from the stomach to the colon. These individuals may benefit from the addition of intravenous metronidazole at a dose of 500 mg every eight hours.  
 
Some severely ill patients with CDI require surgical intervention as a result of toxic megacolon, perforation or impending perforation, necrotizing colitis or rapidly progressive and/or refractory disease with systemic inflammatory response syndrome leading to multiorgan system failure. 
 
Anion-exchange resins such as cholestyramine bind vancomycin as well as toxins; thus, the resin must be taken at least two or three hours apart from the vancomycin. Suggested regimens are colestipol (5 g every 12 hours) or cholestyramine (4 g three or four times daily) for one to two weeks, usually with vancomycin. 
 
Complicated disease 
Described as severe disease with end organ dysfunction like hypotension, ileus, WBC>35000 and lactic acidosis. 
 
Vancomycin 500 mg orally 4 times per day with or without metronidazole 500mg intravenously every 8 hours is the treatment of choice.  
 
Toxic Megacolon 
Emergent surgical exploration is necessary and may need colectomy. 
 
Intravenous immunoglobulin — Intravenous immunoglobulin (IVIG) contains C. difficile antitoxin and has been used in some patients with relapsing or severe C. difficile colitis.  
 
PEARLS:  
  • Maintain contact precautions only for the duration of diarrhea. 
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