Colitis, Antibiotic-Associated

Essentials of Diagnosis

• Most cases of antibiotic-associated diarrhea are not attributable to Clostridioides difficile and are usually mild and self-limited

• Symptoms of antibiotic-associated colitis vary from mild to fulminant almost all colitis is attributable to C difficile

• Diagnosis is established by stool assay in most cases

General Considerations

• Antibiotic-associated diarrhea is common

  • Characteristically occurs during antibiotic exposure, is dose-related, and resolves spontaneously after discontinuation

  • Most cases of diarrhea are mild and self-limited and do not require evaluation or treatment

• Antibiotic-associated colitis is almost always caused by C difficile

  • Colonizes the colon of 3% of healthy adults and 8% of hospitalized patients

  • Releases two toxins: TcdA and TcdB

  • C difficile is the major cause of diarrhea in patients hospitalized for > 3 days, affecting 15 of 1000 patients

  • C difficile–induced colitis most commonly develops after use of ampicillin, clindamycin, fluoroquinolones, and third-generation cephalosporins

  • Symptoms begin during or shortly after antibiotic therapy but may be delayed for up to 8 weeks

• A more virulent strain of C difficile (NAP1)

  • Contains an 18-base pair deletion of the TcdC inhibitory gene, resulting in higher toxin TcdA and TcdB production

  • Is more prevalent among hospital-associated infections (31%) than community-acquired infections (19%)

  • Has been associated with outbreaks of severe disease with up to 7% mortality

Demographics

• Antibiotic-associated colitis is found in

  • Hospitalized or recently hospitalized patients

  • Elderly or debilitated patients

  • Patients with inflammatory bowel disease

  • Persons who have received

• Multiple antibiotics or prolonged antibiotic therapy

• Proton pump inhibitor therapy

• Enteral tube feeding

• Chemotherapy

Symptoms and Signs

• Mild to moderate greenish, foul-smelling watery diarrhea with lower abdominal cramps in most patients

• Physical examination normal, or mild left lower quadrant tenderness

• Stools may have mucus but seldom gross blood

• Fulminant disease

  • Occurs in up to 10 % of patients

  • Characterized by fever; hemodynamic instability; and abdominal distention, pain, and tenderness

  • Most patients have profuse diarrhea (up to 30 stools/day)

  • However, diarrhea may be absent or appear to be improving in fulminant disease due to ileus

Differential Diagnosis

• Antibiotic-associated diarrhea (not related to C difficile)

• Other drug reaction

• Diarrhea due to enteral tube feedings

• Ischemic colitis

• Other bacterial diarrhea

• Inflammatory bowel disease

• Rarely, other organisms (staphylococci, Clostridium perfringens) are associated with pseudomembranous colitis

• Klebsiella oxytoca may cause a distinct form of antibiotic-associated hemorrhagic colitis

Laboratory Tests

• Mild disease: no or minimal leukocytosis

• Severe disease

  • White blood count > 30,000/mcL

  • Serum albumin < 2.5 g/dL (due to protein-losing enteropathy)

  • Elevated serum lactate

  • Rising serum creatinine

• Rapid enzyme immunoassays (EIAs) detect the presence of C difficile toxins TcdA and TcdB with 75–95% sensitivity, confirming active toxin secreting infection

• Nucleic acid amplification tests (eg, PCR assays)

  • Preferred over EIA

  • Amplify the toxin TcdB gene

  • Have a 97–99% sensitivity

  • Able to detect the NAP1 hypervirulent strain

• Glutamate dehydrogenase (a common C difficile antigen) assay

  • Has a high sensitivity and negative predictive value (95%)

  • Negative assay effectively excludes C difficile infection

  • However, a positive assay requires secondary testing with toxin EIA to distinguish colonization from active toxin-producing infection

Imaging Studies

• Abdominal radiographs: useful in detecting colonic dilation and wall thickening

• Abdominal CT

  • Useful in evaluating hospitalized patients with abdominal pain or ileus without significant diarrhea, in whom the presence of colonic wall thickening suggests unsuspected C difficile colitis

  • Also useful in detecting possible perforation

Diagnostic Procedures

• Flexible sigmoidoscopy

  • May show no abnormalities or only patchy or diffuse, nonspecific colitis in mild to moderate symptoms

  • Will show true pseudomembranous colitis (yellow adherent plaques scattered over hyperemic mucosa) in patients with severe illness

• Pseudomembranous colitis may be limited to proximal colon in 10% and therefore missed by sigmoidoscopy

Medications

Initial treatment

• For patients with nonsevere disease,

  • Oral fidaxomicin (200 mg orally two times daily) and vancomycin (125 mg orally four times daily)

    • Equally effective for initial treatment

    • Recurrence rates are lower with fidaxomicin than vancomycin (15% vs 25%)

  • Fidaxomicin may be preferred as first-line treatment for patients believed to be at higher risk for recurrent disease

  • Recommended treatment duration

    • 10 days in most situations

    • Can be extended in patients requiring prolonged antibiotic therapy for other infections

  • Metronidazole (500 mg orally three times daily) is no longer recommended for initial therapy except where vancomycin or fidaxomicin are unavailable

• Bezlotoxumab

  • A monoclonal antibody to C difficile toxin B

  • Approved by the FDA for patients with C difficile infection who are receiving antimicrobial therapy with metronidazole, vancomycin, or fidaxomicin and who are deemed to be at high risk for disease recurrence, including patients

    • Who are immunocompromised

    • Have inflammatory bowel disease

    • Are undergoing dialysis

    • Require continued antimicrobial therapy for ongoing infection

    • Have had prior C difficile recurrences

    • For patients with fulminant disease,

  • Vancomycin 500 mg orally four times daily along with metronidazole 500 mg intravenously every 8 hours are recommended

  • In patient with ileus, vancomycin may be administered by nasoenteric tube and by rectal enema (500 mg in 100 mL normal saline by enema every 6 hours)

  • The efficacy of fidaxomicin for severe or fulminant disease requires further investigation

Treatment of relapse

• Infectious Disease Society of America guidelines recommend that the first recurrence be treated with

  • Fidaxomicin, 200 mg orally twice daily for 10 days or

  • A prolonged tapering regimen of vancomycin:

    • 125 mg orally four times daily for 14 days

    • 125 mg orally twice daily for 7 days

    • 125 mg orally once daily for 7 days

    • Then 125 mg orally every other 2 or 3 days for 2–8 weeks

• Second recurrence should be treated with an additional vancomycin tapering regimen, as above

Surgery

• Total abdominal colectomy or loop ileostomy with colonic lavage may be required in patients with toxic megacolon, perforation, sepsis, or hemorrhage

Therapeutic Procedures

• Discontinue offending antibiotic, if possible

• Fecal microbiota transplantation

  • Recommended for patients with three or more relapses

  • Fecal specimens that have been screened for infectious agents are commercially available

  • The fecal microbiota may be instilled into the patient by one of three methods:

    • Infusion through a colonoscope into the terminal ileum and colon

    • Infusion through a nasoenteric tube into the duodenum

    • Ingestion of multiple freeze-dried capsules (preferred mode of administration)

  • Using all three infusion modalities, multiple case series reported disease remission after a single treatment in over 90% of patients with recurrent C difficile infection

  • However, in 2019, the FDA issued a safety alert regarding two cases of extended-spectrum beta-lactamase E coli infections in immunocompromised patients following fecal transplantation

Follow-Up

• Following treatment, stool assays may remain positive for several weeks after symptom resolution

Prognosis

• Relapse occurs in up to 25% of patients

Prevention

• Fastidious handwashing and use of disposable gloves minimize transmission of C difficile

• Prophylactic administration of probiotics to hospitalized patients within 48 hours of antibiotic initiation reduces the risk of C difficile infection by > 50%

When to Refer

• Lack of improvement after 3–5 days of therapy

• Fulminant colitis or toxic megacolon

• Multiple relapses

• Early surgical consultation for all patients with severe or fulminant disease

When to Admit

• Severe colitis: pain, diarrhea, dehydration, fever (temperature > 40.0°C), abdominal tenderness, leukocytosis