Antibiotic Associated Diarrhoea

Antibiotic associated diarrhoea is otherwise unexplained diarrhoea (3 or more loose stools per day for 2 days or more) occurring during, or up to 8 to 12 weeks after, antibiotic treatment. It affects 5 to 30% of patients receiving antibiotics, and is caused by disruption of the normal gut microbiota.

• Mechanisms:
  • Functional (non-infectious) disturbance of gut flora: reduced carbohydrate fermentation and short chain fatty acid production, osmotic diarrhoea, and increased bile acid effects. This accounts for 80 to 90% of cases, and is generally mild.
  • Clostridioides difficile infection accounts for 10 to 20% of antibiotic associated diarrhoea, and for over 95% of pseudomembranous colitis. Other pathogens include Klebsiella oxytoca (haemorrhagic colitis after penicillins), Clostridium perfringens, and Staphylococcus aureus.
  • Direct drug effects: macrolides (motilin receptor stimulation), and clavulanic acid (increasing intestinal motility).
• Antibiotics most often implicated: amoxicillin clavulanate (10 to 25%), cephalosporins (especially third generation), clindamycin, fluoroquinolones, and ampicillin. The risk is lower with tetracyclines, trimethoprim and aminoglycosides, but no antibiotic is risk free.
• Risk factors: age above 65 years, hospital or care home stay, prolonged or multiple antibiotic courses, proton pump inhibitor use, inflammatory bowel disease, immunosuppression, chemotherapy, enteral feeding, abdominal surgery, previous Clostridioides difficile infection, and serious comorbidity (kidney disease, malignancy).
• Clostridioides difficile infection is the commonest healthcare associated infection in many countries, and community acquired cases make up to 25 to 40% of cases. About 15 to 25% of patients have recurrence after initial treatment, and the recurrence risk increases with each episode (40% after the first recurrence, over 60% afterwards).
• Complications: dehydration and electrolyte disturbance, hypoalbuminaemia, pseudomembranous colitis, toxic megacolon, bowel perforation, sepsis, and death (about 5 to 10% mortality in severe infection, up to 30 to 50% in fulminant disease).

• Mild functional diarrhoea: loose or watery stools, mild cramps and bloating, with no fever, blood or severe pain. It starts within days of the start of antibiotics, and settles within days after stopping the antibiotic.
• Clostridioides difficile infection: watery diarrhoea (3 to 15 stools per day), cramping lower abdominal pain, fever, nausea, anorexia, and leucocytosis. Stool is foul smelling and rarely bloody. Onset can be during therapy or up to 12 weeks later (most within 2 weeks).
  • Moderate: white cell count 15,000 cells/mm3 or below and creatinine below 1.5 mg/dL (133 micromol/L).
  • Severe: white cell count above 15,000 cells/mm3, or creatinine above 1.5 mg/dL (133 micromol/L), or hypoalbuminaemia, or temperature above 38.5 C.
  • Fulminant: hypotension or shock, ileus, megacolon (colonic diameter above 6 cm on imaging), and abdominal distension with reduced stool (ileus can mask diarrhoea).
• Dehydration signs, abdominal tenderness, and distension in severe disease.
• Differential diagnosis: viral and bacterial gastroenteritis, medicine induced diarrhoea (laxatives, magnesium, metformin, colchicine, proton pump inhibitors), enteral feeding diarrhoea, inflammatory bowel disease, ischaemic colitis, microscopic colitis, faecal impaction with overflow, cytomegalovirus colitis, graft-versus-host disease, and coeliac disease.
• Red flags: severe abdominal pain or distension, fever above 38.5 C, hypotension, rising creatinine, white cell count above 15,000 cells/mm3, lactate above 2.2 mmol/L, ileus, peritonism, blood in stool, immunosuppression, and age above 65 years.

• Clinical diagnosis from a history of antibiotic use and diarrhoea. Test for Clostridioides difficile in patients with 3 or more unformed stools in 24 hours without another cause, especially when risk factors exist. Do not test formed stools or asymptomatic patients, and do not repeat tests within 7 days.
• Stool tests:
  • Two step approach (the most accurate): a glutamate dehydrogenase antigen and toxin enzyme immunoassay, with a nucleic acid amplification test (polymerase chain reaction for toxin genes) for discordant results. A positive nucleic acid test alone may indicate colonisation, so interpret with symptoms.
  • A negative toxin and positive polymerase chain reaction means colonisation or low toxin, so treat if symptoms are consistent and no other cause exists.
  • Do not test for cure, because stool may remain positive for weeks.
• Blood tests: full blood count, urea, creatinine, electrolytes, albumin, C-reactive protein, and lactate in severe illness.
• Imaging: abdominal X-ray or CT for suspected megacolon, perforation or ileus. CT can show colonic wall thickening and pericolic stranding.
• Flexible sigmoidoscopy or colonoscopy when the diagnosis is uncertain or the stool test is negative with a strong suspicion, which shows adherent yellow white pseudomembranes. Avoid colonoscopy in fulminant colitis (risk of perforation).
• Rule out other causes of persistent diarrhoea after antibiotics: stool cultures, ova and parasites, Giardia antigen, faecal calprotectin, coeliac serology, and review of medicines.

• Stop or change the inciting antibiotic as soon as possible, and avoid unnecessary new antibiotics. Review the need for the antibiotic (shorten the duration, choose a narrower spectrum).
• Hydration: oral rehydration solution (200 to 400 mL after each loose stool, 2 to 3 L per day), or intravenous Ringer lactate or 0.9% sodium chloride in dehydration, with replacement of potassium and magnesium.
• Mild non-Clostridioides difficile antibiotic associated diarrhoea:
  • Stop the antibiotic if possible, and give fluids. Most cases resolve in 2 to 3 days after cessation.
  • Probiotic: Saccharomyces boulardii 250 to 500 mg orally twice daily, or Lactobacillus rhamnosus GG at 10 billion colony forming units daily, started within 48 hours of the first antibiotic dose and continued for the course and 1 week after. They reduce the risk by about 40 to 50% in healthy outpatients (evidence for protection is moderate). Avoid in severe immunosuppression, central venous catheters, critical illness, and pancreatitis because of rare fungaemia and bacteraemia.
  • Avoid loperamide and opioids when Clostridioides difficile is possible, because they can precipitate toxic megacolon. If Clostridioides difficile is excluded, loperamide 4 mg at first, then 2 mg after each loose stool (maximum 16 mg per day), for up to 48 hours.
• Clostridioides difficile infection:
  • Initial episode, non-severe and severe: fidaxomicin 200 mg orally 12 hourly for 10 days (preferred, with lower recurrence), or vancomycin 125 mg orally 6 hourly for 10 days. Metronidazole 400 to 500 mg orally 8 hourly for 10 days is an alternative only for non-severe infection when neither drug is available.
  • Fulminant infection (hypotension, shock, ileus, megacolon): admit to a high dependency unit, give vancomycin 500 mg orally or by nasogastric tube 6 hourly, plus metronidazole 500 mg IV 8 hourly, and add rectal vancomycin 500 mg in 100 mL of 0.9% sodium chloride every 6 hours as a retention enema when ileus is present. Obtain urgent surgical review: subtotal colectomy (or a loop ileostomy with colonic lavage) is indicated for perforation, worsening lactate, or failure to respond within 48 to 72 hours.
  • First recurrence: fidaxomicin 200 mg orally 12 hourly for 10 days (or an extended pulsed regimen of 200 mg twice daily for 5 days then 200 mg once every other day for 20 days), or vancomycin in a tapered and pulsed regimen (125 mg 6 hourly for 10 to 14 days, then 125 mg 12 hourly for 7 days, then once daily for 7 days, then every 2 or 3 days for 2 to 8 weeks). Use vancomycin 125 mg 6 hourly for 10 days if metronidazole was used for the first episode.
  • Second or further recurrence: faecal microbiota transplantation (by colonoscopy, enema or capsule, or the licensed live biotherapeutic rectal or oral products) after antibiotic treatment of the acute episode, with success in 80 to 90%. Combine with vancomycin tapers where transplantation is not available.
  • Adjuncts: stop unnecessary antibiotics and proton pump inhibitors, strict infection control, and avoid antimotility drugs.
  • Treat for 10 days, and extend to 14 days or longer for slow response or when concurrent systemic antibiotics must continue (continue Clostridioides difficile treatment throughout the course and for 1 week after).
• Infection control (hospital and care home): isolate patients in single rooms with dedicated toilets, contact precautions with gloves and gowns, soap and water hand washing (alcohol rub does not kill spores), sporicidal cleaning with chlorine based agents, and review of antibiotic prescribing (antimicrobial stewardship).
• Special groups:
  • Children: Clostridioides difficile is common in infants under 1 year with colonisation, so test only children over 2 years with significant diarrhoea. Treat with metronidazole 7.5 mg/kg orally 8 hourly for 10 days (maximum 500 mg), or vancomycin 10 mg/kg orally 6 hourly for 10 days (maximum 125 mg per dose) for severe disease. Give oral rehydration solution and zinc, and use probiotics (Saccharomyces boulardii 250 mg twice daily) for prevention in otherwise healthy children.
  • Pregnancy: treat with oral vancomycin 125 mg 6 hourly for 10 days (minimal absorption), or fidaxomicin where the benefits outweigh the limited data. Avoid metronidazole in the first trimester when other options exist.
  • Elderly: higher risk of complications. Monitor creatinine and electrolytes, and admit early. Adjust doses of antibiotics for renal impairment.
  • Immunosuppressed and inflammatory bowel disease: low threshold for testing, early treatment, and surgical review for severe colitis. Review immunosuppressive treatment with the specialist.
  • Renal impairment: fluid and electrolyte care, with oral vancomycin (not systemically absorbed, no adjustment) and fidaxomicin (no adjustment).
  • Patients requiring ongoing antibiotics: choose lower risk antibiotics, and consider co-administration of vancomycin 125 mg orally once daily as prophylaxis in selected recurrent cases (specialist care).
• Follow up: review at 48 to 72 hours for response, because diarrhoea should improve within 3 to 5 days of treatment. Reassess at the end of treatment and at 8 weeks for recurrence. Refer to infectious diseases or gastroenterology for recurrent disease, severe or fulminant infection, or when faecal microbiota transplantation is needed.