The pathogenesis is due to prolonged use of multiple antibiotics, especially broad-spectrum agents with poor intestinal absorption or high biliary excretion. These antibiotics induce a change in the composition and function of the intestinal flora and therefore result in a higher incidence of AAD. A decrease in the colonic anaerobic flora interferes with carbohydrate and bile acid metabolism. Osmotic or secretary diarrhea may occur. Overgrowth of opportunistic pathogens takes place as a result of microbiologic and metabolic alterations.

AAD can be classified into 2 distinct categories:

  1. Diarrhea related to the direct effects of antibiotics

  2. Diarrhea related to an enteric pathogen (primarily C. difficile)

Diarrhea Related to the Direct Effects of Antibiotics


This diarrhea often presents as an annoyance, presenting with frequent loose and watery stools without fever, leukocytosis, or severe abdominal cramps. Diarrhea occurs due to a change in the composition and function of intestinal flora. Additionally, nonantimicrobial effects of antibiotics can occur. Erythromycin can act as a motilin receptor agonist and accelerate the rate of gastric emptying, thus causing diarrhea. The clavulanate in amoxicillin–clavulanate appears to stimulate small bowel motility, thus causing diarrhea. In rare instances, penicillins may cause segmental colitis, resulting in diarrhea. Some antibiotics, such as clindamycin, cephalosporins, ampicillin, amoxicillin, and amoxicillin–clavulanate, can cause both types of diarrhea.

Typically, no pathogens are identified. There is no diagnostic test specific for benign, self-limiting AAD. One should not order routine stool culture for ova and parasites in patients with hospital-acquired diarrhea, especially in immunocompetent patients with a benign presentation.


Effective treatment is generally limited to discontinuation of the implicated agent, with or without therapy with antiperistaltic agents. Probiotics such as live culture yogurt may be helpful.

Diarrhea Related to Enteric Pathogens (Primarily Due to C. difficileInfection)

Enteric pathogen-related diarrhea accounts for 15% to 20% of all AAD cases.

Table 25-2. Antimicrobial Agents That May Induce Clostridium difficile Diarrhea or Colitis

Frequently Associated Occasionally Associated Rarely Associated
Fluoroquinolones, clindamycin, penicillins (broad spectrum), cephalosporins (broad spectrum)
  • Macrolides
  • Trimethoprim
  • Sulfonamides
Aminoglycosides, tetracyclines, chloramphenicol, metronidazole, vancomycin (drugs used to treat C. difficile can rarely cause C. difficile diarrhea)



The cardinal symptom of the disease is diarrhea, which can range from a mild illness to life-threatening pseudomembranous colitis. C. difficile infection (CDI) manifests with a profuse, mucous, foul-smelling diarrhea associated with cramps and tenesmus. Frank bleeding is rare, although fecal occult blood and leukocytes are frequently detected. Constitutional symptoms are common, and include nausea, vomiting, dehydration, and low-grade fever. Mild leukocytosis is frequently present and may occur even in the absence of diarrhea. An occasional leukemoid reaction can be seen. Diarrhea commonly develops during treatment but may appear as late as 8 weeks after discontinuation of antibiotics. CDI should be highly suspected in patients with leukocytosis of unknown etiology even in the absence of diarrhea, especially in the severely ill elderly, hospitalized patient on antimicrobials or those who have recently completed a course of antimicrobials, including antifungal agents.

C. difficile causes diarrhea via toxin-mediated effects on the large bowel. Both C. difficile toxins A and B exhibit potent enterotoxic and cytotoxic effects that are responsible for the clinical manifestations. Toxic megacolon and subsequent perforation are possible complications if the CDI goes untreated. A dramatic clinical picture of marked colonic distention, peritoneal irritation, fever, and elevated white blood count may occur. Hypoalbuminemia, hypovolemia, and ascites are common features.


Cytotoxin assay or tissue culture assays are considered to be the gold standard with 94% to 100% sensitivity and 99% specificity, but cell culture tests are expensive, time-consuming, and rarely used in clinical practice. The most preferred diagnostic method in C. difficile colitis is the enzyme-linked immunosorbent assay (ELISA). ELISA is fast, relatively inexpensive, and has an excellent specificity (99%). Its sensitivity, however, is 60% to 95%. Serial stool determinations on different days are suggested for suspected cases with initial negative results. Polymerase chain reaction (PCR) appears to be a rapid, more sensitive and specific test compared with ELISA, which is important for prompt implementation of treatment and infection control. Major clinical laboratories are adopting PCR as the primary tool to detect C. difficile. Repeat PCR within 7 days is of no utility, unless patients develop new symptoms. Imaging is usually not required in mild cases. Abdominal CT scan in patients with pseudomembranous colitis demonstrates pronounced colonic wall thickening. If suspecting toxic megacolon, a plain abdominal x-ray may show marked colonic distention (>7 cm) or thumbprinting, with or without pneumatosis intestinalis. CT often reveals colonic wall thickening, lumen obliteration, pericolonic fat stranding, and ascites with toxic megacolon.


Indication for treatment:

  1. Patients with typical CDI manifestations and a positive diagnostic assay.

  2. Empirical therapy is indicated in patients with a high suspicion of CDI pending diagnostic test results.

Treatment is not indicated in patients who have a positive diagnostic assay, but are asymptomatic.

The initial step in the treatment of CDI is tapering the antibiotic regimen and cessation of the inciting antibiotic as soon as possible given other comorbid illness. Infection control practices must be implemented, including contact precautions and hand hygiene. Hand hygiene should include washing using soap and water, as this is more effective than alcohol-based agents in removing C. difficile spores.

Treatment of Initial Episode of Nonsevere C. difficile Infection

Metronidazole can be used for initial treatment of nonsevere CDI. The recommended regimen is 500 mg 3 times daily or 250 mg 4 times daily for 10 to 14 days. An alternative agent is oral vancomycin 125 mg orally 4 times daily for 10 to 14 days.

Oral vancomycin should be reserved for the following conditions:

  • The patient has failed therapy with metronidazole.
  • The patient's organism is resistant to metronidazole.
  • The patient is allergic to, or cannot tolerate, metronidazole.
  • The patient is pregnant.

Metronidazole is preferred due to low cost and comparable efficacy, and to limit the spread of vancomycin-resistant enterococci (VRE). Patients with underlying infections, along with C. difficile diarrhea, with prolonged use of antibiotics should continue CDI treatment throughout the course of antibiotic plus 1 additional week after its completion. Routine stool assay is not recommended during the course or following treatment of CDI, in patients who are recovering or symptom-free. Up to 50% of these patients have a positive test.

Treatment of Severe C. difficile Infection

Patients with acute CDI may develop signs of systemic toxicity with or without profuse diarrhea warranting admission to an intensive care unit or emergency surgery. There is no general consensus on the definition of severe CDI.

The following definition has been described in the literature:

  1. White blood cell count of >15,000 cells/μL or a serum creatinine level ≥1.5 times the premorbid condition.

  2. White blood cell count >20,000 cells/μL and an elevated serum creatinine as potential indicators of complicated disease.

  3. One point each was given for age >60 years, temperature >38.3°C, serum albumin <2.5 mg/dL (25 g/L), or peripheral white blood cell count >15,000 cells/μL within 48 hours of enrollment. Two points were given for endoscopic evidence of pseudomembranous colitis or treatment in the intensive care unit. Patients with 2 or more points were considered to have severe disease.

  4. Severe disease is defined as having >10 bowel movements per day, WBC >20,000 cells/μL, or severe abdominal pain.

Decisions regarding treatment are left up to the clinician to decide based on the severity of the disease. Any or all of the above criteria can be used to rate the severity of the disease.

Oral vancomycin 125 or 500 mg (many physicians tend to use a higher dose, although there is no evidence 500 mg is better than 125 mg) orally 4 times daily, plus intravenous metronidazole 500 mg every 8 hours for 10 to 14 days, is suggested. Fecal concentrations in the therapeutic range are achieved with this regimen because of biliary and intestinal excretion of metronidazole. Fidaxomicin (bactericidal) 200 mg twice daily for 10 days is recommended in patients who cannot tolerate vancomycin. In patients with significant ileus, intracolonic vancomycin is recommended. One needs to be aware though that this method involves the risk of perforation. Enemas should be given with caution.

Relapse is defined as complete resolution of symptoms while a patient is on CDI treatment and reappearance of diarrhea and other symptoms after completion of CDI treatment.

  1. First relapses can occur in 25% of patients. Repeat treatment similar to the first episode with oral metronidazole or vancomycin is indicated as suggested above.

  2. For a second relapse, intermittent and tapering vancomycin therapy is suggested. Alternatively, fidaxomicin 200 mg orally twice daily for 10 days can be used.

  3. Subsequent relapses can occur in 65% of cases. Use vancomycin 125 mg orally 4 times daily for 14 days, followed by rifaximin 400 mg twice daily for 14 days. Alternatively, fidaxomicin 200 mg orally twice daily for 10 days can be used.

Other potential agents such as new antibiotics, binding resins, probiotics, intravenous immunoglobulins (IVIG), and fecal bacteriotherapy require further investigation prior to routine use. Urgent surgical evaluation for elderly patients (≥65 years) with a white blood cell count ≥20,000 cells/mL and/or a plasma lactate between 2.2 and 4.9 mEq/L is recommended. In addition, surgical intervention is advisable in the setting of peritoneal signs, severe ileus, or toxic megacolon.




Antibiotic-associated Diarrhea is the most common cause of diarrhea in hospitalized patients, representing an important source of morbidity, mortality, and cost. It is estimated that 10% to 15% of all hospitalized patients treated with antibiotics will develop AAD.






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