15-34: Antibiotic-Associated Colitis

Antibiotic-associated diarrhea is a common clinical occurrence. Characteristically, the diarrhea occurs during the period of antibiotic exposure, is dose related, and resolves spontaneously after discontinuation of the antibiotic. In most cases, this diarrhea is mild, self-limited, and does not require any specific laboratory evaluation or treatment. Stool examination usually reveals no fecal leukocytes, and stool cultures reveal no pathogens. Although C difficile is identified in the stool of 15–25% of cases of antibiotic-associated diarrhea, it is also identified in 5–10% of patients treated with antibiotics who do not have diarrhea. Most cases of antibiotic-associated diarrhea are due to changes in colonic bacterial fermentation of carbohydrates and are not due to C difficile.

Antibiotic-associated colitis is a significant clinical problem almost always caused by C difficile infection that colonizes the colon and releases two toxins: TcdA and TcdB. This anaerobic bacterium is acquired by fecal-oral transmission of spores that colonize the colon of 3% of healthy adults and 8% of hospitalized patients. C difficile colitis is the major cause of diarrhea in patients hospitalized for more than 3 days, affecting up to 15 of every 1000 patients and increasing mean hospital stay costs as much as $30,000. In the United States, there are an estimated 453,000 cases per year with 29,000 associated deaths. Found throughout hospitals in patient rooms and bathrooms, C difficile is readily transmitted from patient to patient by hospital personnel. Fastidious hand washing and use of disposable gloves are helpful in minimizing transmission and reducing infections in hospitalized patients. In hospitalized patients, C difficile colitis occurs in approximately 20% of those who are colonized at admission and 3.5% of those not colonized. In both hospital-associated and community infections, most episodes of colitis occur in people who have received antibiotics that disrupt the normal bowel flora and thus allow the spores to germinate and the bacterium to flourish. Although almost all antibiotics have been implicated, colitis most commonly develops after use of ampicillin, clindamycin, third-generation cephalosporins, and fluoroquinolones. Symptoms usually begin during or shortly after antibiotic therapy but may be delayed for up to 8 weeks. All patients with acute diarrhea should be asked about recent antibiotic exposure. Patients who are elderly; debilitated; immunocompromised; receiving multiple antibiotics or prolonged (more than 10 days) antibiotic therapy; receiving enteral tube feedings, proton pump inhibitors, or chemotherapy; or who have inflammatory bowel disease have a higher risk of acquiring C difficile and developing C difficile–associated diarrhea.

Pathogenic strains of C difficile produce two toxins: toxin TcdA is an enterotoxin and toxin TcdB is a cytotoxin. A more virulent strain of C difficile (NAP1) that contains an 18-base pair deletion of the TcdC inhibitory gene results in higher toxin A and B production. This hypervirulent strain is more prevalent among hospital-associated infections (31%) than community-acquired infections (19%) and has been associated with outbreaks of severe disease with up to 7% mortality.

A. Symptoms and Signs

Most patients report mild to moderate greenish, foul-smelling watery diarrhea 5–15 times per day with lower abdominal cramps. Physical examination is normal or reveals mild left lower quadrant tenderness. The stools may have mucus but seldom gross blood. In most patients, colitis is most severe in the distal colon and rectum. Over half of hospitalized patients diagnosed with C difficile colitis have severe disease as defined by a white blood count greater than 15,000/mcL or serum creatinine greater than 1.5 g/dL.

Fulminant disease occurs in up to 10 % of patients. It is 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 patients with fulminant disease or ileus. Laboratory data suggestive of severe disease include a white blood count greater than 30,000/mcL, serum albumin less than 2.5 g/dL (due to protein-losing enteropathy), elevated serum lactate, and rising serum creatinine.

B. Special Examinations

1. Stool studies

Stool testing for C difficile is recommended in hospitalized patients with dysentery or three or more liquid stools within 24 hours or outpatients with diarrhea persisting longer than 1 week. Three types of diagnostic tests are in common use: (1) an immunoassay for glutamate dehydrogenase (GDH) protein has high sensitivity and negative predictive value (95%) for the detection of toxigenic and nontoxigenic C difficile, though it does not distinguish active infection with toxin secretion from colonization; (2) PCR tests amplify the C difficile toxin gene (usually TcdB); they have extremely high sensitivity (97–99%) for detection of C difficile as well as the ability to detect the hypervirulent NAP1 strain but like the GDH assay cannot distinguish active infection from colonization; (3) rapid enzyme immunoassays (EIAs) detect the presence of C difficile–toxins TcdA and TcdB with 75–95% sensitivity, confirming active toxin-secreting infection. As the initial diagnostic test, most laboratories screen for C difficile with either the PCR toxin gene test or the GDH protein assay. A negative PCR or GDH assay effectively excludes infection. Treatment based on PCR or GDH testing alone may result in unnecessary treatment of patients with C difficile colonization. Therefore, laboratories may perform secondary testing with toxin EIA to distinguish colonization from active toxin-producing infection.

2. Flexible sigmoidoscopy

Flexible sigmoidoscopy is not needed in patients who have typical symptoms and a positive stool test. It may clarify the diagnosis in patients with positive C difficile toxin assays who have atypical symptoms or who have persistent diarrhea despite appropriate therapy. In patients with mild to moderate symptoms, there may be no abnormalities or only patchy or diffuse, nonspecific colitis indistinguishable from other causes. In patients with severe illness, true pseudomembranous colitis is seen. This has a characteristic appearance, with yellow adherent plaques 2–10 mm in diameter scattered over the colonic mucosa interspersed with hyperemic mucosa (eFigure 15–24). Biopsies reveal epithelial ulceration with a classic "volcano" exudate of fibrin and neutrophils. In 10% of cases, pseudomembranous colitis is confined to the proximal colon and may be missed at sigmoidoscopy.

3. Imaging studies

Abdominal radiographs or noncontrast abdominal CT scans are obtained in patients with severe or fulminant symptoms to look for evidence of colonic dilation and wall thickening. Abdominal CT also is useful in the evaluation of hospitalized patients with abdominal pain or ileus without significant diarrhea, in whom the presence of colonic wall thickening suggests unsuspected C difficile colitis. CT scanning is also useful in the detection of possible perforation.

In the hospitalized patient in whom acute diarrhea develops after admission, the differential diagnosis includes simple antibiotic-associated diarrhea (not related to C difficile), enteral feedings, medications, and ischemic colitis. Other infectious causes are unusual in hospitalized patients in whom diarrhea develops more than 72 hours after admission, and it is not cost-effective to obtain stool cultures unless tests for C difficile are negative. Rarely, other organisms (staphylococci, Clostridium perfringens) have been associated with pseudomembranous colitis. Klebsiella oxytoca may cause a distinct form of antibiotic-associated hemorrhagic colitis that is segmental (usually in the right or transverse colon); spares the rectum; and is more common in younger, healthier outpatients.

Severe colitis may progress quickly to fulminant disease, resulting in hemodynamic instability, respiratory failure, metabolic acidosis, megacolon (more than 7-cm diameter), perforation, and death. Chronic untreated colitis may result in weight loss and protein-losing enteropathy.

A. Initial Treatment

To reduce transmission within health care facilities, patients with suspected or proven C difficile infection should be placed on strict contact precautions and health care workers should apply careful handwashing before and after contact. If possible, therapy of the inciting antibiotic should be discontinued as soon as possible. The treatment of an initial episode of C difficile colitis is determined by the severity of disease. For patients with nonsevere disease, oral fidaxomicin (200 mg orally two times daily) and vancomycin (125 mg orally four times daily) are equally effective for initial treatment, but 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 is 10 days in most situations but is 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 when vancomycin or fidaxomicin is unavailable. Symptomatic improvement occurs in most patients within 72 hours. Following treatment, stool assays may remain positive for several weeks after symptom resolution.

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. Early surgical consultation is recommended for all patients with severe or fulminant disease. Total abdominal colectomy or loop ileostomy with colonic lavage may be required in patients with toxic megacolon, perforation, sepsis, or hemorrhage.

Bezlotoxumab is a monoclonal antibody to C difficile toxin B. It was approved by the FDA in 2016 for patients with C difficile infection who are receiving antimicrobial therapy with metronidazole, vancomycin, or fidaxomicin and are deemed at high risk for disease recurrence. In two phase III randomized controlled trials, patients given one intravenous infusion of bezlotoxumab had a lower risk of disease relapse within 12 weeks (16%) than patients given placebo (26%). In light of this modest clinical benefit, bezlotoxumab should be considered only in patients 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, or have had prior C difficile recurrences.

B. Treatment of Relapse

Up to 20% of patients have a relapse of diarrhea from C difficile within 8 weeks after stopping initial therapy. This may be due to reinfection or failure to eradicate the organism. Current Infectious Disease Society of America guidelines recommend that the first recurrence be treated with fidaxomicin 200 mg orally twice daily for 10 days or with a prolonged tapering regimen of vancomycin 125 mg orally four times daily for 14 days; twice daily for 7 days; once daily for 7 days; then every other 2 or 3 days for 2–8 weeks. Second recurrence should be treated with an additional vancomycin tapering regimen, as above.

For patients with three or more relapses, guidelines recommend consideration of fecal microbiota transplantation (FMT), in which a suspension of fecal bacteria from a healthy donor is given to the patient with infection. 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: (1) infusion through a colonoscope into the terminal ileum and colon, (2) infusion through a nasoenteric tube into the duodenum, or (3) ingestion of multiple freeze-dried capsules. Due to its efficacy and relative safety and ease of administration, the oral capsule method has become the preferred mode of fecal administration in most patients. 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. Furthermore, randomized studies have demonstrated significantly higher resolution of C difficile diarrhea with FMT (94%) than vancomycin (31%) and with FMT (92%) versus fidaxomicin (42%) or vancomycin (19%). However, FMT carries the potential risk of transmission of serious, even potentially fatal, infection. However, with proper screening and stool testing of donors, the risk of infections appears to be very low. In 2019, the FDA issued a safety alert regarding two cases of extended-spectrum beta-lactamase E coli infections in immunocompromised patients following FMT. In 2020, the FDA received reports of four patients developing STEC and two patients developing enteropathogenic E coli (EPEC) following FMT; four of the six patients required hospitalization. In addition, the manufacturer reported that two other patients had died following FMT from the STEC donor. Clinicians considering offering FMT must discuss with their patient this potential uncommon but very serious risk.