Clostridium difficile colonizes the human intestinal tract after the normal gut flora has been altered by antibiotic therapy and causes antibiotic-associated colitis. The antibiotics most frequently implicated in predisposition to C. difficile infection are fluoroquinolones, clindamycin, cephalosporins, and penicillins. Additional risk factors include age >65 and recent hospitalization.
A spectrum of clinical manifestations is observed.
- Clinical manifestations of C. difficile–associated diarrhea (CDAD) with colitis include watery diarrhea (≥3 loose stools in 24 hours) with lower abdominal pain and cramping, low-grade fever, and leukocytosis.
- Clinical manifestations of fulminant colitis include diarrhea, severe lower quadrant or diffuse abdominal pain, abdominal distention, fever, hypovolemia, lactic acidosis, hypoalbuminemia, and marked leukocytosis. Diarrhea may be less prominent or absent in patients with prolonged ileus due to pooling of secretions in the dilated, atonic colon. Potential complications include toxic megacolon and bowel perforation.
Recurrence C. difficile infection is defined by complete abatement of symptoms while on appropriate therapy, followed by subsequent reappearance of diarrhea and other symptoms after treatment has ended. Relapse may present within days or weeks of completing treatment for C. difficile; the clinical presentation may be similar to or more severe than the initial presentation.
The diagnosis of C. difficile infection is established via a positive stool test for C. difficile toxins or C. difficile toxin gene. We favor use of polymerase chain reaction for laboratory diagnosis of C. difficile, either alone or as part of an algorithm including initial enzyme immunoassay screening for glutamate dehydrogenase antigen and toxins A and B. The diagnostic approach for suspected recurrent C. difficile is the same as the approach for initial infection.
Laboratory testing should be pursued only in patients with clinically significant diarrhea, since testing cannot distinguish between CDAD and asymptomatic carriage (which does not warrant treatment). For patients with ileus, laboratory diagnosis via perirectal swab for toxin assay or anaerobic culture may be performed.
Radiographic imaging of the abdomen and pelvis is warranted for patients with clinical manifestations of severe illness or fulminant colitis to evaluate for presence of toxic megacolon, bowel perforation, or other findings warranting surgical intervention.
Lower gastrointestinal endoscopy is not warranted in patients with classic clinical manifestations of C. difficile infection, a positive laboratory test, and/or clinical response to empiric treatment. In general, endoscopy may be pursued for circumstances in which an alternative diagnosis is suspected that requires direct visualization and/or biopsy of the bowel mucosa. It may also be helpful for patients with ileus or fulminant colitis in the absence of diarrhea since it may allow visualization of pseudomembranes (severe inflammation of the inner lining of the bowel), a finding that is highly suggestive of C. difficile infection.
Findings of pseudomembranous colitis (severe inflammation of the inner lining of the bowel) on radiographic or endoscopic examination are highly suggestive of C. difficile infection and should prompt laboratory testing if not already performed.
The initial step in the treatment of Clostridium difficile infection (CDI) is cessation of the inciting antibiotic as soon as possible. Infection control practices must be implemented, including contact precautions and hand hygiene. Hand hygiene with soap and water may be more effective than alcohol-based hand sanitizers in removing C. difficile spores, since C. difficile spores are resistant to killing by alcohol. Therefore, use of soap and water is favored over alcohol-based hand sanitization in the setting of a CDI outbreak, although thus far no studies have demonstrated superiority of soap and water in non-outbreak settings.
For initial treatment of nonsevere CDI, we suggest oral metronidazole (Grade 2B).
For treatment of severe CDI, we recommend vancomycin 125 mg four times daily for 10 to 14 days (Grade 1B). For patients with severe disease who do not demonstrate clinical improvement, we suggest treatment with oral vancomycin 500 mg four times daily (Grade 2C); fidaxomicin may be considered in patients who cannot tolerate vancomycin, although more data are needed. In critically ill patients with fulminant or refractory disease, we suggest oral vancomycin 500 mg four times daily and intravenous metronidazole 500 mg every eight hours (Grade 2C); fidaxomicin may be considered in patients who cannot tolerate vancomycin, although more data are needed.
For treatment of severe disease in patients with profound ileus, we suggest addition of intracolonic vancomycin (Grade 2C), but there is risk of colonic perforation. Therefore, use of intracolonic vancomycin should be restricted to patients who are not responsive to oral therapy, and the procedure should be performed by personnel with expertise in administering enemas.
For treatment of a nonsevere initial recurrence of CDI, we suggest oral metronidazole (Grade 2A). Alternatives include oral vancomycin or fidaxomicin.
For treatment of a second recurrence of CDI, we suggest intermittent and tapering vancomycin therapy or fidaxomicin (Grade 2B). For treatment of subsequent recurrences of CDI, we suggest administering either fidaxomicin or vancomycin followed by rifaximin (Grade 2C).
We recommend urgent surgical evaluation for patients with a white blood cell count ≥20,000 cells/microL and/or a plasma lactate between 2.2 and 4.9 mEq/L (Grade 1B). In addition, surgical intervention should be strongly considered in the setting of peritoneal signs, severe ileus, or toxic megacolon.
Potential alternative therapies requiring further investigation prior to routine use include new antibiotic agents, binding resins, intravenous immune globulin, and fecal bacteriotherapy.
We are in agreement with guidelines issued after 2010 that recommend oral vancomycin as first-line therapy for severe CDI. This is in contrast with previous guidelines published in the 1990s that recommended oral metronidazole as initial therapy for both mild and severe C. difficile–associated diarrhea (CDAD). This change reflects reports of frequent metronidazole failures in CDI and studies showing the superiority of oral vancomycin in severe disease.
The major pharmacologic advantage of vancomycin over metronidazole is that vancomycin is not absorbed, so maximal concentrations of the drug can act intracolonically at the site of infection. The major advantage of metronidazole over vancomycin is that the cost of metronidazole is substantially lower. With respect to in vitro activity, risk of relapse, and potential for emergence of vancomycin-resistant enterococci, the drugs appear to be relatively similar.
Oral vancomycin is the preferred therapy for severe or refractory cases. This issue was directly addressed in a prospective, randomized double-blind trial that included 69 patients with severe CDI as defined above. The cure rate was significantly higher with vancomycin (97 versus 76 percent with metronidazole).
Although the data are limited, clinical practice is shifting toward using oral vancomycin as initial therapy for severe CDI. Many have endorsed vancomycin as the preferred therapy for moderate or severe disease caused by the epidemic strain, and most favor its use for all patients with severe and/or complicated disease.
Intracolonic administration of vancomycin via enema (given in combination with intravenous metronidazole) is an option for patients who do not tolerate oral medication, but there is risk of colonic perforation. Therefore, use of intracolonic vancomycin should be restricted to patients who are unresponsive to standard therapies, and the procedure should be performed by personnel with expertise in administering enemas.
We recommend that patients with severe disease be treated with oral vancomycin (125 mg four times daily). For patients with severe disease who do not demonstrate clinical improvement, we suggest increasing the dose of oral vancomycin to 500 mg four times daily. Fidaxomicin may be considered in patients who cannot tolerate vancomycin, although more data are needed. In the setting of ileus, addition of intravenous metronidazole (500 mg every eight hours) is appropriate. Intracolonic vancomycin may be considered in patients with profound ileus.
The standard duration of antibiotic therapy for C. difficile diarrhea is 10 to 14 days; the antibiotic course should be tailored to clinical circumstances for patients with severe disease. Those with an underlying infection requiring prolonged duration of antibiotics should continue CDI treatment throughout the antibiotic course plus one additional week after its completion.
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.
For patients with severe disease who do not demonstrate clinical improvement with oral vancomycin, administration of therapy with fidaxomicin (200 mg orally twice daily) is reasonable. Additional data are needed on the efficacy of fidaxomicin in the setting of severe disease.
For circumstances in which neither vancomycin nor fidaxomicin is available, oral metronidazole (500 mg three times daily or 250 mg four times daily for 14 days) may be administered, although it is less effective than vancomycin.
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 (500 mg every eight hours). Fecal concentrations in the therapeutic range can be achieved with this regimen because of biliary and intestinal excretion of the drug. However, it is uncertain whether intravenous therapy alone is as effective as oral therapy, so oral therapy should be administered whenever feasible.
Intravenous vancomycin has no effect on C. difficile colitis since vancomycin is not excreted into the colon.
Intravenous tigecycline has been used in a small number of patients with severe CDI that was refractory to standard therapy. Given the lack of data, we do not recommend tigecycline for C. difficile colitis.
Intracolonic vancomycin (vancomycin enema) may be an effective adjunctive therapy for patients who cannot tolerate the oral preparation or for patients who have a condition preventing oral vancomycin from reaching the colon such as ileus, megacolon, Hartman’s pouch, ileostomy, or colonic diversion. In a case series of nine patients with refractory symptoms, toxic megacolon, or fulminant colitis, rectal vancomycin was administered in addition to standard antibiotics. Eight patients had complete resolution of symptoms and one patient died from multisystem organ failure.
The optimal dosing of intracolonic vancomycin has not been established by clinical trials, and case descriptions vary widely; rectal vancomycin is often given as a retention enema containing 500 mg in 100 mL of normal saline every six hours. One report suggests that patients with megacolon may benefit from colonoscopic decompression and placement of a tube in the right colon, which can be perfused with a 1 mg/mL solution of vancomycin in normal saline to deliver a total dose of 1 to 2 g per day ; however, this requires further confirmation. Dose adjustments may be required depending on individual circumstances, including extent of colonic disease and patient weight. It is important to note that vancomycin can be absorbed through inflamed colonic mucosa and cause toxicity if it accumulates in patients with renal failure.