A 68-year-old woman complained of a 2-week history of loose stool and abdominal cramps. One month ago she was treated by her primary care physician for a sinus infection with amoxicillin. In addition to diarrhea, she noticed some blood mixed with her stool. She is a diabetic and takes metformin. Her last colonoscopy 2 years ago showed diverticula only.
Treatment of Clostridium difficile infection has four main tenets, which apply to all cases of confirmed Clostridium difficile infection:
- Discontinue the causative antibiotics (if possible)
- Initiate anti-C. difficile antibiotic therapy
- Monitor for, and manage, complications
- Initiate infection control measures.
The choice of antibiotic regimen to treat confirmed Clostridium difficile infection depends on whether it is an initial infection or relapse, and the severity of the infection itself. As noted in Table 50.1, patients aged over 65 years, those with a high white cell count, and those with an elevated creati-nine are at higher risk of severe disease.
Initial Clostridium difficile infection
For initial treatment of uncomplicated Clostridium difficile infection, oral metro-nidazole, 250 mg four times daily for 10-14 days, is the treatment of choice. As it is excreted in the bile, intravenous administration of metronidazole is also effective. The advantages of metronidazole are its low cost, and its comparable efficacy to vancomycin for non-severe Clostridium difficile infection in randomized controlled trials.
The disadvantages are its side-effects, including nausea and metallic taste during therapy. It is worth noting that a recent outbreak in Canada was associated with an unusually high rate (26%) of patients who failed to respond to metronidazole, but this may reflect a higher proportion of patients with severe disease due to the hypervirulent NAP-1/027 strain. Vancomycin 125 mg orally four times daily is an alternative choice, but is not effective if given intravenous as it is excreted primarily by the kidney. The disadvantages to using vancomycin are its higher costs, and concerns about the proliferation of vancomycin-resistant enterococci. Importantly, metronidazole or vancomycin resistance has not been documented in C. difficile.
In severe Clostridium difficile infection oral vancomycin 125 mg four times a day is significantly more effective than metronidazole , and is the drug of choice. In the presence of ileus, or in patients unable to take oral medications, vancomycin may be given via nasogastric tube or as a retention enema (500mg four times per day) , Patients with fulminant colitis require intravenous metronidazole (500mg three times per day), in addition to vancomycin (500 mg four times per day) and review by a surgeon to consider urgent colectomy.
Recurrent Clostridium difficile infection
Recurrence occurs in about 20% of patients of successfully treated patients, regardless of initial therapy, and may result either from environmental re-infection with a different strain of C. difficile or persistence, via spores in the colon, of the same strain responsible for the initial episode. Positive stool toxin tests in patients with recurrence of diarrhea are not always helpful, as colonized patients can produce toxin which is neutralized by antitoxin antibodies, thus preventing colitis. Other causes of diarrhea such as other infections, Inflammatory bowel disease flares, or postin-fectious irritable bowel syndrome may mimic relapse of C. difficile.
The first recurrence is usually treated with a repeat 14-day course of metronidazole or vancomycin, in the same dosage used for the initial episode, with recovery expected in about 80-90%. After the first recurrence patients are at high risk of developing further recurrences, up to 50% in one study. Some patients require treatment for multiple symptomatic recurrences. The following treatment strategies are used in patients with multiple relapse:
- Vancomycin taper and pulse regimen, to eradicate remnant spores as they convert to the vegetative state in the colon
- Vancomycin taper and pulse regimen followed by a 4-week course of probiotics, such as Saccharomyces bou-lardii to prevent re-growth of C. difficile
- Vancomycin for 14 days followed by rifaximin for 14 days.
Other options such as intravenous immunoglobulin, bacterotherapy with fecal transplantation, or toxin binders such as cholestyramine are resorted to in some patients with multiple relapses.
The patient started oral metronidazole 250 mg four times per day for presumed acute Clostridium difficile infection. Her diarrhea resolved within 4 days. A second stool sample prior to initiation of therapy was positive for C. difficile toxin.
A few days after she finished the course of metronidazole the patient was admitted to hospital with profuse watery diarrhea. She has no features of severe disease, but her initial C. difficile toxin test was positive.
Colonization of the colon with Clostridium difficile bacteria can lead to a range of outcomes from asymptomatic carriage, to pseudomembranous colitis, to fulminant colitis. The incidence and severity of this infection have increased in the last 5 years, probably related to the emergence of a highly toxigenic strain associated with hospital outbreaks.
Standard treatment for C difficile-associated diarrhea includes stopping the implicated antibiotics, commencing oral metronidazole therapy, and correction of secondary dehydration. C difficile has not developed resistance to metronidazole or vancomycin, hence initial response to these agents exceeds 90% in clinical trials. Recurrent infection usually responds to re-treatment with metronidazole or vancomycin, or pulse-tapered therapy. Control measures to minimize the risk of hospital-acquired infections remain an important preventative strategy.