Oral vancomycin is not absorbed and the colonic levels are very high (500–1000mg/mL),
several hundred-fold higher than the highest measured minimum inhibitory concentration
(MIC) forC. difficile. Vancomycin, administered via retention enemas, has been shown to be
effective in small, uncontrolled case series of patients with severe or fulminant colitis not
responding to standard therapy (50). It is important to note that parenteral vancomycin has no
activity against CDI. The major drawback with oral vancomycin is the price. The cost per day
with standard dosing (125 mg 4 times daily) is approximately $70 as compared with $2 with
metronidazole. Vancomycin is the drug of choice in pregnant or lactating women. Studies have
shown that a regimen of 125-mg oral vancomycin administered four times daily (current
standard regimen) is as effective as 500 mg four times a day (older standard) (51). However, for
severe/fulminant of CDI the dosing 500 mg four times daily is recommended.
Metronidazole, as opposed to oral vancomycin, is virtually 100% absorbed in the small
bowel and reaches the colon through biliary excretion and increased exudation across the
intestinal mucosa during diarrhea (52). In healthy volunteers without diarrhea, oral and
intravenously administered metronidazole achieve low fecal concentrations but usually
exceeds theC. difficile MIC (34). Side effects of metronidazole include dose-dependent
peripheral neuropathy, nausea, and metallic taste. Metronidazole is typically dosed orally at
500 mg three times daily or 250 mg four times daily.
Resistance to metronidazole has been uncommon. Recently, some strains have shown
increasing resistance (“metronidazole creep”) so it is possible to have metronidazole levels in
the colon below the MIC for some periods of time. One report form Spain reported 6% rate of
resistance to metronidazole (53). Vancomycin resistance has not been reported.
Both vancomycin and metronidazole may promote the development of VRE even though
historically vancomycin has been the one most frequently implicated. The relapse rate is
approximately the same for each drug (15–30%).
Indications for Treatment
Treatment for CDI is dependent on the severity of illness and is divided into mild, moderate,
severe, and relapsing disease, respectively. First, it must be emphasized that treatment is not
indicated in patients who are asymptomatic even with a positive stool toxin assay.
Mild to Moderate Disease
For very mild disease, discontinuation of the inducing agent may be sufficient therapy and no
further antibiotic therapy needed. A Cochrane Library review from 2007 reports uncertainty
whether mild CDI needs to be treated (54). This review did not take into account the newly
emerging epidemic strain, B1/NAP1, which can start with mild disease and escalate rapidly.
Patients with mild disease (defined according to IDSA Draft guidelines from 2007 as
WBC <15,000 cells/mm^3 or rising creatinine <50% higher than prior to CDI), clinical
manifestations of CDI (diarrhea, abdominal pain, or nausea and vomiting), and a positive
diagnostic assay should receive antibiotics for CDI. Current guidelines recommend oral
metronidazole (500 mg 3 times daily or 250 mg 4 times daily) for initial treatment (Table 3).
Metronidazole is favored over oral vancomycin in mild to moderate cases due to its lower cost
and good efficacy. Empiric therapy is appropriate if clinical suspicion is high and the initial
diagnostic assay is pending or negative. One study showed increased mortality among
patients who had an initial false-negative toxin (40).
Severe Disease
Patients with severe CDI (defined according to IDSA Draft guidelines from 2007 as WBC
15,000 cells/mm^3 or rising creatinine>50% higher than prior to CDI) should be treated with
withdrawal of the antibiotic implicated to cause CDI, antibiotics, supportive care, and
consideration for surgery (see below) if the patient’s clinical status fails to improve.
Two recent prospective randomized trials have shown a statistical significant superiority
of oral vancomycin therapy in patients with severe CDI. The recommended dose for severe
disease is 125-mg oral vancomycin four times daily. For patients with severe complicated CDI
(WBC>15,000 cells/mm^3 or rising creatinine>50% higher than prior to CDI plus hypotension,
ileus, toxic megacolon, perforation, need for colectomy, or ICU admission), the recommended
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