Clostridium Difficile Colitis Medication

Initial therapy

Pharmacologic therapy should be tailored according to the severity of C difficile infection. Treatment is not indicated for asymptomatic carriers. In mild cases (ie, patients without fever, abdominal pain, or leukocytosis), cessation of causative antibiotics may be the only treatment necessary. Approximately 15-25% of patients respond to conservative therapy, which allows for reconstitution of normal colonic flora and reduces the risk of relapse. Specific therapy aimed at eradicating C difficile is indicated if symptoms are persistent or if antibiotics cannot be discontinued safely.

Oral metronidazole and vancomycin have similar efficacy rates in treating diarrhea caused by C difficile except for severe disease. The oral administration of these medications is the preferred route because C difficile remains within the colonic lumen without invading the colonic mucosa. Vancomycin is poorly absorbed in the intestinal tract, thereby promoting high concentrations within the intestines while significantly reducing the prevalence of adverse systemic effects. Metronidazole 250mg PO QID for 10 days is the drug of first choice for mild to moderate disease because of its lower cost.

A study by Louie et al compared vancomycin (125 mg orally 4 times daily) with fidaxomicin (200 mg twice daily).^[8] The study found that fidaxomicin had a similar efficacy and significantly lower rate of recurrence of C difficile infection associated with non–North American Pulsed Field type 1 strains. Fidaxomicin was approved by the US Food and Drug Administration in May 2011.

For severe cases, vancomycin 125mg PO QID for 10 days is considered 1st line and higher dosing 250mg PO (or per nasogastric tube) QID may be used if poor absorption is possible due to situations such as ileus. For patients who are unable to tolerate PO medication, IV metronidazole is effective. Excretion of the drug into bile and exudation from the inflamed colon results in bactericidal levels in feces. IV vancomycin is ineffective.

Relapse

Occurs in 20-27% of patients treated with metronidazole or vancomycin. Once a patient has one relapse the risk for a 2nd relapse is 45%. Recurrent infection tends to occur in patients that mount a poor host immune response to C difficile. Persistent disruption of the colonic microbial flora also confers increased risk.

For the first relapse, the choice of antibiotic should be based on severity of C difficile diarrhea/colitis.

For every relapse beyond the first, vancomycin prolonged taper and pulsed regimen is recommended to help clear persistent spores

Probiotics such as Saccharomyces boulardii and Lactobacillus species have shown mixed results in reducing the risk of relapse of C difficile and probiotics are not recommended as a single agent for treatment of active infection. Saccharomyces boulardii for the treatment of C difficile has generated interest because it seems to inhibit the effects of toxins A and B on the human colonic mucosa.

Rifaximin after treatment with vancomycin may also reduce the risk of relapse but rifaximin is not yet FDA approved for this indication.

Nitazoxanide, a medication used to treat parasites has also shown to be as effective as metronidazole in a clinical trial for the treatment of C difficile.

Intravenous immunoglobulin (IVIG) has been reported as an adjunctive treatment for refractory C difficile colitis/diarrhea and severe cases. In some individuals a poor host immune response to C difficile may be a risk factor for lack of clearance of C difficile and may be the reason for the benefit of IVIG.

Cholestyramine binds toxins A and B of C difficile, but the clinical experience of different investigators has shown marked variation in results. Cholestyramine binds vancomycin and should not be used concurrently with vancomycin therapy.

Other investigational therapies include: tolevamer (a toxin binding polymer with no antimicrobial properties), antibiotics ramoplanin and OPT-80 (poor intestinal absorption), and C difficile vaccination.

Fecal transplantation (fecal enemas) has also been reported to repopulate the colonic flora and treat recurrent C difficile. Long-term data from a fecal transplantation clinical trial (>=3 months from the time of fecal transplantion) revealed of the 77 out of 98 patients that could be contacted 91% did not relapse, and of the patients that relapsed all but one were treated successfully with vancomycin or additional fecal transplantation.^[9]

Avoid antidiarrheal agents (eg, diphenoxylate with atropine). They have been reported to increase the duration and severity of symptoms.

Class Summary

To eradicate C difficile infection and/or promote restoration of normal colonic flora.

Metronidazole (Flagyl)

Recommended as the treatment of choice for mild-to-moderate cases. Provides effective therapy, with reported response rates from 95-100%. In vitro activity is bactericidal and dose dependent. Standard dosing has been shown to promote fecal concentrations capable of a 99.99% reduction of C difficile. Relatively inexpensive (approximate wholesale cost for a 10-d supply is $1). Metronidazole IV may be administered to those patients who cannot tolerate PO medications because of its potential to accumulate in the inflamed colon. IV route is not as effective as PO.

Vancomycin (Vancocin)

Has excellent in vitro activity against C difficile. Kills organism by inhibiting cell wall synthesis. Significant luminal levels after PO vancomycin can be obtained because it is poorly absorbed from the GI tract. Major disadvantage is cost. PO vancomycin is relatively expensive, with a wholesale cost of approximately $150 for a 10-d supply. Because of the cost and the concern over the emergence of vancomycin-resistant enterococci strains, its use should be reserved for patients who cannot tolerate metronidazole, patients who do not respond to metronidazole, pregnant patients, and patients < 10 y. Also preferred for severe cases and in patients who are high risk. Unlike IV metronidazole, IV vancomycin is not excreted into the GI lumen; therefore, it is difficult to deliver effective doses by this route.

Bacitracin

Inhibits formation of major components of the bacterial cell wall and is bactericidal.

Alternative therapy, but it is expensive, not as effective as metronidazole or vancomycin in clinical trials, and without sufficient data to warrant its use. Drug is bitter and must be specially prepared in capsule form to prevent nausea. Bacitracin administered PO is only negligibly absorbed from the GI tract.

Fidaxomicin (Dificid)

Macrolide antibiotic indicated for Clostridium difficile -associated diarrhea in adults. Bactericidal against C difficile in vitro, inhibiting RNA synthesis by RNA polymerases.

Class Summary

Bind C difficile toxin and other proteins.

Cholestyramine (Questran)

For diarrhea associated with pseudomembranous colitis. Forms a nonabsorbable complex with bile acids in the intestine, which, in turn, inhibits enterohepatic reuptake of intestinal bile salts.

Also binds vancomycin, which precludes combination therapy. Available as a powder that must be mixed with water prior to ingestion. Efficacy is inferior to metronidazole or vancomycin, but it may have a role under certain circumstances (eg, patients who continue to relapse). Not absorbed from the GI tract.