Pharmacotherapy of C. difficile-associated disease

Metronidazole and vancomycin are recommended for initial treatment of the disease.

Issue: July 2007

ByEdward A. Bell, PharmD, BCPS

Clostridium difficile-associated disease is receiving renewed attention in medical literature, as the incidence and morbidity from this disease is on the rise.

C. difficile is the most common cause of antibiotic-associated diarrhea. Approximately 3% of healthy adults and 20% to 40% of hospitalized patients are colonized with C. difficile in spore form (no disease). C. difficile is transmitted by the fecal–oral route. Spores are able to endure the acidic gastric environment and proceed to the colon, where disease may occur under certain conditions. When an antibiotic is taken by the patient, the balance of gastrointestinal microbiologic flora may become disrupted, allowing C. difficile to convert to a more active form, resulting in pathogenic effects.

C. difficile-associated disease (CDAD) may result in watery diarrhea, fever, malaise and leukocytosis. More severe disease or complications can include pseudomembranous colitis, ileus, toxic megacolon, sepsis and death. Reported mortality rates from CDAD range from 1% to 2% and may increase to between 6% and 30% when pseudomembranous colitis occurs. These symptoms result from toxins produced by C. difficile. Toxins A and B are most characterized and result in enterocyte damage, with the potential for severe fluid loss and inflammation.

Edward A. Bell

A new strain of C. difficile, NAP-1, has recently been recognized, which may be partly responsible for increases in incidence and disease severity of CDAD. NAP-1 appears to produce significantly more toxin A and B than other strains (16- to 23-fold more toxin), and a newly recognized binary toxin produced by NAP-1 may be more pathogenic.

Not all individuals are at equal risk from CDAD. Risk factors for CDAD include advanced age, hospitalization, debilitated condition, recent surgery, nasogastric tube use and antibiotic use. The majority of antibiotics can potentially result in CDAD, although clindamycin, cephalosporins and fluoroquinolones are most commonly reported.

Treatment

Treatment of CDAD includes discontinuation of the offending antibiotics, if the clinical scenario permits, and supportive therapy (fluid and electrolyte replacement). Older reviews of CDAD treatment often stated that mild cases might respond to discontinuation of the responsible antibiotic and supportive treatment alone (ie, no specific therapy). With increasing incidence and morbidity rates, experts are becoming less likely to offer this treatment recommendation. The offending antibiotics should still be discontinued, if possible, but specific therapy is now generally recommended.

Metronidazole, vancomycin

Metronidazole and vancomycin are recommended for initial treatment of CDAD. In two randomized, controlled trials, researchers compared metronidazole and vancomycin and found equal efficacy and recurrence rates. Thus, metronidazole and vancomycin are generally considered equivalent, and metronidazole is usually recommended as first-line therapy for most patients. Reasoning for this first-line status includes metronidazole’s relative low cost and the potential for vancomycin to induce resistance in gastrointestinal flora (eg, Enterococcus faecium).

Several recent reports (not controlled trials) have documented high failure rates with metronidazole, and some experts are now suggesting that vancomycin should be used first-line. There are several national organizations (eg, the CDC, IDSA, etc.) that continue to recommend metronidazole as first-line treatment in most patients.

Metronidazole and vancomycin should be given orally when treating CDAD. Both agents produce high levels in the colon with diarrhea. However, metronidazole is absorbed from the gastrointestinal tract when diarrhea subsides, whereas vancomycin is not absorbed, regardless of whether diarrhea is present. It is because of this and other characteristics that one expert has touted vancomycin as a nearly ideal drug for the treatment of CDAD.

Metronidazole can be given intravenously, if necessary (eg, patient cannot tolerate oral therapy, or the presence of an ileus), although oral administration is generally preferred. Vancomycin is not effective intravenously, as it does not achieve adequate concentrations at the treatment site. Other treatment strategies for patients unable to tolerate oral drug therapy include administration of either drug by nasogastric tube or administration of metronidazole or vancomycin rectally (rectal tube or enema).

Both medications are effective when given orally, with 90% to 97% response rates with initial treatment. Several recent uncontrolled studies have shown lower initial response rates with metronidazole, however. Whether this is due to changes in metronidzole’s efficacy or reflective of patient factors in these studies is not known. Relapses occur in approximately 25% of patients, with metronidazole and vancomycin demonstrating equivalent relapse rates.

When relapse occurs, it is generally recommended that a repeat course of the initial antibiotic be given, as most patients will respond positively. Metronidazole and vancomycin have similar efficacy rates for treatment of the first relapse.

Although metronidazole is generally considered first-line initial therapy, some patients should receive vancomycin initially. These situations include pregnancy and women who are lactating. Some experts recommend vancomycin initially for severe CDAD disease, although there are no data from controlled trials to support this recommendation.

Patients who do not respond to metronidazole initially should be given vancomycin. A positive response should be seen within three to five days, and it is recommended to change treatment agents (ie, change to vancomycin) if noticeable benefit is not realized within five to seven days of treatment. Antiperistaltic drugs should be avoided when treating CDAD, as they may increase retention of C. difficile toxin or result in toxic megacolon.

Relapses

Relapses of CDAD occur in approximately 25% of patients and may re-present re-infection with a new strain of C. difficile or relapse with the initial stain. The first relapse should be treated with the same agent that effectively treated the initial infection, and most patients will respond favorably. The most beneficial treatment for patients with multiple recurrences is not known.

A small number of patients (3% to 6%) may have numerous (eg, six or more) relapses. It is frequently recommended to use vancomycin for the second recurrence if metronidazole was previously used. Several therapies have been suggested for patients with multiple recurrences.

Probiotics have been evaluated, and authors of a recent meta-analysis concluded probiotics were effective for prevention of CDAD. One species that may be useful is Saccharomyces boulardii. Limitations of probiotic use are that the most effective dose and species to utilize are unknown.

Expanded dosing of vancomycin, given as pulsed or tapered doses, may also be useful. One controlled trial demonstrated that high-dose vancomycin (2,000 mg/day) plus S. boulardii was effective therapy for recurrent CDAD. Fecal implants (ie, administering donor stool via nasogastric tube) has been shown to be effective, with the obvious limitation of patient acceptance. Limited case reports have suggested that immunoglobulin therapy may also be beneficial.

The significant morbidity and potential for death from CDAD underlie the continued importance of using antibiotic therapy judiciously. Antibiotics should be prescribed only when indicated and not “easily” (ie, for infections not likely caused by bacteria). Additionally, the importance of good infection control practices cannot be overstated. It has been shown that alcohol-based cleansers do not kill C. difficile spores; soap and water should be used.

For more information:

Edward A. Bell, PharmD, BCPS, is a Professor of Pharmacy at Drake University College of Pharmacy and a Clinical Specialist at Blank Children’s Hospital, Des Moines, Iowa.

Bartlett JG. New drugs for Clostridium difficile infection. Clin Infect Dis. 2006;43:428-431.

McMaster-Baxter NL, Musher DM. Clostridium difficile: Recent epidemiologic findings and advances in therapy. Pharmacotherapy. 2007;27:1029-1039.

Musher DM, Aslam S, Logan N, et al. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis. 2005;40:1586-1590.

Pépin J, Routhier S, Gagnon S, Brazeau J. Management and outcomes of a first recurrence of Clostridium difficile-associated disease in Quebec, Canada. Clin Infect Dis. 2006;42:758-764.

Surowiec D, Kuyumjian AG, Wynd MA, Cicogna CE. Past, present and future therapies for Clostridium difficile-associated disease. Ann Pharmacother. 2006;40:2155-2163.

Teasley DG, Gerding DN, Olson MM, et al. Prospective randomized trial of metronidazole vs. vancomycin for Clostridium-difficile-associated diarrhea and colitis. Lancet. 1983;2:1043-1046.

Wenisch C, Parschalk B, Hasenhündl M, et al. Comparison of vancomycin, teicoplanin, metronidazole and fusidic acid for the treatment of Clostridium difficile-associated diarrhea. Clin Infect Dis. 1996;22:813-818.