Nitazoxanide for the Treatment of Clostridium difficile Colitis
Nitazoxanide for the Treatment of Clostridium difficile Colitis
Abstract & Commentary
By Patricia Cristofaro, MD, and Maria D. Mileno, MD
Patricia Cristofaro is Assistant Professor, Department of Infectious Diseases, Brown University, and Maria D. Mileno is Director, Travel Medicine, The Miriam Hospital; Associate Professor of Medicine and Infectious Diseases; Director, International Travelers' Clinic, Brown University School of Medicine
Dr. Cristofaro reports no financial relationship relevant to this field of study, and Dr. Mileno is a consultant for GlaxoSmithKline, and does research for Merck.
Synopsis: Clostridium difficile diarrhea and colitis have now emerged as common nosocomial infections in hospitals throughout the developed world. Alarmingly, recent epidemiological studies in ambulatory settings have documented C. difficile infection in both adults and children who lack the usual risk factors of prior antibiotic use or hospitalization.1
Source: Musher DM, et al. Nitazoxanide for the treatment of Clostridium difficile colitis. Clin Infect Dis. 2006;43:421-427.
Oral vancomycin alone or combined with either oral or parenteral metronidazole have been workhorses during the current epidemic of nosocomial Clostridium difficile-associated disease. Vancomycin is actually the only drug approved by the US FDA for this purpose. However, due to vancomycin's cost and its potential ability to select for vancomycin-resistant enterococci (VRE), metronidazole has been favored for first line therapy. However, both agents are associated with a substantial rate of recurrence or treatment failures, at a combined rate of about 50%.3 There is a considerable need for new approaches.
Nitazoxanide, a nitrothiazolide, used for the treatment of intestinal parasites such as cryptosporidiosis and giardiasis, has proven in vitro activity against C. difficile. Musher and colleagues report the first study of its use for this new indication, a noninferiority comparison with metronidazole, the mainstay of current therapy.2
Nitazoxanide has pharmacokinetic properties that produce high colonic concentrations. Because it is already approved for treatment of intestinal infections, it is available for off-label use. In the article under discussion, Musher et al have reported the results of a prospective, randomized, double-blind study comparing nitazoxanide to metronidazole for the treatment of hospitalized patients with C. difficile colitis. The study was designed to assess non-inferiority, and they conclude that nitazoxanide is at least as effective as metronidazole.2
This study was divided into 3 oral treatment arms. Thirty-four patients received metronidazole at the dosage of 250 mg, 4 times per day for 10 days, a standard regimen. Forty patients received nitazoxanide at a dosage of 500 mg twice daily for 7 days. Thirty-six patients received the same nitazoxanide regimen for 10 days, thus potentially allowing for the analysis of 76 patients at 7 days and 36 at 10 days. Statistical analysis of the groups showed them to be equivalent in their patient demographics, including severity of co-morbidities.
Data for both primary response and recurrence rates were obtained. The authors concluded that there were no significant differences in the median time to resolution of symptoms, the proportion of patients who were symptom free after 7 days of therapy, or the proportion of patients who had a sustained response at 31 days. After 7 days of treatment there was a trend toward better response in those receiving nitazoxsanide. At 31 days there was a trend toward more sustained response in those who had received at least 7 days of nitazoxanide. The response was even more robust in those who had received 10 days of therapy. However, none of these differences reached statistical significance, possibly because of their small sample size. The authors did succeed in their intended goal of proving non-inferiority to metronidazole.
Commentary
As pointed out by Dr. John Bartlett in the editorial commentary accompanying Musher's study, there are three distinct problems in managing C. difficile infections: management of acute disease, management of recurrent disease, and alternative therapies for those neither seriously ill nor experiencing recurrent disease.4 The "gold standard" for acute disease has been oral vancomycin, and the greatest problem with this agent is ensuring delivery to the colon in the face of complications such as ileus. However, vancomycin, not metronidazole, should be the comparator drug, and Musher et al are planning such a study.
Does nitazoxanide have a role in the treatment of recurrent disease? In this article, Musher et al also report a separate open-label study in which they administered nitazoxanide to 22 patients with C. difficile colitis who had failed metronidazole. Their success rate was similar to that of metronidazole when it was used to treat a first bout of C. difficile colitis. Therefore, nitazoxanide may very well have a role in recurrent disease.
Will nitazoxanide be a niche drug, useful because of reduced cost, better tolerance, less impact on intraluminal microbial ecology or hospital environmental ecology, or lower recurrence rates? Dr. Bartlett believes its use will not be for initial therapy, but for those who do not respond to metronidazole therapy, who have repeated recurrences, or who are unable to tolerate metronidazole. The cost of a 10-day course is currently estimated to be about $240 US.
The reader is advised to await further investigation of this agent, as well as watching for other new approaches under study for this increasing problem with C. difficile colitis, including resins for the absorption of toxins, immune approaches such as monoclonal antibodies, and alteration of gastrointestinal flora thorough the use of probiotics.
References
- Wilson, M. Clostridium difficile and childhood diarrhea: Cause, consequence, or confounder? Clin Infect Dis. 2006;43:814-816. Erratum in: Clin Infect Dis. 2006;43:1232.
- Musher DM, et al. Nitazoxanide for the treatment of Clostridium difficile colitis. Clin Infect Dis. 2006;43:421-427.
- Musher DM, et al. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis. 2005;40:1586-1590.
- Bartlett JG. New drugs for Clostridium difficile infection. Clin Infect Dis. 2006;43:428-431.
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