CDAD: Novel Therapeutics
Abstracts & Commentary
By Stan Deresinski, MD, FACP, Clinical Professor of Medicine, Stanford, Associate Chief of Infectious Diseases, Santa Clara Valley Medical Center, is Editor for Infectious Disease Alert.
Synopsis: Both nitazoxanide and the investigational anionic polymer, tolevamer, may have efficacy comparable to that of standard therapies in the treatment of CDAD. The addition of rifampin to metronidazole is not superior to treatment with metronidazole alone.
Sources: Louie TJ, et al Tolevamer, a Novel Nonantibiotic Polymer, Compared with Vancomycin in the Treatment of Mild to Moderately Severe Clostridium difficile-Associated Diarrhea. Clin Infect Dis. 2006;43:411-420; Musher DM, et al. Nitazoxanide for the Treatment of Clostridium difficile Colitis. Clin Infect Dis. 2006;43:421-427; Lagrotteria D, et al. Prospective, Randomized Inpatient Study of Oral Metronidazole Versus Oral Metronidazole and Rifampin for Treatment of Primary Episode of Clostridium difficile-Associated Diarrhea. Clin Infect Dis. 2006;43:547-552.
Lagrotteria and colleagues enrolled 39 inpatients with a primary episode of Clostridium difficile-associated diarrhea (CDAD) to receive treatment for 10 days with either metronidazole (MET) alone or together with rifampin (RIF). This single-blind study was prematurely discontinued prior to enrolling the planned 100 patients because of loss of funding. Nonetheless, the results were consistent with a lack of benefit from the addition of rifampin to metronidazole. Thus, 65% of MET and 63% of RIF/MET recipients had improved by day 10, and the proportion who relapsed was also similar in the 2 treatment arms.
Louie and colleagues randomized 289 patients with either primary or recrudescent CDAD to treatment with vancomycin for 10 days, or to tolevamer at one of 2 total daily doses (3 g or 6 g) for 14 days. The trial was double-blind. Diarrhea resolved in 91% of vancomycin recipients after a median duration of 2.0 days, in 67% of recipients of 3 grams of tolevamer after a median of 4.0 days, and in 83% of those receiving 6 grams of tolevamer daily after a median of 2.5 days. The 6 gram tolevamer regimen was non-inferior to vancomycin with regard to the primary end point of the study and the time to resolution of diarrhea. The recurrence rates for the 2 treatment arms were 10% for tolevamer and 19% for vancomycin (P = .19).
In a prospective, double-blind trial, Musher and colleagues randomized 142 patients with CDAD to treatment with either metronidazole for 10 days or to nitazoxanide (total of 1 gram daily) for either 7 or 10 days. The response rates in the 3 treatment arms were similar (82.4%, 90.0%, and 88.9%, respectively). There, subsequently, were 4 documented recurrences of CDAD in the metronidazole recipients, 9 in those who received nitazoxanide for 7 days, and 4 in those who received the latter for 7 days. Thus nitazoxanide therapy was not inferior to treatment with metronidazole.
Commentary
The increasing incidence of CDAD, together with the emergence of an epidemic strain (ribotype 029, toxinotype III, NAP-1) of apparently increased virulence, and a perceived reduction in the efficacy of standard therapies, with a possibly increased incidence of recrudescence after treatment, has placed a sharp focus on this disease. Given the seriousness of the problem, together with the volume of words written regarding recommendations for treatment, the amount of quality evidence on which to base therapeutic decisions is remarkably limited. As a result, studies such as the above are welcome.
There have previously been a number of anecdotal reports leading to some recommendations for the addition of rifampin to metronidazole in the treatment of CDAD. The study reviewed here, although quite underpowered, suggests that, at least in primary infection, this strategy does not provide benefit over that seen with the use of metronidazole alone.
Tolevamer is an investigational anion exchange resin without antimicrobial activity that has been demonstrated to neutralize, presumably by binding toxins A and B of C. difficile in an animal model. Cholestyramine has previously been used for this purpose, but clinical evidence for its efficacy is lacking. The study by Lagrotteria and colleagues suggest that this newer anionic polymer has efficacy similar to that of vancomycin in patients with CDAD, approximately three-fourths of whom had primary disease. In addition, since a dose response to tolevemar was observed, it is possible that total daily doses, in excess of 6 grams, may be even more effective.
Nitazoxanide is US FDA-approved for the treatment of giardiasis and cryptosporidiosis, and has in vitro activity against C. difficile at concentrations well below those achieved in the colon after oral administration. The work by Musher et al suggest that its efficacy is similar to that of metronidazole. Nitazoxanide is, however, much more expensive than metronidazole.
A comparison of the results of metronidazole therapy in the 2 trials that utilized this as the standard therapy, indicate the danger of comparing results across trials. The reported response rate to metronidazole given alone in the study by Largoretta et al was only 65%, while it was 82.4% in the study by Musher et al. This difference could be due to varying severity of illness, differing end point definitions, and the like.
While these studies report varying incidences of recrudescent disease, none performed the molecular epidemiologic studies necessary to distinguish relapse from reinfection.
A number of additional agents are being investigated for treatment of CDAD, including the lipoglycodepsipeptide, ramoplanin, the rifamycin, rifaximin, and the benzoxazinorifamycin, rifalazil. Others under investigation include OPT-80 (tiacumicin B), an 18-membered macrocyclic nonabsorbable antibiotic, as well as monoclonal antibodies that neutralize toxins A and B. Perhaps, of most significance (if it works), is that a toxoid vaccine has entered early trials.
Lagrotteria and colleagues enrolled 39 inpatients with a primary episode of Clostridium difficile-associated diarrhea (CDAD) to receive treatment for 10 days with either metronidazole (MET) alone or together with rifampin (RIF).You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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