BETHESDA, MD. — Despite the experience from recent epidemics, the search for effective treatments for Clostridium difficile-associated diarrhea continues, Dr. Mark Miller said at an annual conference on antimicrobial resistance sponsored by the National Foundation for Infectious Diseases.
During the 2002–2004 epidemic of C. difficile-associated diarrhea (CDAD) in Quebec, spontaneous improvement was rare and serious disease developed rapidly. “Many of us remember many of the cases where they're fine today, they start getting diarrhea tonight, and tomorrow afternoon they're in the intensive care unit with hypotension and acute respiratory distress syndrome,” said Dr. Miller, head of infectious diseases at Sir Mortimer B. Davis—Jewish General Hospital in Montreal.
Traditional treatment for CDAD has been to stop the offending antibiotic, which may relieve symptoms in about 20% of patients. “This is probably not true any more,” Dr. Miller said.
Traditionally, oral administration of drug therapy is preferred, even if that means using a nasogastric tube. Metronidazole (250–500 mg four times daily) has been preferred over vancomycin (125–500 mg four times daily) because it is considerably cheaper, reduces the risk of vancomycin-resistant mutations, and has comparable efficacy, tolerability, and relapse rates, compared with vancomycin.
In Quebec, it is currently considered unethical to withhold specific CDAD therapy. Almost all patients are started on empiric therapy before the toxin assay comes back from the laboratory, said Dr. Miller, also a professor of microbiology/immunology at McGill University.
There also have been a few anecdotal or small series reports saying that the clinical response is slower or that the relapse rate is higher with metronidazole than with vancomycin.
According to the latest treatment algorithm developed in Quebec, serious cases of CDAD are started on vancomycin, bypassing metronidazole. Likewise, a patient who fails to improve on metronidazole is switched to vancomycin.
The use of metronidazole and vancomycin together is widespread in many institutions, but the effectiveness of the combination has not been studied. Some physicians are adding rifampin to metronidazole, and others are adding rifampin or bacitracin to vancomycin. Likewise, these combinations have not been studied. “As you start getting a number of different recipes, it means that nobody is very happy with any single recipe,” Dr. Miller said.
In addition, there is a host of adjuvant nonantibiotic therapies available or in the pipeline. Dr. Miller discussed the literature on these therapies and gave his comments:
▸ Probiotics. Probiotics have been suggested as bioprophylaxis or biotherapy. However, the few studies that have been done with standardized probiotics have shown no effect on C. difficile. In a metaanalysis, researchers concluded that there is insufficient evidence for the routine use of probiotics to prevent or treat CDAD (CMAJ 2005;173:167–70). In addition, because a substance's intended use determines how it is regulated in the United States, many probiotic products are not standardized and are poorly quantified.
▸ Prebiotics. Last year a group in the United Kingdom described the use of oligofructose—a so-called prebiotic—for the treatment of CDAD along with conventional therapy. In the study, patients were randomized to conventional therapy alone or in conjunction with 30 days of oligofructose consumption (Clin. Gastroenterol. Hepatol. 2005;3:442–8). Patients taking oligofructose had a substantial increase in beneficial bifidobacteria in the gut. There was also a decreased relapse rate for those on oligofructose.
▸ Toxin binders. Toxin binders, such as cholestyramine and tolevamer, are another avenue of treatment under investigation. These compounds bind to toxins produced by C. difficile, which lead to CDAD.
Cholestyramine is indicated to help reduce serum cholesterol levels but is sometimes used off label to treat CDAD. However, small case series have not shown it to be effective. “I find that all it does is give my patients more GI symptoms of bloating and flatulence and pain. I don't find it very useful,” Dr. Miller said.
Tolevamer is an investigational polymer (Genzyme Corp.) that is designed to selectively bind to C. difficile toxins A and B. A phase II study showed that high-dose tolevamer (6 g/day) was equivalent to oral vancomycin for curing mild to moderate CDAD. Phase III trials are underway to compare the drug with vancomycin and metronidazole.
▸ Immunotherapy. Interest in the use of intravenous immunoglobulin to treat CDAD was sparked when researchers noted that patients with multiple relapses appeared to be deficient in their immunoglobulin G (IgG) response to toxins. High-titer antitoxin A was associated with protection from and recurrence of disease (N. Eng. J. Med. 2000;342:390–7).
Several small case series using IV immunoglobulin for severe or recurrent disease have shown marked clinical responses in most patients. Dr. Miller and his colleagues are currently performing their own retrospective analysis of IV immunoglobulin use during the Quebec outbreak.