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The newest treatment strategy for Clostridium difficile: Worth a look?
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In the world of emerging, resistant pathogens, Clostridium difficile is quickly rising to the top of the more difficult infectious diseases to treat. C. difficile is a gram-positive, anaerobic spore-forming organism that attacks the colonic epithelium and causes cell death.
This can result in C. difficile-associated diarrhea, pseudomembranous colitis, toxic megacolon and death. In the current times of imprudent use of antimicrobials, C. difficile prevalence is increasing, drug resistance and treatment failures are more notable and a potentially epidemic strain (NAP1/BI/027) has been isolated. It is inevitable that treatment strategies must be scrutinized, alternative agents considered, antimicrobial stewardship must take precedence and infection prevention measured employed.
The Society for Healthcare Epidemiology of America (SHEA) and Infectious Diseases Society of America last published treatment guidelines for C. difficile in 1995.
The newest guidelines became available in May. It was the hope of many clinicians that the guidelines would address the most recent studies available around the standard treatment with either oral metronidazole or oral vancomycin but also include insight to alternative treatment strategies, such as nitazoxinide, fidaxomicin, monoclonal antibodies (CD A-1 and CD B-1), IV immunoglobulin therapy and vaccination for C. difficile. These guidelines did not address the newest investigated treatment, fidaxomicin, monoclonal antibody therapy and vaccinations, as these are all still in early trials. An introduction to fidaxomicin will be provided in this column.
Metronidazole and oral route vancomycin have been the gold standard in treatment of C. difficile-associated diarrhea. Relapse rates of C. difficile have been noted as high as 20% to 30%, causing a search for the most superior agent for the treatment of this infectious disease. Zar and colleagues published a pivotal study comparing oral metronidazole 250 mg four times daily to oral vancomycin 250 mg four times daily. The results of this study suggested that oral vancomycin was superior for patients described as severe C. difficile-associated disease, although the study results did not reach statistical significance. For first and second episodes of diarrhea, metronidazole is still recommended, although oral vancomycin should be considered when the patient is experiencing sepsis associated with C. difficile infection (CDI). Some studies have suggested relapse is similarly high in those patients treated with oral vancomycin.
The question of drug resistance has also spurred conversation of, “what is the most effective treatment?” In a recent study from Spain, a resistance rate for metronidazole (minimum inhibitory concentration 32 mg/L) was noted at 6.3%. It is thought that prolonged exposure to metronidazole can be linked to resistance. There have been no described incidences of vancomycin-resistant C. difficile. An earlier study from Spain in 2002 noted that 3% of 415 observers isolated showed intermediate susceptibilities (MIC 4 mcg/mL-16 mcg/mL) to vancomycin. The concern for vancomycin to exert a higher selection pressure than metronidazole for enterococcus is a valid concern. With the concerns of high rates of relapse, drug resistance and treatment failures, other agents are being investigated as alternative treatment strategies.
Other agents
Fidaxomicin (formerly known as OPT-80) is a novel 18-membered macrocyclic anti-infective with selective activity against C. difficile. It has some activity against other aerobic and anaerobic gram-positive pathogens (ie, Propionibacterium and Lactobacillus) but no activity against gram-negative organisms. This agent does not disrupt colonic levels of Bacteroides species. The theory is it exerts selective bacteriocidal activity for C. difficile while sparing normal gastrointestinal flora. Fidaxomicin exhibits bacteriocidal activity by inhibiting the bacterial enzyme RNA polymerase.
Fidaxomicin was studied in two phase 2 trials conducted by Louie and colleagues. The first trial evaluated 50-, 100-, and 200-mg doses orally every 12 hours for 10 days. The study also evaluated suppression of C. difficile quantitative counts, recrudence of C. difficile vegetative and/or spore counts after therapy, re-expression of cytotoxin B in fecal filtrates after treatment and quantitative counts of Bacteroides species as a marker of normal flora.
This phase 2 trial found similar reduced counts of C. difficile in both the fidaxomicin and vancomycin treatment groups. The study also found a statistically significant difference (P=.03) in changes in Bacteroides group count during the 10-day treatment period. This suggests that oral vancomycin disrupts the normal flora during a treatment period. Fidaxomicin at any of the three doses did not suppress Bacteroides group counts. Post-treatment spore counts were comparative between the two groups. Re-expression of C. difficile toxin B was significantly different (P=.03) in the fidaxomicin group compared with vancomycin. The 50-mg fidaxomicin group had one of 10 patients positive for cytotoxin B at days 21 to 28 and the vancomycin group had three of eight patients positive.
The second phase 2 trial included 48 participants with moderately severe CDI to receive 50, 100 or 200 mg orally twice daily for 10 days.
The primary endpoints were clinical cure, which was resolution of diarrhea and abdominal discomfort within 10 days of treatment period and the participant did not require any additional therapy for CDI; time to resolution of diarrhea, defined as time to resolution from first dose of study drug and total relief of symptoms (fewer than three bowel movements/day) without other signs or symptoms such as fever, abdominal pain or elevated white blood count by day 10. The secondary endpoint was recurrence of CDI (more than three unformed stools and a positive stool for toxin A or B within 6 weeks of end of treatment). Outcomes included clinical cure of 71% in the 100 mg/day, 80% in the 200 mg/day and 94% in the 400 mg/day group. Clinical failures were 14%, 13%, 0%, respectively; resolution of diarrhea was 5.5 days, 3.5 days and 3 days, respectively; total relief of symptoms was 37.5%, 50%, and 86.7%, respectively. The secondary outcome was clinical recurrence of 8.3% with the 100 mg/day, 0% in the 200 mg/day and 6.3% in the 400 mg/day group.
The most notable studies evaluating fidaxomicin have been two phase 3 trials. The first trial conducted and presented by Louie and colleagues was a randomized, double blind, multicenter, non-inferiority trial comparing fidaxomicin 200 mg orally every 12 hours for 10 days with vancomycin 125 mg orally four times daily for 10 days. This study included 629 patients who were divided into one of the two arms. The primary endpoint included clinical cure, which was defined as the patient who did not require additional therapy 2 days after treatment was completed. The secondary endpoints included recurrence of CDI, defined as return of diarrhea confirmed by a positive toxin test, and global cure, defined as cure without a recurrence at 4 weeks after treatment ended. Fidaxomicin was shown to be non-inferior to oral vancomycin for clinical cure. The secondary endpoints were also favorable. The recurrence of CDI was lower with fidaxomicin (P=.004), and this group also demonstrated higher global cure than vancomycin (P=.006).
The second trial is a phase 3 randomized, double blind, multicenter trial with 536 participants. The data are not yet published but will likely give more insight into the treatment of CDI with fidaxomicin.
We continue the battle to treat C. difficile. Overuse of antimicrobials will continue to drive the increasing prevalence of CDI. Further insight into development of drug resistance and ongoing drug development will be imperative in understanding the future of treating CDI. An updated perspective on emerging treatment strategies for C. difficile is needed. The much-anticipated 2010 guidelines from SHEA and IDSA were helpful in defining the gold standard treatment strategies, but continued evaluation of future treatment strategies will need evaluation. As our knowledge and insight into C. difficile has grown, the literature base for these treatment strategies has also significantly broadened over the past 5 years. The research is ongoing for future treatment options for this serious and potentially life-threatening infectious disease. Fidaxomicin is making its way to the market with some promising initial trials. Future studies and use in practice will define its place in therapy, but it is worth taking a look.
Kimberly Boeser, PharmD, is the Infectious Disease Clinical Pharmacologist at the University of Minnesota Medical Center, Fairview in Minneapolis, where she coordinates the antimicrobial stewardship program.