WORSENING OUTCOMES AND INCREASED RECURRENCE OF CLOSTRIDIUM DIFFICILE AFTER INITIAL TREATMENT WITH METRONIDAZOLE?
Pepin J, Alary ME, Valiquette L, et al. Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis. 2005;40:1591-1597; and 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.
Information on treatment of colitis caused by Clostridium difficile began to appear in the late 1970s and early 1980s. Since that time there have been a paucity of novel therapies. It has been well-established that both metronidazole and vancomycin can effectively treat this entity. Traditionally metronidazole has been the first-line agent for C. difficile-associated diarrhea (CDAD). The reasons for this are three:
- Randomized controlled trials have shown vancomycin and metronidazole to be equally efficacious;
- The cost of oral vancomycin is substantially more than oral metronidazole; and
- Many experts have cautioned that using vancomycin may contribute to the blooming number of bacteria that are resistant to vancomycin.
Indeed recommendations from the Centers for Disease Control and Prevention’s Healthcare Infection Control Practices Advisory Committee as well as the American Society for Health-System Pharmacists have supported using metronidazole as our initial agent of choice for CDAD (oral vancomycin is actually the only agent that is approved by the Food and Drug Administration for CDAD). Most of our earlier data claim initial response rates to be 88% or better and relapse rates to be somewhere between 5% and 12% when metronidazole is used.
Two new studies have been published raising a red flag on our current standard of practice. Musher, et al., designed a prospective, observational study in which they followed more 200 patients with CDAD that were initially treated with metronidazole. The patient pool came from a Veterans Affairs Medical Center. They all had a positive fecal ELISA for C. difficile toxin and were treated for seven or more days using at least 1.5 grams per day of metronidazole.
Records were reviewed six weeks prior to the diagnosis and then patients were followed for three months after cessation of therapy. Patients were assigned to four outcome groups:
- Complete responders who did not have recurrence over four months;
- Refractory-to-treatment where signs and symptoms of CDAD were present for 10 or more days;
- Recurrence after initial clinical response with signs and symptoms of CDAD and a positive toxin; and
- Clinical recurrence where there was an initial response but a recurrence of signs and symptoms of CDAD without a positive toxin (either the toxin was not present when tested or the test was not done).
Fifty percent were completely cured. Twenty-two percent were refractory to initial therapy. Twenty-eight percent had a recurrence of CDAD within the 90-day period. The mortality was 27%. This was higher among people who had failed to respond to initial therapy (31% versus 21%; p<.05).
Pepin, et al., retrospectively looked at more than 2,000 CDAD cases from one hospital between 1991 and 2004. To be included the patients needed either a positive toxin, endoscopic evidence of pseudomembranous colitis, or histopathologic evidence of pseudomembranous colitis on a biopsy specimen. Patients received at least 1 gram per day of metronidazole for 10 to 14 days. They were considered to have a recurrence if they had diarrhea within two months of the completion of therapy and either a positive toxin at that time or if the attending physician ordered a second course of antibiotics for C. difficile.