Metronidazole: Still First-Line Therapy for Antibiotic-Associated Colitis?

Abstract & Commentary

By Robert Muder, MD, Hospital Epidemiologist, Pittsburgh VA Medical Center, Pittsburgh, Section Editor, Hospital Epidemiology, is associate editor of Infections Disease Alert

Dr. Muder does research for Aventis and Pharmacia.

Synopsis: In a prospective, observational study of 207 patients with Clostridium difficile colitis treated with metronidazole, 22% had symptomatic colitis for > days, and 28% had a relapse within 90 days.

Source: Musher DM, et al. Relatively Poor Outcome After Treatment of Clostridium difficile Colitis With Metronidazole. Clin Infect Dis. 2005;40:1586-1590.

Musher and colleagues followed 207 patients with C. difficile colitis treated with appropriate (at least 1.5 gm/day) doses of metronidazole for at least 7 days. All patients had a positive stool ELISA assay for C. difficile toxin. Fifty percent of patients had a clinical cure within 10 days of the start of treatment with no recurrence. Twenty eight percent of patients had initial resolution of symptoms but suffered a recurrence within 90 days. Twenty-two percent of patients were refractory to treatment, defined as symptomatic after > 10 days of metronidazole therapy. There was no relationship between response to metronidazole therapy and quantity of antibiotics patients received in the 6 weeks preceding onset of colitis. The preceding use of cefepime or vancomycin was, however, significantly associated with metronidazole failure. Susceptibility testing to metronidazole was not performed during this study, but subsequent testing of 18 strains isolated from the hospital showed that none were metronidazole resistant.

Commentary

C. difficile colitis is a frequent complication of antimicrobial therapy. Clinical severity is variable, ranging from loose stools to fulminant colitis with toxic megacolon. Disease is more frequent and more severe in patients with advanced age and serious co-morbid conditions. Historically, C. difficile colitis has responded equally well to treatment with either metronidazole or oral vancomycin, with clinical response rates of > 90%; approximately 20% of successfully treated patients suffer one or more relapses.1 Relapse is associated with low levels of specific immunoglobulin directed against C. difficile toxin.

In the past few years, there is evidence that the epidemiology and clinical presentation of C. difficile colitis is changing. Several centers report an increase in both the frequency and severity of C. difficile colitis. A regional medical center in Quebec noted an abrupt 4-fold increase in the incidence of C. difficile colitis beginning in 2003.2 The proportion of cases with complications (megacolon, perforation, shock, colectomy) increased from 7% to 18%. The proportion of patients suffering a recurrence increased from 21% to 47%.3 During the same period, the University of Pittsburgh Medical Center reported a more than doubling of the incidence of nosocomial C. difficile colitis and an increase in the number of cases complicated by colectomy or death.4

The reasons for this apparent change in the frequency and clinical presentation of C. difficile colitis are not entirely clear. Several reports implicate increasing use of newer quinolones that have significant activity against anaerobes.4,5 There is also evidence that a change in C. difficile toxin production may play a part in more severe disease. In addition to the 2 major toxins, A and B, some C. difficile strains possess a binary toxin, which is an actin specific adenosine diphosphate ribosyltransferase related to toxin E of C. perfringens. Preliminary evidence suggests that the presence of binary toxin may be related to increased severity of colitis.6

Optimal treatment for C. difficile colitis remains an area of uncertainty. Resistance of clinical isolates to the metronidazole and vancomycin is rare. A limited number of randomized trials comparing metronidazole and vancomycin have shown the 2 agents to be comparable. Critically ill patients, however, were excluded. Until additional data or more effective treatments become available, the recommendations provided by Dr. Gerding in an accompanying editorial7 appear to be eminently reasonable. Patients with moderate illness should be treated with metronidazole. Patients with total leukocyte counts of > 20,000 are at high risk for complications and should be treated with oral vancomycin. Patient developing ileus or megacolon should be treated with intravenous metronidazole and enteral vancomycin (via nasogastric tube and/or enema), in addition to aggressive supportive therapy and early surgical consultation for possible colectomy.

References

  1. Bartlett JG. Clinical Practice. Antibiotic-Associated Diarrhea. N Engl J Med. 2002;346:334-339.
  2. Pepin J, et al. Clostridium difficile Associated Diarrhea in a Region of Quebec From 1991 to 2003; A Changing Pattern of Disease Severity. CMAJ. 2004;171:466-472.
  3. Pepin J, et al. Increasing Risk of Relapse After Treatment of Clostridium difficile Colitis in Quebec, Canada. Clin Infect Dis. 2005;40:1591-1597.
  4. Muto CA, et al. A Large Outbreak of Clostridium difficile-Associated Disease With An Unexpected Proportion of Deaths and Colectomies at a Teaching Hospital Following Increased Fluoroquinolone Use. Infect Control Hosp Epidemiol. 2005;26:273-280.
  5. Gaynes R, et al. Outbreak of Clostridium difficile Infection in a Long-Term Care Facility: Association With Gatifloxacin Use. Clin Infect Dis. 38:640-645.
  6. McEllistrom MC, et al. A Hospital Outbreak of Clostridium difficile Disease Associated With Isolates Carrying Binary Toxin Genes. Clin Infect Dis. 2005:40:265-272.
  7. Gerding DN. Metronidazole for Clostridium difficile-Associated Disease: Is It OK For Mom? Clin Infect Dis. 2005;40:1598-1600.