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MEDI-NEWS - Based on Clinical Practice Guidelines for Clostridium difficile Infection in Adults: 2010 Update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol 2010;31:431-55.

April 2010

Clostridium difficile is the primary pathogen behind antibiotic-associated colitis and for 15% to 25% of nosocomial antibiotic-associated diarrhea cases. It is the most commonly recognized cause of infectious diarrhea in health care settings. The incidence rates from surveys of Canadian hospitals conducted in 1997 and 2005 range from 3.8 to 9.5 cases per 10,000 patient-days or 3.4 to 8.4 cases per 1000 admissions in acute-care hospitals.

In recent years, an increase in both the incidence and severity of the disease has been reported with unusually severe and recurrent outbreaks as early as the second half of 2002 through to 2006 in hospitals throughout much of Quebec. The historically low mortality rate from C. difficile (<2% of infected patients) has increased during this period in Montreal hospitals due to the new virulent NAP1/BI/027 strain. The direct 30-day mortality rate was 6.9% and thought to have contributed indirectly to another 7.5% of deaths. The NAP1/BI/027 strain has now become highly prevalent elsewhere, including most other Canadian provinces.

Identifying and Managing Risk Factors

Accurate diagnosis of C. difficile infection (CDI) is crucial because even in an epidemic environment with hospitalized patients having antibiotic-associated diarrhea, only about 30% will have CDI. The most sensitive test is stool culture and is essential for epidemiological studies. Diagnosis of CDI requires the presence of diarrhea (=3 unformed stools in =24 hours) and either a stool test positive for C. difficile toxins or toxigenic C. difficile, or colonoscopic or histopathologic findings revealing pseudomembranous colitis. The median period between exposure and symptomatic infection is two to three days; however, the risk of infection can persist for many weeks after antimicrobial therapy is discontinued as a result of prolonged perturbation of the normal intestinal flora.

It is noteworthy to consider the possibility of CDI in hospitalized patients with unexplained leukocytosis and request stool testing. Advanced age is another important risk factor for acquiring the infection, along with prolonged hospitalization. However, environmental contamination also has an important role in the transmission of C. difficile in health care settings.

Outbreaks have been reported where electronic rectal thermometers or inadequately cleaned commodes or bedpans were shared between patients. Consequently, the guidelines reiterate the removal of environmental sources of C. difficile, including replacement of electronic rectal thermometers with disposables and emphasis on the use chlorine-containing cleaning agents or other sporicidal agents to address environmental contamination especially in areas associated with increased rates of CDI. Compliance with the practice of hand hygiene is essential, as is providing a dedicated commode for each CDI patient and maintaining contact precautions.

All health care facilities should perform a minimum surveillance of CDI by tracking cases with symptom onset at least 48 hours after patient admission. It is recommended to express the rate as the number of cases per 10,000 patient-days.

According to guidelines, virtually every antimicrobial has been associated with CDI through the years. Thus, exposure to antimicrobial agents is the most important modifiable risk factor for the development of CDI.

Treatment Recommendations

When severe or complicated CDI is suspected, it is suggested that empirical treatment be initiated. The use of antiperistaltic agents should be avoided if possible, as they may obscure symptoms and precipitate toxic megacolon. Treatment following diagnosis includes the need to discontinue treatment with the inciting antimicrobial as soon as possible to reduce the risk of recurrence.

In the treatment of CDI, metronidazole and oral vancomycin have been the main antimicrobial agents used for the last 25 years. Two comparative trials carried out in the 1980s and the 1990s found no difference in outcomes between patients treated with either antimicrobial but these included <50 patients per study arm.

With reports of metronidazole treatment failures and the increasing incidence and severity of CDI, Zar et al. conducted a randomized controlled trial to determine which antimicrobial was better in patients with mild or severe disease (Clin Infect Dis 2007;45:302-7). Findings showed that vancomycin 125 mg q.i.d. was superior to metronidazole 250 mg q.i.d. in patients with severe disease, as assessed by a severity score that incorporated six clinical variables.

However, in this study, patients were recruited prior to 2002 and were therefore probably not infected with the NAP1/BI/027 strain of C. difficile. A more recent study carried out after the NAP1/BI/027 strain became prevalent appears to confirm the superiority of oral vancomycin over metronidazole for the treatment of severe CDI (47th ICAAC 2007, abstract K-425a). Thus, for the initial episode of mild to moderate CDI, guidelines recommend oral metronidazole 500 mg t.i.d. for 10 to 14 days and for the initial episode of severe CDI oral vancomycin 125 mg q.i.d. for 10 to 14 days should be used as the drugs of choice.

Similarly, oral vancomycin with or without intravenous (i.v.) metronidazole is the regimen of choice for the treatment of severe complicated CDI. If ileus is present, vancomycin can be given rectally. Oral vancomycin is administered at doses 500 mg q.i.d. and rectally every six hours as a retention enema of 500 mg in approximately 100 mL normal saline. The dose of i.v. metronidazole is 500 mg every eight hours. Colectomy may be considered for severely ill patients.

The same regimen used for the initial episode is usually administered for treatment of the first recurrence but treatment decisions should be based on disease severity using metronidazole, vancomycin or both. Guidelines also emphasize that metronidazole should not be used beyond the first recurrence or for long-term therapy because of the potential for cumulative neurotoxicity. They also recommend that physicians administer vancomycin using a tapered and/or pulsed regimen for the treatment of the second or later recurrence of C. difficile.

Summary

As the guidelines observe, the frequency of further episodes of CDI requiring retreatment remains a concern. Whether these recurrences are the result of a relapse of infection from the original strain or reinfection from new strains is impossible to distinguish clinically. However, several reports have noted an increase in the frequency of recurrences following metronidazole therapy, especially in patients over the age of 65. Using either metronidazole or vancomycin for a first recurrence does not appear to alter the probability of a second recurrence but vancomycin is recommended for the first recurrence in patients with a white blood cell count =15,000 cells/µL or a rising serum creatinine, since these patients are at higher risk of developing complications.

Questions and Answers

This question-and-answer session was conducted with Dr. Vivian Loo, Chief, Department of Microbiology, McGill University Health Centre, Montreal, Quebec.

Q: Why was it important to update the guidelines for the management of C. difficile infection?

A: There have been several outbreaks of C. difficile since 2003 in Canada. Given that the previous guidelines were published in 1995, we needed to take into account the fact that since then there have been many changes in terms of C. difficile epidemiology, diagnosis and treatment. So, it was important to update the guidelines because of these changes.

Q: How has the emergence of the hypervirulent strain of C. difficile modified the treatment of the infection?

A: Very often we don’t know if patients have the hypervirulent strain of C. difficile so we based our treatment recommendations on the clinical status of the patient instead. So if the patient has severe disease, we don’t start off with metronidazole, we go straight to the use of vancomycin. Conversely, if a patient has mild to moderate disease, then we can start off with metronidazole as our initial line of therapy. Many hospitals do not do cultures to identify whether patients have this strain of C. difficile as it takes approximately three to four days to get results back. You also need special typing methods to identify this strain and not all labs have the capacity to do this.

Q: How would the loss of vancomycin as a drug for severe and recurrent episodes affect patient outcome?

A: Vancomycin is one of our main treatment modalities for C. difficile and if we were to lose it, it would really limit our capabilities to adequately treat patients with the infection. There are other medications on the horizon which may help us manage patients, but none of the newer drugs can compare with the experience and the track record we have with vancomycin. So while it is encouraging to know that other treatments are becoming available, we have a certain comfort level with vancomycin as we’ve been using it for so long.