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This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PHYSICIAN PERSPECTIVE Viewpoint based on an article from the journal Clinical Infectious Diseases Mar 2009;48:568-76.

March 2009

Reported by:

Andrew E. Simor, MD, FRCPC

Head, Department of Microbiology, Division of Infectious Diseases, Sunnybrook Health Sciences Centre

Professor of Medicine, University of Toronto, Toronto, Ontario

It is important to acknowledge that C. difficile, a common hospital-acquired (HA) pathogen and a well-recognized cause of infectious diarrhea,¹ is becoming more pernicious.² When compared to a survey conducted in 1997, the Canadian Nosocomial Infection Program Study recently reported a fourfold increase in case-fatality rates (5.7 vs. 1.5%; P<0.001) (Figure 1).³ The increase in case fatalities is likely due to the growing incidence of infection due to the hypervirulent NAP-1/027 strain of C. difficile, which was the cause of a major series of outbreaks in Quebec in 2003.⁴ The characteristic feature of the Quebec and subsequent outbreaks has been an inordinate increase in case fatalities relative to the increase in cases. For example, when the 2003 rates of C. difficile in Quebec were compared to the previous year, the case incidence was increased by fourfold while the case-fatality rate increased tenfold.⁵

Figure 1.

The risk posed by hypervirulent strains of C. difficile has now travelled to other Canadian provinces, the US and Europe. In many Ontario hospitals, 20% to 50% of C. difficile infections are due to NAP-1/027, and outbreaks with high case-fatality rates, such as a recent outbreak associated with 62 deaths at the Joseph Brant Hospital in Burlington, Ontario, are increasingly common. The rising rate of C. difficile-associated fatalities is the primary reason that this infection is now a reportable disease in Quebec, Ontario and Manitoba.

Outbreak control is dependent on an appropriate system of surveillance and a rapid response both in regard to infection control practices and to treatment. A laboratory-based surveillance program should be capable of identifying C. difficile infection within 24 hours seven days a week. Longer intervals to confirmation, a problem particularly common to hospitals that engage outside laboratories, should no longer be considered acceptable. Within the surveillance program, baseline rates should be monitored within specific units and within the hospital as a whole so that deviations can be rapidly detected within the context of both time and space.

A Need for Revision of Treatment Guidelines

Treatment guidelines for C. difficile-associated diarrhea, including those from the Ontario Ministry of Health and by the Infectious Diseases Society of America (IDSA), are being revised to emphasize antibiotic selection on the basis of clinical presentation and risk factors. For first episode infection, metronidazole has been identified as the preferred agent in mild-to-moderate severity, while oral vancomycin is the preferred agent for severe disease or for those at high risk. Severe disease is defined as pseudomembranous colitis. High risk is defined as treatment in an intensive care unit (ICU) or the presence of at least two of the following criteria: age greater than 60; serum albumin level <2.5 mg/dL; peripheral white blood cell count >15,000 cells/mm³; and serum creatinine >2.3 mg/dL.

Antibiotic selection is made irrespective of pathogen strain. Oral metronidazole is prescribed in a dose of 500 mg t.i.d. and oral vancomycin in a dose of 125 mg q.i.d. The duration of treatment is 10 to 14 days. Although a repeat course of metronidazole is acceptable in a first recurrence of C. difficile in patients with mild to moderate disease, vancomycin capsules are preferred for second or subsequent recurrences even in the absence of risk factors or in the presence of mild-to-moderate disease. Oral vancomycin is not appropriate for patients with ileus; rather, intravenous metronidazole is the preferred agent, although supplementation with nasogastric or rectal vancomycin may be considered.

The stratification of treatments by disease severity is supported by randomized and controlled trials. Although metronidazole and vancomycin were once considered comparably effective as first-line therapies for C. difficile-associated diarrhea, several empirical observations, including those made during the Quebec outbreak,⁶ indicated that metronidazole was not as effective in individuals with severe infections. Two subsequent randomized trials comparing metronidazole to vancomycin confirmed that the two agents are similarly effective in patients with mild infection, but that clinical success rates are significantly higher on vancomycin in patients with severe disease.^7,8 In one of the studies, success rates were almost 30% higher when patients with severe C. difficile infection were treated with vancomycin rather than metronidazole (97% vs. 76%; P=0.02). The two drug therapies were associated with equivalent C. difficile relapse rates. These results provided the basis for the revised recommendations.

Adherence to the guidelines for antibiotic selection in C. difficile-associated diarrhea is an important part of an overall infection control strategy designed to prevent outbreaks and limit their scope when they occur. While metronidazole is less expensive than vancomycin, judicious use of potent therapies for severe infections can prevent hypervirulent pathogens from gaining traction. The known risks of failing to control C. difficile provide a strong rationale for offering vancomycin when the anticipated efficacy of metronidazole is in doubt.

It is important to consider post-discharge antibiotic adherence among individuals who have not completed their course of antibiotics before leaving the hospital. In such individuals, the risk of relapse from an inadequate duration of therapy is accompanied by the potential for spread of C. difficile infection into the community. In addition to patient education about the importance of adherence, it may also be necessary to ensure access to prescription medicine, particularly when out-of-pocket costs are incurred in the outpatient setting. In some provinces that do cover outpatient antibiotics, the fees for out-of-formulary drugs such as vancomycin capsules may be circumvented only by a specific request by a clinician-supplied indication for access.

Prompt Diagnosis and Infection Control Practices

There are many causes of HA diarrhea, but the frequency of C. difficile infection demands a high index of suspicion for this etiology. Nosocomial C. difficile infection should be suspected if new-onset watery stools starting at least 72 hours after a hospital admission cannot be readily explained by another etiology. Stool samples for laboratory testing, which make the diagnosis on the basis of characteristic cytotoxins rather than by culture, should be collected promptly. Visualization of pseudomembranes at colonoscopy provides a presumptive diagnosis of C. difficile in advance of laboratory confirmation.

If practical, those antibiotics most closely associated with increased risk of C. difficile, such as newer fluoroquinolones and clindamycin, should be discontinued. In the Quebec outbreak, the odds ratio for exposure to fluoroquinolones and cephalosporin antibiotics among the cases were about four times greater than for controls without infection.⁹

In an outbreak, standard infection control practices should be intensified.¹⁰ The spores of C. difficile, which are relatively resistant to destruction, are readily transported and transmitted without proper hygiene and cleaning. If possible, some degree of relative quarantine should be implemented for patients. The specifics of good infection control practices, such as hand hygiene and appropriate use of gloves, gowns and face shields, have been well disseminated but deserve review when outbreaks occur. Published cleaning protocols for inanimate objects within proximity of the patient, which provide a reservoir for contamination, should be followed closely. An institutional-wide review of antibiotic usage is also appropriate during an outbreak to limit exposure to those agents most closely associated with C. difficile risk.

Prevention, The Most Important Strategy

Traditionally, the risk of C. difficile-associated diarrhea and the risk of life-threatening complications from this infection have been concentrated in elderly patients or otherwise frail individuals, but hypervirulent infections enlarge the population who face the potential for serious consequences. Although mortality due to C. difficile in young individuals remains relatively uncommon, colectomy and death related to this infection have been described in young individuals, including one case series of peripartum women.¹¹

Due to the potential for life-threatening complications from initial infection and the substantial risk for recurrent disease, the most important strategy in the management of HA C. difficile is prevention. Prevention is dependent on strict adherence to good infection control practices, including prudent prescription of antibiotics. Such practices have benefits far beyond reducing the risk of C. difficile, including containment of other forms of antibiotic resistance.¹² While much of the focus on the increasing rates of antibiotic resistance has been on the diminishing options for infection control, the more immediate concern is a strong correlation between resistance and poor outcomes, including death.

The US and many countries in Europe have recorded a steep rise in C. difficile infections over the past decade.¹³ According to the US National Hospital Discharge Survey, case rates per 100,000 hospitalized patients increased from 31 to 84.¹ Although this same degree of rise in incidence has not been observed in Canada, other countries have shared the dramatic increases in case severity. In the UK, there was more than a sevenfold increase in rates of death due to C. difficile between 1999 and 2007.¹⁴ These statistics underline the need to improve strategies to reverse current trends. Success will almost certainly depend on a multifaceted approach for which the main tenets will be strengthening those infection control procedures already in place.

Summary

As the pathogen responsible for the important outbreaks of C. difficile infection in Quebec in 2003, NAP-01/027 has now spread across Canada with some centres now reporting this strain in up to half of cases. Due to increased risk of death from this hypervirulent strain, C. difficile-associated diarrhea is now a reportable disease in several provinces, including Quebec and Ontario. While all hospitals should maintain surveillance programs in order to rapidly detect outbreaks, rational treatment programs also have a role to play in containing this disease. New guidelines emphasize oral metronidazole as the preferred therapy for mild to moderate disease and oral vancomycin as the preferred therapy for those with severe disease or risk factors, such as age over 60. Although hypervirulent C. difficile may increase the proportion of patients with severe disease, antibiotic selection is not based on bacterium strain. Good infection control practices will be critical to containing the growing threat posed by C. difficile-associated disease. Several antibiotics are currently in clinical trials for the management of C. difficile, and may expand the options available for the treatment of this serious infection.

References

1. McDonald LC, Owings M, Jernigan JB. Clostridium difficile infection in patients discharged from US short-stay hospitals, 1996-2003. Emerg Infect Dis 2006;12:409-15.

2. Kelly CP, LaMont JT. Clostridium difficile – more difficult than ever. N Engl J Med 2008;359:1932-40.

3. Gravel et al. Health care-associated Clostridium difficile infection in adults admitted to acute care hospitals in Canada: A Canadian Nosocomial Infection Surveillance Study Program. Clin Infect Dis 2009;48:568-76.

4. Eggerson L, Sibbald B. Hospitals battling outbreaks of C. difficile. CMAJ 2004;171:19-21.

5. Loo et al. A predominantly clonal multi-institutional outbreak of Clostridium difficile-associated diarrhea with high morbidity and mortality. N Engl J Med 2005;353:2442-9.

6. Pépin et al. Increasing risk of relapse after treatment of Clostridium difficile colitis in Quebec, Canada. Clin Infect Dis 2005;40:1591-7.

7. Zar et al. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis 2007;45:302-7.

8. Louie et al. Results of a phase III trial comparing tolevamer, vancomycin, and metronidazole in patients with Clostridium difficile-associated diarrhea. Abstract K-425a. International Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Chicago, 2007.

9. Pépin et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis 2005;41:1254-60.

10. Simor et al. Clostridium difficile in long-term-care facilities for the elderly. Infect Control Hosp Epidemiol 2002;23(11):696-703.

11. Centers for Disease Control and Prevention. Severe Clostridium difficile-associated disease in populations previously at low risk. MMWR Morb Mortal Wkly Rep 2005;54:1201-5.

12. Mulvey MR, Simor AE. Antimicrobial resistance in hospitals: how concerned should we be. CMAJ 2009;180:408-15.

13. Kelly CP. A 76-year-old man with recurrent Clostridium difficile-associated diarrhea. Review of C. difficile infection. JAMA 2009;301:954-62.

14. UK National Statistics. Clostridium difficile: number of deaths increase in 2007. www.statistics.gov.uk/cci/nugget.asp?id=1735.