Clostridium Difficile

John Bartlett, MD
Professor of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland

    Clostridium difficile has recently received increasing attention due to significant recent changes in the epidemiology of infection. Antimicrobial resistance to the antibiotics used to treat C difficile (metronidazole and vancomycin) is rarely a significant issue. However, a growing number of C difficile infections are related to fluoroquinolone use, which was not previously a significant problem.
    C difficile is the most commonly identified bacterial enteric pathogen, accounting for approximately 50% of all bacterial pathogens encountered in patients with diarrhea. The risk of infection is increased among the elderly and among those with exposure to antibiotics in healthcare settings. The most common inducing agents are clindamycin, broad-spectrum β lactams, and fluoroquinolones. C difficile infections usually occur in the hospital, rather than in the community.¹ Studies show only 2% to 3% of healthy adults are colonized by C difficile, but the rate of colonization increases to 20% to 40% with hospitalization. A subset of these individuals get C difficile infection (CDI) with antibiotic exposure. Several rapid toxin assays are available using enzyme immunoassay to detect CDI, but they are limited by relatively poor sensitivity (generally 70%–80%).² A rapid assay with high sensitivity is also available for the enzyme glutamate dehydrogenase, which is a specific marker of C difficile colonization, but a toxin assay is necessary to detect CDI.

   C difficile can cause endemic or epidemic infections, and recent outbreaks of C difficile infection in the United States and Canada have been associated with very high rates of attributable mortality.³ The high mortality rates in these recent infections have been attributed to a novel hypervirulent C difficile strain, NAP-1, which has increased rapidly in prevalence over the last decade. NAP-1 is associated with more disease, greater toxin production, and with more serious disease (including toxic megacolon, leukemoid reaction, renal failure, shock, colectomy, and mortality). NAP-1 C difficile is also more refractory to therapy and more likely to relapse.
    The management of patients with C difficile infection should include the discontinuation of inciting antibiotics, avoidance of antiperistaltic agents, and the initiation of empiric treatment. Current treatment guidelines recommend metronidazole as the preferred antimicrobial agent, with vancomycin as an alternative. In clinical trials, the 2 agents have produced generally similar response rates in patients with mild-to-moderate disease severity; in patients with severe disease, better response rates have been reported with oral vancomycin.^4,5 A potential limitation of metronidazole is poor levels in the colon. In severe cases it may be necessary to do a colectomy, which has been associated with a lower incidence of mortality among patients with severe C difficile infection.⁶

   Options for relapsing disease include fecal transplant, pulse vancomycin (eg, 125 mg every other day for 6 weeks), intravenous immunoglobulin, probiotics, and antibiotics such as rifaximin and nitazoxanide.

References

1. McFarland LV, Mulligan ME, Kwok RY, Stamm WE. Nosocomial acquisition of Clostridium difficile infection. N Engl J Med. 1989;320:204-210.
2. Turgeon DK, Novicki TJ, Quick J, et al. Six rapid tests for direct detection of Clostridium difficile and its toxins in fecal samples compared with the fibroblast cytotoxicity assay. J Clin Microbiol. 2003;41:667-670.
3. Pépin J, Valiquette L, Cossette B. Mortality attributable to nosocomial Clostridium difficile-associated disease during an epidemic caused by a hypervirulent strain in Quebec. CMAJ. 2005;173:1037-1042.
4. Zar FA, Bakkanagari SR, Moorthi KM, Davis MB. A comparison of vancomycin and metronidazole for the treatment of Clostridium difficile-associated diarrhea, stratified by disease severity. Clin Infect Dis. 2007;45:302-307.
5. Louie T. Presented at: Interscience Conference on Antimicrobial Agents and Chemotherapy 2007. September 17-20, 2007; Chicago, IL: Abstract 3826
6. Lamontagne F, Labbé AC, Haeck O, et al. Impact of emergency colectomy on survival of patients with fulminant Clostridium difficile colitis during an epidemic caused by a hypervirulent strain. Ann Surg. 2007;245:267-272.