Clostridium difficile A bug on the rise BY Surabhi Rawal, BSc and Sandra Dial, MD

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Clostridium difficile is a gram-positive rod of the genus Clostridium. Clostridia typically are anaerobic, spore-forming bacilli found in soil as well as in normal intestinal flora of man and animals. Toxin-producing strands cause several well-known diseases, including gas gangrene and necrotic enteritis (Clostridium perfringens), tetanus (Clostridium tetani), food-borne botulism (Clostridium botulinum) and septic shock (Clostridium sordellii), while Clostridium difficile is a leading cause of nosocomial diarrhea and colitis.1

Recently, the epidemiology of C. difficile has been changing, with outbreaks of more severe disease being reported in the U.S., Canada and European hospitals.2-4 There have also been reports of illness in people previously thought to be low-risk (e.g. people who haven't been taking antibiotics recently, children and pregnant women). As a result, C. difficile-associated disease (CDAD) has become an important public health concern.5

What does C. difficile do?
Similarly to the course of other infectious diarrheal illnesses, disease results from ingestion of the organism in question by a susceptible host. As with other pathogenic clostridia, it is toxin produced by the organism that's responsible for the clinical manifestations of the disease. Most strains of C. difficile that affect humans contain two toxins -- A and B -- but disease and outbreaks have also been reported in strains only producing toxin B. Non-toxin producing strains don't cause sickness in humans, but can occasionally be cultured from asymptomatic individuals.4

Clinical symptoms may vary widely. Patients can experience mild-to- severe diarrhea, which is typically watery and non-bloody, although some people develop severe lower abdominal pain with high fever and chills. In certain individuals, the disease can progress to its most severe, life-threatening complication -- fulminant colitis or toxic megacolon accompanied by electrolyte disturbances, hypoalbuminemia, paralytic ileus, septic shock and multiple systems organ failure.6 Recently, we've also observed a pattern of recurrent bouts of diarrhea resulting in progressive weakness, weight loss and subsequent death -- particularly in the elderly.

Who's at risk?
CDAD is primarily a nosocomial infection, and the majority of reported cases have been described in elderly, hospitalized patients who had been exposed to antibiotics.2,7 Other risk factors include intra-abdominal surgery, but it's not clear that all surgery of this kind confers the same risk. In fact, early reports8 as well as our own work suggest that there may be differences in risk dependent on the type of intra-abdominal surgery. Additional risk factors include gastric acid suppressive agents,9 chronic renal failure,10 chemotherapy, immunosuppression11 and inflammatory bowel disease.

What's the role of antibiotics?
Antibiotics are believed to increase the risk of CDAD by their effects on the normal fecal flora; they may facilitate colonization by C. difficile, which can then lead to infection. The propensity to induce CDAD appears to differ among specific antibiotic classes -- a notion that originated from the initial description of "clindamycin"-associated colitis and data from hamster studies. The disparity in risks may be due to differences in the antibiotic properties, such as magnitude and duration of the effects on the fecal flora, the activity against C. difficile and possibly the presence of the drug or its metabolite levels in the intestinal lumen.

But data regarding specific antibiotic risks have been contradictory.12 Many studies that implicate particular antibiotics haven't taken into account differences in risk of exposure to C. difficile, or the severity of the acute illness determining the choice of antimicrobial agent. There may also be patterns of antimicrobial prescribing in hospitals that would make it difficult to determine whether it's the specific antibiotic used or the type of patient to whom it was prescribed that confers the increased risk.6 For example, if intra-abdominal sepsis is a risk factor for CDAD, the antibiotic used in the management of this disease -- likely broad-spectrum -- may acquire a "high C. difficile risk" label because it's typically given to high-risk patients.