The new Clostridium difficile--what does it mean?

Recent experience with influenza, the severe acute respiratory syndrome (also known as SARS), avian influenza, and community-acquired methicillin-resistant Staphylococcus aureus has demonstrated how old pathogens can emerge with increased virulence and challenge scientists to explain their rebirth, clinicians to care for patients, and infection-control personnel to prevent their spread. Clostridium difficile appears to illustrate these challenges. It already has some distinctive features: it causes disease almost exclusively in the presence of exposure to antibiotics, it is the only anaerobe that poses a nosocomial risk, and it produces toxin in vivo only in the colon. About 3 percent of healthy adults and 20 to 40 percent of hospitalized patients are colonized with C. difficile,1,2 which in healthy persons is metabolically inactive in the spore form. The assumption is that perturbation of the competing flora promotes a conversion to vegetative forms that replicate and produce toxins. The characteristic clinical expression is watery diarrhea and cramps, and the characteristic pathologic finding is pseudomembranous colitis. The history of antibiotic-associated colitis began with a multitude of reports early in the antibiotic era, most of them involving surgical patients and generally attributing the condition to S. aureus. In 1974, Tedesco et al.3 reported on a prospective study of 200 consecutive patients given clindamycin, of whom 41 had diarrhea and 20 (10 percent of all those receiving clindamycin) had pseudomembranous colitis. C. difficile was reported as the cause of pseudomembranous colitis in 1978,4 and within three years, toxins A and B were described, the cytotoxin assay became the standard diagnostic test, clinical studies showed that nearly any antibiotic with an antibacterial spectrum could cause this complication, and oral vancomycin became the standard treatment. Studies showed that toxins A and B act by disrupting the actin-cytoskeleton of fibroblasts in tissue culture5 and in intestinal epithelial cells by uridine 5 '-diphosphate glucose dependent glucosylation of Rho proteins.6 In the past 20 years, C. difficile has become the most commonly recognized microbial cause of nosocomial diarrhea, ref lecting high rates of colonization in hospitalized patients3 and the frequent use of antimicrobial agents. The most commonly implicated agent in the 1970s was clindamycin, and in the 1980s it was cephalosporins, but the recent surge of cases suggests that fluoroquinolones may now play a prominent role.6 Many previous reports of C. difficile–induced disease concerned epidemics, but the reports were generally restricted to single institutions or wards. Recently, however, there appears to be a wider distribution. An example is a regional outbreak in Sherbrooke, Quebec, in 2002, in which there were reports of more disease and more serious disease. A retrospective chart review of 1721 cases of C. difficile–associated diarrhea occurring over 13 years showed that the rate of this complication increased by a factor of 4 during this period and that the cases were also increasingly severe; major risk factors were age over 65 years and receipt of fluoroquinolones.7 A similar experience was reported in Pittsburgh8 and at other hospitals in the United States.9 The question is whether these were isolated events or whether there was something different about medical practice, the pathogen, or the antibiotic use involved in them. This issue of the Journal includes two large studies that, taken together, describe a new strain of C. difficile and implicate a possible role of flu-