CHICAGO-A new clindamycin-resistant strain of Clostridium difficile is responsible for outbreaks of nosocomial diarrhea at hospitals in four states.(1,2) Although C difficile diarrhea has long been associated with antibiotic use, the disease was thought to result from the agents' suppressive effect on bowel flora, which can lead to C difficile overgrowth. However, it now appears that the antibiotic susceptibility profile of the organism itself plays a causative role.

Using restriction enzyme analysis, Johnson and colleagues(1) determined that C difficile strain J9 (or one closely related to it) was responsible for the nosocomial diarrhea outbreaks at all four hospitals. These investigators evaluated the role of clindamycin use at each institution (Table 1), tested all isolates from the epidemic strain and isolates of other representative strains identified during the outbreak for clindamycin susceptibility, and assessed the genetic basis for clindamycin resistance.

At the hospitals in New York, Arizona, and Massachusetts, clindamycin use was associated with 35 of the 83 cases of diarrhea caused by the epidemic strain of C difficile. The pooled odds ratio was 4.35 (95% confidence interval, 2.02 to 9.38). Only 12 of the 99 diarrhea cases caused by nonepidemic strains were associated with clindamycin therapy. (Case-control data linking clindamycin use to diarrhea at the Florida hospital were not available.)

All 85 isolates of the epidemic strain of C difficile were highly resistant to clindamycin (Table 2). In contrast, most of the nonepidemic strains were susceptible to this antibiotic. The isolates of the epidemic strain were also highly resistant to erythromycin.

Resistance to macrolide-lincosamide-streptogramin (MLS) antibiotics such as clindamycin and erythromycin is often mediated by a 23S ribosomal RNA methylase encoded by a group of erm genes. DNA testing confirmed that isolates of the epidemic strain contained an ermB-like gene.

"These results cast new light on the relation between antibiotic use and C difficile-associated diarrhea," noted Stuart Johnson, MD, an assistant professor of medicine at the Northwestern University Medical School in Chicago and a coauthor of the study. Specific strains of C difficile may contain an erythromycin-clindamycin resistance gene and significantly increase the risk of C difficile diarrhea when clindamycin is used. It is likely that such strains have a wider geographic distribution than the locations of the four outbreaks studied.

The use of clindamycin has decreased in recent years. Yet, at the same time, the incidence of C difficile diarrhea has increased. Thus, it is unlikely that merely restricting the use of clindamycin will be sufficient to stem all outbreaks of C difficile diarrhea, explained Sherwood L. Gorbach, MD, professor of medicine at Tufts University School of Medicine, Boston, in an editorial3 that accompanied the report. The highest risk for C difficile diarrhea appears to be associated with second- or third-generation cephalosporins, ampicillin, and amoxicillin as well as clindamycin. "It is not just the total use of antibiotics but the specific choice of drugs that seems to propel this modern hospital epidemic," Dr. Gorbach emphasized. To control or prevent outbreaks of C difficile diarrhea, physicians will have to rethink their antibiotic usage patterns.

-Christine M. Olsen, PhD

References
1. Johnson S, Samore MH, Farrow KA, et al. Epidemics of diarrhea caused by a clindamycin-resistant strain of Clostridium difficile in four hospitals. N Engl J Med. 1999;341:1645-1651.
2. Samore MH, Killgore G, Johnson S, et al. Multicenter typing comparison of sporadic and outbreak Clostridium difficile isolates from geographically diverse hospitals. J Infect Dis. 1997;176:1233-1238.
3. Gorbach SL. Antibiotics and Clostridium difficile [Editorial]. N Engl J Med. 1999;341:1690-1691.

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