Epidemics of diarrhea caused by a clindamycin-resistant strain of Clostridium difficile in four hospitals

N Engl J Med. 1999 Nov 25;341(22):1645-51. doi: 10.1056/NEJM199911253412203.


Background: Large outbreaks of diarrhea caused by a newly recognized strain of Clostridium difficile occurred in four hospitals located in different parts of the United States between 1989 and 1992. Since frequent use of clindamycin was associated with the outbreak in one of the hospitals, we examined the resistance genes of the epidemic-strain isolates and studied the role of clindamycin use in these outbreaks.

Methods: Case-control studies were performed at three of the four hospitals to assess the relation of the use of clindamycin to C. difficile-associated diarrhea. All isolates of the epidemic strain and representative isolates of other strains identified during each outbreak were tested for susceptibility to clindamycin. Chromosomal DNA from these representative isolates was also analyzed by dot blot hybridization and amplification with the polymerase chain reaction (PCR) with the use of probes and primers from a previously described determinant of erythromycin resistance - the erythromycin ribosomal methylase B (ermB) gene - found in C. perfringens and C. difficile.

Results: In a stratified analysis of the case-control studies with pooling of the results according to the Mantel-Haenszel method, we found that the use of clindamycin was significantly increased among patients with diarrhea due to the epidemic strain of C. difficile, as compared with patients whose diarrhea was due to nonepidemic strains (pooled odds ratio, 4.35; 95 percent confidence interval, 2.02 to 9.38; P<0.001). Exposure to other types of antibiotics or hospitalization in a surgical ward was not significantly associated with the risk of C. difficile-associated diarrhea due to the epidemic strain. All epidemic-strain isolates were highly resistant to clindamycin (minimal inhibitory concentration, >256 microg per milliliter). DNA hybridization and PCR analysis showed that all these isolates had an ermB gene, which encodes a 23S ribosomal RNA methylase that mediates resistance to macrolide, lincosamide, and streptogramin antibiotics. Only 15 percent of the nonepidemic strains were resistant to clindamycin.

Conclusions: A strain of C. difficile that is highly resistant to clindamycin was responsible for large outbreaks of diarrhea in four hospitals in different states. The use of clindamycin is a specific risk factor for diarrhea due to this strain. Resistance to clindamycin further increases the risk of C. difficile-associated diarrhea, an established complication of antimicrobial use.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Anti-Bacterial Agents / adverse effects*
  • Case-Control Studies
  • Clindamycin / adverse effects*
  • Clostridioides difficile / classification*
  • Clostridioides difficile / genetics
  • Clostridioides difficile / isolation & purification
  • Cross Infection / chemically induced
  • Cross Infection / epidemiology
  • Cross Infection / microbiology
  • Diarrhea / chemically induced
  • Diarrhea / epidemiology*
  • Diarrhea / microbiology*
  • Disease Outbreaks*
  • Drug Resistance, Microbial / genetics
  • Enterocolitis, Pseudomembranous / chemically induced
  • Enterocolitis, Pseudomembranous / epidemiology*
  • Enterocolitis, Pseudomembranous / microbiology
  • Hospitals
  • Humans
  • Microbial Sensitivity Tests
  • United States / epidemiology


  • Anti-Bacterial Agents
  • Clindamycin