Clostridium difficile : epidemiology and antibiotic resistance
Abstract: ABSTRACTClostridium difficile is a spore-forming toxin-producing intestinal bacterium abundant in soils and waters. This pathogen relies on increased growth by a disturbed intestinal microflora and the production of two cytotoxins, toxin A and toxin B, which may cause anything from mild self-limiting C. difficile associated diarrhea (CDAD) to severe and fatal pseudomembranous colitis (PMC). Typically CDAD following antibiotic therapy is due either to overgrowth of endogenous C. difficile or through spores transmitted from the environment. The hospital setting provides frequent antibiotic use and the source of numerous infective spores from CDAD patients, the environment or nursing staff. Today we experience a 10-fold increase of incidence in the US and Canada (1991-2003) apparently due to a current epidemic C. difficile strain (NAP1/027). Current incidence from Canada is estimated to 156/100 000 compared to 50/100 000 in Sweden 1995.In the following thesis, investigations of CDAD in Örebro County in central Sweden resulted in the discovery an epidemic nosocomial C. difficile strain (SE17, serogroup C), found to be clindamycin-resistant. The majority of the isolates carried a gene (ermB) related to this resitance. We found an overall incidence during 1999-2000 of 97/100 000 or, if including recurrent episodes, 135/100 000 i.e. more than 100% increase since 1995. The incidence among hospitalized individuals was 1300-fold that in the community and 78% of episodes were classified as hospital-associated. This reflects a 37-fold difference in antibiotic consumption, as well as the predominance of the resistant SE17 hospital-associated strain (22% of hospital isolates compared to 6% of community isolates, p=0.008). Only 10% of the recurrent cases were found to be reinfections indicating that CDAD is mainly caused by endogenous strains and not by hospital transmission.Recent reports on failure of standard metronidazole therapy urge for alternative treatment agents and fusidic acid has been proven as effective in the treatment of CDAD. We could verify this, but in both treatment groups we found that persistence of C. difficile isolates post-treatment related to an increased risk of recurrent CDAD compared to the patients who were culture negative at follow-up (p=0.03). Most importantly, 55% of patients with follow-up isolates and who had been treated with fusidic acid, the strains had developed fusidic acid resistance. The corresponding pre-treatment identity of isolate genotype indicated selection of mutants. Relating to the known fusA resistance mechanism in Staphylococcus aureus we used the published sequence for this gene in Clostridium perfringens and found homologous fusA in the sequence of the referent strain C. difficile 630. Comparing fusA of the resistant mutants with the initial wild-type isolates, we identified novel mutations in fusA as the genetic key to fusidic acid resistance in C. difficile.
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