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Clindamycin resistant strains of Clostridium difficile isolated from cases of C. difficile associated diarrhea (CDAD) in a hospital in Sweden
Örebro University, Department of Clinical Medicine.
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2002 (English)In: Diagnostic microbiology and infectious disease, ISSN 0732-8893, E-ISSN 1879-0070, Vol. 42, no 2, p. 149-151Article in journal (Refereed) Published
Abstract [en]

Fifty three strains of C. difficile recovered from the stools of 13 patients with clinical C. difficile associated diarrhea (CDAD) were analyzed for the presence of the ermB gene, for toxigenicity and fingerprinting profile by PCR based assays. Forty five percent of the isolates were resistant to clindamycin and positive for the ermB gene. All clindamycin resistant isolates were ermB positive and belonged to the same fingerprinting group, suggesting clonal spread. These preliminary results suggest that clindamycin resistant isolates may be common etiologic agents of CDAD in Sweden.

Place, publisher, year, edition, pages
2002. Vol. 42, no 2, p. 149-151
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
URN: urn:nbn:se:oru:diva-3198DOI: 10.1016/S0732-8893(01)00337-6OAI: oai:DiVA.org:oru-3198DiVA, id: diva2:137291
Available from: 2006-11-23 Created: 2006-11-23 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Clostridium difficile: epidemiology and antibiotic resistance
Open this publication in new window or tab >>Clostridium difficile: epidemiology and antibiotic resistance
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Clostridium 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.

Abstract [sv]

Antibiotikautlöst diarré (AAD) är en följd av antibiotikabehandling och vanligaste orsaken är att tarmbakterien C. difficile växer till och producerar två toxin som utlöser Clostridium difficile assoscierad diarré (CDAD). Sjukdomen orsakar förlängda vårdtider, lidande och risk för förtidig död. Smittsamhet med långlivade sporer på sjukhusavdelningar är välkänt och en tiofaldigt ökad incidens har noterats i Västeuropa under de senaste 10-15 åren. Sviktande behandling samt epidemiska utbrott av högvirulenta C. difficile stammar oroar.

Vi studerade 13 patienter med Clostridium difficile associerad diarré (CDAD) på Infektionskliniken USÖ 1994-96. Klindamycin var den antibiotika som vanligtvis orsakade sjukdomen (8/13) och resistens hos bakterien förklarades med fynd av resistensgenen ermB. Resultaten visade att en epidemisk situation förelåg på infektionskliniken i Örebro och att klindamycin resistens sannolikt orsaken.

Uppföljning gjorde sedan i hela Örebro län 1999-2000 och den årliga incidensen var 97 sjukdomsfall per 100 000 innevånare och 100% högre än i en nationell beräkning från 1995. Huvuddelen av sjukdomsfallen (78 %) var associerade till sjukhusvistelse och risken 1300 ggr högre för den sjukhusvårdade populationen, motsvarande en 37 ggr högre antibiotika förbrukning på sjukhus. Typning av C. difficile stammar avslöjade den nosokomialt spridda ribotypen SE 17 % utgjorde 22% av sjukhusstammarna jämfört med bara 6 % i öppenvård (p=0.008). Denna stam visade sig vara unik för Örebro och återfanns i 36-44 % på tre avdelningar. Vid återfall av CDAD var endast 10 % yttre smittöverföring mot 50 % internationellt och skulle kunna tyda på fungerande hygienrutiner på länets sjukhus.

Från en jämförande behandlingsstudie mellan metronidazol och fusidin syra analyserades vi 88 patienter avseende C. difficile isolat före och efter behandling. De patienter med positiv odling i uppföljning hade behandlingssvikt eller återfall oftare än de där C. difficile försvann (46% respektive 23%, p=0.03). Däremot skilde sig inte behandlingens utgång mellan antibiotikagrupperna. Viktigaste resultatet var dock att av patienterna som fick fusidin syra och hade positiv odling i uppföljning (n=20) så hade 55 % resistensutveckling i ett eller båda av sina isolat efter avslutad behandling. Hos 10/11 av dessa patienter uppvisades samma ribotyp som ursprungsisolatet tydande selektion av muterade bakterier.

Fusidin syra resistens uppkommer hos Staphylococcus aureus genom mutationer i fusA genen. Via datasökning mot publicerat DNA för typstam C. difficile 630 hittades matchande gensekvens. Hos parade känsliga och resistenta C. difficile från12 patienter med uppkommen fusidin syra resistens jämfördes sedan genen och uppvisade 12 mutationer varav 5 av dessa hade identisk aminosyra position som tidigare beskrivits hos fusidin syra resistenta S. aureus. Sammantaget talar dessa helt nya data starkt för en nyupptäckt fusA gen hos C. difficile och att mutationer i denna gen är förklaringen till uppkomst av resistenta C. difficile isolat efter fusidin syra behandling av CDAD.

Place, publisher, year, edition, pages
Örebro: Örebro universitetsbibliotek, 2006. p. 84
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 9
Keywords
Clostridium difficile, antibiotic resistance, epidemiology
National Category
Clinical Science
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-797 (URN)91-7668-511-X (ISBN)
Public defence
2006-12-14, Wilandersalen, M-huset, Universitetssjukhuset, Örebro, 13:00
Opponent
Supervisors
Available from: 2006-11-23 Created: 2006-11-23 Last updated: 2017-10-18Bibliographically approved

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