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Clostridium difficile: epidemiology and antibiotic resistance
Örebro University, Department of Clinical Medicine.
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
Keyword [en]
Clostridium difficile, antibiotic resistance, epidemiology
National Category
Clinical Science
Research subject
Medicine
Identifiers
URN: urn:nbn:se:oru:diva-797ISBN: 91-7668-511-X (print)OAI: oai:DiVA.org:oru-797DiVA, id: diva2:137292
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
List of papers
1. Clindamycin resistant strains of Clostridium difficile isolated from cases of C. difficile associated diarrhea (CDAD) in a hospital in Sweden
Open this publication in new window or tab >>Clindamycin resistant strains of Clostridium difficile isolated from cases of C. difficile associated diarrhea (CDAD) in a hospital in Sweden
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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.

National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-3198 (URN)10.1016/S0732-8893(01)00337-6 (DOI)
Available from: 2006-11-23 Created: 2006-11-23 Last updated: 2017-12-14Bibliographically approved
2. Molecular epidemiology of hospital-associated and community-acquired Clostridium difficile infection in a Swedish county
Open this publication in new window or tab >>Molecular epidemiology of hospital-associated and community-acquired Clostridium difficile infection in a Swedish county
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2004 (English)In: Journal of Clinical Microbiology, ISSN 0095-1137, E-ISSN 1098-660X, Vol. 42, no 8, p. 3635-3643Article in journal (Refereed) Published
Abstract [en]

All episodes of Clostridium difficile associated diarrhea (CDAD) diagnosed in a defined population of 274,000 including one tertiary and two primary hospitals and their catchment areas were studied during 12 months. The annual CDAD incidence in the county was 97 primary episodes per 100,000, and 78% of all episodes were classified as hospital associated with a mean incidence of 5.3 (range, 1.4 to 6.5) primary episodes per 1,000 admissions. The incidence among hospitalized individuals was 1,300-fold higher than that in the community (33,700 versus 25 primary episodes per 100,000 persons per year), reflecting a 37-fold difference in antibiotic consumption (477 versus 13 defined daily doses [DDD]/1,000 persons/day) and other risk factors. Three tertiary hospital wards with the highest incidence (13 to 36 per 1,000) had CDAD patients of high age (median age of 80 years versus 70 years for other wards, P < 0.001), long hospital stay (up to 25 days versus 4 days), or a high antibiotic consumption rate (up to 2,427 versus 421 DDD/1,000 bed days). PCR ribotyping of C. difficile isolates available from 330 of 372 CDAD episodes indicated nosocomial acquisition of the strain in 17 to 27% of hospital-associated cases, depending on the time interval between index and secondary cases allowed (2 months or up to 12 months), and only 10% of recurrences were due to a new strain of C. difficile (apparent reinfection). In other words, most primary and recurring episodes were apparently caused by the patient's endogenous strain rather than by one of hospital origin. Typing also indicated that a majority of C. difficile strains belonged to international serotypes, and the distribution of types was similar within and outside hospitals and in primary and relapsing CDAD. However, type SE17 was an exception, comprising 22% of hospital isolates compared to 6% of community isolates (P = 0.008) and causing many minor clusters and a silent nosocomial outbreak including 36 to 44% of the CDAD episodes in the three high-incidence wards.

National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-15678 (URN)10.1128/jcm.42.8.3635-3643.2004 (DOI)000223286500038 ()
Available from: 2011-05-24 Created: 2011-05-24 Last updated: 2017-12-11Bibliographically approved
3. Frequent emergence of resistance in Clostridium difficile during treatment of C-difficile-associated diarrhea with Fusidic acid
Open this publication in new window or tab >>Frequent emergence of resistance in Clostridium difficile during treatment of C-difficile-associated diarrhea with Fusidic acid
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2006 (English)In: Antimicrobial Agents and Chemotherapy, ISSN 0066-4804, E-ISSN 1098-6596, Vol. 50, no 9, p. 3028-3032Article in journal (Refereed) Published
Abstract [en]

Samples from patients with Clostridium difficile-associated diarrhea (CDAD) that were randomized to fusidic acid (n = 59) or metronidazole (n = 55) therapy for 7 days were cultured for Clostridium difficile in feces on days 1, 8 to 13, and 35 to 40. Of the patients who were culture positive only before treatment, 77% (36/47) were permanently cured (no treatment failure and no clinical recurrence), compared to 54% (22/41) of those with persistence of C. difficile at one or both follow-ups (P = 0.03). A similar association between bacterial persistence and a worse outcome of therapy was seen in both treatment groups. Resistance to fusidic acid was found in 1 of 88 pretherapy isolates available, plus in at least 1 subsequent isolate from 55% (11/20) of patients who remained culture-positive after fusidic acid therapy. In 10 of these 11 patients, the resistant follow-up isolate(s) belonged to the same PCR ribotype as the susceptible day 1 isolate, confirming frequent emergence of resistance to fusidic acid during treatment. Despite this, 5 of these 11 patients were permanently cured with fusidic acid, relative to 5 of 9 patients with susceptible C. difficile at follow-up (P = 1.0). None of the 36 PCR ribotypes of C. difficile identified was associated with any particular clinical outcome or emergence of fusidic acid resistance. In conclusion, culture positivity for C. difficile was common after both fusidic acid and metronidazole therapy and was associated with treatment failure or recurrence of CDAD. Development of resistance in C. difficile was frequent in patients given fusidic acid, but it was without apparent negative impact on therapeutic efficacy in the actual CDAD episode.

National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-15679 (URN)10.1128/AAC.00019-06 (DOI)000240297000019 ()
Available from: 2011-05-24 Created: 2011-05-24 Last updated: 2017-12-11Bibliographically approved
4. Nucleotide polymorphisms in fusA associated with post-therapy fusidic acid resistance in Clostridium difficile
Open this publication in new window or tab >>Nucleotide polymorphisms in fusA associated with post-therapy fusidic acid resistance in Clostridium difficile
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(English)Manuscript (preprint) (Other academic)
National Category
Medical and Health Sciences
Research subject
Medicine
Identifiers
urn:nbn:se:oru:diva-15681 (URN)
Available from: 2011-05-24 Created: 2011-05-24 Last updated: 2017-10-17Bibliographically approved

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