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- Norén, Torbjörn, 1955-
(författare)
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Clostridium difficile : epidemiology and antibiotic resistance
- 2006
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 2. |
- Norén, Torbjörn, et al.
(författare)
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Frequent emergence of resistance in Clostridium difficile during treatment of C-difficile-associated diarrhea with Fusidic acid
- 2006
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Ingår i: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 50:9, s. 3028-3032
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Norén, Torbjörn, et al.
(författare)
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Mutations in fusA associated with posttherapy fusidic acid resistance in Clostridium difficile
- 2007
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Ingår i: Antimicrobial Agents and Chemotherapy. - Washington, DC : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 51:5, s. 1840-1843
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Tidskriftsartikel (refereegranskat)abstract
- In silico, we identified fusA (2,067 bp) in Clostridium difficile 630. Sequencing of fusA in posttherapy fusidic acid-resistant C. difficile isolates from 12 patients with C. difficile-associated diarrhea (CDAD) identified fusA mutations, one or two nonsynonymous substitutions, or in one case a deletion of one codon associated with resistance. Five of these mutations have previously been described in fusA of fusidic acid-resistant Staphylococcus aureus, but seven were novel fusA mutations. Fusidic acid monotherapy for CDAD seemed to rapidly select conserved resistant mutants.
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| 4. |
- Åkerlund, Thomas, et al.
(författare)
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Increased sporulation rate of epidemic Clostridium difficile Type 027/NAP1
- 2008
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Ingår i: Journal of Clinical Microbiology. - 0095-1137 .- 1098-660X. ; 46:4, s. 1530-1533
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Tidskriftsartikel (refereegranskat)abstract
- Clostridium difficile PCR ribotype 027 comprised 0.2% of a collection of Swedish isolates in 1997-2001 (3 of 1,325 isolates). These isolates had lower moxifloxacin MICs than the epidemic type 027 isolates, but they had the same tcdC sequence and toxin yield. Type 027 produced 3- to 13-fold more toxin than did major Swedish types. One epidemic strain (027/NAP1a) sporulated more than did other type 027 isolates, a feature that should contribute to its survival and spread.
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