1 Telemark Biomedical Centre, A/S Telelab, Department of Medical Microbiology, Strømdaljordet 4, PO Box 1868, N-3703 Skien; 2 Department of Microbiology and Virology, University of Tromsø, N-9037 Tromsø, Norway
Received 2 July 2002; returned 9 August 2002; revised 20 August 2002; accepted 20 August 2002
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Abstract |
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Methods: Fusidic acid-resistant and -susceptible clinical isolates of S. aureus from patients with skin infections in the Norwegian county of Telemark and fusidic acid-resistant isolates from other parts of Scandinavia were compared. MICs of fusidic acid for bacterial isolates and pulsed-field gel electrophoresis (PFGE) patterns were investigated. Prevalence data for fusidic acid-resistant S. aureus for the period 19922001 were obtained.
Results: The prevalence of fusidic acid resistance in S. aureus increased from 1992 to 2001. Eighty per cent of the resistant isolates investigated shared an identical PFGE pattern. The same pattern was found in fusidic acid-resistant isolates from other parts of Scandinavia. Fusidic acid-resistant S. aureus was typically found in impetigo bullosa-like skin disease in children mostly in the summer months.
Conclusions: Fusidic acid resistance among S. aureus is increasing in Norway and is predominantly caused by one clone of S. aureus. The clone may spread further to other countries, and dissemination may be facilitated by extensive use of topical fusidic acid.
Keywords: pulsed-field gel electrophoresis, MIC, clonal
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Introduction |
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Since the introduction of fusidic acid in the 1960s, there have been scattered reports of increased resistance,4,5 but the majority of studies have reported a low prevalence of fusidic acid resistance among S. aureus and therefore resistance has not been regarded as a present or potential problem.6 Recently, however, a number of groups have reported fusidic acid resistance to be on the increase.7,8 It is not yet known to what extent these increases represent widespread dissemination of resistant strains, spread of resistance genes or selection of fusidic acid-resistant variants locally.
In the Scandinavian countries, fusidic acid has been used extensively for topical treatment of superficial skin infections for many years, irrespective of the aetiology. Until recently, >90% of S. aureus isolates from Norway were susceptible to fusidic acid.9
In the summer and early autumn of 1999, we noticed a marked increase in enquiries to our laboratory concerning outbreaks of impetigo among children. Impetigo encompasses two different clinical entities. Impetigo contagiosa is caused by Streptococcus pyogenes, but S. aureus can secondarily infect impetigo contagiosa lesions. Impetigo bullosa, a superficial cutaneous disorder occurring predominantly in children, is caused by S. aureus. In impetigo bullosa, an epidermal split caused by exfoliating toxins results in the formation of 12 cm bullae containing neutrophils and staphylococci.10 Bacteriological investigations from these impetigous lesions frequently showed the presence of S. aureus, a majority of which were resistant to fusidic acid. This pattern was repeated in the summer months of 2000 and 2001. Similar observations were reported from other parts of Norway11 and from Sweden.12
The present study was undertaken to determine the prevalence of fusidic acid-resistant S. aureus in our region and to analyse the clonal relationship of such isolates by pulsed-field gel electrophoresis (PFGE).
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Materials and methods |
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Resistance data for S. aureus from 1 January 1992 to 31 December 2001 were retrieved from our laboratory records.
Bacterial strains
Thirty consecutive isolates of fusidic acid-resistant S. aureus from outpatients with the clinical diagnosis of impetigo were collected in August in both 2000 and 2001. Thirty-three of these isolates were chosen randomly for further study. Three additional fusidic acid-resistant isolates, also associated with impetigo outbreaks, were obtained from Førde Central Hospital (Førde, Norway), St Olavs Hospital (Trondheim, Norway) and Växjö Central Hospital (Växjö, Sweden). A fusidic acid-resistant MRSA isolate from Denmark was also included. Fusidic acid-susceptible isolates of S. aureus from ordinary wound infections (n = 10) and both susceptible and resistant isolates from blood cultures (n = 20) were included as controls.
Susceptibility testing
Routine susceptibility testing was done with fusidic acid paper discs (10 µg) on Iso-sensitest medium (IST; Mast Laboratories, Merseyside, UK) with an inoculum of 0.5 McFarland Standard. Isolates growing with an inhibitory zone of <25 mm were defined as being resistant to fusidic acid.
MICs were determined using Etest (AB Biodisk, Solna, Sweden) on IST medium according to the manufacturers instructions.
Pulsed-field gel electrophoresis (PFGE)
PFGE using SmaI was carried out as described in the Nordic PFGE protocol.13 Band patterns were compared visually and differences evaluated as described by Tenover et al.14
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Results |
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Fusidic acid-resistant S. aureus having the PFGE class A pattern showed MICs ranging from 2 to 4 mg/L. MICs for fusidic acid-resistant S. aureus showing other PFGE patterns varied from 1 to >32 mg/L. All resistant isolates identified by disc diffusion were confirmed as resistant by MIC determination using Etest.
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Discussion |
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Genetic typing with PFGE showed that 80% of impetigo-associated fusidic acid-resistant S. aureus belonged to a single DNA class, and corresponding isolates from Sweden and other regions of Norway are of the same DNA class. In contrast, fusidic acid-susceptible isolates are genetically heterogeneous. We conclude, therefore, that the majority of impetigo-associated fusidic acid-resistant S. aureus isolates are closely related members of a single clone. Our results thus strongly suggest that a fusidic acid-resistant S. aureus clone has spread epidemically in Scandinavia in recent years. There is no reason to believe that this clone will respect national boundaries, and it may be the case that increasing fusidic acid resistance reported from North Yorkshire may be due to the spread of this clone to the UK.7
It remains to be determined to what extent this clone is confined to impetigo bullosa and to what extent the increase in fusidic acid resistance that is being observed now is due to the spread of clones, to transmissible resistance or to the accumulation of spontaneous resistance mutations in response to selective pressure. What is clear, however, is that fusidic acid resistance is on the increase and very probably spreading epidemically.
Excessive and indiscriminate use of fusidic acid is likely to exacerbate this situation. In the present epidemiological situation, we would remind clinicians that fusidic acid is only one of several antibiotic and antiseptic compounds suitable for topical treatment of S. aureus infections. We would also encourage microbiologists in countries outside Scandinavia to monitor the development of fusidic acid resistance in S. aureus, particularly in connection with outbreaks of impetigo bullosa.
Further work will focus on what mechanism of resistance is carried in this clone of S. aureus.
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Acknowledgements |
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Footnotes |
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References |
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