Fusidic acid resistance in community isolates of methicillin-susceptible Staphylococcus aureus and fusidic acid prescribing

Brendan W. Mason1,*, Anthony J. Howard2 and John T. Magee1

1 Public Health Laboratory Service, Communicable Disease Surveillance Centre (Wales), Abton House, Wedal Road, Cardiff CF14 3QX; 2 Department of Medical Microbiology and Public Health Laboratory, University Hospital of Wales, Cardiff CF14 4XW, UK

Received 17 October 2002; returned 4 December 2002; revised 13 December 2002; accepted 3 February 2003


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The level of resistance to fusidic acid among community methicillin-susceptible Staphylococcus aureus (MSSA) isolates in the UK and prescriptions for fusidic acid have both doubled over the past 6 years. It is hypothesized that selective pressure arising from topical use of fusidic acid in the community accounts for this increase. A significant correlation was found between prescribing of fusidic acid and resistance at the practice level (Spearman’s rho = 0.46, 95% confidence interval 0.11–0.71, P = 0.01). Further controlled studies are required to determine whether this association is causal.

Keywords: fusidic acid resistance, Staphylococcus aureus, fusidic acid prescribing


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Brown & Thomas1 reported an increase, from 6% in 1998 to 11.5% in 2001, in the rate of resistance to fusidic acid among all methicillin-susceptible Staphylococcus aureus (MSSA) isolates in Bristol. A comparable rise was not observed in methicillin-resistant S. aureus (MRSA) isolates. They suggest that the selective pressures arising from the use of topical formulations of fusidic acid in the community account for this increase in resistance. In support of this hypothesis, Brown & Wise2 reported a general association between the increase, from 8.1% in 1995 to 17.3% in 2001, in the rate of resistance to fusidic acid among community MSSA isolates from 28 centres in the UK and the doubling of prescriptions for fusidic acid over the same period of time. We report the results of a study undertaken to test this hypothesis by investigating the correlation between fusidic acid prescribing and resistance at the practice level.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Data on the susceptibility to fusidic acid in MSSA isolated from routine samples submitted by general practitioners in Cardiff during 2000 and 2001 were collected from the Cardiff Public Health Laboratory. Data on prescribing of fusidic acid by general practitioners during the same period were obtained from Health Solutions Wales. Rates of prescribing, the number of items dispensed per 1000 registered patients per year, and resistance, the number of resistant isolates per 100 MSSA isolates, were calculated for each practice. It was decided a priori, in line with previously published research,3,4 that practices with resistance levels that were based on <50 isolates would be excluded from the analysis. The analysis included data on 6571 isolates from 29 practices with a registered population of 217 236 patients.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Over the 2 year period 31 034 items of fusidic acid were prescribed, most of which (30 876 items, 99.5%) were topical formulations. The prescribing rates for fusidic acid in the 29 practices were 71 items per 1000 population per year, with a range of 26–184 in individual practices (Table 1). The resistance level in the 29 practices was 2.8%, with a range of 0% to 6.9% in individual practices (Table 1). There was a significant correlation between prescribing and resistance at the practice level (Spearman’s rho = 0.46, 95% confidence interval 0.11–0.71, P = 0.01).


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Table 1.  Fusidic acid resistance in community isolates of MSSA and community prescribing of fusidic acid (Cardiff, 2000–2001)
 

    Discussion
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 Materials and methods
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We have previously shown geographically localized effects from antibiotic use in communities by demonstrating a correlation between antibiotic resistance in coliform organisms in urine samples and the use of antibiotics by a general practice with similar methodology.3,4 A causal association between prescribing and resistance is biologically plausible because of the high spontaneous chromosomal mutation frequency for development of fusidic acid resistance in S. aureus, resulting in the emergence of resistant mutants during therapy.5

Correlational studies are limited by their inability to link exposure with disease in individuals or to control for the effects of potentially confounding factors. For example, it is not possible to determine whether one patient was responsible for most isolates or prescriptions. Including repeat isolates has previously been shown to have a negligible effect on the estimate of resistance rates in urinary isolates in community settings.4,6 Sampling bias could result in the observed association if there were systematic differences in specimen-taking behaviour between high- and low-prescribing practices. The MSSA isolates were from samples taken in the community and are less likely than hospital isolates to be subjected to potential bias from variation in screening practices for MRSA.

Published studies on the selection of fusidic acid resistance following topical treatment consist mainly of uncontrolled studies. This is inadequate for differentiating between the alternative hypothesis that increasing resistance is the result of clonal spread within an at-risk population.7 Four patients (4/17, 24%) in a case series derived from all fusidic acid-resistant S. aureus isolates at the Middlesex Hospital bacteriology department in 1971 had previously received topical fusidic acid.8 Twenty-four patients (24/55, 44%) in a consecutive cases series of fusidic acid-resistant S. aureus isolates at the microbiology department of Harrogate District Hospital in 1998 had used topical fusidic acid in the previous 6 months.9 A trial that detected no resistance to fusidic acid in 1010 cases of skin sepsis treated with sodium fusidate ointment is frequently cited as evidence against the selection of resistance; however, all the patients in this trial also received other systemic antibiotics.10

The only published controlled study compared fusidic acid resistance in nasal isolates of S. aureus in 204 patients treated with topical fusidic acid in the previous 8–15 months in primary care with 204 controls matched for age, sex and general practitioner.11 Resistance was identified in 1 of the 74 S. aureus isolates in the treated group and none of the 70 isolates in the control group. This study did not have sufficient power to detect any effect of topical fusidic acid on resistance. If resistant organisms are selected in 0.5% of individuals who are exposed to topical fusidic acid a cohort study would require 2000 in each group to have a power of 80% to detect a relative risk of 50 at the 5% significance level.

Systemic fusidic acid is an important treatment for uncommon but serious infection, in particular osteomyelitis or endocarditis caused by penicillin-resistant staphylococci. Our data support the urgent need for high quality epidemiological studies to determine whether the observed increase in resistance is causally associated with the increased use of topical fusidic acid.


    Acknowledgements
 
We thank Pat Reardon, Health Solutions Wales, for providing prescribing data; Mike Roberts, Public Health Laboratory Service in Wales, for providing laboratory data; and Nathan Lester, Bro Taf Health Authority, for providing practice population data.


    Footnotes
 
* Corresponding author. Tel: +44-29-2052-1997; Fax: +44-29-2052-1987; E-mail: Brendan.mason{at}phls.wales.nhs.uk Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Brown, E. M. & Thomas, P. (2002). Fusidic acid resistance in Staphylococcus aureus isolates. Lancet 359, 803.

2 . Brown, E. M. & Wise, R. (2002). Fusidic acid should be used with restraint. British Medical Journal 324, 1394.[Free Full Text]

3 . Magee, J. T., Pritchard, E. L., Fitzgerald, K. A., Dunstan, F. D. J. & Howard, A. J. (1999). Antibiotic prescribing and antibiotic resistance in community practice: retrospective study, 1996–8. British Medical Journal 319, 1239–40.[Free Full Text]

4 . Howard, A. J., Magee, J. T., Fitzgerald, K. A. & Dunstan, F. D. J. (2001). Factors associated with antibiotic resistance in coliform organisms from community urinary tract infection in Wales. Journal of Antimicrobial Chemotherapy 47, 305–13.[Abstract/Free Full Text]

5 . O’Neil, A. J., Cove, J. H. & Chopra, I. (2001). Mutation frequencies for resistance to fusidic acid and rifampicin in Staphylococcus aureus. Journal of Antimicrobial Chemotherapy 47, 647–50.[Abstract/Free Full Text]

6 . Huovinen, P. (2001). Recording of antimicrobial resistances of urinary tract isolates—effects of repeat sampling on resistance levels. Journal of Antimicrobial Chemotherapy 16, 443–7.

7 . Collignon, P. & Turnidge, J. (1999). Fusidic acid in vitro activity. International Journal of Antimicrobial Agents 12, S45–58.[CrossRef][ISI][Medline]

8 . Pattison, J. R. & Mansell, P. E. (1973). Fucidin-resistant staphylococci in current hospital practice. Journal of Medical Microbiology 6, 235–44.[Medline]

9 . Ravenscroft, J. C., Layton, A. & Barnham, M. (2000). Observations on high levels of fusidic acid resistant Staphylococcus aureus in Harrogate, North Yorkshire, UK. Clinical and Experimental Dermatology 25, 327–30.[CrossRef][ISI][Medline]

10 . Ritchie, I. C. (1966). Economic aspects of surface sepsis: a trial of fucicin ointment. Clinical Trials Journal 529–31.

11 . Gillett, A. P., Johnson, T., Orton, C., Willis, R., Menday, A. P. & Talbot, D. J. (1984). Nasal carriage and antibiotic susceptibility of Staphylococcus aureus in general practice. Journal of the Royal College of General Practitioners 34, 255–7.[ISI][Medline]