1 Microbiology Carmarthenshire, National Public Health Service for Wales, West Wales General Hospital, Carmarthen SA31 2AF; 2 Staphylococcus Reference Laboratory, Health Protection Agency, Specialist and Reference Microbiology Division, London NW9 5HT, UK
Received 9 March 2004; returned 4 May 2004; revised 24 June 2004; accepted 24 June 2004
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Abstract |
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Materials and methods: The Datastore records of the Communicable Disease Surveillance Centre, Wales, UK were reviewed in conjunction with information concerning the prescribing of fusidic acid.
Results: During the 5 year study period (19972001), a rise in the incidence of fusidic acid resistance was noted, particularly among paediatric patients presenting with infected eczema and impetigo, which may be related to the observed increase in prescriptions of topical fusidic acid. Extended phenotypic and genotypic characterization of a limited number (n=31) of isolates from 2002 showed that fusidic acid-resistant strains of S. aureus were typically from patients with impetigo and isolates fell into a single clonal group. Conversely, isolates from other skin disease (eczema, dermatitis and abscesses) were usually susceptible to fusidic acid and proved a diverse group.
Conclusion: This study provides valuable data on the prevalence of fusidic acid-resistant S. aureus, the genetic background of the strains, and their association with clinical disease in both the healthcare environment and community setting in the catchment area served by the Laboratory.
Keywords: impetigo , infections , dermatological infections , antibiotic resistance
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Introduction |
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Based on its high efficacy against Staphylococcus aureus,2 fusidic acid is often used as a topical treatment in skin and soft-tissue infections, and has been used widely against S. aureus over the last 20 years in the UK.3 Despite early reports of the rapid emergence of fusidic acid resistance in vitro, this has not been thought a major problem in clinical practice,3,4 although other recent reports suggest resistance may be escalating.511
Koning et al.4 showed the efficacy of topical fusidic acid as treatment of patients with impetigo. None of their pre-treatment isolates of S. aureus was resistant to fusidic acid, and they concluded that many years of use of topical fusidic acid had not resulted in appreciable resistance in S. aureus in the general population.
This was not in accord with our clinical impression, and a retrospective investigation was therefore undertaken. The selection and detailed characterization of current strains provided us with the opportunity to examine the properties and genetic background of these strains and investigate their association with skin-related infections.
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Materials and methods |
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The Communicable Disease Surveillance Centre, Wales, UK (CDSC) Datastore12 records were searched from 1997 to 2001 for information on clinical isolates of S. aureus from skin swabs from patients attending West Wales General Hospital (WWGH), Carmarthen.
The patients' date of birth, clinical details and antibiotic susceptibility to penicillin, erythromycin, oxacillin and fusidic acid for each isolate were recorded. Only one isolate per patient was entered in the analysis unless more than one antibiotic resistance profile (antibiogram) was evident.
Data on the amount of topical fusidic acid prescribed by WWGH and General Practitioners (GPs) in the catchment area of the hospital between 1997 and 2001 were ascertained from the pharmacy department and local health group pharmacist, respectively.
In an attempt to characterize some isolates more fully, over a 3 month period (September to November 2002), strains of S. aureus isolated from skin swabs were subjected to extensive phenotypic and genotypic analyses. A standard pro forma to ascertain patients' clinical diagnosis, and previous antibiotic treatment was completed for each isolate, either through reviewing the patients' medical records, or sending the pro forma to the relevant GP.
Characterization of S. aureus isolates
The identification of all isolates was confirmed by coagulase testing and reactivity with the Prolex Staph Latex agglutination kit (Prolab). Susceptibility to penicillin, erythromycin, oxacillin and fusidic acid was determined by disc diffusion.13
Phage typing was carried out with the 23 phages of the Basic International Set at 100x routine test dilution (RTD),14 plus the four experimental UK phages 88A, 90, 83C and 932.15 Pulsed-field gel electrophoresis (PFGE) profiles were obtained by macro-restriction of chromosomal DNA with SmaI and a run time of 30 h with pulse switch times of 180 s.16
The toxin profiles were determined using multiplex polymerase chain reaction (PCR)17 to detect genes coding for staphylococcal enterotoxins AE and GJ (sea-see, seg-sej), toxic shock syndrome toxin-1 (tst), exfoliative toxins A and B (eta-etb) and Panton-Valentine Leucocidin (lukF-PV/lukS-PV).1820
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Results |
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The distribution of S. aureus from skin swabs throughout the study period according to WWGH department type is presented in Table 1 together with the fusidic acid susceptibility data. The proportion of fusidic acid-resistant (fusR) strains isolated from swabs from the Paediatric Ward increased from 8.3% in 1997 to 40% in 2001. A similar trend was observed in isolates from patients attending the Paediatric Outpatient Department, where fusR increased from 0% in 1997 to 18% in 2001. The proportion of resistant strains from the Dermatology Outpatient Department decreased over the years from 10.3% in 1997 to 6.7% in 2001. There was an apparent decrease in 1998 (only 2.9% proved fusR).
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Table 2 shows the distribution of S. aureus from skin swabs according to patient age. Overall, there was a trend towards increased fusR rates in 2001 compared to 1997 in all age groups except among those aged 4150 and >60. During this timescale, a more than three-fold and a four-fold increase in resistance was observed in the 1120 and <10 year age groups, respectively.
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Discussion |
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However, there was only one area where we found a decrease in resistant strains from the Dermatology Outpatient Department from 10.3% in 1997 to 6.7% in 2001. We could not explain the reason for such a decrease as there was no change in the topical fusidic acid use policy and there was no change of staff during this period.
Detailed phenotypic and genotypic testing provided evidence that a predominant clone of S. aureus associated with impetigo appears to be circulating and appears to be indistinguishable from other fusR isolates elsewhere in England (personal observation, A. Kearns). These findings mirror those of Österlund et al. who reported a clonal relationship between fusR isolates of S. aureus in Sweden.24 The remaining strains (mainly susceptible to fusidic acid) represent a more diverse group.
General Practitioners' (GPs) prescribing of fusidic acid appears to demonstrate an increase in the period 19972001, but without knowing the number of patients presented to each GP each year during this period, it is difficult to show that this is a genuine trend. Similarly, these data do not take into account any underlying sampling bias. Nevertheless, there has been a rise in the number of fusR S. aureus strains isolated in the catchment area, both in total number and as a percentage of all S. aureus isolated from skin disease among the patient groups studied. The GPs in the catchment area of WWGH are aware of the study and preliminary results were given to them. As a result, some practices have changed their prescribing policy.
It is currently recommended that superficial skin infections are treated by flucloxacillin or erythromycin for 7 days.25 Minor infections may be treated with topical mupirocin or fusidic acid for 5 days.25 There may be concerns about the use of topical mupirocin for the treatment of superficial skin infections in view of the possibility of development of resistance. It is important that laboratories review their susceptibility data regularly, and make antibiotic recommendations accordingly. Whilst resistance to fusidic acid has increased steadily over the 5 years studied, 80.3% of the isolates remained susceptible to oxacillin and 78.6% were susceptible to erythromycin. On this basis, we recommend that GPs and hospital doctors use an alternative for fusidic acid cream for skin infections, such as mupirocin cream, or oral flucloxacillin. Weston et al.7 changed their advice for the treatment of impetigo and recommended oral anti-staphylococcal agents for all mild cases in their area.
In a recent review on antibiotic resistance, Gould considered that there is little doubt that careful antibiotic prescribing can curtail the emergence and reduce the prevalence of resistance.26 Although the incidence of resistance to fusidic acid among S. aureus generally remains low, its use may lead to the emergence of resistance to this agent in previously susceptible strains.27 Ravenscroft et al.21 reported the possible link between high use of topical and oral fusidic acid and the increased pool of resistant organisms in Harrogate, UK.
It is clear that the pharmaceutical industry is actively promoting the use of topical fusidic acid in dermatological conditions. In the context of the apparent emergence of fusidic acid resistance, this is perhaps unwise. S. aureus is one of the most virulent human bacterial pathogens, and numerous studies have documented the importance of this organism as the aetiological agent of both nosocomial and community-acquired bloodstream infection, endocarditis, osteomyelitis and pneumonia,28 and fusidic acid is one antibiotic used in its management, usually in combination with other antibiotics.29 With the increasing emergence of MRSA, and the potential role of fusidic acid in treatment of such cases, we should perhaps recommend using other antibiotics as first line choice for skin conditions, and reserve fusidic acid for the more serious systemic infections. The laboratory will continue to monitor the susceptibility of S. aureus to fusidic acid and advise local GPs and dermatologists. As a result of this study, the laboratory only releases the susceptibility of fusidic acid, for dermatological samples, if resistant.
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Acknowledgements |
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Footnotes |
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References |
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23 . Mason, B. W. & Howard, A. J. (2004). Fusidic acid resistance in the community isolates of methicillin susceptible Staphylococcus aureus and the use of topical fusidic acid: a retrospective case-control study. International Journal of Antimicrobial Agents 23, 3003.[ISI][Medline]
24 . Österlund, A., Edén, T., Olsson-Liljequist, B. et al. (2002). Clonal spread among Swedish children of a Staphylococcus aureus strain resistant to fusidic acid. Scandinavian Journal of Infectious Diseases 34, 72934.[CrossRef][ISI][Medline]
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