Survey, characterization and susceptibility to fusidic acid of Staphylococcus aureus in the Carmarthen area

D. El-Zimaity1,*, A. M. Kearns2, S. J. Dawson1, S. Price1 and G. A. J. Harrison1

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


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Objective: This retrospective study was designed to investigate the possible reasons for an apparent increase in fusidic acid resistance among Staphylococcus aureus.

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 (1997–2001), 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


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
Any doctor using antibiotics should be aware of the increasing worldwide problems with multi-resistant bacteria, with the majority of hospital-associated infections in some countries being caused by these bacteria. Proper use of antibiotics is therefore mandatory for treating bacterial infections of the skin.1

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.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The survey

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 1–80 s.16

The toxin profiles were determined using multiplex polymerase chain reaction (PCR)17 to detect genes coding for staphylococcal enterotoxins A–E and G–J (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


    Results
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
The CDSC, Wales Datastore data from 1997 to 2001 were analysed according to origin of the swabs. After removing all duplicate records, a total of 2476 records were reviewed. A total of 1225 (49.5%) was from males, 1246 (50.3%) from females, and the sex was not stated in five (0.2%). The mean age was 52.7 years (range: newly born to 94 years old). Clinical details were available for 2170 samples and these included impetigo (1.8%), eczema (7.3%), ulcer (5.9%), inflammation (3.7%), or infection (13%). The remainder (68.3%) reported clinical details of rash, fever, tender area, wound or systemic illness.

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 1. Breakdown of fusidic acid susceptibility in S. aureus according to year of isolation and hospital department

 
The proportion of resistant strains from other hospital wards varied from 1.6% in 1998 to 6.9% in 2000. In general, in the period 1997–2001, the Paediatric Ward showed the highest percentage of resistance (21%) followed by the Paediatric Outpatient Department (10.6%) (Table 1).

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 41–50 and >60. During this timescale, a more than three-fold and a four-fold increase in resistance was observed in the 11–20 and <10 year age groups, respectively.


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Table 2. Breakdown of S. aureus isolates and fusidic acid susceptibility according to age group

 
The susceptibility profiles are given in Table 3. Overall, the resistance to penicillin and erythromycin remained fairly static throughout the study period. In contrast, the fusidic acid and oxacillin resistance rates doubled.


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Table 3. Antibiotic profiles of S. aureus isolates between 1997 and 2001

 
An overall decrease in the prescribing of topical fusidic acid (15 g tube) was observed in WWGH over the period from 1997 to 2001 (Table 4). Fusidic acid use increased in Paediatric Ward and Paediatric Outpatient Department from four prescriptions in 1997 to 43 in 2001 whilst the number of prescriptions issued to other hospital wards remained fairly constant.


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Table 4. Total topical fusidic acid prescribed (15 g tube) in 1997–2001 in WWGH

 
The total amount prescribed by 17 GP practices in the catchment area of WWGH between 1997 and 2001 was reviewed (Table 5). In all but one practice (GP 7), the level of prescribing increased during the study period, with one practice (GP 1) showing a 295% increase in 2001 versus 1997.


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Table 5. Total amount of topical fusidic acid (15 g tube) prescribed by GPs in 1997–2001

 
Of the 31 S. aureus strains for which clinical details and a completed pro forma were available, 14 were from patients with clinical diagnosis of impetigo and the remaining 17 presented with other skin disease including eczema, dermatitis, rash psoriasis, or abscess. All 31 strains were characterized phenotypically and genotypically (Table 6).


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Table 6. Phenotypic and genotypic characteristics of 31 strains of S. aureus

 
The majority of strains from the impetigo group (12 of 14; 85.7%) were lysed by group II phages, were fusR, and encoded exfoliatins A and/or B, which are classically associated with impetigo. One of the remaining isolates displayed a distinct phage pattern and was susceptible to fusidic acid and harboured tst. The other isolate was lysed by more than one phage and was fusR. Pulsed-field gel electrophoresis following macro-restriction of chromosomal DNA with SmaI showed all fusR strains were clonal (PFGE type A) (Figure 1a). S. aureus from patients presenting with other skin disease were heterogeneous, displaying a wide range of phage, toxin and PFGE profiles. Only three of 17 (17.6%) strains were fusR, two of which were indistinguishable from PFGE type A (Figure 1b).



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Figure 1. Examples of pulsed-field gel electrophoresis profiles obtained for isolates of S. aureus from (a) patients with impetigo and (b) patients with other skin disease.

 
Two isolates from one patient pre- and post-treatment (numbers 16 and 17) remained susceptible to fusidic acid, whilst in another patient (numbers 18 and 19), S. aureus proved resistant to fusidic acid following therapy.


    Discussion
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
There appears to have been a rise in the incidence of fusidic acid resistance among skin-associated S. aureus strains in the catchment area of the WWGH, Carmarthen throughout the period from 1997 to 2001. Sule et al.6 also found higher rates in dermatology patients, and in younger patients below 20 years old. In our study, the use of topical preparations containing fusidic acid in the preceding 6 months may have been a factor in the emergence of fusR S. aureus strains in children below the age of 10 years. This is consistent with the findings of Ravenscroft et al.21 who reported that 44% of patients with fusidic acid-resistant isolates had been given topical fusidic acid, mainly for chronic skin infections, within the preceding 6 months. Brown & Thomas22 also reported an increase from 6% in 1998 to 11.5% in 2001, in the rate of resistance to fusidic acid among all methicillin-susceptible S. aureus isolates in Bristol. They suggested that the selective pressures arising from the use of topical formulations of fusidic acid in the community accounted for this increase. The level of resistance to fusidic acid among community methicillin-susceptible S. aureus isolates in the UK and prescriptions for fusidic acid have both doubled over the last 6 years.11 Mason & Howard found a statistically significant association between the use of topical fusidic acid, and resistance at the individual patient level.23 Our data support these observations.

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 1997–2001, 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.


    Acknowledgements
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
We thank all the General Practitioners in the catchment area of West Wales General Hospital, Carmarthen, for their valuable help. Also, we wish to thank Mark Ganner and Ilka Rathmann for excellent technical assistance. We would like to specially thank Julie Gilbourne, IT Manager, and Andrew Keen, Laboratory Manager, NPHS Microbiology, Carmarthen for their help and co-operation. We are grateful to Sue Beach, Principal Pharmacist, Medicine Information Services, WWGH, Carmarthen, Kath Haines, Prescribing Support Manager, Carmarthenshire Local Health Group, Burry Port, Dr Mark T. Thomas, Senior Analyst/Programmer, PHLS CDSC Wales, Cardiff, for supplying us with the required data, which made this work possible. We also acknowledge The Medical Records Department (Audit Section) WWGH Carmarthen for their valuable help.


    Footnotes
 
* Corresponding author. Tel: +44-1437-764197; Fax: +44-1267-238394; Email: khalik{at}bigfoot.com


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Acknowledgements
 References
 
1 . Thestrup-Pedersen, K. (1998). Bacteria and the skin: clinical practice and therapy update. British Journal of Dermatology 139, 1–3.

2 . Wilkinson, J. D. (1998). Fusidic acid in dermatology. British Journal of Dermatology 139, 37–40.[CrossRef][ISI][Medline]

3 . Shanson, D. C. (1990). Clinical relevance of resistance to fusidic acid in Staphylococcus aureus. Journal of Antimicrobial Chemotherapy 25, Suppl. B, 15–21.[Abstract]

4 . Koning, S., van Suijlekom-Smit, L. W. A., Nouwen, J. L. et al. (2002). Fusidic acid cream in the treatment of impetigo in general practice: double blind randomised placebo-controlled trial. British Medical Journal 324, 203–6.[Abstract/Free Full Text]

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

6 . Sule, O., Brown, N., Brown, D. F. J. et al. (2002). Fusidic acid cream for impetigo: judicious use is advisable. British Medical Journal 324, 1394–5.[Free Full Text]

7 . Weston, V. C., Boswell, T. C. J., Finch, R. G. et al. (2002). Emergence of resistance to fusidic acid limits its use. British Medical Journal 324, 1395.

8 . Stoddart, B., Collyns, T. & Denton, M. (2002). Problem may be clinically important. British Medical Journal 324, 1395.

9 . Zadik, P. & Young, N. (2002). Resistance trends must be monitored. British Medical Journal 324, 1396.[CrossRef]

10 . Owen, S. E. & Cheesbrough, J. S. (2002). Findings cannot be extrapolated. British Medical Journal 324, 1396.[CrossRef]

11 . Mason, B. W., Howard, A. J. & Magee, J. T. (2003). Fusidic acid resistance in community isolates of methicillin-susceptible Staphylococcus aureus and fusidic acid prescribing. Journal of Antimicrobial Chemotherapy 51, 1033–6.[Abstract/Free Full Text]

12 . Simmons, M. (2003). Complexity theory in the management of communicable diseases. Journal of Hospital Infection 54, 7–92.

13 . Andrews, J. M. for the BSAC Working Party on Susceptibility Testing. (2001). BSAC standardized disc susceptibility testing method. Journal of Antimicrobial Chemotherapy 48, Suppl. S1, 43–57.[Abstract/Free Full Text]

14 . Parker, M. T. (1983). The significance of phage-typing patterns in Staphylococcus aureus. In Staphylococci and Staphylococcal Infections (Easmon, C. S. F. & Adlam, C., Eds), pp. 33–62. Academic Press, London.

15 . Marples, R. R., Richardson, J. F. & de Saxe, M. (1986). Bacteriological characters of strains of Staphylococcus aureus submitted to a reference laboratory related to methicillin resistance. Journal of Hygiene (Cambridge) 96, 217–23.

16 . Kaufmann, M. E. (1998). Pulsed-field gel electrophoresis. In Molecular Bacteriology: Protocols and Clinical Applications (Woodford, N. & Johnson, A. P., Eds), pp. 33–50. Humana Press, Totowa, NJ, USA.

17 . O'Neill, G. L., Aucken, H. M., Mithani, V. et al. (2001). Development and implementation of a PCR-based system for the detection of toxin genes encoded by Staphylococcus aureus. Clinical Microbiology and Infection 7, Suppl. 1, 1–100.[CrossRef]

18 . Becker, K., Roth, R. & Petersa, G. (1998). Rapid and specific detection of toxigenic Staphylococcus aureus: use of two multiplex PCR enzyme immunoassays for the amplification and hybridisation of staphylococcal enterotoxin genes, exfoliation toxin genes, and toxic shock syndrome toxin 1 gene. Journal of Clinical Microbiology 36, 2548–53.[Abstract/Free Full Text]

19 . Monday, S. R. & Bohach, G. A. (1999). Use of multiplex PCR to detect classical and newly described pyrogenic toxin genes in staphylococcal isolates. Journal of Clinical Microbiology 37, 3411–4.[Abstract/Free Full Text]

20 . Lina, G., Piémont, Y., Godail-Gamot, F. et al. (1999). Involvement of Panton-Valentine Leukocidin-producing Staphylococcus aureus in primary skin infections and pneumonia. Clinical Infectious Diseases 29, 1128–32.[CrossRef][ISI][Medline]

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

22 . Brown, E. M. & Thomas, P. (2002). Fusidic acid resistance in Staphylococcus aureus isolates. Lancet 359, 803.

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, 300–3.[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, 729–34.[CrossRef][ISI][Medline]

25 . HPA Guidance Template for Primary Care. [Online.] http://www.hpa.org.uk/infections/topics-az/antimicrobial-resistance/guidance.htm (1 March 2004, date last accessed).

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