Medicines Control Agency, Market Towers, 1 Nine Elms Lane, London SW8 5NQ, UK
![]() |
Introduction |
---|
There is considerable knowledge concerning the clinical, biochemical and genetic aspects of resistance to antifungal agents.3,4 However, sample selection and inadequate information regarding denominators limit current epidemiological data. At present, there is no established national surveillance scheme to identify changes in antifungal susceptibility that are clearly linked to over-the-counter (OTC) use. In addition, there are no large-scale epidemiological surveys of the extent of antifungal drug resistance in the published world literature.
![]() |
Legal basis of classification in the UK |
---|
The recent regulatory atmosphere in the UK has been positive towards deregulation, as it encourages greater flexibility in access to healthcare, may reduce general practitioner (GP) consultation rates for minor illness and the cost to the National Health Service, (NHS) and encourages development of the professional role of the pharmacist.
![]() |
Antifungal agents available without prescription in the UK |
---|
|
![]() |
Definition and mechanisms of fungal resistance |
---|
It is recognized that there is a gulf between the information derived in vitro, and the paucity of information regarding clinical risk.8 In vitro demonstration of resistance does not necessarily equate to in vivo resistance. Other determinants in the selection of resistance include host-related factors, e.g. immunosuppression, the site and severity of infection and drug pharmacokinetics.2 These are especially important in the evaluation of systemic infections.
A summary of mechanisms for the different antifungal classes where agents are currently available without prescription in the UK is shown in Table 2.
|
![]() |
Controlling resistance |
---|
Delaying the initiation of systemic azole therapy.
Optimizing therapy according to pharmacokinetic and pharmacodynamic properties and thus reducing exposure to low concentrations of systemic agents. There is no clear evidence as to what dosing strategy should be used during treatment and prophylaxis to best avoid resistance.3 Experience with other anti-infective agents has led to predictions that continuous treatment with a high dose of drug for as brief a time as is possible to effect cure would result in the least risk, but this needs evaluation in clinical trials.
Use of combination antifungal therapy may be more effective in preventing development of resistance. The combination of amphotericin and flucytosine is currently in use; amphotericin and azoles, azoles and flucytosine, and azoles and terbinafine are being tested.
Use of adjunctive immunostimulatory therapy, e.g. azoles and cytokines.
Use of azoles and efflux pump inhibitors.
Avoidance of prophylactic use of azoles for oral or vaginal candidiasis.
Complementary suggestions include the following:3,9
Substitution of topical agents for systemic antifungals when appropriate, e.g. in infections of the mucous membranes, skin and bladder. It is considered that by reducing the use of systemic antifungal agents exposure of the host flora to the antifungal agent would be minimized, infections caused by fungi often occurring when host flora has been altered.
Avoidance of unnecessary use of antibiotics that may affect the host flora (antibiotic effects on the host flora are recognized to be more frequent than antifungal effects).
Avoidance of therapeutic regimens prone to cause cross-resistance to amphotericin.
Use of standardized methodology for determining resistance, including rapid methods suitable for a clinical laboratory.
![]() |
Potential impact of increasing the availability of OTC antifungal agents |
---|
The availability of oral fluconazole for treatment of vaginal candidal infection and more recently for candidal balanitis, and of nystatin combined with 1% hydrocortisone for topical application, is associated with new potential risks to the public. Both fluconazole and nystatin are members of crucially important families of antifungal drugs. There have been increasing reports of resistance to the azoles in hospitalized patients during the 1990s.11,12 Although reports of nystatin resistance are rare,13 if cross-resistance to amphotericin were to become prevalent, the outlook for patients with systemic fungal infections would be unfavourable.
However, there is very little robust evidence that non-prescription use of topical antifungal agents has been associated with the emergence of resistance.9 Although azoles are associated with cross-resistance, which has a negative impact on their use for systemic life-threatening infections, there is insufficient evidence that the use of topical azoles (e.g. in cream, shampoo, powders or in washing machine detergents) and/or OTC use has been associated with the emergence of resistance or cross-resistance. The resistances of clinical importance are felt to be cryptococcal and candidal resistance. The emergence of resistant Candida species has also coincided with a background of generally increased candidal isolation rates and increased institutional use of azoles. Institutions with similar azole usage patterns have reported increasing or declining incidence of isolation of resistant species.3,9,11,12 It is also important to note that development of resistance during courses of therapy lasting less than several weeks has not been widely reported. In evidence given to the House of Lords Select Committee, reference was made to the uncontrolled OTC availability of fluconazole in Spain and Greece and that there were concerns with regard to azole resistance, in particular with the emergence of Candida glabrata, in these countries (no further details were given).14 There have also been more reports of C. glabrata, from vaginal isolates in the UK, the significance of which is uncertain (PHLS, personal communication). In the UK the only antifungal agent available for systemic use without prescription is only available as a single capsule from pharmacies. It is currently unclear as to whether more-regulated use would cause a reduction in the current prevalence of resistance at an institutional or at a community level.
It is recognized that there is poor compliance with use of topical agents for superficial fungal infections of the skin as symptoms are rapidly relieved whether or not there has been mycological cure.15 It has also been postulated that the treatment period with topical agents for presumptive vulvo-vaginal candidiasis is too short and may contribute to subclinical candidal infection.16 Use of the same agents under the supervision of a physician may improve the situation. However, there is no clear evidence to support this.
There is no robust evidence that restricting the use of OTC antifungal medicines currently available in the UK will reverse or arrest the present situation. At present, there is no national systemic monitoring arrangement prospectively studying trends in antifungal resistance in the UK in order to produce such information.17 Current data are selective in terms of sampling and are almost all derived from a small percentage of patients from intensive care and oncology facilities, and cannot be extrapolated to the community. The data are also rarely denominator controlled. Currently there is no established national surveillance scheme that would be sufficiently sensitive to identify changes in susceptibility that are clearly linked to OTC use, and no agreed level of in vitro resistance accepted by any licensing authorities that would automatically result in a recommendation that a licence should be modified or withdrawn for a particular drug. Industry, government and clinicians should be responsible for establishing a scheme for national surveillance. This should provide accurate information on resistant strains in hospitals and the community, and the clinical outcomes associated with these strains.
It may be that by restricting the non-prescription availability of future agents, a problem that has not yet evolved could be prevented and the future efficacy of new chemically related antifungal agents, if subsequently authorized in the UK, would be enhanced. It is also possible that the local immunosuppression caused by the combination of a mild steroid with many of the topical agents could further encourage the growth of resistant fungi that may be present on initiation of therapy or that may emerge during treatment. Preparations of the same antifungal agent that do not include a steroid may be less favourable to the growth of resistant organisms.
The current situation does not permit assurance that undesirable resistance problems may not occur in the future. There have already been fungal pathogens isolated in the UK that are resistant in vitro to all currently available antifungal agents, e.g. Scedosporium prolificans, and there have been numerous reports of this same pathogen from Spain.17,18 Some agents have not been available for a sufficiently long period and others have been applied topically to superficial mycoses but not to deep mycoses.
With deregulation, the sales of antifungal agents will increase; in the USA since the lifting of the POM status for local antimycotics against vulvo-vaginal candidiasis there has been a doubling of sales.19 The OTC European antifungal market is expected to grow by almost 12% between 1998 and 2003 and the OTC gynaecological antifungal market by 15%.20 This follows a 32% growth in the UK market for antifungal self-medication between 1993 and 1998 and a 230% growth in the UK gynaecological market for antifungal self-medication between 1993 and 1998.20 Thus the primary factor driving the emergence of antifungal resistance, namely selective pressure from increased use and inappropriate use will increase. However, with the exception of oral fluconazole these are topically administered agents for which the risks from such use are deemed to be lower.
![]() |
Other potential contributions to antifungal resistance |
---|
Biocides are agents with antiseptic, disinfectant and/ or preservative properties and are used extensively in cleaning agents and for human use. Comparatively little information exists about antifungal mechanisms of these agents. However, the concentrations required to inhibit growth are often very much lower than fungicidal concentrations. Possible mechanisms of resistance may involve plasmid-mediated transfer, which could potentially contribute to rapid spread.9,23 Comparative studies on the drug resistance of the different classes of antifungal agents against various fungi pathogenic for man, animals and plants may be useful.
![]() |
Conclusion |
---|
The increased use of antifungal agents will lead to increased selective pressure and a theoretical risk of resistance. However, there is very little robust evidence that non-prescription use of topical antifungal agents or of fluconazole as a single tablet has been associated with the emergence of resistance. In addition, there is no established national surveillance scheme that is sufficiently sensitive to identify changes in susceptibility that might be clearly linked to OTC use. However, future proposals for extension in the duration of use of topical OTC antifungal agents or proposals for OTC availability of antifungal medications for systemic use would need careful consideration with respect to the possibility of selecting for resistance. National surveillance data on resistance in hospitals and the community would also be required. Further consideration should be given to the possible contribution of agricultural fungicides to the emergence of azole resistance.
The massive prevalence of fungal dermatological and gynaecological infections, which are usually minor and for which at least moderately effective and very safe topical treatments have been available over the counter for many years, dictates that such treatments should usually remain available at such outlets. However, should patterns of resistance change in the future this position may need to be further reviewed.
![]() |
Acknowledgements |
---|
![]() |
Notes |
---|
![]() |
References |
---|
2 . Marichal, P. & Vanden Bossche, H. (1995). Mechanisms of resistance to azole antifungals. Acta Biochimica Polonica 42, 50916.[ISI][Medline]
3
.
White, T. C., Marr, K. A. & Bowden, R. A. (1998). Clinical, cellular and molecular factors that contribute to antifungal drug resistance. Clinical Microbiology Reviews 11, 382402.
4 . White, T. (1997). Increased mRNA levels of ERG16, CDR and MDR1 correlate with increases in azole resistance in Candida albicans isolates from patients infected with human immunodeficiency virus. Antimicrobial agents and Chemotherapy 41, 14827.[Abstract]
5 . Medicines Control Agency. (1997). Changing the legal classi-fication in the United Kingdom of prescription only medicine for human use. In Medicines Act Leaflet 77. Medicines Control Agency, London.
6 . Medicines Control Agency. (1996). Changing the legal classification in the in the United Kingdom of a medicine for human use from pharmacy to general sale list. In MAL 82. HMSO, London.
7 . National Committee for Clinical Laboratory Standards. (1997). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts: Approved Standard M27-A. NCCLS, Wayne, PA.
8 . Ghannoum, M. A., Rex, J. H. & Galgiani, J. N. (1996). Susceptibility testing of fungi: current status of correlation of in vitro data with clinical outcome. Journal of Clinical Microbioliology 34, 48995.
9 . Klepser, M. E., Ernst, E. J. & Pfaller, M. A. (1997). Update on antifungal resistance. Trends in Microbiology 5, 3725.[ISI][Medline]
10 . Maenza, J. R., Keruly, J. C., Moore, R. D., Chaisson, R. E., Merz, W. G. & Gallant, J. E. (1996). Risk factors for fluconazole resistant Candida in patients with AIDS: prevalence and microbiology. Clinical Infectious Diseases 173, 21925.
11 . Price, M. F., LaRocco, M. T. & Gentry, L. O. (1994). Fluconazole susceptibilities of Candida species and distribution of species recovered from blood cultures over a 5-year period. Antimicrobial Agents and Chemotherapy 38, w14227.
12 . Nguyen, M. H., Peacock, J. E., Morris, A. J., Tanner, D. C., Nguyen, M. L. & Snydman, D. R. (1996). The changing face of candidaemia-emergence of non-Candida albicans species and antifungal resistance. American Journal of Medicine 100, 61723.[ISI][Medline]
13 . Iwata, K. (1992). Drug resistance in human pathogenic fungi. European Journal of Epidemiology 8, 40721.[ISI][Medline]
14 . Finch, R. (1997). Prospect of over-the-counter antibiotics. In Evidence. Resistance to Antibiotics and other Antimicrobial Agents, p. 193. The Stationery Office, London.
15
.
Finlay, A. Y. (1999). Skin and nail fungi-almost beaten. British Medical Journal 319, 712.
16 . Sobel, J. D., Faro, S., Force, R. W., Foxman, B., Ledger, W. J., Nyirjesy, P. R. et al. (1998). Vulvovaginal candidiasis: epidemiologic, diagnostic, and therapeutic considerations. American Journal of Obstetrics and Gynecology 178, 20310.[ISI][Medline]
17 . Denning, D. W. (1997). Memorandum on antifungal agents. In Evidence. Resistance to Antibiotics and other Antimicrobial Agents, pp 4024. The Stationery Office, London.
18 . Hopwood, V., Evans, E. G., Matthews, J. & Denning, D. W. (1995). Scedosporium prolificans, a multi-resistant fungus, from a UK AIDS patient. Journal of Infection 30, 1535.[ISI][Medline]
19 . Ferris, D. G., Dekle, C. & Litaker, M. S. (1996). women's use of over-the-counter antifungal medications for gynecologic symptoms. Journal of Family Practice 42, 595600.[ISI][Medline]
20 . Dudley, J. (1999).The European non-prescription skin care market. In James Dudley Management Skin Care in Europe to 2003. James Dudley Management, Kidderminster, UK.
21 . Pimentel, D., McLaughlin, L., Zepp, A., Lakitan, B., Kraus, T., Kleinman, P. et al. (1991). Environmental and economic effects of reducing pesticide use. Bioscience 41, 4029.[ISI]
22 . Vanden Bossche, H., Marichal, P. & Odds, F. C. (1994). Molecular mechanisms of drug resistance in fungi. Trends in Microbiology 2, 393400.[Medline]
23 . Russell, A. D. & Furr, J. R. (1996). Biocides: mechanisms of antifungal action and fungal resistance. Science Progress 79, 2748.[Medline]