Antifungal therapy for vaginal candida infection – a problem solved?
Antifungal therapy for vaginal candida infection – a problem solved? |
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Summary
Treatment of patients with infrequent recurrences of vulvovaginal candidiasis (VVC) is generally adequate using single-dose antifungal therapy. Studies have shown no significant difference between the clinical and mycological short and long term cure rates of the various antifungal agents used. Also, treating other sites in VVC such as the anus and the gastrointestinal tract was not supported.
In Recurrent Vulvovaginal Candidiasis (RVVC), maintenance therapy has proved efficacy over placebo; however, the weekly regimens could be more efficacious over the daily regimens due to patient’s compliance and preference. The evidence to support the currently used intensive antifungals in the treatment of the initial episodes of RVVC in terms of effectiveness and the time-to-recurrence is still lacking. Proper controlled studies to compare the use of intensive therapy versus standard short course antifungal treatment in RVVC are clearly needed. The choice of therapy will continue to be based on individual clinicians’ preference until this information is available.
Key words: Recurrent; candidiasis; therapy; antifungals
Introduction
About seventy-five percent of women will have had at least one episode of vulvovaginal candidiasis (VVC) during their lives, which is considered as the second most common form of vaginitis after bacterial vaginosis1. VVC usually presents clinically in one of three forms, either as a single acute attack of VVC with less frequent recurrences, or as complicated non-albicans candidiasis, or as a frequently recurrent vulvovaginal candidiasis (RVVC) which may be defined as four attacks of mycologically proved candidiasis within 12 months2,3, and is distinguished from persistent infection by the presence of a symptom-free interval. While acute single episodes of VVC usually respond rapidly to treatment, about 5% will suffer frequent recurrences or chronic infection4.
In 1849, Wilkinson first reported the association between a fungus and vaginal discharge5. Anecdotal antifungal therapies had emerged since then. Specific topical antifungal therapy with gentian violet was introduced in 1935; nystatin became available in 1955 and was mainstay of therapy until the 1970s, when the first imidazoles were marketed. Since the 1970s, several new agents have become available for the treatment of VVC including oral and vaginal azoles.
Pathogenesis
The pathogenesis of the recurring episodes of vulvovaginal candidiasis was obscure, since the overwhelming majority of the patients have no recognized predisposing factors6 such as uncontrolled or poorly controlled diabetes mellitus, pregnancy, long term use of broad spectrum antibiotics, oestrogen therapy or cases of iatrogenic or therapeutic immune suppression. It is postulated that susceptibility to RVVC is immune based, and that these women experience repeated symptomatic episodes as a result of some immunologic dysfunction or deficiency in the cell mediated immune (CMI) component involving T cells5, however, no specific immune dysfunction has been identified to date. It is being postulated that the CMI dysfunction or deficiency is local rather than systemic because women with RVVC are generally not susceptible to other forms of mucosal and/or systemic candidiasis7.
In 1996, Fidel and Sobel8 postulated two theories to explain the presence of recurrent episodes of idiopathic vaginitis in women with RVVC:
(i) recurrences of Candida albicans vaginitis may occur with frequent vaginal reinfection or, alternatively,
(ii) through vaginal relapse following incomplete clearance of the organisms after an episode of
RVVC.
Therapy
Commonly used products that eradicate fungal infections are the imidazoles and polyene macrolides. These products interfere with the sterol chemistry pathways in the cell wall of the fungal cell. The imidazoles interfere with the 14-_-demethylase
enzyme in the conversion of lanosterol to ergosterol. Polyene macrolides, such as nystatin, katamycin, and amphotericin B, also interfere with the formation of ergosterol. The general formula of an azole antimycotic is a pentene ring containing two nitrogen atoms and three carbon atoms to which side chain determines the nature of the imidazoles compound9. Examples of the compounds are miconazole, clotrimazole, ticonazole, ketoconazole, fluconazole, econazole and
butoconazole.
a. Acute vulvovaginal candidiasis
In patients with infrequent recurrences, the current state of using azoles as a first line treatment seems to be satisfactory with the majority of patients. Single day azole regimens have proved efficacy over three or seven-day treatment regimens for single VVC episodes, partly due to noncompliance10,11. The commonly used single day regimens in UK are fluconazole 150mg oral once, or itraconazole 200mg oral in 2 doses 12 hours apart, or clotrimazole 500mg vaginal pessaries once, moreover, there is no indication that any one therapy is consistently better than any other. Clinical cure or improvement for the short-term response in using single-day therapy with fluconazole, clotrimazole and itraconazole in one study12 was 92%, 93% and 92% respectively, with a mycological cure of 83%, 95% and 96% respectively.
b. Complicated (non-albicans) vulvovaginal candidiasis
Not all imidazoles are equally effective against all species of yeasts. For example, Candida glabrata and Candida tropicalis are 10 times less sensitive to the action of miconazole than Candida albicans9. Because of the inherent azole resistance of these fastidious yeasts, a different approach for treatment will be required. Anecdotal reports for the use of intravaginal boric acid 600mg twice daily for 14 days has been described13 with a variable degree of success. Also, the use of combined topical flucytosine and amphotericin B in lubricating jelly per vaginum for 14 consecutive nights was used successfully in refractory vulvovaginal Candida glabrata infections14.
c. Recurrent vulvovaginal candidiasis
The optimal treatment for recurrent vulvovaginal candidiasis has not yet been defined. The strategy of single-day or short-term antifungal therapies is not usually satisfactory. Induction therapy with imidazoles is currently used. This may be delivered via the vagina or orally. Some women prefer oral treatment but single dose regimens such as fluconazole 150 mg by mouth immediately are not always effective in these difficult cases and one or two-weeks courses of fluconazole, itraconazole or ketoconazole may be used4. However, the evidence for the current use of such intensive courses of antifungals in RVVC is lacking, as there are no studies that reported on the comparative effectiveness of different antifungal agents in terms of the time to recurrence of vaginal candidiasis.
Once the symptoms of the initial episode are brought under control, it is clear from most studies that the aim is to prevent recurrence by the use of antimycotic maintenance therapy. However, the optimal dosing interval is not quite clear. Several maintenance regimens have been studied. In one clinical trial, 74 women with recurrent vulvovaginal candidiasis were treated for an acute episode with 400 mg of ketoconazole per day for 14 days15. The women were then randomized to receive one of three treatments: placebo, 400 mg of ketoconazole administered orally for five days after the menses for six months, or 100 mg of ketoconazole administered orally each day for six months. The six-months recurrence rates were 71% for the placebo group, 29% for the cyclic-regimen group and 5% for the daily-regimen group that has shown statistical significance. However, other studies have shown that the weekly administration of 0.8% terconazole vaginal cream is nearly as effective as daily treatment with ketoconazole16. Similar efficacy has been noted for twice-weekly intravaginal treatment with 200 mg of clotrimazole17.
Conclusion
The results of studies of single-dose therapy in the treatment of patients with infrequent recurrences of vulvovaginal candidiasis generally show that there are only small differences between the clinical and mycological short and long term cure rates of the antifungal agents evaluated. Also, there is not enough evidence to support treating other sites in VVC such as the anus and the gastrointestinal tract.
In RVVC, maintenance therapy has proved efficacy over placebo; however, the weekly regimens could be more efficacious over the daily regimens for the patient’s preference and compliance. Also, there is not enough evidence to support the currently used intensive antifungals in the treatment of the initial episodes of RVVC in terms of effectiveness and the time to recurrence of vaginal candidiasis. Proper controlled studies to compare the use of intensive therapy versus standard short course antifungal treatment in RVVC are clearly needed. Until this information is available, the choice of therapy will continue to be based on individual clinicians’ preference.
Acknowledgement
I wish to thank Dr D White, Department of Sexual Medicine, Birmingham Heartlands Hospital,
Birmingham, UK, for his support with this work. Also, Dr J Bingham, Lydia Department, St Thomas’s Hospital, London, UK, who critically reviewed the manuscript.
Address for Correspondence:
Dr A R Habib, Department of GUM, Brookside Centre, Station Way, Aylesbury, Bucks . HP20 2SQ
e-mail: shamhabib@hotmail.com
References
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