Combined Topical Flucytosine and Amphotericin B for Refractory Vaginal Candida Glabrata Infections

212 Sex Transm Inf 2001;77:212–213

Combined topical ﬂucytosine and amphotericin B Case for refractory vaginal Candida glabrata infections report D J White, A R Habib, A Vanthuyne, S Langford, M Symonds

Patients with vaginitis due to highly azole resistant Candida glabrata can be particularly diYcult to treat. We describe three cases of longstanding vaginal candidiasis due to C glabrata. These had failed to respond to local and systemic antifungals. Flucytosine (1 g) and amphotericin B (100 mg) formulated in lubricating jelly base in a total 8 g delivered dose, was used per vagina once daily for 14 days with signiﬁcant improvement, both clinically and microbiologically. (Sex Transm Inf 2001;77:212–213)

Keywords: amphotericin; ﬂucytosine; Candida glabrata

Introduction days combined with clotrimazole 500 mg vagi- Candida glabrata is the second most common nal pessaries for 7 nights, intravaginal painting yeast recovered from the genital tract of women with gentian violet 0.5% aqueous solution for 3 with vaginitis and accounts for about 5% of days, and boric acid 600 mg in gelatine vaginal infections.1 A substantial minority of C capsules once daily for 14 nights. glabrata isolates are azole resistant23 and Intravaginal amphotericin B and flucytosine further resistance may be selected out by non- in lubricating jelly was given at night for 14 curative treatment. Although infections with days. Her symptoms improved and Gram stain this organism are not always associated with and cultures were negative 2 and 5 weeks symptoms and clinical signs4 some aVected following treatment. women have discharge and/or vulvitis and a 56 poor response to antifungal therapy. Case 2 We describe three cases of persistent vaginal A 63 year old woman presented witha6year candidiasis due to C glabrata, unresponsive to history of intermittent vulvo-vaginitis and per- conventional antifungal therapy including sistent isolation of C glabrata on Gram stain boric acid. Flucytosine tablets 500 mg (Center and culture. This had failed to respond to a Specialites Pharmaceutiques Cournon Cedex, variety of diVering types and lengths of azole France) and amphotericin B BP1998 1 mg = therapy. She had had a hysterectomy 5 years 859IU (Bufa BV Uitgeest Holland) were com- before presentation following which she combined in lubricating jelly, Aquagel (Adams menced subcutaneous oestrogen hormone Department of Sexual Healthcare, UK). This was used per vagina replacement implants. One year after the Medicine, with clinical and microbiological cure. Treat- hysterectomy her symptoms of vaginal dis- Birmingham ment was delivered by a unit dose vaginal Heartlands Hospital, charge and vulval soreness became continuous. Birmingham B9 5SS, applicator containing amphotericin 100 mg + She had had some minor symptomatic im- UK flucytosine 1 g based in Aquagel in a total 8 g provement to dydrogesterone and intravaginal D J White delivered dose. This preparation has an un- boric acid. A R Habib known shelf life and is obtainable from the She was treated with itraconazole 100 mg A Vanthuyne pharmacy manufacturing unit, North StaVord- daily combined with nystatin pessaries for 4 shire Hospital, Stoke on Trent ST4 6QG (tel Pharmacy weeks followed by intravaginal boric acid for 2 Manufacturing Unit, 01782 552 289; fax 01782 552 916). The weeks. Despite this, Gram stain and cultures North StaVordshire preparation was compounded no more than 48 remained positive for C glabrata. This was fully Hospital, Stoke on hours before treatment began. sensitive to antifungals in vitro (table 1). Trent ST4 6QG, UK Amphotericin B and flucytosine in lubricat- S Langford ing jelly was given once daily for 14 days. She Case 1 improved symptomatically and follow up swabs Department of A 42 year old woman presented with “recur- Pharmacy, were negative by Gram stain microscopy and rent vaginal thrush” since the age of 19. At Birmingham culture 3, 4, and 8 weeks afterwards. Seven Heartlands Hospital, referral she had had several recent swabs show- Birmingham ing heavy growths of candida species in Gram Table 1 Antifungal sensitivities (NCCLS method Bristol M Symonds stain microscopy despite 3 months’ treatment PHLS mycology reference laboratory) before treatment with with itraconazole 100 mg twice daily for 2 days intravaginal flucytosine/amphotericin B in lubricating gel Correspondence to: every week, two Depo-provera (Pharmacia & D J White, Department of Case 1 Case 2 Case 3 Sexual Medicine, Hawthorn Upjohn) injections, and a number of other House, Heartlands Hospital, unspecified antifungal treatments including Amphotericin B S S — Birmingham B9 5SS, UK courses of nystatin pessaries. None of these Flucytosine S S — [email protected] Fluconazole R S R or A R Habib produced any symptomatic response. Itraconazole R S R [email protected] Vaginal swabs were positive by Gram stain Miconazole — S — Nystatin — S — Accepted for publication and culture for C glabrata which persisted 22 March 2001 despite itraconazole 200 mg once daily for 14 S = sensitive, R = resistant.

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months later she presented witha4week there has previously been no further treatment history of discharge. Microscopy of a Gram available. Intravaginal amphotericin/ stained slide was positive for spores and a non- flucytosine oVers a possible treatment for such albicans yeast (not further speciated) was patients. isolated in culture. She responded symptomati- Topical flucytosine has been used for vaginal cally and microbiologically to nystatin pessa- infections caused by both C albicans9 and anti- ries at night for 14 nights. fungal resistant non-albicans candidiasis10 11 but a suitable formulation has not been available in Case 3 the United Kingdom. Although it is the only A 42 year old woman presented with intracta- available fungicidal agent,1 there are reserva- ble symptoms of “vaginal thrush” which had tions about its topical use because of the started since a hysterectomy 1 year earlier, fol- potential development of flucytosine resist- lowing which she had started unopposed ance, which occurs by mutation of a single oestrogen hormone replacement therapy. gene. The risk of such resistance developing is Microscopy of a Gram stained vaginal slide thought to be reduced by combination with showed spores and C glabrata was isolated polyene antifungals such as amphotericin B which persisted despite dydrogesterone 10 mg with which flucytosine is synergistic in vitro.19 daily for 28 days combined with nystatin Our three cases demonstrate that flucytosine pessaries at night for 14 days, combined nysta- and amphotericin in lubricating jelly may be tin pessaries and itraconazole 400 mg daily for eVective in chronic vaginal C glabrata infection 7 days, and vaginal boric acid 600 mg daily for where all other available agents have failed. 14 days. This treatment was well tolerated in all patients Intravaginal amphotericin B and flucytosine with no or minimal side eVects. in lubricating jelly was given at night for 14 days. Her symptoms improved and microscopy We would like to thank Professor Frank Odds for his initial and cultures were negative 2 and 5 weeks advice and Dr Elizabeth Johnson for help with the results of the antifungal sensitivity tests. following treatment. Contributors: DJW, ARH, and AV collected the patients and wrote the paper; DJW had the idea of using flucytosine and amphotericin intravaginally; MS and SL developed the formu- Discussion lation of amphotericin and flucytosine in lubricating jelly. By comparison with C albicans, C glabrata is intrinsically less sensitive to azole antifungals 1 Odds FC. Candida and candidosis. 2nd ed. London: Bailliere Tindall, 1988. and, because this organism is haploid (unlike C 2 Lynch ME, Sobel JD. Comparative in vitro activity of albicans which is diploid) selection of drug antimycotic agents against pathogenic vaginal yeast iso- 7 lates. J Med Vet Mycol 1994;32:267–74. resistant strains may occur. Persistent vaginal 3 Otero L, Fleites A, Mendez FJ, et al. Susceptibility of Can- C glabrata is more likely to be found in patients dida species isolated from female prostitutes with\par vulvovaginitis to antifungal agents and boric acid. Eur J who are clinically not or partially responsive to Clin Microbiol Infect Dis 1999;18:59–61. azole antifungals, older patients, diabetics, and 4 Geiger AM, Foxman B, Sobel JD. Chronic vulvovaginal 4 candidiasis: characteristics of women with Candida albi- women who have had hysterectomies. Symp- cans, C glabrata and no candida. Genitourin Med 1995;71: toms are, however, not a reliable guide to the 304–7. 5 Redondo-Lopez V, Lynch M, Schmitt C, et al. Torulopsis causative organism. It is therefore important to glabrata vaginitis: clinical aspects and susceptibility to anti- speciate isolates from patients presenting with fungal agents. Obstet Gynecol 1990;76:651–5. 4 6 White DJ, Johnson EM, Warnock DW. Management of problem vaginal candidosis. Because of the persistent vulvo-vaginal candidosis due to azole-resistant relatively small numbers of patients presenting Candida glabrata. Genitourin Med 1993;69:112–14. 7 Kerridge D, Nicholas RO. Drug resistance in the opportun- with this condition, treatment of persistent C istic pathogens Candida albicans and Candida glabrata. J glabrata vaginitis is not evidence based but Antimicrob Chemother 1986;18:39–49. 8 Bingham JS. What to do with the patient with recurrent vul- remains largely anecdotal. Most clinicians vovaginal candidiasis. Sex Transm Inf 1999;75:225–7. would start treatment with intravaginal nysta- 9 Larsson-Cohen U. Treatment of vaginal candidosis with a single dose of a new antimycotic drug, 5-fluorocytosine + tin (the only licensed alternative to azoles in the Candicidin. Castellania 1977;5:81–2. United Kingdom) and then proceed to either 10 Horowitz BJ. Topical flucytosine therapy for chronic recurrent Candida tropicalis infections. J Reprod Med 1986;31: high dose oral itraconazole together with high 821–4. dose intravaginal azole pessaries or nystatin. 11 Fidel PLJ, Vazquez JA, Sobel JD. Candida glabrata: review of epidemiology, pathogenesis, and clinical disease with Following this with intravaginal boric acid 600 comparison to C. albicans. [Review] [185 refs]. Clin Micro- 8 mg at night for 14 days. If this fails however biol Rev 1999;12:80–96.