Background and Importance Candida glabrata (C. glabrata) is the second leading cause of vulvovaginal candidiasis (8% of cases).^1–5

Recommendations to treat azole resistance (AR) Candida glabrata (C. glabrata) vulvovaginal candidiasis (VVC) are intravaginal boric acid capsules (first-line), intravaginal nystatin suppositories (second-line) and, as third-line, flucytosine cream (17% or 15.5%) or amphotericin B cream.^1–4

Vaginal flucytosine and amphotericin are not commercially available, so an extemporaneous formulation has to be developed.

Aim and Objectives To compound flucytosine 15.5% intravaginal gel and to evaluate the effectiveness and safety in an AR C. glabrata VVC patient.

Materials and Methods Literature review to investigate the above-mentioned compounding magistral formulations.

Effectiveness and safety were assessed by clinical monitoring, analytical monitoring and patient interview.

Results A 47-year-old woman with recurrent VVC since March 2020 was treated with oral fluconazole, oral lactobacillus/lingonberry and multiple intravaginal drugs (clotrimazole, nifurantel, nystatin, benzydamine, estriol + lactobacillus and boric acid). In March 2022, a C. glabrata strain was isolated, exhibiting antifungal sensitivity only to caspofungin, flucytosine and micafungin.

Four flucytosine formulations for vaginal application were identified in literature.^5–8 We compounded flucytosine 15.5% gel by reducing fourteen 500 mg flucytosine tablets to a fine powder in a mortar. The powder was then moistened with 5 mL of glycerin to form a smooth paste, which was then added to 40 g of a lubricating vaginal gel base. Shelf-life of was given for 14 days, stored at room temperature. Vaginal applicators were used to apply the gel intravaginally at bedtime for 19 days.

During this period, three active pharmacovigilance interviews were carried out to verify tolerability and side effects. The patient reported only vaginal discharge, no pain, pruritus or rash.

Analytical evaluation (blood count, renal and hepatic function) was performed, without revealing any change. Vaginal culture was negative at week 2, 4 and 6 after treatment. The patient remained asymptomatic until the last evaluation in August 2022.

Conclusion and Relevance The flucytosine 15.5% intravaginal gel formulation fulfilled an unmet need, enabling the effective resolution of AR C. glabrata VVC.

The active monitoring of its use allowed us to collect real context data on safety, verifying the absence of adverse effects and good tolerance.

References

1. Pappas PG, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the infectious diseases society of America. Clin Infect Dis. 2016 Feb 15;62(4):e1–50. doi: 10.1093/cid/civ933. Epub 2015 Dec 16.

2. Centers for disease control and prevention (CDC) ‘Vulvovaginal candidiasis Sexual Transmitted Infections Guidelines 2021.’

3. Uptodate ‘Candida vulvovaginitis in adults: Recurrent infection.’ seen in 21/03/2022.

4. Sobel JD, Chaim W, Nagappan V, et al. Treatment of vaginitis caused by Candida glabrata: use of topical boric acid and flucytosine. Am J Obstet Gynecol 2003;189:1297–1300.

5. White DJ, Habib AR, Vanthuyne A, Langford S, Symonds M. Combined topical flucytosine and amphotericin B for refractory vaginal Candida glabrata infections. Sex Trans Inf 2001;77:212–3.

6. Ricote LoberaI, et al. Poster 55 Congresso SEFH: ‘Gel de Anfotericina B Y Flucitosina en el tratamiento de vulvovaginite recurrente por Candida glabrata: case report.’ 2010.

7. San José B, et al. Hospital formulations for the treatment of non-albicans vulvovaginitis. Eur J Hosp Pharm 2012-000074.152.

8. Micromedex monography ‘Flucytosine’ seen in 17/3/2022.