Treatment of Chronic Vulvovaginal Candidiasis with Posaconazole and Ciclopiroxolamine
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Vol.2, No.6, 513-518 (2010) Health doi:10.4236/health.2010.26077 Treatment of chronic vulvovaginal candidiasis with posaconazole and ciclopiroxolamine Hans-Jürgen Tietz Fungal Infection and Microbiology Institute, Berlin, Germany; [email protected] Received 21 January 2010; revised 30 January 2010; accepted 2 February 2010. ABSTRACT re-infection from sexual partner(s), and recurrent disease as a result of persistent colonization have been postu- Therapy of chronic recurrent vulvovaginal can- lated. This last postulate is supported by studies showing didiasis (VVC) caused by Candida glabrata is recurrent disease to be caused by identical strains in the still rare in comparison to C. albicans infection, vast majority of cases [2]. but therapy remains more difficult. Combination Though C. albicans is the main pathogen in more than therapy with topical antifungals may improve 95% of cases of acute infection [4], other species are therapy outcome, but still standard agents as implicated in chronic infection, chiefly C. glabrata. The fluconazole or itraconazole often fail. Posa- characteristic features of Candida albicans and Candida conazole is a new systemic triazole with a wide glabrata are listed in Table 1. antifungal spectrum including rare Candida The pathogenic role of C. glabrata is disputed, but pa- species. Up to now, no clinical trials with posa- tients who present to a physician with fungal disease conazole in chronic recurrent VVC have been caused by these atypical pathogens always report symp- undertaken. Here, first results of the application toms. Though vaginal discharge is rare, redness, agoniz- of a new therapy regimen consisting of oral ing itching, and a sour-smelling sticky discharge are posaconazole in combination with topical ci- characteristic. A diagnosis of “harmless commensal” is clopiroxolamine are presented. 15 patients with therefore both inappropriate and scientifically inaccurate. chronic recurrent VVC caused by C. glabrata Both organisms are biosafety class 1 organisms. Hence, have been treated. 14 of these patients experi- though low-virulence, they are not apathogenic—unlike enced successful therapy, clinical and myco- Saccharomyces cerevisiae. logical cure 30 days after begin of therapy has been observed. Long-term results are promising, 2. TREATMENT OF PROBLEM FUNGI as in 4 patients clinical and mycologic cure persists for more than 1 year up to now. The therapeutic goal in chronic recurrent VVC is the eradication of the pathogen. The chances of achieving Keywords: Chronic Recurrent Vulvovaginal that goal appear to be good. Unlike C. albicans, non- Candidiasis; VVC; Candida Glabrata; Posaconazole albicans Candida organisms are located predominantly vaginally. Measures to prevent recurrence should be ini- 1. INTRODUCTION tiated before starting therapy [5]. Oral and bowel con- tamination in the patient (3 fecal samples taken on 3 Vulvovaginal candidiasis (VVC) is termed chronic if it different days) should be investigated, which may result recurs four times or more per year at intervals of 8 in measures such as professional dental and denture weeks or less [1]. Literature data suggest that acute vul- cleaning and eradication of pathogens in the mouth and vovaginal candidiasis becomes chronic in 5-8 % of cases bowel with amphotericin B or nystatin (C. glabrata) in [2,3]. Possible, but heatedly debated, risk factors for the form of lozenges or sugar-coated tablets. A hormonal vaginal thrush include prior antibiotic or corticosteroid coil is a potential pathogen reservoir and should ideally therapy, intrauterine contraceptive devices (coil), high- be removed before therapy. The sexual partner should be sugar diet, and certain sexual practices [2]. The etiology involved in treatment too. Colonization of the prostate of chronic recurrent VVC is little understood even today. (sperm sample) and contamination of dentures (smear Gastrointestinal tract as a reservoir for re-infection, tests) in older partners should be investigated. Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/ 514 H. J. Tietz / HEALTH 2 (2010) 513-518 Table 1. Characteristics of C. albicans and C. glabrata as or- ment failures, the treatment approach is not advisable ganisms causing vaginal candidiasis. today [5]. Nevertheless, the options for treating invasive fungal infection of the kind are better now than ever. The Property C. albicans C. glabrata most promising agents according to the current state of Etiology Mostly intra partum Frequently iatrogenic scientific knowledge are the triazole derivative posa- conazole and the echinocandins caspofungin and anidu- Course Acute Chronic lafungin. The latter require intravenous dosing and are Findings Discharge Redness associated with high treatment costs. Since vaginal can- Redness Pruritus didiasis is usually treated in an ambulatory setting, these Pruritus agents are of lesser relevance for treatment. Virulence class 2 (high) 1 (low) Ciclopiroxolamine is the most effective local drug for treating clotrimazole- and nystatin-resistant organisms Pseudomycelium Yes No [8]. It is the antifungal with the broadest spectrum, as Blastospores midsize, oval Small-cell, round well as showing deep penetration and sporicidal activity. Chlamydospores Yes No The mechanism of action is polyvalent. Ciclopiroxola- mine’s activity is not limited to the level of ergosterol Hormone situation Dependent No synthesis. It also targets regions mitochondria and pro- Pathogen susceptibility (S= sensitive, R= re- tein synthesis, making it the ideal combination partner Antifungal sistant) for all systemic antifungals. Inhibition of catalase pro- duction is particularly effective, because it disables me- Clotrimazole S R tabolization of toxic H2O2 occurring in the fungal cell. Nystatin S S All clinically relevant Candida species are sensitive to Ciclopiroxolamine S S ciclopiroxolamine [8]. Posaconazole is a triazole derivative whose mecha- Fluconazole S R nism of action is based on inhibiting ergosterol synthesis Posaconazole S S [9]. It is effective against a variety of fungal pathogens. These include all relevant Aspergillus species, the or- Drug of first choice: - topical Clotrimazole Ciclopiroxolamine ganisms responsible for mycetoma, coccidioidomycosis, - systemic Fluconazole Posaconazole chromoblastomycosis, and refractory pathogens like Mucor and Fusarium [10,11]. The spectrum of action Drug therapy should encompass both a topical and a also includes Candida and especially the problem systemic component. C. glabrata is located deep in pathogens C. glabrata and C. krusei [7,10] which are vaginal tissue-up to 10 layers deep-which explains the resistant to fluconazole, itraconazole and voriconazole. high failure rate for local treatment attempts. C. glabrata Posaconazole’s molecular structure gives it multiple also thrives in surface locations–under the foreskin, docking sites, so different mutations would have to oc- around the clitoris, in the anal folds and pubic hair–and cur simultaneously for it to be ineffective [12]. In con- so the effectiveness of systemic therapy is limited. trast, a single mutation is enough to induce resistance to Therefore, combination therapy seems to be necessary to fluconazole [12]. Posaconazole has linear kinetics up to appropriately treat the patient and avoid recurrence of a dose of 800 mg [9]. Exposure can be increased by di- infection. It needs to be stressed that in addition, patient vision into two divided doses of 400 mg (10 ml suspen- cooperation is crucial, as rigorous, reliable local treat- sion BID), and is further enhanced by dosing together ment is required in conjunction with properly adminis- with high-fat food, e.g. custard made with full-fat milk. tered systemic therapy. It has a high volume of distribution (1744 liters), sug- C. glabrata isolates have very low sensitivity to flu- gesting very good distribution. Posaconazole is metabo- conazole and may be resistant in many cases. Secondary lized to a very slight extent and is primarily eliminated resistance is mainly due to two factors: genetic variabil- with the feces. Posaconazole has the lowest potential for ity of the pathogen, which develops resistance to flu- interactions of all systemic azole derivatives, since in- conazole at doses below 800 mg, and the fact that many teractions with the CYP system are limited to CYP3A4 therapists administer fluconazole doses as low as 150 mg inhibition. The most common side effects reported in [6]. In contrast, in vitro sensitivity to posaconazole is studies involving a total of 2400 subjects and patients high [7]. Until just a few years ago, systemic high-dose were headache and nausea [9]. Posaconazole is approved treatment with 800 mg fluconazole was the treatment of for prevention of systemic infection in high-risk he- first choice [8]. Given the large number of current treat- mato-oncology patients, for salvage therapy of certain Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/ H. J. Tietz / HEALTH 2 (2010) 513-518 515 invasive mould infections and for the treatment of oro- 4. DIAGNOSTIC PROCEDURES pharyngeal candidiasis [9]. Up to now, there is no clini- cal data supporting efficacy in treatment of vaginal can- For species identification, swabs were inoculated onto didiasis. In a murine vaginal model, posaconazole re- chromIDTM Candida agar, bioMérieux Deutschland GmbH, duced the fungal burden of both fluconazole-susceptible Nürtingen, Germany, which is specific for yeast