Open access Protocol BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from Antifungal (oral and vaginal) therapy for recurrent vulvovaginal candidiasis: a systematic review protocol Juliana Lírio,1 Paulo Cesar Giraldo,2 Rose Luce Amaral,2 Ayane Cristine Alves Sarmento,3 Ana Paula Ferreira Costa,3 Ana Katherine Gonçalves3 To cite: Lírio J, Giraldo PC, ABSTRACT Strengths and limitations of this study Amaral RL, et al. Antifungal Introduction Vulvovaginal candidiasis (VVC) is frequent (oral and vaginal) therapy in women worldwide and usually responds rapidly to for recurrent vulvovaginal ► Two independent reviewers will select studies, ex- topical or oral antifungal therapy. However, some women candidiasis: a systematic tract data without different variables and assess develop recurrent vulvovaginal candidiasis (RVVC), which review protocol. BMJ Open the risk of bias, to indicate through evidence-based 2019;9:e027489. doi:10.1136/ is arbitrarily defined as four or more episodes every medicine if there is a more effective antifungal ther- bmjopen-2018-027489 year. RVVC is a debilitating, long-term condition that can apeutic regimen for the treatment of recurrent vul- severely affect the quality of life of women. Most VVC is Prepublication history for vovaginal candidiasis. ► diagnosed and treated empirically and women frequently this paper is available online. ► There may be a limitation of outcome from treat- To view these files, please visit self-treat with over-the-counter medications that could ment variation, routes of administration, different the journal online (http:// dx. doi. contribute to an increase in the antifungal resistance. The doses and quality of the randomised trials used in org/ 10. 1136/ bmjopen- 2018- effective treatment of RVVC has been a challenge in daily the systematic review. 027489). clinical practice. This review aims to assess the efficacy of ► This review and meta-analysis will combine the re- antifungal agents administered orally or intravaginally for sults of various studies that have comparable sizes Received 24 October 2018 the treatment of RVVC, in order to define clinical practices of an effect that can be computed. Accepted 11 March 2019 that will impact on the reduction of the morbidity and ► However, it may be that we have only a small sam- antifungal resistance. ple size and a limited number of studies, which may Methods and analysis A comprehensive search of influence the validity and reliability of the findings. the following databases will be carried out: PubMed, http://bmjopen.bmj.com/ Embase, Scopus, Web of Science, Scientific Electronic Library Online (SciELO), the Cochrane Central Register of arbitrarily defined as at least three symptom- Controlled Trials (CENTRAL), Biblioteca Virtual em Saúde atic episodes in the previous 12 months.1–3 (Virtual Health Library)/Biblioteca Regional de Medicina It is estimated that RVVC affects approxi- (Regional Library of Medicine) (BVS/BIREME), Cumulative mately 138 million women worldwide annu- Index to Nursing and Allied Health Literature (CINAHL) ally and 492 million over their lifetimes.1 2 and in the clinical trials databases ( www. trialscentral. org; Women reported the period of RVVC to be www. controlled- trials. com; www. clinicaltrials. gov). The 1–2 years although a substantial number had on September 30, 2021 by guest. Protected copyright. risk of bias will be assessed according to the Cochrane symptoms for 4 or 5 years and some very Risk of Bias tool. We will perform data synthesis using the much longer, with risk and symptoms lasting Review Manager (RevMan) software V.5.2.3. To assess 4 5 © Author(s) (or their heterogeneity, we will compute the I2 statistic. decades. employer(s)) 2019. Re-use Ethics and dissemination This study will be a review C albicans is responsible for the majority permitted under CC BY-NC. No of infections in women with RVVC; however, commercial re-use. See rights of published data and it is not necessary to obtain ethical and permissions. Published by approval. Findings of this systematic review will be adequate treatment of RVVC requires species BMJ. published in a peer-reviewed journal. determination confirmed by laboratory find- 2 1Obstetrics and Gynecology, Trial registration number CRD42018093817 ings and effective treatment. Universidade Estadual de Several factors have been associated to Campinas, Campinas, SP, Brazil RVVC such as genetic (polymorphism, 2Obstetrics and Gynecology, Universidade Estadual de familial, ethnicity), immune mechanisms Campinas, Campinas, Brazil INTRODUCTION (HIV, uncontrolled diabetes, steroids, anti- 3Universidade Federal do Rio Description of the condition biotics, hormone replacement therapy), Grande do Norte, Natal, Brazil Vulvovaginal candidiasis (VVC) is frequent behavioural (oral sex, oral contraceptive, in women worldwide and usually responds intercourse frequency) and idiopathic.6–10 Correspondence to Dr Ana Katherine Gonçalves; rapidly to topical or oral antifungal therapy. Fluconazole is inexpensive and well-toler- anakatherine_ ufrnet@ yahoo. However, some women develop recurrent ated medication that is easily administered com. br vulvovaginal candidiasis (RVVC), which is orally and is the most used antifungal drug. Lírio J, et al. BMJ Open 2019;9:e027489. doi:10.1136/bmjopen-2018-027489 1 Open access BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from However, in the last decade, fluconazole resistance has to treatment. The lack of clear criteria for indication of been reported of women with RVVC. Earlier epidemio- available drugs and their free use due to self-medication logic studies found that almost all women diagnosed with by women has contributed to the increasing antifungal fluconazole-resistant C albicans had experienced previous resistance found in some clinical trials. exposure to fluconazole.11 The rates of azole resistance are highly variable, and they may be influenced by the How the intervention might work prescribing patterns of clinicians for both the treatment Antifungal agents generally act as fungistatics and most of and prophylaxis. often work by just destroying the cell wall. Nowadays, In addition, it is still important to recognise that the despite the great diversity of antifungal agents available excessive use and overuse of such topical agents have had for vaginal or systemic use and the large number of clin- other adverse consequences such as oedema, irritability ical trials performed, there are actually very few that of the skin and maybe even chronic vulvar pain condition compare their efficacy along with the risk of developing (vulvodynia).12 13 resistance. Furthermore, it is recognised that there are several factors (genetics, polymorphisms, behavioural and host Why it is important to perform this review factors) associated with the pathogenesis of RVVC. In In order to find a rational use of the antifungal medica- this context, it is unlikely to find one regimen fit for all tions available for the treatment of RVVC, as well as the patients. However, no published studies are comparing choice of the best route of administration, it is necessary different antifungal regimens; thus, this review based on to evaluate comparatively the various proposed schemes evidence must be useful for practitioners and physicians. normally used. In this way, the choice of the best treat- ment can be made according to the proven and accept- Description of the intervention able safety and efficacy dictates. Current treatment options for VVC include antifungal By avoiding drugs of doubtful or unproven efficacy, agents sold without a prescription for oral or intravaginal as well as high risk/benefit index, drug combinations of use. Fluconazole has been used extensively while having the same formulations or duplicity of drugs for the same an unknown impact on fungal susceptibility.11 clinical indication, the quality of medical care can be The most commonly used regimen for RVVC consists of improved. 10–14 days of induction therapy with a topical antifungal This study also contributes to the assessment of whether agent or oral fluconazole, 150 mg, followed by fluco- there is a more cost-effective and efficient therapeutic nazole, 150 mg per week for 6 months (strong recommen- approach for the patient and the health system, between dation with high quality evidence).14 15 It was seen that two or more equally effective treatments. If there is similarity of efficacy between different anti- women with RVVC with vulvar excoriation, longer disease http://bmjopen.bmj.com/ time and family history of atopic disease are at greater fungal drugs used in an oral treatment regimen, one can risk of not responding to maintenance treatment with recommend the one that presents less side effects, more fluconazole.16 dosage convenience or even lower cost. In the last decade, isolated cases of women with RVVC In cases of vaginal treatments with superior or similar who have not responded to fluconazole induction therapy efficacy to those used orally, they may be chosen as the have been reported. After excluding lack of adherence first option, especially for patients with oral side effects. to treatment, resistance to fluconazole should be consid- Since the sale of antifungal drugs is not subject to 2 17–19 prescription control by pharmacies, the indiscriminate ered. on September 30, 2021 by guest. Protected copyright. A previous Cochrane review aimed to compare the use of antifungal drugs by self-medication