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ANTIFUNGAL (ORAL AND VAGINAL) THERAPY FOR RECURRENT VULVOVAGINAL CANDIDIASIS: A SYSTEMATIC REVIEW PROTOCOL ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2018-027489

Article Type: Protocol

Date Submitted by the 24-Oct-2018 Author:

Complete List of Authors: Lírio, Juliana; Universidade Estadual de Campinas, Obstetrics and Gynecology Giraldo, Paulo; Universidade Estadual de Campinas Amaral, Rose ; Universidade Estadual de Campinas Sarmento, Ayane Cristine ; Universidade Federal do Rio Grande do Norte Costa, Ana Paula; Universidade Federeal do Rio Grande do Norte Gonçalves, Ana ; Universidade Federal do Rio Grande do Norte,

Keywords: Vulvovaginal candidiasis, TREATMENT, vaginitis, prophylaxis

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For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 1 ANTIFUNGAL (ORAL AND VAGINAL) THERAPY FOR RECURRENT 4 5 2 VULVOVAGINAL CANDIDIASIS: A SYSTEMATIC REVIEW PROTOCOL 6 7 8 3 9 10 4 Juliana Lírio1, Paulo Cesar Giraldo2, Ana Katherine Gonçalves3, Rose Luce do 11 2, 4 4 12 5 Amaral Ayane Cristine Alves Sarmento , Ana Paula Ferreira Costa 13 14 6 1 – Doctor, master's degree in Obstetrics and Gynecology, State University of 15 16 7 Campinas, Campinas,For Brazil. peer review only 17 18 8 2 - Teacher. Department of Obstetrics and Gynecology, State University of 19 Campinas, Campinas, Brazil. 20 9 21 10 3 - Teacher. Department of Obstetrics and Gynecology, Federal University of Rio 22 23 11 Grande do Norte, Natal, Brazil. 24 25 12 4 – Post-Graduate Program in Health Sciences, Federal University of Rio Grande 26 13 do Norte, Natal, Brazil. 27 28 14 29 30 15 *Corresponding author: 31

32 16 Ana Katherine Gonçalves http://bmjopen.bmj.com/ 33 34 17 E-mail address: [email protected] 35 36 18 Phone: 55 84 32154371 37 38 19 39 20 40 on September 27, 2021 by guest. Protected copyright. 41 21 42 43 22 44 45 23 46 47 24 48 25 49 50 26 51 52 27 53 28 54 55 29 56 57 58 1 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 2 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 30 4 5 31 6 7 32 8 33 ABSTRACT 9 10 34 Introduction: Vulvovaginal candidiasis affects up to 75% of women during their 11 12 35 reproductive years. Predisposing factors have been identified and include the use of 13 14 36 antibiotics, pregnancy, diabetes mellitus, genetic factors and behavioral factors. 15 37 However, almost 5% of women suffer from recurrent vulvovaginal candidiasis 16 For peer review only 17 38 (RVVC), which is commonly defined as four or more episodes of VVC during a period 18 19 39 of a year. The effective treatment of RVVC, with adequate control of the symptoms 20 40 and eradication of the fungus, represents a challenge in daily clinical practice. 21 22 41 Recently, a wide variety of drugs and formulations have been made available and 23 24 42 many different antifungal regimens are used for treatment, some of them with 25 26 43 adverse effects that end up reducing women's adherence to treatment. The lack of 27 44 specific clear criteria for the indication of available antifungal treatment and its 28 29 45 abusive use has contributed to an increase in the antifungal resistance verified in 30 31 46 certain clinical trials. This review aims to assess the efficacy of antifungal agents

32 http://bmjopen.bmj.com/ 33 47 administered orally or intravaginally for the treatment of RVVC, in order to define 34 48 clinical practices that will impact on the reduction of the morbidity of this pathology 35 36 49 and on the decrease of resistance to the drugs used. 37 38 50 Methods and analysis: A comprehensive search of the following databases will be 39 51 carried out: PubMed, Embase, Scopus, Web of Science, SciELO, the Cochrane

40 on September 27, 2021 by guest. Protected copyright. 41 52 Central Register of Controlled Trials (CENTRAL), BVS/BIREME, CINAHL, and in the 42 43 53 clinical trials databases (www.trialscentral.org; www.controlled-trials.com; 44 45 54 www.clinicaltrials.gov). Electronic searches will be performed without restriction of 46 55 dates or languages. Two reviewers will independently select trials and extract data 47 48 56 from the original publications. The risk of bias will be assessed according to the 49 50 57 Cochrane Risk of Bias tool. We will perform data synthesis using the Review 51 52 58 Manager (RevMan) software V.5.2.3. To assess heterogeneity, we will compute the 53 59 I2 statistic. 54 55 56 57 58 2 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 3 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 60 Ethics and dissemination: This study will be a review of published data and it is 4 5 61 not necessary to obtain ethical approval. Findings of this systematic review will be 6 7 62 published in a peer-reviewed journal. 8 63 Trial registration number for International Prospective Register of Systematic 9 10 64 Reviews 2018: International Prospective Register of Systematic Reviews 2014: 11 12 65 CRD42018093817 13 14 66 Strengths and limitations of this study 15 16 For peer review only 17 67 - The results obtained in this systematic review will indicate which antifungal 18 19 68 therapeutic regimen is most effective for the treatment of recurrent vulvovaginal 20 69 candidiasis. 21 22 70 - Two independent reviewers will select the studies included in this review, extract 23 24 71 data without different variables and assess the risk of bias. 25 26 72 - There may be a limitation of outcome from treatment variation, routes of 27 73 administration, different doses and quality of the randomized trials used in the 28 29 74 systematic review. 30 31 75 - This review and meta-analysis aims to combine the results of different studies that

32 http://bmjopen.bmj.com/ 76 have comparable sizes of effect that can be computed. 33 34 77 - However, it may be that we have only a small sample size and a limited number of 35 36 78 studies, which may influence the validity and reliability of the findings 37 38 79 39 80

40 on September 27, 2021 by guest. Protected copyright. 41 81 42 43 82 44 45 83 46 84 47 48 85 49 50 86 51 87 52 53 88 54 55 89 56 57 58 3 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 4 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 90 4 5 91 6 7 92 8 93 9 10 94 11 12 95 13 14 96 15 97 16 For peer review only 17 98 18 19 99 INTRODUCTION 20 100 21 22 101 Description of the condition: 23 24 102 Most women will have life-long episodes of vaginal discharge. Many times, 25 26 103 this discharge is caused by vulvovaginitis. Vaginal candidiasis appears as the 2nd 27 104 most frequent cause of vulvovaginitis (25%), being behind bacterial vaginosis.[1] It 28 29 105 is characterized by a process of desquamation and transudation of the vaginal 30 31 106 epithelium, associated with local inflammation of variable intensity, due to vaginal

32 http://bmjopen.bmj.com/ 33 107 colonization by Candida sp., a prerequisite for the disease to occur. About 20 to 25% 34 108 of asymptomatic women have positive vaginal cultures for Candida sp. [2] Candida 35 36 109 species can be commensal organisms or it can transform colonization without 37 38 110 symptoms into an infection. 39 111 The mechanisms of transformation of colonization into infection are

40 on September 27, 2021 by guest. Protected copyright. 41 112 multifactorial and relate to age being over 45, type 1 diabetes mellitus, use of 42 43 113 antibiotics, immunodeficiencies, stress, hormonal changes, pregnancy, obesity, use 44 45 114 of oral contraceptives with high doses of estrogens, life habits, hygiene, clothing, diet 46 115 rich in sugar, and sexual life, among others. 47 48 116 It is estimated that in the US, about 10 million gynecological consultations per year 49 50 117 are attributed to cases of vulvovaginal candidiasis, which actually has other non- 51 fungal causes. [3] Incorrect diagnosis involves a large number of misguided women, 52 118 53 119 who are often erroneously stigmatized as having recurrent vulvovaginal candidiasis 54 55 120 (RVVC). 56 57 58 4 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 5 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 121 The infection caused by Candida sp. affects between 70 and 75% of 4 5 122 women, at least once during their lives, especially young women during menacme. 6 7 123 About 40% to 50% of women will present recurrence and 5% to 8% of adults will 8 124 have recurrent vulvovaginal candidiasis (RVVC), defined as 4 or more episodes in 9 10 125 12 months. 11 12 126 Among the species of Candida, the albicans variant accounts for 85-90% of 13 14 127 the cases, accompanied by the species C. glabrata, C.tropicalis, C. krusei, and C. 15 128 parapsilopis. Studies have shown the presence of another Candida species related 16 For peer review only 17 129 to RVVC, C. duobushaemulonii, which has low sensitivity to fluconazole [4] and 18

19 130 increased resistance to azoles by the species described previously. [5] 20 131 The occurrence of RVVC appears to be primarily due to different 21 22 132 susceptibilities of host factors and not the higher frequency of colonization or the 23 24 133 presence of more virulent strains of Candida sp. [3] A strong association between 25 26 134 atopy and RVVC was observed, and it is possible that an increase in T-cell response 27 135 and decrease in allergy could be used as tools in the treatment of RVVC. [6] Although 28 29 136 evidence has been published suggesting that susceptibility to the development of 30 31 137 RVVC is associated with several factors such as localized vaginal allergic response;

32 http://bmjopen.bmj.com/ 33 138 deficiency in Candida-specific cell mediated immunity; hyperactive neutrophil 34 139 response; presence of functional polymorphism in the genes encoding the protein; 35 36 140 mannose-binding lecithin or interleukin-4 anti-inflammatory cytokine, the causes of 37

38 141 RVVC in most patients remain unexplained. [7] 39 142 Symptoms include vulvovaginal pruritus, irritation, burning, pain,

40 on September 27, 2021 by guest. Protected copyright. 41 143 dyspareunia and vaginal discharge. Clinical signs include erythema of the vulva, 42 43 144 edema, excoriation and formation of fissures, together with erythema and edema of 44 45 145 the introitus and vaginal mucosa and diffuse colpitis. The vaginal discharge may 46 146 show white, flocculent, pasty, eventually greenish, adherent to the mucosa, which 47 48 147 looks like "curdled milk". A non-nodosa white discharge is suggestive of VVC, but is 49

50 148 extremely non-specific. [8] 51 Diagnosis consists of office tests, including vaginal pH measurement, which 52 149 53 150 is almost always below 4.5, and evaluation of saline and 10% potassium hydroxide 54 55 151 (KOH) discharge, important for a differential diagnosis with other causes of 56 57 58 5 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 6 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 152 vulvovaginitis. Direct examination by optical microscopy, fresh and by Gram staining, 4 5 153 should seek to evidence pseudohifas and / or blastospores. In patients with 6 7 154 suggestive symptoms, but with negative microscopy, a culture for fungi in specific 8 155 media (Sabouraud and NiKersen) is useful, since hyphae or blastospores are 9 10 156 identified only with microscopy in about 50% of the cases. [9] In addition, positive 11 12 157 yeast culture allows speciation of the causative organism, which, in turn, may have 13 14 158 important implications for antifungal therapy. Although the culture also allows access 15 159 to the body for the antifungal susceptibility test, this test is rarely used in clinical 16 For peer review only 17 160 practice unless the patient experiences repeated clinical or mycological failure. 18 19 161 Studies have observed that the diagnosis by PCR is more sensitive than culture in 20 162 the detection of Candida species in the vagina. [9, 10] 21 22 163 Description of the intervention: 23 24 164 Current treatment options for vulvovaginal candidiasis include antifungal 25 26 165 agents sold without a prescription for oral or intravaginal use. Fluconazole has been 27 166 used extensively while having an unknown impact on fungal susceptibility. [11] 28 29 167 The most commonly used regimen for RVVC consists of 10 to 14 days of 30 31 168 induction therapy with a topical antifungal agent or oral fluconazole, 150mg, followed

32 http://bmjopen.bmj.com/ 33 169 by fluconazole, 150mg per week for 6 months. (strong recommendation with high 34 170 quality evidence). [12, 13] It was seen that women with RVVC with vulvar excoriation, 35 36 171 longer disease time and family history of atopic disease are at greater risk of not 37

38 172 responding to maintenance treatment with fluconazole. [14] 39 173 In the last decade, isolated cases of women with RVVC who have not

40 on September 27, 2021 by guest. Protected copyright. 41 174 responded to fluconazole induction therapy have been reported. After excluding lack 42 43 175 of adherence to treatment, resistance to fluconazole should be considered. [8, 15- 44 45 176 17] 46 177 A previous Cochrane review aimed to compare the clinical cure rate of 47 48 178 topical versus oral treatment for the treatment of vulvovaginal candidiasis [18] and 49 50 179 found no difference in the efficacy of oral and vaginal treatment but found that 51 women generally preferred oral treatment. The recommended treatment regimen for 52 180 53 181 RVVC, as described in the clinical guidelines [19, 20] whether oral or topical, is not 54 55 182 effective for all women. [15] Side effects reported include headache, abdominal pain 56 57 58 6 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 7 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 183 and nausea with oral treatment [21, 22] and dyspareunia or irritation with vaginal 4 5 184 treatment. [22] In addition, long-term treatments are expensive, and approximately 6 7 185 50% of women experience recurrence of symptoms a few months after treatment 8 186 completion. [23] 9 10 187 Effective treatment of RVVC, with adequate control of symptoms and 11 12 188 eradication of the fungus, represents a challenge in daily clinical practice. Many 13 14 189 antifungal regimens are available for treatment, some of them with adverse effects 15 190 that end up reducing women's adherence to treatment. The lack of clear criteria for 16 For peer review only 17 191 indication of available drugs and their free use due to self-medication by women has 18 19 192 contributed to the increasing antifungal resistance found in some clinical trials. 20 193 21 22 194 How the intervention might work: 23 24 195 Antifungal agents generally act as fungistatics and most often work by just 25 26 196 destroying the cell wall. Nowadays, despite the great diversity of antifungal agents 27 197 available for vaginal or systemic use and the large number of clinical trials 28 29 198 performed, there are actually very few that compare their efficacy along with the risk 30 31 199 of developing resistance.

32 http://bmjopen.bmj.com/ 33 200 34 201 Why it is important to perform this review: 35 36 202 In order to find a rational use of the antifungal medications available for the 37 38 203 treatment of RVVC, as well as the choice of the best route of administration, it is 39 204 necessary to evaluate comparatively the various proposed schemes normally used.

40 on September 27, 2021 by guest. Protected copyright. 41 205 In this way, the choice of the best treatment can be made according to the proven 42 43 206 and acceptable safety and efficacy dictates. 44 45 207 By avoiding drugs of doubtful or unproven efficacy, as well as high risk / 46 208 benefit index, drug combinations of the same formulations or duplicity of drugs for 47 48 209 the same clinical indication, the quality of medical care can be improved. 49 50 210 This study also contributes to the assessment of whether there is a more cost- 51 effective and efficient therapeutic approach for the patient and the health system, 52 211 53 212 between two or more equally effective treatments. 54 55 56 57 58 7 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 8 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 213 If there is similarity of efficacy between different antifungal drugs used in an 4 5 214 oral treatment regimen, one can recommend the one that presents less side effects, 6 7 215 more dosage convenience or even lower cost. 8 216 In cases of vaginal treatments with superior or similar efficacy to those used orally, 9 10 217 they may be chosen as the first option, especially for patients with oral side effects. 11 12 218 Since the sale of antifungal drugs is not subject to prescription control by 13 14 219 pharmacies, the indiscriminate use of antifungal drugs by self-medication and 15 220 without medical prescription has contributed to the increase of antifungal resistance 16 For peer review only 17 221 to these drugs. Knowing the efficacy profile of each drug in the treatment of recurrent 18 19 222 vulvovaginal candidiasis will enable the creation of a treatment protocol for the 20 223 pathology and also decrease the risk of increased antifungal resistance. 21 22 224 23 24 225 25 26 226 OBJECTIVES 27 227 To evaluate the efficacy of different antifungal drugs usually used orally and 28 29 228 vaginally in the treatment of RVVC. 30 31 229

32 http://bmjopen.bmj.com/ 33 230 METHODS 34 231 This systematic review study with probable meta-analysis will follow the 35 36 232 criteria: Preferred Reporting Items for Systematic Reviews and Meta-Analyzes 37 38 233 (PRISMA) guidelines. This protocol has been registered with the International 39 234 Prospective Register of Systematic Reviews, registration number

40 on September 27, 2021 by guest. Protected copyright. 41 235 CRD42018093817. 42 43 236 44 45 237 Criteria for considering studies for this review 46 238 Types of studies: 47 48 239 Randomized, blind, published and unpublished clinical trials evaluating 49 50 240 treatments for recurrent vulvovaginal candidiasis in immunocompetent women will 51 52 241 be considered for inclusion. 53 242 54 55 243 Types of participants: 56 57 58 8 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 9 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 244 Women who will be included in the analysis will have had 4 or more 4 5 245 episodes of vaginal candidiasis confirmed by the presence of symptoms and a 6 7 246 culture or symptoms and positive microscopy. Women with diabetes mellitus and 8 247 pregnant women will be included in the review, but analyzed separately in 9 10 248 subgroups. 11 12 249 Women with immunosuppressive conditions or users of 13 14 250 immunosuppressive drugs will be excluded. 15 251 16 For peer review only 17 252 Types of interventions: 18 19 253 Interventions to be considered will be antifungal treatments: antifungal drugs 20 254 administered intravaginally (e.g. butoconazole, clotrimazole, econazole, 21 22 255 fenticonazole, isoconazole, miconazole, omoconazole, oxiconazole, terconazole, 23 24 256 tioconazole, natamycin, sertaconazole nistatina and amphotericin) or oral 25 26 257 antifungals (e.g. fluconazole, ketoconazole, itraconazole, posaconazole, and 27 258 voriconazole) 28 29 259 The following comparisons will be made: Any treatment versus placebo; 30 31 260 Short duration of treatment versus longer duration of treatment; Systemic versus

32 http://bmjopen.bmj.com/ 33 261 local treatment; Treatment of partner versus placebo; 34 262 Comparison of two different classes of drugs; Comparison of different doses of the 35 36 263 same agent 37 38 264 39 265 Types of outcome measures:

40 on September 27, 2021 by guest. Protected copyright. 41 266 Primary Outcomes: Number of clinical recurrences per patient per year 42 43 267 (recurrence defined as clinical characteristics and positive culture or microscopy); 44 45 268 Proportion of participants with at least one clinical recurrence during the treatment 46 269 and follow-up period; 47 48 270 Secondary outcomes: Time for first recurrence; Number of symptomatic days per 49 50 271 year; Number of mycological recurrences per patient per year; Proportion of 51 participants with at least one recurrence during treatment and follow-up period; 52 272 53 273 Duration of symptoms after starting treatment; Complications; Adverse events and 54 55 274 Patient preference 56 57 58 9 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 10 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 275 4 5 276 Search methods for identification of studies 6 7 277 Electronic searches: 8 278 We will try to identify as many published studies as unpublished ones, which 9 10 279 evaluate the interventions that aim at the control of RVVC. We will use the electronic 11 12 280 search in the databases as the manual search. No language restrictions will be used 13 14 281 15 282 Other sources: 16 For peer review only 17 283 The aim of the computerized bibliographic research will be extended using 18 19 284 the reference lists of selected articles. 20 285 21 22 286 Search strategy: 23 24 287 The search strategy for Pubmed is shown in table 1. 25 26 288 27 289 28 29 290 30 31 291

32 http://bmjopen.bmj.com/ 33 Table 1 Pubmed search strategy 34 Search items 35 1 candida 36 2 candidiasis 37 3 candidosis 38 4 yeasts 39 5 vaginitis 40 on September 27, 2021 by guest. Protected copyright. 41 6 vulvovaginal 42 7 OR /1-6 43 8 antifungal 44 9 butoconazole 45 10 clotrimazole 46 11 econazole 47 48 12 fenticonazole 49 13 isoconazole 50 14 miconazole 51 15 omoconazole 52 16 oxiconazole 53 17 terconazole 54 55 18 tioconazole 56 19 natamycin 57 58 10 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 11 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 20 sertaconazole 4 21 amphotericin 5 6 22 fluconazole 7 23 ketoconazole 8 24 itraconazole 9 25 posaconazole 10 26 voriconazole 11 27 nystatin 12 28 OR/8-28 13 14 27 (randomized controlled Trial) 15 28 (blind method) 16 29 For peer (clinical review Trial) only 17 30 OR/27-30 18 31 7 AND 28 AND 30 19 20 292 21 22 293 Data collection and analysis 23 24 294 Selection of studies: 25 Two review authors (JFL and AKG) will independently evaluate the eligibility 26 295 27 296 for inclusion of the trials identified by the survey. Disagreements will be resolved by 28 29 297 discussion, involving the contribution of a third author (PCG). The trial authors will 30 31 298 be contacted if more information is needed before deciding to include. The selection

32 299 of the study is summarized in a PRISMA flow diagram (figure 1). Thus, papers that http://bmjopen.bmj.com/ 33 34 300 met the criteria will be reviewed in full. After the full review, papers not considered 35 36 301 having adequate methodological quality according to the GRADE guidelines will be 37 38 302 excluded. 39 303 The level of evidence from each study will be defined according to the

40 on September 27, 2021 by guest. Protected copyright. 41 304 Oxford Center for Evidence-Based Medicine definitions. 42 43 305 44 306 45 46 307 47 48 308 Data extraction and management: 49 50 309 We will use the Review Manager software (RevMan 2010) to perform 51 310 statistical analysis. The experimental populations, methods and measurements of 52 53 311 results are considered similar and, in the absence of statistical heterogeneity, we will 54 55 56 57 58 11 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 12 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 312 group the data using a fixed model effect (Higgins 2009). If statistical heterogeneity 4 5 313 is present, we will not group or use a random effects model (Higgins, 2009). 6 7 314 The data will be entered into the Review Manager software (RevMan 5.3), 8 315 which allows the user to enter protocols as well as complete reviews, including text, 9 10 316 study characteristics, comparison tables and study data, as well as perform the 11 12 317 meta-analysis of the inserted data. 13 14 318 To assess safety and efficacy among the proposed treatments, the 15 319 dichotomous data will be extracted from each study and inserted into a 2 × 2 16 For peer review only 17 320 contingency table, with subsequent individual determination of odds ratio (OR), to 18 19 321 obtain a global summary estimate. 20 322 Models of fixed effects or random effects will be chosen depending on the 21 22 323 absence or presence of heterogeneity between the studies. 23 24 324 25 26 325 Risk of bias assessment: 27 28 326 Two independent reviewers, JL and AKM, will apply the Cochrane Risk of 29 30 327 Bias Tool to evaluate the random sequence of generation, allocation concealment, 31 328 blinding of participants, and evaluation of clinical outcomes. We will also evaluate 32 http://bmjopen.bmj.com/ 33 329 data from incomplete results, selective reporting, financing and potential conflicts of 34 35 330 interest associated with individual trials. The risk of bias will be classified using 36 37 331 predetermined criteria as follows: low, high or unclear 38 39 332 Measurements of treatment effect:

40 333 This will be carried out using the RevMan Analyses statistical package in on September 27, 2021 by guest. Protected copyright. 41 42 334 Review Manager 5.3. We will calculate the OR for dichotomous data and weight 43 44 335 mean difference (MD) for continuous data with associated 95% CI. 45 336 46 47 337 48 49 338 50 51 339 Unit of analysis issues: 52 340 For the cure rate of RVVC, the unit of analysis will be defined as 21 and 30 53 54 341 days after the initiation of therapy. For the recurrence rate of RVVC, 3 months and 55 56 57 58 12 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 13 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 342 6 months following the intervention will be considered as short-term and long-term 4 5 343 follow-up, respectively. 6 7 344 8 345 Addressing missing data: 9 10 346 We will try to get any missing data by contacting the first author or co- 11 12 347 authors of the article via phone, email or post. If we do not receive the necessary 13 14 348 information, data will be excluded from our discussion in the Discussion section. 15 349 16 For peer review only 17 350 Assessment of heterogeneity: 18 19 351 Statistical heterogeneity among the studies will be assessed by the I2 20 352 statistic (<25%, without heterogeneity, 25% -50%, moderate heterogeneity, and> 21 22 353 50%, strong heterogeneity). When a significant heterogeneity exists between 23 24 354 included studies (I2> 50%), a random effects model will be used for the analysis; 25 26 355 otherwise, the fixed effects model will be used. In addition, we will use the Egger 27 356 funnel chart to evaluate the possible publication bias. 28 29 357 30 31 358 Assessment of reporting biases:

32 http://bmjopen.bmj.com/ 33 359 We will use the Egger funnel chart to evaluate the possible publication bias. 34 360 A linear regression approach will be used to assess the asymmetry of the funnel plot. 35 36 361 37 38 362 39 363

40 on September 27, 2021 by guest. Protected copyright. 41 364 Data synthesis 42 43 365 This will be carried out using the RevMan Analyses statistical package in 44 45 366 Review Manager V.5.3. For dichotomous outcomes, we will derive the OR and 95% 46 367 CI for each study. Where there is heterogeneity (I² ≥;75%), a random-effect model 47 48 368 will be used to combine the trials to calculate the relative risk (RR) and 95% CI, using 49 50 369 the DerSimonian-Laird algorithm in The Meta for Package, a meta-analysis package 51 for R. 52 370 53 371 Other study characteristics and results will be summarized narratively if the meta- 54 55 372 analysis cannot be performed for all or some of the included studies. 56 57 58 13 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 14 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 373 4 5 374 Sensitivity analyses: 6 7 375 We will conduct sensitivity analyses to explore the robustness of the findings 8 376 regarding the study quality and sample size. Sensitivity analyses will be shown in a 9 10 377 summary table. 11 12 378 13 14 379 Subgroup analyses: 15 380 In the subgroup analysis and heterogeneity investigation, we plan to 16 For peer review only 17 381 perform the following subgroup analyzes: 18 19 382 1. Sexually active versus non-sexually active women 20 383 2. Pregnant vs. Non-Pregnant Women 21 22 384 3. Women with diabetes mellitus versus non-diabetic women 23 24 385 4. Intervention - duration: short versus long treatment 25 26 386 5. Route of administration: topical versus systemic 27 387 6. Candida albicans versus non-albicans 28 29 388 30 31 389 Confidence in cumulative evidence:

32 http://bmjopen.bmj.com/ 33 390 To describe the strength of evidence for the included data, we will use the 34 391 GRADE (Grading of Recommendation Assessment) system, which assigns levels of 35 36 392 evidence and classifies the strength of the recommendation for health issues. The 37 38 393 quality assessment of the evidence will be performed for each outcome analyzed 39 394 using the available evidence set to ensure judgments about the risk of bias,

40 on September 27, 2021 by guest. Protected copyright. 41 395 consistency, openness, accuracy and publication bias. The quality of the evidence 42 43 396 will be identified as high (the true effect is close to that of the effect estimate), 44 45 397 moderate (the true effect is probably close to the estimate of the effect, but there is 46 398 a possibility that it is substantially different), low may be substantially different from 47 48 399 the effect estimate) or very low (the true effect is likely to be substantially different 49 50 400 from the effect estimate). 51 52 401 53 402 Patient and Public Involvement 54 55 56 57 58 14 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 15 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 403 The research will be performed by a wide and comprehensive search of 4 5 404 literature from databases and the individual patient data are not included. Thus, the 6 7 405 authors no involved patients in setting the research question, as well as, the outcome 8 406 measures, the design and implementation of the study, and the dissemination of its 9 10 407 results. 11 12 408 13 14 409 DISCUSSION 15 410 RVVC is a very common and relevant gynecological problem, with an 16 For peer review only 17 411 impact on women's health. We intend to analyze the efficacy and safety of oral and 18 19 412 intravaginal antifungal agents for the treatment of RVVC. In theory, the different 20 413 antifungals have similar efficacies and both routes promote appropriate treatment. 21 22 414 We hope that our analysis will provide information on the most effective therapeutic 23 24 415 regimens for this prevalent disease, in order to justify the elaboration of an effective 25 26 416 treatment protocol. 27 417 28 29 418 Ethics and dissemination 30 31 419 This study will be a review of the previously published data so it will not be

32 http://bmjopen.bmj.com/ 33 420 necessary to obtain approval from the Ethics Committee. Findings from this 34 421 systematic review will be published in a peer-reviewed journal. 35 36 422 37 38 423 39 424 REFERENCES

40 on September 27, 2021 by guest. Protected copyright. 41 425 42 43 426 1. Sobel JD. Vaginal infections in adult women. Med Clin North Am. 44 45 427 1990;74(6):1573-602. 46 428 2. Sobel JD. Vulvovaginal candidosis. The Lancet. 2007;369(9577):1961-71. 47 48 429 3. Linhares IM, Giraldo PC, Caetano ME, Nissan MD, Gonçalves AKdS, Giraldo 49 50 430 HPD. Candidíase vulvovaginal recorrente: fisiopatogênese, diagnóstico e 51 52 431 tratamento. Rev ciênc méd, (Campinas). 2005;14(4):373-8. 53 432 4. Boatto HF, Cavalcanti SD, Del Negro GM, Girao MJ, Francisco EC, Ishida K, et 54 55 433 al. Candida duobushaemulonii: an emerging rare pathogenic yeast isolated from 56 57 58 15 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 434 recurrent vulvovaginal candidiasis in Brazil. Mem Inst Oswaldo Cruz. 4 5 435 2016;111(6):407-10. 6 7 436 5. Whaley SG, Berkow EL, Rybak JM, Nishimoto AT, Barker KS, Rogers PD. 8 437 Azole Antifungal Resistance in and Emerging Non- Species. Front Microbiol. 9 10 438 2016;7:2173-. 11 12 439 6. Neves NA, Carvalho LP, De Oliveira MAM, Giraldo PC, Bacellar O, Cruz AA, et 13 14 440 al. Association between atopy and recurrent vaginal candidiasis. Clin Exp Immunol. 15 441 2005;142(1):167-71. 16 For peer review only 17 442 7. Lev-Sagie A, Nyirjesy P, Tarangelo N, Bongiovanni AM, Bayer C, Linhares IM, et 18 19 443 al. Hyaluronan in vaginal secretions: association with recurrent vulvovaginal 20 444 candidiasis. Am J Obstet Gynecol. 2009;201(2):206.e1-5. 21 22 445 8. Sobel JD. Recurrent vulvovaginal candidiasis. Am J Obstet Gynecol. 23 24 446 2016;214(1):15-21. 25 26 447 9. Powell AM, Nyirjesy P. Recurrent vulvovaginitis. Best Pract Res Clin Obstet 27 448 Gynaecol. 2014;28(7):967-76. 28 29 449 10. Weissenbacher T, Witkin SS, Ledger WJ, Tolbert V, Gingelmaier A, Scholz 30 31 450 C, et al. Relationship between clinical diagnosis of recurrent vulvovaginal candidiasis

32 http://bmjopen.bmj.com/ 33 451 and detection of Candida species by culture and polymerase chain reaction. Arch 34 452 Gynecol Obstet. 2009;279(2):125-9. 35 36 453 11. Giraldo P, von Nowaskonski A, Gomes FA, Linhares I, Neves NA, Witkin SS. 37 38 454 Vaginal colonization by Candida in asymptomatic women with and without a history 39 455 of recurrent vulvovaginal candidiasis. Obstet Gynecol. 2000;95(3):413-6.

40 on September 27, 2021 by guest. Protected copyright. 41 456 12. Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner 42 43 457 L, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update 44 45 458 by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62(4):e1-50. 46 459 13. Rosa MI, Silva BR, Pires PS, Silva FR, Silva NC, Souza SL, et al. Weekly 47 48 460 fluconazole therapy for recurrent vulvovaginal candidiasis: a systematic review and 49 50 461 meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2013;167(2):132-6. 51 14. Donders GGG, Grinceviciene S, Bellen G, Jaeger M, Ten Oever J, Netea MG. 52 462 53 463 Is non-response to fluconazole maintenance therapy for recurrent Candida vaginitis 54 55 56 57 58 16 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 17 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 464 related to sensitization to atopic reactions? Am J Reprod Immunol. 4 5 465 2018;79(4):e12811. 6 7 466 15. Shahid Z, Sobel JD. Reduced fluconazole susceptibility of Candida albicans 8 467 isolates in women with recurrent vulvovaginal candidiasis: effects of long-term 9 10 468 fluconazole therapy. Diagn Microbiol Infect Dis. 2009;64(3):354-6. 11 12 469 16. Bulik CC, Sobel JD, Nailor MD. Susceptibility profile of vaginal isolates of 13 14 470 Candida albicans prior to and following fluconazole introduction - impact of two 15 471 decades. Mycoses. 2011;54(1):34-8. 16 For peer review only 17 472 17. Kennedy MA, Sobel JD. Vulvovaginal Candidiasis Caused by Non-albicans 18 19 473 Candida Species: New Insights. Curr Infect Dis Rep. 2010;12(6):465-70. 20 474 18. Nurbhai M, Grimshaw J, Watson M, Bond C, Mollison J, Ludbrook A. Oral versus 21 22 475 intra-vaginal imidazole and triazole antifungal treatment of uncomplicated 23 24 476 vulvovaginal candidiasis (thrush). Cochrane Database Syst Rev. 25 26 477 2007(4):Cd002845. 27 478 19. Group AE, Spicer JVDUACAGS-CAg. Therapeutic guidelines : antibiotic. 13ed. 28 29 479 ed: North Melbourne, Vic. : Therapeutic Guidelines Limited, 2006.; 2006. 442p p. 30 31 480 20. Pappas PG, Kauffman CA, Andes D, Benjamin DK, Jr., Calandra TF, Edwards

32 http://bmjopen.bmj.com/ 33 481 JE, Jr., et al. Clinical practice guidelines for the management of candidiasis: 2009 34 482 update by the Infectious Diseases Society of America. Clin Infect Dis. 35 36 483 2009;48(5):503-35. 37 38 484 21. Sobel JD, Brooker D, Stein GE, Thomason JL, Wermeling DP, Bradley B, et al. 39 485 Single oral dose fluconazole compared with conventional clotrimazole topical

40 on September 27, 2021 by guest. Protected copyright. 41 486 therapy of Candida vaginitis. Fluconazole Vaginitis Study Group. Am J Obstet 42 43 487 Gynecol. 1995;172(4 Pt 1):1263-8. 44 45 488 22. Stein GE, Mummaw N. Placebo-controlled trial of itraconazole for treatment of 46 489 acute vaginal candidiasis. Antimicrob Agents Chemother. 1993;37(1):89-92. 47 48 490 23. Sobel JD, Wiesenfeld HC, Martens M, Danna P, Hooton TM, Rompalo A, et al. 49 50 491 Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis. N Engl J 51 Med. 2004;351(9):876-83. 52 492 53 493 54 55 494 56 57 58 17 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 18 of 21 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 495 Contributors 4 5 496 JFL and AKG contributed to the design of this review. JFL drafted the protocol 6 7 497 manuscript, and AKG revised it. JFL and AKG developed the search strategies and 8 498 JFL and RLA will implement them. JFL and AKG will track potential studies, extract 9 10 499 data and assess quality. In case of disagreement between the data extractors, PCG 11 12 500 will advise on the methodology and will work as the referee. JFL, AKG, RLA, ACAS, 13 14 501 APFC and PCG will complete the data synthesis. All authors have approved the final 15 502 version for publication. 16 For peer review only 17 503 18 19 504 Funding 20 505 This research received no specific grant from any funding agency in the 21 22 506 public, commercial or not-for-profit sectors 23 24 507 25 26 508 Competing interests 27 509 None declared. 28 29 510 30 31 511 Acknowledgments

32 http://bmjopen.bmj.com/ 33 512 The authors acknowledge the assistance provided by the Post-Graduate 34 513 Program in Obstetrics and Gynecology of UNICAMP in the direction of literary 35 36 514 research. 37 38 515 39 516 Word Count: 3639

40 on September 27, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 18 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 19 of 21 BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 For peer review only 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31

32 http://bmjopen.bmj.com/ 33 254x190mm (96 x 96 DPI) 34 35 36 37 38 39

40 on September 27, 2021 by guest. Protected copyright. 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from

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1 PRISMA 2009 Checklist 2 3 4 Reported Section/topic # Checklist item 5 on page # 6 7 TITLE 8 Title 1 Identify the report as a systematic review, meta-analysis, or both. 9 X 10 ABSTRACT 11 Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, 12 X participants,For and interventions; peer study appraisal review and synthesis methods; only results; limitations; conclusions and 13 implications of key findings; systematic review registration number. 14 15 INTRODUCTION 16 Rationale 3 Describe the rationale for the review in the context of what is already known. X 17 http://bmjopen.bmj.com/ 18 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, X 19 outcomes, and study design (PICOS). 20 21 METHODS 22 Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide X 23 registration information including registration number. 24 Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, X 25 on September 27, 2021 by guest. Protected copyright. language, publication status) used as criteria for eligibility, giving rationale. 26 27 Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify X 28 additional studies) in the search and date last searched. 29 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be X 30 repeated. 31 32 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, X 33 included in the meta-analysis). 34 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes X 35 for obtaining and confirming data from investigators. 36 37 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and X 38 simplifications made. 39 Risk of bias in individual 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was X 40 studies done at the study or outcome level), and how this information is to be used in any data synthesis. 41 42 Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). X 43 Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency 44 (e.g., I2) for each meta-analysis. 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from

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1 PRISMA 2009 Checklist 2 3 4 Page 1 of 2 5 Reported Section/topic # Checklist item 6 on page # 7 8 Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective X 9 reporting within studies). 10 Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating 11 which were pre-specified. 12 For peer review only 13 RESULTS 14 Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at 15 each stage, ideally with a flow diagram. 16 Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and 17 http://bmjopen.bmj.com/ 18 provide the citations. 19 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). 20 21 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each 22 intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. 23 Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 24 Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 25 on September 27, 2021 by guest. Protected copyright. 26 Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 27 28 DISCUSSION 29 Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to X 30 key groups (e.g., healthcare providers, users, and policy makers). 31 32 Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of X 33 identified research, reporting bias). 34 Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 35 36 FUNDING 37 38 Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the X 39 systematic review. 40 41 From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. 42 doi:10.1371/journal.pmed1000097 43 For more information, visit: www.prisma-statement.org. 44 Page 2 of 2 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open 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 ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2018-027489.R1

Article Type: Protocol

Date Submitted by the 29-Jan-2019 Author:

Primary Subject Obstetrics and gynaecology Heading:

Secondary Subject Heading: Infectious diseases http://bmjopen.bmj.com/

Keywords: Vulvovaginal candidiasis, TREATMENT, vaginitis, prophylaxis

on September 27, 2021 by guest. Protected copyright.

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1 2 3 1 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 6 2 7 8 3 ANTIFUNGAL (ORAL AND VAGINAL) THERAPY FOR RECURRENT 9 10 4 VULVOVAGINAL CANDIDIASIS: A SYSTEMATIC REVIEW PROTOCOL 11 12 1 2 2, 13 5 Juliana Lírio , Paulo Cesar Giraldo , Rose Luce do Amaral Ayane Cristine Alves 14 6 Sarmento3, Ana Paula Ferreira Costa3 Ana Katherine Gonçalves3* 15 16 17 7 18 For peer review only 19 8 1 – MD, master's degree in Obstetrics and Gynecology, State University of 20 9 Campinas, Campinas, Brazil. 21 22 10 2 - PhD. Department of Obstetrics and Gynecology, State University of 23 24 11 Campinas, Campinas, Brazil. 25 26 12 3 - PhD. Post-Graduate Program in Health Sciences, Federal University of Rio 27 13 Grande do Norte, Natal, Brazil. 28 29 14 30 31 15 32 33 16 *Corresponding author: 34 35 17 Ana Katherine Gonçalves

36 http://bmjopen.bmj.com/ 37 38 18 E-mail address: [email protected] 39 19 Phone: 55 84 32154371 40 41 20 42 43 21

44 on September 27, 2021 by guest. Protected copyright. 45 22 46 23 47 48 24 49 50 25 51 26 52 53 27 54 55 28 56 57 29 58 30 59 60 31

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1 2 3 32 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 33 6 7 34 ABSTRACT 8 35 Introduction: Vulvovaginal candidiasis (VVC) is frequent in women worldwide 9 10 36 and usually responds rapidly to topical or oral antifungal therapy. However, some 11 12 37 women develop recurrent vulvovaginal candidiasis (RVVC), which is arbitrarily 13 14 38 defined as four or more episodes every year. RVVC is a debilitating, long-term 15 39 condition that can severely affect the quality of life of women. Most VVC is 16 17 40 diagnosed and treated empirically and women frequently self-treat with over-the- 18 For peer review only 19 41 counter medications that could contribute to an increase in the antifungal 20 42 resistance. The effective treatment of RVVC has been a challenge in daily clinical 21 22 43 practice. This review aims to assess the efficacy of antifungal agents 23 24 44 administered orally or intravaginally for the treatment of RVVC, in order to define 25 26 45 clinical practices that will impact on the reduction of the morbidity and antifungal 27 46 resistance. 28 29 47 Methods and analysis: A comprehensive search of the following databases will 30 31 48 be carried out: PubMed, Embase, Scopus, Web of Science, SciELO, the 32 33 49 Cochrane Central Register of Controlled Trials (CENTRAL), BVS/BIREME, 34 50 CINAHL, and in the clinical trials databases (www.trialscentral.org; 35

36 51 www.controlled-trials.com; www.clinicaltrials.gov). The risk of bias will be http://bmjopen.bmj.com/ 37 38 52 assessed according to the Cochrane Risk of Bias tool. We will perform data 39 53 synthesis using the Review Manager (RevMan) software V.5.2.3. To assess 40 41 54 heterogeneity, we will compute the I2 statistic. 42 43 55 Ethics and dissemination: This study will be a review of published data and it

44 on September 27, 2021 by guest. Protected copyright. 45 56 is not necessary to obtain ethical approval. Findings of this systematic review will 46 57 be published in a peer-reviewed journal. 47 48 58 Trial registration number for International Prospective Register of 49 50 59 Systematic Reviews 2018: International Prospective Register of Systematic 51 52 60 Reviews 2014: CRD42018093817 53 54 61 55 56 57 62 58 59 63 60

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1 2 3 64 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 6 65 7 8 66 Strengths and limitations of this study 9 10 11 67 - The results obtained in this systematic review will indicate through evidence- 12 13 68 based medicine if there is a more effective antifungal therapeutic regimen for the 14 69 treatment of recurrent vulvovaginal candidiasis. 15 16 70 - Two independent reviewers will select the studies included in this review, extract 17 18 71 data without differentFor variables peer and review assess the risk only of bias. 19 - There may be a limitation of outcome from treatment variation, routes of 20 72 21 73 administration, different doses and quality of the randomized trials used in the 22 23 74 systematic review. 24 25 75 - This review and meta-analysis aim to combine the results of different studies 26 76 that have comparable sizes of effect that can be computed. 27 28 77 - However, it may be that we have only a small sample size and a limited number 29 30 78 of studies, which may influence the validity and reliability of the findings 31 32 79 33 80 34 35 81

36 http://bmjopen.bmj.com/ 37 82 38 39 83 40 84 41 42 85 43 86

44 on September 27, 2021 by guest. Protected copyright. 45 87 46 47 88 48 49 89 50 51 90 52 91 53 54 92 55 56 93 57 94 58 59 95 60

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1 2 3 96 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 97 6 7 98 8 99 9 10 100 INTRODUCTION 11 12 101 Description of the condition: 13 14 102 Vulvovaginal candidiasis (VVC) is frequent in women worldwide and usually 15 103 responds rapidly to topical or oral antifungal therapy. However, some women 16 17 104 develop recurrent vulvovaginal candidiasis (RVVC), which is arbitrarily defined as 18 For peer review only 19 105 at least three symptomatic episodes in the previous 12 months. [1,2,3]. 20 106 It is estimated that RVVC affects approximately 138 million women 21 22 107 worldwide annually and 492 million over their lifetimes. [1,2]. Women reported the 23 24 108 period of RVVC to be 1-2 years although a substantial number had symptoms for 25 26 109 4 or 5 years and some very much longer, with risk and symptoms lasting decades. 27 110 [4,5] 28 29 111 C albicans is responsible for the majority of infections in women with RVVC; 30 31 112 however adequate treatment of RVVC requires species determination confirmed 32 33 113 by laboratory findings and effective treatment. [2]. 34 114 Several factors have been associated to RVVC such as: genetic 35

36 115 (polymorphism, familial, ethnicity), immune mechanisms (HIV, uncontrolled http://bmjopen.bmj.com/ 37 38 116 diabetes, steroids, antibiotics, hormone replacement therapy), behavioral (oral 39 117 sex, oral contraceptive, intercourse frequency) and idiopathic. [6-10]. 40 41 118 Fluconazole is inexpensive and well-tolerated medication that is easily 42 43 119 administered orally and is the most used antifungal drug. However, in the last

44 on September 27, 2021 by guest. Protected copyright. 45 120 decade, fluconazole-resistance has been reported of women with RVVC. Earlier 46 121 epidemiologic studies found that almost all women diagnosed with fluconazole- 47 48 122 resistant C albicans had experienced previous exposure to fluconazole. [11]. The 49 50 123 rates of azole resistance are highly variable, and they may be influenced by the 51 prescribing patterns of clinicians for both the treatment of and prophylaxis. 52 124 53 125 Additionally, is still important to recognize that the excessive use and 54 55 126 overuse of such topical agents have had other adverse consequences such as 56 57 127 edema, irritability of the skin and maybe even chronic vulvar pain condition 58 128 (vulvodynia). [12,13]. 59 60 129

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1 2 3 130 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 131 6 7 132 Description of the intervention: 8 133 Current treatment options for vulvovaginal candidiasis include antifungal 9 10 134 agents sold without a prescription for oral or intravaginal use. Fluconazole has 11 12 135 been used extensively while having an unknown impact on fungal susceptibility. 13 14 136 [11]. 15 137 The most commonly used regimen for RVVC consists of 10 to 14 days of 16 17 138 induction therapy with a topical antifungal agent or oral fluconazole, 150mg, 18 For peer review only 19 139 followed by fluconazole, 150mg per week for 6 months. (strong recommendation 20 140 with high quality evidence). [14, 15] It was seen that women with RVVC with 21 22 141 vulvar excoriation, longer disease time and family history of atopic disease are at 23 24 142 greater risk of not responding to maintenance treatment with fluconazole. [16]. 25 26 143 In the last decade, isolated cases of women with RVVC who have not 27 144 responded to fluconazole induction therapy have been reported. After excluding 28 29 145 lack of adherence to treatment, resistance to fluconazole should be considered. 30 31 146 [2, 17-19]. 32 33 147 A previous Cochrane review aimed to compare the clinical cure rate of 34 148 topical versus oral treatment for the treatment of vulvovaginal candidiasis [20] and 35

36 149 found no difference in the efficacy of oral and vaginal treatment but found that http://bmjopen.bmj.com/ 37 38 150 women generally preferred oral treatment. The recommended treatment regimen 39 151 for RVVC, as described in the clinical guidelines [21] whether oral or topical, is 40 41 152 not effective for all women. [17] Side effects reported include headache, 42 43 153 abdominal pain and nausea with oral treatment [22, 23, 24] and dyspareunia or

44 on September 27, 2021 by guest. Protected copyright. 45 154 irritation with vaginal treatment. [24]. In addition, long-term treatments are 46 155 expensive, and approximately 50% of women experience recurrence of 47 48 156 symptoms a few months after treatment completion. [25]. 49 50 157 Effective treatment of RVVC, with adequate control of symptoms and 51 eradication of the fungus, represents a challenge in daily clinical practice. Many 52 158 53 159 antifungal regimens are available for treatment, some of them with adverse 54 55 160 effects that end up reducing women's adherence to treatment. The lack of clear 56 57 161 criteria for indication of available drugs and their free use due to self-medication 58 162 by women has contributed to the increasing antifungal resistance found in some 59 60 163 clinical trials.

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1 2 3 164 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 165 6 7 166 How the intervention might work: 8 167 Antifungal agents generally act as fungistatics and most often work by 9 10 168 just destroying the cell wall. Nowadays, despite the great diversity of antifungal 11 12 169 agents available for vaginal or systemic use and the large number of clinical trials 13 14 170 performed, there are actually very few that compare their efficacy along with the 15 171 risk of developing resistance. 16 17 172 18 For peer review only 19 173 Why it is important to perform this review: 20 174 In order to find a rational use of the antifungal medications available for 21 22 175 the treatment of RVVC, as well as the choice of the best route of administration, 23 24 176 it is necessary to evaluate comparatively the various proposed schemes normally 25 26 177 used. In this way, the choice of the best treatment can be made according to the 27 178 proven and acceptable safety and efficacy dictates. 28 29 179 By avoiding drugs of doubtful or unproven efficacy, as well as high risk / 30 31 180 benefit index, drug combinations of the same formulations or duplicity of drugs 32 33 181 for the same clinical indication, the quality of medical care can be improved. 34 182 This study also contributes to the assessment of whether there is a more cost- 35

36 183 effective and efficient therapeutic approach for the patient and the health system, http://bmjopen.bmj.com/ 37 38 184 between two or more equally effective treatments. 39 185 If there is similarity of efficacy between different antifungal drugs used in 40 41 186 an oral treatment regimen, one can recommend the one that presents less side 42 43 187 effects, more dosage convenience or even lower cost.

44 on September 27, 2021 by guest. Protected copyright. 45 188 In cases of vaginal treatments with superior or similar efficacy to those used 46 189 orally, they may be chosen as the first option, especially for patients with oral side 47 48 190 effects. 49 50 191 Since the sale of antifungal drugs is not subject to prescription control by 51 pharmacies, the indiscriminate use of antifungal drugs by self-medication and 52 192 53 193 without medical prescription has contributed to the increase of antifungal 54 55 194 resistance to these drugs. Knowing the efficacy profile of each drug in the 56 57 195 treatment of recurrent vulvovaginal candidiasis will enable the creation of a 58 196 treatment protocol for the pathology and also decrease the risk of increased 59 60 197 antifungal resistance.

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1 2 3 198 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 199 OBJECTIVES 6 7 200 To evaluate the efficacy of different antifungal drugs usually used orally 8 201 and vaginally in the treatment of RVVC. 9 10 202 11 12 203 METHODS 13 14 204 This systematic review study with probable meta-analysis will follow the 15 205 criteria: Preferred Reporting Items for Systematic Reviews and Meta-Analyzes 16 17 206 (PRISMA) guidelines. This protocol has been registered with the International 18 For peer review only 19 207 Prospective Register of Systematic Reviews, registration number 20 CRD42018093817. 21 208 22 209 23 24 210 Criteria for considering studies for this review 25 26 211 Types of studies: 27 212 Randomized, blind, published and unpublished clinical trials evaluating 28 29 213 treatments for recurrent vulvovaginal candidiasis in immunocompetent women 30 31 214 will be considered for inclusion. 32 33 215 34 216 Types of participants: 35

36 217 Women who will be included in the analysis will have had 4 or more http://bmjopen.bmj.com/ 37 38 218 episodes of vaginal candidiasis confirmed by the presence of symptoms and a 39 219 culture or symptoms and positive microscopy. Women with diabetes mellitus and 40 41 220 pregnant women will be included in the review but analyzed separately in 42 43 221 subgroups.

44 on September 27, 2021 by guest. Protected copyright. 45 222 Women with immunosuppressive conditions or users of 46 223 immunosuppressive drugs will be excluded. 47 48 224 49 50 225 Types of interventions: 51 52 226 Interventions to be considered will be antifungal treatments: antifungal 53 227 drugs administered intravaginally (e.g. butoconazole, clotrimazole, econazole, 54 55 228 fenticonazole, isoconazole, miconazole, omoconazole, oxiconazole, terconazole, 56 57 229 tioconazole, natamycin, sertaconazole nystatin and amphotericin) or oral 58 230 antifungals (e.g. fluconazole, ketoconazole, itraconazole, posaconazole, and 59 60 231 voriconazole)

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1 2 3 232 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 233 The following comparisons will be made: Any treatment versus placebo; 6 7 234 Short duration of treatment versus longer duration of treatment; Systemic versus 8 235 local treatment; Treatment of partner versus placebo; 9 10 236 Comparison of two different classes of drugs; Comparison of different doses of 11 12 237 the same agent 13 14 238 15 239 Types of outcome measures: 16 17 240 Primary Outcomes: Number of clinical recurrences per patient per year 18 For peer review only 19 241 (recurrence defined as clinical characteristics and positive culture or microscopy); 20 242 Proportion of participants with at least one clinical recurrence during the treatment 21 22 243 and follow-up period; 23 24 244 Secondary outcomes: Time for first recurrence; Number of symptomatic 25 26 245 days per year; Number of mycological recurrences per patient per year; 27 246 Proportion of participants with at least one recurrence during treatment and 28 29 247 follow-up period; Duration of symptoms after starting treatment; Complications; 30 31 248 Adverse events and Patient preference 32 33 249 34 250 Search methods for identification of studies 35

36 251 Electronic searches: http://bmjopen.bmj.com/ 37 38 252 We will try to identify as many published studies as unpublished ones, which 39 253 evaluate the interventions that aim at the control of RVVC. We will use the 40 41 254 electronic search in the databases as the manual search. No language 42 43 255 restrictions will be used

44 on September 27, 2021 by guest. Protected copyright. 45 256 46 257 Other sources: 47 48 258 The aim of the computerized bibliographic research will be extended using 49 50 259 the reference lists of selected articles. 51 52 260 53 261 54 55 262 56 57 263 58 264 59 60 265

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1 2 3 266 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 267 6 7 268 Search strategy: 8 269 The search strategy for Pubmed is shown in table 1. 9 10 270 11 12 Table 1 Pubmed search strategy 13 Search items 14 1 candida 15 2 candidiasis 16 17 3 candidosis 18 4 For peer yeasts review only 19 5 vaginitis 20 6 vulvovaginal 21 7 OR /1-6 22 8 antifungal 23 9 butoconazole 24 25 10 clotrimazole 26 11 econazole 27 12 fenticonazole 28 13 isoconazole 29 14 miconazole 30 15 omoconazole 31 32 16 oxiconazole 33 17 terconazole 34 18 tioconazole 35 19 natamycin

36 20 sertaconazole http://bmjopen.bmj.com/ 37 21 amphotericin 38 22 fluconazole 39 40 23 ketoconazole 41 24 itraconazole 42 25 posaconazole 43 26 voriconazole

44 27 nystatin on September 27, 2021 by guest. Protected copyright. 45 28 OR/8-28 46 27 (randomized controlled Trial) 47 48 28 (blind method) 49 29 (clinical Trial) 50 30 OR/27-30 51 31 7 AND 28 AND 30 52 271 53 54 55 272 56 57 273 58 59 60 274

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1 2 3 275 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 6 276 Data collection and analysis 7 Selection of studies: 8 277 9 278 Two review authors (JFL and AKG) will independently evaluate the 10 11 279 eligibility for inclusion of the trials identified by the survey. Disagreements will be 12 13 280 resolved by discussion, involving the contribution of a third author (PCG). The 14 281 trial authors will be contacted if more information is needed before deciding to 15 16 282 include. The selection of the study is summarized in a PRISMA flow diagram 17 18 283 (figure 1). Thus,For papers peer that met the review criteria will be only reviewed in full. After the full 19 20 284 review, papers not considered having adequate methodological quality according 21 285 to the GRADE guidelines will be excluded. 22 23 286 The level of evidence from each study will be defined according to the 24 25 287 Oxford Center for Evidence-Based Medicine definitions. A list of excluded studies 26 will be provided, with a brief mention of the reason for exclusion. 27 288 28 289 29 30 290 Data extraction and management: 31 32 291 We will use the Review Manager software (RevMan 2010) to perform 33 292 statistical analysis. The experimental populations, methods and measurements 34 35 293 of results are considered similar and, in the absence of statistical heterogeneity,

36 http://bmjopen.bmj.com/ 37 294 we will group the data using a fixed model effect. If statistical heterogeneity is 38 39 295 present, we will not group or use a random effects model. 40 296 The data will be entered into the Review Manager software (RevMan 5.3), 41 42 297 which allows the user to enter protocols as well as complete reviews, including 43 298 text, study characteristics, comparison tables and study data, as well as perform

44 on September 27, 2021 by guest. Protected copyright. 45 299 the meta-analysis of the inserted data. 46 47 300 To assess safety and efficacy among the proposed treatments, the 48 49 301 dichotomous data will be extracted from each study and inserted into a 2 × 2 50 51 302 contingency table, with subsequent individual determination of odds ratio (OR), 52 303 to obtain a global summary estimate. 53 54 304 Models of fixed effects or random effects will be chosen depending on the 55 56 305 absence or presence of heterogeneity between the studies. 57 58 306 59 60 307

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1 2 3 308 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 309 Risk of bias assessment: 6 7 310 Two independent reviewers, JL and AKM, will apply the Cochrane Risk of 8 311 Bias Tool to evaluate the random sequence of generation, allocation 9 10 312 concealment, blinding of participants, and evaluation of clinical outcomes. We will 11 12 313 also evaluate data from incomplete results, selective reporting, financing and 13 14 314 potential conflicts of interest associated with individual trials. The risk of bias will 15 315 be classified using predetermined criteria as follows: low, high or unclear 16 17 316 18 For peer review only 19 317 Measurements of treatment effect: 20 318 This will be carried out using the RevMan Analyses statistical package in 21 22 319 Review Manager 5.3. We will calculate the OR for dichotomous data and weight 23 24 320 mean difference (MD) for continuous data with associated 95% CI. 25 26 321 27 322 Unit of analysis issues: 28 29 323 For the cure rate of RVVC, the unit of analysis will be defined as 21 and 30 31 324 30 days after the initiation of therapy. For the recurrence rate of RVVC, 3 months 32 33 325 and 6 months following the intervention will be considered as short-term and long- 34 326 term follow-up, respectively. 35

36 327 http://bmjopen.bmj.com/ 37 38 328 Addressing missing data: 39 329 We will try to get any missing data by contacting the first author or co- 40 41 330 authors of the article via phone, email or post. If we do not receive the necessary 42 43 331 information, data will be excluded from our discussion in the Discussion section.

44 on September 27, 2021 by guest. Protected copyright. 45 332 46 333 Assessment of heterogeneity: 47 48 334 Statistical heterogeneity among the studies will be assessed by the I2 49 50 335 statistic (<25%, without heterogeneity, 25% -50%, moderate heterogeneity, and> 51 50%, strong heterogeneity). When a significant heterogeneity exists between 52 336 53 337 included studies (I2> 50%), a random effects model will be used for the analysis; 54 55 338 otherwise, the fixed effects model will be used. In addition, we will use the Egger 56 57 339 funnel chart to evaluate the possible publication bias. 58 340 59 60 341

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1 2 3 342 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 343 Assessment of reporting biases: 6 7 344 We will use the Egger funnel chart to evaluate the possible publication bias. 8 345 A linear regression approach will be used to assess the asymmetry of the funnel 9 10 346 plot. 11 12 347 13 14 348 Data synthesis 15 349 This will be carried out using the RevMan Analyses statistical package in 16 17 350 Review Manager V.5.3. For dichotomous outcomes, we will derive the OR and 18 For peer review only 19 351 95% CI for each study. Where there is heterogeneity (I² ≥;75%), a random-effect 20 352 model will be used to combine the trials to calculate the relative risk (RR) and 21 22 353 95% CI, using the DerSimonian-Laird algorithm in The Meta for Package, a meta- 23 24 354 analysis package for R. 25 26 355 Other study characteristics and results will be summarized narratively if the meta- 27 356 analysis cannot be performed for all or some of the included studies. 28 29 357 30 31 358 Sensitivity analyses: 32 33 359 We will conduct sensitivity analyses to explore the robustness of the 34 360 findings regarding the study quality and sample size. Sensitivity analyses will be 35

36 361 shown in a summary table. http://bmjopen.bmj.com/ 37 38 362 39 363 Subgroup analyses: 40 41 364 In the subgroup analysis and heterogeneity investigation, we plan to 42 43 365 perform the following subgroup analyzes:

44 on September 27, 2021 by guest. Protected copyright. 45 366 1. Sexually active versus non-sexually active women 46 367 2. Pregnant vs. Non-Pregnant Women 47 48 368 3. Women with diabetes mellitus versus non-diabetic women 49 50 369 4. Intervention - duration: short versus long treatment 51 5. Route of administration: topical versus systemic 52 370 53 371 6. Candida albicans versus non-albicans 54 55 372 56 57 373 58 374 59 60 375

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1 2 3 376 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 377 Confidence in cumulative evidence: 6 7 378 To describe the strength of the evidence for the included data, we will use 8 379 the GRADE (Grading of Recommendation Assessment) system, which assigns 9 10 380 levels of evidence and classifies the strength of the recommendation for health 11 12 381 issues. The quality of the evidence will be identified as high (the true effect is 13 14 382 close to that of the effect estimate), moderate (the true effect is probably close to 15 383 the estimate of the effect, but there is a possibility of being substantially different). 16 17 384 The low may be substantially different from effect estimate) or very low (the true 18 For peer review only 19 385 effect is likely to be substantially different from the effect estimate). The studies 20 386 of moderate to high level of evidence will be included in the review. 21 22 387 23 24 388 Patient and Public Involvement 25 26 389 The research will be performed by a wide and comprehensive search of 27 390 literature from databases and the individual patient data are not included. Thus, 28 29 391 the authors no involved patients in setting the research question, as well as, the 30 31 392 outcome measures, the design and implementation of the study, and the 32 33 393 dissemination of its results. 34 394 35

36 395 DISCUSSION http://bmjopen.bmj.com/ 37 38 396 RVVC is a very common and relevant gynecological problem, with an 39 397 impact on women's health. We intend to analyze the efficacy and safety of oral 40 41 398 and intravaginal antifungal agents for the treatment of RVVC. In theory, the 42 43 399 different antifungals have similar efficacies and both routes promote appropriate

44 on September 27, 2021 by guest. Protected copyright. 45 400 treatment. We hope that our analysis will provide information on the most 46 401 effective therapeutic regimens for this prevalent disease, in order to justify the 47 48 402 elaboration of an effective treatment protocol. 49 50 403 51 Ethics and dissemination 52 404 53 405 This study will be a review of the previously published data so it will not be 54 55 406 necessary to obtain approval from the Ethics Committee. Findings from this 56 57 407 systematic review will be published in a peer-reviewed journal. 58 408 59 60 409

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1 2 3 410 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 411 Competing interests or state 6 7 412 None declared 8 413 9 10 414 REFERENCES 11 12 415 13 416 1. Denning DW, Kneale M, Sobel JD, Rautemaa-Richardson R. Global burden of 14 15 417 recurrent vulvovaginal candidiasis: a systematic review. Lancet Infect Dis. 16 418 2018;18(11):e339-e347. 17 18 419 2. Sobel JD. For Recurrent peer vulvovaginal review candidiasis. only Am J Obstet Gynecol. 19 20 420 2016;214(1):15-21. 21 22 421 3. Blostein F, Levin-Sparenberg E, Wagner J, Foxman B. Recurrent vulvovaginal 23 422 candidiasis. Ann Epidemiol. 2017 ;27(9):575-582.e3. 24 25 423 4. Foxman B, Muraglia R, Dietz JP, Sobel JD, Wagner J. Prevalence of recurrent 26 27 424 vulvovaginal candidiasis In 5 European countries and the United States: results 28 from an internet panel survey. J Low Genit Tract Dis 2013;17:340-5. 29 425 30 426 5. Ilkit M, Guzel AB. The epidemiology, pathogenesis, and diagnosis of 31 32 427 vulvovaginal candidosis: a mycological perspective. Crit RevMicrobiol 33 34 428 2011;37:250-61. 35 429 6. Rosentul DC, Delsing CE, Jaeger M, et al. Gene polymorphisms in pattern

36 http://bmjopen.bmj.com/ 37 430 recognition receptors and susceptibility to idiopathic recurrent 38 39 431 vulvovaginal candidiasis. Front Microbiol2014;5:1-7. 40 41 432 7. Ben-Ali M, Corre B, Manry J, et al. Functional characterization of naturally 42 433 occurring genetic variants in the human TLR1-2-6 gene family. Hum Mutat 43

44 434 2011;32:643-52. on September 27, 2021 by guest. Protected copyright. 45 46 435 8. Romani L. Immunity to fungal infections. Nat Rev Immunol 2011;11:275-88. 47 9. Wojitani MD, de Aguiar LM, Baracat EC, Linhares IM. Association between 48 436 49 437 mannose binding lectin and interleukin-1 receptor antagonist gene 50 51 438 polymorphisms and recurrent vulvovaginal candidiasis. Arch Gynecol Obstet 52 53 439 2011;285:149-53. 54 440 10. Nedovic B, Posteraro B, Leoncini E, et al. Mannose-binding lectin codon 54 55 56 441 gene polymorphism and vulvovaginal candidiasis: a systematic 57 58 442 review and meta-analysis. Biomed ResInt 2014;2014:738298. 59 60

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1 2 3 443 11. Marchaim D, Lemanek L, Bheemreddy S, Kaye KS, Sobel JD. Fluconazole- 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 444 resistant Candida albicans vulvovaginitis. Obstet Gynecol. 2012;120:1407-14. 6 7 445 12.Leusink P, van de Pasch S, Teunissen D, Laan ET, Lagro-Janssen AL Leusink 8 446 P, et al. The Relationship Between Vulvovaginal Candidiasis and Provoked 9 10 447 Vulvodynia: A Systematic Review. J Sex Med. 2018;15(9):1310-1321. 11 12 448 13. Leusink P, van Moorsel D, Bor H, et al. Is uncertain vulvovaginal candidiasis 13 14 449 a marker or vulvodynia? A study in a Dutch general practice research database. 15 450 BJGP Open. 2017;31;1(2): 16 17 451 14. Liao X, Qiu H, Li R, et al. Risk factors for fluconazole-resistant invasive 18 For peer review only 19 452 candidiasis in intensive care unit patients: an analysis from the China Survey of 20 453 Candidiasis study. J Crit Care. 2015;30(4):862.e1–e5. 21 22 454 15. Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky- 23 24 455 Zeichner L, et al. Clinical Practice Guideline for the Management of Candidiasis: 25 26 456 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 27 457 2016;62(4):e1-50. 28 29 458 16. Rosa MI, Silva BR, Pires PS, Silva FR, Silva NC, Souza SL, et al. Weekly 30 31 459 fluconazole therapy for recurrent vulvovaginal candidiasis: a systematic review 32 33 460 and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2013;167(2):132-6. 34 461 17. Donders GGG, Grinceviciene S, Bellen G, Jaeger M, Ten Oever J, Netea MG. 35

36 462 Is non-response to fluconazole maintenance therapy for recurrent Candida http://bmjopen.bmj.com/ 37 38 463 vaginitis related to sensitization to atopic reactions? Am J Reprod Immunol. 39 464 2018;79(4):e12811. 40 41 465 18. Bulik CC, Sobel JD, Nailor MD. Susceptibility profile of vaginal isolates of 42 43 466 Candida albicans prior to and following fluconazole introduction - impact of two

44 on September 27, 2021 by guest. Protected copyright. 45 467 decades. Mycoses. 2011;54(1):34-8. 46 468 19. Kennedy MA, Sobel JD. Vulvovaginal Candidiasis Caused by Non-albicans 47 48 469 Candida Species: New Insights. Curr Infect Dis Rep. 2010;12(6):465-70. 49 50 470 20. Nurbhai M, Grimshaw J, Watson M, Bond C, Mollison J, Ludbrook A. Oral 51 versus intra-vaginal imidazole and triazole antifungal treatment of uncomplicated 52 471 53 472 vulvovaginal candidiasis (thrush). Cochrane Database Syst Rev. 54 55 473 2007(4):Cd002845. 56 57 474 21. Group AE, Spicer JVDUACAGS-CAg. Therapeutic guidelines : antibiotic. 58 475 13ed. ed: North Melbourne, Vic. : Therapeutic Guidelines Limited, 2006.; 2006. 59 60 476 442p p.

15 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml BMJ Open Page 16 of 20

1 2 3 477 22. Pappas PG, Kauffman CA, Andes D, Benjamin DK, Jr., Calandra TF, 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 478 Edwards JE, Jr., et al. Clinical practice guidelines for the management of 6 7 479 candidiasis: 2009 update by the Infectious Diseases Society of America. Clin 8 480 Infect Dis. 2009;48(5):503-35. 9 10 481 23. Sobel JD, Brooker D, Stein GE, et al. Single oral dose fluconazole compared 11 12 482 with conventional clotrimazole topical therapy of Candida vaginitis. Fluconazole 13 14 483 Vaginitis Study Group. Am J Obstet Gynecol. 1995;172(4 Pt 1):1263-8. 15 484 24. Stein GE, Mummaw N. Placebo-controlled trial of itraconazole for treatment 16 17 485 of acute vaginal candidiasis. Antimicrob Agents Chemother. 1993;37(1):89-92. 18 For peer review only 19 486 25. Sobel JD, Wiesenfeld HC, Martens M, Danna P, Hooton TM, Rompalo A, et 20 487 al. Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis. N 21 22 488 Engl J Med. 2004;351(9):876-83. 23 24 489 25 26 490 Contributors 27 491 JFL and AKG contributed to the design of this review. JFL drafted the protocol 28 29 492 manuscript, and AKG revised it. JFL and AKG developed the search strategies 30 31 493 and JFL and RLA will implement them. JFL and AKG will track potential studies, 32 33 494 extract data and assess quality. In case of disagreement between the data 34 495 extractors, PCG will advise on the methodology and will work as the referee. JFL, 35

36 496 AKG, RLA, ACAS, APFC and PCG will complete the data synthesis. All authors http://bmjopen.bmj.com/ 37 38 497 have approved the final version for publication. 39 498 40 41 499 Funding 42 43 500 This research received no specific grant from any funding agency in the

44 on September 27, 2021 by guest. Protected copyright. 45 501 public, commercial or not-for-profit sectors 46 502 47 48 503 Competing interests 49 50 504 None declared. 51 52 505 53 506 54 55 507 56 57 508 58 509 59 60 510

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1 2 3 511 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 512 6 7 513 Acknowledgments 8 514 The authors acknowledge the assistance provided by the Post-Graduate 9 10 515 Program in Obstetrics and Gynecology of UNICAMP in the direction of literary 11 12 516 research. 13 14 517 15 518 Word Count: 3639 16 17 519 18 For peer review only 19 520 Figure legends: Figure 1 – Flow Diagram of the search of eligible studies 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35

36 http://bmjopen.bmj.com/ 37 38 39 40 41 42 43

44 on September 27, 2021 by guest. Protected copyright. 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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32 http://bmjopen.bmj.com/ 33 34 35 36 37 38 39

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1 PRISMA 2009 Checklist 2 3 4 Reported Section/topic # Checklist item 5 on page # 6 7 TITLE 8 Title 1 Identify the report as a systematic review, meta-analysis, or both. 9 1 10 ABSTRACT 11 Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, 12 2 participants,For and interventions; peer study appraisalreview and synthesis methods; only results; limitations; conclusions and 13 implications of key findings; systematic review registration number. 14 15 INTRODUCTION 16 Rationale 3 Describe the rationale for the review in the context of what is already known. 4 17 http://bmjopen.bmj.com/ 18 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, 7 19 outcomes, and study design (PICOS). 20 21 METHODS 22 Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide 2 23 registration information including registration number. 2 24 Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, 7 25 on September 27, 2021 by guest. Protected copyright. language, publication status) used as criteria for eligibility, giving rationale. 26 27 Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify 8 28 additional studies) in the search and date last searched. 29 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be 8-9 30 repeated. 31 32 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, 9 33 included in the meta-analysis). 34 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes 10 35 for obtaining and confirming data from investigators. 36 37 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and 10 38 simplifications made. 39 Risk of bias in individual 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was 11 40 studies done at the study or outcome level), and how this information is to be used in any data synthesis. 41 42 Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 11-13 43 Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency 11-13 44 (e.g., I2) for each meta-analysis. 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from

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1 PRISMA 2009 Checklist 2 3 4 Page 1 of 2 5 Reported Section/topic # Checklist item 6 on page # 7 8 Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective 11-13 9 reporting within studies). 10 Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating 12 11 which were pre-specified. 12 For peer review only 13 RESULTS 14 Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at X 15 each stage, ideally with a flow diagram. 16 Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and 17 http://bmjopen.bmj.com/ X 18 provide the citations. 19 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). X 20 21 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each X 22 intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. 23 Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. X 24 Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). 25 on September 27, 2021 by guest. Protected copyright. X 26 Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). X 27 28 DISCUSSION 29 Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to 12 30 key groups (e.g., healthcare providers, users, and policy makers). 31 32 Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of 3 33 identified research, reporting bias). 34 Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. X 35 36 FUNDING 37 38 Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the 16 39 systematic review. 40 41 From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. 42 doi:10.1371/journal.pmed1000097 43 For more information, visit: www.prisma-statement.org. 44 Page 2 of 2 45 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open 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 ForJournal: peerBMJ Open review only Manuscript ID bmjopen-2018-027489.R2

Article Type: Protocol

Date Submitted by the 11-Mar-2019 Author:

Primary Subject Obstetrics and gynaecology Heading:

Secondary Subject Heading: Infectious diseases http://bmjopen.bmj.com/

Keywords: Vulvovaginal candidiasis, TREATMENT, vaginitis, prophylaxis

on September 27, 2021 by guest. Protected copyright.

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml Page 1 of 19 BMJ Open

1 2 3 1 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 6 2 ANTIFUNGAL (ORAL AND VAGINAL) THERAPY FOR RECURRENT 7 VULVOVAGINAL CANDIDIASIS: A SYSTEMATIC REVIEW PROTOCOL 8 3 9 10 4 Juliana Lírio1, Paulo Cesar Giraldo2, Rose Luce do Amaral2, Ayane Cristine Alves 11 3 3 3* 12 5 Sarmento , Ana Paula Ferreira Costa Ana Katherine Gonçalves 13 14 6 15 16 7 1 – MD, master's degree in Obstetrics and Gynecology, State University of 17 18 8 Campinas, Campinas,For Brazil.peer Email: review [email protected] only 19 2 - PhD. Department of Obstetrics and Gynecology, State University of 20 9 21 10 Campinas, Campinas, Brazil. Email: [email protected] / 22 23 11 [email protected] 24 25 12 3 - PhD. Post-Graduate Program in Health Sciences, Federal University of Rio 26 13 Grande do Norte, Natal, Brazil. Email: [email protected] / ana-paula- 27 28 14 [email protected] 29 30 15 31 32 16 33 34 17 *Corresponding author: 35

36 18 Ana Katherine Gonçalves http://bmjopen.bmj.com/ 37 38 E-mail address: [email protected] 39 19 40 20 Phone: 55 84 32154371 41 42 21 43 22

44 on September 27, 2021 by guest. Protected copyright. 45 23 46 47 24 48 49 25 50 51 26 52 27 53 54 28 55 56 29 57 30 58 59 31 60

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1 2 3 64 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 6 65 Strengths and limitations of this study 7 8 66 . 9 10 11 67 - Two independent reviewers will select studies, extract data without different 12 13 68 variables and assess the risk of bias, to indicate through evidence-based 14 69 medicine if there is a more effective antifungal therapeutic regimen for the 15 16 70 treatment of recurrent vulvovaginal candidiasis. 17 18 71 - There may beFor a limitation peer of outcome review from treatment only variation, routes of 19 administration, different doses and quality of the randomized trials used in the 20 72 21 73 systematic review. 22 23 74 - This review and meta-analysis will combine the results of various studies that 24 25 75 have comparable sizes of an effect that can be computed. 26 76 - However, it may be that we have only a small sample size and a limited 27 28 77 number of studies, which may influence the validity and reliability of the findings 29 30 78 31 32 79 33 80 34 35 81

36 http://bmjopen.bmj.com/ 37 82 38 39 83 40 84 41 42 85 43 86

44 on September 27, 2021 by guest. Protected copyright. 45 87 46 47 88 48 49 89 50 51 90 52 91 53 54 92 55 56 93 INTRODUCTION 57 94 Description of the condition: 58 59 60

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1 2 3 95 Vulvovaginal candidiasis (VVC) is frequent in women worldwide and usually 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 96 responds rapidly to topical or oral antifungal therapy. However, some women 6 7 97 develop recurrent vulvovaginal candidiasis (RVVC), which is arbitrarily defined as 8 98 at least three symptomatic episodes in the previous 12 months. [1,2,3]. 9 10 99 It is estimated that RVVC affects approximately 138 million women 11 12 100 worldwide annually and 492 million over their lifetimes. [1,2]. Women reported the 13 14 101 period of RVVC to be 1-2 years although a substantial number had symptoms for 15 102 4 or 5 years and some very much longer, with risk and symptoms lasting decades. 16 17 103 [4,5] 18 For peer review only 19 104 C albicans is responsible for the majority of infections in women with RVVC; 20 105 however adequate treatment of RVVC requires species determination confirmed 21 22 106 by laboratory findings and effective treatment. [2]. 23 24 107 Several factors have been associated to RVVC such as: genetic 25 26 108 (polymorphism, familial, ethnicity), immune mechanisms (HIV, uncontrolled 27 109 diabetes, steroids, antibiotics, hormone replacement therapy), behavioral (oral 28 29 110 sex, oral contraceptive, intercourse frequency) and idiopathic. [6-10]. 30 31 111 Fluconazole is inexpensive and well-tolerated medication that is easily 32 33 112 administered orally and is the most used antifungal drug. However, in the last 34 113 decade, fluconazole-resistance has been reported of women with RVVC. Earlier 35

36 114 epidemiologic studies found that almost all women diagnosed with fluconazole- http://bmjopen.bmj.com/ 37

38 115 resistant C albicans had experienced previous exposure to fluconazole. [11]. The 39 116 rates of azole resistance are highly variable, and they may be influenced by the 40 41 117 prescribing patterns of clinicians for both the treatment of and prophylaxis. 42 43 118 Additionally, is still important to recognize that the excessive use and

44 on September 27, 2021 by guest. Protected copyright. 45 119 overuse of such topical agents have had other adverse consequences such as 46 120 edema, irritability of the skin and maybe even chronic vulvar pain condition 47 48 121 (vulvodynia). [12,13]. 49 50 122 Furthermore, it is recognized that there are several factors (genetics, 51 polymorphisms, behavioral and host factors), associated with the pathogenesis 52 123 53 124 of RVVC. In this context, it is unlikely to find one regimen fit for all patients. 54 55 125 However, no published studies are comparing different antifungal regimens; thus, 56 57 126 this review based on evidence must be useful for practitioners and physicians. 58 127 59 60 128

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1 2 3 129 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 130 6 7 131 8 132 Description of the intervention: 9 10 133 Current treatment options for vulvovaginal candidiasis include antifungal 11 12 134 agents sold without a prescription for oral or intravaginal use. Fluconazole has 13 14 135 been used extensively while having an unknown impact on fungal susceptibility. 15 136 [11]. 16 17 137 The most commonly used regimen for RVVC consists of 10 to 14 days of 18 For peer review only 19 138 induction therapy with a topical antifungal agent or oral fluconazole, 150mg, 20 139 followed by fluconazole, 150mg per week for 6 months. (strong recommendation 21 22 140 with high quality evidence). [14, 15] It was seen that women with RVVC with 23 24 141 vulvar excoriation, longer disease time and family history of atopic disease are at 25 26 142 greater risk of not responding to maintenance treatment with fluconazole. [16]. 27 143 In the last decade, isolated cases of women with RVVC who have not 28 29 144 responded to fluconazole induction therapy have been reported. After excluding 30 31 145 lack of adherence to treatment, resistance to fluconazole should be considered. 32 33 146 [2, 17-19]. 34 147 A previous Cochrane review aimed to compare the clinical cure rate of 35

36 148 topical versus oral treatment for the treatment of vulvovaginal candidiasis [20] and http://bmjopen.bmj.com/ 37 38 149 found no difference in the efficacy of oral and vaginal treatment but found that 39 150 women generally preferred oral treatment. The recommended treatment regimen 40 41 151 for RVVC, as described in the clinical guidelines [21] whether oral or topical, is 42 43 152 not effective for all women. [17] Side effects reported include headache,

44 on September 27, 2021 by guest. Protected copyright. 45 153 abdominal pain and nausea with oral treatment [22, 23, 24] and dyspareunia or 46 154 irritation with vaginal treatment. [24]. In addition, long-term treatments are 47 48 155 expensive, and approximately 50% of women experience recurrence of 49

50 156 symptoms a few months after treatment completion. [25]. 51 Effective treatment of RVVC, with adequate control of symptoms and 52 157 53 158 eradication of the fungus, represents a challenge in daily clinical practice. Many 54 55 159 antifungal regimens are available for treatment, some of them with adverse 56 57 160 effects that end up reducing women's adherence to treatment. The lack of clear 58 161 criteria for indication of available drugs and their free use due to self-medication 59 60

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1 2 3 162 by women has contributed to the increasing antifungal resistance found in some 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 163 clinical trials. 6 7 164 8 165 9 10 166 How the intervention might work: 11 12 167 Antifungal agents generally act as fungistatics and most often work by 13 14 168 just destroying the cell wall. Nowadays, despite the great diversity of antifungal 15 169 agents available for vaginal or systemic use and the large number of clinical trials 16 17 170 performed, there are actually very few that compare their efficacy along with the 18 For peer review only 19 171 risk of developing resistance. 20 172 21 22 173 Why it is important to perform this review: 23 24 174 In order to find a rational use of the antifungal medications available for 25 26 175 the treatment of RVVC, as well as the choice of the best route of administration, 27 176 it is necessary to evaluate comparatively the various proposed schemes normally 28 29 177 used. In this way, the choice of the best treatment can be made according to the 30 31 178 proven and acceptable safety and efficacy dictates. 32 33 179 By avoiding drugs of doubtful or unproven efficacy, as well as high risk / 34 180 benefit index, drug combinations of the same formulations or duplicity of drugs 35

36 181 for the same clinical indication, the quality of medical care can be improved. http://bmjopen.bmj.com/ 37 38 182 This study also contributes to the assessment of whether there is a more cost- 39 183 effective and efficient therapeutic approach for the patient and the health system, 40 41 184 between two or more equally effective treatments. 42 43 185 If there is similarity of efficacy between different antifungal drugs used in

44 on September 27, 2021 by guest. Protected copyright. 45 186 an oral treatment regimen, one can recommend the one that presents less side 46 187 effects, more dosage convenience or even lower cost. 47 48 188 In cases of vaginal treatments with superior or similar efficacy to those used 49 50 189 orally, they may be chosen as the first option, especially for patients with oral side 51 effects. 52 190 53 191 Since the sale of antifungal drugs is not subject to prescription control by 54 55 192 pharmacies, the indiscriminate use of antifungal drugs by self-medication and 56 57 193 without medical prescription has contributed to the increase of antifungal 58 194 resistance to these drugs. Knowing the efficacy profile of each drug in the 59 60 195 treatment of recurrent vulvovaginal candidiasis will enable the creation of a

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1 2 3 196 treatment protocol for the pathology and also decrease the risk of increased 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 197 antifungal resistance. 6 7 198 8 199 9 10 200 OBJECTIVES 11 12 201 To evaluate the efficacy of different antifungal drugs usually used orally 13 14 202 and vaginally in the treatment of RVVC. 15 203 16 17 204 METHODS 18 For peer review only 19 205 This systematic review study with probable meta-analysis will follow the 20 21 206 criteria: Preferred Reporting Items for Systematic Reviews and Meta-Analyzes 22 207 (PRISMA) guidelines. This protocol has been registered with the International 23 24 208 Prospective Register of Systematic Reviews, registration number 25 26 209 CRD42018093817. 27 210 28 29 211 Criteria for considering studies for this review 30 31 212 Types of studies: 32 33 213 Randomized, blind, published and unpublished clinical trials evaluating 34 214 treatments for recurrent vulvovaginal candidiasis in immunocompetent women 35

36 215 will be considered for inclusion. http://bmjopen.bmj.com/ 37 38 216 39 40 217 Types of participants: 41 218 Women who will be included in the analysis will have had 4 or more 42 43 219 episodes of vaginal candidiasis confirmed by the presence of symptoms and a

44 on September 27, 2021 by guest. Protected copyright. 45 220 culture or symptoms and positive microscopy. Women with diabetes mellitus and 46 221 pregnant women will be included in the review but analyzed separately in 47 48 222 subgroups. Women with immunosuppressive conditions or users of 49 50 223 immunosuppressive drugs will be excluded. 51 52 224 53 225 Types of interventions: 54 55 226 Interventions to be considered will be antifungal treatments: antifungal 56 57 227 drugs administered intravaginally (e.g. butoconazole, clotrimazole, econazole, 58 fenticonazole, isoconazole, miconazole, omoconazole, oxiconazole, terconazole, 59 228 60 229 tioconazole, natamycin, sertaconazole nystatin and amphotericin) or oral

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1 2 3 230 antifungals (e.g. fluconazole, ketoconazole, itraconazole, posaconazole, and 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 231 voriconazole) 6 7 232 The following comparisons will be made: Any treatment versus placebo; 8 233 Short duration of treatment versus longer duration of treatment; Systemic versus 9 10 234 local treatment; Treatment of partner versus placebo; 11 12 235 Comparison of two different classes of drugs; Comparison of different doses of 13 14 236 the same agent 15 237 16 17 238 Types of outcome measures: 18 For peer review only 19 239 Primary Outcomes: Number of clinical recurrences per patient per year 20 240 (recurrence defined as clinical characteristics and positive culture or microscopy); 21 22 241 Proportion of participants with at least one clinical recurrence during the treatment 23 24 242 and follow-up period; 25 26 243 Secondary outcomes: Time for first recurrence; Number of symptomatic 27 244 days per year; Number of mycological recurrences per patient per year; 28 29 245 Proportion of participants with at least one recurrence during treatment and 30 31 246 follow-up period; Duration of symptoms after starting treatment; Complications; 32 33 247 Adverse events and Patient preference 34 248 35

36 249 Search methods for identification of studies http://bmjopen.bmj.com/ 37 38 250 Electronic searches: 39 251 We will try to identify as many published studies as unpublished ones, which 40 41 252 evaluate the interventions that aim at the control of RVVC. We will use the 42 43 253 electronic search in the databases as the manual search. No language

44 on September 27, 2021 by guest. Protected copyright. 45 254 restrictions will be used. The list of Databases is shown in table 1. 46 255 47 48 Table 1 - List of Databases 49 PubMed 50 51 Embase, 52 Scopus 53 54 Web of Science 55 SciELO, 56 57 The Cochrane Central Register of Controlled Trials (CENTRAL) 58 BVS/BIREME 59 60 CINAHL

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1 2 3 The clinical trials databases (www.trialscentral.org; www.controlled-trials.com; www.clinicaltrials.gov

4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 256 6 257 Other sources: 7 8 258 The aim of the computerized bibliographic research will be extended using 9 10 259 the reference lists of selected articles. 11 12 260 13 261 Search strategy: 14 15 262 The search strategy for Pubmed is shown in table 2. 16 17 263 18 For Tablepeer 2 - Pubmed review search strategy only 19 Search items 20 1 candida 21 2 candidiasis 22 3 candidosis 23 4 yeasts 24 5 vaginitis 25 6 vulvovaginal 26 7 OR /1-6 27 8 antifungal 28 9 butoconazole 29 10 clotrimazole 30 11 econazole 31 12 fenticonazole 32 13 isoconazole 33 14 miconazole 34 15 omoconazole 35 16 oxiconazole

36 http://bmjopen.bmj.com/ 17 terconazole 37 18 tioconazole 38 19 natamycin 39 20 sertaconazole 40 21 amphotericin 41 22 fluconazole 42 23 ketoconazole 43 24 itraconazole

44 on September 27, 2021 by guest. Protected copyright. 25 posaconazole 45 26 voriconazole 46 27 nystatin 47 28 OR/8-28 48 27 (randomized controlled Trial) 49 28 (blind method) 50 29 (clinical Trial) 51 30 OR/27-30 52 31 7 AND 28 AND 30 53 54 264 55 56 265 57 58 59 266 60

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1 2 3 267 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 6 268 Data collection and analysis 7 Selection of studies: 8 269 9 270 Two review authors (JFL and AKG) will independently evaluate the 10 11 271 eligibility for inclusion of the trials identified by the survey. Disagreements will be 12 13 272 resolved by discussion, involving the contribution of a third author (PCG). The 14 273 trial authors will be contacted if more information is needed before deciding to 15 16 274 include. The selection of the study is summarized in a PRISMA flow diagram 17 18 275 (figure 1). Thus,For papers peer that met the review criteria will be only reviewed in full. After the full 19 20 276 review, papers not considered having adequate methodological quality according 21 277 to the GRADE guidelines will be excluded. A list of excluded studies will be 22 23 278 provided, with a brief mention of the reason for exclusion. 24 25 279 26 Data extraction and management: 27 280 28 281 We will use the Review Manager software (RevMan 2010) to perform 29 30 282 statistical analysis. The experimental populations, methods and measurements 31 32 283 of results are considered similar and, in the absence of statistical heterogeneity, 33 284 we will group the data using a fixed model effect. If statistical heterogeneity is 34 35 285 present, we will not group or use a random effects model.

36 http://bmjopen.bmj.com/ 37 286 The data will be entered into the Review Manager software (RevMan 5.3), 38 39 287 which allows the user to enter protocols as well as complete reviews, including 40 288 text, study characteristics, comparison tables and study data, as well as perform 41 42 289 the meta-analysis of the inserted data. 43 290 To assess safety and efficacy among the proposed treatments, the

44 on September 27, 2021 by guest. Protected copyright. 45 291 dichotomous data will be extracted from each study and inserted into a 2 × 2 46 47 292 contingency table, with subsequent individual determination of odds ratio (OR), 48 49 293 to obtain a global summary estimate. 50 51 294 Models of fixed effects or random effects will be chosen depending on the 52 295 absence or presence of heterogeneity between the studies. 53 54 296 55 56 297 Risk of bias assessment: 57 58 298 Two independent reviewers, JL and AKM, will apply the Cochrane Risk of 59 299 Bias Tool to evaluate the random sequence of generation, allocation 60

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1 2 3 300 concealment, blinding of participants, and evaluation of clinical outcomes. We will 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 301 also evaluate data from incomplete results, selective reporting, financing and 6 7 302 potential conflicts of interest associated with individual trials. The risk of bias will 8 303 be classified using predetermined criteria as follows: low, high or unclear 9 10 304 11 12 305 Measurements of treatment effect: 13 14 306 This will be carried out using the RevMan Analyses statistical package in 15 307 Review Manager 5.3. We will calculate the OR for dichotomous data and weight 16 17 308 mean difference (MD) for continuous data with associated 95% CI. 18 For peer review only 19 309 20 310 Unit of analysis issues: 21 22 311 For the cure rate of RVVC, the unit of analysis will be defined as 21 and 23 24 312 30 days after the initiation of therapy. For the recurrence rate of RVVC, 3 months 25 26 313 and 6 months following the intervention will be considered as short-term and long- 27 314 term follow-up, respectively. 28 29 315 30 31 316 Addressing missing data: 32 33 317 We will try to get any missing data by contacting the first author or co- 34 318 authors of the article via phone, email or post. If we do not receive the necessary 35

36 319 information, data will be excluded from our discussion in the Discussion section. http://bmjopen.bmj.com/ 37 38 320 39 321 Assessment of heterogeneity: 40 41 322 Statistical heterogeneity among the studies will be assessed by the I2 42 43 323 statistic (<25%, without heterogeneity, 25% -50%, moderate heterogeneity, and>

44 on September 27, 2021 by guest. Protected copyright. 45 324 50%, strong heterogeneity). When a significant heterogeneity exists between 46 325 included studies (I2> 50%), a random effects model will be used for the analysis; 47 48 326 otherwise, the fixed effects model will be used. In addition, we will use the Egger 49 50 327 funnel chart to evaluate the possible publication bias. 51 52 328 53 329 Assessment of reporting biases: 54 55 330 We will use the Egger funnel chart to evaluate the possible publication bias. 56 57 331 A linear regression approach will be used to assess the asymmetry of the funnel 58 332 plot. 59 60 333

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1 2 3 334 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 335 6 7 336 Data synthesis 8 337 This will be carried out using the RevMan Analyses statistical package in 9 10 338 Review Manager V.5.3. For dichotomous outcomes, we will derive the OR and 11 12 339 95% CI for each study. Where there is heterogeneity (I² ≥;75%), a random-effect 13 14 340 model will be used to combine the trials to calculate the relative risk (RR) and 15 341 95% CI, using the DerSimonian-Laird algorithm in The Meta for Package, a meta- 16 17 342 analysis package for R. 18 For peer review only 19 343 Other study characteristics and results will be summarized narratively if the meta- 20 344 analysis cannot be performed for all or some of the included studies. 21 22 345 23 24 346 Sensitivity analyses: 25 26 347 We will conduct sensitivity analyses to explore the robustness of the 27 348 findings regarding the study quality and sample size. Sensitivity analyses will be 28 29 349 shown in a summary table. 30 31 350 32 33 351 Subgroup analyses: 34 352 In the subgroup analysis and heterogeneity investigation, we plan to 35

36 353 perform the following subgroup analyzes: http://bmjopen.bmj.com/ 37 38 354 1. Sexually active versus non-sexually active women 39 355 2. Pregnant vs. Non-Pregnant Women 40 41 356 3. Women with diabetes mellitus versus non-diabetic women 42 43 357 4. Intervention - duration: short versus long treatment

44 on September 27, 2021 by guest. Protected copyright. 45 358 5. Route of administration: topical versus systemic 46 359 6. Candida albicans versus non-albicans 47 48 360 49 50 361 Confidence in cumulative evidence: 51 To describe the strength of the evidence for the included data, we will use 52 362 53 363 the GRADE (Grading of Recommendation Assessment) system, which assigns 54 55 364 levels of evidence and classifies the strength of the recommendation for health 56 57 365 issues. The quality of the evidence will be identified as high (the true effect is 58 366 close to that of the effect estimate), moderate (the true effect is probably close to 59 60 367 the estimate of the effect, but there is a possibility of being substantially different).

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1 2 3 368 The low may be substantially different from effect estimate) or very low (the true 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 369 effect is likely to be substantially different from the effect estimate). The studies 6 7 370 of moderate to high level of evidence will be included in the review. 8 371 9 10 372 Patient and Public Involvement 11 12 373 The research will be performed by a wide and comprehensive search of 13 14 374 literature from databases and the individual patient data are not included. Thus, 15 375 the authors no involved patients in setting the research question, as well as, the 16 17 376 outcome measures, the design and implementation of the study, and the 18 For peer review only 19 377 dissemination of its results. 20 378 21 22 379 DISCUSSION 23 24 380 RVVC is a prevalent and relevant gynecological problem, with an impact on 25 26 381 women's health. Considerable progress has been made in understanding the 27 382 pathogenesis of RVVC. It is recognized that diversified factors (genetics, 28 29 383 polymorphisms, behavioral, hormonal and host factor), are involved in this 30 31 384 process. Thus, it is unlikely to find one regimen fit for all patients. However, no 32 33 385 published studies are comparing different antifungal regimens, and in theory, 34 386 differently in the clinical practice, the different antifungals have similar efficacies, 35

36 387 and both routes promote appropriate treatment. In this context, we intend to http://bmjopen.bmj.com/ 37 38 388 identify the most effective and safe oral and intravaginal antifungal agents for 39 389 most women, so this review based on evidence must be useful for practitioners 40 41 390 and physicians. 42 43 391 This analysis will provide information on the most effective therapeutic regimens

44 on September 27, 2021 by guest. Protected copyright. 45 392 for this prevalent disease, to justify the elaboration of an effective treatment 46 393 protocol. 47 48 394 49 50 395 Ethics and dissemination 51 This study will be a review of the previously published data so it will not be 52 396 53 397 necessary to obtain approval from the Ethics Committee. Findings from this 54 55 398 systematic review will be published in a peer-reviewed journal. 56 57 399 58 59 400 60 401

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1 2 3 402 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 403 REFERENCES 6 7 404 8 405 1. Denning DW, Kneale M, Sobel JD, Rautemaa-Richardson R. Global burden of 9 10 406 recurrent vulvovaginal candidiasis: a systematic review. Lancet Infect Dis. 11 407 2018;18(11):e339-e347. 12 13 408 2. Sobel JD. Recurrent vulvovaginal candidiasis. Am J Obstet Gynecol. 14 15 409 2016;214(1):15-21. 16 410 3. Blostein F, Levin-Sparenberg E, Wagner J, Foxman B. Recurrent vulvovaginal 17 18 411 candidiasis. AnnFor Epidemiol. peer 2017 ;27(9):575-582.e3.review only 19 20 412 4. Foxman B, Muraglia R, Dietz JP, Sobel JD, Wagner J. Prevalence of recurrent 21 22 413 vulvovaginal candidiasis In 5 European countries and the United States: results 23 414 from an internet panel survey. J Low Genit Tract Dis 2013;17:340-5. 24 25 415 5. Ilkit M, Guzel AB. The epidemiology, pathogenesis, and diagnosis of 26 27 416 vulvovaginal candidosis: a mycological perspective. Crit RevMicrobiol 28 29 417 2011;37:250-61. 30 418 6. Rosentul DC, Delsing CE, Jaeger M, et al. Gene polymorphisms in pattern 31 32 419 recognition receptors and susceptibility to idiopathic recurrent 33 34 420 vulvovaginal candidiasis. Front Microbiol2014;5:1-7. 35 421 7. Ben-Ali M, Corre B, Manry J, et al. Functional characterization of naturally

36 http://bmjopen.bmj.com/ 37 422 occurring genetic variants in the human TLR1-2-6 gene family. Hum Mutat 38 39 423 2011;32:643-52. 40 41 424 8. Romani L. Immunity to fungal infections. Nat Rev Immunol 2011;11:275-88. 42 425 9. Wojitani MD, de Aguiar LM, Baracat EC, Linhares IM. Association between 43

44 426 mannose binding lectin and interleukin-1 receptor antagonist gene on September 27, 2021 by guest. Protected copyright. 45 46 427 polymorphisms and recurrent vulvovaginal candidiasis. Arch Gynecol Obstet 47 48 428 2011;285:149-53. 49 429 10. Nedovic B, Posteraro B, Leoncini E, et al. Mannose-binding lectin codon 54 50 51 430 gene polymorphism and vulvovaginal candidiasis: a systematic 52 53 431 review and meta-analysis. Biomed ResInt 2014;2014:738298. 54 432 11. Marchaim D, Lemanek L, Bheemreddy S, Kaye KS, Sobel JD. Fluconazole- 55 56 433 resistant Candida albicans vulvovaginitis. Obstet Gynecol. 2012;120:1407-14. 57 58 59 60

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1 2 3 434 12.Leusink P, van de Pasch S, Teunissen D, Laan ET, Lagro-Janssen AL Leusink 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 435 P, et al. The Relationship Between Vulvovaginal Candidiasis and Provoked 6 7 436 Vulvodynia: A Systematic Review. J Sex Med. 2018;15(9):1310-1321. 8 437 13. Leusink P, van Moorsel D, Bor H, et al. Is uncertain vulvovaginal candidiasis 9 10 438 a marker or vulvodynia? A study in a Dutch general practice research database. 11 12 439 BJGP Open. 2017;31;1(2): 13 14 440 14. Liao X, Qiu H, Li R, et al. Risk factors for fluconazole-resistant invasive 15 441 candidiasis in intensive care unit patients: an analysis from the China Survey of 16 17 442 Candidiasis study. J Crit Care. 2015;30(4):862.e1–e5. 18 For peer review only 19 443 15. Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky- 20 444 Zeichner L, et al. Clinical Practice Guideline for the Management of Candidiasis: 21 22 445 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 23 24 446 2016;62(4):e1-50. 25 26 447 16. Rosa MI, Silva BR, Pires PS, Silva FR, Silva NC, Souza SL, et al. Weekly 27 448 fluconazole therapy for recurrent vulvovaginal candidiasis: a systematic review 28 29 449 and meta-analysis. Eur J Obstet Gynecol Reprod Biol. 2013;167(2):132-6. 30 31 450 17. Donders GGG, Grinceviciene S, Bellen G, Jaeger M, Ten Oever J, Netea MG. 32 33 451 Is non-response to fluconazole maintenance therapy for recurrent Candida 34 452 vaginitis related to sensitization to atopic reactions? Am J Reprod Immunol. 35

36 453 2018;79(4):e12811. http://bmjopen.bmj.com/ 37 38 454 18. Bulik CC, Sobel JD, Nailor MD. Susceptibility profile of vaginal isolates of 39 455 Candida albicans prior to and following fluconazole introduction - impact of two 40 41 456 decades. Mycoses. 2011;54(1):34-8. 42 43 457 19. Kennedy MA, Sobel JD. Vulvovaginal Candidiasis Caused by Non-albicans

44 on September 27, 2021 by guest. Protected copyright. 45 458 Candida Species: New Insights. Curr Infect Dis Rep. 2010;12(6):465-70. 46 459 20. Nurbhai M, Grimshaw J, Watson M, Bond C, Mollison J, Ludbrook A. Oral 47 48 460 versus intra-vaginal imidazole and triazole antifungal treatment of uncomplicated 49 50 461 vulvovaginal candidiasis (thrush). Cochrane Database Syst Rev. 51 2007(4):Cd002845. 52 462 53 463 21. Group AE, Spicer JVDUACAGS-CAg. Therapeutic guidelines : antibiotic. 54 55 464 13ed. ed: North Melbourne, Vic. : Therapeutic Guidelines Limited, 2006.; 2006. 56 57 465 442p p. 58 466 22. Pappas PG, Kauffman CA, Andes D, Benjamin DK, Jr., Calandra TF, 59 60 467 Edwards JE, Jr., et al. Clinical practice guidelines for the management of

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1 2 3 468 candidiasis: 2009 update by the Infectious Diseases Society of America. Clin 4 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from 5 469 Infect Dis. 2009;48(5):503-35. 6 7 470 23. Sobel JD, Brooker D, Stein GE, et al. Single oral dose fluconazole compared 8 471 with conventional clotrimazole topical therapy of Candida vaginitis. Fluconazole 9 10 472 Vaginitis Study Group. Am J Obstet Gynecol. 1995;172(4 Pt 1):1263-8. 11 12 473 24. Stein GE, Mummaw N. Placebo-controlled trial of itraconazole for treatment 13 14 474 of acute vaginal candidiasis. Antimicrob Agents Chemother. 1993;37(1):89-92. 15 475 25. Sobel JD, Wiesenfeld HC, Martens M, Danna P, Hooton TM, Rompalo A, et 16 17 476 al. Maintenance fluconazole therapy for recurrent vulvovaginal candidiasis. N 18 For peer review only 19 477 Engl J Med. 2004;351(9):876-83. 20 478 21 22 479 Contributors 23 24 480 JFL and AKG contributed to the design of this review. JFL drafted the protocol 25 26 481 manuscript, and AKG revised it. JFL and AKG developed the search strategies 27 482 and JFL and RLA will implement them. JFL and AKG will track potential studies, 28 29 483 extract data and assess quality. In case of disagreement between the data 30 31 484 extractors, PCG will advise on the methodology and will work as the referee. JFL, 32 33 485 AKG, RLA, ACAS, APFC and PCG will complete the data synthesis. All authors 34 486 have approved the final version for publication. 35

36 487 http://bmjopen.bmj.com/ 37 38 488 Funding 39 489 This research received no specific grant from any funding agency in the 40 41 490 public, commercial or not-for-profit sectors 42 43 491

44 on September 27, 2021 by guest. Protected copyright. 45 492 Competing interests: None declared. 46 493 47 48 494 Acknowledgments 49 50 495 The authors acknowledge the assistance provided by the Post-Graduate 51 Program in Obstetrics and Gynecology of UNICAMP in the direction of literary 52 496 53 497 research. 54 55 498 56 57 499 Word Count: 2.669 58 500 59 60 501 Figure legends: Figure 1 – Flow Diagram of the search of eligible studies

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32 http://bmjopen.bmj.com/ 33 81x60mm (300 x 300 DPI) 34 35 36 37 38 39

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1 1 2 3 Additional File 1. PRISMA Checklist 4 5 6 An Editorial from the Editors-in-Chief of Systematic Reviews details why this checklist was adapted - Moher D, Stewart L & Shekelle P: Implementing PRISMA- 7 P: recommendations for prospective authors. Systematic Reviews 2016 5:15 8 9 Information reported Line 10 Section/topic # Checklist item number(s) 11 Yes No 12 ADMINISTRATIVE INFORMATION Title For peer review only 13 14 Identification 1a Identify the report as a protocol of a systematic review √ 2 15 Update 1b If the protocol is for an update of a previous systematic review, identify as such √ N/A 16 http://bmjopen.bmj.com/ Registration 2 If registered, provide the name of the registry (e.g., PROSPERO) and registration number in the Abstract 59 17 √ 18 Authors Provide name, institutional affiliation, and e-mail address of all protocol authors; provide physical mailing 3-19 19 Contact 3a √ 20 address of corresponding author 21 Contributions 3b Describe contributions of protocol authors and identify the guarantor of the review √ 493-496 If the protocol represents an amendment of a previously completed or published protocol, identify as such and N/A 22 Amendments 4 √ 23 list changes; otherwise, state plan for documenting important protocol amendments 24 Support on September 27, 2021 by guest. Protected copyright. 25 Sources 5a Indicate sources of financial or other support for the review √ 486-488 26 Sponsor 5b Provide name for the review funder and/or sponsor √ N/A 27 N/A 28 Role of sponsor/funder 5c Describe roles of funder(s), sponsor(s), and/or institution(s), if any, in developing the protocol √ 29 INTRODUCTION 30 Rationale 6 Describe the rationale for the review in the context of what is already known √ 98-125 31 Provide an explicit statement of the question(s) the review will address with reference to participants, 199-246 Objectives 7 √ 32 interventions, comparators, and outcomes (PICO) 33 METHODS 34 Specify the study characteristics (e.g., PICO, study design, setting, time frame) and report characteristics 159-253 Eligibility criteria 8 √ 35 (e.g., years considered, language, publication status) to be used as criteria for eligibility for the review 36 Describe all intended information sources (e.g., electronic databases, contact with study authors, trial 248-258 Information sources 9 √ 37 registers, or other grey literature sources) with planned dates of coverage 38 Present draft of search strategy to be used for at least one electronic database, including planned limits, such 260-263; Table 1 Search strategy 10 √ 39 that it could be repeated 40 STUDY RECORDS 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 BMJ Open: first published as 10.1136/bmjopen-2018-027489 on 22 May 2019. Downloaded from

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2 1 2 Information reported Line 3 Section/topic # Checklist item number(s) 4 Yes No 5 Data management 11a Describe the mechanism(s) that will be used to manage records and data throughout the review √ N/A 6 State the process that will be used for selecting studies (e.g., two independent reviewers) through each phase 268-277 Selection process 11b √ 7 of the review (i.e., screening, eligibility, and inclusion in meta-analysis) Describe planned method of extracting data from reports (e.g., piloting forms, done independently, in 279-294 8 Data collection process 11c √ 9 duplicate), any processes for obtaining and confirming data from investigators List and define all variables for which data will be sought (e.g., PICO items, funding sources), any pre-planned 309-318 10 Data items 12 √ 11 data assumptions and simplifications Outcomes and List and define all outcomes for which data will be sought, including prioritization of main and additional 237-246 12 13 √ prioritization outcomes, withFor rationale peer review only 13 Risk of bias in individual Describe anticipated methods for assessing risk of bias of individual studies, including whether this will be 296-302 14 14 √ studies done at the outcome or study level, or both; state how this information will be used in data synthesis 15 16 DATA http://bmjopen.bmj.com/ 17 15a Describe criteria under which study data will be quantitatively synthesized √ 304-307 18 If data are appropriate for quantitative synthesis, describe planned summary measures, methods of handling √ 335-343 19 15b data, and methods of combining data from studies, including any planned exploration of consistency (e.g., I 2, Synthesis 20 Kendall’s tau) 21 15c Describe any proposed additional analyses (e.g., sensitivity or subgroup analyses, meta-regression) √ 350-358 22 15d If quantitative synthesis is not appropriate, describe the type of summary planned √ 342-343 23 Specify any planned assessment of meta-bias(es) (e.g., publication bias across studies, selective reporting 320-331 Meta-bias(es) 16 on September 27, 2021 by guest. Protected copyright. √ 24 within studies) 25 Confidence in cumulative 360-369 17 Describe how the strength of the body of evidence will be assessed (e.g., GRADE) √ 26 evidence 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 Open access Correction

Correction: Antifungal (oral and vaginal) therapy for recurrent vulvovaginal candidiasis: a systematic review protocol

Lírio J, Giraldo PC, Amaral RL, et al. Antifungal (oral and vaginal) therapy for recurrent vulvovaginal candidiasis: a systematic review protocol. BMJ Open 2019;9:e027489. doi: 10.1136/bmjopen-2018-027489.

For this article, an author note has been added below: It has been noted that this publication covers the same topic as a protocol for a systematic review published by Cochrane in 2011 (https://www.cochranelibrary. com/ cdsr/doi/10.1002/14651858.CD009151/full). The authors acknowledge that they were aware of the protocol and should have cited it in the article. However, the authors have stated that they developed their research question and methods independently.

Open access This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/. © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ Open 2019;9:e027489corr1. doi:10.1136/bmjopen-2018-027489corr1

BMJ Open 2019;9:e027489corr1. doi:10.1136/bmjopen-2018-027489corr1 1