Intervention Protocol

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Probiotics for vulvovaginal candidiasis in non-pregnant women

  1. Huan Yu Xie1,
  2. Dan Feng2,
  3. Dong Mei Wei2,
  4. Hui Chen2,
  5. Ling Mei2,
  6. Xun Wang2,
  7. Fang Fang2,*

Editorial Group: Cochrane Sexually Transmitted Infections Group

Published Online: 30 APR 2013

DOI: 10.1002/14651858.CD010496


How to Cite

Xie HY, Feng D, Wei DM, Chen H, Mei L, Wang X, Fang F. Probiotics for vulvovaginal candidiasis in non-pregnant women (Protocol). Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD010496. DOI: 10.1002/14651858.CD010496.

Author Information

  1. 1

    People's Hospital of Deyang City, Department of Obstetrics and Gynecology, Deyang, Sichuan, China

  2. 2

    West China Second University Hospital, West China Women's and Children's Hospital, Department of Obstetrics and Gynecology, Chengdu, Sichuan, China

*Fang Fang, Department of Obstetrics and Gynecology, West China Second University Hospital, West China Women's and Children's Hospital, No. 17, Section Three, Ren Min Nan Lu Avenue, Chengdu, Sichuan, 610041, China. fangf59@yahoo.com.cn.

Publication History

  1. Publication Status: New
  2. Published Online: 30 APR 2013

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Background

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Description of the condition

 

Epidemiology

Vaginitis is one of the most frequent reasons for women to seek medical assistance from obstetrician-gynecologists (Nyirjesy 2008). Vulvovaginal candidiasis (VVC) is estimated to be the second most common form of vaginitis after bacterial vaginosis (Sobel 2007; Martinez 2009a). The incidence of vulvovaginal candidiasis is limited and incomplete, since it is not a reportable disease and is often diagnosed without mycologic confirmatory tests and treated with over-the-counter drugs (Sobel 1998; Nyirjesy 2003). Misdiagnosis is common, and it has been shown that about two-thirds of all over-the-counter drugs for VVC are used without the disease, and that the overuse may increase the risk of resistance to antifungal treatments (Sobel 1998; Sobel 2007).

Approximately 70% to 75% of women experience at least one episode of VVC in their lives (Sobel 1998; Sobel 2007). Age appears to be an important factor in the overall incidence of VVC, such that the episodes of VVC occur mostly during childbearing years and rarely in premenarchal and postmenopausal years (Sobel 1998; Sobel 2007). Approximately 40% to 45% of women will experience two or more episodes of VVC in one year (Sobel 2007; Nyirjesy 2008). An epidemiological study indicates that the frequency of the first diagnosis of VVC increases rapidly after age 17. By the age of 25, 54.7% of female college students will have experienced at least one episode of physician-diagnosed vulvovaginal candidiasis (Geiger 1995). Recurrent vulvovaginal candidiasis (RVVC) is defined as four or more episodes in one year, and affects 5% to 8% of adult women (Foxman 1998; Sobel 1998; Falagas 2006; Sobel 2007; Nyirjesy 2008). It is reported that the incidence of vulvovaginal candidiasis almost doubled from 1980 to 1990, based on the number of prescriptions written to treat VVC during that period (Sobel 2007). The annual combined cost of health care and lost productivity due to vulvovaginal candidiasis in the United States is estimated to be USD1.8 billion, and is projected to reach USD3.1 billion by 2014 (Foxman 2000).

 

Pathology

The vaginal micro-environment is a complex micro-ecological system. Lactobacillus is the most commonly dominant flora in the vaginal micro-ecological system. In normal conditions, vaginal Lactobacilli produce lactic acid, thus acidifying the healthy vagina to a low pH level( ≤ 4.5), which could inhibit the overgrowth of other pathogenic bacteria or Candida. Many species of Lactobacillus also produce other substances, such as hydrogen peroxide (H2O2) and bacteriocin, which further prevent the overgrowth of the pathogenic microbes (Redondo-Lopez 1990; Kledanoff 1991; Sobel 1998; Nyirjesy 2003; Jeavons 2003; Sobel 2007).

The condition of VVC occurs as a result of an imbalance in the normal vaginal microbiota and is characterised by a decrease or depletion of the Lactobacilli spp and a concomitant overgrowth of Candida species. Epidemiological research has shown that Candida organisms can be found in approximate 20% of asymptomatic healthy women (Sobel 2007). Candida organisms gain access to the vaginal lumen and discharge mainly from the adjacent perianal area. Effective anti-Candida defence in the micro-environment of the vagina allows candidal microbes to persist as an avirulent commensal (Bertholf 1983; Beigi 2004; Sobel 2007). There are two important elements during the development of symptomatic VVC: the first is the Candida species' vaginal colonisation, adhesion, invasion and growth, and the second is the transformation from the asymptomatic to the symptomatic phase. Candida enters the vagina through different sources, including local spread from the perineum and gastrointestinal tract, digital introduction, and sexual transmission. Estrogen is believed to be crucial in the maintenance of colonisation. The penetrative ability of hyphae enhances the colonisation by the adherence to vaginal epithelial cells (Redondo-Lopez 1990; Ross 1995; Hillier 1997; Sobel 2007; Nyirjesy 2008). A study indicated that Candida albicans adheres in significantly higher numbers to vaginal epithelial cells than non-albicans Candida species (Soll 1989). The Candida strains isolated from the vaginas of patients with VVC are mainly Candida albicans, while the rest (range 5% to 15%) are non-albicans Candida species. Candida glabrata is considered the most common of non-albicans Candida species (Nyirjesy 2008). However, vulvovaginitis induced by non-albicans Candida cannot be distinguished clinically from that caused by Candida albicans. RVVC is often caused by non-albicans Candidas, which are frequently more resistant to conventional antifungal treatment (Spinillo 1994; Ross 1995; Sobel 2007; Nyirjesy 2008). In recent years, some studies have shown that the widespread and long-term use of antifungal drugs such as azoles, particularly fluconazole, may lead to a pathogen shift and increase the incidence of the non-albicans Candidas such as Candida glabrata. The extensive use of azoles may effectively suppress Candida albicans but facilitate the overgrowth of non-albicans Candida (Sanglard 2002; Hettiarachchi 2010; Mahmoudi 2011). Depressed or reduced protective local immunoregulatory mechanisms, cytokine elaboration and certain genetic polymorphisms may result in increased susceptibility to RVVC (Giraldo 2007).

The overuse of antibiotics, pregnancy, diabetes mellitus, immunosuppression, frequent and dirty sexual activity, use of oral contraceptives, diaphragms, spermicide and intrauterine devices, and vaginal douching are considered as important risk factors for the development of VVC and RVVC. (Sobel 1998; Nyirjesy 2003; Sobel 2007; Nyirjesy 2008).

Vulvovaginal candidiasis can be classified as Uncomplicated VVC and Complicated VVC (Sobel 2007; Nyirjesy 2008; Centers 2010):

Uncomplicated VVC:

  1. Sporadic or infrequent vulvovaginal candidiasis, or
  2. Mild-to-moderate vulvovaginal candidiasis, or
  3. Likely to be Candida albicans infection, or
  4. Non-immunocompromised host

Complicated VVC:

  1. Four or more episodes of candidiasis per year (Complicated vulvovaginal candidiasis), or
  2. Severe symptoms or findings (Severe vulvovaginal candidiasis), or
  3. Non-albicans Candida infection, or
  4. Abnormal host (e.g. uncontrolled diabetes, debilitation, or immunosuppression)

 

Diagnosis

A combination of clinical signs and symptoms, microscopic examination and/or vaginal culture is suggested to diagnose VVC.

Symptoms and signs: Although acute pruritus and vaginal discharge are the common clinical symptoms of VVC, neither of them is specific (Anderson 2004; Sobel 2007). The typical vaginal discharge has been described as 'cottage-cheese-like', and in practice it could vary from watery to thick (Sobel 2007). Patients with VVC may also complain of irritation, soreness, vulvar burning, or dyspareunia. Occasionally, VVC can cause external dysuria by the burning that occurs when urine hits the inflamed vulvar tissues (Eckert 1998). If there is an odor, it is generally insignificant and inoffensive (Sobel 2007). Clinical symptoms may recur or exacerbate in the week before menses. However, none of these is specific (Schaaf 1990; Anderson 2004; Sobel 2007). On vulvar examination, patients may exhibit erythema, swelling, fissures, or excoriations of the labia and vulva, and vaginal signs of erythema or an adherent curd-like vaginal discharge may be found (Sobel 1998; Nyirjesy 2003; Sobel 2007; Nyirjesy 2008).

Most patients with symptoms of VVC can be easily diagnosed when either:
1) saline and 10% potassium hydroxide microscopy examination or Gram stain (63.2% to 65% sensitivity, 97.2% to 100% specificity (Omar 2001; Ilkit 2011)) of vaginal discharge demonstrates Candida species, hyphae, or pseudohyphae; or
2) a vaginal culture test yields a Candida species (Sobel 1998; Sobel 2007; Nyirjesy 2008; Centers 2010).
Because Candida vaginitis is associated with a normal vaginal pH ( < 4.5), pH testing is not useful for diagnosis, but the finding of a normal pH helps to exclude bacterial vaginosis, trichomoniasis, atrophic vaginitis, or some sort of mixed infection (Nyirjesy 2008; Centers 2010).

The 10% potassium hydroxide microscopy examination (50% to 85% sensitivity (Mylonas 2011; Ilkit 2011)) should be taken for all women with symptoms or signs of VVC, and those with a positive result should receive treatment. The gold standard for diagnosis is still the growth of the infecting organism in fungal culture on Sabouraud dextrose agar (Ilkit 2011). Up to 50% of patients with culture-positive symptomatic vulvovaginal candidosis will have negative microscopy (Sobel 2007), so although routine cultures are not necessary if microscopy is positive, vaginal culture should be performed for women with negative microscopy result and a normal pH and who are symptomatic (Sobel 2007; Centers 2010). Vaginal culture is useful to identify the species of Candida (Bieber 2006). In women with complicated VVC, vaginal culture can guide the choice of therapy regimen, since non-albicans species tend to be resistant to the azole drugs (Bieber 2006; Nyirjesy 2008).  Table 1 lists species of Candida isolated from the lower genital tract in women with VVC. Candida identified by vaginal culture in the absence of symptoms or signs is not an indication for treatment, because many women harbor Candida species in the vagina. If the 10% KOH (potassium hydroxide) examination is negative and vaginal culture cannot be done, an empiric treatment may be considered for symptomatic women with any sign of VVC on examination (Centers 2010).

Although polymerase chain reaction (PCR) testing for Candida species is available, its usefulness is limited, because it depends on obtaining PCR for the full spectrum of organisms that can cause VVC, with the associated costs (Trama 2005).

 

Treatment

  • The recommended treatments for Uncomplicated VVC involve a short course of antifungals (Nurbhai 2007; Pappas 2009; Centers 2010).  Table 2 lists the Centers for Disease Control (CDC)-recommended treatments for Uncomplicated VVC (Centers 2010). The oral and topical preparations have similar effects (Pappas 2009; Centers 2010), and treatment with azole drugs results in relief of symptoms and negative cultures in 80% to 90% of patients who complete therapy (Centers 2010).
  • The recommended treatments for Complicated VVC involve an intensive, longer course of antifungals.  Table 3 lists the CDC-recommended treatments for Complicated VVC (Centers 2010).

 

Description of the intervention

Probiotics are defined as live micro-organisms which when administered in adequate amounts exert a health benefit on the host by treating and preventing diseases (Reid 2003a; Falagas 2006; Othman 2007; Sanders 2008). Probiotics are regulated as dietary supplements and foods, consisting of bacteria or yeast. They are available as capsules, tablets, or powders, and may contain a single micro-organism or a mixture of several species.  Table 4 lists common micro-organisms used as probiotics (Kopp-Hoolihan 2001; Senok 2005; Doron 2006; Santosa 2006). Products containing bacteria or yeast are not classified as probiotics, unless they have been shown to be viable and stable at the time of use in sufficient quantity to exert a health benefit. The organisms themselves must be speciated using appropriate molecular methods, and given a designation (Senok 2005; Reid 2005; Doron 2006; Santosa 2006; Vanderhoof 2008).

Probiotics have been shown to confer a wide range of effects, and have been used for the prevention and treatment of various medical conditions and to support wellness. Some of their effects against diarrheal diseases, Crohn's disease, ulcerative colitis, irritable bowel syndrome, bacterial vaginosis, VVC and urinary tract infections have been validated (Senok 2005; Reid 2005; Doron 2006; Santosa 2006; Sanders 2008). Probiotics used in the prevention and treatment of Candida infections include Lactobacillus fermentum RC-14, Lactobacillus fermentum B-54, Lactobacillus rhamnosus GR-1, Lactobacillus rhamnosus GG and Lactobacillus acidophilus (Reid 2001; Jeavons 2003; Reid 2005; Falagas 2006; Martinez 2009a). Administration of probiotics can be oral, intravaginal, or combined (Reid 2004). After the live bacteria in probiotic preparations have colonised the vagina, they grow and reproduce, and their metabolic substances can have toxic effects on Candida species. Evidence indicates that daily oral intake of probiotics leads to transfer of the organisms from the rectum to the vagina, as well as an overall depletion of coliforms and yeasts in the vagina. Certain probiotic strains, including Lactobacillus fermentum RC-14 and Lactobacillus rhamnosus GR-1, are able to remain in the vagina for several months after introduction. Probiotics have been shown to be safe and effective for urogenital infections, with no severe adverse effects (Reid 2003c). The recommended dose is 109 to 1011 colony-forming units of bacteria, by any route of administration (Andreu 2004; Reid 2003c). Probiotic preparations should not be taken together with bismuth preparations, tannic acid, activated charcoal, or tincture. Because of the sensitivity of probiotics to antibiotics, they should not be taken together, to avoid dilution of their effectiveness (Zhang 2008).

Azole antifungals are a group of fungistatic agents with broad-spectrum activity in treating systemic and topical fungal infections. They are classified into two groups: triazoles and imidazoles. The azole antifungals inhibit the cytochrome P450-dependent enzyme lanosterol 14-alpha-demethylase, which converts lanosterol to ergosterol, the main sterol in fungal cell membrane. Depletion of ergosterol damages the cell membrane, resulting in cell death. Topical vaginal agents are applied to the vaginal mucosa, and are available as creams or pessaries. Oral agents are available as tablets or capsules. A Cochrane systematic review shows that both imidazole and triazole antifungal treatment (by oral or intravaginal route of administration) achieve clinical cure in over 80% of women taking them (Nurbhai 2007). However, they can cause many adverse effects, including vomiting, diarrhea, abdominal pain, urination, pelvic cramps, dysmenorrhea, paresthesia, rhinorrhea, headache and dizziness, fever, chills, vaginal burning, stinging, itching and irritation (Faro 1994; Faro1997; Watson 2007; Nurbhai 2007; Centers 2010); more systemic side effects are likely to be reported with oral compared with intravaginal antifungal administration (Nurbhai 2007). The recommended usage of antifungals for VVC is described in the Treatment section. For the half-life, duration and any known interactions with other drugs of all azole antifungals for VVC, we recommend following the internet link The Merck Manual Online, to reference further information.

 

How the intervention might work

The concept of treatment with probiotics stems from a belief that modern humans do not consume or replenish the beneficial microbes in their bodies, and that they can do so by taking probiotics (Reid 2005). The normal vaginal micro-environment is predominantly populated by Lactobacillus species, which tend to suppress growth of other bacterial species (Reid 2004). This dominance of Lactobacilli and their potential ability to resist VVC gave rise to the concept of oral or vaginal instillation of probiotic Lactobacillus strains to restore the vaginal microbiotic balance. The actual mechanism of action of probiotics in the vagina is probably multifactorial; they may block and prevent the Candida species' colonisation, adhesion, invasion and growth by lactic acid, hydrogen peroxide (H2O2) and bacteriocin, which are toxic to Candida species (Reid 2003a; Reid 2003b; Reid 2004; Sobel 2007). It has also been shown that Lactobacillus rhamnosus GR-1 and Lactobacillu reuteri RC-14 may directly influence the vaginal epithelial cells' response to Candida albicans infections (Reid 2003b; Reid 2004; Martinez 2009b). After eliminating most of the Candidas, Lactobacillus could restore and maintain a normal vaginal micro-environment to prevent recurrence (Reid 2003a; Reid 2003b; Reid 2004; Reid 2005).

 

Why it is important to do this review

At present, a growing number of women are troubled by the high incidence and recurrence rates of VVC. Although anti-Candidal agents are quite effective at providing clinical cures for VVC, resistance to the drugs is increasing. In addition, drugs may reduce the normal protective vaginal flora to increase the risk of recurrent infection, and can also cause many adverse effects. The increasing availability of probiotic products makes it important that family physicians understand what to look for when making recommendations (Reid 2005). Nowadays, the use of probiotics in augmenting normal bacterial populations is gradually achieving scientific acceptance (Reid 2003b). Probiotics have already been used for treatment of vulvovaginal inflammations in clinical practice (Reid 2001; Reid 2003a; Reid 2003b; Othman 2007). Some evaluations have shown that probiotics are effective against VVC, and that their adverse effects are minor (Jeavons 2003; Falagas 2006; Martinez 2009a), while others failed to demonstrate their efficacy in VVC (Pirotta 2004; Falagas 2006). There is no consensus on the use of probiotics for treating VVC (Jeavons 2003; Van Kessel 2003). It is therefore necessary to conduct a rigorous systematic review of the available clinical trials, to help determine the effectiveness and safety of probiotics for the treatment of VVC, and to identify strategic areas for future research.

 

Objectives

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

To determine the effectiveness and safety of probiotics for the treatment of vulvovaginal candidiasis (VVC) in non-pregnant women.

 

Methods

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Criteria for considering studies for this review

 

Types of studies

We will include all randomised controlled trials using probiotics, alone or as adjuncts to conventional antifungal drugs, to treat vulvovaginal candidiasis in non-pregnant women. We will not include trials of women with recurrent vulvovaginal candidiasis (RVVC), or trials which recruit women with evidence of co-infection with other vulvovaginal infections.

 

Types of participants

Non-pregnant women diagnosed with vulvovaginal candidiasis, regardless of age and race. Diagnosis of vulvovaginal candidiasis will be confirmed by the presence of symptoms and signs, and a positive microscopic examination, or symptoms and positive vaginal culture. We will exclude trials of women with RVVC, diabetes mellitus, immunosuppressive disorders or taking immunosuppressant medication.

 

Types of interventions

Any probiotic: single or multiple strains, any preparation type, any dosage regimen, any route of administration:

  1. used alone versus placebo or no intervention;
  2. used alone versus conventional antifungal drugs;
  3. used as adjuncts to conventional antifungal drugs (before, during, or after antifungal treatment) versus placebo or no intervention;
  4. used as adjuncts to conventional antifungal drugs (before, during, or after antifungal treatment) versus conventional antifungal drug.

Conventional antifungal drugs described here refer to the common drugs for VVC treatment, such as azole drugs (triazoles and imidazoles) and Nystatin.

 

Types of outcome measures

 

Primary outcomes

  1. Clinical cure rate (disappearance of symptoms and signs), split into 'short-term clinical cure rate (0 to 14 days after treatment)' and 'long-term clinical cure rate (1 month, 3 months and 6 months after treatment)'.
  2. Mycological cure rate (no evidence of fungal infection proved by microscopic examination or vaginal culture), split into 'short-term mycological cure rate (0 to 14 days after treatment)' and 'long-term mycological cure rate (1 month, 3 months and 6 months after treatment)'.
  3. Relapse rate (symptom recurrence confirmed by microscopic examination or vaginal culture at 1 month, 3 months and 6 months after mycological cure).

 

Secondary outcomes

  1. Time to first relapse;
  2. The rate of serious adverse events (death, internal organ injury, severe skin and mucosal injury);
  3. The rate of non-serious adverse events (vomiting, diarrhea, abdominal pain, urination, pelvic cramps, dysmenorrhea, paresthesia, rhinorrhea, headache and dizziness, fever, chills, vaginal burning, stinging, itching and irritation);
  4. The need for any additional treatment at the end of the therapy;
  5. Patient satisfaction with treatment;
  6. Cost effectiveness.

 

Search methods for identification of studies

We will attempt to identify as much relevant Randomized Controlled Trials (RCTs) as possible of “probiotics” for “vulvovaginal candidiasis”, regardless of language, publication date or publication status (published, unpublished, in press, and in progress). We will use both electronic searching in bibliographic databases and handsearching, as described in the Cochrane Handbook.

 

Electronic searches

We will contact the Trials Search Coordinator (TSC) of the Cochrane Sexually Transmitted Infections Group in order to implement a comprehensive search strategy to retrieved all relevant RCTs in electronic databases. For this purpose, we will use a combination of controlled vocabulary (MeSH, EMTREE, DeCS, including exploded terms) and free-text terms for "probiotics" and "vulvovaginal candidiasis", with field labels (title and abstract), wildcards (truncation), proximity operators (adj) and boolean operators (OR, AND). Specifically, will search the following electronic databases:

  • MEDLINE®, Ovid platform (1946 to present),
  • MEDLINE® In-Process & Other Non-Indexed Citations, Ovid platform (1946 to present),
  • MEDLINE® Daily Update, Ovid platform (1946 to present),
  • EMBASE (1947 to present),
  • The Cochrane Central Register of Controlled Trials (CENTRAL), Ovid platform (1991 to present),
  • LILACS, IAHx interface (1982 to present),
  • PsycINFO, Ovid platform (1946 to present),
  • AMED, Ovid platform (1946 to present),
  • CBMdisc and CNKI: inception to present.

For MEDLINE, we will use the Cochrane highly sensitive search strategy for identifying RCTs: sensitivity and precision maximizing version (2008 revision), Ovid format (see Cochrane Handbook). The EMBASE search will be combined with search terms that are currently used by the UK Cochrane Centre to identify EMBASE reports of RCTs for inclusion in CENTRAL (Lefebvre 2008). The LILACS search will be combined with the RCTs filter of IAHx interface.

The search strategies for MEDLINE, EMBASE, AMED, CBMdisc and CNKI, CENTRAL, The STI Specialized Register, PsycINFO and LILACS can be found in Appendix 1, Appendix 2, Appendix 3, Appendix 4, Appendix 5 , Appendix 6 and Appendix 7.

We placed no language restrictions on any of the searches.These searches will be updated within 6 months before publication of the review.

 

Searching other resources

We will attempt to identify other published, unpublished and ongoing relevant RCTs by using the following methods:

  • Searching in the Sexually Transmitted Infections Cochrane Review Group’s Specialized Register, which includes RCTs and controlled clinical trials, from 1944 to 2008, located through electronic searching (MEDLINE, EMBASE and CENTRAL) and handsearching.

  • Searching in trials registers:

- WHO International Clinical Trials Registry Platform ICTRP portal (http://apps.who.int/trialsearch/).

- ClinicalTrials.gov (http://clinicaltrials.gov/).

  • Searching in Web of Science®: inception to present.

  • Searching for grey literature in System for Information on Grey Literature in Europe “OpenGrey” (http://www.opengrey.eu/): inception to present.

  • Searching by contacting with authors of all RCTs identified by others methods. A comprehensive list of RCT included in the review along with the inclusion criteria will be sent to the first author of each included study, asking for any additional studies published or unpublished that might be relevant.

  • Searching by contacting with pharmaceutical companies producing “probiotics” for “vulvovaginal candidiasis”.

  • Handsearching in the following journals: Anatolian Journal of Obstetrics & Gynecology, Current Medical Literature Gynecology & Obstetrics, Current Obstetrics and Gynecology Reports, ISRN Obstetrics and Gynecology, Journal of South Asian Federation of Obstetrics & Gynecology, Obstetrics and Gynecology International, Obstetrics Gynaecology and Reproductive Medicine, Sexual Science: the newsletter of the Society for the Scientific Study of Sexuality and Sexualities.

  • Handsearching of conference proceeding abstracts in the following events:

- The International Society for Sexually Transmitted Diseases Research (ISSTDR) (http://www.isstdr.org/): 2007, 2009 and 2011.

- The British Association for Sexual Health and HIV (BASHH) (http://www.bashh.org/): 2004, 2006, 2007 and 2009.

- International Congress on Infectious Diseases (ICID) (http://www.isid.org/): 2010 and 2012.

- The International Union against Sexually Transmitted Infections (IUSTI) (http://www.iusti.org/): 2011 and 2012.

- International Society for Infectious Diseases (ISID) (http://www.isid.org/): 2011.

- International Meeting on Emerging Diseases and Surveillance (IMED) (http://www.isid.org/): 2007, 2009 and 2011.

- Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) (http://www.icaac.org/): 2011 and 2012.

- The International Federation of Gynecology and Obstetrics (FIGO) (http://www.figo2012.org/home/): 2012.

  • Handsearching within previous systematic reviews and other relevant publications on the same topic.

  • Handsearching within reference lists of all RCTs identified by others methods, including available review articles on the topic, and will contact authors of all RCTs identified by other methods..

 

Data collection and analysis

 

Selection of studies

Two authors (DW and HC) will independently screen all titles and abstracts from the initial search, to exclude trials that do not meet the inclusion criteria for this review. We will obtain the full reports of trials that appear to meet the inclusion criteria, and we will independently assess their eligibility for inclusion. Multiple reports of the same study will be collected. Two authors (DW and HC) will contact the authors of articles if any important information is missing. We will resolve any discrepancies by asking a third author (HX).

 

Data extraction and management

Two authors (LM and XW) will independently extract data, with a form specifically designed for this review which will be previously piloted. The form will be able to extract enough data in order to complete the table of "Characteristic of included studies" with detail. We will resolve any disagreements by referring back to the trial report and through consensus, or by consulting a third author (DF).

We will collect the following information:

  • Study characteristics: year and language of publication, inclusion and exclusion criteria, randomisation process, allocation concealment, blinding, number of withdrawals (participants excluded from analysis or lost to follow-up) and reasons, intention-to-treat analysis and duration of follow-up;

  • Basic participant information: number, mean age and age range of the participants, type of participants (health status, uncomplicated VVC or complicated VVC);

  • Intervention: drug, type (single or multiple), preparation, dosage and route of administration;

  • Outcome: clinical cure rate, mycological cure rate, relapse rate and time to first relapse;

  • Adverse events: serious adverse events and non-serious adverse events;

  • Cost effectiveness: if the data are mentioned and available.

If data from the trial reports are insufficient or missing, we will contact the trial authors for additional information.

 

Assessment of risk of bias in included studies

Two authors (DW and HC) will assess the methodological quality of each trial in terms of randomisation process, allocation concealment, blinding, incomplete outcome data, selective outcome reporting, and other possible sources of bias, and classify them as being at low, unclear, or high risk of bias based on the Cochrane Handbook:

Randomisation process
Low risk: allocation sequence was generated by computer or by a random number table.
High risk: quasi-randomisation, participants were allocated by date of birth, code of hospital admission, etc.
Unclear risk: randomisation stated to have been performed but no method reported.

Concealment of allocation
We regard allocation concealment as particularly important in protecting against bias and will grade as follows:
Low risk: clearly adequate concealment.
High risk: participants or investigators enrolling participants could possibly foresee assignments.
Unclear risk: insufficient information to permit judgment.

Blinding
Were patients, treatment providers and outcome assessors adequately prevented from knowing the allocated interventions during the study?
Low risk
High risk
Unclear risk

Incomplete outcome data
We will assess the risk of bias due to incomplete outcome data as follows:
Low risk: if fewer than 20% of patients were lost to follow-up and reasons for loss to follow-up were similar in both intervention arms.
High risk: if more than 20% of patients were lost to follow-up or reasons for loss to follow-up differed between intervention arms.
Unclear risk: if loss to follow-up was not reported.

Selective outcome reporting
Low risk: if the study protocol is available and all of the study's primary and secondary outcomes that are of interest in the review have been reported in the pre-specified way. If the study protocol is not available but it is clear that the published reports include all expected outcomes.
High risk: not all of the study's pre-specified primary outcomes have been reported; one or more primary outcomes is reported using measurements, analysis methods or subsets of the data that were not pre-specified; one or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis; the study report fails to include results for a key outcome that would be expected to have been reported for such a study.
Unclear risk: insufficient information to permit judgment.

Free of other bias
Low risk: the study appears to be free of other sources of bias.
High risk: there is at least one important risk of bias such as extreme baseline imbalance.
Unclear risk: insufficient information to assess.

Two authors (DW and HC) will independently apply the Risk Of Bias tool, and will resolve differences by discussion or by appeal to a third author (FF). We will present results in a risk of bias graph. The Risk Of Bias findings will be used to inform any meta-analyses in the full review. Summary of Findings tables will be created as well.

 

Measures of treatment effect

We will measure the treatment effect through the clinical cure rate, the mycological cure rate and the recurrence rate under each type of intervention. If enough clinically similar trials are available, we will pool the results in meta-analyses and present results as summary risk ratios (RRs) or hazard ratio (HR) with 95% confidence intervals (CIs) according to the type of outcome.

 

Unit of analysis issues

The primary unit of analysis in meta-analysis will be the person. If the person is not the unit of randomisation, as in the case in cluster-randomised trials, special statistical methods will be used to avoid unit-of-analysis errors; we will conduct the analysis at the same level as the allocation by using a summary measurement from each cluster, and these adjustments will be made following the guidelines in the Cochrane Handbook.

 

Dealing with missing data

Whenever possible, we will contact the original investigators to request missing data. If this is unsuccessful, we will assume treatment failure for missing participants for the primary outcome, as we plan to conduct intention-to-treat analyses. We will conduct sensitivity analyses to explore the impact of studies with missing data, as recommended in the Cochrane Handbook.

 

Assessment of heterogeneity

If there is obvious heterogeneity (populations, interventions, etc), we will conduct subgroup analyses to investigate potential sources of heterogeneity. We will assess statistical heterogeneity in each meta-analysis using the T², I² and Chi² statistics. We will regard heterogeneity as substantial if I² is greater than 40% and either T² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity.

 

Assessment of reporting biases

We will assess reporting bias by constructing a funnel plot. If 10 or more original papers are identified then a funnel plot will be produced in an attempt to identify any publication bias. To test the influence of small-study effects, we will try to explore the grey literature to see if published and unpublished results differ.

 

Data synthesis

We will perform the statistical analyses by using Review Manager 5 software. If the trials are judged to be similar, and in the absence of statistical heterogeneity, we will pool the data using a fixed-effect model, and if statistical heterogeneity is present, we will use a random-effects model. If the outcome data can not be combined, we will describe the outcome separately. We will conduct time-to-event analyses for time to recurrence by extracting data from published curves (Parmar 1998). The quality of the body of evidence will be assessed.

Because the Chi² test has low power when sample sizes or number of studies are small, it may fail to detect heterogeneity. In the event of few trials or small samples, we propose to conduct both a random- and a fixed-effect meta-analysis, even if heterogeneity is not detected.

 

Subgroup analysis and investigation of heterogeneity

If heterogeneity is present, we will explore the potential reasons, using subgroup analysis by:

  1. Probiotics: single versus multiple species.
  2. Route of administration: intravaginal versus oral.
  3. Different bacterial strains: Candida albicans versus non-albicans.
  4. Age group of participants: < 18 years old group versus > 18 years old group.

 

Sensitivity analysis

We will perform a sensitivity analysis to explore whether the results of the review are robust, depending on study quality and studies with loss to follow up >20%. We will exclude studies with a high risk of bias, comparing findings within the remainder of the included studies with the original meta-analysis. If the P value of heterogeneity is close to 0.10, we will perform both fixed-effect and random-effects modelling, and compare the results.

 

Acknowledgements

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

The authors wish to thank the Cochrane Sexually Transmitted Infections Group and the Cochrane Editorial Unit.

 

Appendices

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Appendix 1. MEDLINE (Ovid)

1 exp Candidiasis, Vulvovaginal/
2 (candid$ adj5 vulvovagin$).tw.
3 (candid$ adj5 vagin$).tw.
4 (candida adj5 colpitis).tw.
5 colpitis mycotica.tw.
6 (monilias$ adj5 vulvovagin$).tw.
7 (monilial adj5 vaginiti$).tw.
8 (vagin$ adj5 yeast).tw.
9 (vagin$ adj5 fung$).tw.
10 or/1-9
11 exp Probiotics/
12 probiotic$.tw.
13 exp Lactobacillus/
14 lactobac$.tw.
15 exp Lactobacillus acidophilus/
16 lactic acid bacteria$.tw.
17 exp Bifidobacterium/
18 bifidobacteri$.tw.
19 or/11-18
20 randomized controlled trial.pt.
21 controlled clinical trial.pt.
22 randomized.ab.
23 placebo.ab.
24 clinical trials as topic.sh.
25 randomly.ab.
26 trial.ti.
27 or/20-26
28 exp animals/ not humans.sh.
29 27 not 28
30 10 and 19 and 29

Note: the CENTRAL search strategy doesn’t include the terms #20 - #29.

 

Appendix 2. EMBASE (Ovid)

1 exp vagina candidiasis/
2 (candid$ adj5 vagin$).tw.
3 (candid$ adj5 vulvovagin$).tw.
4 (candida adj5 colpitis).tw.
5 colpitis mycotica.tw.
6 (monilias$ adj5 vulvovagin$).tw.
7 (monilial adj5 vaginiti$).tw.
8 (vagin$ adj5 yeast).tw.
9 (vagin$ adj5 fung$).tw.
10 or/1-9
11 exp probiotic agent/
12 probiotic$.tw.
13 exp Lactobacillus/
14 lactobac$.tw.
15 betabacterium.tw.
16 exp Lactobacillus acidophilus/
17 (acidophilus adj5 bacillus).tw.
18 exp lactic acid bacterium/
19 (lactic adj5 acid adj5 bacteri$).tw.
20 exp Bifidobacterium/
21 bifidobacteri$.tw.
22 or/11-21
23 Clinical Trial/
24 Randomized Controlled Trial/
25 exp randomization/
26 Single Blind Procedure/
27 Double Blind Procedure/
28 Crossover Procedure/
29 Placebo/
30 Randomi?ed controlled trial$.tw.
31 Rct.tw.
32 random allocation.tw.
33 randomly allocated.tw.
34 allocated randomly.tw.
35 (allocated adj2 random).tw.
36 Single blind$.tw.
37 Double blind$.tw.
38 ((treble or triple) adj blind$).tw.
39 placebo$.tw.
40 prospective study/
41 or/23-40
42 case study/
43 case report.tw.
44 abstract report/ or letter/
45 or/42-44
46 41 not 45
47 exp animals/ or exp invertebrate/ or animal experiment/ or animal model/ or animal tissue/ or animal cell/ or nonhuman/
48 human/ or normal human/ or human cell/
49 47 and 48
50 47 not 49
51 46 not 50
52 10 and 22 and 51

 

Appendix 3. AMED (Ovid)

1 exp candidiasis/
2 (Candid$ adj2 Vulvovagina$).tw.
3 (Candid$ adj2 Vulv$).tw.
4 (Candid$ adj2 Vagin$).tw.
5 (vagin$ adj2 fung$).tw.
6 vaginosis.tw.
7 vaginitis.tw.
8 vaginoses.tw.
9 colpitis.tw.
10 (yeast$ adj2 vagin$).tw.
11 or/1-10
12 exp Probiotics/
13 Lactobacill$.tw.
14 Probiotic$.tw.
15 lactic acid bacter$.tw.
16 acidophil$.tw.
17 bifidobacteri$.tw.
18 or/12-17
19 11 and 18

 

Appendix 4. CBMdisc and CNKI

1 exp Candidiasis, Vulvovaginal/
2 (Candid$ adj2 Vulvovagina$).tw.
3 (Candid$ adj2 Vulv$).tw.
4 (Candid$ adj2 Vagin$).tw.
5 (vagin$ adj2 fung$).tw.
6 vaginosis.tw.
7 vaginitis.tw.
8 vaginoses.tw.
9 colpitis.tw.
10 (yeast$ adj2 vagin$).tw.
11 or/1-10
12 exp Probiotics/
13 exp Lactobacillus/
14 Probiotic$.tw.
15 Lactobacill$.tw.
16 lactic acid bacter$.tw.
17 exp Lactobacillus acidophilus/
18 acidophil$.tw.
19 bifidobacteri$.tw.
20 or/12-19
21 11 and 20
22 randomized controlled trial.pt.
23 controlled clinical trial.pt.
24 randomized.ab.
25 placebo.tw.
26 clinical trials as topic.sh.
27 randomly.ab.
28 trial.ti.
29 (crossover or cross-over or cross over).tw.
30 or/22-29
31 21 and 30

 

Appendix 5. Sexually Transmitted Infections Cochrane Review Group’s Specialized Register

Using the terms “probiotic” and “lactobacillus” in title, abstract and keywords.

 

Appendix 6. PSYCHINFO (Ovid)

1 exp Gynecological Disorders/
2 exp Infectious Disorders/
3 (Candid$ adj2 Vulvovagina$).tw.
4 (Candid$ adj2 Vulv$).tw.
5 (Candid$ adj2 Vagin$).tw.
6 (vagin$ adj2 fung$).tw.
7 vaginosis.tw.
8 vaginitis.tw.
9 vaginoses.tw.
10 colpitis.tw.
11 (yeast$ adj2 vagin$).tw.
12 or/1-11
13 Probiotic$.tw.
14 Lactobacill$.tw.
15 lactic acid bacter$.tw.
16 acidophil$.tw.
17 bifidobacteri$.tw.
18 or/13-17
19 12 and 18

 

Appendix 7. LILACS (iAHx interface)

(mh:(Candidiasis Vulvovaginal)) OR (ti:(candidiasis vulvovaginal)) OR (ab:(candidiasis vulvovaginal)) OR (ti:(moniliasis vulvovaginal)) OR (ab:(moniliasis vulvovaginal)) OR (ti:(vaginitis monilial)) OR (ab:(vaginitis monilial)) AND (mh:(Probióticos)) OR (ti:(probiótico$)) OR (ab:(probiótico$)) OR (mh:(Lactobacillus)) OR (ti:(Lactobacillus)) OR (ab:(Lactobacillus))

RCTs filter:

((PT:"ensayo clinico controlado aleatorio" OR PT:"ensayo clinico controlado" OR PT:"estudio multicéntrico" OR MH:"ensayos clinicos controlados aleatorios como asunto" OR MH:"ensayos clinicos controlados como asunto" OR MH:"estudios multicéntricos como asunto" OR MH:"distribución aleatoria" OR MH:"método doble ciego" OR MH:"metodo simple-ciego") OR ((ensaio$ OR ensayo$ OR trial$) AND (azar OR acaso OR placebo OR control$ OR aleat$ OR random$ OR enmascarado$ OR simpleciego OR ((simple$ OR single OR duplo$ OR doble$ OR double$) AND (cego OR ciego OR blind OR mask))) AND clinic$)) AND NOT (MH:animales OR MH:conejos OR MH:ratones OR MH:ratas OR MH:primates OR MH:perros OR MH:gatos OR MH:porcinos OR PT:"in vitro")

 

Contributions of authors

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

Huanyu Xie and Dan Feng developed the protocol and will be in charge of searching for studies, quality assessment, data extraction, data analysis, and review development.

Fang Fang developed the protocol and will be in charge of the data analysis, review development, and offering clinical expertise.

Dongmei Wei will participate in searching for studies and quality assessment.

Hui Chen will participate in searching for studies and quality assessment.

Ling Mei will participate in the data extraction and data analysis.

Xun Wang will participate in the data extraction and data analysis.

 

Declarations of interest

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support

There is no conflict of interest.

 

Sources of support

  1. Top of page
  2. Background
  3. Objectives
  4. Methods
  5. Acknowledgements
  6. Appendices
  7. Contributions of authors
  8. Declarations of interest
  9. Sources of support
 

Internal sources

  • West China Secondary Hospital, Sichuan University, China.

 

External sources

  • No sources of support supplied

References

Additional references

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  2. Abstract
  3. Background
  4. Objectives
  5. Methods
  6. Acknowledgements
  7. Appendices
  8. Contributions of authors
  9. Declarations of interest
  10. Sources of support
  11. Additional references
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