Candidiasis (vulvovaginal)

Abstract

Introduction

Vulvovaginal candidiasis is estimated to be the second most common cause of vaginitis after bacterial vaginosis. Candida albicans accounts for 85% to 90% of cases.

Methods and outcomes

We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of drug treatments for acute vulvovaginal candidiasis in non-pregnant symptomatic women? What are the effects of alternative or complementary treatments for acute vulvovaginal candidiasis in non-pregnant symptomatic women? What are the effects of treating asymptomatic non-pregnant women with a positive swab for candidiasis? We searched: Medline, Embase, The Cochrane Library, and other important databases up to October 2013 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Results

We found 23 studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions.

Conclusions

In this systematic review, we present information relating to the effectiveness and safety of the following interventions: alternative or complementary treatments; douching; drug treatments; garlic; intravaginal preparations (nystatin, imidazoles, tea tree oil); oral fluconazole; oral itraconazole; and yoghurt containing Lactobacillus acidophilus (oral or intravaginal).

Key Points

Vulvovaginal candidiasis is characterised by vulval itching and may also present with abnormal 'cheese-like' or watery vaginal discharge.

• Vulvovaginal candidiasis is estimated to be the second most common cause of vaginitis after bacterial vaginosis. Candida albicans accounts for 85% to 90% of cases.

• Risk factors include pregnancy (and other situations where oestrogen levels are increased), diabetes mellitus, immunosuppression, and systemic antibiotics. Incidence increases with the onset of sexual activity, but associations with different types of contraceptives are unclear.

Intravaginal imidazoles seem to reduce symptoms of acute vulvovaginal candidiasis in non-pregnant symptomatic women.

• Intravaginal imidazoles (butoconazole, clotrimazole, miconazole) may reduce symptoms compared with placebo, and all seem to have similar efficacy compared with each other.

• Intravaginal imidazoles (clotrimazole, miconazole, and econazole) and oral imidazoles (fluconazole or itraconazole) may be equally effective at achieving clinical cure.

Oral itraconazole seems to reduce persistent symptoms at 1 week compared with placebo, but we don’t know whether it is more effective compared with oral fluconazole.

Intravaginal nystatin seems to reduce symptoms compared with placebo, but we don't know how it compares with intravaginal imidazoles, oral fluconazole, or oral itraconazole.

The benefits of other intravaginal treatments to treat acute attacks remain unclear, and some may be associated with serious adverse effects.

• We found no RCT evidence comparing intravaginal tea tree oil with other interventions listed in the review.

• We found no RCT evidence comparing garlic or yoghurt, used vaginally or orally, with other interventions listed in the review.

• We found no RCT evidence comparing douching with other interventions listed in the review, but observational studies suggest it is associated with serious adverse effects such as PID and infections, endometritis, and ectopic pregnancy.

We found no RCT evidence comparing the effects of alternative or complementary treatments with other interventions listed in the review in asymptomatic non-pregnant women with a positive swab for candidiasis.

We found no RCT evidence on the effects of drug treatments in asymptomatic non-pregnant women with a positive swab for candidiasis.

Clinical context

General background

Vulvovaginal candidiasis is a symptomatic vaginitis (inflammation of the vagina and/or vulva) caused by infection with a Candida yeast. Asymptomatic prevalence has been reported in 10% of women. This review looks at possible treatment options for acute vulvovaginal candidiasis in non-pregnant symptomatic women.

Focus of the review

This review includes evidence on the impact of commonly used treatments, including drug treatments and alternative or complementary treatments (garlic, douching, tea tree or yoghurt) over clinical cure rates and adverse effects in non-pregnant women with vulvovaginal candidiasis.

Comments on evidence

We found 23 studies that met our inclusion criteria. Most RCTs were heterogeneous, small, and many had weak methods (poorly described randomisation, inadequate concealment and blinding, and definitions of cure based on mycology results rather than symptoms), making difficult to draw definitive conclusions

Search and appraisal summary

The update literature search for this review was carried out from the date of the last search, March 2009 to November 2013. For more information on the electronic databases searched and criteria applied during assessment of studies for potential relevance to the review, please see the Methods section. Searching of electronic databases retrieved 75 studies. After deduplication and removal of conference abstracts, 36 records were screened for inclusion in the review. Appraisal of titles and abstracts led to the exclusion of 27 studies and the further review of nine full publications. Of the nine full articles evaluated, one RCT was added at this update, making a total of 23 studies included in this review.

Additional information

Oral and intravaginal imidazoles are secreted in maternal milk, therefore, they should not be administered to women who are breastfeeding. Intravaginal nystatin may be acceptable, as it is unlikely to be absorbed systemically. Before prescribing imidazoles, it is necessary to know the local resistance to these drugs, and to note that they may interact with other drugs (e.g., oral anticoagulants, phenytoin).

About this condition

Definition

Vulvovaginal candidiasis is defined as symptomatic vaginitis (inflammation of the vagina), which often involves the vulva (erythema and swelling), caused by infection with a Candida yeast. The predominant symptom is vulvar itching. Abnormal vaginal discharge (which may be minimal — a 'cheese-like' material or a watery secretion) may also be present. Vulvar burning, soreness, and irritation are also common symptoms, and these may be accompanied by dysuria or dyspareunia, which worsen during the week prior to menses. Differentiation from other forms of vaginitis requires the presence of yeast on microscopy of vaginal fluid.

Incidence/ Prevalence

Vulvovaginal candidiasis is estimated to be the second most common cause of vaginitis after bacterial vaginosis. Estimates of its incidence are limited and often derived from women who attend hospital clinics. Asymptomatic prevalence has been reported in 10% of women, so identification of vulvovaginal Candida is not necessarily indicative of candidal disease. Self-reported history of at least one episode of vulvovaginal candidiasis has been as high as 72%.

Aetiology/ Risk factors

Candida albicans accounts for 85% to 90% of cases of vulvovaginal candidiasis. Candida glabrata accounts for almost all of the remaining cases, and treatment failure with azoles is common (around 50%) in patients with C glabrata vaginitis. Development of symptomatic vulvovaginal candidiasis probably represents increased growth of yeast that previously colonised the vagina without causing symptoms. Risk factors for vulvovaginal candidiasis include pregnancy and other situations that increase oestrogen levels (e.g., contraceptive use and oestrogen therapy), diabetes mellitus, immunosuppression, and systemic antibiotics. The evidence that different types of contraceptives are associated with risk factors is contradictory. The incidence of vulvovaginal candidiasis rises with initiation of sexual activity, but we found no direct evidence that vulvovaginal candidiasis is sexually transmitted.

Prognosis

We found few descriptions of the natural history of untreated vulvovaginal candidiasis. Discomfort is the main complication and can include pain while passing urine or during sexual intercourse.

Aims of intervention

To alleviate symptoms, with minimal adverse effects of treatment.

Outcomes

Clinical cure rates, either measured in the short term (5–15 days) or in the medium term (3–6 weeks) after treatment; adverse effects. The definition of clinical cure varies among RCTs but often includes both complete resolution of symptoms and culture negative for Candida. As Candida may colonise the vagina asymptomatically, we have reported relief of symptoms preferentially where possible.

Methods

Clinical Evidence search and appraisal October 2013. The following databases were used to identify studies for this review: Medline 1966 to October 2013, Embase 1980 to October 2013, and The Cochrane Database of Systematic Reviews 2013, issue 9 (1966 to date of issue). Additional searches were carried out in the Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) database. We also searched for retractions of studies included in the review. Titles and abstracts identified by the initial search, run by an information specialist, were first assessed against predefined criteria by an evidence scanner. Full texts for potentially relevant studies were then assessed against predefined criteria by an evidence analyst. Studies selected for inclusion were discussed with an expert contributor. All data relevant to the review were then extracted by an evidence analyst. Study design criteria for inclusion in this review were: published RCTs and systematic reviews, at least single-blinded and containing more than 20 individuals, of whom more than 80% were followed up. There was no minimum length of follow-up. We excluded all studies described as 'open', 'open label', or not blinded unless blinding was impossible. We included RCTs and systematic reviews of RCTs where harms of an included intervention were assessed, applying the same study design criteria for inclusion as we did for benefits. In addition, we use a regular surveillance protocol to capture harms alerts from organisations such as the FDA and the UK Medicines and Healthcare products Regulatory Agency (MHRA), which are added to the review as required. Where a systematic review did not pool results for the RCTs that it included, we have only reported those RCTs that were of sufficient quality. We included only those RCTs in which most participants were non-pregnant women (e.g., we sought RCTs that excluded pregnant women, or RCTs in which pregnant women represented <20% of the participants). For the two questions on symptomatic non-pregnant women, we included RCTs only if recruitment was restricted to non-pregnant women with both symptoms of vaginal candidiasis and laboratory confirmation of candidal infection. We excluded treatment trials where cure was defined solely on the basis of mycological results. We excluded studies of women with HIV infection or trichomoniasis. To aid readability of the numerical data in our reviews, we round many percentages to the nearest whole number. Readers should be aware of this when relating percentages to summary statistics such as relative risks (RRs) and odds ratios (ORs). We have performed a GRADE evaluation of the quality of evidence for interventions included in this review (see table). The categorisation of the quality of the evidence (high, moderate, low, or very low) reflects the quality of evidence available for our chosen outcomes in our defined populations of interest. These categorisations are not necessarily a reflection of the overall methodological quality of any individual study, because the Clinical Evidence population and outcome of choice may represent only a small subset of the total outcomes reported, and population included, in any individual trial. For further details of how we perform the GRADE evaluation and the scoring system we use, please see our website (www.clinicalevidence.com).

Table.

GRADE Evaluation of interventions for Candidiasis (vulvovaginal).

Important outcomes	Clinical cure rates
Studies (Participants)	Outcome	Comparison	Type of evidence	Quality	Consistency	Directness	Effect size	GRADE	Comment
What are the effects of drug treatments for acute vulvovaginal candidiasis in non-pregnant symptomatic women?
6 (1092)	Clinical cure rates	Oral fluconazole versus oral itraconazole	4	−2	0	0	0	Low	Quality point deducted for weak methods and incomplete reporting of results
3 (712)	Clinical cure rates	Intravaginal imidazoles versus placebo	4	−1	0	−1	0	Low	Quality point deducted for no ITT analysis; directness point deducted for high rates of attrition, especially in the placebo arm
22 (at least 790 women)	Clinical cure rates	Intravaginal imidazoles versus each other	4	−2	0	0	0	Low	Quality points deducted for no ITT analysis and for incomplete reporting
20 (at least 2721)	Clinical cure rates	Intravaginal imidazoles versus oral fluconazole or oral itraconazole	4	−1	0	−1	0	Low	Quality point deducted for lack of allocation concealment; directness point deducted for not reporting results of comparisons versus oral fluconazole and oral itraconazole separately
1 (70)	Clinical cure rates	Intravaginal imidazoles versus intravaginal nystatin	4	−2	0	0	0	Low	Quality points deducted for lack of blinding and incomplete reporting of results
1 (95)	Clinical cure rates	Oral itraconazole versus placebo	4	−1	0	0	0	Moderate	Quality point deducted for sparse data
1 (50)	Clinical cure rates	Intravaginal nystatin versus placebo	4	−1	0	−1	+1	Moderate	Quality point deducted for sparse data. Directness point deducted for uncertainty about definition of outcome. Effect-size point added for OR <0.2

We initially allocate 4 points to evidence from RCTs, and 2 points to evidence from observational studies. To attain the final GRADE score for a given comparison, points are deducted or added from this initial score based on preset criteria relating to the categories of quality, directness, consistency, and effect size. Quality: based on issues affecting methodological rigour (e.g., incomplete reporting of results, quasi-randomisation, sparse data [<200 people in the analysis]). Consistency: based on similarity of results across studies. Directness: based on generalisability of population or outcomes. Effect size: based on magnitude of effect as measured by statistics such as relative risk, odds ratio, or hazard ratio.

Glossary

Low-quality evidence

Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.

Moderate-quality evidence

Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.

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