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 a male sexual partner to resolve symptoms and prevent recurrence in non-pregnant women with symptomatic acute vulvovaginal candidiasis? What are the effects of alternative or complementary treatments for symptomatic recurrent vulvovaginal candidiasis in non-pregnant women? What are the effects of treating a male sexual partner in non-pregnant women with symptomatic recurrent vulvovaginal candidiasis? 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 March 2009 (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 61 systematic reviews, RCTs, or observational 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 (boric acid, nystatin, imidazoles, tea tree oil); oral fluconazole; oral itraconazole; treating a male sexual partner; and yoghurt containing Lactobacillus acidophilus (oral or vaginal).

Key Points

Vulvovaginal candidiasis is characterised by vulval itching and 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, diabetes mellitus, and systemic antibiotics. Incidence increases with the onset of sexual activity, but associations with different types of contraceptives are unclear.

• Recurrent symptoms are common, but are caused by candidiasis in only one third of cases.

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

• Intravaginal imidazoles (butoconazole, clotrimazole, miconazole) reduce symptoms compared with placebo and all seem to have similar efficacy compared with each other. RCTs suggest that single-dose regimens may be as effective as multiple-dose regimens.

• Intravaginal imidazoles and oral fluconazole or itraconazole seem equally effective in treating acute attacks.

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

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

• We found no RCT evidence assessing intravaginal boric acid or tea tree oil.

• We found no RCT evidence assessing garlic or yoghurt, used intravaginally or orally.

• We found no RCT evidence on efficacy of douching, but it is associated with serious adverse effects such as PID and infections, endometritis, and ectopic pregnancy.

• Oral fluconazole and itraconazole are likely to be beneficial in preventing recurrence of infection.

• Treating the woman's male sexual partner does not reduce symptoms or prevent recurrence in the woman.

About this condition

Definition

Vulvovaginal candidiasis is defined as symptomatic vaginitis (inflammation of the vagina), which often involves the vulva, caused by infection with a Candida yeast. Predominant symptoms are vulval itching and abnormal vaginal discharge (which may be minimal, a "cheese-like" material, or a watery secretion). Differentiation from other forms of vaginitis requires the presence of yeast on microscopy of vaginal fluid. Recurrent vulvovaginal candidiasis is commonly defined as four or more symptomatic episodes a year.

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 and self-reported history of at least one episode of vulvovaginal candidiasis has been as high as 72%. Recurrent symptoms are common but are caused by candidiasis in only one third of cases.

Aetiology/ Risk factors

Candida albicans accounts for 85% to 90% of cases of vulvovaginal candidiasis. 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, diabetes mellitus, 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. Balanitis in male partners of women with vulvovaginal candidiasis can occur, but it is rare.

Aims of intervention

To alleviate symptoms and prevent recurrence, with minimal adverse effects of treatment.

Outcomes

Acute vulvovaginal candidiasis: Clinical cure rates, either measured in the short term (5–15 days) or medium term (3–6 weeks) after treatment; adverse effects of treatment. The definition of clinical cure varies among RCTs, but often includes both complete resolution of symptoms and culture negative for Candida. In the option on treating a male sexual partner, we also assessed symptomatic recurrence confirmed by positive culture. Recurrent vulvovaginal candidiasis: Symptomatic recurrence confirmed by positive culture, quality of life, and adverse effects of treatment.

Methods

Clinical Evidence search and appraisal March 2009. The following databases were used to identify studies for this review: Medline 1966 to March 2009, Embase 1980 to March 2009, and The Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Clinical Trials, Issue 1, 2009. Additional searches were carried out using these websites: NHS Centre for Reviews and Dissemination (CRD) — for Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA), Turning Research into Practice (TRIP), and NICE. Abstracts of the studies retrieved from the initial search were assessed by an information specialist. Selected studies were then sent to the author for additional assessment, using pre-determined criteria to identify relevant studies. Study design criteria for inclusion in this review were: published systematic reviews and RCTs in any language, 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 required to include studies. We excluded all studies described as "open", "open label", or not blinded unless blinding was impossible. We also searched for cohort studies on specific harms of named interventions. 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 from the target population (e.g., to answer the questions for non-pregnant women, we sought RCTs that excluded pregnant women, or RCTs in which pregnant women represented <20% of the participants). We excluded treatment trials where cure was defined solely on the basis of mycological results. We excluded studies of women with HIV infection. RCTs also excluded women with diabetes mellitus. For questions on symptomatic women, we included RCTs only if recruitment was restricted to women with both symptoms of vaginal candidiasis and laboratory confirmation of candidal infection. In the questions on treatment and preventing recurrence, we have searched for RCTs comparing all of the listed drug and non-drug interventions versus each other and reported all RCTs of sufficient quality. 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, Recurrence 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?
3 (712)	Clinical cure rates	Intravaginal imidazoles versus placebo	4	−1	0	0	0	Moderate	Quality point deducted for no ITT analysis
22 (at least 900 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
7 (901)	Clinical cure rates	Single- versus multiple-dose intravaginal imidazoles	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
6 (1048)	Clinical cure rates	Different durations of multiple-dose regimen of intravaginal imidazoles	4	–2	0	0	0	Low	Quality points deducted for no ITT analysis and for incomplete reporting
19 (2579)	Clinical cure rates	Intravaginal imidazoles versus oral fluconazole or oral itraconazole	4	0	0	−1	0	Moderate	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.
6 (1092)	Clinical cure rates	Oral fluconazole versus oral itraconazole	4	−1	0	0	0	Moderate	Quality point deducted for incomplete reporting of results
1 (90)	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	+2	Unset	Quality point deducted for sparse data. Directness point deducted for uncertainty about definition of outcome. Effect-size points added for OR <2
What are the effects of alternative or complementary treatments for acute vulvovaginal candidiasis in non-pregnant symptomatic women?
1 (108)	Clinical cure rates	Intravaginal boric acid versus intravaginal nystatin	4	−1	0	0	0	Moderate	Quality point deducted for sparse data
1 (55)	Clinical cure rates	Yoghurt containing Lactobacillus acidophilus (oral or vaginal) versus placebo	4	−1	0	−1	0	Low	Quality point deducted for sparse data. Directness point deducted for use of co-intervention.
What are the effects of treating a male sexual partner to resolve symptoms and prevent recurrence in non-pregnant women with symptomatic acute vulvovaginal candidiasis?
1 (40)	Clinical cure rates	Oral itraconazole versus placebo	4	−1	0	0	+1	High	Quality point deducted for sparse data. Effect-size point added for OR 0.5–0. 2
1 (42)	Clinical cure rates	Topical natamycin versus placebo	4	−2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
1 (42)	Recurrence rates	Topical natamycin versus placebo	4	−2	0	0	0	Low	Quality points deducted for sparse data and incomplete reporting of results
What are the effects of drug treatments for recurrent vulvovaginal candidiasis in non-pregnant symptomatic women?
1 (283)	Recurrence rates	Oral fluconazole versus placebo	4	0	0	0	+1	High	Effect-size point added for RR 2–5
1 (114)	Recurrence rates	Oral itraconazole versus placebo	4	−1	0	0	+1	High	Quality point deducted for sparse data. Effect-size point added for OR 2–5
1 (44)	Recurrence rates	Oral itraconazole versus intravaginal imidazoles	4	−3	0	0	0	Very low	Quality points deducted for sparse data, lack of blinding, and for differences in follow-up between groups
2 (89)	Recurrence rates	Intravaginal imidazoles versus placebo	4	−1	−1	0	0	Low	Quality point deducted for sparse data. Consistency point deducted for conflicting results
1 (23)	Recurrence rates	Regular prophylaxis versus as-required treatment	4	−2	0	0	0	Low	Quality points deducted for sparse data and for lack of blinding
What are the effects of alternative or complementary treatments for symptomatic recurrent vulvovaginal candidiasis in non-pregnant women?
2 (79)	Recurrence rates	Yoghurt containing Lactobacillus acidophilus (oral or vaginal)	4	−3	−1	−1	0	Very low	Quality points deducted for sparse data, poor follow-up, and incomplete reporting of results. Consistency point deducted for conflicting results. Directness point deducted for including women without recurrent vulvovaginal candidiasis

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

Balanitis

is inflammation of the glans penis. The foreskin is often involved (balanoposthitis).

High-quality evidence

Further research is very unlikely to change our confidence in the estimate of effect.

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.

Very low-quality evidence

Any estimate of effect is very uncertain.

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