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. 2022 Jan 10;1(1):CD009151.
doi: 10.1002/14651858.CD009151.pub2.

Treatment for recurrent vulvovaginal candidiasis (thrush)

Georga Cooke  1 , Cathy Watson  2 , Laura Deckx  1 , Marie Pirotta  2 , Jane Smith  3 , Mieke L van Driel  1
Affiliations

Treatment for recurrent vulvovaginal candidiasis (thrush)

Georga Cooke et al. Cochrane Database Syst Rev. .

Abstract

Background: Recurrent vulvovaginal candidiasis (RVVC) affects up to 5% of women. No comprehensive systematic review of treatments for RVVC has been published.

Objectives: The primary objective was to assess the effectiveness and safety of pharmacological and non-pharmacological treatments for RVVC. The secondary objective was to assess patient preference of treatment options.

Search methods: We conducted electronic searches of bibliographic databases, including CENTRAL, MEDLINE, Embase, and CINAHL (search date 6 October 2021). We also handsearched reference lists of identified trials and contacted authors of identified trials, experts in RVVC, and manufacturers of products for vulvovaginal candidiasis.

Selection criteria: We considered all published and unpublished randomised controlled trials evaluating RVVC treatments for at least six months, in women with four or more symptomatic episodes of vulvovaginal candidiasis in the past year. We excluded women with immunosuppressive disorders or taking immunosuppressant medication. We included women with diabetes mellitus and pregnant women. Diagnosis of RVVC must have been confirmed by presence of symptoms and a positive culture and/or microscopy. We included all drug and non-drug therapies and partner treatment, assessing the following primary outcomes: • number of clinical recurrences per participant per year (recurrence defined as clinical signs and positive culture/microscopy); • proportion of participants with at least one clinical recurrence during the treatment and follow-up period; and • adverse events.

Data collection and analysis: Two authors independently reviewed titles and abstracts to identify eligible trials. Duplicate data extraction was completed independently by two authors. We assessed risk of bias as described in the Cochrane Handbook for Systematic Reviews of Interventions. We used the fixed-effects model for pooling and expressed the results as risk ratio (RR) with 95% confidence intervals (CI). Where important statistical heterogeneity was present we either did not pool data (I2 > 70%) or used a random-effects model (I2 40-70%). We used the GRADE tool to assess overall certainty of the evidence for the pooled primary outcomes.

Main results: Studies: Twenty-three studies involving 2212 women aged 17 to 67 years met the inclusion criteria. Most studies excluded pregnant women and women with diabetes or immunosuppression. The predominant species found on culture at study entry was Candida albicans. Overall, the included studies were small (<100 participants). Six studies compared antifungal treatment with placebo (607 participants); four studies compared oral versus topical antifungals (543 participants); one study compared different oral antifungals (45 participants); two studies compared different dosing regimens for antifungals (100 participants); one study compared two different dosing regimens of the same topical agent (23 participants); one study compared short versus longer treatment duration (26 participants); two studies assessed the effect of partner treatment (98 participants); one study compared a complementary treatment (Lactobacillus vaginal tablets and probiotic oral tablets) with placebo (34 participants); three studies compared complementary medicine with antifungals (354 participants); two studies compared 'dermasilk' briefs with cotton briefs (130 participants); one study examined Lactobacillus vaccination versus heliotherapy versus ciclopyroxolamine (90 participants); one study compared CAM treatments to an antifungal treatment combined with CAM treatments (68 participants). We did not find any studies comparing different topical antifungals. Nine studies reported industry funding, three were funded by an independent source and eleven did not report their funding source. Risk of bias: Overall, the risk of bias was high or unclear due to insufficient blinding of allocation and participants and poor reporting. Primary outcomes: Meta-analyses comparing drug treatments (oral and topical) with placebo or no treatment showed there may be a clinically relevant reduction in clinical recurrence at 6 months (RR 0.36, 95% CI 0.21 to 0.63; number needed to treat for an additional beneficial outcome (NNTB) = 2; participants = 607; studies = 6; I² = 82%; low-certainty evidence) and 12 months (RR 0.80, 95% CI 0.72 to 0.89; NNTB = 6; participants = 585; studies = 6; I² = 21%; low-certainty evidence). No study reported on the number of clinical recurrences per participant per year. We are very uncertain whether oral drug treatment compared to topical treatment increases the risk of clinical recurrence at 6 months (RR 1.66, 95% CI 0.83 to 3.31; participants = 206; studies = 3; I² = 0%; very low-certainty evidence) and reduces the risk of clinical recurrence at 12 months (RR 0.95, 95% CI 0.71 to 1.27; participants = 206; studies = 3; I² = 10%; very low-certainty evidence). No study reported on the number of clinical recurrences per participant per year. Adverse events were scarce across both treatment and control groups in both comparisons. The reporting of adverse events varied amongst studies, was generally of very low quality and could not be pooled. Overall the adverse event rate was low for both placebo and treatment arms and ranged from less than 5% to no side effects or complications.

Authors' conclusions: In women with RVVC, treatment with oral or topical antifungals may reduce symptomatic clinical recurrences when compared to placebo or no treatment. We were unable to find clear differences between different treatment options (e.g. oral versus topical treatment, different doses and durations). These findings are not applicable to pregnant or immunocompromised women and women with diabetes as the studies did not include or report on them. More research is needed to determine the optimal medication, dose and frequency.

Trial registration: ClinicalTrials.gov NCT00915629.

PubMed Disclaimer

Conflict of interest statement

Georga Cooke: no conflicts of interest Cathy Watson: no conflicts of interest Laura Deckx: no conflicts of interest Marie Pirotta: no conflicts of interest Jane Smith: no conflicts of interest Mieke L van Driel: no conflicts of interest

Figures

1
1
Study flow diagram.
2
2
Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.
3
3
Risk of bias summary: review authors' judgements about each risk of bias item for each included study.
4
4
Forest plot of comparison: 1 Drug treatment versus placebo/no treatment (excluding partner treatment) (Comparison 1), outcome: 1.1 Clinical recurrence at 6 months.
5
5
Forest plot of comparison: 1 Drug treatment versus placebo/no treatment (excluding partner treatment) (Comparison 1), outcome: 1.2 Clinical recurrence at 12 months (6 months active, 6 months observation).
6
6
Forest plot of comparison: 2 Oral drug treatment versus topical drug treatment (Comparison 2), outcome: 2.1 Clinical recurrence at 6 months.
7
7
Forest plot of comparison: 2 Oral drug treatment versus topical drug treatment (Comparison 2), outcome: 2.2 Clinical recurrence at 12 months (6 months active, 6 months observation).
1.1
1.1. Analysis
Comparison 1: Drug treatment versus placebo/no treatment (excluding partner treatment) (Comparison 1), Outcome 1: Clinical recurrence at 6 months
1.2
1.2. Analysis
Comparison 1: Drug treatment versus placebo/no treatment (excluding partner treatment) (Comparison 1), Outcome 2: Clinical recurrence at 12 months (6 months active, 6 months observation)
1.3
1.3. Analysis
Comparison 1: Drug treatment versus placebo/no treatment (excluding partner treatment) (Comparison 1), Outcome 3: Mycological recurrence at 6 months
1.4
1.4. Analysis
Comparison 1: Drug treatment versus placebo/no treatment (excluding partner treatment) (Comparison 1), Outcome 4: Mycological recurrence at 12 months
2.1
2.1. Analysis
Comparison 2: Oral drug treatment versus topical drug treatment (Comparison 2), Outcome 1: Clinical recurrence at 6 months
2.2
2.2. Analysis
Comparison 2: Oral drug treatment versus topical drug treatment (Comparison 2), Outcome 2: Clinical recurrence at 12 months (6 months active, 6 months observation)
2.3
2.3. Analysis
Comparison 2: Oral drug treatment versus topical drug treatment (Comparison 2), Outcome 3: Mycological recurrence at 6 months
3.1
3.1. Analysis
Comparison 3: Oral drug treatment versus oral drug treatment (Comparison 3), Outcome 1: Clinical recurrence at 6 months
3.2
3.2. Analysis
Comparison 3: Oral drug treatment versus oral drug treatment (Comparison 3), Outcome 2: Clinical recurrence at 12 months
4.1
4.1. Analysis
Comparison 4: Comparison of different doses of the same agent (Comparison 4), Outcome 1: Clinical recurrence at 6 months
4.2
4.2. Analysis
Comparison 4: Comparison of different doses of the same agent (Comparison 4), Outcome 2: Clinical recurrence at 12 months
4.3
4.3. Analysis
Comparison 4: Comparison of different doses of the same agent (Comparison 4), Outcome 3: Mycological recurrence at 6 months
4.4
4.4. Analysis
Comparison 4: Comparison of different doses of the same agent (Comparison 4), Outcome 4: Mycological recurrence at 12 months
5.1
5.1. Analysis
Comparison 5: Short duration versus long duration of the same treatment (Comparison 5), Outcome 1: Clinical recurrence at 6 months
6.1
6.1. Analysis
Comparison 6: Partner treatment versus placebo/no treatment (Comparison 6), Outcome 1: Clinical recurrence at 6 months
6.2
6.2. Analysis
Comparison 6: Partner treatment versus placebo/no treatment (Comparison 6), Outcome 2: Clinical recurrence at 12 months (6 months active, 6 months observation)
6.3
6.3. Analysis
Comparison 6: Partner treatment versus placebo/no treatment (Comparison 6), Outcome 3: Mycological recurrence at 6 months
6.4
6.4. Analysis
Comparison 6: Partner treatment versus placebo/no treatment (Comparison 6), Outcome 4: Mycological recurrence at 12 months
7.1
7.1. Analysis
Comparison 7: Complementary and alternative medicine versus drug treatments (Comparison 7), Outcome 1: Clinical recurrence at 6 months
7.2
7.2. Analysis
Comparison 7: Complementary and alternative medicine versus drug treatments (Comparison 7), Outcome 2: Clinical recurrence at 12 months
7.3
7.3. Analysis
Comparison 7: Complementary and alternative medicine versus drug treatments (Comparison 7), Outcome 3: Clinical recurrence at 24 months
8.1
8.1. Analysis
Comparison 8: Non‐drug treatment versus other treatment (Comparison 8), Outcome 1: Clinical recurrence at 6 months
9.1
9.1. Analysis
Comparison 9: Vaccination versus other treatment (Comparison 9), Outcome 1: Mean number of clinical recurrences per participant per year
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References to studies awaiting assessment

ACTRN12614001258640 {published data only (unpublished sought but not used)}
    1. ACTRN12614001258640.A randomized, double-blinded study investigating the safety and efficacy of daily low-dose oral fluconazole versus weekly fluconazole in patients with chronic vulvovaginal candidiasis. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=1261... 2 December 2012.
ChiCTR‐IPR‐15006314 {published data only (unpublished sought but not used)}
    1. ChiCTR-IPR-15006314.Multi-center clinical study on JUC Spray Dressing under the patent technology "Physical Antimicrobial Film" in preventing the recurrence of vulvovaginal candidiasis (VVC). http://www.chictr.org.cn/showproj.aspx?proj=10772 14 April 2015.
ChiCTR‐TRC‐10000833 {published data only (unpublished sought but not used)}
    1. ChiCTR-TRC-10000833.The clinical research of Chinese herb XiangLian Suppository in the treatment of recurrent vulvovaginal candidiasis. http://www.chictr.org.cn/showproj.aspx?proj=8703 28 March 2010.
EUCTR2010‐021502‐38‐DE {published data only}
    1. EUCTR2010-021502-38-DE.Study for measuring vaginal interleukins in patients with cervical neoplasia (CIN 1-3) or chronic vaginal candidiasis with phenyl-4-butyrate [STUDIE ZUR MESSUNG DER VAGINALEN INTERLEUKINE BEI PATIENTINNEN MIT ZERVIKALEN NEOPLASIEN (CIN 1-3) ODER CHRONISCHER CANDIDIASIS VAGINALIS UNTER BEHANDLUNG MIT 4PHENYL-BUTYRATE]. https://www.clinicaltrialsregister.eu/ctr-search/trial/2010-021502-38/DE 11 November 2010. [2010-021502-38]
EUCTR2011‐004718‐40‐IT {published data only}
    1. EUCTR2011-004718-40-IT.Activities of Metronidazole + Clotrimazole in the treatment and prophylaxis of recurrent vaginal infections recurrent Candida albicans and Candida albicans spp non albicans. https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_nu... 8 March 2012. [2011-004718-40]
EUCTR2013‐002480‐26‐PL {published data only (unpublished sought but not used)}
    1. EUCTR2013-002480-26-PL.Study of the efficacy and safety of treatment with total freeze-dried culture of Lcr Regenerans® administered intravaginally in the prevention of recurrent vulvovaginal candidiasis.International, randomized, phase III, multi-centre, 2-arm, parallel group, double-blind, placebo-controlled superiority trial.. https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-002480-26/PL 30 July 2014. [EUCTR2013-002480-26-PL]
NCT00479947 {published data only (unpublished sought but not used)}
    1. NCT00479947.Use of Oral Probiotics as an Adjunctive Therapy to Fluconazole in the Treatment of Yeast Vaginitis. http://clinicaltrials.gov/show/NCT00479947 30 May 2007. [NCT00479947]
NCT00915629 {published data only}
    1. NCT00915629.Prevention of Recurrent Vulvovaginal Candidiasis With Lactibiane Candisis 5M®. https://clinicaltrials.gov/ct2/show/NCT00915629 8 June 2009.
NCT02251093 {published data only (unpublished sought but not used)}
    1. NCT02251093.Study of the Efficacy and Tolerance of Intra-vaginal Treatment With a Total Freeze-dried Culture of Lcr Regenerans® in the Prevention of Relapses of Recurrent Vulvovaginal Candidiasis. https://clinicaltrials.gov/ct2/show/NCT02251093 26 September 2014.
Rabiee 2013 {published data only}
    1. IRCT2012102911302N1.Comparison of clinical response to vaginal cream zataria multiflora and boric acid in patients with recurrent vulvovaginal candidiasis. http://en.irct.ir/trial/11581 17 December 2012. [IRCT2012102911302N1]
    1. Rabiee M, Akbari H, Naseri M, Bekhradi R, Nikzad M, Torkestani F.Comparison of clinical response to Zatariamultiflora vaginal cream and boric acid inpatients with recurrent vulvovaginal candidiasis. Scientific-ResearchJournal of Shahed University 2013;102:1-8.
RBR‐892mp4 {published data only (unpublished sought but not used)}
    1. lRBR-892mp4.Effectiveness of therapeutic exercise applied to the pelvic floor muscles to prevent recurrence of Vulvovaginitis and improve female sexuality: randomized clinical trial. http://www.ensaiosclinicos.gov.br/rg/RBR-892mp4/ 17 June 2015. [RBR-892mp4]
Russo 2019 {published data only}
    1. Russo R, Superti F, Karadja E, De Seta F.Randomised clinical trial in women with Recurrent Vulvovaginal Candidiasis: Efficacy of probiotics and lactoferrin as maintenance treatment. Mycoses 2019;62:328–335. - PubMed
Zivaljevic 2012 {published data only}
    1. Zivaljevic B, Golubovic I, Seratlic J, Nikolic P, Simic D, Magdic I, et al.Efficiency of Fenticonazole for the Treatment of Vaginal Candidiasis. Srpski Arhiv Za Celokupno Lekarstvo 2012;140(7-8):469-474. - PubMed

References to ongoing studies

EUCTR2019‐000925‐27‐SK {published data only}
    1. A phase IIb/III, parallel-arm, randomized, active-controlled, double-blind, double-dummy, multicenter, non-inferiority study in patients with recurrent vulvovaginal candidosis to compare the clinical efficacy, safety and tolerability of topically administered ProF-001 (Candiplus®) to oral fluconazole. ICTRP. [URL: https://trialsearch.who.int/?TrialID=EUCTR2019-000925-27-SK]
    1. A Phase IIb/III Study of Prof-001 for the Treatment of Patients With Recurrent Vulvovaginal Candidiasis (RVVC). clinicaltrials.gov. [URL: https://clinicaltrials.gov/ct2/show/NCT04734405]
NCT04029116 {published data only}
    1. A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Oral Ibrexafungerp (SCY-078) Compared to Placebo in Subjects With Recurrent Vulvovaginal Candidiasis (VVC). ClinicalTrials.gov. [https://clinicaltrials.gov/ct2/show/NCT04029116]
NCT04208555 {published data only}
    1. A Randomized Comparison of Boric Acid Versus Terconazole in Treatment of Recurrent Vulvovaginal Candidiasis. ClinicalTrials.gov. [URL: https://clinicaltrials.gov/ct2/show/NCT04208555]
NCT04292704 {published data only}
    1. NCT04292704. clinicaltrials.gov. [URL: https://clinicaltrials.gov/ct2/show/record/NCT04292704]

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