Management of recurrent vulvovaginal candidosis: Narrative review of the literature and European expert panel opinion

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Experts found that menopausal women only rarely develop Candida infections and that this mostly occurs after using antibiotics, with poorly controlled diabetes, or when on hormone replacement therapy.

“In line with reports from the literature (Hoffmann et al., 2014; Al Halteet et al., 2020), experts also found that menopausal women only rarely develop Candida infections and that this mostly occurs after using antibiotics, with poorly controlled diabetes, or when on hormone replacement therapy.”

• cites Hoffmann et al., 2014Not checked yet

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• cites Al Halteet et al., 2020Not checked yet

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• AssumptionRests on an assumption: The expert panel's opinions and experiences are representative of real-world management of RVVC across Europe.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In the experience of the meeting experts, fertile women are the most frequently affected with the highest frequency in those between 25 and 40 years of age.

“In the experience of the meeting experts, fertile women are the most frequently affected with the highest frequency in those between 25 and 40 years of age.”

• AssumptionRests on an assumption: The expert panel's opinions and experiences are representative of real-world management of RVVC across Europe.

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The expert panel confirmed that, in acute VVC episodes, C. albicans is the most frequently encountered organism, whereas in patients with RVVC, especially those on long-term maintenance treatment, non-albicans species are found at higher rates.

“The expert panel confirmed that, in acute VVC episodes, C. albicans is the most frequently encountered organism, whereas in patients with RVVC, especially those on long-term maintenance treatment, non-albicans species are found at higher rates.”

• AssumptionRests on an assumption: The expert panel's opinions and experiences are representative of real-world management of RVVC across Europe.

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Several panel members had similar patient experiences.

“Several panel members had similar patient experiences.”

• AssumptionRests on an assumption: The expert panel's opinions and experiences are representative of real-world management of RVVC across Europe.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The panel members' experience was that their patients with RVVC suffered a high social and emotional burden, which is often not perceived or understood by the public or policy makers.

“The panel members’ experience was that their patients with RVVC suffered a high social and emotional burden, which is often not perceived or understood by the public or policy makers.”

• AssumptionRests on an assumption: The expert panel's opinions and experiences are representative of real-world management of RVVC across Europe.

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In European guidelines and according to the Infectious Diseases Society of America guidelines, four or more symptomatic episodes of VVC per year are needed for RVVC diagnosis.

“In the European guidelines and according to the Infectious Diseases Society of America guidelines, four or more symptomatic episodes of VVC per year are needed for this diagnosis (Pappas et al., 2015; Sherrard et al., 2018; Farr et al., 2021a; McKloud et al., 2021).”

• cites Pappas et al., 2015 sourceNot checked yet

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• cites Sherrard et al., 2018 sourceNot checked yet

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• cites Farr et al., 2021aNot checked yet

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Recurrent vulvovaginal candidosis (RVVC) is a chronic, difficult-to-treat vaginal infection caused by Candida species, affecting women of all ages and ethnic and social backgrounds.

“Recurrent vulvovaginal candidosis (RVVC) is a chronic, difficult to treat vaginal infection, caused by Candida species, which affects women of all ages and ethnic and social background.”

• Also stated in: § Introduction · plain

  “Recurrent vulvovaginal candidosis (RVVC) is a debilitating, chronic vaginal infection (Denning et al., 2018) caused by Candida albicans (C. albicans) and non-albicans pathogenic fungus species (Sherrard et al., 2018; Farr et al., 2021a).”

• cites Denning et al., 2018 sourceNot checked yet

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• cites Sherrard et al., 2018 sourceNot checked yet

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• cites Farr et al., 2021aNot checked yet

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Primary RVVC is idiopathic, with unknown predisposing factors, and occurs in otherwise healthy immunocompetent women of whom the majority has no discernible precipitating or causative factors.

“Primary RVVC is idiopathic, with unknown predisposing factors, and occurs in otherwise healthy immunocompetent women of whom the majority has no discernible precipitating or causative factors.”

• cites Fischer and Bradford, 2011Not checked yet

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• cites Lema, 2017Not checked yet

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The probability of women developing RVVC in European countries before the age of 50 is 24%.

“According to a recent study, the probability of women developing RVVC in European countries before the age of 50 is 24% (Blostein et al., 2017).”

• cites Blostein et al., 2017 sourceNot checked yet

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The highest prevalence rate of RVVC (9%) is observed in women aged 25 to 34 years, with a global prevalence of about 7% in 15- to 54-year-old women.

“The highest prevalence rate (9%) is observed in women aged 25 to 34 years, with a global prevalence of about 7% in 15- to 54-year-old women (Denning et al., 2018; Sherrard et al., 2018; Farr et al., 2021a).”

• cites Denning et al., 2018 sourceNot checked yet

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• cites Sherrard et al., 2018 sourceNot checked yet

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• cites Farr et al., 2021aNot checked yet

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Two forms of RVVC exist: primary and secondary.

“It is generally accepted that two forms of RVVC exist (Lema, 2017).”

• cites Lema, 2017Not checked yet

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RVVC is considered a multifactorial disorder, the symptoms of which are governed by the interaction between Candida (species and virulence factors), the Lactobacilli population, the microenvironment (estrogen, inflammatory status, and oxidative stress), and the host (genetic factors, immune status, and behavioral factors).

“RVVC is considered a multifactorial disorder, the symptoms of which are governed by the interaction between Candida (species and virulence factors), the Lactobacilli population, the microenvironment (estrogen, inflammatory status, and oxidative stress), and the host (genetic factors, immune status, and behavioral factors).”

• cites Rosati et al., 2020 sourceNot checked yet

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• cites Van Riel et al., 2021Not checked yet

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In the United States, RVVC is defined as three or more episodes of symptomatic vulvovaginal candidosis in less than one year.

“For instance, in the United States (US), RVVC is defined as three or more episodes of symptomatic vulvovaginal candidosis (VVC) in less than one year (Workowski et al., 2021).”

• cites Workowski et al., 2021Not checked yet

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Secondary RVVC has known predisposing factors including an estrogenized vagina, postmenopausal hormone replacement therapy, diabetes mellitus, atopy, antibiotic/corticosteroid use, or pregnancy.

“Secondary RVVC, in contrast, has known predisposing factors including an estrogenized vagina (postmenarchal and premenopausal), postmenopausal hormone replacement therapy, diabetes mellitus, atopy, antibiotic/corticosteroid use, or pregnancy (Fischer and Bradford, 2011; Lema, 2017).”

• cites Fischer and Bradford, 2011Not checked yet

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• cites Lema, 2017Not checked yet

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RVVC affects approximately 138 million women per year worldwide, with a global annual prevalence of 3,871 per 100,000 women.

“RVVC affects approximately 138 million women per year worldwide (projected to reach an estimated 158 million by 2030), with a global annual prevalence of 3,871 per 100,000 women (Denning et al., 2018).”

• cites Denning et al., 2018 sourceNot checked yet

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RVVC is inconsistently and arbitrarily defined in clinical practice guidelines.

“RVVC is inconsistently and arbitrarily defined in the clinical practice guidelines (Denning et al., 2018).”

• cites Denning et al., 2018 sourceNot checked yet

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C. albicans accounts for the majority of all documented RVVC cases (74%), followed by non-albicans species including C. glabrata and C. krusei found in about 14% and 6% of RVVC cases, respectively.

“C. albicans accounts for the majority of all documented RVVC cases (74%), followed by the non-albicans species, including C. glabrata and C. krusei found in about 14% and 6% of RVVC cases, respectively (Ignjatovic et al., 2020).”

• cites Ignjatovic et al., 2020Not checked yet

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Dose-dependent susceptibility and high azole resistance rates have been reported for non-albicans Candida species, such as C. glabrata or C. krusei.

“Dose-dependent susceptibility and high azole resistance rates have been reported for non-albicans Candida species, such as C. glabrata (Richter et al., 2005; Ignjatovic et al., 2020) or C. krusei (Bitew and Abebaw, 2018).”

• cites Richter et al., 2005Not checked yet

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• cites Ignjatovic et al., 2020Not checked yet

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• cites Bitew and Abebaw, 2018Not checked yet

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Vaginal infections are an extremely common reason for women to seek advice and care from a physician, pharmacist, or peer, often leading to over- or misdiagnosis of VVC/RVVC.

“Vaginal infections are an extremely common reason for women to seek advice and care from a physician, pharmacist, or even peer, often leading to over- or misdiagnosis of VVC/RVVC (Sihvo et al., 2000; Lema, 2017).”

• cites Sihvo et al., 2000Not checked yet

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• cites Lema, 2017Not checked yet

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The increase in resistance to existing antifungals and the increasing virulence observed in some species mean that susceptibility testing is required in difficult-to-cure patients.

“The increase in resistance to existing antifungals and the increasing virulence observed in some species mean that susceptibility testing is required in difficult to cure patients (Hassan et al., 2021; Moreira et al., 2021).”

• cites Hassan et al., 2021Not checked yet

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• cites Moreira et al., 2021Not checked yet

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Among non-albicans species of Candida, C. glabrata is the most common and difficult to predict response to conventional therapy and to eradicate due to its reduced susceptibility to azoles.

“Among the non-albicans species of Candida, C. glabrata is the most common and difficult to predict response to conventional therapy and to eradicate due to its reduced susceptibility to azoles (Kennedy and Sobel, 2010).”

• cites Kennedy and Sobel, 2010Not checked yet

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Susceptibility testing in vitro and identification of species by PCR can be used to detect infections resistant to antifungals and undetected clinical Candida, respectively.

“Susceptibility testing in vitro and identification of species by PCR can be used to detect infections resistant to antifungals and undetected clinical Candida, respectively (Moreira et al., 2021; Sovianti and Devi, 2021).”

• cites Moreira et al., 2021Not checked yet

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• cites Sovianti and Devi, 2021Not checked yet

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Median time to clinical and mycological relapse was 10.2 and 8.4 months, respectively.

“Median time to clinical and mycological relapse was 10.2 and 8.4 months, respectively.”

• cites Sobel et al., 2004 sourceNot checked yet

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Oral fluconazole is highly effective at reducing acute episodes during maintenance therapy, but long-term remission after stopping the regimen is only present in about half of patients.

“Although oral fluconazole is highly effective at reducing acute episodes during maintenance therapy, long-term remission after stopping the regimen is only present in about half of patients (Sobel et al., 2004; Donders et al., 2008a).”

• cites Sobel et al., 2004 sourceNot checked yet

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• cites Donders et al., 2008aNot checked yet

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Adherence to the ReCiDiF regimen was good, and 72% of women were still on maintenance therapy after 1 year.

“Overall, adherence to the ReCiDiF regimen was good, and 72% of women were still on the maintenance therapy after 1 year ( Supplementary Tables 2 – 4 ).”

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Candida species are opportunistic pathogens that can be present in the vagina without producing symptoms, can cause sporadic easy-to-treat infections, or can cause recurrent symptomatic infections (RVVC).

“Candida species are opportunistic pathogens that can be present in the vagina without producing symptoms (asymptomatic), can be present and cause sporadic, easy to treat infections (symptomatic episodic VCC), or can cause recurrent symptomatic infections, which may be difficult to treat successfully (RVVC) (Moreira et al., 2021; Sovianti and Devi, 2021).”

• cites Moreira et al., 2021Not checked yet

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• cites Sovianti and Devi, 2021Not checked yet

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In the ReCiDiF regimen, at least 40% of women had been Candida positive on microscopy at least once and 50% were recolonized with Candida at least once during the year.

“In the ReCiDiF regimen (Donders et al., 2008a), excluding the approximately 10% of women who did not respond to the induction therapy, up to 79% of women were free of disease at 12 months; but at least 40% had been Candida positive on microscopy at least once and 50% were recolonized with Candida at least once during that year.”

• cites Donders et al., 2008aNot checked yet

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Hypersensitive reactions to Candida antigens lead to symptomatic disease and vulvodynia.

“The existence of such hypersensitive reactions to Candida antigens, leading to symptomatic disease (Bernstein and Seidu, 2015) and vulvodynia (Falsetta et al., 2015), has extensively been studied and reported in the literature.”

• cites Bernstein and Seidu, 2015Not checked yet

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• cites Falsetta et al., 2015Not checked yet

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During follow-up, 93.6% of 51 women reported benefits during the maintenance regimen, but 80.9% described relapse after discontinuing the weekly treatment.

“During follow-up, 93.6% of 51 women reported benefits during the maintenance regimen, but 80.9% described relapse after discontinuing the weekly treatment (Collins et al., 2020).”

• cites Collins et al., 2020 sourceNot checked yet

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Relapse rates with oral itraconazole reach 47.6%, and with topical clotrimazole, they can be as high as 64% to 84.9% at 12 months.

“Likewise, relapse rates with oral itraconazole reach 47.6% (Fong, 1992), and, with topical clotrimazole, it can be as high as 64% (Fong, 1992) to 84.9% (Roth et al., 1990) at 12 months ( Supplementary Tables 2 and 3 ).”

• cites Fong, 1992Not checked yet

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• cites Roth et al., 1990Not checked yet

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Limited awareness of recommended diagnostic practices among healthcare practitioners and a lack of access to point-of-care tools contribute to broad guideline non-adherence.

“Research evidence suggests that limited awareness of recommended diagnostic practices among healthcare practitioners and a lack of access to point-of-care tools contribute to broad guideline non-adherence (Nyirjesy et al., 2020).”

• cites Nyirjesy et al., 2020Not checked yet

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Two comprehensive reviews on the effects of probiotics against symptomatic VVC have highlighted scarce and low-quality evidence, with a need for robust randomized trials.

“Two comprehensive reviews (Xie et al., 2013; Shenoy and Gottlieb, 2019) on the effects of probiotics against symptomatic VVC have highlighted the scarce and low-quality evidence, with a need for robust randomized trials to ascertain whether probiotics can have a beneficial effect on the (adjuvant) treatment of acute VVC or in the prevention of recurrences in patients with RVVC.”

• cites Xie et al., 2013Not checked yet

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• cites Shenoy and Gottlieb, 2019Not checked yet

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In clinical practice, recurrence affects 45.5% of patients, and positive cultures for Candida have been detected in 56% of patients with RVVC after long-term use of boric acid ovules.

“In clinical practice, however, recurrence affects 45.5% (Iavazzo et al., 2011) of patients, and positive cultures for Candida have been detected in 56% of patients with RVVC after long-term use of boric acid ovules (Guaschino et al., 2001).”

• cites Iavazzo et al., 2011Not checked yet

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• cites Guaschino et al., 2001Not checked yet

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There are no trials addressing the optimal duration of suppressive therapy, as the majority of trials have used 6 months maintenance as standard.

“However, there are no trials addressing the optimal duration of suppressive therapy as the majority of trials have used 6 months maintenance as standard (Saxon et al., 2020).”

• cites Saxon et al., 2020Not checked yet

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Rapid onset of symptom relief, safety compared with already known medications, simple therapy schedules, avoidance of drugs metabolized by the liver, and resistance to or failure on fluconazole may drive women's treatment preferences.

“Rapid onset of symptom relief, safety compared with already known medications, simple therapy schedules, avoidance of drugs metabolized by the liver, and resistance to or failure on fluconazole may drive women’s treatment preferences (Martens, 2018).”

• cites Martens, 2018Not checked yet

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One intramuscular single dose of NDV-3A was safe, generated rapid and robust B- and T-cell immune responses, and reduced the frequency of symptomatic episodes of RVVC for up to 12 months in women aged <40 years.

“One intramuscular single dose of NDV-3A was safe, generated rapid and robust B- and T-cell immune responses, and reduced the frequency of symptomatic episodes of RVVC for up to 12 months in women aged <40 years.”

• cites Edwards et al., 2018Not checked yet

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In vitro and in vivo preliminary evidence has indicated that the development of resistance against the combination of topical miconazole and domiphen bromide did not occur and has highlighted the potential for this combination therapy to treat Candida biofilm-related infections.

“In vitro and in vivo preliminary evidence has indicated that the development of resistance against the combination did not occur and has thus highlighted the potential for this combination therapy to treat Candida biofilm-related infections (Tits et al., 2021).”

• cites Tits et al., 2021Not checked yet

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Idiopathic non-responders, relapse, resistance, inadequate prophylaxis, and women's choices, habits, and behaviors challenge the success of RVVC treatment.

“Idiopathic non-responders, relapse, resistance, inadequate prophylaxis, and women’s choices, habits, and behaviors challenge the success of RVVC treatment (Lema, 2017).”

• cites Lema, 2017Not checked yet

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Oteseconazole showed strong activity against azole-resistant C. albicans and non-albicans species, such as C. glabrata and C. krusei, in the treatment of chronic RVVC, with affected patients showing no recurrence for a duration of 48 weeks.

“Oteseconazole showed strong activity against azole-resistant C. albicans and non-albicans species, such as C. glabrata and C. krusei, in the treatment of chronic RVVC, with affected patients showing no recurrence for a duration of 48 weeks (Brand et al., 2018).”

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Ibrexafungerp is an oral β-1,3-D-glucan synthase inhibitor (GSI) of the enfumafungin-derived triterpenoid class of antifungals (echinocandins).

“For instance, ibrexafungerp is an oral β-1,3-D-glucan synthase inhibitor (GSI) of the enfumafungin-derived triterpenoid class of antifungals (echinocandins) (Gamal et al., 2021).”

• cites Gamal et al., 2021 sourceNot checked yet

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According to some, the mycological cure rate may reach 100% with topical boric acid.

“According to some, the mycological cure rate may reach 100% (Iavazzo et al., 2011) with topical boric acid.”

• cites Iavazzo et al., 2011Not checked yet

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The European Chemicals Agency issued a warning against the application of boric acid, as there is insufficient data on potential fertility impairment and it may be embryotoxic during pregnancy.

“However, the European Chemicals Agency issued a warning against the application of boric acid, as there is insufficient data on potential fertility impairment and it may be embryotoxic during pregnancy (Prutting and Cerveny, 1998).”

• cites Prutting and Cerveny, 1998Not checked yet

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