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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. A long-term prophylactic maintenance regimen with antifungals is often necessary. In most clinical practice guidelines, oral fluconazole is recommended as the first-line treatment. Although clinical resistance to antifungal agents remains rare, overexposure to azoles may increase the development of fluconazole-resistant C .  albicans strains. In addition, non-albicans Candida species are frequently dose-dependent susceptible or resistant to fluconazole and other azoles, and their prevalence is rising. Available therapeutic options to treat such fluconazole-resistant C. albicans and low susceptibility non- albicans strains are limited. Ten experts from different European countries discussed problematic issues of current RVVC diagnosis and treatment in two audiotaped online sessions and two electronic follow-up rounds. A total of 340 statements were transcribed, summarized, and compared with published evidence. The profile of patients with RVVC, their care pathways, current therapeutic needs, and potential value of novel drugs were addressed. Correct diagnosis, right treatment choice, and patient education to obtain adherence to therapy regimens are crucial for successful RVVC treatment. As therapeutic options are limited, innovative strategies are required. Well- tolerated and effective new drugs with an optimized mechanism of action are desirable and are discussed. Research into the impact of RVVC and treatments on health-related quality of life and sex life is also needed., Competing Interests: GD, IS, JP, PH, FS, JB, JK, JV, BS, and WM are expert consultants to the pharmaceutical industry, including Gedeon Richter. RC is an employee at Gedeon Richter.This study received funding from Gedeon Richter Plc. The funder had the following involvement with the study: design and collection of data, and on the decision to submit the manuscript for publication. Authors led the analysis and interpretation of data, and the writing of the manuscript. All authors declare no other competing interests., (Copyright © 2022 Donders, Sziller, Paavonen, Hay, de Seta, Bohbot, Kotarski, Vives, Szabo, Cepuliené and Mendling.)

Approximately 70-75% of women will have vulvovaginal candidosis (VVC) at least once in their lifetime. In premenopausal, pregnant, asymptomatic and healthy women and women with acute VVC, Candida albicans is the predominant species. The diagnosis of VVC should be based on clinical symptoms and microscopic detection of pseudohyphae. Symptoms alone do not allow reliable differentiation of the causes of vaginitis. In recurrent or complicated cases, diagnostics should involve fungal culture with species identification. Serological determination of antibody titres has no role in VVC. Before the induction of therapy, VVC should always be medically confirmed. Acute VVC can be treated with local imidazoles, polyenes or ciclopirox olamine, using vaginal tablets, ovules or creams. Triazoles can also be prescribed orally, together with antifungal creams, for the treatment of the vulva. Commonly available antimycotics are generally well tolerated, and the different regimens show similarly good results. Antiseptics are potentially effective but act against the physiological vaginal flora. Neither a woman with asymptomatic colonisation nor an asymptomatic sexual partner should be treated. Women with chronic recurrent Candida albicans vulvovaginitis should undergo dose-reducing maintenance therapy with oral triazoles. Unnecessary antimycotic therapies should always be avoided, and non-albicans vaginitis should be treated with alternative antifungal agents. In the last 6 weeks of pregnancy, women should receive antifungal treatment to reduce the risk of vertical transmission, oral thrush and diaper dermatitis of the newborn. Local treatment is preferred during pregnancy., (© 2021 The Authors.Mycoses published by Wiley-VCH GmbH.)

The oestrogenised vagina is colonised by Candida species in at least 20% of women; in late pregnancy and in immunosuppressed patients, this increases to at least 30%. In most cases, Candida albicans is involved. Host factors, particularly local defence mechanisms, gene polymorphisms, allergies, serum glucose levels, antibiotics, psycho-social stress and oestrogens influence the risk of candidal vulvovaginitis. Non-albicans species, particularly Candida glabrata, and in rare cases also Saccharomyces cerevisiae, cause less than 10% of all cases of vulvovaginitis with some regional variation; these are generally associated with milder signs and symptoms than normally seen with a C. albicans-associated vaginitis. Typical symptoms include premenstrual itching, burning, redness and odourless discharge. Although itching and redness of the introitus and vagina are typical symptoms, only 35-40% of women reporting genital itching in fact suffer from vulvovaginal candidosis. Medical history, clinical examination and microscopic examination of vaginal content using 400× optical magnification, or preferably phase contrast microscopy, are essential for diagnosis. In clinically and microscopically unclear cases and in chronically recurring cases, a fungal culture for pathogen determination should be performed. In the event of non-C. albicans species, the minimum inhibitory concentration (MIC) should also be determined. Chronic mucocutaneous candidosis, a rarer disorder which can occur in both sexes, has other causes and requires different diagnostic and treatment measures. Treatment with all antimycotic agents on the market (polyenes such as nystatin; imidazoles such as clotrimazole; and many others including ciclopirox olamine) is easy to administer in acute cases and is successful in more than 80% of cases. All vaginal preparations of polyenes, imidazoles and ciclopirox olamine and oral triazoles (fluconazole, itraconazole) are equally effective (Table ); however, oral triazoles should not be administered during pregnancy according to the manufacturers. C. glabrata is not sufficiently sensitive to the usual dosages of antimycotic agents approved for gynaecological use. In other countries, vaginal suppositories of boric acid (600 mg, 1-2 times daily for 14 days) or flucytosine are recommended. Boric acid treatment is not allowed in Germany and flucytosine is not available. Eight hundred-milligram oral fluconazole per day for 2-3 weeks is therefore recommended in Germany. Due to the clinical persistence of C. glabrata despite treatment with high-dose fluconazole, oral posaconazole and, more recently, echinocandins such as micafungin are under discussion; echinocandins are very expensive, are not approved for this indication and are not supported by clinical evidence of their efficacy. In cases of vulvovaginal candidosis, resistance to C. albicans does not play a significant role in the use of polyenes or azoles. Candida krusei is resistant to the triazoles, fluconazole and itraconazole. For this reason, local imidazole, ciclopirox olamine or nystatin should be used. There are no studies to support this recommendation, however. Side effects, toxicity, embryotoxicity and allergies are not clinically significant. Vaginal treatment with clotrimazole in the first trimester of a pregnancy reduces the rate of premature births. Although it is not necessary to treat a vaginal colonisation of Candida in healthy women, vaginal administration of antimycotics is often recommended in the third trimester of pregnancy in Germany to reduce the rate of oral thrush and napkin dermatitis in healthy full-term newborns. Chronic recurrent vulvovaginal candidosis continues to be treated in intervals using suppressive therapy as long as immunological treatments are not available. The relapse rate associated with weekly or monthly oral fluconazole treatment over 6 months is approximately 50% after the conclusion of suppressive therapy according to current studies. Good results have been achieved with a fluconazole regimen using an initial 200 mg fluconazole per day on 3 days in the first week and a dosage-reduced maintenance therapy with 200 mg once a month for 1 year when the patient is free of symptoms and fungal infection (Table ). Future studies should include Candida autovaccination, antibodies to Candida virulence factors and other immunological experiments. Probiotics with appropriate lactobacillus strains should also be examined in future studies on the basis of encouraging initial results. Because of the high rate of false indications, OTC treatment (self-treatment by the patient) should be discouraged., (© 2015 Blackwell Verlag GmbH.)

Candida (C.) species colonize the estrogenized vagina in at least 20% of all women. This statistic rises to 30% in late pregnancy and in immunosuppressed patients. The most often occurring species is Candida albicans. Host factors, especially local defense deficiencies, gene polymorphisms, allergic factors, serum glucose levels, antibiotics, psychosocial stress and estrogens influence the risk for a Candida vulvovaginitis. In less than 10% of all cases, non-albicans species, especially C. glabrata, but in rare cases also Saccharomyces cerevisiae, cause a vulvovaginitis, often with fewer clinical signs and symptoms. Typical symptoms include premenstrual itching, burning, redness and non-odorous discharge. Although pruritus and inflammation of the vaginal introitus are typical symptoms, only less than 50% of women with genital pruritus suffer from a Candida vulvovaginitis. Diagnostic tools are anamnesis, evaluation of clinical signs, the microscopic investigation of the vaginal fluid by phase contrast (400 x), vaginal pH-value and, in clinically and microscopically uncertain or in recurrent cases, yeast culture with species determination. The success rate for treatment of acute vaginal candidosis is approximately 80%. Vaginal preparations containing polyenes, imidazoles and ciclopiroxolamine or oral triazoles, which are not allowed during pregnancy, are all equally effective. C. glabrata is resistant to the usual dosages of all local antimycotics. Therefore, vaginal boric acid suppositories or vaginal flucytosine are recommended, but not allowed or available in all countries. Therefore, high doses of 800 mg fluconazole/day for 2-3 weeks are recommended in Germany. Due to increasing resistence, oral posaconazole 2 × 400 mg/day plus local ciclopiroxolamine or nystatin for 15 days was discussed. C. krusei is resistant to triazoles. Side effects, toxicity, embryotoxicity and allergy are not clinically important. A vaginal clotrimazole treatment in the first trimester of pregnancy has shown to reduce the rate of preterm births in two studies. Resistance of C. albicans does not play a clinically important role in vulvovaginal candidosis. Although it is not necessary to treat vaginal candida colonization in healthy women, it is recommended in the third trimester of pregnancy in Germany, because the rate of oral thrush and diaper dermatitis in mature healthy newborns, induced by the colonization during vaginal delivery, is significantly reduced through prophylaxis. Chronic recurrent vulvovaginal candidosis requires a "chronic recurrent" suppression therapy, until immunological treatment becomes available. Weekly to monthly oral fluconazole regimes suppress relapses well, but cessation of therapy after 6 or 12 months leads to relapses in 50% of cases. Decreasing-dose maintenance regime of 200 mg fluconazole from an initial 3 times a week to once monthly (Donders 2008) leads to more acceptable results. Future studies should include candida autovaccination, antibodies against candida virulence factors and other immunological trials. Probiotics should also be considered in further studies. Over the counter (OTC) treatment must be reduced., (© 2012 Blackwell Verlag GmbH.)

For sporadic acute Candida vaginitis, any oral or local antifungal therapy can be used. For women with recurrent vulvo-vaginal candidosis (RVC), on the other hand, such simple approaches are insufficient, regardless of the product chosen. Instead, RVC should be managed as any other chronic disease and requires long-term, prophylactic, suppressive antifungal treatment. A regimen using individualized, decreasing doses of oral fluconazole (the ReCiDiF regimen) was proven to be highly efficient and offered great comfort to the patients. During this regimen, it is crucial that patients are carefully examined by anamnestic, clinical, microscopic and culture-proven absence of Candida. If a relapse occurs, the medication is adjusted and efforts are taken to find a possible triggering factor for the reactivation of the infection. Care has to be taken not to accumulate 'don't do's', unless the efficiency of a measure has been proven, by trying to eliminate one risk factor at a time for 2 months. Known possible triggers to be kept in mind are (1) antibiotic use, (2) use of specific contraceptives, especially combined contraceptive pills, (3) disturbed glucose metabolism, (4) the use of personal hygienic products, and (5) tight clothing or plastic panty liners. In therapy-resistant cases, non-albicans infection must be ruled out, and alternative therapies should be tried. Boric acid is proven to be efficient in most of these resistant cases, but other non-azoles like amphotericin B, flucytosine, gentian violet, and even caspofungin may have to be tried. As a final remark it has to be said that many patients feel poorly understood and inefficiently managed by many care-givers, increasing their feelings of guilt and sexual inferiority. Therefore, attention has to be given to take the disease seriously, follow strict treatment regimens, and advise precisely and based on individual evidence concerning any possible risk factors for recurrence. In case of therapy-resistant vulvo-vaginitis, reconsider your diagnosis and/or consider referral to specialized therapists., (Copyright © 2010 S. Karger AG, Basel.)

Chronic Candida vulvovaginitis cannot, at present, be treated effectively with local or oral antimycotic medication. Göttlicher & Meyer [Vulvovaginalmykose. Klinische Ergebnisse einer epidemiologischen Langzeitstudie, Thieme, Stuttgart (1998); Mycoses41 (1998) 49] formulated a hypothesis to explain this fact. They say that stress is the main cause of vulvovaginal mycosis, and that frequently cited predisposing somatic risk factors are not causing the illness. Two research projects were carried out to test this hypothesis. The first project was conceived to provide direct evidence for two empirical statements derived from the Göttlicher-Meyer hypothesis: (i) stress as a predictor of vulvovaginitis is least valid as the commonly assumed somatic factors and (ii) combinations of factors that reliably discriminate index women from symptom-free women point to aspects of psychosocial development, particularly stress, and not to somatic factors. Between March and November 1999, 309 successive patients were randomly chosen from those successively treated in one in-patient and two out-patient settings. Of those chosen, 117 had had at least one episode of vaginal candidosis within the 2 years prior to enlistment in the study. The remaining 192 patients had experienced no such illness. For the 117 index patients both of the above empirical statements were confirmed by statistical analyses. The second project was designed to test predictions concerning the ineffectiveness of traditional antimycotic treatment derived from the Göttlicher-Meyer hypothesis. Three different empirical statements were derived from the hypothesis--each based on the assumption of a Poisson distribution of relapses that remains uninfluenced by treatment attempts. Each of the statements was tested and confirmed in independent samples--the first in the sample used in project one, the second in a sample of 206 women insured by public Healths Management Organizations (HMOs) and the third in a sample of 179 women insured by private HMOs. Each patient had evidenced Candida albicans vulvovaginitis at least once in the time interval between 1996 and 2000. Statistical analyses confirmed each of the empirical statements, thereby substantiating the Göttlicher-Meyer hypothesis. The authors conclude that (i) psychosocial factors, particularly stress, are the primary causes of Candida albicans vulvovaginitis. Accompanying somatic factors are of little statistical significance in explaining occurrence and relapse. (ii) Traditional antimycotic treatment influences only the symptoms of the illness, not its causes, and has no effect on the probability of a relapse. Increased treatment effectiveness can be achieved only at the cost of a complete re-orientation concerning the causes of vaginal mycosis. Interventions designed to strengthen the patients' immune response are among the most promising.

Two topical formats containing clotrimazole [500 mg single dose vaginal tablet (VT) or 10% single dose vaginal cream (VC) for intravaginal use] combined with additional clotrimazole cream for topical application to the vulval area (Canesten 1 Combi, Bayer AG, Leverkusen, Germany) were compared with oral fluconazole 150 mg single dose treatment of vulvovaginal mycosis (VVM) in a single-blind clinical study. The objective of the study was to demonstrate the equivalent efficacy of the clotrimazole combination therapies (VT + 1% cream and VC + 2% cream), and fluconazole 150 mg oral capsule (Diflucan 1, Pfizer Gmbh, Karlsruhe, Germany) in terms of overall response defined as clinical cure and mycological resolution. Overall, combination therapies containing either clotrimazole 500 mg VTs or clotrimazole 10% VC were as effective as a single dose fluconazole 150 mg oral tablet in treating VVM with rates for overall response being 66%, 61% and 60%, respectively, after 14 days. There were no significant differences in the time to onset of symptom relief in the clotrimazole 500 mg tablet group and clotrimazole 10% VC compared with fluconazole 150 mg oral capsules. Only 50% of 88 patients across treatment groups with mycological recurrence also experienced return of symptoms over the entire 8 week follow-up period. All treatments administered were safe and well-tolerated and the number of patients experiencing adverse events was low.

The Guideline vulvovaginal candidosis, as passed by three German medical societies, is presented.

Sexual partners often harbour identical yeast strains in the vagina, in the orointestinal tract and in semen in cases of recurrent vulvovaginal candidoses. Specimen were collected from vagina, oral cavity and faeces of the patients, and from semen, oral cavity and faeces of their male partners. Mycological cultures were grown on Sabouraud glucose-agar and, if positive, specified by Candida-ID-Agar (BioMérieux), by formation of chlamydospores on rice agar, and by biochemotyping with the System Walkaway (Dade) or the API-32C system (BioMérieux). A polymerase chain reaction finger-printing technique with the T3B oligonucleotide as single primer was used for strain typing. Candida albicans was isolated from the vagina of 18 out of 21 patients, the vagina of one patient harboured a strain of Candida glabrata. The cultures obtained from vagina, oral cavity and faeces were genetically identical in 12 patients. From the partners of 15 patients C. albicans was cultured in at least one of the clinical samples. Identical strains were observed for eight of 15 couples, whereas four of these identical strains were cultured from semen. Further prospective investigations will prove whether a consequent treatment of both partners will eradicate identical yeast strains and will be able to improve the results of treatment in such women.

Due to its pathogenety Candida albicans is the most frequent yeast in cases of vaginal candidosis, probably mostly caused by local immunological weakness. In 5-30% one can expect a vaginal yeast colonisation depending on age, estrogen influence, pregnancy and dispositions by illness. Prepartal vaginal yeast colonisation should be treated to protect the newborn. The only typical symptom of acute vaginal candidosis is itching. Beside history and clinical symptoms, examination of vaginal secretion by phase contrast microscopy and the yeast culture are cornerstones of the diagnosis. Antimycotic resistance should be investigated only by specialists. Acute Candida albicans vaginitis should be treated locally by one or three day therapy. Candida glabrata vaginitis can be treated with high doses of oral fluconazole.

Yeast colonization of the vagina is found in about 30% of all pregnant women. Premature infants are severely endangered by generalized fungal infections due to their immature immune system. The objective of this study was to elucidate the relationship between vaginal yeast colonization of the mothers and Candida septicemia in their premature babies. In a prospective study, running from 12/1994 to 8/1996, 176 mothers, facing probable premature birth, were investigated, when hospitalized, for vaginal yeast colonization. 150 premature infants (birth weights ranging from 550 to 2390 g) of these mothers were culturally examined for yeasts in specimens from the mouth, ear, stool and urine immediately after birth as well as once weekly in the following weeks. The patients were divided into two groups. In group A, oral prophylaxis with nystatin was practiced only in infants with at least one positive yeast culture. In group B, all patients received nystatin prophylaxis. Candida septicemia developed one or two weeks after birth mainly in infants with birth weights below 1000 g. Primary oral prophylaxis with nystatin lowers considerably the risk of developing Candida infection.

Sexual partners harbour often identical yeast strains in the vagina, orointestinal tract and sperm in cases of recurrent vulvovaginal candidoses. Mycologic cultures from the vagina, mouth and stool of the patient and from the mouth and sperm of her partner were cultured on Sabouraud-Glucose-Agar and, if positive, specified by Candida ID-Agar (Biomerieux), rice agar and the system Walk away (Dade). Equal species were compared by DNR-fingerprinting using PCR. The vagina of 22 women was in 21 cases infected by Candida albicans and in one case by Candida glabrata. The culture of mouth or stool of 18 women was in 11 cases identical with those of the vagina. In 13 cases of 18 sexual male partners Candida albicans was found being identical with the strain of the female partner in 8 cases. 4 of the identical strains were grown from the sperm. Future prospective investigations shall prove whether a consequent treatment of both partners to eradicate all identical yeasts is able to improve the treatment results in such women.

Fungal vaginal infections/colonisations can be divided into a symptomatic vaginal candidiasis and an asymptomatic vaginal Candida-carriage. The latter seems to be a predisposing factor for the development of a symptomatic vaginal candidiasis. The fungal organism isolated most frequently is Candida albicans, followed by Candida glabrata, which was previously also known as Torulopsis glabrata. To a lower extend, other Candida species such as Candida tropicalis and Candida krusei can be prevalent in the vulvovaginal region. Predisposing factors for vaginal candidiasis are gravidity, diabetes mellitus or a therapy with immunosuppressive agents. Also gestagenes showed to be a pre-disposing factor for vaginal candidiasis. Divergent results concerning the predisposition to vaginal candidiasis or colonisation due to oral contraception have so far been reported. Therefore we performed a study with two healthy collectives of female volunteers (n = 2 x 60) which were different concerning the taking of oral contraceptives. Overall, in 17% of the subjects (20/120) yeast could be cultured out of the vaginal secretions. There was no evidence for a higher rate of Candida-colonisation in subjects taking oral contraceptives. Further, there was no evidence for a relationship between the length of the taking of oral contraceptives and the rate of vaginal yeast-carriage. Also the type of oral contraceptive (combination or sequential contraceptive) had no influence on the frequency of Candida-carriage. Candida albicans was the most prevalent yeast (16/20), followed by Candida glabrata (4/20).

In 42 women with chronically recurrent and 20 women with acute Candida albicans vulvovaginitis, as well as 14 women with Candida glabrata vaginitis, the following investigations were carried out: determination of protein content and secretory immunoglobulin A (sIgA) in the cervicovaginal secretion by a self-modified ELISA technique; determination of immunocells and cellbound IgA in the cervicovaginal secretion by immunofluorescence and nephelometric analysis of IgA in the serum. The results were compared with those of 77 pre-menopausal non-pregnant women with or without intake of anti-ovulants, 17 healthy pregnant women and four hysterectomised pre-menopausal women. Due to inflammation, women with acute and chronically recurrent Candida albicans vulvovaginitis had a higher protein content in the cervicovaginal secretion than healthy women. However, the content of secretory IgA was not increased but even slightly decreased in chronic cases. The number of macrophages and granulocytes in the vaginal content was not increased compared with healthy patients. In only a few cases was IgA detected on yeast cells and in the cervicovaginal secretion by fluorescence microscopy. In chronically-relapsing vaginal candidosis, the frequency of the serotype B of C. albicans was strikingly high. Women with Candida glabrata vaginitis showed lower values of secretory sIgA in the vaginal secretion compared with healthy patients as well as women with vaginitis caused by C. albicans. However, like healthy women, they had normal protein values in the cervicovaginal secretion and also lower values of IgA in the serum compared with women of C. albicans vulvovaginitis patients. Macrophages and granulocytes were demonstrable in the cervicovaginal secretion just as in healthy persons. Women with C. glabrata vaginitis showed a more conspicuous, although not a significantly more frequent, binding of IgA to budding cells demonstrated by fluorescence microscopy than women with C. albicans.

Eighteen patients with chronically recurrent vaginal candidosis showed low T-lymphocyte counts twice as frequent as a control group of 55 women. The patients were treated with azoles locally and lymphocyte stimulating pentapeptide thymopentin. The prolongation of disease-free intervals and a cure was mainly seen in the patients with low T-cell values before therapy. In vitro-proliferation assays upon stimulation with Candida albicans bore no correlation with the course of the disease. We suspect a failure in the co-operation of the immune cells, caused by differing strong responses to the Candida albicans stimulation.

Patients with a mycologically confirmed vaginal mycosis were treated either with one 100-mg vaginal ovule of clotrimazole each for 6 days, or with one 200-mg vaginal ovule of clotrimazole each for 3 days, or with one 500-mg vaginal ovule of clotrimazole for 1 day, the ovule having been supplied in a novel, acid formulation. 24, 48 and 72 h after the last dose, samples of secretion were taken from the fornix vaginae. The intravaginal secretion levels were determined semiquantitatively on the basis of the measured inhibition zones obtained with Candida albicans growth on agar plates, and the levels obtained with the different treatment regimens were compared. The vaginal secretion levels after a single 500-mg dose of the new formulation were higher, even after 3 days, than those measured in the 6-day treatment, while administration of 200 mg clotrimazole on 3 days resulted in no increase of the secretion levels over those seen in 6-day treatment with 100 mg.

Before the beginning of radium therapy a vaginal yeast contamination of 9,7% was found of 113 patients with different genital carcinomas. However, the incidence of vaginal yeast contamination increased suddenly to 30,9% under the contac irradiation therapy with radium. The radiation effect of radium is not sufficient for a "selfsterilisation" of the radium-carrier in the case of yeast contamination. Therefore, a chemic desinfection of the radium-carriers is principly necessary. The significance of radium therapy with respect to vaginal yeast contamination is discussed and the recommendation is made that routine mycological supervision be carried out on all patients with gynaecological carcinomas and appropriate antimycotic therapy initiated where necessary.