Geburtshilfe Frauenheilkd 2021; 81(04): 398-421
DOI: 10.1055/a-1345-8793
GebFra Science
Guideline/Leitlinie

Vulvovaginal Candidosis (Excluding Mucocutaneous Candidosis): Guideline of the German (DGGG), Austrian (OEGGG) and Swiss (SGGG) Society of Gynecology and Obstetrics (S2k-Level, AWMF Registry Number 015/072, September 2020)

Article in several languages: English | deutsch
Alex Farr
1   Universitätsklinik für Frauenheilkunde, Medizinische Universität Wien, Wien, Austria
,
Isaak Effendy
2   Hautklinik, Klinikum der Stadt Bielefeld, Bielefeld, Germany
,
Brigitte Frey Tirri
3   Frauenklinik, Kantonsspital Baselland, Liestal, Switzerland
,
Herbert Hof
4   MVZ Labor Limbach und Kollegen, Heidelberg, Germany
,
Peter Mayser
5   Facharzt für Haut- und Geschlechtskrankheiten, Biebertal, Germany
,
Ljubomir Petricevic
1   Universitätsklinik für Frauenheilkunde, Medizinische Universität Wien, Wien, Austria
,
Markus Ruhnke
6   Klinik für Hämatologie, Onkologie und Palliativmedizin, Helios Klinikum Aue, Aue, Germany
,
Martin Schaller
7   Hautklinik, Zentrum für Dermato-Onkologie, Universität Tübingen, Tübingen, Germany
,
Axel P. A. Schäfer
8   Facharzt für Frauenheilkunde und Geburtshilfe, Berlin, Germany
,
Birgit Willinger
9   Abteilung für Klinische Mikrobiologie, Medizinische Universität Wien, Wien, Austria
,
Werner Mendling
10   Deutsches Zentrum für Infektionen in Gynäkologie und Geburtshilfe, Wuppertal, Germany
› Author Affiliations
 

Abstract

Aim The aim of this official guideline, published and coordinated by the German (DGGG), Austrian (OEGGG) and Swiss (SGGG) Societies of Gynecology and Obstetrics in collaboration with the DMykG, DDG and AGII societies, was to provide consensus-based recommendations obtained by evaluating the relevant literature for the diagnosis, treatment and management of women with vulvovaginal candidosis.

Methods This S2k guideline represents the structured consensus of a representative panel of experts with a range of different professional backgrounds commissioned by the Guideline Committee of the above-mentioned societies.

Recommendations This guideline gives recommendations for the diagnosis, management, counseling, prophylaxis and screening of vulvovaginal candidosis.


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I  Guideline Information

Guidelines program of the DGGG, OEGGG and SGGG

For information on the guidelines program, please refer to the end of this guideline.


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Citation format

Vulvovaginal Candidosis (Excluding Mucocutaneous Candidosis): Guideline of the German (DGGG), Austrian (OEGGG) and Swiss (SGGG) Society of Gynecology and Obstetrics (S2k-Level, AWMF Registry Number 015/072, September 2020). Geburtsh Frauenheilk 2021; 81: 398 – 421


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Guideline documents

The complete long version and a slideshow version of this guideline as well as a list of the conflicts of interest of all of the authors are available in German on the homepage of the AWMF: http://www.awmf.org/leitlinien/detail/ll/015-072.html


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Guideline authors

See [Tables 1] and [2].

Table 1 Lead author and/or coordinating guideline author.

Author

AWMF professional society

Priv.-Doz. DDr. Alex Farr

Austrian Society of Gynecology and Obstetrics (OEGGG), Germany Society of Gynecology and Obstetrics (DGGG)

Table 2 Contributing guideline authors.

Author

Mandate holder

DGGG working group/AWMF/non-AWMF professional society/
organization/association

Prof. Dr. Isaak Effendy

German Diabetes Society (DDG)

Priv.-Doz. DDr. Alex Farr

OEGGG/DGGG

Dr. med. Brigitte Frey Tirri

Swiss Society of Gynecology and Obstetrics (SGGG)

Prof. Dr. Herbert Hof

German-speaking Mycological Society (DmykG)

Prof. Dr. Peter Mayser

German Diabetes Society (DDG)

Prof. Dr. Werner Mendling

German Society of Gynecology and Obstetrics (DGGG)

Prof. Dr. Ljubomir Petricevic

Austrian Society of Gynecology and Obstetrics (OEGGG)

Prof. Dr. Markus Ruhnke

German-speaking Mycological Society (DmykG)

Prof. Dr. Martin Schaller

German Diabetes Society (DDG)

Priv.-Doz. DDr. Axel Schäfer

Working Group on Infections and Immunology (AGII)

Prof. Dr. Birgit Willinger

German-speaking Mycological Society (DmykG)


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Abbreviations

Ab: antibodies
BMI: body mass index
C : Candida
CDC: Centers for Disease Control and Prevention
CF: cystic fibrosis
ECHA: European Chemicals Agency
GBS: group B Streptococcus
GDM: gestational diabetes mellitus
IUS: intrauterine system
KOH: potassium hydroxide
Lcr35: Lactobacillus casei rhamnosus 35
LNG: levonorgestrel
MIC: minimal inhibitory concentration
MPA: medroxyprogesterone acetate
OTC: over-the-counter
PCR: polymerase chain reaction
PVP-I: povidone-iodine
RVVC: recurrent vulvovaginal candidosis
VVC: vulvovaginal candidosis
 


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II  Guideline Application

Purpose and objectives

The purpose of this guideline is to provide optimal care for patients with vulvovaginal candidosis in outpatient, semi-inpatient and inpatient care settings. Other objectives are the prevention and early detection of vulvovaginal candidosis. The aim is to describe targeted diagnostic procedures and treatments for cases with specific symptoms. This should prevent unnecessary treatment and thereby also reduce the potential for patients to develop resistance to treatment.


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Targeted care settings

  • outpatient care

  • semi-inpatient care

  • inpatient care

  • specialized care


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Target user groups/target audience

  • hospital-based gynecologists

  • gynecologists in private practice

  • hospital-based dermatologists

  • dermatologists in private practice

  • hospital-based microbiologists

  • microbiologists in private practice


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Additionally

  • general practitioners

  • hospital-based midwives

  • midwives in private practice

  • nursing staff

  • biomedical analysts

  • medical and scientific societies and professional associations

  • health policy institutions and decision-makers at regional and national levels

  • funding bodies


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Adoption and period of validity

The validity of this guideline was confirmed by the executive boards/heads of the participating professional societies/working groups/organizations/associations as well as by the boards of the DGGG, the DGGG Guideline Commission, the SGGG and the OEGGG in September 2020 and was thus approved in its entirety. This guideline is valid for the period from 1st September 2020 through to 31st August 2025. Because of the contents of this guideline, this period of validity is only an estimate.


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III  Methodology

Basic principles

The method used to prepare this guideline was determined by the class to which this guideline was assigned. The AWMF Guidance Manual (version 1.0) has set out the respective rules and requirements for different classes of guidelines. Guidelines are differentiated into lowest (S1), intermediate (S2), and highest (S3) class. The lowest class is defined as consisting of a set of recommendations for action compiled by a non-representative group of experts. In 2004, the S2 class was divided into two subclasses: a systematic evidence-based subclass (S2e) and a structural consensus-based subclass (S2k). The highest S3 class combines both approaches.

This guideline has been classified as S2k.


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Grading of recommendations

A grading of evidence based on the systematic search, selection, evaluation and synthesis of an evidence base which is then used to grade the recommendations is not envisaged for S2k guidelines. The different individual statements and recommendations are only differentiated linguistically, not by the use of symbols ([Table 3]).

Table 3 Grading of recommendations.

Level of obligation to comply with the recommendation

Terminology

Strong recommendation, highly binding

must/must not

Recommendation, moderately binding

should/should not

Open recommendation, not binding

may/may not


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Statements

Expositions or explanations of specific facts, circumstances or problems without any direct recommendations for action included in this guideline are referred to as “statements”. It is not possible to provide any information about the grading of evidence for these statements.


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Achieving consensus and level of consensus

At structured NIH-type consensus-based conferences (S2k/S3 level), authorized participants attending the session vote on draft statements and recommendations. The process is as follows. A recommendation is presented, its contents are discussed, proposed changes are put forward, and finally, all proposed changes are voted on. If a consensus is not achieved (> 75% of votes), there is another round of discussions, followed by a repeat vote. Finally, the extent of consensus is determined based on the number of participants ([Table 4]).

Table 4 Level of consensus based on extent of agreement.

Symbol

Level of consensus

Extent of agreement in percent

+++

Strong consensus

> 95% of participants agree

++

Consensus

> 75 – 95% of participants agree

+

Majority agreement

> 50 – 75% of participants agree

No consensus

< 51% of participants agree


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Expert consensus

As the term already indicates, this refers to consensus decisions taken specifically with regard to recommendations/statements made without a prior systematic search of the literature (S2k) or where evidence is lacking (S2e/S3). The term “expert consensus” (EC) used here is synonymous with terms used in other guidelines such as “good clinical practice” (GCP) or “clinical consensus point” (CCP). The strength of the recommendation is graded as previously described in the chapter on the grading of recommendations; it is only expressed semantically (“must”/“must not” or “should”/“should not” or “may”/“may not”) without the use of symbols.


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IV  Guideline

1  Definition

Consensus-based recommendation 1.E1

Expert consensus

Level of consensus ++

The terms “candidosis” and “Candida vulvovaginitis” should be used in preference to the term “candidiasis”.

VVC is an infection of the substantially estrogenized vagina and vestibulum, which can spread to the external surface of the labia minora and the labia majora as well as to the intercrural and perianal region. There are no known cases of candidosis of the cervix or the endometrium. Congenital fetal candidosis and Candida amnionitis are very rare but possible. The terms “candidosis” or “Candida albicans vulvovaginitis” are preferred [1]. The ending “-iasis” should be reserved for parasitic infections (e.g., trichomoniasis) [2] but is often used because of its widespread use in English-language texts.


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2  Microbiology

Consensus-based statement 2.S1

Expert consensus

Level of consensus +++

The most commonly detected fungal organism in premenopausal, pregnant, asymptomatic, healthy women and women with acute VVC (with no history of chronic recurrent VVC) is Candida albicans.

In vitro, Candida albicans forms blastospores, germ tubes, pseudomycelia, and true mycelia as well as chlamydospores on special culture medium. Candida glabrata only forms blastospores. Pseudohyphae formation (with the exception of C. glabrata and some other Candida types, which occur in the form of blastospores) is an indication of infection [3], [4]. In premenopausal, pregnant, asymptomatic and healthy women as well as women with acute VVC, C. albicans is the causative species in 85 – 95% of cases. This species (spp.) is very similar to C. africana which can only be identified with the help of special diagnostic procedures [5], [6]. Precise epidemiological data for this are lacking. There are regional differences in the distribution of Candida species, although studies from German-speaking [7], [8] and English-speaking [9] areas report similar numbers. In a retrospective PCR-based analysis of 93 775 cervicovaginal smears over 4 years which were taken to evaluate the cause of VVC, C. albicans was present in 89%, C. glabrata in 7.9% and other Candida species in less than 2% of cases [10]. Non-Candida albicans types, particularly C. glabrata, are found more often in postmenopausal, diabetic, and immunosuppressed women [8], [11], [12], [13], [14], [15], [16]. C. krusei, C. guilliermondii, C. tropicalis, C. parapsilosis and other species may cause vulvovaginitis and its typical symptoms in individual cases [4], [8], [17], [18], [19]. Saccharomyces cerevisiae is basically apathogenic and therefore causes no symptoms [20], [21], even if it is present as a commensal organism in 1 – 2% of vaginal cultures [8], [15].


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3  Virulence factors

Consensus-based statement 3.S2

Expert consensus

Level of consensus +++

The step from colonization to vaginitis is still not well understood and confirms the importance of host factors.

The pathogenesis of VVC depends not only on the virulence of the pathogen but also on the individualʼs predisposition and immune response. Yeast pathogens are generally typical opportunists which can cause infection when the local or systemic immune response is weak. It is still not clear why simple colonization with Candida in a healthy person can result in an acute, highly infectious disorder.

The lack of knowledge about the shift from colonization to vaginitis confirms the importance of host factors [22]. Colonization is followed by adherence to the vaginal epithelium, then by invasion, infection and inflammation aided by the pathogenʼs virulence factors. Fungal components are created during pseudohyphae formation, stimulating strong chemotaxis by granulocytes which then causes inflammation [23].

Adherence of Candida cells [24] to the vaginal wall is facilitated by mannoproteins [25], [26]. The ability to form (pseudo) hyphae and secrete hydrolytic proteins are relevant virulence factors [27], [28], [29], which are correlated with pathogenicity [30], [31]. Siderophores and pH tolerance [32] as well as the presence of enzymes which allow Candida albicans to survive in macrophages [33] are other important mechanisms for the development of infection.

In an acute infection, the formation of virulence factors and immune-inflammatory factors appears to activate the inflammasomes of the vaginal epithelial cells. Components of the fungal wall such as glucan, mannan and chitin bind to specific macrophage receptors and stimulate different cytokines [34]. One of the preconditions for invasion by Candida is the yeast-hypha transition, which is encouraged by the presence of estrogens, as fungi contain cytoplasmic estrogen receptors [35].


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4  Genital colonization

Consensus-based statement 4.S3

Expert consensus

Level of consensus +++

Simple colonization with Candida species is common, often transient, and usually does not require treatment unless it occurs during pregnancy.

As colonization is connected to vaginal estrogenization, it is far less common in girls who have not yet begun menstruating or women after menopause (who are not taking hormone replacement therapy) and they almost never have VVC [36]. Overall, there is no clear indication for an increased incidence of candidosis in gynecology, neither acute nor chronic recurrent disease. According to the results from culture-based detection methods, around 30% of pregnant women are affected in the third trimester of pregnancy [8], [16].

The use of PCR significantly improves the detection of vaginal colonization [37]. However, the extent of vaginal colonization will vary at different times in each individual. It should be noted that positive findings for C. glabrata usually only indicate colonization. Risk factors for colonization with Candida spp., which occurs in around 70% of all young healthy women, are reported to be recent sexual intercourse, injection of the ovulation inhibitor medroxyprogesterone acetate (MPA) and colonization with lactobacilli and group B Streptococcus (GBS) [38].

The partnerʼs sperm may be colonized by the identical Candida strain found in the vagina [39], even though the partner may be asymptomatic. Candida balanitis requires treatment; however, temporary redness of the glans after sexual intercourse with a Candida-colonized woman may also be a reaction. It is not clear whether colonization of the partnerʼs genital tract or of the orointestinal tract of both partners could play a role as the source of chronic recurrent episodes of Candida vaginitis [4], [40].


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5  Predisposing host factors

Consensus-based recommendation 5.E2

Expert consensus

Level of consensus +++

Around 70 – 75% of all women will suffer from VVC at least once in their lifetime, although there are some higher risk groups for whom, in addition to appropriate diagnosis and treatment of VVC, the aim should also be to eliminate the predisposing host factor (where possible).

5.1  Diabetes mellitus

Patients with diabetes mellitus suffer more often from VVC, and treatment usually fails when serum glucose levels are not within normal ranges [11], [41]. Increased glycemia in vaginal tissue increases fungal adhesion and fungal growth and predisposes vaginal epithelial cells to bind yeast cells. Moreover, glucose levels of 10 – 11 mmol/l impairs the hostʼs defense mechanism. Hyperglycemia reduces neutrophil migration and weakens their chemotactic and phagocytic ability, increasing the hostʼs susceptibility to VVC [42], [43]. Antidiabetic SGLT2 inhibitors increase glycosuria, thereby also increasing the number of episodes of VVC [44], [45], [46]. If diabetic women experience recurrent episodes of VVC, their antidiabetic medication may need to be checked and adjusted [47].


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5.2  Antibiotics

Women with prior vaginal Candida colonization have a 33% higher risk of developing VVC after treatment with antibiotics [48], [49], [50], [51]. The most commonly prescribed and most effective prophylaxis against VVC is to take 150 mg fluconazole when also taking antibiotics, with fluconazole taken either at the beginning and at the end of the course of antibiotics or just once a week. Another option consists of taking oral or vaginal probiotics when taking antibiotics [52].


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5.3  Vaginal microbiota

Lower numbers of lactobacilli were found in women with VVC compared to those without VVC [53]. Certain lactobacilli have an antagonistic effect on Candida species [54], [55]. This antagonistic effect has been reported for special strains such as Lactobacillus rhamnosus [56], [57], [58], [59], [60]. The protection proved by lactobacilli is primarily based on the ability of lactobacilli to adhere to vaginal epithelial cells, thereby inhibiting the growth of pathogens [61].


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5.4  Hormonal factors

The glycogen stored in the vaginal epithelium under the influence of estrogen serves as a nutritive medium for fungi [62]. Estrogens also promote the formation of inhibitors by epithelial cells which hinder the antimycotic function of granulocytes, leading to leukocyte anergy [23], [47], [63]. Because of the association with estrogen levels and high glycogen levels, VVC symptoms are usually reported mid-cycle or in the luteal phase of the menstrual cycle, with symptoms decreasing rapidly during menstruation [62]. Postmenopausal women are significantly more often affected by VVC if they are taking hormone replacement therapy [64].


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5.5  Contraceptives

It has been reported that taking oral contraceptives increases the incidence of VVC, but this appears to depend on the dosage of the estrogen component [65]. Progestogens by themselves appear to exert a protective effect against VVC [47], [66]. As regards the use of contraceptive coils, Donders et al. [43] recommend that women with chronic RVVC and women who have an increased risk of VVC should avoid levonorgestrel-releasing intrauterine systems (LNG-IUS).


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5.6  Genetic factors

Genetic factors (e.g., gene polymorphisms of mannose-binding lectin [67], [68] and non-secretor phenotypes of AB0 and Lewis blood groups) may also be responsible for relapses of VVC [69]. As infection equals colonization plus disposition, immunosuppressed women suffer more often from VVC [70]. Ab-producing B cells are considered to offer some protection against VVC [71], [72], [73], [74], [75]. Women with atopic diathesis and type I allergies develop VVC more often than healthy women do [76].


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5.7  Lifestyle factors

Sexual behavior may result in a relapse of VVC [48], [77], [78]. It is presumed that psychosocial stress may trigger chronic RVVC due to immunosuppression [79], [80]. Candidosis has a negative impact on patientsʼ work life and social life. Some specialists are also of the opinion that patientsʼ diet may be relevant for the development of VVC [81], [82].


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6  Clinical symptoms

Consensus-based statement 6.S4

Expert consensus

Level of consensus +++

The main symptom of VVC is itching, although not all women who complain of itching actually have VVC. In addition to itching, affected women often also complain of vaginal redness, soreness, burning, dyspareunia and dysuria. These symptoms by themselves are not sufficient to reliably differentiate between the causes of vaginitis.

Premenopausal women usually suffer from vaginal candidosis, which can spread to the vestibulum and the vulva, while postmenopausal women primarily experience symptoms in the groin/inguinal area and the vulva. Candida cervicitis is unknown. In premenopausal women, symptoms typically occur prior to menstruation, when estrogen-induced cell proliferation and progesterone-induced cytolysis release glycogen which is then metabolized by lactobacilli, leading to increased tissue glucose levels [83].

From a clinical and therapeutic standpoint, differentiating between complicated and uncomplicated cases is recommended [4]. In around 90% of cases, itching is the most important although not the most reliable symptom; only 35 – 40% of women who complain of itching actually have VVC [8], [37], [84]. Vaginal discharge may vary. At the start of an episode of VVC, the consistency of discharge is often thin, usually whitish and curdy, while there may be no discharge at all in cases with chronic RVVC [42], [85]. In contrast to bacterial vaginosis, the discharge occurring with VVC does not have an offensive smell [42].

In addition to itching of the vulva and/or in the vagina, most patients with VVC complain of vaginal redness, soreness, burning, dyspareunia and dysuria [42]. But these symptoms by themselves often do not permit the clinician to reliably differentiate between the causes of vaginitis. Itching and redness are not always present in VVC [84]. The labia minora may be edematous, while burning fissuring is common, especially in cases with RVVC.

Typical VVC symptoms are usually caused by C. albicans; C. glabrata vaginitis is rare and usually only occurs in late premenopause and perimenopause [9], [17], [86], [87], [88]. C. krusei vaginitis [19] and C. parapsilosis vaginitis [18] have a similar presentation as C. glabrata vaginitis, with only mild clinical symptoms. Saccharomyces cerevisiae are an unlikely cause of vaginitis [20], [21], [89]. Dermatologically, vulvar candidosis is differentiated into vesicular, eczematoid and follicular forms. Women with secondary vestibulodynia often report VVC prior to an episode of vestibular pain.

Overall, VVC symptoms result in a reduction of patientsʼ quality of life comparable to that of patients suffering from bronchial asthma or chronic, obstructive bronchitis. VVC is therefore also associated with significantly lower productivity in professional and daily life [90].


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7  Diagnostic procedures

Consensus-based recommendation 7.E3

Expert consensus

Level of consensus +++

The diagnosis of VVC must be based on a combination of clinical examination and microscopic evidence of (pseudo) hyphae, although in unclear cases, diagnostic procedures should be expanded to include culture tests.

7.1  Necessary diagnostic procedures

Consensus-based recommendation 7.E4

Expert consensus

Level of consensus +++

The first diagnostic step must consist of microscopic examination of the discharge using a saline solution and 400 × magnification.

To obtain a diagnosis, (pseudo) hyphae must be present to allow detection of Candida-related vaginitis and differentiate it from asymptomatic colonization. The diagnosis must be based on the patientʼs history, a gynecological examination, and microscopic examination of the vaginal discharge using a saline solution (or alternatively a 10% potassium hydroxide solution) at a magnification of at least 400 × (10 × ocular lens plus 40 × objective lens) under a light microscope or phase-contrast microscope [20], [91]. pH measurement may also be done, if necessary. Blastospores or (pseudo) hyphae are found on microscopic examination in around 50 – 80% of cases with acute VVC [4], [92]. An increased number of leukocytes may be found in the discharge, although that is not always necessarily the case. If no blastospores or (pseudo) hyphae are found on microscopic examination, the number of pathogens is probably so low that microscopic examination, which has a low sensitivity, will be negative. As culturing is more sensitive and because infection may be triggered even if the fungal load is low, culturing and determination of species should be done, especially in patients with chronic RVVC. As resistance is not correlated with the MIC, their identification is not of primary importance [83], [93], [94].

The typical medium used in the culture-based diagnosis of Candida species is Sabouraud 2% glucose agar. Other media include CHROMagar and Mikrostix-Candida. Chromogenic culture media offer the opportunity to identify specific Candida spp. immediately, based on their pigmentation, making it easier to identify and differentiate mixed cultures when several different yeast strains are present. In such cases, the patient will typically be suffering from C. albicans vaginitis, while the generally resistant C. glabrata often remains in situ following treatment. C. glabrata is usually only present in the form of colonization and treatment is not required if symptoms are absent. In vitro sensitivity testing should only be considered if non-Candida albicans species are present and in cases with chronic recurrent infection.

Modern DNA hybridization testing of the vaginal discharge obtained from the speculum used for the gynecological examination has a sensitivity and specificity of up to 96.3% for the detection of Candida spp. [95]. Detection based on whole genome sequencing has the highest sensitivity and specificity of all Candida diagnostic procedures [96].


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7.2  Unnecessary diagnostic procedures

Consensus-based statement 7.S5

Expert consensus

Level of consensus +++

Serological tests, particularly tests to determine antibody levels, are not useful for diagnosing VVC.


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8  Therapy

Consensus-based recommendation 8.E5

Expert consensus

Level of consensus +++

Acute VVC should be treated either with topical or oral antifungals, according to the individual womanʼs requirements, while the primary therapy for chronic RVVC should be oral therapy, possibly in the form of long-term suppressive therapy.

8.1  Therapy for acute Candida vaginitis

Consensus-based statement 8.S6

Expert consensus

Level of consensus +++

The use topical or oral imidazole derivates, polyenes or ciclopiroxolamine to treat acute VVC will result in the same therapeutic success. Treatment of an asymptomatic sexual partner is not indicated in cases with acute VVC.

Asymptomatic vaginal colonization does not require treatment, even if high numbers of pathogens are present, as long as the patient is immunocompetent and does not suffer from chronic RVVC. If infection is present, the patient will require treatment even when the pathogen count is low. There are numerous therapeutic options [97]. The following substances are used for treatment: azoles prevent the conversion of lanosterol to ergosterol in yeast cell membranes [98]; polyenes form complexes using the ergosterol in yeast cell membranes and changing their permeability [99]; ciclopirox olamine hampers important iron-dependent enzymes through the formation of chelate [100]. A lower-dosage suppressive therapy may be considered for patients with chronic RVVC. Such a regimen would consist of 200 mg oral fluconazole 3 days per week (for 1 week); if the patient is then symptom-free and mycology tests are negative, maintenance therapy is continued with 200 mg oral fluconazole once a week for 2 months, then every 2 weeks for 4 months, and finally once a month for 6 months.

Vaginal suppositories and creams are available in dosages and preparations for treatments lasting between 1 and 3 days or between 6 and 7 days [101]. Alternative treatment options for non-pregnant women consist of oral triazoles (fluconazole, itraconazole, posaconazole, voriconazole), polyenes (nystatin) [4], [102], [103], or ciclopirox olamine ([Table 5]) [104].

Table 5 Treatment options for acute Candida vaginitis.

Topical therapy (for a first-time manifestation)

Clotrimazole

200 mg vaginal tablets 1 × daily for 3 days

single 500 mg vaginal tablet

Econazole

150 mg vaginal suppository 2 × daily every 12 hours

150 mg vaginal suppository 1 × daily for 3 days

Fenticonazole

600 mg vaginal capsule 1 × daily

Repeat if required

Isoconazole

150 mg vaginal suppository 2 × daily every 12 hours

150 mg vaginal suppository 1 × daily for 3 days

single 600 mg vaginal suppository

Alternative therapies (in cases with a massive first-time manifestation)

Fluconazole

single oral 150 mg dose

50 mg orally 1 × daily for 7 – 14 days

100 mg orally 1 × daily for 14 days

For immunosuppressed patients

Itraconazole

100 mg orally 2 × 2 capsules daily postprandial

100 mg orally 1 × 2 capsules daily for 3 days

Nystatin

100 000 IU vaginal tablet for 14 days

200 000 IU vaginal tablet for 6 days

Ciclopiroxolamine

50 mg (1 applicator filling) 1 × daily for 6 – 14 days

poss. procured through an international pharmacy


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8.2  Side effects

Consensus-based statement 8.S7

Expert consensus

Level of consensus +++

All established vaginal and topical antifungals are well tolerated.

All established vaginal and topical antifungals are tolerated well. Azoles and ciclopirox olamine may cause slight local burning in 1 – 10% of cases [7], [103]. Unfortunately, local irritation leads to a reduction in patient compliance and may be mistakenly interpreted as resistance to therapy [105]. Allergic reactions are possible but rare. Hydrophilic fluconazole and lipophilic itraconazole rarely cause any side effects when administered using standard dosages. In systemic therapy, however, itraconazole causes significantly more side effects than fluconazole (e.g., anaphylactoid reactions, headaches, etc.). With systemic azole therapy, it is important to be aware of possible interactions with other therapeutic agents, particularly if they are metabolized through cytochrome P450 3A4 enzymes. Prior to any topical application of azole antifungal agents, patients must be informed that these agents may impair the functionality and reliability of rubbers diaphragms and latex condoms.


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8.3  Development of resistance

Consensus-based recommendation 8.E6

Expert consensus

Level of consensus +++

Unnecessary antifungal therapies may lead to resistance due to selection of less susceptible strains and must therefore be avoided.


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8.4  Therapy of non-Candida albicans vaginitis

Consensus-based recommendation 8.E7

Expert consensus

Level of consensus +++

Cases with chronic RVVC and non-Candida albicans vaginitis should be investigated to see whether the reported symptoms point to mycosis and (after assessment for resistance) an alternate antifungal agent should generally be used. This particularly applies when treating infections caused by Candida glabrata.

Although when Candida glabrata is detected, it is often only an indication of colonization, standard vaginal or oral treatments will be unsuccessful when treating true Candida glabrata vaginitis. Topical administration of nystatin or ciclopirox olamine may be considered for Candida glabrata vaginitis.

Candida krusei vaginitis is resistant to fluconazole and itraconazole and partially resistant to posaconazole and some imidazoles. After starting primary therapy with topical 100 mg clotrimazole for 2 weeks, therapy with ciclopirox olamine [20] or nystatin [19] may be initiated. There are almost no studies on the effects of treatment because such cases are very rare.

While C. dubliniensis is sensitive to imidazole, it tends to develop resistance to fluconazole, particularly when patients are receiving long-term therapy [106]. Vaginitis caused by C. tropicalis and C. guilliermondii should be treated like a conventional C. albicans vaginitis. C. kefyr is apathogenic and therefore unlikely to be the cause of vaginitis.


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8.5  Therapy of chronic recurrent Candida vaginitis

Consensus-based recommendation 8.E8

Expert consensus

Level of consensus +++

Long-term antifungal treatment may be carried out to treat chronic RVVC, although the level of evidence for different treatment regimens is low.

Therapy of acute VVC takes 1 – 7 days and consists of the short-term administration of a typical active agent or the administration of a single dose, with cure rates reported to be more than 80%. However, this does not apply to chronic RVVC. As infection equals colonization plus disposition and therapies against disposition have not yet been tested, topical or oral maintenance therapies (suppressive therapies) are recommended for chronic RVVC to prevent relapse [107], [108], [109], [110], [111].

The results of therapies with 500 mg topical clotrimazole, 100 mg oral ketoconazole or 150 mg oral fluconazole are comparable, but it should be noted that ketoconazole is no longer available. In a randomized placebo-controlled study of 387 women treated with 150 mg fluconazole once a week for 6 months, 42.9% of patients who received fluconazole and 21.9% of patients who received placebo were disease-free after 12 months [110]. Topical nystatin appears to be similarly effective to treat chronic RVVC, particularly non-Candida albicans and fluconazole-resistant strains [102].

For cases of chronic RVVC, Donders et al. [68], [112] recommend an initial dose of 200 mg fluconazole on 3 days in the first week, followed by a maintenance regimen once the patient is symptom-free or fungi can no longer be detected, consisting of a single dose of 200 mg fluconazole per month for a period of one year ([Fig. 1]). With this regimen, about 90% were disease-free after 6 months and 77% after one year [68], [112]. Women with familial atopy, longer duration of symptoms, or severe vaginal abrasion have a higher risk of not responding to fluconazole maintenance therapy [113]. Fluconazole suppressive therapy appears to be highly effective in preventing VVC symptoms but it is rarely curative [114]. Relapse often occurs after maintenance therapy is discontinued.

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Fig. 1 Maintenance therapy with fluconazole in patients with chronic recurrent vulvovaginal candidosis.

Sexual behavior does not appear to be a risk factor for non-response to fluconazole maintenance therapy in patients with chronic RVVC [115]. Asymptomatic sexual partners of patients who suffer from chronic RVVC do not require treatment to reduce the recurrence rates of these women [115]. If a patientʼs partner experiences symptoms or yeast is detected on his penis or in his sperm, a single dose of 150 mg fluconazole may be indicated for the partner. For women with an intrauterine pessary who suffer from chronic RVVC, removal of the intrauterine device should be considered, as affected women receiving maintenance therapy only became recurrence-free after the intrauterine pessary was removed.


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8.6  Therapy during pregnancy

Consensus-based recommendation 8.E9

Expert consensus

Level of consensus +++

During pregnancy, particularly in the first trimester of pregnancy, VVC must be treated with topical clotrimazole to avoid the risk of fetal malformation or early miscarriage.

Several retrospective studies [116], [117], [118], [119] and a prospective randomized study [120] have reported a significant reduction in preterm births after vaginal treatment with clotrimazole in women who had VVC in the first trimester of pregnancy. An Australian study with a relatively small number of cases reported a tendency to a lower preterm birth rate following treatment with clotrimazole in the first trimester of pregnancy [121]. Another retrospective study reported an increased preterm birth rate in women with recurrent asymptomatic Candida colonization in early pregnancy [122].

Almost all healthy neonates born at term who are colonized with C. albicans from the maternal vagina during vaginal birth develop oral thrush and/or diaper dermititis in the first year of life, with the incidence peaking in the 2nd–4th week of life [123], [124]. Topical treatment over 6 – 7 days in the last few weeks of pregnancy of pregnant women with Candida colonization is therefore recommended to prevent colonization and subsequent infection of neonates during vaginal birth.

The administration of fluconazole in typical gynecological dosages of 150 – 300 mg/day was long considered harmless during pregnancy, although it was not approved for use in pregnant women. Low doses of ≤ 150 mg do not appear to be associated with an embryopathic risk [125]. However, an increased incidence of fetal tetralogy of Fallot has been reported following a cumulative dose of 150 – 6000 mg fluconazole in the first trimester of pregnancy [126]. The same working group reported an increased risk of miscarriage after oral fluconazole therapy in early pregnancy [127]. Dequalinium chloride can be an alternative treatment option [128], [129], [130].


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8.7  Self-medication

Consensus-based recommendation 8.E10

Expert consensus

Level of consensus +++

Patients must be treated for VVC after a correct and medically confirmed diagnosis based on patient history, clinical examination, fresh specimens, and culturing, where required.

More than 80% of cases self-medicate with OTC (over-the-counter) drugs, usually clotrimazole or fluconazole, to treat VVC [38], [131]. According to one study, however, only one third of women who self-medicated with vaginal antifungal agents actually suffered from VVC [132]. Patients should therefore only be treated for VVC after receiving a correct, medically confirmed diagnosis to prevent the development of resistance and side effects.


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8.8  Importance of probiotics

Consensus-based statement 8.S8

Expert consensus

Level of consensus +++

Probiotics appear to have a positive prophylactic effect on the prevention of VVC, although the evidence for this is limited.

Because of the antagonistic effect of certain Lactobacillus strains against Candida-related vulvovaginitis, probiotics are viewed as a natural approach for the prophylaxis and treatment of infections. Extragenital locations such as the bowel serve as reservoirs for recolonization in women with chronic RVVC [133], meaning that it could be useful to consider administering oral probiotics to women with chronic RVVC as well as to women for whom antifungal agents are contraindicated [134], [135]. Probiotics may be an effective prophylactic strategy against VVC, for example, to prevent Candida glabrata vaginitis [136]. Probiotics may also be directly effective; as fungicides, they inhibit the growth of Candida and limit adhesion to epithelial cells [137].


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8.9  Alternative and complementary medicine

Consensus-based statement 8.S9

Expert consensus

Level of consensus +++

There are a number of different therapeutic alternatives for the treatment of VVC, but they are seldom evidence-based.

Boric acid exhibits antibacterial, antifungal and antiviral activity as well as having antiseptic and astringent properties. It is applied in the form of topical powder and helps to curb the growth of Candida spp. It alleviates itching and inflammation and expedites healing. Its application should be limited to off-label use in exceptional cases. Povidone-iodine (PVP-I) has a germicidal effect against bacteria, fungi and viruses, as it inhibits biofilm develop. The administration of PVP-I therefore usually results in a relatively rapid alleviation of VVC symptoms [134]. Propolis has also been described as a promising alternative for the treatment of VVC. It has antimicrobial, anti-inflammatory, antiseptic, hepatoprotective, antitumoral, immunomodulatory, wound-healing, anesthetic and antioxidative properties [134], [138]. Salvina officinalis is another alternative therapy option [139], as is therapy with progestogens [66], [140].


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9  Outlook

9.1  Immunotherapies

Consensus-based statement 9.S10

Expert consensus

Level of consensus +++

To date, there are no approved immunotherapies against Candida vaginitis.


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9.2  Future research

Consensus-based statement 9.S11

Expert consensus

Level of consensus +++

There is a comprehensive need for preclinical, translational and clinical research into VVC and chronic RVVC.


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Funding

Funding for this guideline was provided by the German Society of Gynecology and Obstetrics (DGGG).


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Conflict of Interest/Interessenkonflikt

The conflicts of interest of the authors are listed in the long version of the guideline./Die Interessenkonflikte der Autoren sind in der Langfassung der Leitlinie aufgelistet.

Acknowledgements

The authors would like to thank Valentina Sustr, Monika Nothacker, Simone Bucher, Susanne Blödt, Ulrike Weber and Paul Gaß for their kind support when preparing this guideline.


Correspondence/Korrespondenzadresse

Priv.-Doz. Dr. med. univ. Dr. scient. med. Alex Farr
Universitätsklinik für Frauenheilkunde
Abteilung für Geburtshilfe und Feto-Maternale Medizin
Medizinische Universität Wien
Währinger Gürtel 18 – 20
1090 Wien
Austria   

Publication History

Received: 21 December 2020

Accepted after revision: 23 December 2020

Article published online:
14 April 2021

© 2021. Thieme. All rights reserved.

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Zoom Image
Fig. 1 Maintenance therapy with fluconazole in patients with chronic recurrent vulvovaginal candidosis.
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Fig. 1 Erhaltungstherapie mit Fluconazol bei Patientinnen mit chronischer RVVC.