Figure

Vulvovaginal candidiasis (VVC) infections are a common occurrence in women and other people with vaginas that result in a substantial public health and economic burden. In the US, an estimated 1.35 million outpatient visits occur annually for VVC, representing a twofold increase over the last decade.1 Annually in the US, VVC costs an estimated $368 million, which does not include lost productivity such as being away from work or monies spent on self-prescribed over-the-counter treatments.1

Approximately 75% of women will have at least one symptomatic VVC occurrence in their lifetime.1 Fifty percent of women will have periodic infections. Recurrent infections are defined as four or more episodes per year. Recurrent VVC (RVVC) occurs in 8% to 10% of all women.2,3 Women with RVVC and providers who care for them become frustrated by the seeming ineffectiveness of many available treatments to sustain clearance of symptomatic infections. Often considered a nuisance infection, RVVC negatively affects quality of life. Women with RVVC report decreased physical function, general health, vitality, social functioning, and more mental health issues when compared with women without frequent infections.4 With the availability of new oral antifungal agents and the rise of VVC infections and cost, NPs who care for women will benefit from revisiting RVVC risk, diagnosis, and treatment options.

Candida is a genus comprised of about 200 species of host-dependent, Gram-positive fungi that include Candida albicans, C. glabrata, and C. tropicalis.3 More than 90% of VVC infections are caused by C. albicans. The remaining 10% of VVC infections are typically caused by C. glabrata or C. tropicalis. Approximately 25% of women have vagina flora that include Candida species without any symptoms of candidiasis. Imbalance between the vagina's microbiota and colonized Candida species results in symptomatic infection. In addition, the prevalence of asymptomatic Candida in other body orifices is common: Candida is found at a rate two times higher in the mouth and three to four times higher in the rectum than in other body areas.3,5 The presence of Candida does not indicate an infection; however, its presence coupled with symptoms support a clinical diagnosis of VVC.

Predisposing factors

VVC is most prevalent among women of childbearing age.3 VVC is uncommon prior to puberty and in postmenopausal women; however, it is often overdiagnosed in these two populations.6 Why some women are predisposed to RVVC is not well understood; however, there can be contributing factors that increase one's risk. If a postmenopausal woman is on hormone therapy, her risk increases.2 RVVC is more likely in women with systemic diseases such as diabetes mellitus type 1 and type 2 and in the presence of immune compromise, such as HIV infection.2,7-10 Approximately 25% to 35% of women who take broad-spectrum penicillin antibiotics will develop VVC.7,11 Chronic stress is a predisposing factor in RVVC.7,12 In a study of Cambodian women, researchers found that frequent douching was associated with RVVC.13 Periodically, researchers have examined relationships between clothing styles or habits and RVVC, but women's clothing styles or habits that may contribute to RVVC have not been studied recently. Thong-style underwear and wearing underwear while sleeping were not found to be associated with RVVC; however, the use of underwear without a cotton gusset has been associated with RVVC, as has use of pantyliners and pantyhose.14-16 Genetics also play a role in RVVC. Polymorphisms found on certain genes alter macrophage surface proteins that in turn affect immune responses, increasing a woman's susceptibility to RVVC.17-19

Whether VVC can be transmitted through sexual activity remains unclear. RVVC is prevalent in sexually active women. Women who engage in sexual activity with both men and women are more prone to acquiring symptomatic RVVC compared with women who are sexually inactive or who have exclusively same-sex partners.20 Treating sex partners does not reduce RVVC.21,22

Research has demonstrated mixed results in establishing an association between combined hormonal contraception (CHC) and RVVC.7,23 Researchers hypothesize that the estrogen portion of CHC alters the biome by increasing glycogen production that leads to Candida overgrowth.7,23 Studies on the role of intrauterine devices (IUDs) in RVVC development have also yielded inconclusive results. Women who have an IUD may be colonized with Candida species but are not more symptomatic than women without IUDs.7,24 The IUD strings may encourage colonization of Candida species.7 RVVC does not appear to increase sexually transmitted infection acquisition.23

Diagnosis

Most symptoms of VVC are largely nonspecific and can be present in other causes of vaginal biome imbalance.25,26 Vulvar pruritus is the predominant symptom. Vaginal discharge, vulvar burning, irritation, external dysuria, and dyspareunia are also common. Relying on symptoms alone can often lead to both misdiagnosis and overtreatment of fungal infections.25,27 Older women may not present with the typical acute symptoms. In some cases, VVC discharge may vary in appearance from the characteristic abundant white flocculent consistency to a scant gray or granular appearance. There is no odor with VVC unless the patient has additional factors that affect the vaginal biome. The vaginal pH found with VVC is consistent with the vagina's normal acidic pH of 3.5 to 4.5. If the provider tests the vaginal pH, care needs to be taken to sample from the mid-portion of the vagina to avoid false pH elevations from cervical mucus, blood, semen, medications, lubricants, or other substances.6 The vulva may be erythematous and edematous. Vulvar fissures and excoriations may be found.

If possible, the provider should perform a wet mount mixed with potassium hydroxide to test for Candida presence. VVC diagnosis is supported when spores, hyphae, or a few white blood cells are seen; however, the absence of hyphae or spores on a wet mount does not exclude the possibility of VVC.25,28 In the absence of the ability to perform a wet mount, or if the wet mount's results are equivocal, a yeast culture is helpful.26,29 Cultures for patients with RVVC should undergo fungal susceptibility testing to investigate for drug-resistant strains of Candida.26

Antigen or polymerase chain reaction (PCR) probe testing is highly sensitive (91%-96%) and specific (94%-99%) and has been shown to be superior to microscopy and culture.30-32 If available, rapid point-of-care PCR probe testing has also been shown to be more sensitive and specific than microscopy or culture; however, there is currently no FDA-approved test available in the US.29,30,32 In addition, PCR probe testing is more expensive than microscopy and culture.29 Asymptomatic vaginal yeast found incidentally on cervical cytology is not necessary to treat.2,21

Women who self-diagnose VVC are often incorrect in doing so, as many vaginal infections and normal vaginal milieu can mimic yeast symptoms.5 The symptoms of bacterial vaginosis, mixed vaginitis, and trichomoniasis, as well as characteristics of normal vaginal flora, can be confused with those of VVC.5,25,33 The accuracy of self-diagnosis of VVC is reported at 34%. Self-prescribed treatment may therefore be inappropriate.5,6 If a woman successfully diagnoses and treats herself for VVC that is sensitive to azoles, a yeast culture should return negative results 1 week after treatment.3

Vaginal flora physiology

Ecological communities of organisms known as the microbiota exist throughout the human body. These communities are present on both external body surfaces and in orifices and are primarily made up of bacteria, fungi, protists, and other organisms.34,35 The lower female reproductive tract has a unique microbiome that aids in the protection against opportunistic infections. Bacteria from the Lactobacillus family are the predominant species present in normal vaginal flora.36Lactobacilli have established themselves as the dominant organism within the vaginal microbiome through production of lactic acid, bacteriocins, and hydrogen peroxide. In combination, these antimicrobial substances inhibit the growth of competing and invasive microorganisms.36 Dysbiosis is a term utilized to describe a vaginal microbiome where lactobacilli are not the predominate organisms. Loss of protective properties from lactobacilli can increase risk for VVC as well as sexually transmitted infections and pregnancy complications.35

Vaginal candidiasis pathophysiology

In small numbers, yeast from the Candida family can be a part of the normal vaginal flora. As a colonizer, Candida adheres to vaginal epithelium. Patients may be asymptomatic despite Candida colonization.25,36 Dysbiosis occurs when Candida growth is triggered or when the vaginal microbiome is altered and protective defenses break down.25Candida overgrowth is suspected to be related to the organism's ability to morph from a budding yeast to a hyphal mycelial growing organism.36 As yeast cells mature into hyphal Candida, the fungal load increases, which eventually leads to symptomatic VVC. More recent literature has demonstrated that Candida does have the potential to cause biofilm development on vaginal mucosa; however, the impact of biofilms on the treatment of VVC is not well understood.37,38

Complicated VVC (CVVC) is defined as infection that is resistant to azole treatment, present in an immunocompromised host, recurrent, or caused by a non-albicans Candida species. RVVC is a subcategory of CVVC. RVVC is defined as four or more episodes of symptomatic VVC in 12 months, with the patient being asymptomatic between episodes.25,26 New symptomatic episodes should not be empirically diagnosed and should warrant a full diagnostic workup including a fungal culture.26 Around 10% to 20% of cases of RVVC are caused by non-albicans Candida. Fungal cultures for recurrent episodes should entail antifungal susceptibility testing to better inform pharmacologic choices.26

Treatment of uncomplicated VVC

Treatment for the uncomplicated VVC infection is straightforward. Use of an intravaginal antifungal agent for 1 to 3 days or a single dose of fluconazole 150 mg orally should suffice.6,29 Intravaginal azole therapy and oral fluconazole are equally effective with a 90% cure rate.6 Single-dose fluconazole is effective, safe, and well tolerated. Since its introduction in the 1990s, oral fluconazole has become inexpensive, and it now dominates sporadic VVC treatment. Although generally well tolerated, oral fluconazole use may result in drug interactions, allergic reactions, and azole resistance, and the literature surrounding its use during pregnancy raises varying degrees of concern.

Pregnant individuals with VVC warrant special consideration. Pregnancy may trigger VVC due to high hormone levels that affect vaginal pH.7 Topical azoles are the treatment of choice during pregnancy. Although there are no adequate or well-controlled studies, retrospective epidemiologic studies suggest that the use of fluconazole in pregnancy may be linked to spontaneous abortion and congenital abnormalities.39-42 In a recent meta-analysis, Budani and colleagues found a statistically significant correlation between maternal use of fluconazole at any dose during the first trimester and heart defects in the offspring.39 The authors of the meta-analysis state that fluconazole should be considered a human teratogen.

In contrast, according to the seminal essential resource Briggs Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk, the risk of adverse outcomes associated with the use of small doses of fluconazole, such as the amount used to treat an isolated VVC infection, is low.43 However, as fluconazole is not approved for use in pregnancy due to safety concerns, use of fluconazole during pregnancy should be carefully considered with the potential risks explained to the mother.40

In the last 6 weeks of pregnancy, women with VVC should receive topical azole treatment aimed at reducing the risk of vertical transmission, including resultant oral thrush and diaper dermatitis in the newborn.21

Fluconazole and topical azoles are compatible with lactation.43 Mothers who took fluconazole during breastfeeding reported no serious reactions in the infants.41

Treatment of RVVC

Episodes of RVVC will often require prolonged treatment to aid in the prevention of further symptoms and recurrences. Treatment is dependent on fungal culture results and can last up to 6 months. Azole-susceptible Candida can often be treated with use of traditional azoles, most often fluconazole. The most utilized treatment regimen starts with an induction phase of fluconazole 150 mg orally every 72 hours for three doses followed by a maintenance phase of 150 mg of oral fluconazole weekly for 6 months.26 Fluconazole acts as a strong prophylactic agent; however, cure is rarely achieved, and recurrence rates are high.44

Topical regimens can also be used for RVVC caused by azole-susceptible Candida. Commonly, topical treatment is miconazole 2% vaginal cream applied nightly for 7 nights, followed by a maintenance regimen of miconazole 1,200 mg vaginal suppository weekly for 6 months.25 Most women will achieve symptom relief with this regimen; however, episodes of recurrence in the first 6 months are high.

Traditionally, treatment of azole-resistant Candida, which includes C. glabrata and C. krusei, has been challenging because over-the-counter topical regimens only cover C. albicans. Azole-resistant Candida may be treated with topical agents such as boric acid capsules, nystatin, amphotericin B cream, or flucytosine cream.26 Azole-resistant medications are typically dosed daily for 14 days; treatment with nystatin should be followed by a prolonged maintenance regimen.

Newer options for RVVC

Recognizing the need for treatment options, researchers have developed new antifungal agents. For the first time since the release of fluconazole in the 1990s, the FDA recently approved two oral antifungal medications for use in VVC: oteseconazole (Vivjoa) and ibrexafungerp (Brexafemme). These agents should ideally be reserved for patients with culture-proven azole-resistant Candida or established allergy, resistance, or intolerance to traditional azoles.44 Primary care providers may refer patients with RVVC to gynecology specialists familiar with RVVC treatment options or providers who specialize in treatment of chronic vulvar and vaginal disorders if they become uncomfortable moving forward with treatment or if treatment is unsuccessful.

Oteseconazole (Vivjoa). Oteseconazole is an oral tetrazole that is FDA approved for treatment of RVVC. Oteseconazole is highly active against Candida including azole-resistant C. albicans and non-C. albicans species. Oteseconazole was specifically designed to inhibit the CYP51 enzyme lanosterol, which offers less concern for drug-drug interactions and adverse reactions than traditional azoles.44 Given its superior potency to fluconazole for the treatment of drug-resistant Candida, oteseconazole was studied as a treatment possibility for RVVC. Phase 2 and 3 drug trials demonstrated that oteseconazole was superior to placebo and traditional treatment in the elimination of RVVC.45,46 Additionally, patients treated with oteseconazole were more likely to demonstrate fungal clearance on repeat cultures; oteseconazole is considered fungicidal.45-47

Although oral fungistatic fluconazole is commonly used for management of RVVC, it does not have FDA approval for such use.44 Compared with oral fluconazole used for RVVC, oteseconazole offers a shorter duration of treatment owing to its enhanced potency and long half-life. Oteseconazole should be taken with food. Adverse reactions are considered mild to moderate and include headache and gastrointestinal upset.48 According to the prescribing information, oteseconazole is contraindicated in females of reproductive potential and during pregnancy and lactation because of potential risks to the fetus or breastfed infant. Rat embryo toxicity studies demonstrated ocular abnormalities.49 Depending on pharmacy site of purchase, the list price for Vivjoa is about $2,907 for a supply of 18 capsules, although cost to patient may vary based on insurance coverage.50,51

Ibrexafungerp (Brexafemme). Ibrexafungerp is an oral medication that is FDA approved for both VVC and RVVC.52 The new antifungal option works by inhibiting the formation of beta-D-glucan leading to loss of fungal cell wall integrity and eventual cell lysis. Ibrexafungerp has broad anti-Candida coverage including azole-resistant strains.

When utilized for VVC, ibrexafungerp 300 mg (two 150-mg tablets) is dosed twice over the course of 1 day for a total treatment dosage of 600 mg. Ibrexafungerp may be taken with or without food. Given the short treatment duration, no known renal or hepatic dose adjustments are needed.53 Patients who are taking medications that are strong CYP3A4 inducers (such as phenobarbital, phenytoin, St. John's wort, and others) should take a reduced dose of 150 mg twice per day for a total treatment dosage of 300 mg.

In December 2022, the FDA approved ibrexafungerp for use for RVVC. A phase 3 drug study demonstrated superiority of ibrexafungerp over placebo for resolution of symptoms and clearance of cultures in patients with RVVC.54 To decrease the incidence of RVVC, recommended dosing of ibrexafungerp is 300 mg twice for 1 day once per month for 6 months. Adverse reactions are generally mild to moderate and include dizziness and gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and diarrhea.44,52,53 Ibrexafungerp should not be taken by pregnant or lactating patients. Prior to initiation of treatment, the provider should verify that the patient is not pregnant. Effective contraception should be utilized for 4 days following exposure to the medication, and patients taking the medication long term for RVVC require reliable contraception throughout treatment and for 4 days after the last dose.53 Ibrexafungerp's list cost is $570 for a 1-day regimen.50 Depending on the pharmacy used, ibrexafungerp's current list cost ranges from $3,100 to $3,400 for a 6-month course of treatment for RVVC, although cost to patient may vary based on insurance coverage.51

Alternative therapies

Research findings that support the use of Lactobacillus orally or intravaginally to prevent RVVC are limited.55 Use of alternative therapies such as oral ingestion or vaginal placement of yogurt or garlic have not demonstrated efficacy in clinical trials.12 Oral or vaginally placed probiotics are not currently recommended.6,26 Medical-grade honey is currently being researched as an adjunct to promote protective vaginal biofilms that may have an antifungal effect; however, more research is needed.56

Conclusion

VVC and RVVC reduce quality of life and impose a heavy financial burden. In the absence of azole resistance, drug intolerance, or allergy to azoles, the roles for oteseconazole and ibrexafungerp are unclear. Even with insurance, costs for oteseconazole and ibrexafungerp may be prohibitive for routine use. As providers gain insight from further research and confidence from use—and, hopefully, as these drugs' prices decrease—oteseconazole and ibrexafungerp's places in clinical practice may become clearer. Until then, oral fluconazole and topical medications will remain the cornerstone of treatment. NPs who care for people with VVC and RVVC need to incorporate an evidence-based plan of care, which includes definitive diagnosis and subsequent treatment choice.

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Cloudfront.net. 2022. http://d1io3yog0oux5.cloudfront.net/_b74ab29ee08f7c716ae5e6710e5dba4b/scynexis/news/2022-08-04_SCYNEXIS_Presents_Positive_Data_from_Its_Pivotal_298.pdf. Accessed March 22, 2023. 55. Falagas ME, Betsi GI, Athanasiou S. Probiotics for prevention of recurrent vulvovaginal candidiasis: a review. J Antimicrob Chemother. 2006;58(2):266–272 doi:10.1093/jac/dkl246. 56. van Riel SJ, Lardenoije CM, Oudhuis GJ, Cremers NA. Treating (recurrent) vulvovaginal candidiasis with medical-grade honey-concepts and practical considerations. J Fungi (Basel). 2021;7(8):664. doi:10.3390/jof7080664.