INTRODUCTION — Vulvovaginal candidiasis (VVC) is one of the most common causes of vulvovaginal itching and discharge. The disorder is characterized by inflammation in the setting of Candida species. Treatment is indicated for the relief of symptoms.
This topic will discuss the treatment of uncomplicated, complicated, and recurrent vulvovaginal candidiasis (RVVC). Related topics on the clinical presentation and diagnosis of vulvovaginal candidiasis and the general approach to females with vaginitis are presented separately:
●(See "Candida vulvovaginitis: Clinical manifestations and diagnosis".)
●(See "Vaginal discharge (vaginitis): Initial evaluation".)
In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. However, we encourage the reader to consider the specific counseling and treatment needs of transgender and gender diverse individuals.
INDICATIONS — Treatment is indicated for relief of symptoms. Ten to 20 percent of reproductive-age females who harbor Candida species are asymptomatic; these individuals do not require therapy [1].
OUR APPROACH — The treatment regimen is based on whether the woman has an uncomplicated infection (90 percent of patients) or complicated infection (10 percent of patients). Criteria are listed in the table (table 1).
Oral versus topical treatment — A variety of oral and topical preparations, many available over the counter and in single-dose regimens, is available for the treatment of uncomplicated vulvovaginal candidiasis (table 2) [2]. In randomized trials, oral and topical antimycotic drugs achieved comparable clinical cure rates, which are in excess of 90 percent; short-term mycologic cure is slightly lower (70 to 80 percent) [3-6]. Studies that have assessed patient preference consistently reported a preference for the convenience of oral treatment [4]. However, topical treatments have fewer side effects (eg, possible local burning or irritation), while oral medication may cause gastrointestinal intolerance, headache, rash, and transient liver function abnormalities. In addition, oral medications take a day or two longer than topical therapy to relieve symptoms. The absence of superiority of any formulation, agent, or route of administration suggests that cost, patient preference, and contraindications are the major considerations in the decision to prescribe an antifungal for oral or topical administration [6].
If topical therapy is chosen, vulvar treatment alone is not adequate to eradicate the vaginal reservoir of organisms, even in those whose main symptoms are vulvar [7]. While vulvar treatment can improve vulvar symptoms, vaginal therapy is necessary to fully treat the disease.
Uncomplicated infection
Criteria — Criteria for uncomplicated infection include all of the following (table 1) [8]:
●Sporadic, infrequent episodes (≤3 episodes/year)
●Mild to moderate signs/symptoms
●Probable infection with Candida albicans
●Healthy, nonpregnant individual
●Immunocompetent individual
Initial azole treatment — We suggest use of oral fluconazole, given that most people consider oral drugs more convenient than those applied intravaginally. Fluconazole maintains therapeutic concentrations in vaginal secretions for at least 72 hours after the ingestion of a single 150 mg tablet [9]. Side effects of single-dose fluconazole (150 mg) tend to be mild and infrequent. However, although fluconazole interacts with multiple drugs, interactions are rare at the dose used to treat vulvovaginal candidiasis. Since fluconazole is now available in a generic form, a single-dose regimen of fluconazole is less expensive than over-the-counter topical antifungals.
Azole resistance is rarely reported for vaginitis caused by C. albicans [10]. Thus, in vitro susceptibility tests are typically not indicated unless compliant patients with a culture-proven diagnosis have no response to adequate therapy.
Uncomplicated infections usually respond to treatment within a couple of days. There is no medical contraindication to sexual intercourse during treatment, but it may be uncomfortable until inflammation improves. Treatment of sexual partners is not indicated. (See 'Sex partners' below.)
Triterpenoid initial treatment (ibrexafungerp) — Ibrexafungerp (commercial name Brexafemme) is a single-day oral triterpenoid antifungal for use in females with uncomplicated vulvovaginal candidiasis [11]. Unlike fluconazole, which inhibits fungal growth, ibrexafungerp kills Candida species by inhibiting formation of the fungal cell wall and is the first in its class [12]. Patients who may benefit from this therapy include those who are allergic to fluconazole and other triazoles, do not tolerate fluconazole or other triazoles, and/or have candida infections that are resistant to fluconazole. Clinical trials have demonstrated ibrexafungerp results in higher clinical cure rates compared with placebo, but comparison of efficacy with conventional azole treatment has not been studied [13,14].
●Prescribing information – Ibrexafungerp is prescribed as four tablets of 150 mg each [11]. The patient should take two tablets by mouth twice in one day (ie, two in the morning and two at night).
●Drug interactions – Individuals using strong CYP3A inhibitors should reduce the dose to 150 mg twice in one day because of increased exposure to ibrexafungerp. Individuals taking strong or moderate CYP3A inducers may have significantly reduced exposure and are advised to use another antifungal treatment or avoid co-treatment with ibrexafungerp and CYP3A inducers.
●Pregnancy and lactation – The drug should not be given to pregnant individuals because of concern for fetal harm based on animal studies. Human data for both pregnancy and lactation are lacking.
While the single-day regimen and oral dosing are appealing, the cost may be prohibitive for many. For patients who present with fluconazole treatment failure or recurrent vulvovaginal symptoms, the most common reason for inadequate azole response is that the vaginal symptoms are from another cause (eg, trichomoniasis) or, rarely, mixed infection. Thus, clinicians are encouraged to confirm the diagnosis of candidal vulvovaginitis before prescribing ibrexafungerp for fluconazole treatment failure. Discussion of extended ibrexafungerp treatment for recurrent VVC is below. (See 'Triterpenoid extended treatment' below.)
Complicated infections
Characteristics — Characteristics of complicated infections include one or more of the following criteria (table 1) [8]:
●Severe signs/symptoms
●Candida species other than C. albicans, particularly C. glabrata
●Pregnancy, poorly controlled diabetes, immunosuppression, debilitation
●History of recurrent (≥3/year) culture-verified vulvovaginal candidiasis (see 'Recurrent vulvovaginal candidiasis' below)
The treatment of complicated infection is summarized in the table and described in more detail below (table 3).
Patients with severe symptoms or immunocompromise — Individuals with severe inflammation or host factors suggestive of complicated infection (eg, immunosuppression) may need longer courses of oral or topical antimycotic drugs [15]. It is unknown whether one route is more effective than the other, as comparative trials of topical versus oral treatment of complicated infection have not been performed.
Given the convenience of oral therapy, we take the following approach:
●Preferred – For treatment of complicated infections, we suggest treatment with oral fluconazole 150 mg for two to three sequential doses, 72 hours apart; number of doses depending on the severity of the infection (table 3) [6,15].
●Alternative – An alternative option is oral ibrexafungerp 150 mg tablets. Twice daily treatment may be prescribed for individuals with severe vulvovaginal candidiasis [13,14]. The optimal duration of therapy is not known. (See 'Triterpenoid initial treatment (ibrexafungerp)' above.)
Individuals with HIV infection often respond to short-course therapy and do not need extended treatment unless symptoms are particularly severe or recurrent. The efficacy of this approach was supported by a trial that randomly assigned 556 women with severe or recurrent candidiasis to therapy with a single dose of fluconazole (150 mg) or two sequential doses given three days apart [16]. Severity of disease was based upon a scoring system involving degree of pruritus and physical signs (erythema, edema, excoriation/fissure formation). The two-dose regimen resulted in significantly higher clinical cure/improvement rates at evaluation on day 14 (94 versus 85 percent) and day 35 (80 versus 67 percent) in women with severe, but not recurrent, disease. However, the response to therapy was lower in the 8 percent of women infected with nonalbicans Candida.
If the patient prefers topical therapy, observational series report that complicated patients require 7 to 14 days of topical azole therapy (eg, clotrimazole, miconazole, terconazole) rather than a one- to three-day course [6,17].
For severe Candida vulvar inflammation (vulvitis), topical corticosteroids (eg, clotrimazole-betamethasone or nystatin-triamcinolone) can be applied to the vulva for 48 hours until the antifungals exert their effect.
Candida glabrata — C. glabrata has low vaginal virulence and rarely causes symptoms, even when identified by culture. Every effort should be made to exclude other coexistent causes of symptoms and only treat for C. glabrata vaginitis when all other potential sources of the vaginal symptoms have been addressed. When treatment is elected, we prefer vaginal boric acid.
●Vaginal boric acid – Moderate success (65 to 70 percent) in women infected with this organism can be achieved with intravaginal boric acid (600 mg capsule once daily at night for two to three weeks) (table 3) [15,18,19]. Boric acid capsules can be fatal if swallowed.
Better results (>90 percent cure) have been achieved with intravaginal flucytosine cream or amphotericin B cream 3=4% (given as 5 g nightly for two weeks) used in combination with vaginal boric acid [19]. Neither boric acid capsules nor flucytosine or amphotericin B cream is available commercially and must be made by a compounding pharmacy.
●Azole therapy – Treatment failure with azoles is common (around 50 percent) in patients with C. glabrata vaginitis [18].
●Voriconazole – There are no good data regarding use of oral voriconazole for C. glabrata vaginitis, and it should not be used to treat vulvovaginal candidiasis. Anecdotal reports suggest poor response, rare cures, and the potential for toxicity.
●Ibrexafungerp – Ibrexafungerp is single-day oral triterpenoid antifungal for use in post-menarchal females with vulvovaginal candidiasis [11]. While it may be a treatment option for C glabrata, supporting data for this population are lacking. (See 'Triterpenoid initial treatment (ibrexafungerp)' above.)
●Nystatin – Although there are also no good data on the efficacy of nystatin, which is available as a pessary in some parts of the world, anecdotally, many clinicians consider nystatin the drug of choice for C. glabrata. One or two pessaries of 100,000 units nystatin are inserted into the vagina nightly for 14 days [20]. Alternatively, a suppository can be prepared by a compounding pharmacy. Potential side effects include burning, redness, and irritation.
Candida krusei — C. krusei is usually resistant to fluconazole but is highly susceptible to topical azole creams and suppositories, such as clotrimazole, miconazole, and terconazole (table 3). We treat for 7 to 14 days. It is also likely to respond to oral itraconazole or ketoconazole (itraconazole 200 mg twice daily for 7 to 14 days or ketoconazole 400 mg daily for 7 to 14 days), but these oral agents have variable toxicity, so topical therapy is advised for first-line therapy. Idiosyncratic hepatotoxicity secondary to ketoconazole therapy is a concern but rare in this setting. In vitro susceptibility testing is indicated in compliant patients with culture-proven diagnosis of C. krusei and no response to a conventional course of one of these nonfluconazole therapies.
Pregnancy — For pregnant persons with symptomatic Candida vulvovaginitis, we suggest application of a topical imidazole (clotrimazole or miconazole) vaginally for seven days rather than treatment with an oral azole because of potential risks with oral azole therapy in pregnancy (table 3) [21-23]. Treatment of pregnant people is primarily indicated for relief of symptoms; vaginal candidiasis is not associated with adverse pregnancy outcomes [24]. This approach is consistent with statements from the United States Centers for Disease Control and Prevention, the US Food and Drug Administration, and others [17,25-27].
During pregnancy, we avoid oral azole therapy, particularly during the first trimester, because it may increase the risk of miscarriage and its impact on birth defects is unclear [23]. Oral fluconazole therapy does not appear to increase the risk of stillbirth or neonatal death [23,28]. Since topical therapy is an effective alternative to oral dosing, we prefer vaginal treatment until more data are available to support the safety of low-dose oral treatment.
●Miscarriage – A cohort study of over 3300 women who received 150 to 300 mg oral fluconazole between 7 and 22 weeks of pregnancy reported an approximately 50 percent increased risk of miscarriage in exposed women compared with either unexposed women or women treated with vaginal azole therapy [21]. Stillbirth risk did not differ among the groups, although stillbirth was a relatively rare outcome. A subsequent larger population cohort study that evaluated over 320,000 pregnancies reported exposure to oral fluconazole during early pregnancy was associated with a two- to threefold increased risk of miscarriage compared with no exposure (risk for doses of ≤150 mg and >150 mg, respectively) [23]. These studies contrast with two earlier, smaller cohort studies, totaling just over 1500 women, that did not report an association between oral fluconazole and miscarriage [29,30]. As the larger studies likely had greater power to detect an increase in miscarriage risk, we prefer to avoid oral azole therapy for pregnant individuals, particularly in the first trimester.
●Birth defects – The impact of fluconazole on birth defects is difficult to assess, in part because of the variability across studies for drug dose, gestational age, duration of exposure, and method of exposure assessment and the lack of consistency across the reported birth defects. Overall, the data appear reassuring for people who took low-dose fluconazole (150 mg) before realizing that they were pregnant [31], although an increased risk of cardiac and musculoskeletal anomalies cannot be definitively excluded, especially at higher doses [23,32].
The challenge of reaching a definitive conclusion regarding risk of birth defects is highlighted by the following data:
•Multiple small epidemiologic studies did not report an increased risk of birth defects after first-trimester use of a single low dose of fluconazole 150 mg [29,30,33-37]. However, the limited size of these studies may have reduced their ability to detect an outcome difference.
•Larger studies reported an association between oral fluconazole exposure, particularly at higher doses, and multiple types of birth defects.
-Case reports described a pattern of birth defects (abnormalities of cranium, face, bones, and heart) after first-trimester exposure to high-dose fluconazole therapy (400 to 800 mg/day) [38,39].
-The United States National Birth Defects Prevention Study (delivery dates from 1997 to 2011), including over 31,000 mothers of children with birth defects, reported an association with first-trimester fluconazole use and cleft lip with cleft palate (odds ratio [OR] 5.53, 95% CI 1.68-18.24) and d-transposition of the great arteries (OR 7.56, 95% CI 1.22-35.45), but the study was limited by exposure self-report and small total number of cases (six and three, respectively) [40].
-Analysis of the Quebec Pregnancy Cohort (1998 to 2015), a Canadian population cohort study including over 220,000 pregnancies, reported an 80 percent increased risk of cardiac septal closure anomalies following first-trimester exposure to fluconazole at doses >150 mg (adjusted OR 1.81, 95% CI 1.04-3.14, 13 exposed cases), but no association was noted at doses up to 150 mg for overall congenital malformations or for cardiac septal defects [23].
-A study of over 1.9 million pregnancies from the United States Medicaid Analytic eXtract database (2000 to 2014) reported first-trimester oral fluconazole exposure was associated with an increased risk of musculoskeletal malformations (adjusted relative risk [RR] 1.30, 95% CI 1.09-1.56), but not oral clefts or conotruncal cardiac anomalies, compared with unexposed pregnancies or pregnancies exposed to topical azoles [32]. In addition, the risk of musculoskeletal malformation increased with increasing doses of fluconazole exposure, although not all increases were statistically significant (fluconazole 150 mg: adjusted RR 1.29, 95% CI 1.05-1.58; fluconazole >150 to 450 mg: adjusted RR 1.24, 95% CI 0.93-1.66; fluconazole >450 mg: adjusted RR 1.98, 95% CI 1.23-3.17). The overall association would result in approximately 12 additional musculoskeletal anomalies per 10,000 exposed pregnancies. Study advantages included use of a large and diverse patient sample, use of both unexposed and active comparator groups (topical azole therapy), use of validated algorithms to define outcomes, and use of prescription data (to avoid recall bias). Limitations included small numbers of rare outcomes and inability to confirm that filled prescriptions were used by the patients.
Although treatment of vaginal Candida colonization in healthy pregnant persons is unnecessary, in Germany, treatment is recommended in the third trimester because the rate of oral thrush and diaper dermatitis in mature healthy newborns is significantly reduced by maternal treatment [41].
There is less information about the pregnancy safety profile of terconazole, a triazole, than for imidazoles. Vaginal nystatin is another option for treatment. As discussed above, a pessary is available in some parts of the world. One or two pessaries of 100,000 units nystatin are inserted into the vagina nightly for 14 days [20]. Alternatively, a suppository can be prepared by a compounding pharmacy. Potential side effects include burning, redness, and irritation. We do not use boric acid in pregnant persons.
RECURRENT VULVOVAGINAL CANDIDIASIS
Definition and testing — Recurrent vulvovaginal candidiasis (RVVC) is defined as three or more episodes of symptomatic infection within one year, which is a change from the prior definition of four or more episodes in one year [15,42-44]. Vaginal cultures should always be obtained to confirm the diagnosis and identify less common Candida species, if present. The role of molecular tests for diagnosis and management of RVVC is not yet known. (See "Candida vulvovaginitis: Clinical manifestations and diagnosis", section on 'Diagnostic approach'.)
As discussed above, recurrent disease is usually due to relapse from a persistent vaginal reservoir of organisms or endogenous reinfection with identical strains of susceptible C. albicans [45]; however, rarely, a new strain of Candida is responsible for the infection.
Epidemiology and pathophysiology — Most people with RVVC are otherwise healthy and RVVC remains idiopathic in its origin. However, contributing factors have been identified and potential mechanisms are under study.
●Frequency – Estimating the incidence and prevalence of RVVC is challenging because the symptoms are not exclusive to Candida infection, many individuals self-treat, and treatment is often empiric. In an internet survey study of over 7000 women across seven countries, the estimated probability of RVVC after an episode of VVC, by age 50, ranged from 14 to 28 percent, with a mean of 23 percent [46].
●Contributing mechanisms
•Microbiology – Longitudinal DNA-typing studies suggest that, in most people, recurrent disease is due to relapse from a persistent vaginal reservoir of organisms or endogenous reinfection with the identical strain of susceptible C. albicans [45,47]. Infection due to a different Candida species (eg, C. glabrata) have been reported in 10 to 20 percent of patients with RVVC [15]. Risk factors are apparent in only a minority of those with recurrent disease. (See "Candida vulvovaginitis: Clinical manifestations and diagnosis", section on 'Risk factors'.)
•Altered immune response – Evidence has accumulated linking or defining an association of recurrent episodes of symptomatic infection with vaginal mucosal immune hyper-reactivity to the fungus [48]. This suggests the occurrence of dysregulated immune reactivity in the pathogenesis of RVVC [49]. Vaginal hyper-reactivity involves interleukin-22 (IL-22)-, IL-10-, and IL-17-producing regulatory T cells. The role of IL-17 in protection against mucosal Candida infections has been established [50]. IL-17 plays a role in controlling C. albicans infection as it induces vaginal epithelial cells to produce antimicrobial peptides. Studies in women with mucocutaneous candidiasis and RVVC have confirmed the genetic basis for these infections. Different mutations and polymorphisms in innate immune genes alter the vaginal mucosal immune response against Candida [51].
•Genetic polymorphisms – RVVC has also been associated with decreased in vivo concentration of mannose binding lectin (MBL) and increased concentration of IL-4. Two specific gene polymorphisms, variants in the MBL and IL-4 alleles, can account for this finding in some individuals. The prevalence of a variant MBL gene is higher in women with RVVC than in controls without candidiasis [52,53]. Since the direct interaction of MBL with C. albicans is an important component of the host's ability to resist candidiasis, impairment of this interaction in MBL-deficient individuals, such as those with certain MBL polymorphisms, appears to predispose these individuals to recurrent vulvovaginal candidal infection [52,54-57]. In general, those with RVVC mount a strong inflammatory response when exposed to small amounts of Candida, whereas unaffected individuals may not mount any inflammatory response and remain asymptomatic. IL-4 blocks the anti-Candida response mediated by macrophages; thus, elevated IL-4 levels result in inhibition of local defense mechanisms.
Recurrent treatment
Azoles
Fluconazole extended treatment — Based on the available data and personal experience, we use fluconazole induction followed by prolonged treatment for nonpregnant patients with RVVC (table 3) [58-62]. While oteseconazole appears to have higher long-term efficacy, it is also harder to obtain and higher cost [62,63]. We take the following approach:
●Induction regimen – Initial induction therapy with fluconazole, 150 mg orally every 72 hours for three doses, followed by maintenance oral fluconazole 150 mg once per week for six months.
●Trial of drug discontinuation – Therapy is then discontinued, at which point some patients achieve a prolonged remission, while up to 55 percent relapse [60].
●Treatment of relapse – A short-term relapse, with culture confirmation of the diagnosis, merits reinduction therapy with three doses of fluconazole, followed by repeat weekly maintenance fluconazole therapy, this time for one year. A minority of treated patients persist in relapsing as soon as fluconazole maintenance is withdrawn (fluconazole-dependent RVVC). Symptoms in these patients can be controlled by months or years of weekly fluconazole.
Given the safety profile of low-dose fluconazole, most experts do not suggest any laboratory monitoring; however, if other oral imidazoles (ketoconazole, itraconazole) are used, particularly if taken daily, then monitoring liver function tests is recommended. Idiosyncratic hepatotoxicity secondary to ketoconazole therapy is a concern but rare in this setting.
Although drug interactions are reported with fluconazole and several oral agents (eg, warfarin, rifampin), such interactions are extremely unlikely with maintenance fluconazole due to the low plasma concentrations accompanying the once-weekly 150 mg dosing regimen. Accordingly, no additional testing is needed.
Of note, decreasing gastrointestinal Candida colonization by oral administration of nystatin does not prevent recurrent symptomatic vaginal infection [42].
Oteseconazole — Oteseconazole is an azole antifungal drug for use in individuals with RVVC that is more potent against Candida species, including Candida glabrata, compared with fluconazole [62-66]. Use of the drug is restricted to adult females who are not of reproductive potential; the drug is contraindicated in those who have the ability to become pregnant, are pregnant, or are lactating. Concerns for embryo-fetal toxicity are based on rat studies that reported retinal abnormalities in offspring and because of the long half-life (138 days) of the drug [62]. Oteseconazole should be taken with food to aid absorption.
Two dosing regimens are available [64]:
•Single-drug regimen – Oteseconazole 600 mg orally on day 1, oteseconazole 450 mg orally on day 2, and, starting on day 14, oteseconazole 150 mg orally once a week for 11 weeks (ie, once a week dosing during weeks 2 through 12) [63,64]. The regimen is available in a blister pack that indicates the dose and timing [62]. In an industry-sponsored trial comparing induction and maintenance with either oteseconazole (n = 123) or fluconazole/placebo (n = 62), the oteseconazole regimen was associated with fewer culture-confirmed VVC infections compared with fluconazole/placebo (5.1 versus 42.2 percent, respectively) during the 48-week maintenance phase [63]. Nearly one-quarter of study participants in each group discontinued early; the most common reasons were initial treatment failure (14 percent) and loss to follow-up (5 percent).
•Dual-drug regimen – The dual-drug regimen involves initial treatment of the acute infection with fluconazole (150 mg orally given on days 1, 4, and 7) followed by suppressive therapy with oteseconazole (150 mg orally once a day for seven days on days 14 through 20 followed by oteseconazole 150 mg orally once a week) [64]. In two trials including patients with a history of RVVC and confirmed acute candida vulvovaginal infection, oteseconazole recipients had fewer RVVC episodes and experienced a greater recurrence-free time interval compared with patients receiving placebo during the 48-week study period [67]. Disease recurrence was experienced by 4 to 7 percent of the oteseconazole group compared with 39 to 43 percent of the placebo group. Additionally, oteseconazole treatment resulted in a greater mean time to RVVC recurrence compared with placebo (46 to 47 weeks compared with 28 to 33 weeks). The efficacy of dual-drug treatment compared with extended fluconazole only is not yet known.
Alternative azole regimens — Alternative approaches for treatment of RVVC include:
●Repeat treatment as needed – Treat each recurrent episode as an episode of uncomplicated infection (table 2) [17].
●Longer duration of treatment – Treat each recurrent episode with longer duration of therapy (eg, topical azole for 7 to 14 days or fluconazole 150 mg orally on day 1, day 4, and day 7) [17].
●Induction followed by prolonged treatment – The Infectious Diseases Society of America (IDSA) recommends 10 to 14 days of induction therapy with a topical or oral azole, followed by fluconazole 150 mg once per week for six months (clotrimazole 200 mg vaginal cream twice weekly is a nonoral alternative) [6]. The goal of long-term treatment with fluconazole is symptom control rather than cure [62].
Evidence for azole suppressive therapy — A meta-analysis of 23 trials reported continued antifungal treatment (oral or topical) probably reduced clinical recurrence at six months compared with placebo or no treatment (risk ratio 0.36, 95% CI 0.21-0.63, number needed to treat=2, 607 participants), but available data were limited to small trials with high risk of bias from insufficient blinding [61].
Multiple observational studies of nonpregnant women with RVVC have reported that antifungal maintenance suppressive therapy taken for six months after an initial induction regimen resulted in negative cultures [3,68]. The best available option in nonpregnant persons is fluconazole 150 mg orally once per week for six months [6]. However, maintenance therapy is only effective for preventing recurrent infection as long as the medication is being taken. This was illustrated in a trial of 387 women with RVVC treated with open-label fluconazole (150 mg orally at 72-hour intervals for three doses) and then randomly assigned to weekly doses of fluconazole (150 mg) or placebo for six months [58]. The maintenance therapy phase was begun two weeks after initiation of treatment in patients who were clinically cured. Study drugs were discontinued in patients diagnosed with recurrent candidal infection during follow-up visits.
●The proportion of patients who remained disease-free was significantly higher in the fluconazole group (91 versus 36 percent at 6 months, 73 versus 28 percent at 9 months, and 43 versus 22 percent at 12 months).
●The mean time to recurrence in the fluconazole and placebo groups was 10.2 and 4.0 months, respectively.
●Resistant isolates of C. albicans or superinfection with C. glabrata were not observed.
Although this regimen of maintenance fluconazole was convenient, safe, and as effective as other therapies, long-term cure of recurrent vulvovaginal candidiasis was not achieved in one-half of the patients studied. Episodes of recurrent candidiasis resumed when maintenance therapy was discontinued.
Fluconazole resistance — In persons with RVVC, there is some evidence that frequent and prolonged use of fluconazole can infrequently select for fluconazole resistance in C. albicans strains previously susceptible to fluconazole, which limits the options available for treating these individuals.
●Assess drug minimum inhibitory concentration (MIC) – In patients with refractory vulvovaginal candidiasis with persistently positive C. albicans cultures, MICs to various antifungals can be tested by using the broth microdilution method conducted in accordance with Clinical and Laboratory Standards Institution criteria and breakpoints [69]. (See "Antifungal susceptibility testing".)
●Increase azole dose based on MIC – In a study of 25 women with refractory Candida vaginitis and a C. albicans isolate with fluconazole minimum inhibitory concentration (MIC) ≥2 micrograms/mL, those with fluconazole MIC values of 2 or 4 micrograms/mL were treated successfully by increasing fluconazole dose to 200 mg twice weekly [70]. In the author's experience, a higher dose of fluconazole was not effective for women with MIC ≥4 micrograms/mL. These individuals should be evaluated for cross-resistance to itraconazole and ketoconazole as some patients can be treated effectively with long-term maintenance daily imidazole therapy. However, use of itraconazole or ketoconazole requires intermittent hepatic function testing. Idiosyncratic hepatotoxicity secondary to ketoconazole therapy is a concern but rare in this setting.
●Treatment of pan-azole resistance – Azole resistance has been reported in non-C. albicans infections [27]. Persons with severe RVVC infection and high-level pan azole resistance do not have options other than topical boric acid or nystatin suppositories [71]. (See 'Boric acid' below.)
Triterpenoid extended treatment — Extended treatment with ibrexafungerp, an oral triterpenoid drug, is an option for suppression of RVVC. In a phase 3 trial evaluating patients with RVVC treated with fluconazole followed by extended treatment with either ibrexafungerp or placebo, more patients in the ibrexafungerp arm remained without evidence of RVVC (65.4 versus 53.1 percent, respectively) at test of cure (study week 24) [72]. In the trial, patients initially received fluconazole 150 mg orally every 72 hours (three days) for a total of three doses and then began either ibrexafungerp (300 mg orally twice a day, for one day, every four weeks for a total of six dosing days) or oral placebo with the same dosing regimen [73,74]. Long-term benefit of treatment of RVVC caused by C. albicans is not yet known as follow-up was limited to three months rather than the typical six months following cessation of monthly ibrexafungerp. In addition, as the study population mainly included patients with C. albicans, it is not known if patients with non-albicans Candida isolates, which constitute 10 to 15 percent of usual isolates, will similarly experience prophylactic benefit [62]. Common side effects included headaches and GI disturbances (diarrhea, nausea).
While Ibrexafungerp offers patients who have not responded to azoles or who have azole-resistant infections with another treatment option, the cost of this treatment regimen may be prohibitive. In addition, Ibrexafungerp should not be used by pregnant or lactating individuals. (See 'Triterpenoid initial treatment (ibrexafungerp)' above.)
Gentian violet — Topical gentian violet was widely used prior to the availability of the topical azole intravaginal antifungal creams and suppositories. Use of this agent has largely been abandoned because azole antimycotics are more effective (potent) and because gentian violet is messy and inconvenient (eg, it permanently stains clothes). However, it is useful as a vulvar antipruritic and for occasional refractory cases of vulvovaginal candidiasis, especially those demonstrating azole resistance [75]. The drug is applied to affected areas of both the vulva and vagina daily for 10 to 14 days.
Boric acid — We believe vaginal boric acid has no role in treatment of recurrent vulvovaginitis due to C. albicans, unless azole resistance is demonstrated by in vitro tests [76]. There are no safety data on long-term use of vaginal boric acid, which causes significant local irritation and has the potential for toxicity (including death) if ingested by accident. A course of boric acid (600 mg intravaginal boric acid vaginal suppositories daily for two weeks) may be considered for cases of proven azole-resistant infection or non-albicans RVVC [15,27]; these cases are rare. Sexual partners who come into contact with vaginal boric acid could develop irritation or dermatitis of the exposed area, but the duration of risk is not known.
Immunotherapy — Local vaginal hypersensitivity to C. albicans has been proposed as the cause of recurrent infection in some women [77]. Immunotherapy of candidal vaginitis for both prevention and treatment is a therapeutic approach under investigation [78]. A prophylactic vaccine would need to induce a host immune response against fungal virulence traits without altering the tolerance/inflammation balance of the vaginal environment, whereas a therapeutic vaccine indicated for women with RVVC could enhance or rectify tolerance/inflammation imbalance in the vagina [79]. Two vaccines are in development.
Behavioral changes — Although not based upon data from randomized trials, implementing a change in one or more behavioral factors (eg, avoidance of panty liners, pantyhose, cranberry juice, and topical lubricants) to see if there is improvement may be beneficial in rare women [80]. Attempts should be made to eliminate or reduce risk factors for infection if present (eg, improve glycemic control, switch to lower estrogen dose oral contraceptive). (See "Candida vulvovaginitis: Clinical manifestations and diagnosis", section on 'Risk factors'.)
Management of sexual dysfunction and the marital discord that frequently accompany chronic vaginitis should also be addressed.
Probiotics and dietary changes — There is no evidence that individuals with RVVC have vaginal flora deficient in lactobacilli, and therefore we do not recommend use of probiotic lactobacilli [59,81,82]. Although there is a popular belief that ingestion or vaginal administration of yogurt or other agents containing live lactobacilli decreases the rate of candidal colonization and symptomatic relapse, the few studies in this area have a number of methodologic flaws (eg, no control group, short follow-up) and small numbers of subjects [83-87]. The value of administering live lactobacilli to women with recurrent infection has been refuted in other studies [80,88], and this approach should be considered unproven. The quality of probiotics varies worldwide; in the United States, these products are not standardized and are often of poor quality. The US Food and Drug Administration has cautioned against using probiotics with bacteria or yeast in immunocompromised patients [89].
In the absence of controlled studies evaluating the role of diet in preventing and controlling candida vaginitis, no specific diets are recommended. Occasional patients report precipitation of episodic vaginitis after consuming beer or refined sugar products, especially when consumed in excess. Under these circumstances, avoidance of recognized precipitating food items or alcohol is prudent but frequently insufficient to resolve symptoms.
Testing for HIV infection — Vulvovaginal candidiasis occurs more frequently and has greater persistence, but not greater severity, in human immunodeficiency virus (HIV)-infected women with very low CD4 counts and high viral load; however, this population is likely to manifest other acquired immune deficiency syndrome-related sentinel conditions [90]. HIV testing of patients only for the indication of RVVC is not justified, given that recurrent Candida vaginitis is a common condition in individuals without HIV infection and the majority of cases occur in uninfected people. The microbiology of vulvovaginal candidiasis in HIV-infected women is similar to that in HIV-negative women [91].
Those with risk factors for acquisition of HIV should be counseled and offered screening. These risk factors are described in detail separately. (See "Screening for sexually transmitted infections".)
SPECIAL POPULATIONS
Allergy to fluconazole — The incidence of fluconazole allergy in patients with acute Candida vaginitis is unknown but uncommon. The author has seen patients with allergic symptoms, varying from rash to, occasionally, angioedema. It is important to recognize that fluconazole is one member of the azole class of drugs, and it is difficult to distinguish between patients with allergy to fluconazole alone versus those with allergy to the entire azole class. Therefore, other oral azoles such as ketoconazole (Nizoral) or itraconazole (Sporanox) should not be prescribed to patients with true fluconazole allergy. However, patients with fluconazole allergy can receive topical azoles, such as miconazole or clotrimazole. For those patients with fluconazole allergy manifested by angioedema or severe rash, the author has resorted to use of topical agents instead of weekly fluconazole 150 mg. Both miconazole and clotrimazole can be prescribed on a once-weekly high-dose regimen, 500 to 1500 mg, depending on the dose commercially available locally. Other options include nystatin per vagina 100,000 units daily for seven days for acute vaginitis or boric acid per vagina for seven days. Discussion with an allergist is recommended. There are no data on the efficacy of fluconazole desensitization, which is theoretically possible.
Sex partners — Although sexual transmission of Candida species can occur, most experts do not recommend treatment of sexual partners since sexual activity is not a significant cause of infection or reinfection. Although the bulk of evidence from randomized trials does not support treatment of sexual partners [92-95], in individuals with recurrent vulvovaginitis, this issue remains controversial. At least one organization states no recommendation can be made as supporting data are lacking [15].
Treatment of symptomatic men is reviewed separately. (See "Balanitis in adults".)
Breastfeeding individuals — Nystatin does not enter breast milk and is compatible with breastfeeding. Fluconazole is excreted in human milk, but the American Academy of Pediatrics considers the use of fluconazole compatible with breastfeeding [96], as no adverse effects have been reported in breastfed infants or infants treated with parenteral fluconazole [97]. There is no information on the effect of miconazole, butoconazole, clotrimazole, tioconazole, or terconazole on nursing infants, but systemic absorption after maternal vaginal administration is minimal, hence topical use in nursing mothers is reasonable.
Females taking tamoxifen — Tamoxifen is widely used and recommended as an effective estrogen receptor blocker in patients with breast cancer. Paradoxically, tamoxifen may result in "agonist" or estrogen-like benign manifestations in the vagina, characterized by mild discharge and increased risk of Candida vulvovaginitis. We treat individuals taking tamoxifen who also have recurrent vulvovaginal candidiasis (RVVC) with maintenance fluconazole therapy. (See 'Recurrent treatment' above.)
Male partners with postcoital hypersensitivity reaction — In a variant syndrome, male partners of individuals with vaginal Candida colonization develop immediate postcoital itching and burning with redness and a rash of the penis. This postcoital syndrome probably represents an acute hypersensitivity reaction to Candida organisms or antigens in the partner's vagina, even in the absence of symptomatic vulvovaginitis.
Males with recurrent postcoital symptoms do not benefit from topical antimycotic therapy since the key to eradicating symptoms lies in eliminating Candida organisms from the lower genital tract of the female sexual partner. This often requires the female partner to follow a long-term maintenance antimycotic regimen.
A postcoital shower and application of a topical low-potency corticosteroid to the penis may provide symptomatic relief within 12 to 24 hours (table 4). Penile cultures may remain positive for Candida despite normal physical findings.
Incidental finding — Treatment of Candida identified on a Pap smear of an asymptomatic person is not indicated because up to 20 percent of reproductive-aged women will be colonized with Candida species [98,99]. Similarly, individuals with Candida noted on an intrauterine device that was cultured after removal do not require treatment in the absence of symptoms.
PREVENTION — Oral nystatin does not prevent vaginal candidiasis, and lactobacillus (oral or vaginal) does not prevent postantibiotic vulvovaginitis. In women susceptible to symptomatic yeast infections when taking antibiotic therapy, a dose of fluconazole (150 mg orally) at the start and end of antibiotic therapy may prevent postantibiotic vulvovaginitis [91]. (See "Candida vulvovaginitis: Clinical manifestations and diagnosis", section on 'Risk factors'.)
COMPLEMENTARY AND ALTERNATIVE MEDICINE — There is no evidence from randomized trials that garlic, tea tree oil, yogurt (or other products containing live Lactobacillus species), or douching is effective for treatment or prevention of vulvovaginal candidiasis due to Candida albicans [100].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Gynecologic infectious diseases (non-sexually transmitted)".)
SUMMARY AND RECOMMENDATIONS
●Treatment indications – Treatment is indicated to relieve symptoms. Asymptomatic individuals and sexual partners do not require treatment. (See 'Indications' above.)
●Treatment options – A variety of oral and topical preparations, many available over the counter and in single-dose regimens, are available for the treatment of uncomplicated vulvovaginal candidiasis (table 2). The absence of superiority of any formulation, agent, or route of administration suggests that cost, patient preference, and contraindications are the major considerations in the decision to prescribe an antifungal for oral or topical administration. (See 'Oral versus topical treatment' above.)
●Selection of treatment regimen – The treatment regimen is based on whether the person has an uncomplicated infection (90 percent of patients) or complicated infection (10 percent of patients). Criteria are listed in the table (table 1). (See 'Uncomplicated infection' above.)
•Uncomplicated infections
-Criteria for uncomplicated infection include all of the following: sporadic, infrequent episodes (≤3 episodes per year); mild to moderate symptoms; probable Candida albicans infection; and healthy, immunocompetent, and nonpregnant patients (table 1) [8]. (See 'Criteria' above.)
-For individuals with uncomplicated candida vulvovaginitis, we suggest a single dose of oral fluconazole (150 mg) for treatment rather than multidose and topical regimens (Grade 2C). (See 'Initial azole treatment' above.)
•Complicated infections – Individuals with complicated infection do not meet the criteria for uncomplicated candida vulvovaginitis (table 1). These require longer courses of therapy than those with uncomplicated infection (table 3). (See 'Complicated infections' above.)
-For people with severe symptoms or immunocompromise, we suggest fluconazole (150 mg) in two sequential doses given three days apart rather than topical antimycotic agents (Grade 2C). (See 'Patients with severe symptoms or immunocompromise' above.)
-For individuals with Candida glabrata infection, we suggest intravaginal boric acid (600 mg capsule once daily at night for two weeks) (Grade 2C). Alternative treatments include intravaginal nystatin pessary 100,000 units daily, amphotericin B, or flucytosine cream. (See 'Candida glabrata' above.)
-For individuals with Candida krusei infection, we suggest treatment with a topical azole (cream or suppository) other than fluconazole (table 3) (Grade 2C). Candida krusei is usually resistant to fluconazole but is highly susceptible to clotrimazole, miconazole, and terconazole. (See 'Candida krusei' above.)
-For pregnant persons, we suggest a topical imidazole (clotrimazole, miconazole) vaginally for seven days rather than a nystatin pessary or an oral azole (Grade 2C). Case reports have described a pattern of birth defects (abnormalities of cranium, face, bones, and heart) after first trimester exposure to high-dose oral azole therapy (400 to 800 mg/day) and cohort studies have reported conflicting data on risk of miscarriage. (See 'Pregnancy' above.)
●Recurrent vulvovaginal candidiasis (RVVC) – For individuals with recurrent vulvovaginitis (≥3 episodes/year), we suggest suppressive maintenance therapy rather than treatment of individual episodes (Grade 2B). We prescribe initial induction therapy with fluconazole 150 mg every 72 hours for three doses, then maintenance fluconazole 150 mg once per week for six months. Patients who do not respond to fluconazole therapy, or who have resistant infections, can use ibrexafungerp monthly for six months. Those with recurrent infection should try to eliminate or reduce risk factors for infection. (See 'Fluconazole extended treatment' above.)
●Fluconazole allergy – The incidence of fluconazole allergy in patients with acute Candida vaginitis is unknown but uncommon. Individuals with fluconazole allergy, including angioedema and severe rash, can receive topical azoles such as miconazole or clotrimazole. (See 'Allergy to fluconazole' above.)
