Candida vulvovaginitis in adults: Recurrent infection

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. While most females will experience a sporadic Candida infection, a small percentage of patients will experience recurrent infection.

This topic will discuss the treatment of recurrent vulvovaginal candidiasis (RVVC). Related topics on the clinical presentation and diagnosis of vulvovaginal candidiasis, treatment of sporadic infection, and the general approach to patients with vaginitis are presented separately:

●(See "Candida vulvovaginitis: Clinical manifestations and diagnosis".)

●(See "Candida vulvovaginitis in adults: Treatment of acute infection".)

●(See "Vaginitis in adults: 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. We encourage the reader to consider the specific counseling and treatment needs of transgender and gender-expansive individuals.

CLINICAL POINTS

Definition — Recurrent vulvovaginal candidiasis (RVVC) is defined as three or more episodes of symptomatic infection within one year; this definition is mainly based on expert opinion and is a change from the prior definition of four or more episodes in one year [1-5].

Need for laboratory testing — Vaginal cultures should always be obtained to confirm the diagnosis of RVVC and identify non-albicans Candida species (most commonly C. glabrata and C. krusei, but there are others), if present. The role of molecular tests for diagnosis and management of RVVC has not been fully elucidated. (See "Candida vulvovaginitis: Clinical manifestations and diagnosis", section on 'Diagnostic approach'.)

Asymptomatic patients — Asymptomatic patients with VVC identified for other reasons (ie, nucleic acid amplification test [NAAT] or culture for evaluation of vaginal discharge, pap smear) do not require treatment [6]; 10 to 20 percent of reproductive-age females harbor Candida species and, in the absence of symptoms, these patients do not require therapy [7].

Testing for HIV infection — Human immunodeficiency virus (HIV) testing of patients diagnosed solely with RVVC is not justified given that RVVC is a common condition in individuals without HIV infection and that most cases occur in uninfected people. The microbiology of vulvovaginal candidiasis is similar for HIV-infected and HIV-uninfected women [6]. Vulvovaginal candidiasis occurs more frequently and has greater persistence, but not greater severity, in HIV-infected patients with very low CD4 counts and high viral load; however, this population is likely to manifest other acquired immune deficiency syndrome-related sentinel conditions [8].

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".)

EPIDEMIOLOGY AND PATHOPHYSIOLOGY — Recurrent disease is usually due to a relapse from a persistent vaginal reservoir of organisms or endogenous reinfection with identical strains of susceptible C. albicans [9]; however, rarely, a new strain of Candida is responsible for the infection. Most people with RVVC are otherwise healthy and the pathway(s) behind relapse are not fully understood. Contributing factors have been identified and potential mechanisms are under study.

Disease 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 patients 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 [10]. An earlier survey study that defined RVVC as ≥4 infections over 12 months reported a 9 percent prevalence [11].

Intrinsic factors — Contributory factors that are inherent to the patient and therefore unchangeable include the following:

●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 [9,12]. Infection due to a different Candida species (eg, C. glabrata) have been reported in 10 to 20 percent of patients with RVVC [3]. 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 RVVC with vaginal mucosal immune hyperreactivity to the fungus [13,14]. This suggests the occurrence of dysregulated immune reactivity in the pathogenesis of RVVC [15]. Vaginal hyperreactivity involves interleukin (IL)-4-, IL-10-, and IL-22-producing regulatory T cells. IL-17 may play a role in controlling C. albicans infection as it induces vaginal epithelial cells to produce antimicrobial peptides but its role in human disease is unclear. In mice, the role of IL-17 in protection against mucosal Candida infections has been established in the oral cavity [16]. In humans, studies in patients 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 [17].

●Genetic polymorphisms – Multiple genetic polymorphisms have been identified in conjunction with RVVC and more are likely to be elucidated [18,19]. As examples, RVVC has been associated with decreased in vivo concentration of mannose-binding lectin (MBL) and increased concentration of IL-4 [20]. Two specific gene polymorphisms, variants in the MBL and IL-4 alleles, can account for this finding in some individuals.

•Mannose-binding lectin (MBL) – The prevalence of a variant MBL gene is higher in patients with RVVC than in controls without candidiasis [21-23]. 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 [20,21,24-26].

•Interleukin-4 (IL-4) – 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 [27,28].

●Bacterial vaginosis – In some patients, recurrent BV infection precedes RVVC infection. While antibiotic treatment of BV likely contributes to yeast infection, there is some thought that the dysbiosis and inflammatory changes associated with BV are risk factors for RVVC infection as well [29]. (See "Bacterial vaginosis: Recurrent infection".)

External triggers — In contrast to the intrinsic factors above, external factors may initiate an attack of acute vaginitis. In our experience, antibiotic use (most common), sexual activity, recent bacterial vaginosis, and diet can trigger acute vaginitis in some patients. Genetic susceptibility to Candida infection may be necessary for antibiotics to trigger an attack, which would explain why antibiotic use does not result in Candida VVC in all patients following drug exposure. Other drugs that may predispose to RVVC include immunosuppressants, 17-β estradiol, and sodium-glucose cotransporter receptor-2 (SGLT2) inhibitors [30-32].

INITIAL DRUG TREATMENT — The aims of treatment are initial relief and continued suppression of symptoms. The clinician must choose both the drug and duration of therapy. For nonpregnant patients, we generally take the following approach:

Nonpregnant — We take the following approach to treatment of nonpregnant persons with RVVC (algorithm 1):

Fluconazole — We treat nonpregnant patients with oral fluconazole induction therapy followed by extended oral fluconazole maintenance (six months or longer) [3,29,33-40]. The role of maintenance therapy is suppression of symptoms and not eradication of organisms [29,41]. We prefer oral fluconazole to other azoles (ie, oteseconazole) or ibrexafungerp as fluconazole is generally well tolerated, easy to use, low cost, and readily available. While oteseconazole appears to have higher long-term efficacy, it has many restrictions to use and is higher cost [29,42]. Patients with fluconazole allergy or intolerance can be treated with ibrexafungerp.

Empiric regimen — Candida albicans is the causative organism in 80 to 90 percent of patients with RVVC [3]. We take the following approach for patients with confirmed C. albicans or those whose isolate test results are not yet available (algorithm 1):

●Initial extended fluconazole regimen

•Induction – Fluconazole, 150 mg, orally every 72 hours for three doses

followed by

•Maintenance – Fluconazole, 150 mg, orally once per week for six months

●Trial of drug discontinuation – After six months, the drug is stopped and the patient is observed for sustained remission or symptom relapse (up to 55 percent of patients experience symptom relapse, typically within six months) [35]. Patients who remain asymptomatic are observed. Those with symptom relapse undergo repeat testing and targeted treatment. (See 'Symptom recurrence' below.)

Efficacy — Treatment with extended oral fluconazole results in greater sustained remission compared with placebo but is similar to that of topical azoles [36]. During maintenance treatment, more than 80 percent of patients report controlled symptoms and improved quality of life [33,43]. However, symptoms recur in more than half of patients after stopping maintenance [41].

●Compared with placebo – In a meta-analysis of four trials including 518 RVVC patients treated for initial infection, six months of fluconazole maintenance resulted in fewer clinical recurrences compared with placebo maintenance (17 versus 63 percent, relative risk [RR] 0.29, 95% CI 0.14-0.62) [36]. However, by 12 months (ie, six months after stopping fluconazole maintenance therapy), fluconazole treatment effect was sustained but less pronounced compared with placebo (59 versus 77 percent, respectively, RR 0.77, 95% CI 0.68-0.88).

●Compared with topical azoles – In meta-analysis of three trials totaling 106 RVVC patients treated for recurrent infection, clinical recurrence rates were statistically similar at 6 and 12 months of follow-up [36].

•Six months – Clinical recurrence rates at the end of six months of treatment with either oral or topical azole were 21 and 12 percent, respectively (RR 1.66, 95% CI 0.83-3.31).

•Twelve months – Clinical recurrence rates at the end of 12 months (six months of maintenance treatment followed by six months of observation) for oral or topical treatment were 47 and 49 percent (RR 0.95, 95% CI 0.71-1.27).

Adverse effects and monitoring

●Laboratory monitoring generally not indicated – 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.

●Potential drug interactions – 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.

Oteseconazole — Oteseconazole is an azole antifungal drug for use in individuals with RVVC; this agent is more potent against Candida species, including Candida glabrata, compared with fluconazole [29,42,44-46]. Its use is limited by drug restrictions.

●Restrictions – Oteseconazole use is valuable but limited only to patients who are postmenopausal, have undergone bilateral tubal ligation, or have undergone hysterectomy. It should not be used in patients of reproductive potential, including those who could 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 [29].

●Dosing options – While two dosing regimens are available [44], the single-drug approach is generally preferred for simplicity (algorithm 1). Oteseconazole should be taken with food to aid absorption.

•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) [42]. The regimen is available in a blister pack that indicates the dose and timing [29].

•Dual-drug regimen – The dual-drug regimen involves initial induction treatment with fluconazole followed by maintenance suppression with oteseconazole. Dosing is as follows [44]:

-Day 1, day 4, and day 7: Fluconazole 150 mg orally

-Days 14 through 20: Oteseconazole 150 mg orally once daily for 7 days

-Beginning on day 28: Oteseconazole 150 mg orally once a week (ie, every 7 days) for 11 weeks (ie, weeks 4 through 14) [44].

●Efficacy – Initial data from three trials suggest that oteseconazole (induction and maintenance) treatment is at least as good as fluconazole, and likely better, but data directly comparing the two drugs are not yet available. In three clinical trials involving a total of 656 patients randomized to induction treatment followed by maintenance with oteseconazole or placebo, 12-month recurrence rates ranged from 4 to 7 percent for oteseconazole compared with 39 to 43 percent for placebo [44,47]. 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) [47]. The efficacy of extended oteseconazole compared with extended fluconazole is not yet known.

●Adverse effects – In the initial drug trials, the most commonly reported adverse reactions were headache (7.4 percent) and nausea (3.6 percent) [44].

Ibrexafungerp — Extended treatment with ibrexafungerp, an oral triterpenoid drug, is an option for suppression of RVVC for patients who have not responded to azoles, not tolerated azoles, or have an azole-resistant infection (algorithm 1). While ibrexafungerp offers another treatment option, drug availability and cost may limit use.

●Restrictions – Ibrexafungerp should not be used by pregnant or lactating individuals [48].

●Dosing – Ibrexafungerp provides a non-azole oral drug treatment option. The induction and maintenance doses are the same.

•Induction – Ibrexafungerp 300 mg orally (two 150 mg tablets) taken approximately 12 hours apart (ie, 300 mg taken in the morning and again in the evening) [48].  

•Maintenance – Ibrexafungerp 300 mg orally (two 150 mg tablets) taken twice in one day is repeated every four weeks for a total of six dosing days (ie, extended treatment for six months) [48].

●Efficacy – In a phase 3 trial evaluating patients with RVVC treated with fluconazole followed by extended treatment with either ibrexafungerp (n = 130) or placebo (n = 130), more patients in the ibrexafungerp arm remained without evidence of RVVC (65.4 versus 53.1 percent, respectively) at six-month test of cure (study week 24) [48]. However, long-term benefit of treatment is not yet known as follow-up was limited to three months post-treatment rather than the typical six months. 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 [29].

●Adverse effects – Common side effects included headaches and gastrointestinal disturbances (diarrhea, nausea) [48].

Pregnant — For pregnant persons with test-confirmed RVVC, we treat with extended courses of topical azoles only (algorithm 2). Patients require both induction and maintenance suppressive treatment. Longer courses of induction therapy followed by maintenance for the duration of pregnancy may be required to adequately suppress symptoms. Patients are reassessed after delivery.

●Drugs and dosing – Drug selection is based on prior patient response (if any) as well as drug availability and cost. Data specific to pregnant persons are generally limited. Once symptoms are controlled for several days, then the patient is changed to maintenance suppressive therapy. The aim is to use the lowest maintenance dose and frequency that keeps the patient symptom-free. Should symptoms recur while on therapy, induction treatment is repeated and then followed by maintenance with the drug, dose, and frequency that adequately suppressed symptoms.

Options include (algorithm 2) [5,29,37]:

•Clotrimazole 1% cream

-Induction – 1 applicatorful (approximately 5 g) in vagina daily for 7 to 14 days

-Maintenance – 1 applicatorful (approximately 5 g) in vagina two to three times a week for duration of pregnancy

Clotrimazole 2% cream is also reasonable. At this dose, duration of induction therapy is three to five days, as needed to control symptoms. This is followed by maintenance at a frequency that controls symptoms.

Or

•Miconazole 2% cream

-Induction – 1 applicatorful (approximately 5 g) in vagina daily for 7 to 14 days

-Maintenance – 1 applicatorful (approximately 5 g) in vagina two to three times a week OR miconazole 1200 mg suppository in vagina once weekly for duration of pregnancy

Other miconazole regimens include miconazole 4% cream and high-dose suppository. Induction with miconazole 4% cream is given daily for three to five days, as needed to control symptoms. This is followed by maintenance with miconazole 4% cream at a frequency that controls symptoms (typically 1 to 3 times a week). Alternately, miconazole 1200 mg vaginal suppository can be used once a week for the duration of the pregnancy.

Or

•Nystatin suppository 100,000 units (may require preparation by a compounding pharmacy).

-Induction – One suppository in vagina for 14 nights  

-Maintenance – Vaginal suppository use is slowly tapered to the lowest frequency that controls the patient's symptoms. Patients whose symptoms are controlled on the nightly regimen reduce frequency to every other night for several weeks. If symptoms remain controlled, the frequency is reduced again to two to three times a week. If symptoms worsen at any point, the patient returns to the frequency that controlled symptoms. Treatment is continued for the duration of pregnancy.

●Drugs we avoid – We do not use oral fluconazole, oteseconazole, or ibrexafungerp due to concerns for fetal harm. (See "Candida vulvovaginitis in adults: Treatment of acute infection", section on 'Pregnancy'.)

•Oral fluconazole has been associated with increased risk of pregnancy loss and possibly congenital malformations [49].

•Oteseconazole and ibrexafungerp are not for use in pregnancy or lactation because of concerns for potential harm based on animal data [44,48].

Additionally, terconazole labelling states "it should not be in the first trimester" unless use is essential to the welfare of the patient and it "may bed be used during the second and third trimester if potential benefits outweighs the possible risks to the fetus" [50]. We do not use boric acid or dequalinium chloride because safety of long-term use has not been established. Pregnant patients have been given short courses (<24 hours) of dequalinium chloride for reduction of group B streptococcus infection [51].

●Adverse effects – Potential side effects of topical therapy include burning, redness, and irritation.

Lactating — Lactating patients may use oral fluconazole but not oteseconazole or ibrexafungerp [44,48,52-55]. Topical miconazole and clotrimazole are minimally absorbed from the vagina and thus are considered reasonable for use in lactating patients [56,57]. As butoconazole, tioconazole, and terconazole have not been studied during lactation, miconazole or clotrimazole use is preferred [58-60].

PREFERENCE FOR EXTENDED VERSUS EPISODIC TREATMENT — We suggest extended treatment rather than episodic. Patients generally prefer low-intensity prophylactic maintenance therapy to treatment of each recurrence (which requires repeat testing and induction). Our typical regimen is induction therapy with oral fluconazole followed by six months of maintenance with weekly fluconazole. Additional details for fluconazole dosing and efficacy are presented below. (See 'Fluconazole' above.)

●Extended duration of treatment – Support for an extended duration of treatment comes from a meta-analysis and other small trials [33,36].

•Six-month recurrence risk (active therapy) – Extended treatment with a combination of azole drugs (oral or topical) rather than placebo or no treatment reduced both clinical recurrence risk (23 versus 65 percent, relative risk [RR] 0.36, 95% CI 0.21-0.63, 607 participants) and mycological recurrence risk (29 versus 71 percent, RR 0.44, 95% CI 0.25-0.78, 568 participants) [36].

As an example of the anticipated absolute effect, VVC recurrence over six months would be expected in:

-233 per 1000 patients receiving extended azole treatment

-647 per 1000 patients receiving placebo or no treatment

•Twelve-month recurrence risk (active therapy followed by observation) – Analysis of studies comparing six months of active azole treatment (oral or topical) followed by six months of observation, the clinical recurrence risk remained lower for the treatment group but became more comparable with placebo or no treatment (63 versus 78 percent, RR 0.80, 95% CI 0.72-0.89, 585 participants) [36]. Mycological recurrence risk was similar between the groups based on a smaller sample size (75 versus 85 percent, RR 0.90, 95% CI 0.79-1.03, 189 participants).

As an example of the anticipated absolute effect, recurrence at 12 months would be expected in:

-625 per 1000 patients receiving extended azole treatment

-781 per 1000 patients receiving placebo or no treatment

It is important to recognize that the trials included in the meta-analysis had small sample sizes with important methodologic limitations.

●Episodic and other alternatives to extended treatment – Alternate regimens include variations of episodic treatment or treatment duration.

•Episodic treatment as needed – Rather than use extended maintenance therapy, patients may treat each recurrent episode as an acute uncomplicated infection (table 1) [3]. This approach may appeal to patients who prefer fewer overall days of medication but is generally a higher intensity approach as patients must be retested and retreated with conventional therapy for each episode. (See "Candida vulvovaginitis in adults: Treatment of acute infection", section on 'Uncomplicated infection'.)

•Longer duration of episodic treatment – In this approach, each recurrent episode is treated with longer duration of conventional therapy (eg, topical azole for 7 to 14 days or fluconazole 150 mg orally on day 1, day 4, and day 7) [3,37,61]. Some patients may prefer repeat treatments of 7 to 14 days total duration rather six or months or more of maintenance therapy.

•Longer induction followed by maintenance – Several societies recommend 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) [40,62].

SYMPTOM RECURRENCE — Management of confirmed RVVC depends on the timing of the recurrence relative to use of maintenance therapy. More than half of patients will experience symptom recurrence following cessation of maintenance prophylaxis because the underlying causal factors that contributed to lower genital tract infection remain unchanged [36]. Maintenance therapy is prescribed for symptom control but is not curative.

Retest and confirm compliance — When symptoms recur, patients are again tested to confirm yeast infection and exclude other causes of symptoms [29]. If yeast are reconfirmed, empiric treatment is restarted, as discussed above. Additionally, testing is performed to identify non-albicans species (eg, culture) and drug-resistant organisms (for patients with history of drug-resistant infection or whose symptoms recur on fluconazole maintenance). As drug-resistance testing takes additional time and generally increases cost, we do not perform such testing routinely. (See 'Need for laboratory testing' above.)

The fluconazole regimen is repeated and tailored as needed once isolate test results are available. (See 'Empiric regimen' above.)

Relapse off therapy — More than 50 percent of treated patients will experience symptom recurrence as soon as fluconazole maintenance is withdrawn (ie, fluconazole-dependent RVVC) [29,36]. As recurrence off therapy is generally not related to fluconazole resistance, fluconazole treatment is reasonably repeated.

Patients may elect:

●Episodic treatment – Treat each recurrence episode with oral fluconazole (See "Candida vulvovaginitis in adults: Treatment of acute infection", section on 'Oral fluconazole'.)

Or

●Induction and continued maintenance – Patients are again treated with fluconazole induction followed by maintenance for continued suppression of symptoms. In this scenario, maintenance therapy may be extended to a year or more. This approach is mainly based on clinical experience as few studies assess beyond six months of therapy [29,36]. (See 'Fluconazole' above.)

The ultimate duration of maintenance therapy is determined by the patient's preferences around continuing suppressive treatment (or stopping and observing) and prior response. In our experience, patients generally prefer low-intensity maintenance therapy to treatment of every recurrence (which requires repeat testing and repeat induction therapy). (See 'Fluconazole' above.)

Relapse on maintenance therapy — For patients whose relapse occurred during fluconazole maintenance, we confirm the drug was being used consistently and correctly. We perform isolate and drug sensitivity testing because relapse that occurs during fluconazole maintenance is concerning for fluconazole-resistant organisms (including non-albicans Candida or fluconazole-resistant C. albicans).

Non-albicans Candida species — Non-albicans Candida species have been observed in 10 to 20 percent of patients with RVVC [3]. Non-albicans Candida species most commonly include C. glabrata and C. krusei, but there are others.

Treatment of RVVC with non-albicans species is extended to six months or longer (algorithm 3). Drug selection is driven by the species, drug contraindications and interactions, patient preferences for oral or vaginal treatment, availability, and cost. We typically offer vaginal boric acid first because it has demonstrated efficacy, is generally available, and has few contraindications [29]. Other therapies include ibrexafungerp, nystatin, and voriconazole, although supporting data are very limited. Dequalinium chloride is an alternate therapy for RVVC available in some countries but we do not have clinical experience with this drug [63,64].

The treatment of non-albicans Candida is discussed in detail in related content. (See "Candida vulvovaginitis in adults: Treatment of acute infection", section on 'Non-albicans Candida species'.)

Azole-resistant infection

●When to suspect – Azole resistance is suspected when symptoms and signs are refractory while on appropriately dosed and used azole drugs (any azole) or as breakthrough infection while on maintenance fluconazole therapy. Drug-resistance testing is performed to identify azole-resistant organisms.

In persons with RVVC, there is some evidence that repeated and prolonged use of fluconazole can infrequently select for fluconazole resistance in C. albicans strains previously susceptible to fluconazole, which limits the treatment options. Differences in genetic mutations have been reported between fluconazole-susceptible and fluconazole-resistant Candida species [19].

●Management – The rare patient with azole-resistant organisms is treated similarly to patients with non-albicans infections (algorithm 3). Azole-resistant species are typically C. albicans. (See "Candida vulvovaginitis in adults: Treatment of acute infection", section on 'Non-albicans Candida species'.)

•Assess drug minimum inhibitory concentration (MIC) – In patients with refractory vulvovaginal candidiasis with persistently positive C. albicans cultures, susceptibility tests utilizing MICs to various antifungals can be measured by using the broth microdilution method conducted in accordance with Clinical and Laboratory Standards Institution criteria and breakpoints [65]. A vaginal sample is cultured and the organisms are then tested. (See "Antifungal susceptibility testing".)

•Increase azole dose based on MIC

-MIC >2 to 4 – These patients may respond to higher doses of fluconazole or, in some cases, ketoconazole or itraconazole. In a study of 25 patients with refractory VVC and a C. albicans isolate with fluconazole 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 [66]. In the author's experience, a higher dose of fluconazole has not been effective for patients with MIC >4 micrograms/mL [29]. 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.

-MIC >4 – These patients have fluconazole-resistant infection. Treatment options include vaginal boric acid suppositories, nystatin suppositories, oral ibrexafungerp, or oteseconazole. Selection is based on availability and contraindications. Treatment duration is based on sporadic versus recurrent infection. Sporadic infections are treated for 7 to 14 days (longer duration for more severe symptoms). Patients with recurrent infection may require treatment for six months or more.

•Treatment of pan-azole resistance – Azole resistance has been reported in non-C. albicans infections [67]. Persons with severe RVVC infection and high-level pan-azole resistance are treated with ibrexafungerp, vaginal boric acid, or nystatin suppositories [68]. Dosing is as discussed in each drug discussion.

-(See 'Ibrexafungerp' above.)

-(See 'Vaginal boric acid' below.)

LIFESTYLE

Behavioral changes — Attempts should be made to eliminate or reduce medical risk factors for infection (eg, improve glycemic control, switch to lower estrogen dose oral contraceptive). As an adjunct to drug therapy, it is reasonable to change behavioral factors that could exacerbate symptoms, although there is little evidence that this is helpful (eg, avoid panty liners, douching, tight clothing, pantyhose, cranberry juice, and topical lubricants) [29,62,69]. (See "Candida vulvovaginitis: Clinical manifestations and diagnosis", section on 'Risk factors'.)

Probiotics and diet — Probiotic use has not been associated with long-term clinical or mycological cure [70].

●Lactobacilli – There is no evidence that individuals with RVVC have vaginal flora deficient in lactobacilli, and therefore we do not recommend use of probiotic lactobacilli [34,62,71,72]. Although there is a popular belief that ingestion or vaginal administration of yogurt or other agents containing live lactobacilli decreases the rate of Candida colonization and symptomatic relapse, the few studies have methodologic limitations (eg, no control group, short follow-up) and small numbers of subjects [73-77]. The value of administering live lactobacilli to patients with recurrent infection has been refuted in other studies [69,78], 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 (FDA) has cautioned against using probiotics with bacteria or yeast in immunocompromised patients [79].

●Dietary changes – In the absence of controlled studies evaluating the role of diet in preventing and controlling VVC, 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.

Sexual and psychosocial health — Patients with RVVC may develop sexual dysfunction and/or relationship difficulties [62,80]. Clinicians should inquire about the impact of RVVC on other aspects of the patient's life and provide access to appropriate counseling and support. (See "Overview of sexual dysfunction in females: Management".)

SGLT2 inhibitor drugs — Sodium-glucose cotransporter receptor-2 (SGLT2) inhibitors have been associated with RVVC [30]. We discuss alternate diabetes treatment options with patients using these drugs and their providers.

TREATMENTS WITH LIMITED USE

Topical azoles — Topical azoles are commonly used in pregnant patients and as an alternate to oral therapy. Patients can reasonably use topical azole induction and maintenance rather than oral azole treatment as small trials report similar efficacy [36]. (See 'Efficacy' above.)

Vaginal boric acid — Vaginal boric acid is used for a limited set of patients, including those with azole-resistant C. albicans, intolerance or allergy to azoles, or non-albicans Candida [81,82]. There is no role for vaginal boric acid in treatment of RVVC to usual C albicans. Boric acid can cause death if taken orally.

●Dosing – Patients initially try induction treatment alone. Those in whom recurrence occurs quickly repeat induction treatment and then start maintenance therapy.

•Induction – Vaginal boric acid (600 mg suppositories) daily for two to three weeks [3,67,83].

•Maintenance – Vaginal boric acid (600 mg suppositories daily) for two to three months. The patient then slowly titrates down the dose. As data-supported regimens are lacking, we have the patient reduce the frequency gradually. Patients who do well with several months of daily vaginal boric acid then reduce to every other day for a few weeks, then once a week for a few weeks, and then stop. If symptoms recur, the process is repeated and the patient maintained on the lowest frequency of vaginal boric acid that suppressed symptoms.

●Drug safety – There are limited safety data on long-term use of vaginal boric acid, which may cause local irritation and has the potential for toxicity (including death) if taken orally by accident. Sex partners who have contact with vaginal boric acid could develop irritation or dermatitis of the exposed area, but the duration of risk following treatment is not known. While an observational study reported that 35 RVVC patients tolerated extended boric acid maintenance therapy (average duration 13 months) with minimal irritation, data from large trials are not available [83,84].

Gentian violet — Topical gentian violet was widely used prior to the availability of the topical azole intravaginal antifungal creams and suppositories. This agent has largely been abandoned because azole antimycotics are more effective (potent) [85] and because gentian violet is messy and inconvenient (eg, it permanently stains clothes). However, it is useful to treat vulvar itching and for occasional refractory cases of vulvovaginal candidiasis, especially those demonstrating azole resistance [86]. The drug is applied to affected areas of both the vulva and vagina daily for 10 to 14 days.

Vaginal nystatin — Vaginal nystatin may be used as an alternative to vaginal boric acid. Dosage is 100,000 units daily (as a pessary or suppository). Vaginal nystatin is given nightly for 14 nights for induction treatment. Patients with recurrent infection require maintenance therapy for six months or more. Dosing for all patients is the same as for pregnant persons. (See 'Pregnant' above.)

Therapies not in use

●Immunotherapy – Local vaginal hypersensitivity to C. albicans has been proposed as the cause of recurrent infection in some patients [87,88]. Immunotherapy of VVC for both prevention and treatment is a therapeutic approach that has been investigated [89]. 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 patients with RVVC could enhance or rectify tolerance/inflammation imbalance in the vagina [90].

●Imiquimod – Imiquimod, a topical Toll-like receptor 7 agonist that activates immune cells and is typically used to treat condylomata acuminata, has been used for RVVC in at least one case report [91]. Until larger studies supporting the safety and efficacy of this approach are available, we do not advise using imiquimod for RVVC. The impact of imiquimod treatment of condylomata acuminata on candidiasis is not known.

●Oral nystatin – Decreasing gastrointestinal Candida colonization by oral administration of nystatin does not prevent recurrent symptomatic vaginal infection [1].

UNIQUE POPULATIONS — Discussions addressing patients with fluconazole allergy, sex partners, lactating individuals, patients taking tamoxifen, male partners with postcoital symptoms, and patients with Candida as an incidental finding are presented in related content. (See "Candida vulvovaginitis in adults: Treatment of acute infection", section on 'Unique populations'.)

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)".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Vulvovaginal yeast infection (The Basics)")

●Beyond the Basics topic (see "Patient education: Vaginal yeast infection (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Definition and clinical points – Recurrent vulvovaginal candidiasis (RVVC) is defined as three or more episodes of symptomatic infection within one year. RVVC should be confirmed as the cause of symptoms prior to treatment and non-albicans Candida species should be identified, if present. (See 'Clinical points' above.)

●Treatment – The aims of treatment are initial relief and continued suppression of symptoms. Asymptomatic individuals with incidentally identified Candida species do not require treatment. (See 'Initial drug treatment' above.)

•Nonpregnant patients – For nonpregnant patients, we take the following approach (algorithm 1):  

-Choice of agent – We suggest oral fluconazole rather than other drugs (algorithm 1) (Grade 2C). Extended fluconazole treatment is associated with longer disease-free periods and longer time to relapse compared with placebo. Oteseconazole or ibrexafungerp are reasonable treatment alternatives but use is limited by restriction criteria, availability, and cost. Topical azole drugs have demonstrated efficacy but patients generally prefer extended treatment with oral than vaginal drugs. (See 'Fluconazole' above.)

-Dosing – For nonpregnant patients, we prescribe (algorithm 1):

Induction – Fluconazole 150 mg orally every 72 hours for three doses (ie, days 1, 3, and 7)

followed by

Maintenance – Fluconazole 150 mg orally once per week for six months

-Trial off medication – After six months, the patient stops the drug and observes for sustained remission or symptom relapse. Approximately half of patients will experience sustained remission. (See 'Empiric regimen' above.)

•Pregnant persons – Pregnant patients require both induction and maintenance suppressive treatment. For those with test-confirmed RVVC, we treat with extended courses of topical drugs only (algorithm 2). Longer courses of induction therapy followed by maintenance for the duration of pregnancy may be required to adequately suppress symptoms. (See 'Pregnant' above.)

●Extended versus episodic treatment – For individuals with confirmed RVVC due to suspected or proven Candida albicans, we suggest extended treatment to provide sustained symptom relief rather than treat individual episodes as they occur (Grade 2B). Patients generally prefer low-intensity maintenance therapy to treatment of every recurrence (which requires repeat testing and repeat induction therapy). (See 'Preference for extended versus episodic treatment' above.)

●Repeat testing for symptom recurrence – If symptoms recur, we repeat laboratory testing to confirm infection and identify species. Additionally, for patients with a history of fluconazole-resistant organisms, we repeat drug-susceptibility/resistance testing. As no treatment is clearly superior to another, we take the following treatment approach based on the assumption that most isolates are C. albicans and tailor treatment as isolate data become available. (See 'Empiric regimen' above.)

•Relapse off fluconazole maintenance – If RVVC is confirmed, we suggest 12 months or longer of oral fluconazole maintenance rather than six months of maintenance therapy (Grade 2C). In our experience, azole resistance is an unlikely mechanism of disease recurrence in patients who initially respond to extended fluconazole treatment but then recur off treatment (ie, fluconazole-dependent RVVC). (See 'Fluconazole' above.)

•Relapse during fluconazole maintenance – For patients with confirmed relapse during fluconazole maintenance who are consistently and correctly using the drug, isolate and drug -resistance testing guide treatment. Options include vaginal boric acid, ibrexafungerp, and oteseconazole. Drug selection is driven by patient preferences, contraindications, drug-drug interactions, availability, and cost.

-Non-albicans Candida species – Non-albicans Candida species most commonly include C. glabrata and C. krusei, but there are others. Patients with non-albicans species require a different treatment approach (algorithm 3). (See "Candida vulvovaginitis in adults: Treatment of acute infection", section on 'Non-albicans Candida species'.)

-Azole drug resistance – Azole resistance is determined with susceptibility tests measuring minimum inhibitory concentrations to various antifungal drugs. The rare patient with azole-resistant organisms is treated similarly to patients with non-albicans Candida infections (algorithm 3). (See "Candida vulvovaginitis in adults: Treatment of acute infection", section on 'Non-albicans Candida species'.)

●Fluconazole intolerance or allergy – Ibrexafungerp is the preferred treatment for patients with fluconazole allergy (uncommon) or intolerance. Alternately, individuals with fluconazole allergy, including angioedema and severe rash, can receive topical azoles (eg, miconazole or clotrimazole) or vaginal boric acid. (See "Candida vulvovaginitis in adults: Treatment of acute infection", section on 'Allergy to fluconazole'.)