Recurring vulvovaginal candidiasis

The therapeutic role of long-term flukonazole

Szerző:
Dr. Timea Tisza

Approximately 5% of all women are affected by recurring vulvovaginal candidiasis (RVVC), which is defined as at least 4 episodes of yeast-caused vulvovaginitis in a 12-month period. The factors leading to RVVC are complex and incompletely understood. Some data suggest that problems associated with locally acquired mucous membrane immunity and the cellular immune response predispose patients to RVVC, i.e., the symptomatic infection is more closely tied to factors of the host system, than to the characteristics of the pathogen.

The pathogen in most cases is Candida albicans. It is recommended that the diagnosis be confirmed by a fungal culture, and identification and resistance be examined in order to select the optimal treatment. The treatment consists of induction and maintenance phases. In the case of oral flukonazole therapy, 150 mg of flukonazole is administered every three days during the induction period (Days 1, 4 and 7), followed by a maintenance period of 6 months, during which 150 mg flukonazole is taken weekly. According to a degressive prophylactic regimen, the therapy is carried out over 12 months. A relapse rate of 30-50% is expected once any therapy is discontinued. The exploration and prevention of predisposing factors can lead long-term therapeutic success.

75% of all women will experience simple vulvovaginal candidiasis (VVC) at some time in their lifetime. In contrast, recurring vulvaginal candidiasis (RVVC) affects only 5% of pre-menopausal women. Patients with RVVC are often self-treated with over-the-counter topical treatments, and the long-term use of local vaginal antimycotic substances often lead to irritative inflammation of the vulva. Establishment of the exact diagnosis is therefore essential since, due to the assumed VVC, the infectious agent can be identified using mycological examination in only 28% of self-treated patients. Most patients therefore utilize these OTC treatments to no avail. There are more than 100 species and 200 strains of Candida. The most common pathogenic agent of VVC is Candida albicans. Recurring, chronic and persisting VVC are concepts that are often used interchangeably, whereas their appearance, occurrence and principles of treatment differ.

Recurring vulvovaginal candidiasis (RVVC)

Recurring VVC is characteristic during the reproductive stage of life, although it sometimes rears its head after menopause, most frequently in women who use estrogen supplements or who undergo immune-suppressive treatment. Recurring VVC is defined as more than 4 VVC episodes during a 12-month period, or at least 3 episodes which are not linked to the use of antibiotics. Symptom-free periods are typical between episodes. Induction and maintenance treatments are recommended with this clinical picture. Delayed relapses of more than 3 months may be treated as episodes.

Chronic VVC

Definition and treatment of chronic VVC is problematic. One possible definition of chronic VVC is that it does not respond to two weeks of the usual antimycotic treatment. In this clinical picture, the symptoms are often very mild, with flare-ups from time to time, primarily on certain days of the menstrual cycle. Patients primarily complain of premenstrual vulval itching and burning sensations. Systemic antibiotic treatment exacerbates the condition, and non-specific vulvitis is common.

We can distinguish between recurring and chronic infection with a post-treatment controlling culture, but this is questionable as Candida colonization can be demonstrated in many asymptomatic women. Long-term treatment or other therapy is recommended if the colonization persists in asymptomatic patients. If long-term local antimycotic treatment leads to vulval irritation, oral therapy may be more favorable.

Predisposing factors in VVC

Numerous factors are suspected of eliciting VVC episodes. Objective studies and results of analyses, however, are not available to support these suspicions. Among these factors are high carbohydrate diet, use of sanitary pads and tight, non-aerating clothing. Other factors which probably elicit VVC are broad-spectrum antibiotics, corticosteroid treatment, oral contraceptives with high hormonal content, spermicide creams and certain types of sexual behavior, such as oral sex (cunnilingus). It is not known, whether or not these triggering factors play a role in development of RVVC. A few publications report a correlation between atopic habitus, seasonal rhinitis and RVVC. According to recent studies, intrauterine and intravaginal contraceptive devices which can be used for one month can contribute to the development of VVC and RVVC through the formation of biofilm on their surface. The factors leading to RVVC are complex and poorly understood. According to our current understanding, predisposition of the host system and vaginal reinfection may be responsible for recurring VVC. Some authors suggest that problems associated with locally acquired mucous membrane immunity and the cellular immune response predispose patients to RVVC, i.e., the symptomatic infection is more closely tied to factors of the host system, than to the characteristics of the pathogen. Several studies refute the intestinal reservoir theory, because no difference was found between the patient and control groups in terms of the amount of intestinal yeast, and they also found that rectally sampled yeast cultures were negative in cases where relapses occurred following long-term ketonazole treatment.

The role of the male partner in RVVC is not clear. According to some studies, the treatment of the partner helps prevent relapses, and that the demonstration of Candida colonization and its treatment in the male sexual partner may be an important factor in prevention of RVVC. In another study, 80% of women with RVVC had partners who were not Candida-infected or were infected with another species of Candida. The results of other researchers indicate that the sexual behavior (oral sex, masturbation by hand with saliva as lubricant) is the salient factor in the development of recurring Candida vulvovaginitis, rather than the colonization by Candida of the male partner. Sexual practices can have a role in the development or prevention of RVVC; relapses can be prevented by preventing mechanical trauma during intercourse with the use of a generous amounts of lubricant and moderation physical activity.

According to official guidelines, sexual transmission is not the cause of RVVC and the treatment of the partner is recommended only if symptoms exist.

Studies addressing the “relapse or reinfection” dilemma show that the demonstrable strains of the virus tend to be the same in sequential episodes, indicating that colonization persists for some time.

Therapeutic principles

It is essential that the patient be informed about appropriate hygienic procedures. Excessive washing and the use of irritating products, washing mitts, sponges, cosmetic preparations (e.g., scented soaps, bubble baths, feminine deodorant sprays, talcum powders) should be avoided. Tight underwear made of synthetic fibers and pantyhose all cause increased perspiration and should also be avoided. Before recommending a therapeutic scheme, the patient’s preferences, practical and financial options should be considered, as well as psychological/psychosexual issues.

The effectiveness of oral and locally applied treatments is similar but, interestingly, women usually prefer the oral treatment in spite of the fact that it is more expensive and riskier in terms of systemic side effects. In addition, symptomatic treatment is favored over prophylactic, in spite of the fact that the number of relapses is much lower in the case of prophylactic therapy.

Timing of prophylactic therapy

The day of the menstrual cycle on which a relapse is most likely to develop is disputed. Clinical evidence is very inconsistent: some authors claim that the vaginal flora becomes instable around the time of menses, which predisposes the patient to VVC. Others claim that women are most sensitive in the luteal phase (from the 20th day onward), when there are high levels of both estrogen and progesterone. According to other theories, VVC develops most frequently from the 14th day on. In one study, treatments were undertaken during the 6 days of menses, while in another treatment was carried out after the menses. Treatment also depends on the susceptibility of the individual patient, but more studies are required to define the ideal timing of monthly prophylaxis.

Studies and therapeutic recommendations associated with the long-term (maintenance) treatment of recurring vulvovaginalis candidiasis with oral flukonazole

Most specialists agree that it is advisable to continue maintenance treatment for 6 moths following clinical remission.

One of the first and most thorough studies related to the long-term use of flukonazole was carried out by Sobel and colleagues in 2004 on a large number of patients. In a randomized, double-blind, placebo-controlled multicentric study, they treated and tracked 387 women with recurring vulvovaginal candidiasis for one year.

Clinical remission was achieved by administering 150 mg flukonazole three times at 72 hour intervals (induction treatment), followed by weekly150 mg doses of flukonazole or placebo for 6 months. Patients were tracked for another 6 months.

The study confirmed that weekly doses of flukonazole, taken for 6 months, effectively reduced the development of relapses.

In a 2008 study, Donders and colleagues relate their experience with a digressive prophylactic treatment regimen. 136 women with recurrent vaginal candidiasis were treated according the following regimen in the ReCiDiF study: all patients received a 600 mg induction dose in the first week, after which 117 women were treated with 200 mg flukonazole weekly for 2 months, 200 mg flukonazole every two weeks for 4 months and 200 mg flukonazole monthly for 6 months. Tracking of the patients consisted of wet mount microscopy and yeast culture of vaginal secretions monthly in the first six months, and every two months in the second six months. On a case by case basis, the therapy was only continued if both the microscopic and cultured results were negative. Among the women whose induction treatment was successful, 101 (90%) were healthy after 6 weeks of maintenance treatment and 80 women (77%) remained healthy one year later. The unsuccessfully treated patients generally had had more relapses before the treatment, had suffered from the disorder for a longer period of time and had been much more frequently infected with non-albicans candida strains than the successfully treated patients. No serious side effects were experienced. Individualized, digressive prophylactic maintenance oral flukonazole therapy was deemed to be effective in treating the relapses of recurring vulvovaginal candidiasis.

A further examination of the patients participating in the ReCiDiF study showed that there is a correlation between the polymorphism of the mannose-binding lectin (MBL) gene and resistance to flukonazole. MBL plays an important role in immediate identification of the pathogen. Numerous clinical data confirms that sensitivity to the pathogen increases significantly when this molecule is missing or is present at low levels. Significant variations can occur in the amount of MBL in the serum of various individuals; the difference in concentration can reach a thousand-fold. Distinction is made between phenotypes on the basis of low, medium and high levels.

Donders et al also found that polymorphism of the MBL2 coded 54 gene was more frequent in patients who suffered from RVVC than in control individuals. The presence of the B allele was associated with a better responsiveness to maintenance flukonazole treatment, than in patients who did not display this polymorphism. The authors concluded that the RVVC which develops as a result of low MBL levels is more effectively treated with antimycotics than those in which the disorder develops as a result of different mechanisms.

IDSA (Infectious Diseases Society of America) guideline

Azole-resistant Candida albicans infections are extremely rare. Following treatment of the eliciting factors (e.g., diabetes), a two week induction treatment followed by at least 6 months of suppressive treatment is recommended. The most convenient and best tolerated therapy is the weekly 150 mg oral flukonazole treatment, which is effective in more than 90% of all patients. Following cessation of the treatment, a relapse rate of 40-50% is to be expected. If the flukonazole treatment cannot be carried out, 2×200 mg or 1×500 mg clotrimazole can be applied locally weekly, or another intermittent azole therapy used.

CDCguideline

The CDC guideline emphasizes, that a sample for culture should be taken from RVVC patients to confirm the clinical diagnosis and to identify the rare species, including non-albicans species, with special attention to Candida glabrata (which does not form pseudophyphae or hyphae, and are therefore difficult to indentify by microscope). Candida glabrata and other non-albicans Candida species can be demonstrated in 10-20% of RVVC patients. Standard antimycotic treatments of these species are not as effective as for Candida albicans.

Each episode caused by Candida albicans responds well to short-term local or oral azole treatment. Nevertheless, in the interest of improving clinical and microbiological effectiveness, some specialists revomemnd a longer induction treatment before beginning the longer-term maintenance phase of treatment. The induction treatment consists of 7-14 days of local treatment, or oral treatment on the 1st, 4th and 7th days of 100 mg, 150 mg, or 200 mg flukonazole tabets each in the interest of achieving mycotic remission.

The first line of maintenance treatment is a weekly dose of 100 mg, 150 mg or 200 mg of flukonazole for 6 months. In the event that this treatment is not practical, 2×200 or 1×500 mg clotrimazole treatment may be considered. A relapse rate of 30-50% is to be expected following cessation of treatment. Azole-resistant Candida albicans occurs rarely in vaginal isolations, making resistance analysis unncessary.

Hungarian STD procedural guideline on RVVC

Treatment timed to menstrual cycle (beginning on the first day of menses) is recommended in the case of frequent relapses.

Therapeutic regimens utilized in Hungary

The prevalent therapeutic regimen for the treatment of recurring yeast-caused vulvovaginitis: 150 mg flukonazole or 2×200 mg itrakonazole weekly during the 1st month, every two weeks during the 2nd month for 3 months, monthly from the 5th month on.

Personal experience

A total of 499 vaginal specimens were taken for mycologic analysis from women at the medical offices of Medartis Bt and Körúti Orvosi Centrum for diagnostic or screening tests between 01.01.2007 and 04.30.2009.

The samples were transported at room-temperature to the laboratories of Laborigo Kft and Corden International Kft (TRANSWAB for aerobes and anaerobes MW171 Transport Medium Charcoal (MW and E, England), cultured on Sabouraud agar (supplemented with streptoymcin and penicillin) at 37° C for 5 days.

Identification was carried out based on the color reaction on CHROMagar Candida medium (BD Germany). This was supplemented with a microscopic morphological examination following 48 hours culture on corn agar medium and with sugar assimilation and fermentation trials.

The resistance test was carried out on Mueller-Hinton 2% glucose, 0.5 ug/ml methylene blue culture medium innoculated with 0.5 McFarland fungal inoculum, with application of Neo-Sensitabs (Rosco Diagnostics, Denmark), at 35°C for 20-24 hours. Assessment based on diameter of zones, according to the manufacturer’s instructions.

There were 173 which were positive for yeast (173/499 = 34.6%). The 173 positive samples were sourced from 149 patients, of which 24 had recurring infection (24/499 = 5%).

Of the 173 positive vaginal samples, 92.4% (160/173) were Candida albicans, 2% (4/173) were Candida krusei, 4% (7/173) were Candida glabrata, and 1% (2/173) were Saccharomyces cerevisiae.

Resistance to 5 antimycotics was tested: fukonazole, econazole, ketokonazole, itrakonazole, nytstatin. All 160 Candida albicans cultures were 100% sensitive to all of these antimycotics. The 4 Candida krusei cultures were resistant to flukonazole, while of the 7 Candida glabrata cases, 6 were moderately sensitive to flukonazole, 1 was resistant. The 2 Saccharomyces cerevisiae were sensitive to all 5 antimycotics.

Of the 149 positive yeast cases, recurring vulvovaginalis candidiasis was determined in 24 cases. 13 of these patients were treated according the therapeutic regimen most frequently used in Hungary, i.e, 150 mg flukonazole weekly for 1 month, every two weeks for 3 months, and monthly from the 5th month on. The regimen was effective in 8 patients, of whom 3 reported recurring symptoms upon cessation of the treatment. The regimen was ineffective in 5 patients, 2 of whom did not even respond to the weekly does of 150 mg flukonazole; they were subsequently treated with itrakonazole, which proved to be effective. In 3 other patients, symptoms and complaints occurred when flukonazole was taken in shorter intervals than 2 weeks.

Summary

The diagnosis of recurring yeast-caused vulvovaginitis must be underpinned in every case with a fungal culture followed by identification of the pathogen,;resistance-testing of the non-albicans strains is also recommended. The following regimen for treating RVVC is recommended: 150 mg oral flukonazole every three days (1st, 4th and 7th days) to begin (induction period), followed by weekly doses of 150 mg flukonazole for 6 months (maintenance treatment).

If we wish to use the 12-month digressive regimen, a culture must be examined following the induction treatment to ensure the efficacy of the therapy.

Treatment of the sexual partners is indicated only if there are symptoms. Treatment should be supplemented with guidelines on lifestyle and the possible underlying illnesses and predisposing factors should be researched and treated.

Acknowledgements

I am thankful to Dr. Mónika Pásztor and Judit Lukács (Corden International Kft) and Dr. Krisztina Latkóczy (LabOrigo Kft) for identifying yeast and carrying out the sensitivity analyses.

Heartfelt gratitude to Dr. Viktória Várkonyi and Dr. Gyula Simon for their assistance in editing the manuscript.