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Recurrent Candidiasis

Treatments of vulvovaginal candidiasis

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An episode of vulvovaginal candidiasis(VVC) can be inconvenient, but recurrent vulvovaginal candidiasis (RVVC) can be life altering. RVVC is defined as four or more episodes of VVC in a year. An estimated 75% of women experience one episode of VVC in their lifetime, typically in their reproductive years.1 RVVC affect up to 8% of premenopausal women.2 VVC costs approximately $1 billion a year in terms of diagnosis and treatment charges and lost productivity.3

Background

RVVC can be caused by several species of Candida organisms. The most common species is Candida albicans. Women with RVVC have a slight increase in non- C albicans species; Candida glabrata is the second most common one isolated. The clinical signs and symptoms are identical for all Candida species, as well as other vulvovaginal infections. This makes an accurate diagnosis difficult.4

Understanding the exact organism causing the infection is important to direct appropriate treatment. Non-C albicans species have decreased sensitivity to the complete class of azoles and polyene antifungal treatments, which are the most common treatments for VVC.5 Without identification of the specific species, patients may not obtain effective treatment to eliminate the infection, resulting in recurrence.

The pathogenesis of VVC is not completely understood. Candida is thought to gain access to the vaginal environment through the perianal region. The vagina normally has effective anti-Candida defense mechanisms that allow the persistence of Candida in an asymptomatic state. Something must then change in the host environment for the organism to produce pathological effects.3

Sexual transmission may play a role in the source of infection. An estimated 20% of partners of infected women have Candida on their penises.3 But evidence does not show improved recurrence rates when asymptomatic sexual partners of women with RVVC are treated.1

Several studies suggest that genetics increase a woman's susceptibility to RVVC. Donders et al6 discovered that one codon change on the MBL2 gene increased the occurrence of RVVC. MBL is the protein that triggers the initial immune response to Candida. The study documented a threefold increase in MBL2 polymorphisms in women with RVVC compared to controls.6 Other studies have shown that VVC occurs more often in black women and women with blood type ABO-Lewis non-secretor phenotype. Women with diabetes are also more prone to Candida colonization. More specifically, women with type 2 diabetes are more frequently colonized with Candida glabrata. Women without diabetes have also reported an increase in RVVC incidence when consuming a diet high in refined sugars.3

Impaired immune function can also predispose a woman to RVVC. Allergies are thought to increase the frequency of VVC due to a defective CD4 T helper 1 type cell-mediated immune reactivity or to an aggressive response by polymorphonuclear neturophils.7 Women with HIV and other immunosuppressive diseases, such as systemic lupus erythematous, also have an increase in RVVC due to a deficiency in cell-meditated immunity.8 One study found that women who had RVVC had decreased morning rise cortisol levels. This is an impaired immune response due to chronic stress and may be influential in the recurrence of VVC.9

Antibiotics may contribute to vaginal colonization of Candida because they eliminate the natural protective flora, allowing the overgrowth of yeast and an estimated colonization increase from 10% to 30%. Finally, estrogen may increase VVC infections by allowing yeast to adhere to vaginal epithelial cells. It is through this mechanism that VVC infections increase during pregnancy. Despite frequent anecdotal reports, the evidence that colonization increases with estrogen-containing hormonal contraceptives is equivocal.3

Recognizing the clinical signs and symptoms is the first step in diagnosis. As mentioned, VVC and RVVC have identical clinical scenarios. Symptoms can include vulvar itching and soreness, vaginal discharge, dyspareunia and dysuria. Clinical findings include erythema of the vagina and vulva, vaginal fissures and edema, white cheese-like or watery purulent discharge, and satellite lesions.7 A vaginal pH swab will show normal pH levels, and a wet smear with KOH will feature pseudohyphae or budding yeast. However, an estimated 50% of patients have negative microscopy.3 Vaginal cultures should be obtained to identify the organism. Commonly, providers fail to include a culture and RVVC is misdiagnosed. When clinical evidence of RVVC is present, a woman should have two separate negative Candida cultures at two separate appointments to effectively rule out RVVC.4

After reaching an accurate diagnosis, understanding the proper treatment is the next step. The patient should be educated that the main goal of treatment is to control symptoms and recurrences, not to cure. This will allow the patient to better manage her expectations. Educating women about the previously mentioned predisposing factors and behaviors can identify possible changes she can make to eliminate recurrences. Unfortunately, many women have no obvious predisposing causes.4

Treatment

The recommended treatment for C albicans that causes RVVC is to start with an antifungal induction and then initiate a maintenance regimen. It is important to first control the initial infection symptoms. After symptoms have subsided, the patient should be cultured for C albicans. If the results are negative, a 6-month maintenance regimen can be initiated. Without the maintenance regimen, approximately half of women with RVVC have another clinical infection within 3 months.8

An initial induction treatment for 7 to 14 days with an intravaginal azole or nystatin is recommended. Another option is oral fluconazole (100, 150 or 200 mg) every third day for a total of three doses.10, 11 Oral and topical treatments are equally effective.8 Therefore, patient preference and adherence help determine which therapy regimen is best.

Maintenance therapy should be started once the patient is in mycological remission. Oral fluconazole (100, 150 or 200 mg) once a week for 6 months is the suggested first-line treatment.10, 11 Other regimens include ketoconazole 100 mg daily or once-weekly clotrimazole 500-mg suppository. Both regimens can prevent breakthrough recurrences, but fluconazole and clotrimazole have better safety profiles.3

One study involving decreasing doses of fluconazole for maintenance therapy had optimistic results. Women were started on fluconazole 200 mg weekly for 2 months, then 200 mg biweekly for 4 months, followed by 200 mg monthly for 6 months. After 1 year, 77% of the women were disease-free. This was compared to a study of a weekly fluconazole 6-month regimen. After 1 year, only 57% of women were disease-free.12 During pregnancy, topical treatments for 7 days is reccomended.10, 11

After completion of maintenance therapy, an estimated 30% to 50% of women are likely to relapse.10 Azole antifungals are fungistatic, not fungicidal, therefore Candida may not be completely eliminated. After maintenance therapy is completed, observe the patient for relapses. If a recurrence is proven to be RVVC and caused by the same organism, initiate induction therapy again and follow with a 12-month maintenance treatment. A small number of women may need to be on maintenance therapy for several years to control infections.4

Despite the recommended guidelines of induction therapy followed by maintenance therapy, a recent survey of providers showed a wide variation in treatment approaches. Only 50% of responders followed current guidelines and only 57% reported doing confirmatory diagnostic testing. This poor adherence may be from a lack of confidence in the guidelines, hence the high relapse rates of RVVC. This further highlights the difficulty in managing women with RVVC and the need for an effective long-term treatment.13

The best treatment approach to non- C albicans, most commonly C glabrata infections, is not clear. As previously mentioned, C glabrata species are less susceptible to azoles and polyene antifungals and are slightly more common in women with RVVC.5 Short courses of these treatments should be avoided once there is a confirmatory diagnosis.

A recent literature review of boric acid treatment of RVVC found that 600 mg of boric acid in vaginal suppositories twice a day for 14 days was an effective option.14 Reported side effects were a local burning sensation, watery discharge and erythema.14 Boric acid suppositories are only available at compounding pharmacies. However, patients can make the capsules themselves, for approximately 30 cents for a 2-week treatment course. Pharmacies charge $10 to $20 for the same treatment course.15

The long-term safety of boric acid is unknown. Long-term use is currently advised against since it may cause systemic absorption and toxicity. Intravaginal use during the first trimester of pregnancy should be avoided because a teratogenic effect cannot be ruled out.14

The CDC recommends initial therapy for C glabrata using a topical 7- to 14-day treatment with a non-fluconazole azole drug. To treat recurrence, it recommends 600 mg of boric acid in a gelatin capsule vaginally once daily for 2 weeks.10 Boric acid treatment is also supported by ACOG. When boric acid regimens fail, ACOG recommends referring to a specialized practitioner.11

One study examined flucytosine for the treatment of C glabrata when boric acid failed. The retrospective review found a 90% cure rate after only a 2-week course with 5 grams of intravaginal flucytosine. Although this is an effective option, flucytosine is not widely available and is more expensive than boric acid. Long-term therapy with flucytosine is not recommended because it may cause bone marrow and gastrointestinal toxicity.5

CAM Therapies

With high recurrence rates and repetitive failed treatments, women can become frustrated with standard medical treatments and often look to alternative methods. A recent survey determined that 88% of providers were aware of their patient's complementary and alternative medicine (CAM) use but only 50% recommended CAM. When CAM was recommended, it was most commonly as a supplement to conventional treatment.16 It is important for providers to become familiar with CAM treatments in order to best inform patients.

Unfortunately, evidence about the effectiveness of CAM treatments is not substantial. Probiotics like L acidophilus are popular but have mixed results. Jurden et al17 reviewed L acidophilus effectiveness in bacterial vaginosis (BV) and VVC. Some studies showed that consuming L acidophilus yogurt decreased BV episodes but not VVC. It also included a smaller study with low continuation rates that showed a decrease in VVC recurrences with increased yogurt consumption. Other CAM therapies had no effects on BV or VVC. Although evidence is inconclusive, L acidophilus does not appear harmful and could possibly benefit patients.17

Changes in a woman's hygienic practices may help eliminate recurrences. Wiping from front to back after toileting is always a recommended good practice but not proven. Avoiding tight clothing and wearing only cotton underwear may also be helpful. There are also reports of organic sanitary napkin use decreasing RVVC episodes. Other studies recommend no panty liner use at all.7

Although evidence is varied, simple behavioral changes may help decrease recurrences and have no negative consequences. An interesting study looked at RVVC and the use of Dermasilk briefs. Dermasilk is a fabric that contains an antimicrobial agent; the briefs are available online for about $50 a pair and have been used successfully with other dermatologic disorders. When used in conjunction with fluconazole 150 mg/week for 6 months, Dermasilk users had a statistically significant decrease in erythema, itching, burning and recurrences compared to women who wore cotton underwear.18

RVVC is a complex disorder. A correct diagnosis is imperative to determine the best treatment options. If conventional treatments are not successful, CAM options may provide unexpected relief of symptoms. More research on unconventional treatment options is needed, as are improved treatment guidelines.  

Amber Tabor is a women's health nurse practitioner at an OB/GYN practice in Temecula, Calif.                                                                                                        

References

1. Watson C, Calabretto H. Comprehensive review of conventional and non-conventional

methods of management of recurrent vulvovaginal candidiasis. Austr NZ J Obstet Gynaecol. 2007;47(4):262-272.

2. Beikert FC, et al. Recurrent vulvovaginal candidosis: focus on the vulva. Mycoses. 2011;54(6):e807-e810.

3. Sobel JD. Vulvovaginal candidosis. Lancet. 2007;369(9577):1961-1971.

4. Sobel JD. Management of patients with recurrent vulvovaginal candidiasis. Drugs. Year;63(11):1059-1066.

5. Sobel JD, et al. Treatment of vaginitis caused by Candida glabrata: use of topical boric acid and flucytosine. Am J Obstet Gynecol. 2003;189(5):1297-1300.

6. Donders G, et al. Mannose-binding lectin gene polymorphism and resistance to therapy in women with recurrent vulvovaginal candidiasis. BJOG. 2008;115(10):1225-1231.

7.Watson C. Not that itch again: dealing with recurrent vulvovaginal candidiasis. Nurs Women's Health. 2008;12(3):216-223.

8. Maintenance suppressive azole antifungal regimens are a major advance in controlling

recurrent vulvovaginal candidiasis. Drugs & Therapy Perspectives. 2004;20(7):7-11.

9. Ehrström S, et al. Signs of chronic stress in women with recurrent candida vulvovaginitis. Am J Obstet Gynecol. 2005;193(4):1376-1381.

10. Disease Characterized by Vaginal Discharge, Vulvovaginal Candidiasis. CDC 2010 Sexually Transmitted Diseases Treatment Guidelines. http://www.cdc.gov/std/treatment/2010/vaginal-discharge.htm

11. Vaginitis. ACOG Practice Bulletin No. 72. Obstet Gynecol. 2006;107(5):1195-1206.

12. Donders G, et al. Individualized decreasing-dose maintenance fluconazole regimen for recurrent vulvovaginal candidiasis (ReCiDiF trial). Am J Obstet Gynecol. 2008;199(6):613.e1-9.

13. Watson C, Pirotta M. Recurrent vulvovaginal candidiasis- current management. Austr Fam Physician. 2011;40(3):149-151.

14. Iavazzo C, et al. Boric acid for recurrent vulvovaginal candidiasis: the clinical evidence. J Women's Health. 2011;20(8):1245-1255.

15. Prutting SM, Cerveny JD. Boric acid vaginal suppositories: a brief review. Infect Dis Obstet Gynecol. 1998;6(4):191-194.

16. Watson C, et al. Use of complementary and alternative medicine in recurrent vulvovaginal candidiasis-Results of a practitioner survey. Complement Ther Med. 2012;20(4):218-221.

17. Jurden L, et al. Clinical Inquiry: Can probiotics safely prevent recurrent vaginitis? J Fam Pract. 2012;61(6):357-368.

18. D'Antuono A, et al. Use of Dermasilk briefs in recurrent vulvovaginal candidosis: safety and effectiveness. Mycoses. 2012;55(3):e85-e89.




     

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