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Vulvovaginal candidiasis (VVC) is a common condition, and an estimated 75% of all women will experience an infection with candida yeast during their lifetime. Ninety percent of these infections are caused by Candida albicans.(3) The availability of nonprescription products for treatment of VVC allows pharmacists to play a role in counselling patients about when and how to self-treat and when to see a physician for evaluation or follow-up. Pharmacists must have an understanding of VVC, particularly its treatment options, so that they can make evidence-based recommendations to both patients and physicians.
Pregnancy: Pregnant women may also be predisposed to VVC. It is thought that the increased susceptibility of the vagina to candida infection during pregnancy is related to elevated levels of glycogen and reproductive hormones. Candida strains have been cultured from the vagina in 10% to 20% of pregnant women, and the incidence of symptomatic VVC is two times higher in pregnant women than in women who are not pregnant.(7) Gestational diabetes may also predispose a pregnant woman to VVC.
Topical agents have been recommended as first-line therapy for treatment of VVC in pregnancy.(5)(8)(9)(12) A systematic review found that triazole antifungals (e.g., terconazole) are as effective as imidazole antifungals (e.g., clotrimazole) when used during pregnancy.(13) Furthermore, data from five comparative studies suggested that imidazole antifungals are more effective than nystatin in the treatment of VVC in pregnancy.
By Suzanne I. Singh, PharmD
Vulvovaginal candidiasis (VVC) is a common condition, and an estimated 75% of all women will experience an infection with candida yeast during their lifetime. Ninety percent of these infections are caused by Candida albicans.(3) The availability of nonprescription products for treatment of VVC allows pharmacists to play a role in counselling patients about when and how to self-treat and when to see a physician for evaluation or follow-up. Pharmacists must have an understanding of VVC, particularly its treatment options, so that they can make evidence-based recommendations to both patients and physicians.
Symptoms can mask STD
An accurate diagnosis of VVC is essential to initiate appropriate treatment. A first episode with signs and symptoms suggestive of VVC should always be confirmed by a physician so that women are accurately diagnosed and, if needed, treated for a sexually transmitted disease such as herpes, human papilloma virus, gonorrhea, or chlamydia.
It may also be prudent to consider referral to a physician for women with recurrent infections. One study showed that only one third of women who self-diagnosed VVC actually met the diagnostic criteria for the condition, and that women with a previous diagnosis of VVC were no more accurate in diagnosing subsequent infections than women without a previous diagnosis.(6)
Although VVC is not a sexually transmitted disease, women may benefit from their physician's guidance if cross-transmission of C. albicans from the sexual partner is a possibility.
Goals of treatment
The treatment of VVC with medication is aimed at resolving symptoms, eradicating infection, and preventing complications and recurrence.
A variety of antifungal agents have been used (see Table 2). Imidazole antifungals include clotrimazole, miconazole, and tioconazole, and triazole antifungals including terconazole and fluconazole. Fluconazole is available orally, whereas the other azole antifungals are used intravaginally. Nystatin, a polyene antifungal agent, and boric acid have also been used intravaginally in the management of VVC.(7)(8)
The choice of antifungal for both uncomplicated and complicated forms of VVC should take into account the comparative efficacy, adverse effects, interactions, convenience, and cost of the available agents, as well as the woman's preference (so as to maximize adherence).
Uncomplicated VVC
Treatment with azoles results in relief of symptoms and negative results on culture in 80% to 90% of women with uncomplicated VVC who complete therapy.(9) A review of 17 clinical trials found no statistically significant differences between oral and intravaginal azole antifungal treatments for clinical or mycological cure of uncomplicated VVC at short-term and long-term follow-up.(10) Similarly, no statistically
Suzanne I. Singh, PharmD, is Clinical Pharmacist, Primary Care, at Mount Sinai Hospital in Toronto. She wrote this paper as a Doctor of Pharmacy student at University of Toronto. She thanks Debora Kwan, MSc, for her guidance. significant differences in clinical or mycological cure rates were observed between or within oral and intravaginal antifungal formulations administered as single-dose or multiple-dose treatments.(10)
Intravaginal nystatin may also be used for VVC, but it is generally considered a second-line agent since it is less active against C. albicans than the azole antifungals.(4) Intravaginal administration of boric acid capsules has also been effective, with cure rates of up to 90%, but this is generally considered a second-line agent because the capsules are not as readily available as the other drugs. Boric acid tends to be reserved for resistant VVC, for which it is very effective.(8)
Complicated VVC
[Graph Not Transcribed]
Diabetes mellitus: Diabetes mellitus may predispose women to VVC, and symptomatic infections may reflect uncontrolled diabetes.(7) Increased glucose levels in the genital tissues enhance yeast adhesion and growth, and vaginal epithelial cells have a greater propensity to bind to C. albicans in women with diabetes than in those without this condition.(11) There is a paucity of clinical trials specifically examining the treatment of VVC in women with diabetes, so treatment recommendations have been extrapolated from evidence in women without diabetes.(11) It is thought that women with uncontrolled diabetes may not respond as well to short-term therapies; efforts to improve glycemic control have been recommended, and a more prolonged duration of antifungal therapy (i.e., seven to 14 days) may be necessary.(9)
Pregnancy: Pregnant women may also be predisposed to VVC. It is thought that the increased susceptibility of the vagina to candida infection during pregnancy is related to elevated levels of glycogen and reproductive hormones. Candida strains have been cultured from the vagina in 10% to 20% of pregnant women, and the incidence of symptomatic VVC is two times higher in pregnant women than in women who are not pregnant.(7) Gestational diabetes may also predispose a pregnant woman to VVC.
Topical agents have been recommended as first-line therapy for treatment of VVC in pregnancy.(5)(8)(9)(12) A systematic review found that triazole antifungals (e.g., terconazole) are as effective as imidazole antifungals (e.g., clotrimazole) when used during pregnancy.(13) Furthermore, data from five comparative studies suggested that imidazole antifungals are more effective than nystatin in the treatment of VVC in pregnancy.
Feature Uncomplicated VVC[*] |
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Severity Mild or moderate |
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Frequency Sporadic |
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Organis [Symbol Not Transcribed] [eta] Candida albicans |
|
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Host Normal |
|
|
Feature Complicated VVC[[Symbol Not Transcribed] [dagger]] |
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Severity Severe |
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Frequency Recurrent |
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Organis [Symbol Not Transcribed] [eta] Non-albicans species |
of Candida |
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Host Abnormal |
(e.g., uncontrolled |
diabetes, pregnancy) |
[*] A woman with all of these features is defined as having uncomplicated VVC
[[Symbol Not Transcribed] [dagger]] A woman with any of these features is defined as having complicated VVC
Drug Formulation Strength Usual dosage[*] |
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Nonprescription |
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Clotrimazole (e.g., Canesten) Vaginal cream 1% One applicatorful vaginally HS [Symbol Not Transcribed] [times] 6 nights |
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2% One applicatorful vaginally HS [Symbol Not Transcribed] [times] 3 nights |
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10% One applicatorful vaginally HS [Symbol Not Transcribed] [times] 1 night |
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Vaginal tablet 100 mg One tablet vaginally HS [Symbol Not Transcribed] [times] 6 nights |
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200 mg One tablet vaginally HS [Symbol Not Transcribed] [times] 3 nights |
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500 mg One tablet vaginally HS [Symbol Not Transcribed] [times] 1 night |
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Topical cream[[Symbol Not Transcribed] [dagger]] 1% Apply small amount to the vulva up to BID PRN [Symbol Not Transcribed] [times] 7 days |
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Miconazole (e.g., Monistat) Vaginal cream 2% One applicatorful vaginally HS [Symbol Not Transcribed] [times] 6 nights |
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Vaginal suppository 100 mg One suppository vaginally HS [Symbol Not Transcribed] [times] 6 nights |
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Vaginal ovule 400 mg One ovule vaginally HS [Symbol Not Transcribed] [times] 3 nights |
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1200 mg One ovule vaginally HS [Symbol Not Transcribed] [times] 1 night |
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Topical cream[[Symbol Not Transcribed] [dagger]] 2% Apply small amount to the vulva up to BID PRN [Symbol Not Transcribed] [times] 7 days |
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Tioconazole (e.g., Gynecure) Vaginal ointment 6.5% One applicatorful vaginally HS [Symbol Not Transcribed] [times] 1 night |
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Vaginal ovule 300 mg One ovule vaginally HS [Symbol Not Transcribed] [times] 1 night |
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Topical cream[[Symbol Not Transcribed] [dagger]] 1% Apply small amount to the vulva up to BID PRN [Symbol Not Transcribed] [times] 7 days |
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Boric acid (compounded Vaginal capsules 600 mg One capsule vaginally once or twice daily [Symbol Not Transcribed] [times] 14-28 days |
by pharmacy) |
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Prescription |
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Nystatin (e.g., Mycostatin) Vaginal cream 25,000 units/g Apply 4 g vaginally HS [Symbol Not Transcribed] [times] 14 nights |
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Terconazole (e.g., Terazol) Vaginal cream 0.4% One applicatorful vaginally HS [Symbol Not Transcribed] [times] 7 nights |
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0.8% One applicatorful vaginally HS [Symbol Not Transcribed] [times] 3 nights |
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Vaginal suppositories 80 mg One suppository vaginally HS [Symbol Not Transcribed] [times] 3 nights |
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Fluconazole (e.g., Diflucan) Oral tablet 150 mg One tablet orally [Symbol Not Transcribed] [times] 1 dose |
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HS = at bedtime, BID = twice daily, PRN = as needed. |
[*] Medication should be continued throughout menstruation; consult product monographs for further information
[[Symbol Not Transcribed] [dagger]] Available in combination packs
Overall, single-dose azole treatment seemed as effective as three- and four-day azole treatment courses.(13) However, in two of the trials reviewed, which involved 81 women treated with azole antifungals, a seven-day treatment was more effective than a four-day treatment and as effective as a 14-day treatment. These data would suggest that a treatment course lasting approximately seven days may be preferred for pregnant women being treated with azole antifungals.(13)
The safety of topical antifungals in pregnancy has been reviewed (see Table 3). Available data suggest that nystatin is the safest alternative during all trimesters of pregnancy because of minimal systemic absorption. Retrospective and prospective studies suggest that azole antifungals may be safe during pregnancy, although most manufacturers caution against their use during the first trimester because of limited experience.(13) Fluconazole is teratogenic and embryotoxic at high doses in rats and is assigned to risk category C by US Food and Drug Administration (category C means that either animal studies indicate a fetal risk and there have been no controlled studies of women, or there are no available reports of studies of women or animals). Observational evidence from humans and animals suggests a dose-related risk of teratogenicity in humans.(13) The benefits and risks of therapy with fluconazole must be weighed carefully because of the limited number of controlled studies in pregnant women.
Drug FDA Pregnancy Systemic Embryotoxic Human Trials |
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Risk Category Absorption in Animals |
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Azole antifungals |
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Clotrimazole B Up to 3% to 10% Yes Safe in second and third trimesters |
(e.g., Canesten) |
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Miconazole C 1.4% Yes Possible increased risk of |
(e.g., Monistat) spontaneous abortion |
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Tioconazole C Negligible Yes No data |
(e.g., Gynecure) |
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Terconazole C 5% to 16% Yes Safe in second and third trimesters |
(e.g., Terazol) |
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Polyene antifungals |
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Nystatin A Negligible No data Safe in all trimesters |
(e.g., Mycostatin) |
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FDA = US Food and Drug Administration. |
Recurrent VVC
Fewer than 5% of women experience recurrent VVC (RVVC), defined as the occurrence of at least four specific episodes within one year or at least three episodes unrelated to antibiotic therapy within one year.(14) Species such as Candida glabrata and Candida parapsilosis are responsible for up to one-third of recurrent infections.(3)
Each individual episode of RVVC caused by C. albicans responds well to short-duration oral or topical azole therapy. However, to maintain clinical and mycological control, specialists recommend a longer duration of initial therapy (e.g., seven to 14 days of topical therapy or repeat dose of oral fluconazole three days after the first dose) to achieve mycological remission. Then, a maintenance antifungal regimen may be initiated. Suitable maintenance regimens include weekly administration of fluconazole or daily therapy with any topical azole.(14)
Antifungal resistance, which can lead to treatment failure, may be suspected in women experiencing RVVC. The options for managing resistance are limited. In general, agents with a different mechanism of action should be considered. Boric acid for the treatment of RVVC has been studied, and there is limited evidence for the use of nystatin.(14)
Adverse effects
The most common adverse effects associated with intravaginal azoles and nystatin are local irritation, stinging, burning, itching, and pain. These reactions may be related to the vehicle and not the actual drug itself.(7) Irritation may be a dose-related effect and may be reduced by choosing a lower-strength formulation administered over a longer period.(8)
Irritation tends to be more common with intravaginal administration of boric acid than with other intravaginally administered drugs.(8) Single-dose oral fluconazole is generally well tolerated, the most common adverse effect being stomach upset. Other, less common adverse reactions include dry mouth, rash, dizziness, and headache.(7)
Interactions
Topical formulations such as intravaginal creams and suppositories are oil-based and thus may weaken latex condoms and diaphragms.(9) This increases the chances of a condom breaking during sexual intercourse, and the rubber in cervical caps or diaphragms may break down faster and wear out sooner. Women are generally advised to wait three days after treatment with an oil-based intravaginal product before using a condom or diaphragm;(15) they should refer to condom product labelling for further information.
Although uncommon, a clinically significant interaction between topical miconazole and warfarin may occur. Although there is minimal systemic absorption of miconazole in healthy women of child-bearing age, it is hypothesized that vaginal atrophy may be partly responsible for altered systemic uptake of this drug.(16)(17) Miconazole may inhibit cytochrome P450 3A4 and 2C9 isoenzymes and thus inhibit the metabolism of warfarin. This interaction may result in elevated international normalized ratios (INRs) and increase the risk of bleeding in women taking warfarin. If this drug combination is used, consideration should be given to increasing the frequency of INR monitoring (e.g., every two days), and the woman should monitor for symptoms of bleeding.(8)
Fluconazole is another drug that inhibits cytochrome P450 3A4 and 2C9 isoenzymes, and clinically significant interactions between fluconazole and drugs metabolized via this route (e.g., warfarin) may therefore occur.(7) Clinically significant hypoglycemia may be precipitated by the use of fluconazole in combination with oral hypoglycemic agents; one death has been reported because of hypoglycemia occurring in association with combined use of fluconazole and glyburide. In pharmacokinetic studies, clinically significant hypoglycemia was observed when fluconazole was used for a period of seven days. Blood glucose concentrations should be monitored if fluconazole is used concomitantly with oral sulfonylureas for a prolonged duration.(18)
Summary
Optimal treatment for VVC depends on whether the infection is uncomplicated or complicated. (A suggested approach to managing VVC is illustrated in Figure 1.)
Symptoms
[Graph Not Transcribed]
- Mild to severe vaginal itching
- Abnormal vaginal discharge -- minimal, "cheese-like" material, watery secretion
- Acute discomfort or vulvar, labial, or vaginal pain
Diagnosis
- Symptoms as above
- Observation of yeast on microscopy of vaginal fluid(1)
VVC is uncomplicated (approximately 90% of cases) or complicated (approximately 10%) (see Table 1).(2)
FIRST-LINE AGENTS
On the basis of the evidence to date, azole antifungals may be considered as first-line agents for uncomplicated VVC, topical preparations being as effective as oral formulations, regardless of the duration of therapy.
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(4) Marrazzo J. Vulvovaginal candidiasis. BMJ 2002;325:586.
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(11) Bohannon NJ. Treatment of vulvovaginal candidiasis in patients with diabetes. Diabetes Care 1998;21:451-6.
(12) King CT, Rogers PD, Cleary JD, et al. Antifungal therapy during pregnancy. Clin Infect Dis 1998;27:1151-60.
(13) Young GL, Jewell D. Topical treatment for vaginal candidiasis (thrush) in pregnancy [Cochrane Review]. In: The Cochrane Library, Issue 3, 2002. Oxford: Update Software.
(14) Ringdahl E. Treatment of recurrent vulvovaginal candidiasis. Am Fam Physician 2000;61:3306-12.
(15) Topical azoles. USPDI information for patients [product information]. Available from: http://www.drugs.com (accessed May 2003).
(16) Murty M. Miconazole-warfarin interaction: increased INR. Can Adverse Drug React Newsl 2001;11:1-2.
(17) Thirion DJ, Zanetti LA. Potentiation of warfarin's hypoprothrombinemic effect with miconazole vaginal suppositories. Pharmacotherapy 2000;20:98-9.
(18) Pfizer Canada. Diflucan[Symbol Not Transcribed] [registered symbol] 150 [product monograph]. 2000.
Copyright Keith Health Care Communications Nov 2003