Vulvovaginal candidiasis: topical vs. oral therapy - includes patient information sheet

Author: Marla J. Tobin
Date: May 15, 1995

Vulvovaginal candidiasis is extremely common. It may be treated with topical or oral antifungal medications. Topical therapy is efficacious and well-tolerated in most women. Oral therapy should be reserved for rare cases of severe and recalcitrant infection but should not be used in pregnant women, patients with diabetes or those using concomitant medications. An understanding of the pharmacotherapeutic characteristics of both oral and topical medications is a vital element in ensuring a favorable therapeutic outcome.

Vulvovaginal candidiasis is one of the most common vaginal infections, with approximately 13 million cases reported annually in the United States.[1] It is estimated that three out of four women will experience at least one vulvovaginal candidal infection during their childbearing years, and that about half of these women will have at least one recurrence.[2] Approximately 5 percent of women will experience recurrent infections (i.e., four or more confirmed, symptomatic episodes in one year).[3] Host-related factors that may account for the recurrence of vulvovaginal infections are the use of hormonal preparations (including high-estrogen oral contraceptives) and broadspectrum antimicrobial agents; pregnancy; uncontrolled diabetes mellitus; wearing tight-fitting, synthetic-fiber clothing; local allergy and compromised immune function.[3-5]

Evidence suggests that the overall incidence of human mycoses has risen, especially the incidence of vaginal mycotic disease.[6] While most of these vaginal infections continue to be caused by Candida albicans, there appears to be an increase in the proportion of infections caused by Candida species other than C. albicans, many of which are resistant to traditional treatment.[4,7-10]

Because of the frequent occurrence of vulvovaginal candidiasis, treatment regimens are needed that not only produce rapid resolution of the infection, but also pose a minimal risk of untoward events, especially in women who are pregnant, who have diabetes or who take concurrent medications.

Topical Antifungal Preparations

Despite the availability of several oral antifungal drugs, topical agents remain the most widely used compounds in the management of vulvovaginal candidiasis.[11] The rationale for use of topical antifungal agents as first-line treatment is based on the superior benefit-to-risk ratio of topical therapy compared with that of systemic therapy. It is a general maxim of clinical practice that topical disorders should be treated with topical therapy, thus restricting the potential for adverse reactions and drug interactions.

Various topical antifungal preparations may-be used for the treatment of vulvovaginal candidiasis, including creams, lotions, suppositories and vaginal tablets. Until the introduction of the new triazole compound terconazole (Terazol), most topical antifungal agents used in the treatment of vulvovaginal candidiasis were imidazoles (e.g., clotrimazole [GyneLotrimin, Mycelex]) or polyenes (e.g., nystatin [Mycostatin]). Table 1 lists the formulations and dosages of the available topical preparations for vulvovaginal candidiasis.

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The overall clinical and mycologic cure rates in immunocompetent patients with acute vulvovaginal candidiasis are extremely high. For example, the average clinical and mycologic cure rate among patients treated with a polyene such as nystatin ranges from 75 to 80 percent, while the average clinical and mycologic cure rate associated with the use of imidazole derivatives is in the range of 85 to 90 percent.[8,12] Studies of the only available topical triazole, terconazole, have reported clinical cure rates of 85 to 90 percent.

An important consideration when choosing among the many alternatives is that not all agents are equally effective against nonalbicans species of Candida. Candida tropicalis and Candida glabrata, in particular, can be 10 times less sensitive to the older imidazoles than C. albicans.[4] The use of imidazoles in shorter and shorter courses may have resulted in a shift to more resistant organisms. The over-the-counter availability of imidazoles may also be accelerating the selection of resistant nonalbicans species. Terconazole is more effective against nonalbicans Candida species than imidazoles and is equally efficacious in the treatment of C. albicans infections.

The long-term outcome in women with recurrent vulvovaginal candidiasis is more problematic. Studies have shown that traditional topical antifungal therapy results in symptomatic improvement in most patients, but that an appreciable percentage of patients have recurrence of symptoms within a relatively short time.[12-14] For this reason, many clinicians recommend that patients with recurrent vulvovaginal candidiasis be maintained on long-term (six months) antifungal therapy, such as ketoconazole (Nizoral), 100 mg orally, or clotrimazole, 500-mg vaginal suppositories once per week, which is usually effective in suppressing symptoms for the duration of treatment.[3,14-16]

Oral Antifungal Agents

Systemic therapy for vulvovaginal candidiasis should be reserved for rare cases of severe, recalcitrant infection in patients who do not have a concomitant sexually transmitted disease (STD) and who have proved to be compliant with previous courses of topical antifungal therapy. Since recurrent vulvovaginal candidiasis is often linked to concomitant STDs (i.e., human papillomavirus, herpesvirus, Chlamydia, bacterial vaginosis), proper diagnosis to rule out an STD is imperative before aggressive oral antifungal therapy is considered. The risks of oral therapy are too high to justify routine use in less critically affected patients, particularly those who are pregnant (possibly unknowingly), breast feeding or diabetic, or who are using concomitant medications.

Several oral antifungal agents may be used in the treatment of vulvovaginal candidiasis (Table 2). The three orally active antifungals currently available in the United States are azole derivatives: the imidazole ketoconazole, the triazole fluconazole (Diflucan), and the triazole itraconazole (Sporanox). However, at this time only fluconazole has been approved by the U.S. Food and Drug Administration for treatment of vulvovaginal candidiasis.

[TABULAR DATA OMITTED]

Some clinicians advocate oral antifungal agents as a more convenient and more "compliance-enhancing" alternative to topical agents in the long-term management of recurrent infections.[3,8] However, systemic therapy has a number of drawbacks (Table 3).

TABLE 3

The use of oral antifungals during pregnancy is not recommended.[19,20] Since the oral triazoles (and possibly ketoconazole) are excreted in breast milk, caution should also be exercised when administering these drugs to breast-feeding women.

Topical Antifungal Agents

in Women with Diabetes

Diabetes mellitus is another factor predisposing women to vulvovaginal candidiasis, which occurs more often in diabetic patients than in the population as a whole.[6,8] Symptomatic infection's can be associated with uncontrolled diabetes. Diabetic control may be further compromised if an oral antifungal agent is used, because of the potential for interaction between oral azoles and oral hypoglycemic agents. Therefore, except under unusual circumstances, a topical agent should be used as first-line treatment in diabetic women.

A diagnosis of vulvovaginal candidiasis in a diabetic patient may lead the physician to discuss the importance of blood glucose control to prevent future outbreaks of candidiasis. In addition, the patient must be encouraged to keep the vulvar area clean and dry, which will help prevent the growth of yeast.

Potential for Drug-drug Interactions

Although no significant drug-drug interactions have been reported with topical antifungal agents, many interactions have been described with oral antifungal agents. For example, a recent cross-sectional, observational study conducted at an urban hospital in Australia reported that 35 out of 76 patients treated with fluconazole over a 12-week period were concurrently receiving potentially interactive drugs, such as cyclosporine (Sandimmune), warfarin (Coumadin, Panwarfin), theophylline, phenytoin (Dilantin) and rifampin (Rifadin, Rimactane), and that nine of the patients had experienced 10 possible adverse drug interactions.[21]

Table 4 lists some of the drugs that have the greatest potential to interact with oral azoles. One of the chief drug-drug interactions that may occur in patients with vulvovaginal candidiasis is a reaction between oral azoles and oral contraceptives, particularly contraceptives containing estrogen.[8,22] Given that most women who develop vulvovaginal candidiasis are of childbearing age (precisely the population most likely to be using oral contraceptives), this presents a clinical problem. The problem is compounded by the fact that oral azoles are not recommended for use by young women who are not using a reliable method of birth control or by women who may be trying to become pregnant.[18] Hormone replacement therapy may also be affected by oral azoles, since both the hormone and the azole may compete for the same binding sites.

Oral antifungal agents may also interact with another widely used class of drugs, the nonsedating antihistamines, such as terfenadine (Seldane) and astemizole (Hismanal), with the potential for serious adverse cardiovascular effects, including death, ventricular tachycardia and torsades de pointes.[22] As previously noted, oral antifungal agents may also increase the bioavailability of oral hypoglycemic agents, potentially producing symptoms of hypoglycemia.[22] And, finally, it should be noted that the efficacy of oral azoles may be altered by the concomitant use of histamine [H.sub.2] receptor antagonists.[22]

Adverse Effects

Overall, both topical and oral antifungal drugs are well tolerated.[8] The most common side effects associated with the use of topical agents include local reactions, such as stinging, burning, irritation, pruritus and pain.[11,23-26] These reactions occur in about 7 percent of women who use azole antifungal creams.[3] The adverse reactions may be related to the vehicle and may not be true drug reactions.

Other, less common side effects include increased frequency of micturition, dyspareunia, rhinorrhea, headache, fever, chills, pelvic cramps, dysmenorrhea and paresthesias.[12,23,24,26,27]

The risk of potentially serious, possibly even life-threatening, side effects is considerably higher with oral antifungal agents than with topical preparations. In the case of ketoconazole, about 10 percent of patients report mild gastrointestinal disorders (e.g., nausea, vomiting, abdominal pain).[8] Of greater concern is the possibility of anaphylaxis, androgen biosynthesis blockade and hepatotoxicity, which are associated with ketoconazole therapy.[20] While the growing trend of shorter courses of drug therapy has reduced the risk of hepatic injury to only about one in every 70,000 users,[20] this is a factor to consider when prescribing ketoconazole, particularly for certain high-risk populations (e.g., older patients, those with preexisting liver disease, alcoholics).[20]

About 5 percent of patients who use fluconazole for the treatment of recurrent vulvovaginal candidiasis experience mild gastrointestinal symptoms.[23,28,29] Other, less common adverse reactions include dry mouth, rash, dizziness and headache.[28,29] In addition, a higher incidence of liver function test abnormalities has been reported in patients receiving fluconazole than in patients using a topical preparation, such as clotrimazole (5.1 percent versus 3.7 percent).[20] More troublesome are isolated reports of angioedema[30] and anaphylaxis.[31] It is not clear if an association exists between the use of fluconazole and epidermal necrolysis in an immunocompetent patient.

Itraconazole has also been associated with systemic reactions. Seven to 10 percent of patients experience minor disturbances that are primarily gastrointestinal in nature.[6,20] Among the other side effects that have been reported are fever, edema, hypertension, malaise, dizziness, headache, psychiatric effects and transient faintness.[14,22,25] Reversible changes in liver function tests with itraconazole therapy have a low reported incidence (0.9 percent), while the incidence of hepatic reactions is rare.[6,20,25]

REFERENCES

[1.] Weisberg M. Considerations in therapy for vulvovaginal candidiasis: when and whom to treat. In: Sobel JD, ed. Clinical perspectives: terconazole, an advance in vulvovaginal candidiasis therapy. New York: McGraw-Hill, 1988:1-8. [2.] Hurley R. Recurrent candida infection. Clin Obstet Gynaecol 1981;8:209-14. [3.] Sobel JD. Pathogenesis and treatment of recurrent vulvovaginal candidiasis. Clin Infect Dis 1992; 14(Suppl 1):S148-53. [4.] Horowitz BJ. Mycotic vulvovaginitis: a broad overview. Am J Obstet Gynecol 1991;165(4 Pt 2): 1188-92. [5.] Nixon SA. Vulvovaginitis: the role of patient compliance in treatment success. Am J Obstet Gynecol 1991;165(4 Pt 2):1207-9. [6.] Scudamore JA, Tooley PJ, Allcorn RJ. The treatment of acute and chronic vaginal candidosis. Br J Clin Pract 1992;46:260-3. [7.] Horowitz BJ, Giaquinta D, Ito S. Evolving pathogens in vulvovaginal candidiasis: implications for patient care. J Clin Pharmacol 1992;32:248-55. [8.] Sobel JD. Candidal vulvovaginitis. Clin Obstet Gynecol 1993;36:153-65. [9.] Redondo-Lopez V, Lynch M, Schmitt C, Cook R, Sobel JD. Torulopsis glabrata vaginitis: clinical aspects and susceptibility to antifungal agents. Obstet Gynecol 1990;76:651-5. [10.] Boag FC, Houang ET, Westrom R, McCormack SM, Lawrence AG. Comparison of vaginal flora after treatment with a clotrimazole 500 mg vaginal pessary or a fluconazole 150 mg capsule for vaginal candidosis. Genitourin Med 1991;67:232-4. [11.] Corson SL, Kapikian RR, Nehring R. Terconazole and miconazole cream for treating vulvovaginal candidiasis. A comparison. J Reprod Med 1991; 36:561-7. [12.] Sobel JD, Schmitt C, Meriwether C. Clotrimazole treatment of recurrent and chronic candida vulvovaginitis. Obstet Gynecol 1989;73(3 Pt 1):330-4. [13.] Fong IW. The value of chronic suppressive therapy with itraconazole versus clotrimazole in women with recurrent vaginal candidiasis. Genitourin Med 1992;68:374-7. [14.] Sobel JD. Recurrent vulvovaginal candidiasis. A prospective study of the efficacy of maintenance ketoconazole therapy. N Engl J Med 1986;315: 1455-8. [15.] Balsdon MJ, Tobin JM. Recurrent vaginal candidosis: prospective study of effectiveness of maintenance miconazole treatment. Genitourin Med 1988; 64:124-7. [16.] Del Palacio A. Fungal skin and soft tissue infections. Curr Opin Infect Dis 1992;5:687-94. [17.] O'Connor MI, Sobel JD. Epidemiology of recurrent vulvovaginal candidiasis: identification and strain differentiation of Candida albicans. J Infect Dis 1986; 154:358-63. [18.] Merkus JM. Treatment of vaginal candidiasis: orally or vaginally? J Am Acad Dermatol 1990;23(3 Pt 2):568-72. [19.] Timonen H. Shorter treatment for vaginal candidosis: comparison between single-dose oral fluconazole and three-day treatment with local miconazole. Mycoses 1992;35:317-20. [20.] Hay RJ. Risk/benefit ratio of modern antifungal therapy: focus on hepatic reactions. J Am Acad Dermatol 1993;29:S50-4. [21.] Tett S, Carey D, Lee HS. Drug interactions with fluconazole [Letter]. Med J Aust 1992;156:365. [22.] Physician's desk reference. 48th ed. Oradell, N.J.: Medical Economics Data, 1994:1097-8. [23.] Stein GE, Christensen S, Mummaw N. Comparative study of fluconazole and clotrimazole in the treatment of vulvovaginal candidiasis. DICP 1991;25:582-5. [24.] Ernest JM. Topical antifungal agents. Obstet Gynecol Clin North Am 1992;19:587-607. [25.] Stein GE, Mummaw N. Placebo-controlled trial of itraconazole for treatment of acute vaginal candidiasis. Antimicrob Agents Chemother 1993;37:89-92. [26.] Clark C, Cooper CL, Gordon SF, et al. A multicenter comparison of one-dose ticonazole ointment with three-dose terconazole cream in vulvovaginal candidiasis. J Women's Health 1993;2:189-96. [27.] Patel HS, Peters MD 2d, Smith CL. Is there a role for fluconazole in the treatment of vulvovaginal candidiasis? Ann Pharmacother 1992;26:350-3. [28.] Osser S, Haglund A, Westrom L. Treatment of candidal vaginitis. A prospective randomized investigator-blind multicenter study comparing topically applied econazole with oral fluconazole. Acta Obstet Gynecol Scand 1991;70:73-8. [29.] Brammer KW, Feczko JM. Single-dose oral fluconazole in the treatment of vaginal candidosis. Ann N Y Acad Sci 1988;544:561-3. [30.] Abbott M, Hughes DL, Patel R, Kinghorn GR. Angio-oedema after fluconazole [Letter]. Lancet 1991;338:633. [31.] Neuhaus G, Pavic N, Pletscher M. Anaphylactic reaction after oral fluconazole [Letter]. BMJ 1991; 302:1341.

The Author

MARLA J. TOBIN, M.D. has a private practice in Higginsville, Mo. Dr. Tobin graduated from the University of Missouri-Columbia School of Medicine and completed a residency in family medicine at Duke-Watts Family Medicine Residency, Durham, N.C.

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