Obstet Gynecol Clin N Am 30 (2003) 671 684

Vulvovaginal candidiasis
Paul Nyirjesy, MDa,*, Jack D. Sobel, MDb
Department of Obstetrics and Gynecology, Drexel University College of Medicine, Philadelphia, PA, USA b Division of Infectious Diseases, Department of Internal Medicine, Wayne State University School of Medicine, 3390 John R Street, Detroit, MI 48201, USA
a

For any clinician involved in the health care of women, vaginitis is a commonly encountered complaint and one of the most frequent reasons for patient visits to obstetricians/gynecologists [1]. Of the many causes of vaginal infections, vulvovaginal candidiasis (VVC) is believed to be one of the most common causes, and it has a significant impact on health care costs. Over-the-counter (OTC) sales of antifungal vaginal medications were reported to be approximately $269 million in 1995 [2] and are estimated to have increased significantly since then. Using a random digit-dialing survey of 2000 women representative of the United States population, Foxman et al [2] found that 6.5% of women aged 18 or older reported at least one presumed episode of VVC in the previous 2 months. They concluded that 55.7% of women will experience at least one symptomatic episode of VVC in their lifetime, and this cumulative probablility seems to be higher for African-American women than for other women. Taking into account the associated costs of VVC, such as medical and treatment expenses, travel costs, and time missed from work, they estimated that the total annual costs for VVC in the United States in 1995 was $1.8 billion. VVC is a common problem with significant social costs. VVC is best defined as the spectrum of patients who harbor Candida organisms in their vaginas [3]. If one views VVC as a continuum, different women with VVC will fall in different points. Some women with VVC are completely asymptomatic, whereas others may develop frequent or severe symptoms. Certain patients may develop primarily vulvar instead of vaginal manifestations of VVC. In recognition of the broad range of VVC, it was proposed in 1998 that VVC be classified into uncomplicated or complicated disease (Box 1). It has been estimated that 80% to 90% of women with VVC have uncomplicated VVC. This classification system has important therapeutic implications, because women with complicated VVC seem to be less likely to respond to standard short courses of antifungal therapy.

* Corresponding author. 245 N. 15th Street, 16th Floor, New College Building, Philadelphia, PA, 19102. E-mail address: pnyirjesy@comcast.net (P. Nyirjesy). 0889-8545/03/$ see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S0889-8545(03)00083-4

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Box 1. Classification of vulvovaginal candidiasis Uncomplicated VVC (all of the listed criteria) Sporadic or infrequent symptomatic episodes Mild to moderate symptoms Candida albicans infection Normal, nonpregnant woman Complicated VVC (any of the listed criteria) Recurrent episodes ( 4 episodes per year) Severe symptoms or findings Non-albicans yeast species Abnormal host (eg, diabetes, immunosuppression) From Sobel JD, Faro, S, Force RW, Foxman B, Ledger WJ, Nyirjesy P, et al. Vulvovaginal candidiasis: epidemiologic, diagnostic, and therapeutic considerations. Am J Obstet Gynecol 1998;178: 203 11; with permission.

Multiple prospective studies have validated the relevance of this classification system to predicting the outcome with treatment. For example, in a study that compared a week of topical clotrimazole cream to a single dose of oral fluconazole, patients with severe VVC were less likely to respond to either agent [4]. In another study that compared one versus two doses of fluconazole in women with severe or recurrent VVC (RVVC), women with an infection caused by non-albicans Candida sp and women with an underlying medical disease, such as diabetes, were much more likely to fail either therapy [5]. When discussing VVC, one must recognize that symptoms are a function of the infectious microorganism and the host response and that not all yeast infections are the same.

Microbiology Numerous studies suggest that C albicans is responsible for most symptomatic episodes of VVC [3]. Because vaginal yeast cultures are not routinely obtained in the management of uncomplicated VVC, it is difficult to assess whether the microbiology of VVC is changing as antifungal therapy and self-treatment in particular become more common. In specialized centers that treat women with complicated VVC, a broad variety of non-albicans species of Candida are encountered and may account for up to 30% of complicated VVC cases (Box 2) [5,6]. Studies from specialized centers are hampered by the referral bias of their patient populations and possible regional differences, however. Even in women with RVVC, more than 90% of infections may be secondary to C albicans [7]. Of the non-albicans yeast species implicated as causes of VVC, Candida glabrata is the most common [5 7].

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Box 2. Microbiology of vulvovaginal candidiasis C albicans ( 90% of cases) C glabarata Candida parapsilosis Candida krusei Candida lusitaniae Candida tropicalis Saccharomyces cerevisiae

Epidemiology and pathogenesis Because VVC is not a reportable disease and because there are no active surveillance studies in the United States, prevalence estimates have relied mainly on self-reported history of physician diagnosis. This history, in turn, may be hampered by several different factors: recall bias, accuracy of diagnosis, patient selection, referral bias, and confounding effects of widespread use of OTC antifungal agents. Epidemiologic data suggest that by age 25, half of all college women will experience at least one physician-diagnosed episode of VVC [8]. Age seems to be an important risk factor in the incidence of VVC, with an increase in the second decade of life and with the initiation of sexual activity [9]. Among college women, VVC seems to be more common among African-American women than white women [9]. Although most clinicians consider VVC more common in pregnancy, little published information supports this view. RVVC, defined as four or more attacks of symptomatic Candida vaginitis in the previous 12 months, may occur in as many as 8% of women of reproductive age [10]. With complicated and uncomplicated VVC, two elements are important in the development of a symptomatic episode. The first consists of vaginal colonization by Candida sp, followed by the transformation from the asymptomatic state to a symptomatic infection. There are distinct factors for colonization and transformation. Candida enters the vagina through any of a number of different sources, including local spread from the perineum and gastrointestinal tract, digital introduction, sexual transmission, and orogenital sex. Estrogen is believed to be crucial in the maintenance of colonization. Whatever the mechanism of entry, colonization seems to be a relatively common event. In one study that followed HIV-positive and HIV-negative women over 7 years, more than 80% of HIVnegative women had at least one positive culture for Candida [11]. Vaginal colonization as measured by culture techniques is frequently intermittent. Longterm typing studies suggest that colonization, once it occurs, may be caused by persistence of a single strain of Candida in many women with recurrent VVC (RVVC), although new strains of C albicans or other species of yeast also may be introduced [12]. Epidemiologic studies and anecdotal experience suggest that various factors, listed in Box 3, may be important in the development of VVC and RVVC. Some

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Box 3. Factors involved in symptomatic uncomplicated and complicated vulvovaginal candidiasis Microbial factors Species of yeast Resistant C albicans strains Host factors Medical conditions Diabetes or other abnormality in glucose metabolism Antibiotic use Immunosuppression (primary or medication induced) HIV Systemic lupus erythematosus Other conditions requiring corticosteroid use Vulvar dermatoses Behavioral Sexual factors, especially orogenital sex Contraception Hormone therapy or local estrogen administration Douching and use of feminine hygiene products Dietary factors Primary Lewis antigen secretor status Local immunologic factors Other local defense factors

of these factors are discussed in further detail. These factors may affect colonization, transformation to symptomatic infection, or both. Microbial factors Even in women with complicated VVC, more than 90% of cases are caused by C albicans [7]. Most of these strains are susceptible to available antimycotic agents, and true resistance of C albicans isolates remains rare in patients with VVC [13,14]. It should be noted, however, that current azole therapy is fungistatic. In women with RVVC, it is believed that small numbers of Candida may persist in the vagina, even during therapy, and later provide a reservoir for relapsing infection by

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the same identical organism [12]. In contrast, non-albicans Candida sp demonstrate variable, often reduced, susceptibility to specific azole agents. The presence of C glabrata, the second leading cause of VVC, is associated with a much lower response to standard antimycotic therapy [5]. Diabetes mellitus and glucose metabolism Patients with diabetes are less likely to respond to antimycotic therapy [5], and they may be more prone to developing infections caused by C glabrata [15]. Anecdotally, patients occasionally report that an excess of refined sugars seems to trigger a symptomatic episode of VVC, but few data have supported this clinical observation. A recent finding that women with RVVC exhibited an impaired tolerance for glucose despite having a similar incidence of overt or preclinical diabetes than controls suggests that glucose metabolism sometimes may play a role in the development of symptomatic Candida vaginitis [16], although the role of a low carbohydrate diet in managing VVC remains controversial. Antibiotic use Recent antibiotic use is frequently reported by some women as a predictable precipitating factor for isolated and recurrent VVC [17]. The presumed mechanism is an antibiotic-induced decrease in lactobacilli, which facilitates an overgrowth with Candida. The inability to find an association between an absence of vaginal lactobacilli and VVC raises the possibility that other mechanisms may be at play, however [18]. Estrogen Endogenous and exogenous estrogens are believed to play a role in the pathogenesis of VVC. Epidemiologically, VVC is rare in premenarchal females, and it decreases in frequency in postmenopausal women. Oral contraceptives have been suspected of contributing to RVVC, but epidemiologic data are conflicting, and their causal role is still controversial [19]. Estrogen therapy may contribute to RVVC in postmenopausal women by prolonging the at-risk period in women who are prone to RVVC premenopausally. Anecdotally, the authors have noticed that the risk of getting VVC seems increased in postmenopausal women who receive topical estrogen, particularly when in conjunction with antibiotics. Occasionally, tamoxifen or other estrogen agonists also may contribute to the development of RVVC in postmenopausal women [20]. Immunosuppression In a small number of women, RVVC may be the result of systemic immunodeficiency caused by either illness or systemic therapy with corticosteroids or similar drugs. In HIV-infected women, vaginal colonization with Candida is substantially increased, but the frequency of RVVC is only modestly increased,

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with attack rates of VVC significantly lower than oropharyngeal candidiasis [11]. In clinical practice, immunosuppression seems to be a rare cause of VVC, and an evaluation for an underlying illness is only indicated if other elements in the patients history or examination suggest a need for it. Behavioral factors Various behavioral factors have been proposed as a cause of VVC and RVVC. Sexual factors, particularly orogenital sex [9], may contribute to the introduction of microorganisms from the partners mouth or saliva or may facilitate symptomatic disease because of microtrauma to the vulva and the vestibule. Although sexual intercourse alone may not be associated with increased Candida colonization [21], contraceptive practices may contribute to VVC; oral contraceptives [9], use of a diaphragm and spermicide [21], and the use of an intrauterine device [22] have been associated with an increased risk of infection. Spinillo et al have identified douching as a risk factor in women with RVVC caused by C glabrata [23]. Primary RVVC In approximately half of women with RVVC, no factors that contribute to the risk of VVC may be identified. Although women with RVVC have increased Candida colonization rates [24], it is not known whether this enhanced colonization is vagina specific or occurs elsewhere at extragenital sites, such as the gastrointestinal tract. In some women, enhanced colonization may be explained by genetic predispositions. For example, women who are nonsecretors of Lewis antigens, glycoproteins that may potentially inhibit the binding of Candida to vaginal mucosa, are associated with a greater risk of RVVC [25] African-American women also may be at increased risk for VVC [9]. It has been postulated that a reduction in or lack of lactobacilli in the vagina may provide an environment that is more conducive to colonization and transformation. This hypothesis has led many women with VVC to treatments with yogurt or lactobacillus preparations [26], but data regarding such therapy are limited to one small study [27]. An association between lack of lactobacilli and VVC has not been noted [18], and women with RVVC have similar numbers and types of Lactobacillus sp as controls [28]. Another mechanism at play with RVVC may pertain to an innate host immunologic or other deficiency. In contrast to previous hypotheses, as reviewed by Fidel and Sobel [29], current data indicate that most women with RVVC display normal systemic cell-mediated immune responses to Candida, although local vaginal immune responses may differ. The role of impaired or altered local vaginal Candida-specific immune reactivity predisposing to recurrent RVVC has been suggested [29]. One view is that depressed or reduced protective local immunoregulatory mechanisms and cytokine elaboration result in increased susceptibility to RVVC. Another view suggests that an abnormal heightened or increased sensitivity is induced. The finding that vaginal epithelial cells collected from

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healthy women exhibit anti-Candida activity in vitro and that such activity is reduced in cells of women with RVVC suggests that other innate host factors play a role in preventing yeast infections [30].

Diagnosis The clinical symptoms of VVC are nonspecific, and clinicians should keep in mind that a broad variety of infectious and noninfectious diseases can cause a similar array of symptoms. To obtain an accurate diagnosis, a thorough evaluation is necessary. Patients with symptomatic VVC may complain of vulvovaginal itching, irritation, soreness, or burning. Traditionally, clinicians have thought of candidiasis as a vaginal problem, but the term vulvovaginal candidiasis highlights the fact that VVC represents a spectrum of vulvar and vaginal complaints and that many women exhibit only vulvar symptoms and signs. Although most women commonly think of VVC as a cause of an abnormal thick, white, cheesy discharge, many symptomatic women do not notice any change in their vaginal secretions. If it is associated with significant vestibular or vulvar inflammation, VVC also may cause dysuria because of the burning that occurs when urine hits the inflamed vulvar tissues. During symptomatic episodes, many women with VVC complain of dyspareunia. The physical examination of a patient should begin with an inspection of the vulva, looking for signs of erythema, edema, or skin fissures. In the authors experience, VVC is a frequent yet overlooked cause of acute vulvar and labial erythema and edema. After insertion of the speculum, the vagina should be inspected for the presence of vaginal thrush and other signs of VVC, such as erythema or erosions. In women who complain of vaginal symptoms, the standard tests that should be performed consist of a vaginal pH measurement, saline, and 10% potassium hydroxide microscopy. Although the vaginal pH is generally not affected by VVC and remains less than 4.5 in premenopausal women, the finding of a normal pH helps to exclude bacterial vaginosis, trichomoniasis, atrophic vaginitis, or some sort of mixed infection. With saline microscopy, the examiner should look closely for either blastospores or pseudohyphae. The background vaginal flora may otherwise appear normal or somewhat decreased, and white blood cells are most often noticeably absent. Because it lyses vaginal epithelial cells, the addition of 10% potassium hydroxide solution to the patients specimens may make it easier to visualize fungal elements. Microscopy is the mainstay in the diagnosis of VVC; however, studies show that in academic settings, microscopy has a sensitivity of 50% at best and misses a substantial percentage of cases in women with symptomatic VVC [6,31]. C glabrata, the second leading cause of VVC, only produces blastospores, which may be more difficult to recognize by microscopy. Over the past few years, it also has become increasingly recognized that microscopy also may result in falsepositive results. In a study of 61 women who were diagnosed as having VVC on the basis of clinical examination and microscopy in a university-based outpatient

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gynecology clinic, Ledger et al [32] found that 49% had a negative yeast culture and yeast polymerase chain reaction result. Given significant rates of false-positive and false-negative results with the standard clinical evaluation, clinicians always should be prepared to obtain a vaginal yeast culture in women with a compatible clinical syndrome and normal pH in whom the diagnosis cannot be definitively established with microscopy. Culturing for yeast is particularly useful in women with complicated VVC, because information about the type of species causing the infection may help to influence the choice of antimycotic therapy.

Misdiagnosis Over the past decade, the trend has been for women to rely increasingly on selfdiagnosis and self-treatment of VVC. When topical antimycotic agents were approved for OTC use, the basic assumption was that women with a prior episode of VVC were relatively accurate with self-diagnosis. Chaponis et al [33] found that in 100 women with a prior episode of diagnosed VVC, 82% could accurately recognize VVC. The perceived benefits of OTC antifungal agents include convenience, the ability to initiate antimycotic therapy rapidly, empowerment of women, and the potential to reduce health care costs. With the availability of OTC antifungal agents, Lipsky et al [34] estimated a decrease in direct and indirect health care costs of $63.75 million from 1990 to 1994. Later studies of other patient populations have suggested that the accuracy of self-diagnosis is poorer than previously suggested, however. In a study of 601 women recruited from various medical and community sites in Augusta, Georgia, Ferris et al [35] found that only 11% of women with no diagnosis and 34.5% of women with a prior diagnosis of VVC could recognize accurately the classic scenario for candidiasis. Both groups were particularly poor at recognizing bacterial vaginosis, with an accuracy of 3.2% and 4.4%, respectively. In 105 women with chronic vaginal symptoms, Nyirjesy et al [26] noted that 73% of their patients had self-treated for VVC, whereas only 28% had VVC at the time of their evaluation. In an effort to evaluate further what proportion of symptomatic women who purchased OTC antifungal products actually had VVC, a prospective multicenter study found that only 34% had pure VVC and another 20% had VVC with either bacterial vaginosis or trichomoniasis [36]. It is notable that only 95 women were enrolled in this study and that patient recruitment was described as extremely difficult. Although self-diagnosis and self-treatment may be inaccurate in many women, it is clear that most women are eager to avoid an office evaluation for vaginitis and are more than happy to self-treat. Misdiagnosis potentially could end up increasing health care costs for individuals who do not have VVC, however, and a delay in treatment could have an adverse impact if the patient is using an antifungal agent for the wrong problem (eg, pelvic inflammatory disease or a urinary tract infection). As many clinicians recognize, vaginitis is frequently managed through a telephone consultation. Telephone diagnosis offers many of the advantages of

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self-diagnosis, with the added benefit that patients receive validation by a clinician that they do have VVC. Allen-Davis et al [37] sought to evaluate the accuracy of telephone diagnosis in a Denver-based study. A total of 485 women underwent a prospective structured telephone nurse interview and were diagnosed over the phone. All of the women were offered an evaluation to corroborate their diagnosis. Of the 253 women who completed the study protocol, there was poor agreement between the telephone diagnosis and the actual diagnosis. Poor agreement also was noted between practitioners and the actual diagnosis, although the data did not show whether this outcome was caused by false-negative results, which could be attributed to the well-recognized limitations of standard office tests, or falsepositive results. Finally, one also should recognize that optimal diagnostic techniques are frequently not used in clinical practice. In a review of 52 medical records of patients referred to a tertiary care center because of chronic vulvovaginal complaints, Wiesenfeld and Macio [38] noted that 42% of the referring physicians did not perform microscopy as part of any evaluation of vaginitis and that vaginal pH tests were performed at only 3% of office visits. Because many women with VVC may be misdiagnosed, it is clear that one should use a culture to corroborate firmly the diagnosis in women with complicated VVC.

Treatment For patients with uncomplicated VVC, various therapies are available for treatment (Table 1). The mainstays of current therapy are azole agents, which are

Table 1 Therapy for vulvovaginal candidiasis Drug Nystatin Butoconazole Clotrimazole Formulation 100,000 U vaginal tablet 2% sustained release cream 2% cream 1% cream 2% cream 100 mg vaginal suppository 200 mg vaginal suppository 500 mg vaginal suppository 2% cream 100 mg vaginal suppository 200 mg vaginal suppository 1200 mg vaginal suppository 0.4% cream 0.8% cream 80 mg vaginal suppository 2% cream 6.5% cream 150 mg oral tablet Dose 100,000 U/14 d 5 g/1 d 5 g/7 d 5 g/7 d 5 g/3 d 100 mg/7 d 200 mg/3 d 500 mg/1 d 5 g/7 d 100 mg/7 d 200 mg/3 d 1200 mg/1 d 5 g/7 d 5 g/3 d 80 mg/3 d 5 g/3 d 5 g/1 d 150 mg/1 d

Miconazole

Terconazole

Tioconazole Fluconazole

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available in various formulations (eg, creams, suppositories, tablets) and can be administered either topically or orally. All azoles function through a similar mechanism of action: inhibition of cell wall metabolism. Azoles are all fungistatic agents. Other antifungal agents, such as topical boric acid, flucytosine, and gentian violet, may play a more important role in the management of complicated VVC. In terms of therapeutic efficacymost commonly defined as clinical cure (resolution of signs and symptoms) and mycologic cure (negative follow-up fungal culture)in women with uncomplicated VVC, cure rates of 80% to 90% can be expected with all the agents listed in Table 1 [4]. With topical therapy, the main side effect is localized burning in 5% to 10% of patients as a result of an allergic or irritant reaction; some patients may object to the inherent messy nature of a cream or suppository. Oral therapy with a single dose of fluconazole has been shown to be as effective as a 7-day course of clotrimazole [4] and a 3-day course of topical terconazole [39]. Systemic side effects, such as gastrointestinal intolerance, headache, and rash, are mild, infrequent, and self-limited. Although first-trimester exposure to single-dose fluconazole has not yet been associated with adverse effects on pregnancy [40], fluconazole is a category C drug in pregnancy; most clinicians tend to treat patients with topical therapy during pregnancy to limit the amount of drug exposure. Overall, the success rate with the treatment of uncomplicated VVC is so high that lack of response often implies an incorrect initial diagnosis. Persistent symptoms mandate re-evaluation, which should include a vaginal yeast culture. Given the multitude of treatment options and competing claims by various manufacturers, it may be difficult for a clinician to select the appropriate agent for a particular patient. Health care providers have the opportunity to tailor the therapy to the individual patients desires. Short courses of therapy are highly effective, and the route of therapy should be dictated by patient, not physician, preference. In terms of patient preference, several surveys have shown that most, but not all, women would rather use oral therapy [39,41]. If other factors are equal, asking the individual patient which route she prefers easily identifies her choice. Other factors to consider in the uncomplicated patient include compliance, cost, ability to insert vaginal preparations, history of response or adverse reactions to prior treatments, and duration of therapy. Severe vulvovaginal candidiasis In most studies of VVC, the severity of the infection was not specifically addressed as a predictor of outcome. Patients with severe episodes of symptomatic VVC are less likely to respond to standard antifungal therapy regimens, however [4,5]. In a prospective study, 556 women with severe or recurrent VVC were randomly assigned to either a single-dose or two-dose (every 3 days) regimen of oral fluconazole (150 mg). The two-dose treatment group had significantly higher clinical cure rates on day 14 (94% versus 85%) and day 35 (80% versus 67%) [5]. In patients with severe symptoms or extensive findings, clinicians should consider

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offering a longer course of therapy. In patients who prefer topical therapy, it seems reasonable to suggest at least 7 days of topical therapy. Recurrent vulvovaginal candidiasis In patients with RVVC, a culture is strongly recommended to confirm the diagnosis and determine the species of the infecting organism. Most of these cultures are positive for C albicans. In a woman with RVVC who receives a conventional course of treatment with an antifungal agent to induce an initial mycologic cure, up to 70% can expect recurrence with a symptomatic episode within 6 months [42]. With maintenance antifungal regimens, most patients can achieve satisfactory alleviation or control of their symptomatic episodes. Treatment options that have been studied and shown to be effective include ketoconazole (100 mg) orally daily [42], clotrimazole (500 mg) suppositories weekly [43], and fluconazole (150 mg) orally once weekly [7]. Because of liver toxicity associated with the use of ketoconazole, the latter two agents are preferred as maintenance regimens. In approximately 50% of women, they no longer have symptomatic relapses after stopping a 6-month course of maintenance therapy [7]. For women who do, even longer courses of maintenance therapy may be required to suppress their infections. Controlled studies to date have failed to demonstrate a benefit to treating a womans partner [44]. Other approaches, such as hormonal manipulation with depot medroxyprogesterone, use of yogurt, desensitization to Candida antigen, and a low carbohydrate diet, lack sufficient data to support recommendation of their use. Non-albicans Candida infections Although clinical and in vitro resistance to C albicans is fortunately rare, nonalbicans Candida sp are less likely to respond to azole antifungal therapy [5,45,46]. Boric acid (600 mg) administered daily in a gelatin capsule seems to be effective, particularly for C glabrata infections [47]. Initial therapy should be for a minimum of 14 days. In patients with RVVC, the authors recommend a maintenance regimen of 6 to 8 weeks. Topical flucytosine for vaginal use has been described as a treatment for resistant Candida tropicalis infections [48] and has been shown to eradicate most C glabrata infections that fail to respond to boric acid [49]. The cost for getting this medication compounded is extensive, however, and there are concerns about acquisition of resistance with prolonged use. The role of combination therapy for markedly resistant infections remains unstudied.

Summary VVC represents a spectrum of disease. Although there is a clear need for better use of diagnostic modalities and development of better treatment alternatives, most patients with VVC, even the complicated cases, at least have the perspective of achieving adequate control of their symptoms. Future advances, particu-

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larly in the area of home diagnostics, may help to optimize use of currently available medicines.

References
[1] Kent HL. Epidemiology of vaginitis. Am J Obstet Gynecol 1991;165:1168 76. [2] Foxman B, Barlow R, DArcy H, Gillespie B, Sobel JD. Candida vaginitis: self-reported incidence and associated costs. Sex Transm Dis 2000;27:230 5. [3] Sobel JD, Faro S, Force RW, Foxman B, Ledger WJ, Nyirjesy P, et al. Vulvovaginal candidiasis: epidemiologic, diagnostic, and therapeutic considerations. Am J Obstet Gynecol 1998;178: 203 11. [4] Sobel JD, Brooker D, Stein GE, Thomason J, Wermeling DP, Weinstein L, et al. Single oral dose fluconazole compared with conventional topical therapy of Candida vaginitis. Am J Obstet Gynecol 1995;172:1263 8. [5] Sobel JD, Kapernick PS, Zervos M, Reed BD, Hooton T, Soper D, et al. Treatment of complicated Candida vaginitis: comparison of single and sequential doses of fluconazole. Am J Obstet Gynecol 2001;185:363 9. [6] Nyirjesy P, Seeney SM, Grody MHT, Jordan CA, Buckley HR. Chronic fungal vaginitis: the value of cultures. Am J Obstet Gynecol 1995;173:820 3. [7] Sobel JD, Hillier S, Smolenski L, Martens M, Danna P, Panzer H, et al. Management of recurrent vulvovaginal candidiasis (RVVC) with maintenance suppressive weekly fluconazole: a multicenter study [abstract LB-8]. In: Programs and abstracts of the 42nd Interscience Conference of Antimicrobial Agents and Chemotherapy. San Diego; September 27 30, 2002. [8] Hurley R, Delouvois J. Candida vaginitis. Postgrad Med J 1979;55:645 7. [9] Geiger AM, Foxman B. Risk factors for vulvovaginal candidiasis: a case-control study among university students. Epidemiology 1996;7:182 7. [10] Foxman B, Marsh JV, Gillespie B, Sobel JD. Frequency and response to vaginal symptoms among white and African American women: results of a random digit dialing survey. J Womens Health 1998;7(9):1167 74. [11] Ohmit SE, Sobel JD, Schuman P, Duerr A, et al. A longitudinal study of mucosal Candida colonization and candidiasis among HIV-seropositive and at-risk HIV-seronegative women. J Infect Dis 2003;188:118 27. [12] Vazquez JA, Sobel JD, Demitriou R, Vaishampayan J, Lynch M, Zervos MJ. Karyotyping of Candida albicans isolates obtained longitudinally in women with recurrent vulvovaginal candidiasis. J Infect Dis 1994;170:1566 9. [13] Lynch ME, Sobel JD. Comparative in vitro activity of antimycotic agents against pathogenic vaginal yeast isolates. J Med Vet Mycol 1994;32:267 74. [14] Sobel J, Zervos M, Reed BD, Hooton T, Soper D, Nyirjesy P, et al. Fluconazole susceptibility of vaginal isolates obtained from women with complicated Candida vaginitis: clinical implications. Antimicrob Agents Chemother 2003;47(1):34 8. [15] DeLeon EM, Jacober SJ, Sobel JD, Foxman B. Prevalence and risk factors for vaginal Candida colonization in women with type I and type II diabetes. BMC Infect Dis 2002;2:1 11. [16] Donders GG, Prenen H, Verbeke G, Reybrouck R. Impaired tolerance for glucose in women with recurrent vaginal candidiasis. Am J Obstet Gynecol 2002;187:989 93. [17] Spinillo A, Capuzzo E, Acciano S, DeSantolo A, Zara F. Effect of antibiotic use on the prevalence of symptomatic vulvovaginal candidiasis. Am J Obstet Gynecol 1999;180:14 7. [18] Hawes SE, Hillier SL, Benedetti J, Stevens CE, Koutsky LA, Wolner-Hannsen P, et al. Hydrogen peroxide-producing lactobacilli and acquisition of vaginal infections. J Infect Dis 1996;174: 1058 63. [19] Reed BD, Gorenflo DW, Gillespie BW, Pierson CL, Zazove P. Sexual behaviors and other risk factors for Candida vulvovaginitis. J Womens Health Gend Based Med 2000;9:645 55.

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