VULVOVAGINITIS

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VULVOVAGINITIS When Candida Becomes a Problem Jack D. Sobel, MD

Vulvovaginitis caused by the Candida species is extremely common, widespread, and affects all strata of society. The overwhelming majority of infections are uncomplicated and respond well to conventional antifungal therapy, regardless of route of administration or duration of therapy. Complicated Candida infections, although representing a minority of episodes, still constitute an enormous challenge to our therapeutic skills (Table 1). As indicated in Display Box 1, genital infection by Cundida becomes a problem under a variety of circumstances including host and microorganism factors.

Display Box 1. Problematic Candida Vulvovaginit is 1. Wrong diagnosis. 2. Right diagnosis but Candida is innocent bystander Azole-resistant Candida albicans non- albicans Candida infection mixed infection sensitive Candida but abnormal host: diabetes mellitus “antibiotic-prone’’ idiopathic recurrent CV steroid dependent? HIV positive?? estrogen

PROBLEMS IN DIAGNOSIS OF CANDlDA VAGINITIS

Symptoms of Candida vaginitis (CV) include pruritus, burning, irritation, soreness, burning on micturition, dyspareunia, and change in discharge.’ Typical signs include erythema, edema, excoriation, pustule formation, and labial fissures. In spite of the multiplicity of clinical characteristics, these features are remarkably nonspecific and can be caused by a variety of infectious and noninfectious types of vulvovaginitis. A comprehensive list of causes of vulvovaginitis is shown in Display Box 2. The most common reason patients fail to respond to antifungal therapy is incorrect diagnosis. For eons, practitioners have prided themselves on their ability to diagnose Candida vaginitis on the basis of an astute clinical examination. Dermatologists are no exception to this phenomenon. These clinical signs and symptoms can be caused by a myriad of causes. Diagnosis of CV on the basis of clinical examination alone is simply unacceptable.14 These same limitations apply to selfdiagnosis by women. On the other hand, diagnosis of CV can be made simply by measurement of vaginal pH and routine microscopy (saline 10% KOH). Regrettably, few physicians avail themselves of these simple tests, and no inexpensive alternative tests are currently available. Even if

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From the Division of Infectious Diseases, Detroit Medical Center, Wayne State University School of Medicine, Detroit, Michigan

DERMATOLOGIC CLINICS VOLUME 16 NUMBER 4 * OCTOBER 1998

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Table 1. CLASSIFICATION OF CANDlDA VULVOVAGlNlTlS (CV) Uncomplicated

Complicated

Sporadichnfrequent CV and Mild-to-moderate CV Likely to be C. albicans add Normal, nonpregnant host

Recurrent CV or Severe CV Non-albicans Candida sp. or Abnormal host (e.g., uncontrolled diabetes) Debilitation Immunosuppression

Traumatic Atrophic vaginitis Postpuerperal atrophic vaginitis Desquamative inflammatory vaginitis (steroid-responsive) Erosive lichen planus Collagen vascular disease, Behqets, pemphigus syndromes Idiopathic

NORMAL pH, MICROSCOPY AND CULTURE-NEGATIVE VAGINITIS

the physician performs these simple, rapid, and inexpensive side-room tests, the diagnosis of CV may remain elusive when the microscopy tests are negative in spite of a compatible clinical picture and a normal vaginal pH. False negative microscopy studies occur in 10% to 30% of women with acute symptomatic CV. Accordingly, a vulvovaginal swab culture is essential in elucidation of the diagnosis, when microscopy fails to provide an answer. Differentiating CV from bacterial vaginosis or trichomoniasis is simple and should not constitute a challenge. Occasionally mixed vaginal infections due to more than one pathogen occur. Similarly, consecutive episodes of vaginitis should not be assumed to be due to the same cause or mechanism. All episodes require physical examination and laboratory confirmation.

Display Box 2. Causes of Vulvovaginitis In Women INFECTIOUS VAGINITIS Bacterial vaginosis (40% to 50%) Vulvovaginal candidiasis (20% to 25%) Trichomonal vaginitis (15% to 20%) LESS COMMON Atrophic vaginitis with 2" bacterial infection Foreign body with 2" infection Desquamative inflammatory vaginitis (clindamycin-responsive) Streptococcal vaginitis (Group A) Ulcerative vaginitis associated with Staphylococcus aureus and toxic shock syndrome Idiopathic vulvovaginal ulceration associated with HIV NONINFECTIOUS VAGINITIS Chemicalhrritant Allergic, hypersensitivity, and contact dermatitis (lichen simplex)

Not infrequently, symptomatic normal pH vulvovaginitis fails to yield a diagnosis when a negative yeast culture is obtained. A variety of noninfectious causes can provoke an indistinguishable syndrome. The most common cause of this culture-negative vulvovaginitis is a contact dermatitis or vulvitis, including chemical or irritant vulvitis, as well as hypersensitivity reactions.25Symptoms and signs of such reactions are extremely common, sometimes transient, but more often chronic and indistinguishable from Candida vaginitis. Causes include soaps, deodorants, underwear, detergents, minipads and pads, spermicides, douche solutions, and vaginal lubricants. An episode may follow excessive or repetitive exposure to a hot tub or jacuzzi with chemically-treated water and especially hyperchlorinated indoor swimming pools. Excessive use of minipads is another frequent cause of an irritant vulvitis. A significant but frequently unrecognized cause of symptomatic vulvovaginitis is local application of azole antimycotics. Although overall these antifungal vaginal agents have proven remarkably effective, local side effects characterized by burning, itching, soreness, erythema, and edema are by no means infrequent, especially with repeated application.

CANDlDA AS THE INNOCENT BYSTANDER Recognizing the value of performing vaginal and vulvar yeast cultures has resulted in physicians performing more cultures than in previous years. The one drawback of this approach is that a positive vaginal yeast culture may be found in 10% to 15%of asymptomatic healthy women at any given time.2 Accordingly, at least the same chance of obtaining a

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positive vaginal culture exist in any symptomatic patient. Therefore, a positive culture in the absence of positive microscopy must always be viewed in this context with caution. A negative culture virtually excludes the likelihood of CV, a positive culture in a symptomatic woman with positive microscopy proves the diagnosis of CV, but the same positive culture with negative microscopy, although strongly suggestive of the diagnosis, will be a "false negative" in 10% to 15% of these patients. In this latter context, only elimination of the yeast, preferably by using an oral antifungal agent together with simultaneous resolution of signs and symptoms, permits verification of the diagnostic significance of the positive culture. If symptoms, persist after cultures become negative, another source or cause of the symptoms should be sought. RESISTANT CANDlDA A LBlCANS

Most microbiological studies indicate that 80% to 95% of clinical isolates responsible for Candida vaginitis are C. albicans.", l5 In spite of the availability of topical imidazoles for more than two decades and oral azoles for more than a decade, resistant strains of C. albicans have been extremely slow in emerging. Reports of clinical and in vitro resistance occurring in women with symptomatic vaginitis due to C. albicans are extremely rare.22 This is stark contrast to the dramatic increase in resistant strains of C. albicans causing oral thrush and Candida esophagitis in patients with advanced AIDS.'O However, these two anatomic sites are strikingly different and studies of pathogenesis of vaginal and oral candidiasis reveal enormous differences in microbiology, virulence factors of organisms, and host predisposing factors. Nevertheless, there are occasional reports of resistant C. albicans causing Candida vaginitis and there is a need for constant surveillance studies to monitor susceptibility patterns. Management of azole-resistant Candida vaginitis depends upon the in vitro susceptibility pattern. Given the rarity of resistance today, no clear picture has emerged; hence the frequency of cross resistance among azoles is largely unknown. Most of the anecdotal reports of azole resistance have described fluconazole resistance with or without cross-resistance to other azoles. Initial management can be successful with topical boric acid or

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flucytosine, sharing no cross-resistance with azoles. Any therapy should be prescribed for 7 to 14 days rather than using a short-course regimen. NO N-ALBEANS CANDlDA VAG INlTlS

In contrast to the paucity of data on C. albicans resistance, much has been written about the increased incidence of vaginitis due to non-albicans Candida species, predomi~ hard facts nantly C. g l a b r ~ t a .Unfortunately are few and far between, and accurate statistics are just not available. More physicians are reporting clinically resistant vaginitis due to C. glabrata confirmed by vaginal culture. Whether this is due to the increased number of cultures obtained, increased awareness, or a true change in epidemiology is not known, but it is likely that all of these factors apply. If an increased prevalence of C. glabrata now exists, the extent and severity of this increase have not been quantitated. Much conjecture has appeared as to the explanation for increased non-albicans Candida including widespread abuse of over-thecounter (OTC) antifungals, use of single dose oral and topical azole regimens, both prescription and OTC, and finally the use of long term maintenance regimens of oral azoles.zl Vaginitis due to C. glabrata has been poorly studied; however, a number of risk factors and clinical characteristics have emerged (Display Box 3). Infection tends to occur in older women, often with underlying associated disease (e.g., diabetes mellitus). There is invariably a history of recent exposure to azoles. The clinical picture, although indistinguishable from C. albicans vaginitis, tends to be more indolent, chronic with more burning than itching, and often accompanied by a watery discharge. Vaginal pH is often slightly elevated. Display Box 3. Clinical Characteristics of Vaginitis due to Candida glabrafa

history of previous azole exposure older women underlying disease is frequent (e.g., diabetes mellitus) mixed infections (e.g., bacterial vaginosis) more indolent, burning more than itching, often chronic discharge frequently absent absence of pseudohyphae on microscopy azole resistance

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Overall, C. glabrata isolates have intrinsic, reduced susceptibility to all azoles with minimal inhibitory concentrations (MICs) predictably higher than those observed with C. albicuns.I3 Nevertheless, the MICs are still for the most part below the concentrations achievable in the vagina with oral azoles and especially with topical azoles. The therapeutic achievable ratio in vaginal secretions (i.e., the ratio of the achievable local concentration to the MIC of the organism) is nevertheless considerably lower with systemic azoles, especially if the latter are prescribed in a short duration regimen. Strains of overtly azoleresistant C. glabrata are not infrequent and may emerge longitudinally with time in any individual. The presence of an azole-resistant C. glabrata isolate usually comes to the attention of the clinician when the patient fails to respond to conventional therapy or relapses frequently. Given the initial clinical hint, microscopy usually confirms the diagnosis, and budding yeast without hyphae are seen on microscopy (Fig. 1).Cultures to identify the Candida species are indicated, although susceptibility tests may not be initially needed. Therapy for C. glabrata remains problematic.12,l9 The first principle is never to use short course, especially single dose, regimens. If the isolate is treatment-naive and the patient has not received several recent courses of azoles, then conventional long duration azole regimens, both oral or topical, are frequently adequate; however, often the symptomatic patient has recently received and failed on these agents, hence an azole should not be prescribed empirically. Before resorting to susceptibility tests, often a trial of vaginal boric acid capsules 600 mg once to twice daily for 14 days will be worthwhile, achieving cure in about 70% of patients.I9 Alternatively, topical flucytosine can be made up and prescribed for the same d ~ r a t i o nA . ~maintenance regimen is usually not indicated unless the initial response is followed by fairly rapid relapse (less than 3 months). Boric acid and flucytosine cannot be used long term, hence a reasonable maintenance regimen after remission is once more achieved, consisting of vaginal nystatin at 100,000 units daily. Failure to control the infection with the above measures mandates in vitro susceptibility tests and selection of active agents, often used in combination. A variety of other non-albicans Candida species are reported not infrequently to cause

Figure 1. Light microscopy of saline preparations reveals multiple budding yeast, absence of pseudohyphae, and clue cells in this mixed infection of Candida glabrata and bacterial vaginosis.

vaginitis. Most will still respond to conventional therapy. C . krusei is intrinsically resistant to fluconazole, but will respond favorably to all other agents. Saccharornyces cerevisiae resembles C . glabrata and can be treated with boric acid or flucyto~ine.~~ RECURRENT VAGINITIS DUE TO AZOLE-SENSITIVE C. ALBlCANS

The enigma of frequently recurring Candida albicans vaginitis in adult women is exactly that, an enigma.16 Only rarely is an underlying cause of this increasingly common problem apparent (e.g., uncontrolled diabetes mellitus, patients on high-dose steroids or other immunosuppressives). Associated HIV infection has not been proven to cause recurring episodes of Candida vaginitis. Similarly, patients with undiagnosed diabetes rarely present with recurring C. vaginitis and thousands of unnecessary glucose tolerance tests are performed each year. In a minority of women, repeated bouts of Candida vaginitis predict-

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ably follow repeated courses of antibiotics. While oral contraceptives may predispose to recurring yeast infections, once the pattern of recurrence is established, stopping the oral contraception rarely ends the problem. There is some preliminary but unsubstantiated evidence that hormone replacement therapy not only extends the period of female vulnerability to Candida vaginitis, but may also predispose to infection in a small number of patients.21 Nevertheless, in the majority of women with recurrent candidiasis, no underlying cause or precipitating factor is apparent. Accordingly, given the predictable susceptibility of C. albicans responsible for most episodes, attention has focused on three other areas. No evidence has emerged that highrisk women lack a protective vaginal flora, hence yogurt or such therapy has no theoretical biological basis? nor are there satisfactory data showing exogenous probiotic therapy to be efficacious.20Too many data are anecdotal. Sexual transmission remains surrounded by controversy. In some women, sexual transmission of Candida, especially by the oragenital route, undoubtedly occurs, but in a minority of women only.8,24 Could this be an explanation in any given patient with recurring infections? An indirect answer is provided by pointing out that most controlled studies have failed to show a therapeutic benefit by treating the male sexual partner: but Spinel1 did show benefit in one such Most investigators do not advocate antifungal treatment for the sexual ~ a r t n e r . ~ Finally we are left with the possibly of an acquired Candida antigen(s)-specific immune problem that only manifests in the vagina. One theory claims that patients lose their capacity to express what little protective immunity the mucosa has against Candida. This allows uncontrolled proliferation, germination, and therefore mucosal invasion (i.e., immune tolerance is replaced by immune paral~ s i s )On . ~ the other hand, some advocate the exact opposite, i.e., local vaginal immune tolerance of commensal Candida is replaced by an exaggerated hyperimmune response resulting in acute intolerance or sensitization to Candida antigen^.^ There is evidence that both may occur or coexist. Patients with frequently recurring infections can be easily handled by long-term maintenance antifungal regimens. Following induction therapy to achieve clinical remission and negative vaginal cultures, maintenance regimens with topical or the more con-

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venient oral imidazole or triazole systemic agents are highly effective in suppressing recurrent Candida vaginitis.21Regimens include daily dosages of ketoconazole 100 mg or itraconazole 50 to 100 mg, or weekly fluconazole 100 mg.I7,l8 Topical treatment includes weekly clotrimazole 500 mg. Cessation of the maintenance regimen .after 6 months predictably is accompanied by rapid relapse in about half the ~ 0 r n e n . lAccordingly, ~ return to a frequent relapsing pattern necessitates reinstitution of the aforementioned maintenance azole regimens for longer periods of 12 months or more. Breakthrough infections while on the prophylactic regimens mandate culture confirmation and in the compliant patient require susceptibility testing to exclude the rare but possible acquisition of an azole-resistant strain of C. albicans or switch to non-albicans Candida species. References 1. Berg AO, Heidrich FE, Fihn SD, et al: Establishing the cause of symptoms in women in a family practice. JAMA 251:620-625, 1984 2. Drake TE, Maibach H I Candida and candidiasis: Cultural conditions, epidemiology, and pathogenesis. Postgrad Med 53233-93, 1973 3. Fidel PJ Jr, Sobel JD: Immunopathogenesis of recurrent vulvovaginal candidiasis. Clin Microbiol Rev 9:335-348, 1996 4. Fong IW: The value of treating the sexual partners of women with recurrent vaginal candidiasis with ketoconazole. Genitourin Med 68:174-176, 1992 5. Geiger A, Foxman 8,Sobel JD: Recurrent vulvovaginal candidiasis: Characteristics of women with Candida albicans, C. glabvata and no Candida. Genitourin Med 71:304-307, 1995 6. Hilton E, Isenberg HD, Alperstein P, et al: Ingestion of yogurt containing Lactobacillus acidophilus as prophylaxis for candidal vaginitis. Ann Intern Med 116~353-353,1992 7. Horowitz B: Topical flucytosine therapy for chronic recurrent Candida tropicalis infections. J Reprod Med 31~821-824, 1986 8. Horowitz B, Edelstein SW, Lippman L: Sexual transmission of Candida. Obstet Gynecol 69:883-886, 1987 9. Horowitz BJ, Giaquinta D, Ito S Evolving pathogens in vulvovaginal candidiasis: Implications for patient care. J Clin Pharmacol 32:248-255, 1992 10. Ng TTC, Denning DW Fluconazole resistance in Candida in patients with AIDS: A therapeutic approach. J Infect Dis 26:117-125, 1993 11. Odds FC: Candidiasis of the genitalia. In Odd FC (ed): Candida and candidosis: A review and bibliography, ed 2. London, Balliere Tindall, 1988, pp 124135 12. Redondo-Lopez V, Lynch M, Schmitt C, et al: Torulopsis glabrata vaginitis: Clinical aspects and susceptibility to antifungal agents. Obstet Gynecol 76:651655, 1990 13. Rex JH, Rinaldi MG, Pfaller MA: Resistance of Can-

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didu species to fluconazole. Antimicrob Agents Chemother 39:l-8, 1995 14. Schaaf VKM, Perex-Stable EJ, Borchardt K: The limited value of symptoms and signs in the diagnosis of vaginal infections. Arch Intern Med 150:1929-1933, 1990 15. Sobel JD Epidemiology and pathogenesis of recurrent vulvovaginal candidiasis. Am J Obstet Gynecol 152:924-934, 1985 16. Sobel JD. Pathogenesis and treatment of recurrent vulvovaginal candidiasis. Clin Infect Dis 14(Suppl): S148-153, 1992 17. Sobel JD: Recurrent vulvovaginal candidiasis. A prospective study of the efficacy of maintenance ketoconazole therapy. N Engl J Med 3151455-1458, 1986 18. Sobel JD Treatment of recurrent vulvovaginal candidiasis with maintenance fluconazole. Int J Gynaecol Obstet 3717-34, 1992 19. Sobel JD, Chaim W. Treatment of Cundidu glubrutu vaginitis: A retrospective review of boric acid therapy. Clin Infect Dis 246494552, 1997 20. Sobel JD, Chaim W: Vaginal microbiology of women

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with acute recurrent vulvovaginal candidiasis. J Clin Microbiol3k2497-2502, 1996 Sobel JD, Far0 S, Force RW, et a1 Vulvovaginal candidiasis: Epidemiologic, diagnostic, and therapeutic considerations. Am J Obstet Gynecol 1998;178 (in press) Sobel JD, Vazquez JA. Symptomatic vulvovaginitis due to resistance Cundidu albicuns in a female who was not infected with human immunodeficiency virus. Clin Infect Dis 22:72&727, 1996 Sobel JD, Vazquez J, Lynch M, et al: Vaginitis due to Saccharomyces cerevisiae: Epidemiology, clinical aspects, and therapy. Clin Infect Dis 16:93-99, 1993 Spinillo A, Carrata L, Pizzoli G Recurrent vulvovaginal candidiasis: Results of a cohort study of sexual transmission and intestinal reservoir. J Reprod Med 37343-347, 1992 Summer PR Clinical evidence of a dermatologic etiology for recurrent vulvovaginal candidiasis in immunocompetent patients. Investigational Summit on Cutaneous Antifungal Therapy. San Francisco, California, October 23, 1993

Address reprint requests to Jack D. Sobel, MD Harper Hospital 3990 John R Detroit, MI 48201