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11. 12.

13. 14.

15.

of intraepithelial neoplasia of the cervix with human papillomavirus types. IntJ Gynecol PathoI1989;8:15-25. The 1988 Bethesda System for Reporting Cervical/Vaginal Cytological Diagnoses. JAMA 1989;262:931-4. Wilcynski SP, Bergen S, Walker J, Liao S-Y, Pearlman LF. Human papillomaviruses and cervical cancer: analysis of the histopathologic features associated with different viral types. Hum PathoI1988;19:697-704. Barnes W, Delgado G, Kurman RJ, et al. Possible prognostic significance of human papilloma virus type in cervical cancer. Gynecol Oncol 1988;29:267-73. Kurman RJ, Schiffman MH, Lancaaster WD, et al. Analysis of individual human papillomavirus types in cervical neoplasia; a possible role for type 18 in rapid progression. AM J OBSTET GYNECOL 1988; 159:293-6. Twiggs LB, Okagaki T, Clark B, Fukushima M, Ostrow R, Faras A. A clinical, histopathologic, and molecular biologic investigation of vulvar intraepithelial neoplasia. Int J Gynaecol Pathol 1988;7:48-55.

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16. BuscemaJ, Naghashfar Z, Swada E, Daniel R, Woodruff JD, Shah K. The predominance of human papillomavirus type 16 in vulvar neoplasia. Obstet Gynecol 1988;71: 601-6. 17. Planner RS, Hobbs JB. Intraepithelial and invasive neoplasia of the vulva in association with human papillomavirus infection. J Reprod Med 1988;33:503-9. 18. Rosenberg SK, Greenberg MD, Reid R. Sexually transmitted papillomaviral infection in men. Obstet Gynecol Clin North Am 1987;14:495-511-2. 19. Barraso R, de Brux J, Croissant 0, Orth G. High prevalence of papillomavirus-associated penile intraepithelial neoplasia in sexual partners of women with cervical intraepithelial neoplasia. N Engl J Med 1987;317:916-23. 20. Gal D, Friedman M, Mitrani-Rosenbaum S. Transmissability and treatment failures of different types of human papillomavirus. Obstet Gynecol 1989;73:308-11.

Mycotic vulvovaginitis: A broad overview Benson J. Horowitz, MD Hartford, Connecticut The incidence of mycotic vulvovaginitis is rising dramatically in the United States mainly because of an increase in infections caused by Candida species. Accurate diagnosis depends on culture techniques that will yield correct identification of fungal pathogen(s). Recurrences are common and require culture specimens from sexual partners and appropriate antifungal therapy. The imidazoles and more recently the broader spectrum triazoles are used for vaginal therapy. (AM J OBSTET GYNECOL 1991 ;165:1188-92.)

Key words: Mycotic vulvovaginitis, Candida species, fungal infections, antifungal agents In the United States alone, 13 million cases of mycotic vulvovaginitis occur annually.! During the past decade, the population of women 18 years of age and older has increased approximately 13%, whereas the number of prescriptions written annually for vulvovaginal candidiasis has increased more than 53%. In the United Kingdom, the number of cases of vaginal candidiasis reported in sexually transmitted disease clinics has increased from 21,000 in 1972 to 38,000 in 1982.2 Candida species were the third most frequently reported pathogens associated with nosocomial bloodstream infections as reported by Horan et aI.' in the National Nosocomial Infections Surveillance System between January 1985

From the Department of Obstetrics and Gynecology, University of Connecticut School of Medicine. Reprint requests: Benson J. Horowitz, MD, S.H.E. Medical Associates, 449 Farmington Ave., Hartford, CT 06105. 610132261

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and August 1988. This report indicates that in 1984 Candida was ranked eighth, thereby indicating a trend toward increasing prevalence of Candida. Interestingly, in the 1988 National Nosocomial Infections Surveillance System report, 35% of the yeast species were nonalbicans. These data and the daily experiences of clinicians affirm the impression that human mycoses in general and vaginal mycotic disease in particular are on the rise. The advent of immunosuppressive disease created iatrogenically with the use of cyclosporine in patients undergoing transplantation, pathologically in patients with acquired immunodeficiency syndrome, or chemotherapeutically in patients with cancer creates premature death not by the disease process but by the opportumstIc infection by the lowly one-celled fungus-the yeast. It is evident that knowledge of and familiarity with fungi are of the utmost importance to physicians of all medical disciplines. As the human ex-

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perience evolves, association with the most primitive of organisms, the yeast, becomes more intimate. Classification

The study of fungi has been complicated by their attempted inclusion into the plant or the animal kingdom. This confusion was created by the fact that some fungal processes are shared by both plants and animals. The dilemma was remedied by the establishment of a third kingdom called the kingdom of fungi. As a result, there are now three kingdoms: plants, animals, and fungi . The taxonomic classification of the kingdom of fungi as it pertains to human disease is in the form phylum Deuteromycota, form class Blastomycetes, and form family Cryptococcaceae. The six genera of the form family Cryptococcaceae are of particular interest to the practicing vulvovaginologist. These genera are Cryptococcus, Malassezia, Rhodotorula, Candida, Trichosporon, and Geotrichum. Members of all of these genera have been found in women with vulvovaginal complaints. The most important members of the genus Candida in human clinical disease are: C. albicans, C. tropicalis, C. glabrata, C. krusei, C. parapsilosis, C. pseudotropicalis, C. lusitaniae, and C. rugosa. C. stellatoidea has recently been incorporated in C. albicans, and Torulopsis glabrata was renamed C. glabrata! Currently the most frequent and important systemic and vaginal yeasts are C. albicans, C. tropicalis, C. glabrata, and C. parapsilosis. In a random study population of women with vulvovaginitis caused by a fungus ,' C. albicans was found in at least 65% of patients. Twenty-three percent of these patients harbored C. tropicalis. In this study, Cryptococcus ungulaticus, Trichosporon beigelii, and Saccharomyces cerevisiae were also found. Three percent of the study population with vulvovaginitis had dermatophytes. In a study of 2184 isolates from 18 studies from 1963 to 1987,6 C. albicans was cultured in 84.2 %, C. tropicalis in 5.3%, and C. glabrata in 5.5% of patients. Morphology

Recognition of the morphology of fungal species leads to proper diagnosis. There are only three anatomic structures that the clinician must recognize for diagnostic purposes: the pseudomycelia, the blastospore, and the chlamydospore. The pseudomycelia is the long filamentous form with its arborization of branches. It is called a pseudomycelia because of its lack of segmentation. The blastospore is the collection of small refractile bodies resembling a group of glass beads, and the chlamydospore is a terminal birefractile sphere at the end of a pseudomycelia. Recognition of these structures is necessary to achieve therapeutic goals. Emphasis on filamentous forms versus budding

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forms is misplaced because depending on environmental conditions, the organism will assume either of these two anatomic structures. When the yeast assumes the filamentous form, candidal adherence is facilitated. The three candidal organisms of greatest prevalence, namely, C. albicans, C. tropicalis, and C. glabrata, are easily recognized by their morphology. The albicans organism consists of pseudohyphae, blastospores (blastoconidia), and chlamydospores (chlamydoconidia). The tropicalis organism has no terminal chlamydospore, and the organism appears as great clusters growing on a central stem. The glabrata organism contains no pseudohyphae and no chlamydospores but is only a collection of blastospores. Biochemistry

The most important biochemical characteristics of yeasts are their ability to ferment and assimilate sugars. The specific sugar that is metabolized has been used as the traditional method of fungal identification. The tools of molecular biology offer more exact methods of identification; however, for the average clinician the former method is sufficient. The fermentation and assimilation patterns are easy ways to identify the particular species. Both five- and six-carbon atom sugars are metabolized. The efficiency of a yeast to convert sugars to carbon dioxide and ethanol cannot be duplicated by the chemist. Because of this, the brewing industry relies on the biochemical processes of the yeast in an anaerobic environment to make alcohol, and the baking industry relies on this process in an aerobic environment to leaven baked goods by the production of carbon dioxide. In a study? that used sugar chromatography,7 those cases of vulvovaginitis labeled recurrent or culture positive revealed a greater amount of sugar in the urine than in normal persons. From this work it was deduced that the amount of sugar substrate consumed by a woman was of importance in the continuation and persistence of vulvovaginal infections. Pathophysiology and pathogenicity

The familiar reddening of the vaginal and vulvar tissues and the recognition of satellite lesions caused by candidal infection are easily recognized by the clinician. The pathogenesis of the reddening and the symptoms of itching, burning, and discharge are probably produced by the production of alcohol in the microaerophilic environment of the vagina. Other factors affecting the pathogenicity of the organism are sugar substrates,7 dressing patterns,8. 9 antibiotic therapy,lO· II activated reservoirs,12-14 antifungal bacterial factors, 15 adherence phenomena,16.17 immunologic hypersensitivity,1 8-20 fungal species,' and certain forms of contraceptives! 1

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Transmission of candidal organisms from a male partner to the vagina has been studied by several authors. 14 • 22. 23 In a recent study of the male consorts of women who had culture-proved Candida vulvovaginitis, 33% had the same organism in their oral cavities, 36% in their rectal cavities, and 15% in their ejaculates. Results of prostatic cultures were negative; however, results of ejaculate cultures were positive. This suggests that the organisms reside in the seminal vesicles where fructose is abundant. In contrast, consorts of women without symptoms had negative results for cultured Candida orally and in their ejaculate. 14 Laboratory identification

The techniques for laboratory diagnosis of yeast infections have been simplified, and rapid diagnostic kits are available. Sabouraud's dextrose medium impregnated with chloramphenicol used as the basic culture medium for Candida is easily obtained from local suppliers. Thayer-Martin medium, an anaerobic culture medium used predominantly for the isolation of the gonococcus, may support the growth of yeast when Sabouraud's dextrose medium fails. After 5 days of incubation in ordinary conditions of light and temperature, the white mucoid colonies can be transferred to species identification kits. Incubation at 37" C with serum produces "germ tubes" (the Reynolds-Braude phenomenon). Germ tubes are produced by C. albicans and some species of C. tropicalis. Just as it is necessary to identify bacteria because the individual characteristics of these organisms are important for therapy, so is it true of yeasts. Each of these yeasts have different characteristics. The nature of these differences will be of importance in the design of antifungal preparations and in the spectrum of recurrent and relapsing disease. The use of culture kits provides the clinician with irrefutable evidence of a mycotic infection, indicates the exact species of the organism, provides information concerning sexual transmission, and delineates reservoirs. This information is essential in the treatment of recurring and relapsing disease. Cell wall biochemistry and modes of action

Yeast organisms have a unique cell wall, and the biochemical pathways in the cell wall are important for its integrity. These pathways are more similar to those of the plant kingdom than to those of the animal kingdom. The sterol pathways proceed from squalene through squalene 2,3 oxide to lanosterol, and on to ergosterol. Antifungal agents are specifically designed to interfere with these biochemical pathways. The enzymes of the cytochrome P-450 group are particularly vulnerable, and this accessibility provides an opportunity for pharmacologic effectiveness. Yeast cell walls also consist of

October 1991 Am J Obstet Gynecol

the polysaccharides glucan, mannan, and chitin, protein, lipids, and in some cases capsular polysaccharides. 24 Mannoproteins are the main antigenic components of the cell wall. Yeast cells also contain estrogen receptors in the cell wall. Yeasts do not proliferate without estrogen support. Pathogen susceptibility

In 1972 Van Cutsem and Thienpont;' testing miconazole's effectiveness against various species of yeasts, found that it took 10 times more miconazole to eradicate C. tropicalis and C. glabrata than C. albicans. 25 Takada et aU 6 reported that the minimum inhibitory concentration of imidazole antimycotics, including econazole, miconazole, and clotrimazole, against C. glabrata was two to four times higher than that against C. albicans isolates. These data unequivocally support the concept that all species of Candida are not the same and that recurrence and relapse may be from ineffective concentrations of antifungal agents. Aspects of selection

The prevalence of non-albicans species in the 1970s, as tabulated in nine studies, approximates 9.9%.6 In the 1980s, seven studies revealed a prevalence of 21.3%. During this same period, the incidence of C. glabrata increased from 4.6% to 6.7%, and C. tropicalis increased from 1.3% to 8.2%. Data from clinical studies demonstrated an increase in non-albicans species from 9% in 1971 to 14% in 1987. The increase in C. tropicalis has been the most dramatic. Although the exact cause of this non-albicans selection is unknown, there is some evidence that antifungal therapy itself may be the cause. Redondo-Lopez et al. 27 concluded that most patients in whom C. glabrata was isolated were treated previously with a multitude of antifungal agents and that iatrogenic factors select for the presence of C. glabrata. Kerridge and Nicholas 28 found that strains of C. glabrata were more resistant to the imidazoles than were C. albicans. They noted that C. glabrata is haploid and C. albicans is diploid. This may account for increased drug resistance. Horowitz et al. 5 and Merz and Sanford 29 described strains of C. tropicalis with the ability to forego the 14-a-demethylation pathway in the cell wall, making these organisms resistant to imidazole therapy. All these data suggest that the non-albicans species are more resistant to imidazole and polyene macrolide therapy and that the therapy itself created the non-albicans selection. The second theory involves the use of shorter courses of imidazole therapy. Support for this theory can be found from the history of such infections in patients with neutropenia.3()·32 Increased numbers of systemic infections caused by C. tropicalis, C. glabrata, and other

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non-albicans species were related to the routine use of prolonged, low-dose prophylactic polyenes and imidazoles to prevent oral and systemic candidiasis, Takada et aL" described replacement of initial C. albicans vaginitis with C, glabrata in patients treated with clotrimazole. Therapy

Commonly used products that eradicate fungal infections are the imidazoles and polyene macrolides. These products interfere with the sterol chemistry pathways in the cell wall of the fungal cell. The imidazoles interfere with the 14-a-demethylase enzyme in the conversion of lanosterol to ergosterol. Interference is also noted in side-chain cleavage, the desmolase reaction, and the 1113-hydroxylase enzyme. Polyene macrolides, such as nystatin, katamycin, and amphotericin B, also interfere with the formation of ergosterol. The general formula of an azole antimycotic is a pentene ring containing two nitrogen atoms and three carbon atoms to which side chains are added. The configuration of the side chain determines the nature of the imidazole compound. Examples of the compounds are miconazole, clotrimazole, tioconazole, ketoconazole, and butoconazole. Not all imidazoles are equally effective against all species of yeasts. For example, C. tropicalis and C. glabrata are 10 times less sensitive to the action of miconazole than is C. albicans. Rhodotorula is particularly insensitive to the action of miconazole. For this reason, other agents have been devised and they fall into two classes: a new azole antifungal, the triazole, and the pyrimidines. The development of the triazole compounds, specifically terconazole, addressed several of the difficulties of the imidazoles. A triazole is distinguished from an imidazole by the addition of a third nitrogen atom in the pentene ring. Attached to the ring is a side chain. The configuration of the side chain is designed to make the compound more lipophilic for better cell-wall penetrability. Although both imidazoles and triazoles interfere with the cytochrome P-450 isoenzymes, the triazole is more potent. This potency increases the susceptibility of C. tropicalis and C. glabrata to terconazole. The biochemical configuration also creates enhanced antifungal action at lower pharmaceutical concentrations. Although azole compounds interfere with cytochrome P-450 processes both in the fungal and mammalian vaginal cell, the chemical structure of the triazole makes it more selective. The ideal antifungal agent, one that would interfere only with the fungal cell, is as yet unattainable; however, the enhanced selectivity of the triazole results in less vaginal irritation. 34 • 35 Greater selectivity also allows for the devel-

Mycotic vulvovaginitis: A broad overview

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opment of compounds of greater concentration over shorter periods of time. In contrast to the azoles, a pyrimidine is a six-carbon atom ring with four carbon atoms, two unsaturated bonds, and two nitrogen atoms. The pyrimidine acts in a totally different way in that it is converted to 5-ftuorouracil when carried into the nucleus of the fungal cell where it actively destroys deoxyribonucleic acid and ribonucleic acid helices. Recurrence and relapse

Recurrent and relapsing fungal infections cause great frustration to both patient and care provider. The management of these cases requires accurate diagnosis, which is crucial to appropriate therapy. Unless culture techniques are available, misdiagnoses will be frequent. Anaerobic lactobacilli, MobiluncUJ, and Actinomyces can be mistaken for fungi. Recurrent fungal vulvovaginitis requires culture specimens from all partners l4 • 36 and appropriate fungal therapy directed at the source of the contagion. Vaginal therapy includes the imidazoles and more currently the triazoles; oral therapy, clotrimazole oral troches or nystatin pastilles; gastrointestinal candidiasis, nystatin tablets or powder or ketoconazole; and for ejaculate candidiasis, ketoconazole or fluconazole tablets. Prophylactic therapy with ketoconazole during the first 5-days of the menstrual cycle for six cycles or daily for 6 months was effective in preventing the symptoms of candidal vaginitis. However, symptoms returned after discontinuation of therapy.ll The continued application of current knowledge and the new therapies being developed will significantly aid the clinician in the quest for complete therapeutic success.

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1. Weisberg M. Considerations in therapy for vulvovaginal candidiasis: when and whom to treat. In: Sobel j, ed . Clinical perspectives: terconazole, an advance in vulvovaginal candidiasis therapy. 1st ed. New York: McGrawHill , 1988:2. 2. BinghamjS. Vulvovaginal candidiasis-an overview. Acta Derm Venereol Suppl 1986;121:39-46. 3. Horan T, Culver D, javis W, et al. Pathogens causing nosocomial infections. The Antimicrobic Newsletter 1988;5:65-7. 4. Rippon jw. Medical mycology. 2nd ed. Philadelphia: WB Saunders, 1982:490. 5. Horowitz BJ , Edelstein SW, Lippman L. Candida tropicalis vulvovaginitis. Obstet Gynecol 1985;66:229-32. 6. Odds FC. Candida and candidosis. 2nd ed. London: Balliere Tindall, 1988. 7. Horowitz Bj, Edelstein SW, Lippman L. Sugar chromatography studies in recurrent Candida vulvovaginitis. j Reprod Med 1984;29:44 1-3. 8. Elegbe lA, Botu M. A preliminary study on dressing patterns and incidence of candidiasis. Am] Public Health 1982;72: 176-7. 9. Heidrich FE, Berg AO, Bergman]]. Clothing factors and vaginitis.] Fam Pract 1984;19:491-4.

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