Vaginitis: Differential Diagnosis and Management

VAGINITIS Differential Diagnosis and Management VAGINITIS Differential Diagnosis and Management Sebastian Faro,MD, ...

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VAGINITIS

Differential Diagnosis and Management

VAGINITIS Differential Diagnosis and Management

Sebastian Faro,MD, PhD Clinical Professor Department of Obstetrics, Gynecology, and Reproductive Sciences The University of Texas—Houston Health Sciences Center Attending Physician The Woman’s Hospital of Texas Houston, Texas

BOCA RATON LONDON NEW YORK WASHINGTON, D.C

Published in the USA by The Parthenon Publishing Group 345 Park Avenue South New York, NY 10010, USA This edition published in the Taylor & Francis e-Library, 2005. “To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk.” Published in the UK by The Parthenon Publishing Group 23–25 Blades Court Deodar Road London, SW15 2NU, UK Copyright ©2004,The Parthenon Publishing Group Library of Congress Cataloging-in-Publication Data Faro, Sebastian. Vaginitis: differential diagnosis and management/Sebastian Faro. p.; cm. Includes bibliographical references and index. ISBN 1-84214-159-7 (alk. paper) 1. Vaginitis. 2. Vagina-Diseases. 3. Diagnosis, Differential. I. Title. [DNLM: 1. Vaginitis-diagnosis. 2. Diagnosis, Differential. 3. Vaginitis-drug therapy. WP 255 F237v 2003] RG268.F37 2003 618.1’5–dc22 2003061739 British Library Cataloguing in Publication Data Faro, Sebastian Vaginitis: differential diagnosis and management 1. Vaginitis-Diagnosis 2. Vaginitis-Treatment I. Title 618.1’5 ISBN 0-203-50011-3 Master e-book ISBN

ISBN 0-203-59625-0 (Adobe eReader Format) ISBN 1-84214-159-7 (Print Edition) No part of this book may be reproduced in any form without permission from the publishers except for the quotation of brief passages for the purpose of review Composition by The Parthenon Publishing Group, London, UK

CONTENTS

Color illustrations

v

1.

Healthy vaginal ecosystem

1

2.

Vulvitis

10

3.

Bacterial vaginosis

14

4.

Bacterial vaginitis

26

5.

Vulvovaginal candidiasis

35

6.

Trichomoniasis

58

7.

Atrophic vaginitis

86

8.

Desquamative vaginitis

92

9.

Cytolytic vaginosis

96

Index

99

COLOR ILLUSTRATIONS

Figures 1 and 2 Gram stains of vaginal fluid demonstrating wellestrogenized squamous epithelial cells and large gram-positive bacilli characteristic of Lactobacillus. Note the homogenous appearance of the cytoplasm of the squamous cells, the distinct nucleus, and cell membrane. There is a relative absence of other bacteria. Also note that there are no bacteria adhering to the squamous cells

vi

Figure 4 Gram stain of vaginal fluid from a patient developing bacterial vaginosis. Note adherent Gram-negative rods to cytoplasmic membranes of the squamous epithelial cells. Bacteria in vaginal tend to occur in aggreagates; this is typical of flora dominated by Gardnerella vaginalis

Figure 5 Gram stain of vaginal fluid from a patient with developing bacterial vaginosis. Bacteria adhering to squamous epithelial cells. Note individual freefloating bacteria in the vaginal fluid. The nucleus of the squamous epithelial cells and cell membranes can be identified

vii

Figure 6 Gram stain of vaginal fluid from a patient with bacterial vaginosis. Note that the bacteria adhering to the squamous cells have obliterated the nuclei and cell membrane. There are numerous free-floating bacteria in the vaginal fluid. This microplutopaple is typical of the vaginal fluid from a patient with bacterial vaginosis

Figure 7 Atrophic smear showing large number of intermediate and basal cells. Reproduced with permission from Brown D. Atrophic and postirradiation vaginitis. In Horowitz BJ, Mårdh P-A, eds. Vaginitisand Vaginosis. New York: Wiley-Liss, 1991; 169–79

viii

Figure 8 Cytolytic vaginosis. Note large number of lactobacili and dissolution of epithelial cells. Reproduced with permission from Cibley LJ, Cibley LJ. Cytolytic vaginosis: a common cause of vaginitis. In Horowitz BJ, Mårdh P-A, eds. Vaginitisand Vaginosis. New York: Wiley-Liss, 1991;181–87

ix

Figure 9 Note erythema of the labia majora and labia minora. The labia majora are swollen and there is a pustule in the right labia

Figure 10 Wet prep of vaginal discharge from a patient with candidiasis. Note the hyphae among the squamous epithelial cells

Figure 11 Wet prep diluted with saline and viewed under phase contrast microscopy. Note that the squamous cells are well estrogenized and the

x

relative absence of white blood cells. The hyphae are characteristic of Candida ablicans

Figure 12 Wet prep from a patient with vaginal candidiasis. Note the presence of budding yeast cells and the absence of hyphae. This patient had Candida glabrata vaginitis

Figure 13 Gram stain of Trichomonas vaginalis. Note the elliptical shape and flagella

xi

Figure 14 Wet prep with vaginal fluid from a patient with Trichomonas vaginalis vaginitis. T. vaginalis can assume a spherical shape that is larger than white blood cells; note the variety of T. vaginalis shapes and absence of lactobacilli

Figure 15 Phase contract microscopy of Trichomonasvaginalis vaginitis. One trichomonad has an elliptical shape and another has assumed an amoeboid characteristic

xii

Figure 16 Cytolytic vaginosis. White vaginal discharge mimicking candidal infection (through colposcope, x6). Reproduced with permission from Cibley LJ, Cibley LJ. Cytolytic vaginosis: a common cause of vaginitis. In Horowitz BJ, Mårdh P-A, eds. Vaginitis andVaginosis. New York: Wiley-Liss, 1991; 181– 87

Figure 17 Cytolytic vaginosis. Excess lactobacilli with naked squamous cell nuclei (Nomarski, x160). Reproduced with permission from Cibley LJ, Cibley LJ. Cytolytic vaginosis: a common cause of vaginitis. In Horowitz BJ, Mårdh P-A, eds. Vaginitis andVaginosis. New York: Wiley-Liss, 1991; 181–87

1. HEALTHY VAGINAL ECOSYSTEM

INTRODUCTION The vaginal ecosystem is a complex biosphere, made up of a variety of constituents existing in a delicate equilibrium. The ecosystem contains many types of bacteria that are constantly secreting and releasing metabolic products such as acids, carbohydrates, and proteins, and cellular debris from the disruption of dying bacterial cells like nucleic acids, fatty acids, and sugars. The host is also constantly secreting metabolic products and cellular debris into this ecosystem. This microflora consists of, among other organisms, Gram-positive and Gram-negative aerobic, facultative and obligate anaerobic bacteria. The most common bacterial species isolated from the vagina are listed in Table 1. Both non-pathogenic and pathogenic bacteria are among the numerous bacteria present. However, it is important to understand that any bacterium, given the appropriate inoculum size and proper environmental conditions, can become pathogenic and cause disease. In a healthy vaginal ecosystem the microflora is dominated by Lactobacillus spp. When the ecosystem becomes disrupted or unbalanced, the pathogenic bacteria gain dominance and pose a potential threat to the individual’s general health. Although Table 1 represents the bacteria most commonly isolated from the healthy vagina, it is by no means a complete list. Other bacteria, such as Pseudomonas spp., Staphylococcus aureus and Haemophilus influenzae, have also been isolated from the vagina of healthy individuals.

2 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENT

Table 1 Bacteria Commonly isolated from a healthy vaginal ecosystem

THE VAGINAL ECOSYSTEM The vagina is a potentially tubular organ lined by stratified squamous epithelial cells. There are no mucus-secreting cells within the vaginal epithelium; mucus is produced by the periurethral glands, Skene’s glands, and the glands that exit from the medial inferior aspect of the labia minora, known as Bartholin’s glands. The discharge found within the vagina arises from a transudate secreted through the vaginal epithelium and from the cervix. Therefore, the vaginal discharge is a composite of fluid, cells, and cellular debris that is derived from the vaginal transudate and cervical secretions, as well as fluid secreted from the endometrium and fallopian tubes. The average amount of vaginal discharge a woman of reproductive age not on hormonal therapy produces on a daily basis is 1–3 g1. The vaginal secretions contain a variety of compounds, including proteins, carbohydrates, urea, and fatty acids. The carbohydrates are a mixture of simple and complex sugars. Glucose, maltose, maltotriose, maltotetraose, and free glycogen have all been isolated from vaginal fluid2. The proteins in vaginal fluid are derived from a transudate of serum proteins and proteins produced by the upper genital tract and cervix. The major proteins found in vaginal fluid are

HEALTHY VAGINAL ECOSYSTEM 3

albumin and immunoglobulins, and amino acids are also present3. These constituents of the vaginal ecosystem provide an excellent culture medium for the endogenous vaginal microflora (Table 1). Since there are a tremendous number of genera and species of bacteria and other microorganisms that constitute the endogenous flora, many of which are pathogenic, a mechanism has evolved to regulate the ratio of nonpathogenic to pathogenic bacteria, which allows the ecosystem to be maintained in a healthy state. The microflora is in this healthy state when the dominant bacterium is a non-pathogen and the ratio of the non-pathogen to pathogen is approximately 200:1. The balance is maintained by specific species of Lactobacillus and the substances they produce that inhibit the growth of pathogenic bacteria. A healthy vaginal ecosystem has definite characteristics (Table 2). By using simple office techniques that do not require a significant amount of time to perform the physician can easily recognize these characteristics. It is important that each obstetrician/gynecologist becomes very familiar with these characteristics. Typically only one species of Lactobacillus resides in the vagina. In a healthy state, the species of Lactobacillus that both resides and is dominant in the vagina is a species that produces a significant amount of organic acids, including lactic acid, and secretes hydrogen peroxide (H2O2) and a bacteriocin frequently referred to as lactocin. Lactobacillus has evolved as the dominant bacterium in a healthy vaginal ecosystem because of its ability to grow at a relatively low pH: less than 4.5 but greater than 3.8. However, not all species of Lactobacillus can be considered ‘good’ species or capable of producing the necessary compounds to maintain the vaginal ecosystem in a balanced or healthy state. The most common species isolated from women considered to have a healthy vaginal ecosystem are Lactobacillus crispatus,L. gasseri, L. iners, and L. jensenii4. The various bacterial constituents of the endogenous microflora (Table 1) can be divided into two groups, the non-pathogenic and pathogenic bacteria (Table 3). These designations are based on the probability that a particular bacterium can initiate infection, and accepting the premise that any bacterium can initiate infection if presented with favorable environmental conditions. Lactobacillus can cause infections such as chorioamnionitis and maternal and neonatal


Table 2 Characteristics of a healthy vaginal ecosystem

*wet prep (normal saline dilution of the vaginal discharge), wipe the lateral vaginal wall with a cotton- or Dacrontipped applicator, immerse the applicator in 2–3 ml of normal saline and shake vigorously. Remove the applicator and press it to a glass slide to release 1–2 drops of the diluted discharge, cover with a glass coverslip and view under 40x magnification; WBC, white blood cells

bacteremia5. Gardnerella vaginalis has also been demonstrated to cause chorioamnionitis as well as septic shock6. Bacteria and other microorganisms can be introduced into the vaginal ecosystem from the patient’s own fecal flora, for example Bacteriodes spp. Microorganisms can also be introduced from the exogenous environment through objects introduced into the vagina and by sexual intercourse, for example Chlamydia trachomatis and Neisseria


Table 3 Endogenous bacteria of the vaginal ecosystem

gonorrhoeae, as well as skin-to-skin contact during sexual activity, for example human papillomavirus. Other bacteria found in the vaginal ecosystem either do not grow at a pH below 4.0, or grow poorly at pH values of 4.0–4.57–9. Through the production of organic acids, especially lactic acid, Lactobacillus provides an environment that can be considered hostile to the growth of other bacteria. Lactobacillus grows very well at a pH ≥ 5 5 and, through the production of lactic acid, very quickly lowers the pH to below 4.5. However, Lactobacillus does not compete well for nutrients and yields to other bacteria when growing in their midst. When appropriate environmental changes occur within the vagina, the number of lactobacilli decrease, the other bacteria become dominant, and an alteration in the vaginal microflora results. The alteration in the vaginal microflora and ecosystem can cause the patient to become symptomatic. With the symptoms depending on the condition that has evolved, the patient can remain asymptomatic, as is seen with bacterial vaginosis, or when group B Streptococcus or Escherichia coli become dominant. Lactobacillus appears to control the growth of other bacteria through at least three mechanisms. Lactobacillus produces lactic acid, to maintain the vaginal pH between 3.8 and 4.2, H2O2, and bacteriocin or lactocin. Lactobacillus is not capable of breaking down H2O2 into hydrogen and water because it lacks heme protein catalase and does not use the cytochrome oxidase system. This results in the production of large amounts of H2O2, which is secreted into the environment. H2O2 has been shown to be toxic to some bacteria11–13. This antibacterial activity is enhanced by the enzyme peroxidase in the


presence of the halide ion14. Peroxidase enzymes are found in many cells and cellular products: for example, milk and saliva contain lactoperoxidase, neutrophils and monocytes contain myeloperoxidase, eosinophils contain eosinophil peroxidase, and human cervical mucus contains peroxidase15−17. There is little doubt that Lactobacillus plays a significant role in maintaining the balance of the endogenous microflora. In addition to lactic acid, other organic acids, and H2O2, Lactobacillus produces a bacteriocin that inhibits the growth of bacteria12. This bacteriocin is of low molecular weight and is active against a variety of bacteria, for example E. coli,S. agalactiae, G. vaginalis, and Prevotella spp.7,18,19. As long as Lactobacillus maintains dominance, the pathogenic bacteria that constitute part of the endogenous vaginal microflora remain suppressed. Thus, the vaginal ecosystem remains in a healthy state and there is no potential threat to the health of the individual. Garner and Dukes20 were the first to report the near absence of Lactobacillus and its replacement by other endogenous vaginal bacteria. They also reported that Lactobacillus was rarely observed in women with Haemophilus vaginalis infection, now known as bacterial vaginosis. The number of lactobacilli present in a healthy vaginal microflora is ≥ 106 cfu/ml of vaginal fluid whereas other bacteria within the endogenous microflora are present in a concentration ≤ 103 cfu/ml of vaginal fluid. When viewing bacteria microscopically, the concentration required to see the bacteria is ≤ 103 cfu/ml of fluid. Therefore, it appears that lactobacilli play a key role in maintaining the vaginal ecosystem and the microflora in a healthy state. Loss of Lactobacillus dominance can result in bacterial vaginosis or bacterial vaginitis. Once the pathogenic bacteria become dominant the health of the patient becomes threatened, especially if the patient is undergoing invasive procedures that are performed through the lower genital tract. PELVIC INFECTIONS The majority of pelvic infections that occur in the gynecologic and obstetric patient are derived from the patient’s own endogenous vaginal microflora. In fact, excluding sexually transmitted organisms, the incidence of pelvic infections caused by exogenous bacteria is low.


The most frequent non-endogenous vaginal bacteria to cause pelvic infections are Staphylococcus aureus and Listeriamonocytogenes, and these bacteria are uncommon. Antibiotic prophylaxis is frequently administered to patients delivering by Cesarean section, especially if they have labored, and women having a hysterectomy. The patient who has labored with ruptured membranes for greater than 2 hours is at risk for the development of postpartum endometritis. The patient scheduled to have a hysterectomy, especially a vaginal hysterectomy, is at risk for the development of a postoperative pelvic infection. During labor, bacteria from the vagina ascend into the cervix and colonize the endocervical epithelium. These bacteria eventually advance to the decidua and the chorionic membranes and amniotic fluid. Infection is established through reproduction, adherence to host cells, and invasion into deeper tissue. Although antibiotic prophylaxis is given, the amount of bacteria is excessive and they are not all in a vulnerable state; therefore, the antibiotic is not effective. If the patient has a Lactobacillus-dominant flora to begin with, then there is no significant threat of infection and the antibiotic administered for prophylaxis is effective. Patients undergoing a vaginal hysterectomy are at risk for developing a postoperative pelvic infection if they have an altered vaginal microflora. There are several reasons why the vaginal hysterectomy places the patient at risk for development of a postoperative infection: (i) the procedure is performed through a contaminated site, namely the vagina; (ii) if an altered vaginal microflora is present the numbers of bacteria are high, i.e. there is a large inoculum; (iii) the pelvic peritoneum is constantly abraded and traumatized during the procedure; (iv) dead space is created; (v) necrotic tissue is left behind; and (vi) a foreign body, a suture, is left in the traumatized and necrotic tissue. These features, combined with the presence of a high inoculum of virulent bacteria, create conditions appropriate for infection. Again, administering an antibiotic prophylactically will, in most cases, prove ineffective. The reasons for this are: (i) the inoculum is too large; (ii) the bacteria are not all vulnerable while the antibiotic concentration is high enough to be effective; (iii) the presence of necrotic tissue and suture lowers the required inoculum to initiate infection; and (iv) because of decreased


tissue vascularity at the operative site, antibiotics will not reach the tissue that is colonized in a sufficient concentration to be effective. The best method for preventing postoperative infection is to screen the patient prior to surgery to determine the status of the endogenous vaginal microflora. If the patient does not have a Lactobacillus-dominant vaginal microflora, then treatment should be initiated to correct the condition and return the vaginal microflora to a Lactobacillus-dominant state. REFERENCES 1.

2.

3. 4.

5. 6. 7. 8.

9.

10. 11.

Moghissi KS.Vaginal fluid constituents. In Beller F, Schumacher GFB, eds. TheBiology of Fluids of the Female Genital Tract. Amsterdam: Elsevier, 1979; 1–30 Sumawong V, Gregoire AT, Johnson WD, Rakoff AE. Identification of carbohydrates in vaginal fluid of normal females. Fertil Steril 1952; 13: 270–80 Paavonen J. Physiology and ecology of the vagina. Scand J Infect Dis 1983; 40 (Suppl):31–5 Vasquez A, Jakobsson T, Ahrne S, Forsum U, Molin G. Vaginal Lactobacillus flora of healthy Swedish women. /Clin Microbiol 2002; 40:2746–9 Cox SM, Phillips LE, Faro S, et alLactobacillemia of amniotic fluid origin. Obstet Gynecol 1986; 68:134–5 Lee W, Clark SL, Giebel R, et alSeptic shock during pregnancy. Am J ObstetGynecol 1988; 159:410–16 Aroutcheva A, Gariti D, Simon M, et al.Defense factors of vaginal lactobacilli. Am J Obstet Gynecol 2001; 185:375–9 Simoes JA, Aroutcheva AA, Shott S, Faro S. Effect of metronidazole on the growth of vaginal lactobacilli in vitro. Infect Dis Obstet Gynecol 2001; 9:41–5 Aroutcheva A, Simoes JA, Shott S, Faro S. The inhibitory effect of clindamycin on Lactobacillus in vitro. Infect Dis Obstet Gynecol 2001; 9: 239–44 Dahiya RS, Speck ML.Hydrogen peroxide formation by lactobacilli and its effect on Staphylococcus aureus. J Dairy Sci 1968; 51:1068–72 Thompson R, Johnston A. The inhibitory action of saliva on the diphtheria bacillus: hydrogen peroxide, the inhibitory agent produced by salivary streptococci. J Infect Dis 1950; 88:81–5


12.

13.

14. 15. 16.

17. 18.

19.

20.

Wheater DM, Hirsch A, Mattick TR. Possible identity of ‘lactobacillin’ with hydrogen peroxide produced by lactobacilli. Nature ( London)1952; 170:623–4 Eschenbach DA, Davick PR, Holmes KK, et alPrevalence of hydrogen peroxide producing Lactobacillus species in normal women and women with bacterial vaginosis. /Clin Microbiol 1989; 27:251–6 Klebanoff SJ. lodination of bacteria: a bactericidal mechanism. J Exp Med 1967; 126:1063–78 Klebanoff SJ. Myeloperoxidase-halide-hydrogen peroxide antibacterial system. /Bacteriol 1968; 95:2131–8 Klebanoff SJ. Myeloperoxidase-mediated antimicrobial systems and their role in leukocyte function. In Schultz J, ed. Biochemistry of Phagocytic Process. Amsterdam: North-Holland Publishing Company, 89–110 Reite B, Oram JD. Bacterial inhibitors in milk and other biological fluids. Nature 1967; 216:328–30 Aroutcheva AA, Simoes JA, Faro S. Antimicrobial protein produced by vaginal Lactobacillus acidophilus that inhibits Gardnerella vaginalis. Infect Dis Obstet Gynecol2001; 9:33–9 Simoes JA, Aroutcheva A, Heimler I, Shott S, Faro S. Bacteriocin susceptibility of Gardnerella vaginalis and its relationship to biotype, genotype, and metronidazole susceptibility. Am J Obstet Gynecol 2001; 185:1186–90 Gardner HL, Dukes CD. Haemophilus vaginalis vaginitis. Am J Obstet Gynecol 1955; 69:962–76

2. VULVITIS

Often, conditions that affect the vulva are mistaken for vaginitis, resulting in unnecessary treatments and expense. These treatments may even cause alterations in the endogenous vaginal microflora that result in symptomatic vaginosis or vaginitis. Additionally, the various creams, ointments, suppositories, and emulsions may cause a hypersensitivity reaction in the tissues of the vulva. Therefore, it is extremely important that the physician establishes and locates the precise anatomical site where the patient’s symptoms are originating. This can easily be achieved by having the patient point, with her index finger, to the area that is bothersome. The patient with an inflammatory condition of the vulva (vulvitis), for example vulvadynia, vestibulitis, vulva hyperplasia, or lichen sclerosus (Table 4), is often extremely uncomfortable, has difficulty sitting for a prolonged period, and cannot have sexual intercourse. Therefore she may not be able function at full capacity. The physician should take a detailed history with regard to onset of first symptoms. This is important because when given an opportunity to consider her condition, the patient often will relate that her symptoms began long before the vulvitis became chronic. It is important that the physician allow the patient ample time to not only describe her condition, but also explain the factors that impinge on her condition. The physician must establish that her symptoms are actually related to a clinical condition that can be detected on the vulva or the vagina, or both. The vulvar dystrophies are a group of conditions that are placed together based on gross and histopathologic characteristics. The vulvar dystrophies, or nonneoplastic epithelial disorders, are divided

VULVITIS 11

Table 4 Vulvar condition that may be mistaken for viginitis

into three categories: squamous cell hyperplasia, lichen sclerosus, and other dermatoses1. Once the vulva is examined and found to be free of changes, attention should be given to the vestibule. The urethra, Skene’s glands, Bartholin’s glands, and the epithelium of the vestibule should be examined for erythema, induration, and purulent discharge. The examiner should also check each of these areas for pain associated with gentle pressure, drainage, blisters, ulcers, or growths. Patients commonly mistake vestibulitis for vulvovaginal candidiasis. Vestibulitis is defined by the presence of erythema, burning or pain, and pain when gentle pressure is applied to the involved areas. The areas most commonly affected are the lower aspect of the medial aspect of the labia minora and posterior fourchette; the etiology of vestibulitis is unknown. Another condition of the vulva that may be confused with vulvovaginal candidiasis is lichen sclerosus. Patients with lichen sclerosus present with itching, soreness, dyspareunia, and dysuria, while the skin of the vulva tends to become pale and, eventually, the area of involvement is well demarcated and becomes white and smooth2. With lichen sclerosus, the skin also becomes fragile because of the development of fissures and erosions. The most commonly affected sites are the medial aspect of the labia majora, the labia


minora, the clitoris (often the clitoris becomes edematous), the posterior fourchette, and the perineum. When these areas are simultaneously involved, the clinical presentation of the hypopigmented areas takes on a configuration resembling an hourglass. Progression of the disease can result in scarring and destruction of the normal vulvar anatomy. Agglutination of the labia and clitoral hood also develops, and the posterior fourchette becomes extremely fragile leading to fissuring and lacerations that are extremely painful. If left untreated, the patient with perianal involvement can develop adhesions that, upon defecation, can become painful and bleed2. Contact dermatitis is another condition that is often misinterpreted as vulvar candidiasis. Contact dermatitis patients often present with itching and eczema, and the eczema may be secondary to atopy or to an exogenous irritant or allergic contact. The skin of the vulva becomes erythematous and edematous, and excoriations may be present. Vesicles can also develop and an exudate may be present. If the condition arises secondary to an irritant the symptoms begin immediately, but if there was an allergic reaction the symptoms begin 24–48 hours after contact with the allergen occurred3. Thus, patients presenting with vulvar pruritus, erythema, excoriation, and edema should be considered to have vulvovaginal candidiasis until proven otherwise. Specimens should be obtained from the vulva and vagina for the detection of yeast and microscopic examination of the specimens should be performed by wet prep with and without potassium hydroxide. A specimen from each site should also be used to inoculate Nickerson’s or Sabourad’s agar. If microscopic examination does not reveal the presence of yeast this should not be interpreted as meaning that yeast are not present. While waiting for confirmation from the cultures, the physician can prescribe Mycolog II® cream, which is a combination of nystatin, an antifungal agent, and a steroid, triamcinolone acetonide, to be applied to the vulva. This should provide some relief until a definite diagnosis can be obtained. The pH of the vaginal discharge should also be obtained. A pH lower than 4.5 will, in most instances, rule out a bacterial alteration of the vaginal ecosystem. If this is the case, the microscopic examination should reveal the presence of large bacillary forms, which is consistent with the presence of Lactobacillus.

VULVITIS 13

The physician should never prescribe treatment without performing an examination of the vulva and vagina. Only once a correct diagnosis is established can a definitive management program be instituted. This approach avoids the unnecessary administration of numerous treatment regimens, reduces the cost to the patient, and lessens the likelihood of the patient losing confidence in her physician. REFERENCES 1. 2.

3.

Kaufman RH, Faro S. Benign Disease of the Vulva and Vagina. St. Louis: Mosby, 1994; 260–82 Neill SM. Vulvar lichen sclerosus. In Black MM, McKay M, Brande PR, eds. Obstetric and Gynecologic Dermatology. Philadelphia: MosbyWolfe, 1995 McKay M. Vulvitis and vulvovaginitis: cutaneous considerations. Am J Obstet Gynecol1991; 165:1176–82

3. BACTERIAL VAGINOSIS

INTRODUCTION In a pure state, bacterial vaginosis (BV) is a non-inflammatory process and is not an infection. The organisms that constitute BV are all derived from the endogenous microflora, and these bacteria are present in a concentration that exceeds 106 bacteria/ml of vaginal fluid. In the presence of BV, the concentration of Lactobacillus is less than 103 bacteria/ml of vaginal fluid. These bacterial concentrations are significant considering the potential for infection when BV exits. In the obstetric patient BV has been associated with preterm labor, premature rupture of amniotic membranes, premature delivery, septic abortion, chorioamnionitis, and postpartum endometritis; in the gynecologic patient it is associated with endometritis, posthysterectomy pelvic infection, and salpingitis. Even though there are no hard data that demonstrate a cause and effect relationship between these conditions and BV, there are data that show a strong correlation between BV and some of the aforementioned infections. Although there is controversy concerning the role of BV in diseases of the genital tract, there is no doubt that the bacterial constituents that make up BV are almost all significant pathogens capable of causing serious infections. EPIDEMIOLOGY Among women in the reproductive age group, BV is considered the most common alteration of the vaginal ecosystem; 50% of women

BACTERIAL VAGINOSIS 15

with BV are asymptomatic1. Risk factors shown to be associated with the development of BV are: sexual activity, multiple partners, frequency of intercourse, and douching2–5. Additional factors that can influence the status of the vaginal microflora are smoking and the presence of a pessary in the vaginal canal. In a study examining the influence of a vaginal pessary on the endogenous vaginal microflora, the presence of a pessary was found to have an adverse effect on the microflora. The presence of a vaginal pessary was associated with a relative risk of 3.3 (odds ratio, OR 4.37; 95% confidence interval, CI 2.15–9.32, p=0.0002)6. Bacterial vaginosis was found in 32% of those women with a pessary compared with 10% in women without one. Bacterial vaginosis is not simply an alteration in the vaginal microflora but is the result of changes that occur continuously, likely on a daily basis. Studies of microflora in a healthy vaginal ecosystem revealed that there are transient shifts in bacterial dominance in women without vaginal infections, and the shifts appear to be associated with menses7–11. Schwebke and co-workers12 performed daily vaginal cultures of 60 patients over a 6-week period. These investigators found that 22% of the patients had a Lactobacillusdominant flora (normal flora) as graded according to Nugent’s score. Transient vaginal flora was common, and 6% of the patients had BV. Schwebke and co-workers also found that a history of BV, multiple sexual partners, and receptive oral sex were associated with an unstable flora. Therefore, while the endogenous vaginal microflora may appear to be dominated by Lactobacillus, many women actually have a vaginal microflora that is transitional; they do not later develop BV but instead revert to a Lactobacillus-dominant vaginal microflora. The factors that cause alterations in the vaginal microflora to continue along a path that results in BV are not known. MICROBIOLOGY The microbial and physiologic changes initiated in the vagina that result in an alteration in the balance of the vaginal ecosystem and allow BV to develop have not been elucidated. However, there is no doubt that the one change that must occur is a decrease in the hydrogen ion


concentration, or an increase in pH. The pH of a healthy or Lactobacillus-dominant vaginal microflora is 3.8–4.2. Lactobacillus, producing lactic acid and other organic acids, maintains this pH. Although Lactobacillus, like other bacteria found in the vagina, prefers a pH of 5 when grown on culture media, it cannot compete well at this pH when placed in the vaginal environment. Because the other bacteria present, such as Streptococcus spp., Enterococcus spp., Escherichia coli, and Prevotella spp., are more vigorous competitors than Lactobacillus, it cannot maintain its dominance. Thus, growth of Lactobacillus is inhibited and microbial dominance is assumed by another genus or multiple genera. It appears that when conditions in the vaginal environment are favorable for Gardnerella vaginalis, this bacterium assumes dominance. G. vaginalis grows well at a pH of 5 and above, and as it grows it causes the pH to rise further and the oxygen content of the vaginal environment to become depleted. Decreases in the vaginal oxygen concentration also occur when facultative anaerobes grow. When the vaginal environment becomes oxygen depleted, the facultative anaerobic bacteria switch to anaerobic metabolism. When the oxygen concentration reaches a critically minimal level, the obligate anaerobic bacteria begin to grow and eventually take over as the dominant bacteria in the vaginal ecosystem (Figure 3). In order for the vaginal ecosystem to maintain a Lactobacillusdominant microflora, the necessary species of Lactobacillus must be able to produce a significant amount of lactic acid, hydrogen peroxide (H2O2), and bacteriocin or lactocin. Thus, the bacterial make-up of the vagina undergoes significant changes. When Lactobacillus is the dominant genus, its concentration is ≥ 10 6 bacteria/ml of vaginal fluid and the pathogenic bacterial genera are present in a concentration of ≤ 103 bacteria/ml of vaginal fluid. This balance is challenged by a number of variables (Table 5). Newton and co-workers 13 demonstrated that African-American women were more likely than Caucasian women to have an altered vaginal microflora. This altered vaginal microflora is most likely the result of behavioral factors, hormonal changes, physiological status of the vagina, and hygiene13. In addition to the significance of race, these authors found that specific species of Lactobacillus affect the growth of other bacteria.


Figure 3 Graphic depiction of the effect of increasing pH and decreasing oxygen concentration on the growth of the endogenous microflora of the vagina. Lines represent growth of A, Gardnerella vaginalis; B, facultative anaerobes; C, Lactobacillus spp.; and D, obligate anaerobic bacteria

The number of genera that can be isolated from the lower genital tract exceeds 17–20. The number depends upon the amount of time spent isolating the bacteria and the use of culture techniques or polymerase chain reaction (PCR) to detect specific DNA sequences14. G. vaginalis appears to play a pivotal role in the development of BV. In one study, G. vaginalis was isolated from: 87.5% of women with BV, 34% of women with a vaginal microflora considered to be intermediate BV (using the Nugent’s scoring system), and 26% of women with healthy vaginal microflora15. There are eight biotypes of G. vaginalis and biotype 5 was isolated most frequently from women with a healthy vaginal ecosystem (p=0.0004). Investigators found that biotypes 5 and 7 were typically resistant to metronidazole but no specific biotype was associated with BV. G. vaginalis was also isolated from more than 98% of the women with BV16–18. The microorganisms that make up the microflora of BV are complex and consist of a variety of bacteria, but are dominated by obligate anaerobic bacteria (Table 6). The bacterial make-up of BV is dominated by G. vaginalis Gramnegative obligate anaerobes as well as Mycoplasma hominis, M. genitalis,


Table 5 Factors that can cause alternations in the endogenous vagina microflora

and Ureaplasmaurealyticum. The bacteria that consistently appear to be present in high numbers in women with BV are Gardnerella spp., obligate anaerobes, and genital mycoplasmata19. These same bacteria can be found in the vaginas of women with a healthy vaginal microflora. Thus, BV does not come about because these organisms are introduced into the vagina—they are already present—but because there is a shift in the hydrogen ion concentration from an acid pH (pH < 4.5) to a less acidic pH (pH > 5), and these bacteria grow as Lactobacillus is suppressed. Thus, BV is an alteration in the endogenous microflora of the vagina and not an infection. However because BV consists, microbiologically, of numerous pathogenic bacteria, this condition has the potential to cause significant infectious morbidity in patients undergoing changes in the reproductive tract. These changes could be intentional, such as pregnancy, or for diagnostic or treatment purposes. DIAGNOSIS The characteristics of BV are quite distinct, thus separating it from other conditions of the vagina (Table 7). It is important to realize that when BV is present in the absence of other conditions, such as trichomoniasis or cervicitis, there are relatively few white blood cells (WBC) in the discharge. The presence of a significant number of WBC, i.e. more than 5 per high-power field (hpf), indicates that there is an inflammatory process present in addition to BV20,21. Therefore, the physician must inquire as to the patient’s sexual practices, frequency of contact, number of contacts, and method of contraception. If a barrier method is not part of the patient’s


Table 6 Bacteria that constitute bacterial vaginosis

Adapted with permission from Hill GB. The microbiology of bacterial vaginosis. Am J Obstet Gynecol 1993; 169:450–4

contraceptive regimen then she is at risk for contracting any number of cervical infections. It is not necessary to perform a culture of the vaginal discharge. When microscopically viewing a multitude of bacterial morphotypes, if the above criteria (Table 7) are met BV is present. A culture would not prove to be beneficial because most commercial laboratories will not process the specimen for anaerobes. If anaerobic bacteriology is performed, the laboratory personnel will attempt to identify all anaerobic bacteria that are present. If a culture must be obtained, ask the laboratory personnel to document the presence of Gardnerella spp. This is important because the presence of this bacterium taken with the presence of other characteristics should be enough to establish the diagnosis of BV. If WBC are present and no pathogen can be identified, then a specimen from the vagina should be obtained to culture for the possible presence of Trichomonas vaginalis. Cervical specimens should also be obtained for the isolation of Chlamydia trachomatis and Neisseria gonorrhoeae. If the patient’s history suggests that Herpes exposure may have occurred, a cervical and labial specimen for Herpes Simplex virus (HSV) should be obtained. The physician should also consider the possibility of HSV type I if the patient and her partner practice orogenital sex. Another consideration is the presence of human


Table 7 Diagnostic characteristic of vaginal discharge in a patient with bacterial vaginosis

papillomavirus (HPV) in the vagina and cervix. If the patient has condyloma that is not very apparent, a specimen can be collected from the vaginal walls, as well as the cervix, for the detection of HPV. The patient will often complain of a copious vaginal discharge but the quantity is difficult to establish. One question that can be asked, if trying to determine whether the quantity of discharge is excessive, is whether the patient needs to wear a pad on a daily basis. It should not be too difficult to establish if the patient has BV or not, but relying on pH alone is insufficient. A pH of 5 or higher, a positive whiff test, and the presence of clue cells establish a diagnosis of BV. There may be an associated condition that is indicated by the presence of WBC and requires further testing to determine the specific associated condition, e.g. trichomoniasis, chlamydia, or gonorrhea. It is important that the physician perform a thorough evaluation of both the lower and upper genital tracts when numerous WBC are present in the vaginal discharge, as this could indicate the presence of pelvic inflammatory disease, even if the patient has no symptoms of upper genital tract infection. TREATMENT The treatment of BV is based on the presence of an overgrowth of obligate anaerobic bacteria. However, the fact that there is a


significant decrease in the hydrogen ion concentration or increase in pH should be taken into consideration. The advocated treatment regimens all have about the same efficacy, approximately 65–75%22. This low success rate is likely because of the failure to re-establish the appropriate pH in the vaginal ecosystem, thus preventing Lactobacillus from regaining dominance. The antimicrobial agents of choice are clindamycin and metronidazole. If the patient’s microflora has not progressed to one that is dominated by obligate anaerobic bacteria, but is in an intermediate stage or dominated by G. vaginalis, these antibiotic treatments will likely fail since these agents are not active against this bacterium. Therefore, when examining the vaginal discharge, if clue cells and aggregates of bacteria are seen one should suspect the vaginal microflora is in transition and most likely dominated by G. vaginalis. This diagnosis can be reenforced by a positive whiff test or the presence of a fish-like odor. Successful treatment for this stage of BV development can be accomplished by administering a first-generation cephalosporin. Treatments for established BV are: Oral antibiotic agents (1)Metronidazole 250 mg three times a day for 7 days; (2)Metronidazole 500 mg twice a day for 7 days; (3)Metronidazole 2 g as a single dose; or (4)Clindamycin 300 mg twice a day for 7 days. Intravaginal preparations (1)Clindamycin cream 2% one applicator-full at bedtime for 7 nights; or (2)Metronidazole gel 0.75% one applicator-full twice a day for 7 days Available variations of the intravaginal medications are metronidazole gel dosed for 5 days and clindamycin ovules for 3 days. There is no significant advantage in terms of efficacy with the shorter dosage regimens compared with standard regimens. It has been the author’s


experience that these shorter dosing regimens tend not to be as effective (this is anecdotal information). When treating BV, it is important to consider the pH of the vaginal environment. A patient treated for BV should be examined 1 week after completion of therapy. If the vaginal pH has not returned to the normal range of 3.8–4.2, there is a good chance that her BV will return or a bacterium other than Lactobacillus will become dominant. When examining the vaginal discharge microscopically, the physician should focus on the noticeable absence of bacteria. Following treatment, it is not uncommon to find that the vaginal discharge appears relatively healthy. The squamous epithelial cells are well estrogenized, there are no clue cells, and WBC are scarce, but there is a noticeable absence of bacteria. If the vagina is checked and the pH is 5 or higher, this should indicate that the vaginal ecosystem has not been restored to a healthy state. This patient should then be treated with a vaginal acidifying agent, such as boric acid vaginal capsules 600 mg twice a day for 14 days, Aci jel® one applicatorfull twice a day for 14–21 days, or Relagard® vaginal gel one applicator-full twice a day for 14–21 days. Although there are no published reports addressing this issue, I have found that when the vaginal pH is restored to 4.5 or lower there is a better chance for achieving restoration of a healthy vaginal ecosystem characterized by a microflora dominated by Lactobacillus. TREATMENT OF CHRONIC, PERSISTENT, OR RECURRENT BACTERICAL VAGINOSIS It is difficult to define recurrent BV, but for practical purposes as far as the patient is concerned, if she has a second episode of BV then it is recurrent. However, it is probably appropriate to say that if a patient has four or more episodes of BV within a 12-month period, it could be considered recurrent. If the patient experiences only brief periods of time without BV, for example 1–3 weeks, then it would be fair to label her condition as chronic. If the patient has no or only extremely brief periods without BV symptoms, then the condition could be labeled as persistent BV. Treatment of these conditions requires a comprehensive approach. A detailed history should be repeated with a focus on the use of


genital hygiene products, sexual practices, and medications, especially antibiotic use and herbal remedies. Patients will often take a daily antibiotic for acne and fail to mention this because they are only taking one antibiotic a day. However, a single dose of antibiotic can affect the composition of the vaginal microflora. Patients should refrain from sexual activity because there appears to be a relationship between the frequency of sexual intercourse and the recurrence of BV. Although there appears to be a similar relationship between the risk factors associated with acquisition of sexually transmitted diseases (STDs) and the acquisition of BV, the latter is not considered an STD23. However, many women report that they have recurrent episodes of BV only after having sexual intercourse with their partner. These are usually women in long-term monogamous relationships. In those cases, treatment of the male sexual partner with oral metronidazole appears to have some benefit. Patients with chronic and/or persistent BV should be treated with a combination of an oral agent, either metronidazole or clindamycin, and an intravaginal acidifying agent. If re-examination reveals a noticeable decrease in the bacteria but the pH has not decreased to within the normal range, then the intravaginal administration of the acidifying agent should continue. The use of the antimicrobial agent should be limited because continued administration will result in further alterations of the vaginal microflora. I will close this discussion with the fact that at present BV is not considered an infection but rather an alteration of the endogenous microflora. Therefore, it does not seem plausible that BV can be successfully corrected with an antimicrobial agent. Successful treatment of BV depends upon restoring the vaginal ecosystem to a healthy state. REFERENCES 1.

2.

Hillier S, Holmes KK. Bacterial vaginosis. In Holmes KK, Mardh P, Sparling F, eds. Sexually Transmitted Diseases,2nd edn. New York: McGraw-Hill1989; 547–59 Amsel R, Totten PA, Holmes KK, et al.Nonspecific vaginitis: diagnostic criteria and microbial and epidemiologic associations. Am J Med 1983; 74:14–22


3.

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10. 11.

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Barbone F, Austin H, Louv WC, Alexander WJ.A follow-up study of methods of contraception, sexual activity, and rates of trichomoniasis, candidiasis and bacterial vaginosis. Am J Obstet Gynecol 1990; 163:510– 14 Moi H. Prevalence of bacterial vaginosis and its association with genital infections, inflammation, and contraceptive methods in women attending sexually transmitted disease and primary health clinics. Int J STD AIDS 1990; 1:86–94 Wolner-Hanssen P, Eschenbach DA, Paavonen J, et alAssociation between vaginal douching and acute pelvic inflammatory disease. /Am Med Assoc 1990; 263:1936–41 Alnaif B, Drutz HP. Bacterial vaginosis increases in pessary users. Int Urogynecol J 2000; 11:219–22 Bartlett JG, Onderdonk AB, Drude E, et al.Quantitative bacteriology of the vaginal flora. /Infect Dis 1977; 136:271–7 Sautter RL, Brown WJ. Sequential vaginal cultures from normal young women. /Clin Microbiol 1980; 11:479–84 Johnson SR, Petzold CR, Galask RP. Qualitative and quantitative changes of the vaginal microbial flora during the menstrual cycle. Am J Reprod Immunol 1985; 9:1–5 Priestley CJ, Jones BM, Dahr J, Goodwin L. What is normal vaginal flora? Genitourin Med 1997; 73:23–8 Schwebke JR, Morgan SC, Weiss H. The use of sequential selfobtained vaginal smears for detecting changes in vaginal flora. /Infect Dis 1997; 24:236–9 Schwebke JR, Richey CM, Weiss HL. Correlation of behavior with microbiological changes in vaginal flora. J Inf Dis 1999; 180; 1632–6 Newton ER, Piper JM, Shain RN, Perdue ST, Peairs W. Predictors of the vaginal microflora. Am J Obstet Gynecol 2001; 184:845–53 Hillier SL, Krohn MA, Rabe LK, Klebanoff SJ, Eschenbach DA. The normal vaginal flora, H2O2-producing lactobacilli, and bacterial vaginosis in pregnant women. Clin Infect Dis 1993; 16(Suppl 4 4):S273– 81 Aroutcheva AA, Simoes JA, Behbakht K, Faro S. Gardnerella vaginalis isolated from patients with bacterial vaginosis and from patients with healthy vaginal ecosystems. Clin Inf Dis 2001; 33:1022–7 Catlin BW. Gardnerella vaginalis characteristics, clinical considerations, and controversies. Clin Microbiol Rev 1992; 5:213–37 Eschenbach DA. History and review of bacterial vaginosis. Am J Obstet Gynecol 1993; 169:441–5


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Altrichter T, Heizmann WR. Gardnerella vaginalis: transport, microscopy, testing resistance. Geburtshilfe Frauenheilkunde 1994; 54: 606–11 Hill GB. The microbiology of bacterial vaginosis. Am J Obstet Gynecol 1993; 169:450–4 Peipert JF, Ness RB, Soper D, Bass D. Association of lower genital tract inflammation with objective evidence of endometritis. Infect Dis Obstet Gynecol 2000; 8:83–7 Steinhandler L, Peipert JF, Heber W, Montagno A, Cruickshank C. Combination of bacterial vaginosis and leukorrhea as a predictor of cervical chlamydial or gonococcal infection. Obstet Gynecol 2002; 99: 603–7 Schmitt C, Sobel JD, Meriwether C. Bacterial vaginosis: treatment with clindamycin cream versus oral metronidazole. Obstet Gynecol 1992; 79:1020–3 Nilsson U, Hellberg D, Shoubnikova M, Nilsson S, Mardh PA.Sexual behavior risk factors associated with bacterial vaginosis and Chlamydia trachomatis infection. Sex Transm Dis 1997; 24:241–6

4. BACTERIAL VAGINITIS

INTRODUCTION Bacterial vaginitis can be considered a pathologic entity separate from bacterial vaginosis, candidiasis, and trichomoniasis. It can originate from the introduction of a bacterium that overgrows the dominant bacterium of the vaginal ecosystem, or an alteration within the ecosystem that causes Lactobacillus to lose dominance. In addition, one or more of the endogenous pathogenic bacteria can gain dominance. It is possible that when a significant alteration in the vaginal ecosystem occurs, one or more of the endogenous bacteria can become dominant and produce symptoms that are recognized as vaginitis. CLINICAL PRESENTATION The patient with bacterial vaginitis, regardless of the offending bacterium, typically presents with a copious purulent vaginal discharge. There can also be an associated discomfort that is frequently described as ‘soreness’. The vaginal discharge has a pH of 5 or higher, and this is consistent with a decrease in Lactobacillus growth and favorable to the growth of pathogenic bacteria. The vaginal epithelium is erythematous and at times beefy red. It is imperative that the physician rule out other causes of a purulent vaginal discharge, such as trichomoniasis and cervicitis, especially cervicitis caused by Chlamydia trachomatis and Neisseria gonorrhoeae. Leukorrhea commonly occurs in patients with acute salpingitis; therefore, a work-up for the presence of sexually transmitted agents is

BACTERIAL VAGINITIS 27

indicated in patients with purulent vaginal discharge whose behavior places them at risk for contracting a sexually transmitted disease. Evaluation of a patient with purulent vaginal discharge begins with obtaining a detailed history with regard to medications, especially antimicrobial agents taken within the last 30 days. It should be determined whether the patient practices douching, and if so how often and which specific douching agent is used. The physician should also obtain a detailed sexual history, determining whether the patient and her partner practice cunnilingus and/or anal intercourse. The frequency of sexual intercourse can be significant because semen is alkaline and if the patient is having sexual intercourse with significant frequency, then it may be the ejaculate that is causing a significant change in the hydrogen ion concentration. Although some believe there is no such thing as too much sex, ‘too much of a good thing’ may have a negative impact on the vaginal ecosystem. The evaluation of the lower and upper genital tract should be meticulous. The external genitalia should be examined for the presence of discharge, especially discharge originating from the glandular organs of the vestibule and discharge from the vagina. The normal amount of vaginal discharge is estimated to be approximately 4–6 ml per day1. Discharge spilling out from the vagina, causing the patient to wear a pad on a daily basis, is abnormal. This increase in the amount of discharge may be because of a vaginal, uterine, or fallopian tube infection or an increase in estrogen production. The labia majora, crural folds, and labia minora should be inspected for the presence of excoriations, fissures, ulcerations, and erythematous areas with the presence of central pustules. The urethra should be examined for the presence of purulent discharge. This should be done by visual inspection and then followed with gentle palpation to determine if there is any expressible discharge. Additionally, Skene’s and Bartholin’s glands should be inspected for the spontaneous presence of discharge and then gently palpated to determine if any discharge can be expressed. If discharge is emitted from any of these organs, specimens should be sent for both Gram’s stain and the detection of C. trachomatis, N. gonorrhoeae, and aerobic, facultative, and obligate anaerobic bacteria. The vaginal examination begins by noting the discharge amount (does it appear excessive), color, and pH. A pH of 5 or higher is


indicative of an altered vaginal microflora. A specimen of the vaginal discharge should then be examined microscopically. The maturity of squamous epithelial cells should be noted—that is, do they appear naviculated (well estrogenized) or are there numerous intermediate and parabasal cells present. The well-estrogenized squamous cell to basal cell ratio should exceed 10:1. This helps to determine whether or not the patient has sufficient endogenous estrogen or if atrophic vaginitis exists. The number of white blood cells (WBC) seen under 40x magnification should not be greater than 5 per hpf. The presence of more than five WBC/40x magnification is consistent with an inflammatory state. The color of the vaginal epithelium should also be noted. In a healthy vaginal ecosystem the epithelium is pink, and if estrogen is present in sufficient concentration the wall is rugated. In the absence of estrogen, the epithelium can appear pale and smooth. In advanced stages of atrophic vaginitis the epithelium can be erythematous. The major difference between atrophic vaginitis and bacterial vaginitis is that when the former is present the number of basal cells far exceeds the number of naviculated squamous epithelial cells (Figure 7). The endogenous microflora in patients with bacterial vaginitis and atrophic vaginitis will be altered. In both conditions the pH is at or above 5, Lactobacillus is no longer the dominant bacterium, and there are numerous WBC. The discharge can be purulent in both conditions. In atrophic vaginitis a single bacterium can be dominant, as is the case with bacterial vaginitis. The potential pathogenic bacteria outgrow Lactobacillus when the pH is 5 or more. If no pathogen, such as T. vaginalis or Candida, is identified, specimens of the vaginal discharge should be sent for culture. The specimen should be sent for the culture and identification of aerobic, facultative, and obligate anaerobic bacteria. STREPTOCOCCAL VULVOVAGINITIS Interestingly, the streptococci are commonly found as commensal bacteria in the vagina. It is not uncommon to isolate a and ≥ streptococci, as well as group B hemolytic Streptococcus. In fact the latter can be found to colonize the vagina in up to 25–30% of women who are asymptomatic.


Patients with group B streptococcal (GBS) vaginitis (Streptococcus agalactiae) typically present with erythema and maceration of the vaginal introitus and perianal area. They also have a copious, odorless, watery discharge that is yellow to white. The vaginal epithelium is erythematous2. Since the year 2001, the author has treated ten patients with a diagnosis of GBS vaginitis (unpublished). The patients’ symptoms ranged from copious discharge alone to copious discharge associated with vaginal soreness. The diagnosis was based on the following: (1)copious white to yellow to greenish, odorless discharge; (2)erythema of the vaginal epithelium; (3)vaginal pH of greater than 5; and (4)microscopic examination of the vaginal discharge revealed: a. well-estrogenized squamous epithelium; b. absence of intermediate and parabasal cells; c. ratio of squamous:parabasal epithelial cells was usually above 10:1; d. Lactobacillus was noticeably absent; and e. cocci, typically in chains, were the dominant bacterial morphotype. Patients are usually treated with oral penicillin, ampicillin, or amoxicillin. However, if the outcome is successful it is usually shortlived and recurrence is frequent. Improved success has been achieved by combining orally administered penicillin, ampicillin, or amoxicillin with the intravaginal administration of a vaginal acidifying agent such as boric acid, 600 mg suppositories twice a day for 14 days, or Aci jel®, one applicator-full twice a day for 3–4 weeks. Honig and coworkers2 treated their two patients with clindamycin and cotrimoxazole several times. These investigators found that during asymptomatic periods, GBS could not be recovered from the vagina; however, when the symptoms returned the bacterium could easily be recovered from the vagina. They also found that after repeated courses of clindamycin therapy the organism became resistant to clindamycin. These investigators prescribed chlorhexidine 5%


intravaginal gel but this treatment did not prove to be any more efficacious than the previous treatments. In our unpublished study, vaginal cultures obtained from each patient revealed a single bacterial dominance and this was reported as a heavy growth of group (≥ -hemolytic streptococci by commercial laboratories. Patients were treated with benzathine penicillin, 2.4 million units intramuscularly and there was initial resolution but then relapse. Neither the oral administration of ampicillin or amoxicillin was particularly efficacious. One patient responded to two courses of doxycyline, 100 mg twice a day for 10 days. Thus, individual antibiotic regimens must be tried as treatment for patients with GBS vaginitis. No one regimen appears to be effective in the treatment of all cases of GBS vaginitis. STAPHYLOCOCCAL VAGINITIS Staphylococcus can be isolated from the vagina but it is relatively uncommon. Investigators have reported that Staphylococcus aureus was isolated from the vagina of 5–15% of women with a healthy vaginal ecosystem3,4. However, S. aureus colonization of the skin is common. Aly and co-workers5 reported that 67% of asymptomatic women were found to harbor S. aureus on their vulva. This is an interesting finding because while S. aureus is commonly found to colonize the vulvar skin it is unusual to find it in the vagina. This finding implies that there is some mechanism in the vagina that inhibits the colonization and growth of S. aureus. S. aureus did cause a significant problem in the 1980s when numerous toxic shock syndrome cases were reported. Shands and coworkers6 reported that toxic shock syndrome occurred in menstruating women who were using tampons and had vaginal colonization of S. aureus. This was later found to be caused by specific rare strains capable of producing the exotoxin that caused this disease. COLIFORM VAGINITIS The vaginal microflora can become altered and then one of the coliform bacteria might gain dominance. Probably the most common


coliform is Escherichia coli. Because of the close proximity of the rectum, these bacteria can colonize the perineum, the vestibule, and the vagina. Although this bacterium is commonly isolated from the anatomical sites adjacent to the vagina and is a common cause of urinary tract infection, it is not a common vaginal isolate. It has been reported to be present in the vaginas of 12% of women with a healthy vaginal ecosystem7. Obtaining a specimen for culture can be of assistance when examining and evaluating a patient for vaginitis once all common causes have been ruled out. A report indicating that the vagina is colonized and dominated by one particular bacterium can be significant. However, if the report states that there are several bacteria present and the growth of each is light, then the growth is not significant. A pH ≥ 5 is also significant, but if the vaginal pH is ≥ 4.5 it is not worth culturing for bacteria. A yeast culture might prove more rewarding. For patients with a variety of coliforms the existence of a rectovaginal fistula should be considered. The patient should also be investigated for the possible existence of diverticulitis and ulcerative colitis, since these conditions can result in occult fistula formation and cause constant seeding of the vagina with bacteria from the sigmoid and rectosigmoid colon. Wiseniewski and co-workers8 described a case of sigmoid colon vaginal fistula in which the patient has significant vaginitis caused by contamination with a variety of coliforms originating from the colon. Although a variety of vaginitis causes have been described, including Shigella vaginitis, Entamoeba histolytica vaginitis, Schistosoma haematobium vaginitis, these are uncommon and not frequently seen in the United States. CYTOLYTIC VAGINOSIS In 1982 Cibley and Cibley9 described a vaginitis that was characterized by an overgrowth of normal lactobacilli with a profuse vaginal discharge that tends to be thick or pasty, and a pH less than 4.5 (Figure 8). The characteristics of cytolytic vaginosis were initially described as Döderlein cytolysis and were reported by Bibbo in Papanicolaou smears10. The diagnosis of cytolytic vaginosis is based on the following:


(1)the absence of a pathogen; (2)the absence of bacterial vaginosis; (3)the absence of bacterial vaginitis; (4)the presence of an apparent overgrowth of Lactobacillus; (5)a vaginal pH of < 4.5; (6)a relative absence of WBC; (7)profuse desquamation of squamous epithelial cells; (8)disruptive squamous cells; (9)naked nuclei; a. a great deal of cellular debris; and b. intermediate squamous cells. (10)vulvar burning and itching; (11)vaginal burning; (12)dyspareunia; and (13)increased symptoms in the luteal phase. The etiology of this condition is also unknown. While there appears to be an overgrowth of Lactobacillus, whether or not the Lactobacillus present is a beneficial species is not known. It may be that the species of Lactobacillus that gained dominance adapted to acidic conditions and is not affected by the lactocin produced by the Lactobacillus species that can maintain a healthy vaginal ecosystem. It is interesting to note that when viewing the vaginal discharge of a patient with cytolytic vaginosis microscopically, the absence of other bacteria is noticeable and the large number of lactobacilli is impressive. Treatment At this time, antibiotics do not have a place in the treatment of cytolytic vaginosis. This is not an infection and the relative absence of WBC indicates that this is not an inflammatory disease. Since this condition is associated with an acid environment, Cibley and Cibley9 recommended sodium bicarbonate douches (30–60 g of sodium bicarbonate in a liter of warm water) two to three times a week. When the patient notes improvement, douching should be tapered off to once a week and eventually as needed.


SUMMARY Individuals presenting with complaints of vaginitis, like vaginal burning, soreness, itching, or a combination of symptoms and a copious purulent discharge, should be evaluated in a systematic manner. Localization of the disease must be established at the vulva, the vestibule and glands of the vestibule, the vagina, the cervix, and the uterus. The existence of a common pathogen like Trichomonas or Candida, infection of the cervix, and the presence of vaginal warts, must be ruled out. The microscopic examination of the vaginal discharge should reveal the presence of a dominant bacterium other than Lactobacillus. If one sees predominantly small rods or coccal forms, then a vaginal culture could prove beneficial. Treatment should be directed at the bacterium identified and broadspectrum antibiotics should not be used. An attempt to correct the vaginal alteration can be put forth with the use of acidifying agents such as boric acid vaginal suppositories, 600 mg each, administered twice a day for 14 days. REFERENCES 1. 2. 3. 4.

5. 6.

7.

Godley MJ. Quantitation of vaginal discharge in healthy volunteers. Br J ObstetGynaecol1985; 92:739–42 Honig E. Mouton JW, van der Meijden WI. Can group B streptococci cause symptomatic vaginitis. Infect Dis Obstet Gynecol 1999; 7:206–9 Larsen B, Galask RP. Vaginal microbial flora: composition and influences of host physiology. Ann Intern Med 1982; 96:926–30 Guinan ME, Dan BB, Guidotti RJ, et al.Vaginal colonization with Staphylococcusaureus in healthy women: a review of four studies. Ann Intern Med 1982; 96:944–7 Aly R, Britz MB, Maibach HI. Quantitative microbiology of human vulva. Br JDermatol 1979; 101:445–8 Shands KN, Schmid GP, Dan BB, et alToxic-shock syndrome in menstruating women. Association with tampon use and Staphylococcus aureus and clinical features in 52 cases. N Engl J Med 1980; 303:1436– 42 Chow AW, Percival-Smith R, Barlett KH, Goldring AM, Morrison BJ. Vaginal colonization with Escherichia coli in healthy women. Determination of relative risks by quantitative culture and multivariate statistical analysis. Am J Obstet Gynecol1986; 154:120−6


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Wisniewski PM, Coonrod T, Thonet MA, Horn AS. Early diagnosis of diverticular colovaginal fistula with colposcopy. A case report. /Reprod Med 1988; 33:705–8 Cibley LJ, Cibley LJ. Cytolytic vaginosis: a common cause of vaginitis. In Horowitz BJ, Mardh, P-A, eds. Vaginitis and Vaginosis. New York: Wiley-Liss 1991:181–7 Bibbo M, Weid GL.Microbiology and inflammation of the female genital tract. In Wied GL, Keebler CM, Koss L, Reagan JW, eds. Compendium on DiagnosticCytology. Tutorials on Cytology,6th edn. Chicago: University of Chicago Press, 1988; 54–62

5. VULVOVAGINAL CANDIDIASIS

INTRODUCTION Vulvovaginal candidiasis (VVC) is probably the most commonly perceived abnormal condition affecting a woman’s lower genital tract. There is no doubt that this perception has been fueled by the availability of over-the-counter antifungal products for the treatment of VVC. Almost every time a woman experiences itching, burning, discomfort, or abnormal discharge of the lower genital tract she will diagnose herself with a ‘yeast infection’. While approximately 75% of women will experience at least one episode of yeast vulvovaginitis in their lifetime, about 50% will experience more than one episode and 5% will have recurrent episodes1. The problem with VVC is that in a symptomatic patient it is difficult to know if it is an infection or an overgrowth of the endogenous yeast present as part of the endogenous vaginal microflora. Approximately 15–20% of women in the reproductive age group are colonized by yeast; this is referred to as asymptomatic endogenous carriage2. Typically, acute symptomatic episodes of VVC are responsive to one of the many antifungal agents available. However, these infected women usually do not have predisposing factors that can be linked to their recurrent episodes of VVC. For a patient who complains of vulvovaginal pruritus and burning, has erythema, and has a vaginal pH less than 4.5 but no yeast identified on microscopic examination with potassium hydroxide (KOH), some physicians recommend that a specimen be obtained for culture and identification of yeast. A positive yeast culture is interpreted as the cause of her symptoms.


However, this may not be a valid interpretation of the culture results since 15–20% of women are asymptomatic carriers of Candida. Perhaps the culture results should be viewed as any other result obtained from an area where numerous microorganisms reside; the quantity of yeast recovered should be the determining factor. If the culture returns with scant versus heavy yeast growth, this may not be the cause of her symptoms. If the patient with scant growth of yeast is treated with an antifungal agent and her symptoms resolve, the diagnosis is definite. If she then returns with her symptoms and the subsequent culture is positive, the diagnosis is recurrent VVC and she is treated again, and again, and again. I believe that this scenario characterizes the problem. Can we determine which patient is an asymptomatic carrier of Candida, and which patient may have a normal background of Candida and symptoms suggestive of candidiasis, but Candida is not the cause of her symptoms? MYCOLOGY The genera Candida, Torulopsis, and Rhodotorula are all yeast that do not have a sexual stage (do not form ascospores). The principal genus is Candida, which is comprised of approximately 81 species that all produce pseudohyphae. If Torulopsisglabrata is included in the genus Candida (C. glabrata), then this is an exception as this species only produces budding forms without the development of pseudohyphae3. Rhodotorula produces a carotenoid pigment. C. albicans produces B vitamins that stimulate growth of Lactobacillus in vitro, while Lactobacillus has been shown to enhance, as well as inhibit, the growth of C. albicans4–6.C.albicans also has been demonstrated to stimulate the growth of Staphylococcus in vitro7 Members of the Enterobacteriaceae, such as Escherichiacoli, have been shown to have an inhibitory, although weak, effect on the growth of C. albicans8,9. Additionally, C. albicans has been shown to produce a factor that can inhibit the growth of Neisseria gonorrhoeae in vitro10. Thus, it appears that when colonizing the lower genital tract Candida is able to compete in this environment, especially at the more acidic pH, by producing inhibitor compounds that affect the growth of the bacteria found in this ecosystem.

VULVOVAGINAL CANDIDIASIS 37

Candida is able to grow over a wide pH range of 3 to 8. The typical pH of the vagina in a healthy state is 3.8–4.5, while if the microflora is skewed the pH can range from 4.5 to 6. Therefore, it is not surprising to find Candida in a variety of situations, for example in the presence of bacterial vaginosis or vaginitis (BV) or trichomoniasis, an inflammatory vaginitis. Candida reproduces when buds develop from blastospores. The blastospore can be ovoid, elongated, or spherical. C. albicans is pleomorphic; that is, it can grow as a budding yeast, can produce pseudohyphae, and when grown in serum can produce true hyphae. The cell wall of Candida serves three important functions: it serves as the outer containment of the cell maintaining its shape; it undergoes metabolic turnover during growth and reproduction; and it serves as the point of contact between the organism and the host during infection. The cell wall is a multi-layered polymer of glucan and mannan polysaccharides containing chitin, protein, and lipid. Although the cell wall is a multi-layered structure it is flexible, allowing the organism to appear as ovoid, budding yeast, pseudohypae, and hyphae. This polymorphic appearance can lead to confusion when viewing the patient’s vaginal discharge through a microscope. If the organism is present in its ovoid form, it may be overlooked or not recognized as yeast. Therefore, a culture should be obtained for patients with symptoms suggestive of VVC. The polymorphism of C. albicans is of interest to mycologists and clinician researchers because it is believed that this capability to change morphology is related to the organism’s pathogenicity (Table 8). EPIDEMIOLOGY Yeast are ubiquitous and found in almost all habitats. In the human body, yeast make up part of the microbial ecology of the gastrointestinal and lower genital tracts. Although the microbial ecology is complex, bacteria typically outnumber yeast. Yeast can also be found in the oral cavity of up to 20% of healthy individuals. Colonization of the rectum occurs in up to 25% of healthy individuals. Colonization of the oral cavity and rectum has important


Table 8 Definition of morphologic forms of candida albicans

Table 9 Candida species isolated from humans

implications in women with recurrent or chronic vulvovaginal candidiasis. Candida has been isolated from the vagina in up to 37% of healthy, asymptomatic non-pregnant women11,12. Asymptomatic carriage of yeast can be a significant problem, since large numbers of yeast can be isolated from the vaginas of healthy women: for example, concentrations of yeast cells as high as 106 and 107 yeast cells per ml of vaginal fluid have been isolated from approximately 15% of asymptomatic women13,14. There are well over 80 species of yeast; however, only nine species have been isolated from humans (Table 9). Candida vulvovaginitis is a common problem and the exact incidence is unknown; however, it is believed that 75% of all women will experience one episode of vulvovaginitis caused by Candida1. As previously mentioned, it is estimated that 50% of individuals who have one yeast infection will experience at least one additional episode, and approximately 5% will have recurrent infections15. C. albicans continues to be the most common cause of vulvovaginitis16. There is concern that non-albicans species, specifically C. glabrata, are


increasing in frequency as a cause of VVC. Approximately 50–55% of college women will be treated for confirmed VVC by the time they are 20 years old, and 75% will have had one confirmed episode in their lifetime16–18. Some investigators consider VVC to be a sexually transmitted disease. Indeed there is no doubt that, in some patients with chronic recurrent vulvovaginitis, treating the sexual partner does result in resolution of recurrent disease. Candida has been isolated from the male sexual partners of women with vulvovaginal candidiasis18,19. The frequencyof VVC does increase with the onset of sexual activity; there also appears to be an association between VVC and the practice of orogenital sex19 There has been a great deal of theorizing regarding risks that predispose the patient to vulvovaginal yeast infections. Other than diabetes, immunosuppression, and pregnancy, sufficient data to establish cause and effect relationships between suspected risk factors do not exist. The truth of the matter is, perfectly healthy women develop vulvovaginal yeast infections. The basic problem is determining who has a true yeast ‘infection’ and who has developed an alteration in their vaginal ecosystem, permitting the endogenous yeast to grow and become symptomatic. Remember, Candida, especially C. albicans, can be grown from the lower genital tract of healthy asymptomatic women. The precise proportion of healthy women who harbor yeast and are asymptomatic is unknown, but studies indicate the figure may be up to 30%. This creates a problem for the clinician making a diagnosis and determining treatment. CLINICAL PRESENTATION AND DIAGNOSIS The patient with symptoms attributed to candidiasis can have any one of a variety of conditions that mimic VVC (Table 10). It is important that when evaluating the patient suspected of having VVC consideration be given to other possible etiologies, especially when yeast are not observed in the patient’s vaginal discharge. The physician should not automatically come to the diagnosis of VVC but should establish the diagnosis by documenting the presence of yeast in the vagina and vulva.


Table 10 Differential diagnosis in the patient with vulvovaginitis

The patient with VVC presents with vulvovaginal burning and itching. There is an increase in these symptoms, especially burning, with or shortly after sexual intercourse. The labia become erythematous and swollen (Figure 9). Frequently excoriations are present and the diabetic patient is at risk of the development of cellulitis, which can progress to necrotizing fasciitis. Therefore if the labia are markedly swollen and there is an advancing erythema extending beyond the labia, secondary bacterial infection should be suspected. The patient should be discouraged from trying to diagnose herself with a yeast infection. In a study of 365 women previously diagnosed with VVC, only 35% were able to correctly diagnose recurrent VVC20. The vaginal discharge should be evaluated as follows: (1)The pH should be determined. Although yeast prefer a more acidic pH, they can be found at any pH. A pH of 4.5 or less rules out bacterial vaginosis and bacterial vaginitis, but a pH of 5 or more does not rule out the possible existence of yeast. (2)An aliquot of the vaginal discharge should be obtained by wiping the lateral vaginal wall with a cotton- or Dacron-tipped applicator. The applicator should be immersed in 2 ml normal saline and vigorously agitated. The applicator should then be touched to a glass slide so one or two drops of the diluted vaginal discharge is present on the slide. Two slides should be prepared and concentrated KOH should be added to the diluted vaginal discharge. The KOH will dissolve all non-chitinous material, leaving the yeast intact. The specimens should be covered with a glass cover slip (Figures 10 and 11). (3)The specimens of vaginal discharge should be viewed under 40x magnification. If budding yeasts cells or hyphal elements are observed, the diagnosis of VVC is established (Figure 12). (4)A specimen should also be obtained for culture and identification of yeast. This is important because if the patient does not respond to treatment, knowing that she is colonized by a non-albicans species will help in directing further antifungal treatment.


Although cultures are now being touted as the gold standard, they should not be used indiscriminately21. Following treatment, if the patient is asymptomatic and no yeast are observed on microscopic examination of the vaginal discharge, a specimen of the vaginal discharge should not be cultured (a test of cure culture). It is important to remember that approximately 37% of healthy asymptomatic women can have yeast as part of their normal endogenous vaginal microflora22. Patients with recurrent or chronic persistent VVC should have documentation that they are infected, and a culture should only be obtained to determine if they are infected with a non-albicans species. As mentioned, recurrent VVC affects approximately 5% of patients and is defined as four or more infections occurring annually. The majority of patients who experience recurrent VVC are typically healthy and have no obvious or recognizable predisposing factors23. Studies trying to determine the relationship between recurrent VVC and the strain of Candida revealed that individuals with early recurrent episodes—less than 6 months—were likely to have the same strain as the previous infection. Infections recurring more than 6 months apart were likely to have a different strain24. The source of Candida has not been established. It was believed that the rectum served as the reservoir; however, treatment with oral nystatin has not been effective in reducing recurrences, and recurrent VVC occurs in the absence of rectal colonization25. The difficulty in managing a patient with recurrent vulvovaginitis is determining if she is experiencing an exacerbation of an existing colonization or has developed reinfection. Odds26 demonstrated that to obtain a positive culture from a vaginal specimen, the concentration of yeast must be at least 103 yeast cells per ml of vaginal fluid in order to develop one colony on agar medium. Therefore, when a patient who has been treated subsequently becomes asymptomatic, if microscopic examination does not reveal the presence of hyphal forms and the culture is negative, she will be considered cured. If she should experience another yeast infection in the following 30–60 days this will be considered a reinfection. The difficulty in this case is establishing if this is an exacerbation of pre-existing candidiasis, if there was a change in the vaginal ecosystem that stimulated overgrowth of endogenous Candida, or if there is a new infection.


Table 11 Factors associated with recurrent vulvovaginal candidiasis

Attempts have been made to establish risk factors that predispose an individual to recurrent VVC (Table 11). The vaginal environment that favors the growth of yeast is acidic, with a sufficient concentration of glucose. Again, the problem associated with recurrent and chronic persistent VVC is that these conditions are frequently found in women who are healthy. Their vaginal ecosystems are not in a state of significant imbalance because even though they are colonized with Candida and are often symptomatic, there is normal colonization by Lactobacillus. This latter fact alone indicates that the vaginal ecosystem is not imbalanced because in order to support significant growth of Lactobacillus, the ecosystem must be in balance. Most likely, the patient with recurrent VVC is not being reinfected since most of these women do not have exogenous risk factors, e.g. douching (especially with compounds that can alter the vaginal ecosystem like Betadine®), multiple sexual partners, or a diet that may contribute to an increased vaginal glucose concentration. One theory that persists is that women with recurrent and/or chronic VVC have significant rectal colonization. This rectal colonization provides a source for repeated vaginal colonization. Odds and Abbott found that the oral cavities and rectums of women with VVC were colonized by the same yeast, which was determined by typing27. Some investigators also found 100% of patients with VVC had rectal colonization; however, this has not been substantiated by other investigators25,28,29. Treatment regimens that include either oral nystatin or ketoconazole have not been shown to eliminate rectal colonization. Antibiotic therapy has been associated with vaginal colonization by Candida. It is believed that antibiotics reduce the vaginal bacterial flora and allow the growth of Candida. The possibility exists that when bacteria like Lactobacillus crispatus or other hydrogen peroxide- and


lactocin-producing lactobacilli are the dominant organisms in the vagina, Candida is suppressed. One study30 demonstrated that ingesting yogurt, which contains L. acidophilus, daily for 6 months could decrease Candida vaginal and rectal colonization and vaginal infection. However, this was a small study and should be repeated with a large number of patients before this can be recommended as part of the therapeutic regimen for treatment of recurrent VVC30. Two clinical studies demonstrated an increase in vaginal yeast colonization from 10 to 30% following 2–3 weeks of tetracycline use31,32. Animal studies, specifically in the rat, demonstrated that two organisms, Lactobacillus and Candida, exist in a commensal relationship within the gastrointestinal tract, each colonizing specific sites. Lactobacillus colonizes the stratified squamous epithelium and Candida colonizes, and attaches to, the secretory mucosal cells33. When the animals received tetracycline, the lactobacilli were significantly reduced in number to levels below detection and the yeast increased in number to colonize the entire mucosal surface. Following the discontinuation of tetracycline and administration of lactobacilli, the original microflora of the stomach was re-established. This is an extremely interesting area since the vagina is a complex ecosystem containing numerous microorganisms living together in a variety of relationships. When a condition of the vagina requires treatment with antimicrobial agents it is important to remember that these agents can have far-reaching effects. There is little doubt that the non-specific effects of the antimicrobial agents can influence the status of the microecology, thus giving rise to additional problems. Therefore, when prescribing antimicrobial agents the physician should administer a narrow-spectrum antimicrobial that will have the least scatter effect, thereby reducing the possible disturbance to the associated microorganism in the ecosystem. Another potential area that has received significant attention is the role of sexual behavior related to recurrent VVC. Several studies have shown that the penis is asymptomatically colonized in 5–25% of the male sexual partners of women with symptomatic VVC. Penile colonization with yeast is four times more prevalent among these males than among those whose sexual partners do not have VVC26,34–36. However the male is often asymptomatic. Sobel29 reported that in 100 women with VVC, three male partners


developed Candida balanoposthitis. Additionally, 20% of the male partners developed an acute hypersensitivity reaction, which is a severe itch and redness shortly after intercourse that disappears without treatment within 24 hours29. However, these findings do not explain the male who develops erythema of the head and coronal sulcus of the penis associated with persistent chronic itching. While these individuals report significant burning shortly following intercourse, they do not develop balanoposthitis but require treatment. There is no doubt that the male penis can become colonized with yeast when exposed to a vagina colonized by a significant number of yeast. Whether or not the penis becomes colonized and re-inoculates the female most likely depends upon the inoculum size. The local immunity of the lower genital tract may play a vital role in the pathogenesis of VVC, especially in patients with recurrent disease. In one study of women with recurrent VVC, immunoglobulin A (IgA) and the secretory component of IgA were found to be absent from the patients’ cervicovaginal secretions37. These investigators found that IgG was present in the cervicovaginal secretions of 94% and IgA in 73% of the controls, and in women with VVC IgG was found in 36% and IgA in 32% (p < 0.001). The secretory component of IgA was found in cervicovaginal secretions of 13% of women with infection and 79% of uninfected women (p < 0.001)37. Witkin postulated that women who experience recurrent VVC developed a transient and local inhibition of cell-mediated immunity38. VVC is more frequently found in patients with diabetes mellitus, individuals on steroid therapy, individuals taking broad-spectrum antibiotics, pregnant patients, and individuals with immunologic dysfunction. All individuals with one or more of these risk factors suffer from impairment of their cellmediated immunity. Patients with insulindependent diabetes have a defect in interlukin-2 (IL-2) synthesis, while patients taking broad-spectrum antibiotics can experience suppression of phagocytic function, and pregnant women often have selective inhibition of their cellular immune responses. Therefore, all of these patients may be at an increased risk of developing recurrent VVC39–41. Hobbs and coworkers42 demonstrated in vitro a reduced lymphocyte proliferative response to Candida antigens in 65% of 23 women with recurrent VVC. Witkin


and co-workers43 also showed a decreased lymphocyte proliferative response in patients with recurrent VVC. These investigators also demonstrated that serum from patients with recurrent VVC inhibited the pr oliferative response to Candida of lymphocytes obtained from women without VVC. Witkin and colleagues44 confirmed this lack of proliferative response in lymphocytes in 73% of 65 women with recurrent VVC. These women did not have predisposing factors and possessed lymphocytes that did not have the inherent cellular ability to proliferate in vitro in response to Candida antigen stimulation. A healthy endogenous vaginal microflora is probably the most important defense against an overgrowth of Candida. Lactobacillus apparently plays a pivotal role in suppressing or inhibiting Candida overgrowth3. Like other microorganisms, Candida produces substances that can inhibit the growth of other microbes. When VVC is present, there is a reduction in the number of lactobacilli present in the colonized vagina45,46. The prevention of Candida adhering to vaginal squamous epithelial cells was observed when the vaginal squamous cells were preincubated with lactobacilli in vitro47. Typically VVC does not occur in association with other abnormal conditions or infections. However, there are exceptions because VVC has been observed with BV, trichomoniasis, C. trachomatis, and N. gonorrhoeae. In fact, the presence of an increased number of white blood cells (WBC) in the vaginal discharge should alert the physician to look for an infection, such as trichomoniasis or cervicitis. The following characteristics can be identified in a patient with VVC: (1)Vulvar erythema (2)Vulvar edema (3)Vulvar excoriations (4)White patsy to liquid discharge present on the vulva (5)Vaginal epithelium is erythematous (6)Vaginal discharge Patients complaining of vulvovaginal itching and/or burning, and who have a white to slate-gray discharge with a pH of less than 4.5 but no evidence of yeast, i.e. no hyphal forms or budding yeast on microscopic examination of the vaginal discharge, should have a specimen of the


vaginal discharge cultured for the isolation and identification of yeast. There are times when the wet prep contains only small, elliptical, individual yeast cells that go unnoticed by the examiner but the culture returns positive. An additional benefit of the culture, if positive, is the identification of the species. If the isolated yeast is a species other than C. albicans, then it may be resistant to the typical antifungals used for treatment. The physician can then institute therapy with Butoconazole® 2%, Terazol®, Tioconazole®, or boric acid vaginal suppositories or capsules (Table 12). The presence of WBC and yeast may indicate the presence of an additional condition, such as cervicitis. Again, the physician should look for a cervical infection. If the patient has risk factors, then cervical specimens should be obtained f or C. trachomatis and N. gonorrhoeae, and if the Pap smear is abnormal then a specimen should be obtained for human Papillomavirus (HPV). If the vaginal pH is 5 or more, then T. vaginalis should be considered. The patient may also present with vaginal burning shortly after sexual intercourse, which may persist for 24 hours. This could be followed by a mild vulvar pruritus that lasts 1–2 days. The patient’s sexual partner may also complain of penile burning shortly after intercourse that lasts for a day or two. These patients should be examined and a specimen for culture and identification of yeast should be obtained. There is little doubt of the value of a vaginal culture, especially in the patient with signs and symptoms of VVC but without fungal elements detected in the vaginal discharge. Several investigators have demonstrated the value of a vaginal culture when evaluating a patient with suspect vaginitis. Handa and Stice48 cultured 40 women with cyclic vulvitis and found 61.5% to be positive for yeast. These investigators found that 54% of the isolated yeast were C. albicans, while the remaining isolates were C. glabrata, C. tropicalis, C. krusei, C. parapsilosis, and Saccharomyces cerevisiae. These patients frequently have Candida and should be treated vigorously because they often will manifest symptoms consistent with VVC. In addition, their partners may serve as a source of reinfection. Therefore, their partners should be treated with a topical agent such as Mycostatin® cream. In a study of 4228 women with symptomatic lower genital tract infection49, candidiasis was detected in 3351 cases (79%): C. albicans was identified in 1431 (43%) of these cases, and non-albicans


Table 12 Available antifungal agents

species were found in 1920 (57%). These investigators also found that among the non-albicans species the most frequently isolated were C. glabrata (63%), C. tropicalis (21%), and C. krusei (15%). Additionally, these investigators found that C. albicans was most frequently isolated in patients using oral contraceptive hormones while women previously treated with topical antimicrobial agents were more frequently infected with non-albicans species. However, these associations were not statistically significant. C. albicans was also isolated more frequently in women whose partners reported symptoms consistent with the presence of penile candidiasis. In summary, the diagnosis and management of VVC can be approached as follows: (1)Obtain a detailed history regarding the start of symptoms and factors that aggravate the conditions; (2)Determine if the patient has been treated with oral antibiotics within the last 14 days; (3)Determine if the patient has recently used intravaginal medications, home remedies, or has been douching and if so determine what agent was used; (4)Determine the anatomic location of her symptoms; (5)Describe the physical findings and location of all abnormal findings; (6)Obtain a specimen from the vulva for culture and microscopic examination (differential diagnosis, Table 13);


Table 13 Differential diagnosis of vaginitis

(7)Obtain a specimen from the vagina for culture and microscopic examination; (8)Determine the vaginal pH. A pH ≥ 5 indicates that the vaginal microflora is altered. If yeast are also found, this suggests that two conditions are present; (9)The presence of WBC in a patient with a cervix can indicate the presence of cervicitis; and (10)If no yeast are present, a specimen for culture should be obtained. Interpreting the vaginal discharge with microscopic examination: (1)Squamous cells should be estrogenized. More basal cells than well-estrogenized squamous cells, or the appearance of a large number of basal cells and intermediately mature estrogenized squamous cells instead of well-estrogenized squamous cells suggests an estrogen deficiency, for example developing or established atrophic vaginitis. (2)A pH ≥ 5 5 indicates an alteration in the endogenous vaginal microflora. The absence of WBC indicates that Lactobacillus may no longer be the dominant bacterium. If there are numerous morphologic bacteria present, look for clue cells. The presence of clue cells and the absence of a dominant bacterial morphotype indicates BV. (3)Numerous WBC, i.e. > 5 WBC/high-power field at 40x magnification, indicate the presence of either an infection or


hypersensitivity reaction. First, search for the presence of T. vaginalis, if this is not found consider obtaining a specimen for T. vaginalis culture. Also examine the cervix for signs of cervicitis and obtain specimens for the detection of C. trachomatis and N. gonorrhoeae. If the patient’s Pap smear is abnormal, obtain a specimen for HPV. (4)Fungal elements will present as either individual elliptical cells, budding cells, elliptical cells with a short germ tube, or hyphal elements. The presence of any of these elements in a patient with vulvovaginal erythema, itching, and/or burning establishes a diagnosis of VVC. Treatment should be initiated if fungal elements are found on the microscopic examination of the vaginal discharge. Treatment should also be initiated in the patient who has symptoms consistent with VVC, but whose microscopic examination does not confirm the presence of fungal elements. TREATMENT Initial episode Patients experiencing their initial episode of VVC can be treated with any of the antifungal topical agents (Table 12). The importance of initiating treatment is to establish if the patient has a yeast infection and if the yeast is a hyphal-producing species. If the examiner finds only budding yeast in the vaginal discharge it is significantly possible that the patient will not respond to typical antifungal agents. The patient should be examined within 1–2 weeks of completing treatment to determine if her condition has resolved. There is no need to culture the individual experiencing her first episode if yeast are documented on microscopic examination of the vaginal discharge. If the patient has symptoms and physical findings consistent with VVC, but microscopic examination of her vaginal discharge does not reveal yeast, then a vaginal specimen should be obtained for the culture of yeast. Patients who experience a recurrent episode of VVC but have less than four episodes in a year, should be treated with one of the


antifungal agents listed in Table 12. Again a culture should be obtained to ensure that the patient is colonized with C. albicans and not a non-albicans species. The presence of a recurrence, although not chronic or persistent yeast vaginitis, can imply that the initial treatment was not satisfactory. If the patient became asymptomatic after initial treatment, the number of yeast may have been reduced to a number that was low enough not to initiate symptoms. When conditions in the vagina are appropriate for the increased growth of yeast, the increased number causes symptoms. The patient with a true recurrent yeast infection, i.e. more than four infections in a 12-month period, presents a problem similar to the patient with persistent or chronic VVC. It is important to review the patient’s hygiene because she may be re-inoculating herself from possible rectal colonization. Another possible source of re-infection or re-inoculation is orogenital sex. If either her or her partner’s oral cavity becomes colonized, they could transmit the yeast to one another via fellatio and cunnilingus. Thus, in the patient with recurrent VVC it may be prudent to culture both the oral cavity and the rectum to determine if yeast is present. Sobel50 found that oral colonization occurred in 20 of 48 women (42%) with recurrent VVC and rectal colonization occurred in 35 of 48 (73%) of the patients. Sobel also reported that 80% of the rectal isolates were identical to the vaginal isolates, and patients with positive oral cultures were usually found to have positive rectal cultures. In the male sexual partners of women with VVC, Sobel also found that 26% had positive penile cultures. None of these patients had positive oral cultures. Seven male partners with negative penile cultures were found to have positive oral cultures for Candida, and these isolates were identical to those from their female partner’s vagina. Although this was a relatively small study and the investigator did not report on the sexual practices of the patients in the study, the data does indicate that the male partner can become colonized and it is possible that yeast was transmitted via sexual contact. When attempting to treat a patient with recurrent or chronic VVC, it is not unreasonable to inquire if the patient and her partner practice orogenital sex, and whether or not they have anal intercourse. If there is oral-genital contact and/or anal intercourse, then the


treatment regimen should provide antifungal coverage for these sites as well as the vagina. Suggested management for the patient with recurrent VVC: (1)obtain a detailed history, including diet, medications, and sexual practices; (2)thoroughly examine the external genitalia, and note the presence of discharge, consistency, presence of erythema, edema, swelling, excoriations, skin changes (such as thickening, graying, or thinning), and other lesions; (3)determine the vaginal pH. A pH ≥ 5 may indicate the presence of more than one infection or abnormal condition; (4)obtain a specimen from the vagina for culture and identification of yeast; and (5)examine a portion of the vaginal discharge microscopically and record the observations accurately. Treatment regimens for recurrent VVC: (1)boric acid vaginal capsules, 600 mg, inserted intravaginally twice a day for 10–14 days; (2)oral nystatin lozenges or pastilles, 400 000 IU q.i.d for 10 days in an attempt to reduce the oral and rectal colonization; (3)re-examine the patient within 1 week after completion of therapy, determine the pH, and perform both a microscopic examination of the vaginal discharge and a culture. The culture is needed to determine if yeast is still present and the identity of the yeast. If the patient is asymptomatic, there are no physical findings of candidiasis or vaginitis, and the pH is < 4.5, therapy can be considered successful; (4)begin suppressive therapy—fluconazole 150 mg once a month at the time of menses for 6 months. Alternative suppressive therapies include fluconazole 150 mg once a week for 6 weeks, and intravaginal applications of butoconazole 2% cream (Gynazol-1®) once a month for 6 months or weekly for 6 weeks. Patients with recurrent VVC who participate in orogenital sex or anal intercourse should be treated as above but they should also be


administered nystatin lozenges or pastilles. Evans and co-workers51 successfully treated 28 oral candidiasis patients with 200 000 IU of nystatin four times a day for 7 days. Of the 45 patients initially enrolled in their study, 36 were culture positive for Candida and completed follow-up. A total of 28 (78%) patients had a satisfactory response, and 22 (61%) had complete resolution of symptoms and signs of infection, but only ten (28%) were culture negative. A total of 23 (88%) had clinical improvement and three (11.5%) failed therapy. There has been much discussion in the literature regarding the emergence of resistant Candida strains. Resistance of C. albicans has not emerged as a significant problem. In a recent study by Bauters and co-workers52, 612 women were studied and 39 (6.3%) had clinical VVC. These investigators found an overgrowth of Candida colonization in 20% of the women, with C. albicans the most frequently isolated species (68.3%), C. glabrata second (16.3%), and C. parapsilosis third in 6.9% of the women. Other species isolated were C. humicola (in two women), C. krusei (one), C. lusitaniae (one), Rhodotorula spp. (three), and S. cerevisiae (one). Among the 84 isolates of C. albicans, 24 were resistant to fluconazole. Among the 20 isolates of C. glabrata, three were considered resistant to fluconazole52. Nyirjesy and colleagues21 report treatment outcomes for 74 patients diagnosed with chronic VVC. They found that 68% of the isolates were C. albicans and 32% were non-albicans species. They reported that all 51 of 51 patients were successfully treated with fluconazole but seven patients experienced recurrent disease. Among the non-albicans group, two of eight responded to fluconazole, three of six responded to itraconazole, four of seven responded to clotrimazole, and 11 of 15 responded to intravaginal boric acid21. Spinillo and co-workers53 evaluated 472 isolates of Candida from women with VVC. They isolated C. albicans in 379 women (86.5%), C. glabrata in 40 (9.1%), C. parapsilosis in seven (1.6%), C. pseudotropicalis in four (0.9%), C. tropicalis in two (0.5%), C. krusei in two (0.5%), C. kefir in two (0. 5%), and S. cerevisiae in two (0.5%). Again, C. albicans was the most commonly isolated followed by C. glabrata and the ratio of almost 10: 1 appears to hold steady in most studies. These investigators reported testing 100 isolates of C. albicans to a variety of azoles (miconazole, econazole, clotrimazole, ketoconazole, isoconazole) as well as nystatin and 5-fluorocytosine. They found that approximately 20–40% had an


intermediate sensitivity to the azoles, 2% were resistant to nystatin, and 11% had an intermediate sensitivity to 5-fluorocytosine. Among the non-albicans species (17–44 isolates were tested) intermediate sensitivity to these same agents ranged from one to 26 isolates. Therefore, when evaluating patients with chronic VVC, culture is important not only to demonstrate the presence of Candida but also to determine the species. Performing sensitivities, at this point in time, appears to be warranted because when the fungus does not respond to one azole there is a high probability that it will not respond to an alternative azole. Boric acid vaginal capsules appear to be a good primary choice for treatment of VVC in patients who do not respond to azole therapy as well as those with a diagnosis of recurrent disease. It does not appear that the use of boric acid vaginal capsules provides satisfactory results when therapy is stopped. Guaschino and colleagues54 demonstrated that boric acid vaginal therapy was effective both while therapy was ongoing and when maintained for suppressive therapy, but when the therapy was withdrawn relapses occurred. Patients who fail to respond to boric acid therapy should be referred to an infectious disease specialist. If this is not rewarding, then I suggest contacting an obstetrician/gynecologists who specializes in infectious disease. REFERENCES 1. 2. 3. 4.

5. 6.

Horowitz BJ. Mycotic vulvovaginitis: a broad overview. Am J Obstet Gynecol 1991; 165:1188–92 Bingham JS. What to do with the patient with recurrent vulvovaginal candidiasis. Sex Transm Infect 1999; 75:225–7 Odds FC. Candida and Candidiasis. Baltimore: University Park Press, 1997; 8–15 Wilson TE, Goaz PW. The oral yeast Lactobacillus relationship. III. Growth enhancement of Lactobacillus casei by Candida albicans and saliva. J Dent Res 1960; 39:365–71 Duillot N. Elaboration par Lactobacillus acidophilus d’un produit actif contre Candida albicans. Ann Inst Pasteur 1958; 95:194–207 Young G, Krasner RI, Yudofsky PL. Interactions of oral strains of Candidaalbicans and lactobacilli. J Bacteriol 1956; 72:525–9


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Virtanen I. Observations on the symbiosis of some fungi and bacteria. Ann MedExp Biol Fenn 1951; 29:352–8 Hummel RP, Maley MP, Miskell PW, Altemeier WA.Suppression of Candidaalbicans by Escherichia coli. J Trauma Injury Infect Crit Care 1975; 15:413–18 Hummel RP, Oestreicher EJ, Maley MP, Macmillan BG. Inhibition of Candidaalbicans by Escherichia coli in vitro and in germfree mouse. J Surg Res 1973; 15:53–8 Hipp SS, Lawton WD, Chen NC, Gaafar HA. Inhibition of Neisseria gonorrhoeae by a factor produced by Candida albicans. Appl Microbiol 1974; 27:192–6 Hilton AL, Warnock DW. Vaginal candidiasis and the role of the digestive tract as a source of infection. Br J Obstet Gynecol 1975; 82: 922–6 Sinski JT, Kelley LM, Reed GL. Pagano—Levin Candida test medium: evaluation using vaginal samples. /Clin Microbiol 1975; 1: 206–11 Lindner JG, Plantema FH, Hoogkamp—Korstanje JA. Quantitative studies of the vaginal flora of healthy women and of obstetric and gynecological patients. / Med Microbiol 1978:11:233–41 Barlett JG, Polk BF. Bacterial vaginal flora of the vagina. Quantitative study. RevInf Dis 1964; 6(Suppl 1 1):S57–72 Haefner HK. Current evaluation and management of vulvovaginitis. Clin ObstetGynecol 1999 ;42:184–95 Sobel JD, Faro S, Force RW, et alVulvovaginal candidiasis: epidemiologic, diagnostic, and therapeutic considerations. Am J Obstet Gynecol 1998; 178:203–11 Geiger AM, Foxman B, Gillespie BW. The epidemiology of vulvovaginal candidiasis among university students. Am J Public Health 1995; 85:1146–8 Sobel JD. Vaginitis. NEngl J Med 1997;337:1896–903 Horowitz BJ, Edelstein SW, Lippman L. Sexual transmission of Candida. ObstetGynecol 1987; 69:883–6 Ferris DG, Dekle C, Litaker MS. Women’s use of the over-thecounter antifungal medications for gynecologic symptoms. J Fam Prac 1996; 42:595–600 Nyirjsey P, Seeney SM, Grody MH, Jordan CA, Buckley HR. Chronic fungal vaginitis: the value of cultures. Am J Obstet Gynecol 1995; 173: 820–3


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Anonymous. 1998Guidelines for treatment of sexually transmitted diseases. Centers for Disease Control and Prevention. MMWR Morbid Mortal Wkly Rep 1998; 47(RR-1):1–111 Sobel JD. Management of recurrent vulvovaginal candidiasis with intermittent ketoconazole prophylaxis. Obstet Gynecol 1985:65:435–40 O’Conner MI, Sobel JD. Epidemiology of recurrent vulvovaginal candidiasis: identification and strain differentiation of Candida albicans. J Infect Dis 1986; 154:358–63 Milne JD, Warnock DW. Effect of simultaneous oral and vaginal treatment on the rate of cure and relapse in vaginal candidosis. Br J Vener Dis 1979; 55:362–5 Odds FC. Genital candidosis. Clin Exp Dermatol 1982; 7:345–54 Odds FC, Abbott AB. A simple system for the presumptive identification of Candida albicans and differentiation of strains within the species. Sabouraudia 1980; 18:301–17 Miles MR, Olsen L, Rogers A. Recurrent vaginal candidiasis. Importance of an intestinal reservoir. J Am Med Assoc 1977; 238:1836– 7 Sobel JD. Epidemiology and pathogenesis of recurrent vulvovaginal candidiasis. Am J Obstet Gynecol 1985; 152:924–35 Hilton E, Isenbergver HD, Alperstein P, France K, Bornstein MT. Ingestion of yogurt containing Lactobacillus acidophilus as prophylaxis for candidal vaginitis. Ann Intern Med 1992; 116:353–7 Caruso LJ. Vaginal moniliasis after tetracycline therapy. Am J Obstet Gynecol 1964; 90:374–9 Oriel JD, Waterworth PM. Effects of minocycline and tetracycline on the vaginal yeast flora. /Clin Pathol 1975; 28:403–6 Savage DC. Microbial interference between indigenous yeast and lactobacilli in the rodent stomach. /Bacteriol 1969; 98:1278–83 Rodin P, Kolator B. Carriage of yeasts on the penis. Br Med J 1976; 1: 1123–4 Thin RN, Leighton M, Dixon MJ. How often is genital yeast infection sexually transmitted ?Br Med J 1977; 2:93–4 Davidson F. Yeasts and circumcision in the male. Br J Vener Dis 1977; 53:121–2 Romero-Piffiguer MD, Vucovich PR, Riera CM. Secretory IgA and secretory component in women affected by recidivant vaginal candidiasis. Mycopathologia 1985; 91:165–70 Witkin SS. Immunology of recurrent vaginitis. Am J Reprod Med 1987; 15:34–7


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Kaye WA, Adri MN, Soeldner JS, et alAcquired defect in interleukin-2 production in patients with type 1 diabetes mellitus. N Engl J Med 1986; 315:920–4 Seelig MS. Mechanisms by which antibiotics increase the incidence and severity of candidiasis and alter the immunological defenses. Bacteriol Rev 1966; 30:442–59 Purtilo DT, Hallgren HM, Yunis EJ. Depressed maternal lymphocyte response to phytohaemagglutinin in human pregnancy. Lancet 1972; 1: 769–71 Hobbs JR, Brigden D, Davidson F, Kahan M, Oates JK Immunological aspects of candidal vaginitis. Proc R Soc Med 1977; 70 [Suppl 4] :11–4 Witkin SS, Yu IR, Ledger WJ. Inhibition of Candida albicans induced lymphocyte proliferation by lymphocytes and sera from women with recurrent vaginitis. Am J Obstet Gynecol 1983:147:809–11 Witkin SS, Hirsch J, Ledger WJ. A macrophage defect in women with recurrent Candida vaginitis and its reversal in vitro by prostaglandin inhibitors. Am JObstet Gynecol 1986; 155:790–5 Auger P, Joly J. Microbial flora associated with Candida albicans vulvovaginitis. Obstet Gynecol 1980; 55:397–401 Narayanan TK, Rao GR. Beta-indoleethanol and beta-indolelactic acid production by candida species: their antibacterial and autoantibiotic action. Antimicrob Agents Chemother 1976; 9:375–80 Sobel JD, Myers PG, Kaye D, Levison ME. Adherence of Candida albicans to human vaginal and buccal epithelial cells. J Infect Dis 1981; 143:76–82 Handa VL, Stice CW. Fungal culture findings in cyclic vulvitis. Obstet Gynecol 2000; 96:301–3 Parazzini F, DiCintio E, Chiantera V, Guaschino S. Determinants of different Candida species infections of the genital tract in women. Sporachrom Study Group. European J Obstet Gynecol Repro Biol 2000; 93:141–5 O’Conner MI, Sobel JD. Epidemiology of recurrent vulvovaginal candidiasis: identification and strain differentiation of Candida albicans. J Infect Dis 1986; 154:358–63 Evans WK, Shepherd FA, Feld R, Mullis B. Nystatin lozenges: a useful treatment for oral candidiasis in cancer patients. Cur Therap Res 1987; 42; 1201–9 Bauters TG, Dhont MA, Temmerman MI, Nelis HJ. Prevalence of vulvovaginal candidiasis and susceptibility to fluconazole in women. Am J Obstet Gynecol 2002; 187:569–74


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Spinillo A, Nicola S, Michelone G, et alFrequency and significance of drug resistance in vulvovaginal candidiasis. Gynecol Obstet Invest 1994; 38:130–3 Guaschino S, De Seta F, Alberico S, et al.Efficacy of maintenance therapy with topical boric acid in comparison with oral itraconazole in the treatment of recurrent vulvovaginal candidiasis. Am J Obstet Gynecol2001; 184; 598–602

6. TRICHOMONIASIS

INTRODUCTION In 1836, Donné described the protozoan Trichomonas vaginalis1. In 1936 Hohne demonstrated the relationship between the presence of T. vaginalis in the vagina and symptoms localized to the vagina, such as increased vaginal discharge. In 1940, Trussell and Plass inoculated the vaginas of healthy volunteers with pure cultures of T. vaginalis and established acute symptomatic vaginitis1. This fulfilled Koch’s postulates2. In 1947, Trussell published a monograph on T. vaginalis describing infection of the lower genital tract3. Subsequent to the work of Trussell, T. vaginalis has been the subject of intense study because of the suspected related infectious complications associated with vaginal trichomoniasis, including premature labor, premature rupture of amniotic membranes (PRAM), postoperative pelvic infections, and salpingitis. Although effective antimicrobial therapy (metronidazole) has been available in the United States since 1963, urogenital trichomoniasis continues to be one of the world’s most prevalent sexually transmitted diseases (STD). This is because the patients can have either asymptomatic infection or the presence of persistent and chronic recurring infection. In rare instances, the patient may be allergic to metronidazole. The absence of effective alternatives to be used in these patients can result in the failure to eradicate the trichomonads. Finally, the emergence of T. vaginalis strains resistant to metronidazole, although rare, has been documented4. Trichomonads that parasitize humans are unique because each species occupies a

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specific anatomical site in the host. Each species also has a distinct structure, function, and relationship with its host. T. vaginalis adapted to the vaginal environment of pregnant women, and infection during pregnancy is associated with an increase in the severity of symptoms, but the reason for this increase in symptomatic infection has not been defined. T. vaginalis has been recognized for decades as a significant vaginal pathogen and continues to be a perplexing problem. The lifecycle of this organism has not been delineated, while the pathophysiology of symptomatic and asymptomatic infection is not understood. A significant area yet to be elucidated is the interaction of T.vaginalis with endogenous microbes of the lower genital tract. Is there a relationship between T. vaginalis and other microbes with regard to infections of the lower and upper genital tract? Does T. vaginalis play a role in pelvic inflammatory disease (PID), infertility, PRAM, premature labor, or postoperative pelvic infections? While vaginitis and vaginosis are the most common problems the gynecologist addresses in the ambulatory setting, the incidence of trichomoniasis appears to have decreased in the United States and Scandinavia5. In 1995, the World Health Organization estimated that there were 170 million cases of trichomoniasis in the world6. MICROBIOLOGY There are three species of Trichomonas: T. tenax, T. vaginalis, and T. faecalis. These organisms belong to the order Trichomonadida and the family Trichomonadidae. T. vaginalis, a common urogenital pathogen, is the most investigated of all the trichomonads. The morphology of T. vaginalis is influenced by the physiologic conditions of the urogenital organs. The pH, temperature, oxygen concentration, availability of nutrients and ionic concentration of the microenvironment, and the vaginal ecosystem, are all important for determining the structural configuration of the organism. When T. vaginalis is grown in pure culture, the morphology tends to be pearshaped or oval7 (Figure 13). The organism has five flagella: four are distinct and can be observed at its anterior end while the fifth is part of the undulating membrane8. When environmental conditions become unfavorable, the organism assumes a spherical form. This stage is considered to be a pseudocyst; however, some investigators


believe that these are degenerative forms because when the environmental conditions that favor survival of the trichomonads return, the pseudocysts do not regenerate into viable trichomonads9,10. Trichomonads also have the ability to adhere to squamous epithelial cells lining the vagina via the axostyle that originates at the nucleus and longitudinally traverses the parasite. Axostyles penetrate the posterior aspect of the parasite and terminate in a sharp point that permits the parasite to attach to the epithelial cells lining the vagina11. When viewing T. vaginalis using light microscopy, it is common to see granules within the parasite. These granules are intracellular organelles that have been shown to be catalase negative11. These structures produce molecular hydrogen and have been named hydrogenosomes, and they play an important role in the metabolism of the organism12. The hydrogenosomes function as mitochondria13. A feature that sets T. vaginalis apart from other trichomonads is the presence of three parallel rows of hydrogenosomes along the axostyle. In addition to hydrogenosomes, glycogen granules can also be observed within the parasite. T. vaginalis also contains other organelles, such as lysosome-like organelles, for example phagosomes14–17. As stated above, the physiologic condition of the vagina influences the structural configuration and morphology of T. vaginalis, so it is important to recognize that the vaginal ecosystem exists in a delicate and dynamic equilibrium. Indeed, the vaginal ecosystem is extremely complex and not very well understood. It appears that this delicate balance is not solely dependent on host factors, but also is dependent upon the symbiotic or commensal relationship between the host and the endogenous microbes of the vagina. The interactions between the microbes, metabolic and immune status of the host, and factors from the exogenous environment that are introduced into the ecosystem, all play a significant role in determining whether organisms such as T. vaginalis will be successful in colonizing and infecting the vagina. While these relationships are not well understood, it becomes apparent to the physician when treatment of T.vaginalis vaginitis is unsuccessful. When an organism, such as T. vaginalis, is introduced into the vaginal ecosystem it may develop a symbiotic or commensal

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relationship, where it exists in harmony with a host, or it may not develop a foothold and thus be eradicated by the host. It may also alter the ecosystem by creating an environment that allows it to flourish. It is generally accepted that 25–50% of women with trichomoniasis are asymptomatic, and that the trichomonas has reached such a harmonic existence with the vaginal ecosystem. It is as though the trichomonads have adapted to the vaginal ecosystem and can coexist; the relationship of the protozoan with the host when in the asymptomatic state is therefore symbiotic or commensal. The numbers of trichomonads must be maintained below a significant threshold that will prevent the ecosystem from shifting to a state that would be more favorable for the trichomonads, and would permit them to flourish and become the dominant organism in the ecosystem. When a shift in the vaginal environment that favors the survival of the trichomonads occurs, trichomonas evolves to an antagonistic state with the lactobacilli and other commensal bacteria. In a healthy vaginal ecosystem, the non-pathogenic bacteria are dominant members of the microflora of the vagina, with lactobacilli as a predominant member. Lactobacilli exert their dominance through the production of lactic acid, hydrogen peroxide, and bacteriocin. Through these factors, lactobacilli are able to suppress the growth of all other bacteria within the ecosystem and maintain dominance. If conditions that permit T. vaginalis to flourish evolve, growth of the pathogenic bacteria is favored and this results in the suppression of Lactobacillus spp., as well as other non-pathogenic bacteria. T. vaginalis appears capable of assuming different forms within the vagina (Figures 14 and 15). Although the lifecycle of T. vaginalis has not been elucidated, the organism has been observed to divide in culture. Both oversized and undersized forms with and without flagella have been observed. Forms have also been identified with a dividing nucleus and with multiple nuclei. These various forms are considered present in response to unfavorable growth conditions and different stages in the lifecycle11. These interpretations have been questioned and the various forms may represent stages in the development of mononuclear flagellated organisms18,19. It is these various forms that may be present in patients who have been treated but which go undetected when the vaginal discharge is examined microscopically. Thus, the patient is considered adequately treated


but, in reality, the organism has been merely ‘suppressed’. Once the antiparasitic agent is removed from the vaginal environment, the organism resumes its infection state after a suitable recovery period. Microscopic examination of vaginal fluid from patients on antiparasitic therapy also often fails to reveal the presence of the so-called ‘cystic’ form of the organism. When therapy is complete, the cystic form may persist. If the vaginal fluid is not cultured for trichomonads, the patient may harbor the parasite, and when conditions favorable to the growth of the trichomonads return, so does the infection. T. vaginalis can be cultured in Diamond’s medium, which provides all the nutritional requirements of the obligate parasite20–22. Themacromolecules that T. vaginalis requires in vivo, especially purines, pyrimidines, and lipids, are provided in the vaginal environment via phagocytosis of host and bacterial cells23,24. Diamond’s medium (TYI-33) is a nutrient broth containing trypticase, yeast extract, iron, fetal bovine serum, and a vitamin–107Tween 80 complex25. Diamond’s medium is commercially available and suitable for use in the physician’s office to culture T. vaginalis from the vagina. The physician can simply swab the vagina, place the swab into the Diamond’s medium, and swirl the swab vigorously for several seconds. The swirling action liberates the trichomonads from the swab so it can be removed and discarded. The culture can then be incubated in an ambient air incubator or held at room temperature. Microscopic examination of a drop of culture fluid will reveal the presence of trichomonads. EPIDEMIOLOGY It is estimated that there are 170 million cases of vaginal trichomoniasis in the world each year26. It is also estimated that each year 3 million cases of vaginal trichomoniasis occur in the United States alone26. While T. vaginalis has not been implicated in upper genital tract infections to the degree that Chlamydia trachomatis and Neisseria gonorrhoeae have, it has been associated with PID, human immunodeficiency virus (HIV) infection, and adverse pregnancy outcome. Moodley and co-workers27 found that women with HIV and vaginal trichomoniasis had a significantly higher risk of developing PID

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than HIV-negative women infected with T. vaginalis. These investigators studied 577 women who complained of vaginal discharge and 119 women with a clinical diagnosis of PID. They found that 76 (64%) of the 119 women with PID also had HIV, compared with 312 (54%) of the 577 women with discharge only. They concluded that there was no association between HIV and PID (p = 0.6)27. Interestingly, these investigators found that the prevalence of STD was high in this study population; however, the only statistically significant sexually transmitted organism was T. vaginalis. The prevalence of N. gonorrhoeae in all study participants was 12% (p = 0. 067), while the prevalence of C. trachomatis (p = 0.8) and T. vaginalis p = 0.03) was 11 and 29% respectively. A 69% prevalence (p = 0.7) of bacterial vaginosis (BV) was also reported. In women not infected with HIV, but either complaining of vaginal discharge or diagnosed with PID, the prevalence was: BV 58 of 308 women (19%), T. vaginalis 25 of 308 (8%), N. gonorrhoeae eight of 308 (2.6%), and C. trachomatis five of 308 (1.6%)27. When it occurs in pregnant women, T. vaginalis vaginitis has been viewed as a factor causing an increase in poor pregnancy outcome. Other investigators found an independent association between T. vaginalis vaginitis and PRAM, delivery of a preterm infant, and birth of a low-birth-weight infant28–30. Several authors have attempted to demonstrate poor pregnancy outcome in women with T. vaginalis vaginitis. However, Klebanoff and co-workers31 were unable to demonstrate a beneficial effect—prevention of preterm delivery—of treating asymptomatic T. vaginalis vaginitis in pregnant women. T. vaginalis is a fastidious protozoan that depends on its host for survival; it cannot survive outside the host. The lack of knowledge about the T. vaginalis life cycle makes it difficult to understand how the organism is able to survive in unfavorable conditions. The absence of a cyst or spore stage should make it difficult for the protozoan to survive exposure to desiccation, high temperature, or unfavorable hydrogen ion concentrations. However, when the organism is outside the confines of the host, it can survive if the humidity of the environment is sufficient to prevent desiccation. The protozoan has been isolated from baths, and poorly chlorinated water in whirlpools, hot tubs, and swimming pools32,33. Interestingly, studies demonstrate that T. vaginalis can survive in vaginal exudates, outside the vagina, at


10°C for up to 48 h33. The organism has also survived up to 3 h in urine, and up to 6 h in ejaculated semen34. The protozoan has also been found to survive in moist washcloths at a temperature of 35° C35,36. One-third of washcloths contaminated with T. vaginalis were found to contain viable trichomonads after up to 3 h, and 10% had viable protozoans up to 24 h following contamination36. In one study, 37% of women with vaginal trichomoniasis left contaminated urine on toilet seats after voiding, and 36% of the samples contained viable trichomonads. Toilet seats seeded with vaginal exudates containing viable trichomonads were found to have viable organisms up to 45 min following deposition of the contaminated fluid37,38. Although this evidence suggests that T. vaginalis can exist outside the host for brief periods, there has not been confirmation that the protozoan can be transmitted via non-sexual contact. Therefore, it is generally accepted that transmission and acquisition of T. vaginalis is primarily, and almost exclusively, through sexual intercourse or sexual contact between a contaminated or infected individual and a non-infected individual37,38. Transmission of T. vaginalis can occur between lesbian couples via mutual masturbation. This occurred in a couple reported to be in a monogamous relationship who did not have sex with males. They also did not use sexual instruments, for example penetrating instruments40. This does raise the question of whether a previous partner was bisexual and transmitted the infection. Infected discharge, or discharge containing trichomonads, can be transmitted via any carrier. Transmission to newborn infants may occur during the birthing process as the infant passes through the birth canal. There have been three cases of T. vaginalis pneumonia in newborn infants and no other pathogen was recovered from these infants41,42. The number of sexual partners that an individual is exposed to is directly related to their risk of contracting trichomoniasis. This, in turn, is related to the number of individuals infected with T. vaginalis within the pool of contacts. The age group at greatest risk for acquiring trichomoniasis is between 20 and 30 years of age, which is also the age group that participates in the greatest frequency of heterogenous sexual activity. However, unlike gonorrhea and chlamydia which tend to decrease in frequency as the population ages, the frequency of trichomoniasis infection tends to increase in women

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30–40 years of age35,43. The greatest risk factors for acquiring trichomoniasis are: race, use of contraceptives other than condoms, and a history of STD. African-American women are at a greater risk for trichomoniasis than Hispanic or Caucasian women. This also appears to be true for N. gonorrhoeae infection35,43. Individuals not using contraceptive pills are two times as likely to acquire trichomoniasis than individuals who use them44,45. Males appear to serve as asymptomatic carriers and are both an important vector and reservoir for transmission to their sexual contacts or partners. It has been hypothesized that the male may be symptomatic and present as though he has non-gonococcal, nonchlamydial urethritis or prostatitis46–48. Inonestudy T. vaginalis was isolated from 50 of 447 males evaluated at an STD clinic49. The protozoan was also isolated from nine (17%) of 52 males who had sexual contact with women known to have vaginal trichomoniasis. The males usually became symptomatic within 24 h following contact with an infected sexual partner. A total of 27 of 52 (52%) infected males had symptoms of urethritis49. A pure trichomonal infection in the male produces a clear-to-slight purulent urethral discharge. PATIENT EVALUATION AND DIAGNOSIS Trichomoniasis may be asymptomatic or symptomatic. It is estimated that 25–50% of women infected with T. vaginalis are asymptomatic and have a vaginal pH less than 4.550. Interestingly, approximately 33– 35% of women with asymptomatic infection or colonization develop symptomatic infection within 6 months51. When introduced into the vagina, T. vaginalis has an incubation period of 4–28 days in approximately 50% of infected individuals52. Once in the vaginal environment, T. vaginalis can induce an acute infection, a chronic infection, or establish an asymptomatic state. Once in the vaginal environment, the parasite must interact with host factors and the endogenous vaginal microflora. If an asymptomatic state is to be established, the organism must develop a symbiotic or perhaps commensal relationship. Therefore, the numbers of trichomonads must be kept below a crucial threshold so they will not alter the equilibrium of the vagina, thereby allowing Lactobacillus spp. to maintain dominance. As long as these conditions are maintained,


trichomonads will go unnoticed and undetected. If an infection, like known exposure, is suspected, culture of the vaginal discharge should reveal the presence of T. vaginalis. Patients with acute T. vaginalis infection typically have a copious yellow or green to dirty gray discharge. Patients with both trichomoniasis and BV often complain of a foul vaginal discharge. In many cases they often present with significant vulvar erythema and swelling. Acute infection is often accompanied by the presence of petechial hemorrhages on the vaginal epithelium. Approximately 2% of patients with acute cervical-vaginal infection will have petechial hemorrhages in the vaginal and cervical epithelia53. The patient’s symptoms tend to worsen during their menses. Patients with chronic infection usually have mild symptoms with a scant discharge, but they can also have a copious discharge. The symptoms are usually pruritus and dyspareunia. Since the patient with chronic infection may be asymptomatic, or have mild symptoms, the disease goes undetected and this group of patients serves as a vector for transmission of the disease54. T. vaginalis infection is not restricted to the vagina and cervix; it can also involve the entire urogenital tract. Trichomonas infection can cause a Bartholin’s gland abscess, salpingitis, pyosalpinx, endometritis, and infertility, and is also associated with an increase in HIV transmission55–59. Because trichomoniasis in the male is usually asymptomatic, they serve as an important vector in the transmission because they carry the protozoan and can readily transmit the organism to a sexual partner. Although usually asymptomatic, infection in the male can be mildly symptomatic or acute. The asymptomatic carrier is only identified after his sexual contact is infected, while the male with an acute symptomatic infection usually develops profuse urethritis characterized by a clear to mucopurulent discharge, dysuria, mild pruritus, or burning immediately following sexual intercourse60. Complications associated with trichomoniasis in women are non-gonococcal, non-chlamydial urethritis. The patient with symptomatic vaginal trichomoniasis typically presents with a malodorous discharge. The color of the discharge can vary from green to dirty gray and is typically liquid in consistency. The discharge may be frothy or non-frothy, and patients can report itching, soreness, and dyspareunia. The vaginal epithelium may be

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spotted by petechial hemorrhages, which will appear on the cervix in 2% of cases. This is referred to as a ‘strawberry cervix’. Clinicians should not rely solely on the clinical presentation because other STDs can present with similar findings, and the frothy discharge is seen in only 12% of patients with trichomoniasis35,53,61–63. Using solely clinical criteria to establish the diagnosis of trichomoniasis will correctly identify only 12% of infected patients51. The diagnosis of trichomoniasis vaginitis is usually established by identifying motile trichomonads on microscopic examination of vaginal discharge. However, this method is not very accurate and depends on the observer’s experience. Identification by microscopic examination of vaginal fluid infected with T. vaginalis has a sensitivity between 38 and 82%64−66. At the present time, the gold standard for establishing a trichomoniasis diagnosis is a broth culture. This will be the case until a polymerase chain reaction (PCR) test becomes commercially available. The disadvantage of using broth culture in a clinical setting is that it takes 2–7 days incubation period for the culture to become positive53,67. This delay allows the patient to transmit the disease if she is left untreated during the time the culture is incubated. The Papanicolaou stain (Pap smear) does offer a reliable method to diagnose because it is commonly used in gynecology. However, there is approximately a 48% error rate in diagnosis because of falsepositive and false-negative reports68. To establish a diagnosis of vaginal trichomoniasis, a characterization of the vaginal discharge should be conducted. The discharge should be characterized by its color, consistency, and the presence of gas (froth), and should be whiffed before and after mixing with KOH, to determine if it has an odor. The vaginal pH should be determined and if it is above 4.5, a microscopic examination of the vaginal discharge should be performed. A cotton- or Dacron-tipped swab should be used to obtain a specimen from the lateral vagina. The swab should then be placed in 2 ml of saline and agitated vigorously, then removed and discarded. One to two drops of the diluted discharge should then be examined under 40x magnification. The observer will note estrogenized squamous epithelial cells, more than five white blood cells (WBC) per high-power field (hpf), a variety of bacterial morphotypes, and the presence of motile (flagellated) ovoid shaped


protozoans. If protozoans are not seen then the discharge should be cultured. The presence of numerous WBC, a variety of bacterial morphotypes, a pH above 4.5, and a malodorous or fish-like smelling discharge indicates the presence of both BV and an accompanying infection. The presence of numerous WBC, in fact more than five per 40x magnification, is highly suggestive of either an infection or an accompanying inflammatory process. This finding should be the impetus for the physician to begin screening for genital tract infection. The patient’s cervix should be sampled for the presence of C. trachomatis and N. gonorrhoeae. Other STDs to be considered are Herpes Simplex virus (HSV) and Human Papillomavirus (HPV). The presence of WBC in the vaginal discharge, and the failure to detect a pathogen when examining the vaginal discharge microscopically, should also lead the physician to obtain a vaginal specimen for the culture of T. vaginalis. One common dilemma confronting all physicians is the presence of WBC in the vaginal discharge but no detectable pathogen when the discharge is examined microscopically. Since the most common method of diagnosing vaginal trichomoniasis is by microscopic examination of an un-dyed specimen of vaginal discharge, the presence of trichomonads is often undetected. Currently there is no commercially available rapid method of detection that has both a high degree of sensitivity and specificity. (Sensitivity is defined as the percentage of culture-positive specimens identified as positives by microscopy or other tests, while specificity is defined as the percentage of culture-negative specimens identified as negative by microscopy or other tests.) Using the characteristics of the vaginal discharge is not associated with a high degree of sensitivity or specificity. Approximately 50% of women with a discharge characteristic of trichomoniasis are not infected53,69. The specificity and sensitivity of microscopic examination compared with culture to determine if the patient has vaginal trichomoniasis has been reported to range from 96 to 100% and 38 to 82%, respectively68,70 . However, Robertson and co-workers71 did not confirm the high specificity with microscopy reported by others. They compared the standard wet prep with a centrifuged specimen examined under phase

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contrast microscopy with culture and could not confirm ten of 44 wet prep specimens identified as positive by standard light microscopy. In an attempt to enhance the accuracy of establishing the correct diagnosis of vaginal trichomoniasis, the Gram stain has been used. Cree72 detected T. vaginalis in only 66% of 249 individuals with culture-proven infection. Cree also reported a false positive rate of 7%. However, Sorbrepena73 was able to identify T. vaginalis in twice as many individuals using Gram stain than with wet prep. The presence of trichomonads is often reported in the Pap smear. In a study comparing Pap smear with culture and microscopic examination of vaginal discharge for the detection of trichomoniasis, the Pap smear was found to be inferior. In this study, 126 trichomoniasis infections were diagnosed on Pap smear but could not confirmed by other methods73. Perl studied 1199 patients and found 666 to be positive for trichomoniasis on Pap smear but only 37% could be confirmed by culture68. New methodology is constantly being developed that will improve the physician’s ability to establish a correct diagnosis. Several new, socalled ‘rapid’ tests are available but none are truly rapid—that is, yielding a diagnosis while the patient is completing her examination— and they are all more costly. The only meaningful rapid test that has a practical clinical application is one that can produce reliable results within 5–10 min and is not expensive. If the test cannot yield results while the patient is being evaluated, then the test is not particularly useful. Microscopic examination of a diluted specimen of vaginal discharge (the wet prep) continues to be a fairly reliable method for diagnosing abnormalities of the lower genital tract with regard to the vaginal ecosystem. One group of investigators75 found that examining the vaginal discharge microscopically at the time a Pap smear is obtained proved to be beneficial in the management of the patient and reduced the need for repeat Pap smears, except for the management of cellular abnormalities. These investigators also found that the presence of inflammatory cells on Pap smear was associated with BV (p < 0.0001), excess WBC (p < 0.0001), trichomoniasis (p < 0. 0001), and positive cervical cultures for N. gonorrhoeae and C. trachomatis (p < 0.0001)75. The zeal for developing new, rapid, and reliable tests for diagnosing trichomoniasis is based on the belief that: (1) many


physicians do not examine the vaginal discharge microscopically; (2) many physicians lack the experience to perform a thorough examination of vaginal discharge; and (3) examination of the vaginal discharge is too time consuming. A significant amount of information can be gained from a thorough evaluation of the vaginal discharge but unfortunately this simple examination is frequently not performed. TREATMENT The standard treatment for uncomplicated T. vaginalis vaginitis is oral metronidazole. Oral, or in rare instances parenteral, metronidazole is preferred to intravaginally administered metronidazole because the trichomonads commonly infect other sites in the lower genital tract. Successful treatment of the infected woman also depends upon removing her exposure to a contaminated or infected partner. Therefore the sexual partner, male or female, must also be treated. Prevention of transmission is accomplished by prohibiting infected penile or vaginal discharge from coming in contact with the partner’s genitalia. Management of the sexual partner is of paramount importance if the patient under treatment is to be cured of her infection. All people who have come into contact with the infected patient should be treated, and if possible treatment should occur simultaneously among all potentially infected individuals. If this cannot be accomplished, the patient in question should refrain from sexual intercourse until her partner or partners can be treated. If the woman’s partner takes metronidazole and the woman is shown to be cured of her infection, but subsequent to having sexual intercourse becomes infected, then it can be assumed that her partner may have a prostate infection. Of course, this is based on the following: (1) she has not had sexual intercourse with a different partner; (2) he has not had sexual intercourse with a different partner; and (3) he has taken a full course of therapy. Males who develop trichomoniasis of the prostate gland require a prolonged course of metronidazole treatment. Prostate infection with T. vaginalis was first demonstrated in 1936 in expressed prostatic fluid obtained from husbands of women infected with T. vaginalis76. Isolation of trichomonads from men who have had sexual intercourse with women infected with T. vaginalis ranges from 9 to

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10%77,78. Interestingly, in males diagnosed with urethritis but failing to respond to several courses of antibiotics not active against T. vaginalis, 85% were subsequently found to be infected with the protozoan79,80. However, one difficulty with these studies was that the patients were not evaluated for the presence of N. gonorrhoeae,C. trachomatis, Mycoplasma hominis, Ureaplasma urealyticum, or HSV. It may be that infection in the male tends to be asymptomatic and it is often difficult to document the presence of a protozoan. Several studies have demonstrated the presence of T. vaginalis in asymptomatic husbands and the sexual partners of infected women35,81,82. In one investigation, 30 husbands of infected women were cultured; 60% of the husbands were found to be positive for T. vaginalis and 61% of the males were asymptomatic83. The percentage of male sexual contacts of infected women who subsequently develop symptomatic urethritis and are found to be positive for T. vaginalis ranges from 16 to 83%84. Sexual partners treated simultaneously may not respond in a similar manner. The trichomonads present in all infected tissue may not all be killed, and adequate levels of metronidazole may not be achieved in sufficient concentration in all infected tissues. The male infected with T. vaginalis possesses significant problems, for example, treating the infected prostate gland is often difficult and requires prolonged administration of metronidazole. Infection in the male may involve various sites, like the epididymis, posthitis (infection of the foreskin), balanitis (infection of the glans penis), and may result in draining sinus of the median raphe37,42,85–89. Infection in males also appears to occur easily. In 1963 Weston and Nicol90 examined male sexual partners 2 days after being exposed to infected females and recovered T. vaginalis from 70% of the males. Interestingly, increasing the time between sampling of the male and exposure correlated with a decrease in recovery rate of the protozoan. Only 30% of the exposed males had positive T. vaginalis cultures when sampled 14 days after exposure to an infected female. Thirty days following exposure, only 23% of the males remained positive and subsequent examination failed to recover trichomonads. T. vaginalis in males can be summarized thus: (1)symptomatic infection is common;


(2)males exposed to infected females should be considered colonized, whether symptomatic or asymptomatic; (3)symptomatic male infection is typically diagnosed as urethritis and these individuals typically have a purulent discharge; and (4)prostatitis is uncommon. Thus, a physician responsible for the health of women should remember that all women with documented vaginal trichomoniasis should be considered a vector for the transmission of T. vaginalis. Finally, when treating a woman for vaginal trichomoniasis it is imperative that her sexual partners be treated, whether they are symptomatic or not. The only anti-trichomonal agent approved for use in the United States is metronidazole, which was approved for use in 1963. An azomycin, a nitroimidazole drug, isolated from a species of Streptomyces lead to the discovery of synthetic agents that have activity against T. vaginalis. Metronidazole was one of these agents and it was subsequently found to have activity against Giardia lamblia, and can also be used in the treatment of amebiasis90−92. Theanaerobic activity of metronidazole was discovered accidentally: a woman was treated with metronidazole for vaginal trichomoniasis and she was also known to have acute ulcerative gingivitis that simultaneously responded to the treatment for vaginal trichomoniasis93. Davis and co-workers94 confirmed that metronidazole was effective in the treatment of Vincent’s stomatitis and the drug inhibited Fusobacterium necrophorum94,95. Nitroimidazole available in countries other than the United States are: nimorazole (Nagogin®), tinidazole (Fasigyn®), ornidazole, secnidazole, carnidazole, and misonidazole96,97. Tinidazole is similar to metronidazole in its spectrum of activity against parasites and obligate anaerobic bacteria. The minimum trichomonicidal concentration is lower than that for metronidazole98,99. T. vaginalis resistant to metronidazole are usually resistant to tinidazole, but there have been reports of strains resistant to the former agent but sensitive to tinidazole100,101. Metronidazole, when taken orally, is almost completely absorbed by the gastrointestinal tract and approximately 95% of this antimicrobial agent is bioavailable. The serum half-life is

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Table 14 Adverse effects of metronidazole

approximately 8.5 h102. Peak serum levels are reached 1–3 h after oral administration. If metronidazole is taken after a meal, absorption is delayed and peak serum levels are not reached for 3 h102,103. Metronidazole is metabolized by the liver into at least five different metabolites104. Approximately 20% of the daily dose is excreted in the urine and feces. Studies have demonstrated small amounts of mutagenic derivatives and an acetamide have been found in the urine of patients receiving metronidazole105. When metronidazole is administered vaginally as a cream or suppository, absorption occurs with peak levels of 0.2 μ g/ml within 12–24 h of a 500 mg dose. Absorption is greater when metronidazole is in cream form as opposed to a suppository106. Adverse effects associated with metronidazole are listed in the Table 14. Patients receiving metronidazole therapy should be strongly advised not to imbibe alcoholic beverages, or take medication containing alcohol, because they may develop severe abdominal pain (a disulfiram-like reaction)107. Individuals taking anticonvulsant medication or warfarin should be warned that metronidazole could enhance the action of these medications108. The standard regimens for trichomoniasis treatment are based on the assumption that the organism is likely to infect the vagina, urethra, bladder, Skene’s glands, and Bartholin’s glands; therefore, metronidazole should be administered via a route that will achieve adequate serum and tissue levels. The most expedient and inexpensive route is oral. The standard dosing regimens are 2 g administered as a single dose; 250 mg three times a day or 500 mg twice a day for 7 days. Some physicians favor the 2-g single oral dose regimen because it can be taken once so compliance is greater. However, this can cause considerable gastric distress. When trichomoniasis is diagnosed accidentally, perhaps by Pap smear, the patient should be examined


and the diagnosis confirmed. If the patient is not treated, she may serve as a vector for T. vaginalis transmission and is likely to experience acute exacerbations of infection. She is also likely to develop an abnormal Pap smear in the future108. If she is treated but does not have trichomoniasis, she is being unnecessarily exposed to an antibiotic. If the exposed male is left untreated, he may infect approximately 24% of the women with whom he has had sexual contact109. Metronidazole has been effective in the treatment of T. vaginalis and most strains are sensitive to concentrations of less than 1–16 ug/ ml110–112. Under normal anaerobic concentrations most strains of T. vaginalis are sensitive to metronidazole at a concentration of 3 μ g/ml or less, and under aerobic conditions sensitivity occurs at a concentration of 25 μ g/ml or less113. Although T. vaginalis has remained relatively sensitive to metronidazole, resistance to this antimicrobial agent has been reported114. In one study, vaginal fluid was obtained from 911 women; T. vaginalis was detected in 82 (9%), and two isolates were found to have a low-level resistance to metronidazole115. Some investigators have found patients infected with resistant strains but were able to treat these patients successfully by increasing the dose of metronidazole116–119. Patients who appear to have intractable or resistant trichomoniasis should be managed by first having the organism isolated and its sensitivity or resistance to metronidazole determined. Isolates that have an aerobic minimal lethal dose (MLD) greater than 50 μ g/ml but lower than 200 μ g/ml will be moderately sensitive; those with an MLD over 200 μ g/ml will be resistant116. Thus, patients with moderate sensitivity to metronidazole may be successfully treated with a total daily dose of 2–3.5 g per day for 7–14 days. Oral and vaginal administration of metronidazole can be combined for treatment. In cases where higher doses of oral metronidazole cannot be tolerated, the drug can be given intravenously. Metronidazole doses exceeding 2 g per day can induce nausea, vomiting, gastrointestinal discomfort, headache, peripheral neuropathy, and seizures that usually appear within 72 h of beginning treatment (Table 15). Patients who continue to demonstrate a failure to respond to metronidazole, even at higher doses, can be treated with tinidazole.

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Table 15 Recommended treatment regimens

Although tinidazole is not currently available in the United States, it can be obtained in Canada; however, it is expected that tinidazole will become available in the United States in the near future. Sobel and coworkers reported that tinidazole therapy was successful treatment for refractory trichomoniasis in 22 of 24 patients120. Metronidazole and tinidazole are not themselves active or cytocidal against T. vaginalis, but their metabolic products are active agents. Metronidazole enters the protozoan through diffusion and is activated in the hydrogenosomes of the organism23,121,122. The nitro group is reduced anaerobically by the enzyme pyruvate-ferredoxin oxidoreductase122. This reaction yields cytotoxic nitro radical-ion intermediates that break DNA strands of the protozoan123. In vitrostudies have demonstrated also that the effect of metronidazole on T. vaginalis is rapid, causing cessation of cell division and motility within 1 h, while cell death occurs within 8 h of exposure to the drug124. TREATMENT IN THE PREGNANT PATIENT Some investigators have attempted to demonstrate an association between T. vaginalis vaginitis, PRAM, and premature delivery128,129. However, other investigators failed to show any association between T. vaginalis vaginitis and poor pregnancy outcome31,130,131. Thus, the significance of T. vaginalis vaginitis in pregnant and non-pregnant women, especially those who are to have pelvic surgery, most likely rests in the fact that these women have an altered vaginal microflora. Whether or not T. vaginalis vaginitis has an adverse effect on pregnancy outcome will most likely remain unresolved because this protozoan infection is associated with, and probably is responsible for, the alteration in vaginal flora. The shift in vaginal flora can be skewed towards a Gram-positive, Gram-negative facultative, or obligate anaerobic bacteriology. Significant increases in the pathogenic vaginal endogenous flora can, and does, result in an increased risk for


postpartum endometritis and post-hysterectomy pelvic cellulitis and abscess formation. Screening symptomatic pregnant patients by either wet mount or culture is beneficial, whereas when asymptomatic patients were screened, culture (94.5%) proved to be better than wet mount (70%)132. These investigators also found that in the inner-city population in Denver, Colorado, 9.4% of 1175 pregnant women had T. vaginalis vaginitis. Approximately 18.2% of the 110 infected women complained of symptoms consistent with vaginitis132. Both pregnant and non-pregnant women complaining of symptoms associated with vaginitis should be thoroughly evaluated. However, at the individual’s first prenatal visit, in an attempt to enhance the patient’s ability to maintain the pregnancy, it is in the patient’s best interest to evaluate the vaginal ecosystem. This can be easily done by the physician determining the vaginal pH. If the pH is 4.5 or higher, a wet prep should be obtained and examined microscopically. The presence of WBC (> 5/hpf) should be an indication to determine if T. vaginalis infection is present. Cervical specimens for the detection of C. trachomatis and N. gonorrhoeae should also be obtained. Treatment of the pregnant patient with T. vaginalis vaginitis is no different than treatment of the non-pregnant patient. Struthers133 published a review of metronidazole use in pregnancy over approximately four decades and found that the drug did not have a teratogenic effect, no matter in which trimester it was taken. One of the studies reviewed by Struthers was by Rosa and coworkers134, who used a database of 104 339 pregnant women who delivered normal babies and 6564 infants with anomalies. Among these women, 1083 received metronidazole in the first trimester. Of these, 1020 were normal and 63 had some anomaly. The relative risk of an abnormality being associated with metronidazole was 0.92. Pregnant women can be treated safely for trichomoniasis with metronidazole in the first, second, and third trimesters. However, when administering any therapeutic agent to a pregnant woman the risk-benefit ratio must be determined. An asymptomatic pregnant woman who’s Pap smear indicates the presence of T. vaginalis should be evaluated to determine if she indeed has vaginal trichomoniasis. If the patient is proven to harbor T. vaginalis, but is asymptomatic, one may elect to hold off on therapy until the second trimester, but

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Sylvestre L, Belanger M, Gallai Z. Urogenital trichomoniasis in the male: review of the literature and report on treatment of 37 patients by a new nitroimidazole derivative (Flagyl). Can Med Assoc J 1960; 83: 2295–9 Kawamura N. Trichomoniasis of the prostate. Jpn J Clin Urol 1973; 27: 335–44 Gallai Z, Sylvestre L. The present status of urogenital trichomoniasis. A general review of the literature. Appl Ther 1966; 8:773–8 Fullilove RE Jr. Trichomonas vaginalis in men. J Med Soc NJ1983; 80: 94–6 Wilcox RR. Epidemiological aspects of human trichomoniasis. Br J Vener Dis 1960; 36:167–74 Jennison RF. Incidence of Trichomonas vaginalis in marital partners. Br J VenerDis 1960; 36:163–6 Counts WE, Silva-Inzunza B, Tallman B. Genitourinary complications of nongonococcal urethritis and trichomoniasis in males. Urol Int 1959; 9:189–208 Kuberski T. Trichomonas vaginalis associated with nongonococcal urethritis and prostatitis. Sex Transm Dis 1980; 7:135–6 Catterall RD. Diagnosis and treatment of trichomonal urethritis in men. Br J Med J 1960; 2:113–15 13–15 Wilson A, Ackers JP. Urine culture for the detection of Trichomonas vaginalis in men. Br J Vener Dis 1980; 56:46–8 Watt L, Jennison RF. Incidence of Trichomonas vaginalis infection of the median raphae of the penis. Br J Vener Dis 1960; 36:163–6 Soendjojo A, Pindha S. Trichomonas vaginalis infection of the median raphe of the penis. Sex Transm Dis 1981; 8:255–7 Sowmini CN, Vijayalakshmi K, Chellamuthiah C, Sundaram SM.Infections of the median raphe. Report of three cases. Br J Vener Dis 1973; 49:469–74 Dural P, Roiron V, Sibulet H, Borel LJH. Trial of an anti-trichomonal derivative of imidazole (8823 R.P.). Comptes Roehdus Soc Franc Gyn 1959; 29:36–9 Powell SJ, MacLeod I, Wilmot AJ, Elsdon-Dew R. Metronidazole in amoebic dysentery and amoebic liver abscess. Lancet 1966; II(7477): 1329–31 Schneider J. Treatment of giardiasis (lambliasis) with metronidazole. Bull SocPathol Exot1961; 54:84–8 Shinn DLS. Metronidazole in acute ulcerative gingivitis. Lancet 1962; I: 1191–203

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94. 95. 96. 97. 98.

99.

100. 101.

102.

103. 104.

105.

106.

107. 108. 109.

Davies AH, McFadden JA, Squires S. Treatment of Vincet’s stomatitis with metronidazole. Br Med J 1964; 1:1149 Tally FP, Sutter VL, Finegold SM. Metronidazole versus anaerobes. In vitro data and initial clinical observations. Calif Med 1972; 17:22–6 Miller MW, Howes HL, English AR. Tinidazole, a potent new antiprotozoal agent. Antimicrob Agents Chemother 1969; 9:257–60 Muller M. Action of clinically utilized 5-nitromidazoles on microorganisms. Scand J Infect Dis 1981; 26:31–41 Howes HL Jr, Lynch JE, Kivlin JL.Tinidazole, a new antiprotozoal agent: Effect on Trichomonas and other protozoa. Antimicrob Agents Chemother 1969; 9:261–6 Forsgren A. Wallin J. Tinidazole—a new preparation for Trichomonas vaginalis infections. I. Laboratory evaluation. Br J Vener Dis 1974; 50: 146–7 Sears SD, O’Hare J. In vitro susceptibility of Trichomonas vaginalis to 50 antimicrobial agents. Antimicrob Agents Chemother1988; 32:144–6 Hamed KA, Studemeister AE. Successful response of metronidazoleresistant trichomonal vaginitis to tinidazole. A case report. Sex Transm Dis 1992; 19:339–40 Houghton GW, Smith J, Thorne PS, Templeton R. The pharmacokinetics of oral and intravenous metronidazole in man. / Antimicrob Chemother 1979; 5:621–3 Levison ME. Microbiological agar diffusion assay for metronidazole concentrations in serum. Antimicrob Agents Chemother 1974; 5:466–8 Stambaugh JE, Feo LG, Manthei RW. The isolation and identification of the urinary oxidative metabolites of metronidazole in man. J Pharmacol Exp Ther 1968; 161:373–81 Stambaugh JE, Feo LG, Manthei RW. Isolation and identification of the major urinary metabolites of metronidazole. Life Sci 1967; 6:1811– 19 Alper MM, Barwin BN, McLean WM, McGilveray IJ, Sved S. Systemic absorption of metronidazole by the vaginal route. Obstet Gynecol 1985; 65:781–4 Winter D, Stanescu C, Sauvard S. The effect of metronidazole on the toxicity of ethanol. Biochem Pharmacol 1969; 18:1246–8 Koss IG, Wolinksa WH. Trichomonas vaginalis cervicitis and its relationship to cervical cancer. Cancer1959; 12:1 171–93 Watt L, Jennison RF. Incidence of Trichomonas vaginalis in marital partners. BrJ Vener Dis 1960; 36:163–70


110.

111.

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114. 115.

116.

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118. 119.

120.

121.

122. 123.

Korner B, Jensen HK. Sensitivity of Trichomonas vaginalis to metronidazole, tinidazole, and nifuratel in vitro. Br J Vener Dis 1976; 52:404–8 McFadzean JA, Pugh IM, Squires SL, Whelan JP. Further observations on strain sensitivity of Trichomonas vaginalis to metronidazole. Br J Vener Dis 1969; 45:161–2 Nielsen R. Trichomonas vaginalis. II. Laboratory investigations in trichomoniasis. Br J Vener Dis 1973; 49:531–5 Ralph ED, Darwish R, Austin TW, Smith EA, Pattison FL.Susceptibility of Trichomonas vaginalis strains to metronidazole: response to treatment. SexTransm Dis 1983; 10:119–22 Robinson SC. Trichomonal vaginitis resistant to metronidazole. Can Med Assoc J 1992; 86:665 Schmid G, Narcisi E, Moreno H, et al.Prevalence of metronidazoleresistant Trichomonas vaginalis in a gynecology clinic. /Reprod Med 2001; 46:545–9 Pereyra AJ, Lansing JD. Urogenital trichomoniasis: treatment with metronidazole in 2002 incarcerated women. Obstet Gynecol 1964; 24: 499–508 Lossick JG, Muller M, Gorrell TE. In vitro drug susceptibility and doses of metronidazole required for cure in cases of refractory vaginal trichomoniasis. J lnfect Dis 1986; 153:948–55 Forsgren A, Forssman L. Metronidazole-resistant Trichomonas vaginalis. Br JVener Dis 1979; 55:351–3 Kulda J, Vojtechovska M, Tachezy J, Demes P, Kunzvova E. Metronidazole resistance of Trichomonas vaginalis as a cause of treatment failure in trichomoniasis—a case report. Br J Vener Dis 1982; 58:394–9 Sobel JD, Nyirjesy P, Brown W. Tinidazole therapy for metronidazole-resistant vaginal trichomoniasis. Clin Infect Dis 2001; 33: 1341–6 Muller M, Lindmark RG. Uptake of metronidazole and its effect on viability in trichomonads and Entamoeba invadens under anaerobic and aerobic conditions. Antimicrob Agents Chemother1976; 9:696–700 Muller M. Reductive activation of nitroimidazoles in anaerobic microorganisms. Bichem Pharmacol 1986; 35:37–41 Tocher JH, Edwards DI. Evidence for the direct interaction of reduced metronidazole derivatives with DNA bases. Biochem Pharmacol 1994; 48:1089–94

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124.

125. 126.

127. 128.

129.

130. 131. 132.

133. 134.

Nielsen MH. In vitro effect of metronidazole on the ultrastructure of Trichomonas vaginalis donne. Acta Pathol Microbiol Scand Sect B Microbiol 1976; 84:93–100 Caro-Paton T, Carvajal A, Rodriguez Pinilla E, et alIs metronidazole teratogenic? A meta-analysis. Br J Clin Pharmacol 1997; 44:179–82 Burtin P, Taddio A, Ariburnu O, Einarson TR, Koren G. Safety of metronidazole in pregnancy: a meta-analyis. Am J Obstet Gynecol 1995; 172:525–9 Piper JM, Mitchel EF, Ray WA. Prenatal use of metronidazole and birth defects: no association. Obstet Gynecol 1993; 82:348–52 Hardy PH, Hardy JB, Rosenbaum RC, et alPrevalence of six sexually transmitted disease agents among pregnant inner-city adolescents and pregnancy outcome. Lancet 1984; 2:333–7 Minkoff H, Grunebaum AN, Schwarz RH, et al.Risk factors for prematurity and premature rupture of membranes; a prospective study of the vaginal flora in pregnancy. Am J Obstet Gynecol 1984; 150: 965–72 Mason PR, Brown IM. Trichomonas in pregnancy. Lancet 1980; 1025– 6 Ross SM, Van Middelkoop A. Trichomonas infection in pregnancy— does it affect perinatal outcome? S Afr Med J 1983; 63:566–7 Heine RP, McGregor JA, Jones W, et al Trichomonas vaginalis: diagnosis and clinical characteristics in pregnancy. Infect Dis Obstet Gynecol 1994; 1:228–34 Struthers BJ. Metronidazole appears not to be a human teratogen: review of literature. Infect Dis Obstet Gynecol 1997; 5:326–35 Rosa FW, Baum C, Shaw M. Pregnancy outcome after first-trimester vaginitis drug therapy. Obstet Gynecol 1987; 69:751–5

7. ATROPHIC VAGINITIS

INTRODUCTION Vaginal atrophy develops in all women when estrogen depletion occurs at menopause. However, not all women with vaginal atrophy develop atrophic vaginitis. The estrogen concentration in perimenopausal women is approximately 120 ng/ml and after menopause begins its concentration decreases to approximately 19 ng/ ml1. The predominant hormone produced by the postmenopausal ovary is androstenedione and this hormone is converted in the peripheral fatty tissue to estrogen. Testosterone is also produced in the ovary and most of this is converted into estradiol in the ovaries. Thus there is an endogenous supply of estrogen as long as the postmenopausal ovaries continue to function. However, the decrease in estrogen is significant and the vaginal epithelial surface loses its folds, or rugae, and thickness, then becomes thin and pale. The vaginal tissue loses its elasticity and its ability to distend, thus it becomes shorter and narrower. These changes result in the patient experiencing dyspareunia and avoiding sexual intercourse. There are noticeable changes in the appearance of vaginal squamous epithelial cells in the absence of sufficient estrogen (Figure 7). There is also a lack of mature or naviculated squamous epithelial cells and a significant increase in intermediate and parabasal cells. Physiological changes within the vaginal ecosystem also occur. The most noticeable change is a decrease in the available glycogen, creating an insufficient supply of carbohydrate, which results in a decrease in Lactobacillus growth. The decrease in Lactobacillus growth results in a decrease in

ATROPHIC VAGINITIS 87

acid production and, in turn, the vaginal pH rises above 5 allowing the non-lactobacilli to grow. Once non-lactobacilli gain dominance, the vaginal discharge can change from white to dirty gray or purulent, depending upon the number of white blood cells (WBC) present. Once this condition is established, the patient’s status changes from vaginal atrophy to atrophic vaginitis. It also appears that women who smoke enhance the development of atrophic vaginitis2. Those women whose ovaries produce testosterone and androstenedione, and continue to be sexually active appear to experience less severe atrophic changes3. Women whose ovaries have become completely non-functioning are more likely to develop vaginal atrophy4. CLINICAL PRESENTATION Patients often develop vaginal atrophy without knowing the process occurs. Individuals who have infrequent sexual intercourse will note tightness in their vagina during intercourse. Because of the lack of lubrication, as well as shortness and narrowing of the vagina, these patients eventually complain of pain and discomfort. These individuals will often refuse to have sexual intercourse. At this point, the patient may come to the physician if their husband or sexual partner encourages them to do so. The development of vaginal spotting, profuse discharge, or vaginal burning is the most likely reason patients seek a physician’s assistance. The most frequently reported symptoms are: (1)vaginal narrowing and shortness; (2)vaginal spotting or bleeding, especially during or after intercourse; (3)development of a urethral carbuncle; (4)dysuria; (5)vulvar burning; (6)vulvar pruritus (7)dyspareunia; and (8)watery discharge that is dirty gray to purulent. Pelvic examination reveals:


(1)vaginal epithelium is pale, may observe petechial hemorrhages; (2)severe thinning of the vaginal epithelium results in a deep erythema of the vagina; (3)vaginal walls have lost their rugae and are smooth; (4)fissures are commonly observed on the medial aspect of the labia minora, posterior fourchette, and vestibule; and (5)synechiae can develop between opposing vaginal walls that have become denuded. Patients with vaginal atrophy sometimes develop urinary tract infections (UTI) as well as urinary in continence 5–7. The postmenopausal woman with urinary incontinence should not be subjected to a comprehensive evaluation of the urinary tract as the initial step in the work-up. The evaluation should begin by obtaining a clean catch urine specimen. If the patient has a copious discharge an evaluation of the vagina should be performed, i.e. physician inspection, determination of the vaginal pH, and microscopic examination of the vaginal discharge. Following completion of the pelvic examination, a lubricated tampon (place estrogen cream on the surface of the tampon) should be inserted into the vagina and the patient asked to provide a clean catch urine specimen. If the patient has atrophic vaginitis, and has copious discharge, the urine specimen will be contaminated by a variety of bacteria from the vagina. Once the specimen has been obtained the tampon should be removed. When evaluating the patient with urinary incontinence the presence of a UTI should be ruled out. If the patient exhibits signs of vaginal atrophy and vaginitis, a trial of estrogen therapy should be administered. If the patient continues to complain of urinary incontinence once the vagina has been restored to a healthy state, a comprehensive evaluation of the lower urinary tract should be conducted. TREATMENT The treatment for vaginal atrophy and atrophic vaginitis is estrogen replacement, administered either orally or intravaginally. Estrogen administered in the form of an intravaginal cream results in plasma


Table 16 Estrogen replacement therapy for treatment of vaginal atrophy and atrophic vaginitis

concentrations of estrone and estradiol similar that obtained with orally administered estrogen 8,9. For this reason, oncologists do not want patients with breast cancer to use estrogen cream administered intravaginally. Initially, the absorption of estrogen from the vagina is low because of the decreased vascularity; however, with continued treatment both the vascularity of the vagina and estrogen absorption increase10. Various forms of estrogen that are used for the treatment of vaginal atrophy and atrophic vaginitis (Table 16). REFERENCES 1. 2. 3.

4.

5. 6. 7. 8.

Pandit L, Ouslander JG. Postmenopausal vaginal atrophy and atrophic vaginitis. Am J Med Sci 1997; 314:228–31 Kalogeraki A, Tamiolakis D, Relakis K, et alCigarette smoking and vaginal atrophy in postmenopausal women. In Vivo 1996; 10:597–600 Leiblum S, Bachmann G, Kemmann E, Colburn D, Swartzman L. Vaginal atrophy in the postmenopausal woman. J Am Med Assoc 1983; 249:2195–8 Dupont A, Dupont P, Cusan L, et al.Comparative endocrinological and clinical effects of percutaneous estradiol and oral conjugated estrogens as replacement therapy in menopausal women. Maturitas 1991; 13:297–311 Eskin BA. The Menopause: Comprehensive Management, 3rd edn. New York: McGraw-Hill Health Professional Division, 1994; 382 Brown KH, Hammond CB. Urogenital Atrophy. Obstet Gynecol Clin North Am 1997; 15:13–32 Smith P. Estrogen and urogenital tract. Acta Obstet Gynecol Scand 1993; 72:1–26 Whitehead MI, Minandi J, Kitchen Y, Sharples MJ. Systemic absorption of estrogen from Premarin vaginal cream. In Cook I, ed.


9.

10.

11.

12.

13.

14.

15.

16. 17.

18.

19.

The Role ofEstrogen/Progesterone in the Management of Menopause. Lancaster: MTP Press 1978; 63–71 Englund DE, Johansson ED. Plasma levels of oestrone, oestradiol and gonadotrophins in postmenopausal women after oral and vaginal administration of conjugated equine oestrogens (Premarin). Br J Obstet Gynecol 1978; 85:957–64 Heimer GM, Englund DE. Effects of vaginally-administered oestriol on postmenopausal urogenital disorders: a cytohormonal study. Maturitas 1992:14:171–9 Englund DE, Victor A, Johanssen EDB. Pharmacokinetics and pharmacodynamic effects of vaginal oestradiol administration from silastic rings in post-menopausal women. Marturitas 1981; 3:125–33 Nash HA, Brache V, Alvarez-Sanchez F, Jackanicz TM, Harmon TM. Estradiol delivery by vaginal rings: potential for hormone replacement therapy. Maturitas 1997; 26:27–33 Fraser IS, Ayton R, Murkies Aet alA multicenter Australian trial of low dose estradiol therapy for symptoms of vaginal atrophy using a vaginal ring as delivery system. Maturitas 1995; 22(Suppl):S41 Henriksson L, Stjernquist M, Boquist L, Cedergren I, Selinus I. A oneyear multicenter study of efficacy and safety of a continuous, low-dose, estradiolreleasing vaginal ring (Estring) in postmenopausal women with symptoms and signs of urogenital aging. Am J Obstet Gynecol 1996; 174:85–92 Henriksson L, Stjernquist M, Boquist L, Alander U, Selinus I. A comparative multicenter study of the effects of continuous low-dose estradiol released from a new vaginal ring verus estradiol vaginal pessaries in postmenopausal women with symptoms and signs of urogenital atrophy. Am J Obstet Gynecol 1994; 171:624–32 Nachtigall LE. Clinical trial of the estradiol vaginal ring in the U.S. Maturitas 1995; 22 (Suppl): S43–7 Barentsen R, van der Weijer PH, Schram JH. Continuous low dose estradiol released from a vaginal ring versus estriol vaginal cream for urogenital atrophy. Eur J Obstet Gynecol Reprod Biol 1997; 71:73–80 Eierman W. The effect of low dose estradiol in the treatment of atrophic vaginitis: A double blind controlled study. The urogenital estrogen deficiency syndrome. Proc Int Workshop, Copenhagen, November 1986 Mettler L, Olsen PG. Long-term treatment of atrophic vaginitis with low-dose oestradiol vaginal tablets. Maturitas 1991; 14:23–31


20.

21.

22.

23.

24.

Eriksen PS, Rasmussen H. Low-dose 17beta-estradiol vaginal tablets in the treatment of atrophic vaginitis: A double-blind placebo controlled study. Eur JObstet Gynecol Reprod Biol 1992; 44:137–44 Nilsson K, Heimer G. Low-dose oestradiol in the treatment of urogenital oestrogen deficiency—a pharmacokinetic and pharmacodynamic study. Maturitas 1992; 15:121–7 Felding C, Mikkelson AL, Clausen HV, Loft A, Larsen LG. Preoperative treatment with oestradiol in women scheduled for vaginal operation for genital prolapse. A randomised, double-blind trial. Maturitas 1992; 15:241–9 Raz R, Stamm WE. A controlled trial of intravaginal estriol in postmenopausal women with recurrent urinary tract infections. N Engl J Med 1993; 329:753–6 Rigg LA, Milanes B, Villanueva B, Yen SS. Efficacy of intravaginal and intranasal administration of micronized estradiol-17beta. /Clin Endocrinol Metab 1977; 45:1261–4

8. DESQUAMATIVE VAGINITIS

INTRODUCTION Desquamative vaginitis is a condition that resembles atrophic vaginitis, except that the individual does not have estrogen deficiency. The condition was described in 1965 by Gray and Barnes1, who termed it desquamative inflammatory vaginitis because of the large numbers of white blood cells (WBC) and squamous epithelial cells present in the vaginal discharge. In 1968, Gardner2 described eight cases of vaginitis that resembled atrophic vaginitis, but the patients had an estrogen deficiency. Lynch3, in 1975, suggested that desquamative vaginitis is a variety of lichen planus because the patient also had buccal and gingival plaque similar to that seen in lichen planus patients. Edwards and Friedrich4 reported five cases of desquamative vaginitis in patients with oral lesions similar to those seen with lichen planus, then suggested that desquamative vaginitis is caused by erosive lichen planus. CLINICAL PRESENTATION AND DIAGNOSIS Desquamative inflammatory vaginitis presents with erythema of the vaginal epithelium, especially the posterior fornix and portio of the cervix. Typically the areas of erythema are a deep, fiery red with welldefined borders. Superficial ulcerations and bleeding also accompany this condition. Occasionally, a gray pseudomembrane develops over the inflamed tissue, which can be easily removed. A characteristic of these ulcerations is the development of a narrow reticulated border at

DESQUAMATIVE VAGINITIS 93

Table 17 Clinical characteristics of desquamative inflammatory vaginitis

the periphery of the ulcers and the presence of non-erosive lichen planus lesions found elsewhere on the skin or mucus membranes (Table 17)5. In an attempt to determine the microbiologic etiology, Gardner cultured a variety of pathogens from patients in his case study (Table 18)2. He concluded that desquamative inflammatory vaginitis was not caused by an infection because no common bacterium was isolated. However, Gardner did not have the ability to culture and identify obligate anaerobic bacteria. Sobel6 reported that 51 patients with desquamative inflammatory vaginitis had a diffuse exudative vaginitis, exfoliation of squamous epithelial cells, and purulent discharge. Sobel did not find a common bacterium but did note a significant decrease in Lactobacillus. These patients all had a diffuse exudative purulent vaginal discharge, an increase in the number of parabasal cells, an elevated vaginal pH, and the presence of a large number of Gram-positive cocci6. The increase in vaginal pH to 5 or more is inhibitory to the growth of Lactobacillus and favors growth of the non-lactobacilli pathogenic bacteria. The presence of an overgrowth, in some patients, by Gram-positive cocci suggests that Streptococcus agalactiae might possibly be an etiologic agent.


Table 18 Pathogens isolated from the vagina of patients with desquamative inflammatory vaginitis in a study by Gardner2

TREATMENT The treatment for desquamative inflammatory vaginitis has been the use of intravaginal corticosteroids: 12.5 mg vaginal suppositories inserted twice a day for 2 months7. This is followed by the administration of 12.5 mg vaginal suppositories once a day for 2 months and then maintenance therapy of 12.5 mg intravaginal suppositories one to three times a week7. When Sobel treated 51 patients with 2% clindamycin intravaginal suppositories, more than 95% of his patients achieved improvement but 30% relapsed. It appears that the etiology of desquamative vaginitis is still unknown, but the basic underlying alteration is an increase in pH that results in a decrease in the growth and presence of lactobacilli. The net result is that bacterial growth within the vagina is reduced and there is a large number of WBC. Thus, it appears that the best approach to treatment is the administration of steroids intravaginally. The steroids need to be administered for a prolonged period and tapered down once there is noticeable improvement. The patient will be required to remain on a maintenance dose for a further prolonged period. When vaginal steroids are discontinued, the patient may experience a relapse. If this occurs, steroid therapy should be reinstituted.

DESQUAMATIVE VAGINITIS 95

REFERENCES 1. 2. 3.

4. 5. 6.

7.

Gray LA, Barnes ML. Vaginitis in women, diagnosis and treatment. Am J ObstetGynecol1965; 92:125–36 Gardner HL. Desquamative inflammatory vaginitis: a newly defined entity. AmJ Obstet Gynecol 1968; 102:1102–5 Lynch PJ. Desquamative inflammatory vaginitis with oral lichen planus. In Friedrich EG Jr., Josey WE, eds. Proceedings of the Second International Congress ofthe International Society for the Study of Vulvar Disease. Key Biscayne, FL, January 9–11, 1975 Edwards L, Friedrich EG, Jr. Desquamative vaginitis: lichen planus in disguise. Obstet Gynecol 1988; 71:832–6 Pelisse M. The vulvo-vaginal-gingival syndrome. A new form of erosive lichen planus. Int J Dermatol 1989; 28:381–4 Sobel JD. Desquamative inflammatory vaginitis: a new subgroup of purulent vaginitis responsive to topical 2% clindamycin therapy. Am J Obstet Gynecol 1994; 171:1215–20 Mann MS, Kaufman RH. Erosive lichen planus of the vulva. Clin Obstet Gynecol 1991; 34:605–13

9. CYTOLYTIC VAGINOSIS

INTRODUCTION Cytolytic vaginosis, also referred to as Döderlein cytolysis, appears to be a common alteration in the vaginal ecosystem1. Cytolytic vaginosis is similar in gross appearance to the discharge that is seen with vaginal candidiasis. When examining a patient with cytolytic vaginosis, physicians often do not see yeast but still treat the patient with an antifungal agent, and the patient’s condition does not resolve. CLINICAL PRESENTATION AND DIAGNOSIS The external genitalia do not undergo any changes with cytolytic vaginosis, unlike with candidiasis. The patient with vaginal candidiasis often has vulvar involvement, i.e. the labia and crural folds are erythematous, pruritic, and/or burn. However, the patient with cytolytic vaginosis can complain of vaginal pruritis and burning, dyspareunia, and vulvar burning when micturating (vulvar dysuria). The patient’s symptoms intensify during the luteal phase of the menstrual cycle2. The microflora of patients with cytolytic vaginosis does not shift to a flora dominated by facultative or obligate anaerobes but is dominated by Lactobacillus. In fact, there appears to be an overgrowth of lactobacilli. The pH of the vagina and the vaginal discharge remains between 3.5 and 4.5. The hydrogen ion concentration is maintained by the growth of lactobacilli. Production by lactobacilli of lactic acid and other organic acids maintains this hydrogen ion concentration and suppresses the growth of other

CYTOLYTIC VAGINOSIS 97

Table 19 Characteristics of cytolytic vagionis

bacteria3. The most common Lactobacillus species found in the vagina are Lactobacillus crispatus, L. gasseri, L.jensenii, and L. iners4. The physical findings of vaginal discharge are quite distinct in patients with cytolytic vaginosis (Table 19). The most important diagnostic aides are microscopic examination of the vaginal discharge and culture for Trichomonasvaginalis and Candida (Figures 16 and 17). Interestingly, there are relatively few white blood cells (WBC) present in the vaginal discharge. This is important because it implies that there is a low probability that the patient has acute cervicitis or endometritis. However, to be complete, if the patient’s history places her at risk for possible infection with Chlamydia trachomatis and Neisseriagonorrhoeae, specimens for detection of these organisms should be obtained from the endocervix. TREATMENT Cibley and Cibley2 recommend vaginal douching with sodium bicarbonate, 30–60 g in a liter of water, two to three times a week. Once there appears to be improvement, the douching frequency should be tapered off to once a week as needed. However, douching should be done with little pressure and preferably in the sitting or standing position, which helps reduce the possibility of douching


solution entering the upper genital tract. Some investigators believe that there is an association between douching and the development of pelvic infection. The goal of treatment is not to significantly increase the pH since this can result in a decrease in Lactobacillus growth and an increase in the growth of other bacteria. Therefore, it would be detrimental to maintaining a balanced vaginal ecosystem to raise the pH above 4.5. Perhaps the administration of intravaginal clindamycin cream (2%) or metronidazole can effectively lower the concentration of Lactobacillus while suppressing the growth of obligate anaerobic bacteria. Clindamycin will also have an inhibitory effect on Gram-positive bacteria, except the enterococci. Additionally, clindamycin would not have a suppressive effect on the Gram-negative facultative bacteria. Therefore, the administration of oral or intravaginal antibiotics should not be for a prolonged period of time in order to avoid selection of resistant bacteria, which could become the dominant bacteria of the vaginal ecosystem. REFERENCES 1. 2.

3. 4.

Düderlein A. Die Scheidensekretunter Suchungen. Zentralbl Gynakol 1982; 18:10–14 Cibley LJ, Cibley LJ. Cytolytic vaginosis: a common cause of vaginitis. In Horowitz BJ, Mardh PA, eds. Vaginitis and Vaginosis.New York: Wiley-Liss, 1991; 181–7 Aroutcheva A, Gariti D, Simon M, et al.Defense factors of vaginal lactobacilli. Am J Obstet Gynecol 2001; 185:375–9 Vasquez A, Jakobsson T, Ahrne S, Forsum U, Molin G. Vaginal lactobacillus flora of healthy Swedish women. /Clin Microbiol 2002; 40: 2746–9

INDEX

acidifying agents 22, 23 amniotic fluid 6 antibiotic prophylaxis 6 atopy 12

resistance 51 species isolated from humans 38 candidiasis 9, 25, 95. See also vulvovaginal candidiasis (VVC) cellulitis 39, 75 cephalosporin 21 cervicitis 18, 25, 45 Cesarean section 6 Chlamydia trachomatis 3, 19, 25, 27, 45, 62 chorioamnionitis 13 chorionic membranes 6 clindamycin 21, 23, 29, 98 clue cells 21, 22 coliform vaginitis 30 contact dermatitis 11 Corynebacterium spp. 3 culture 12, 16, 30, 34, 67, 68 cytolytic vaginosis vii, xiii, 30–32, 95–98 treatment 32, 97–98 characteristics 97 clinical presentation and diagnosis 95–97

bacterial vaginitis 5, 25–33 clinical presentation 25–28 bacterial vaginosis iv, vi, 5, 13–23, 25 constituent bacteria 18 diagnosis 18–21 epidemiology 13–15 Haemophilus vaginalis 5 microbiology 15–17 risk factors 13 treatment 21–23 bacteriocin 3, 5, 16 Bacteriodes spp. 3 blastospores 36 basal cells vi boric acid 22, 29, 33, 45, 52 burning 11, 32, 34, 39 Candida xi, 33, 34–52, 94, 95 balanoposthitis 43 Candida albicans and Lactobacillus 36, 42 morphologic forms 37 cell wall 36

Diamond’s medium 61 discharge xiii, xiv–2, 28, 95 abnormal 34 99


diagnostic characteristics and evaluation 19, 27, 40, 67 microscopic examination 22, 33, 44–45, 49, 88 purulent 11, 25, 66, 91 dyspareunia 11, 32, 87 dysuria 11, 66, 87

hypersensitivity 9, 43 hysterectomy 6

eczema 11 edema 12 endometrium xiv Enterobacter spp. 2,3 Enterococcus spp. 2,3,15 epithelium endocervical 6 vaginal xiv, 25, 27 vestibular 11 erythema 11, 12, 28, 34, 39 Escherichia coli 2, 3, 5, 15, 30, 36, 94 estrogen 27, 85, 88 Eubacterium spp. 2

labia vii, 39 majora 11, 27 minora xiv, 11, 27 lactic acid 16 Lactobacillus iv, vii, xiii, 2,3,12, 13, 16, 28, 30–32, 61 and Candida albicans 36, 42 common species isolated from women 3 dominance 5, 6, 8, 15, 21, 25, 65 in healthy vaginal ecosystem xiv, 2, 3 inhibition of pathogenic bacteria 5 lactocin 3, 5, 16 leukorrhea 25 lichen planus 91 lichen sclerosus 9, 11

fallopian tubes xiv, 27 Fusobacterium spp. 2,3,72 Gardnerella spp. iv, 3, 15, 17, 18, 21 Giardia lamblia 72 glands Bartholin’s xiv, 11, 27, 66 periurethral xiv Skene’s xiv, 11, 27 Herpes Simplex virus 19, 67 human immunodeficiency virus (HIV) 62, 66 human papillomavirus 3, 19, 45, 67 hydrogen ion concentration in bacterial vaginitis 25–27 in bacterial vaginosis 15, 17, 21 hydrogen peroxide (H2O2) 3, 5, 16

itching 11, 32, 34, 39, 66 ketoconazole 42 Klebsiella spp. 2

menopause 85 metronidazole 17, 21, 23, 69, 72– 75 adverse effects 73 microscopic examination 12, 34, 68 Morganella spp. 2,3 Mycoplasma 17, 70 necrotizing fasciitis 39 Neisseria gonorrhoeae 3, 19, 25, 27, 36, 45, 62, 97 nitroimidazole 72 non-pathogenic bacteria 3

INDEX 101

Nugent’s score 15, 17 nystatin 12, 41, 42 Pap smear 45, 67, 69, 73 pathogenic bacteria 3 pelvic examination 87 pelvic infections 6–8, 13 pelvic inflammatory disease (PID) 59, 62 Peptococcus spp. 2,3 Peptostreptococcus spp. 2,3 peroxidase 5 postpartum endometritis 6, 13 premature delivery 13, 75 premature rupture of amniotic membranes 13, 75 preterm labor 13 Prevotella spp. 2,3,15 Proteus spp. 2 pruritus 34, 45, 66 rectovaginal fistula 30 Saccharomyces cerevisiae 45 salpingitis 13, 25, 66 septic abortion 13 squamous cells iv, vi, ix, xiii,xiv, 22, 27, 32, 44, 85, 91 staphylococcal vaginitis 29 Staphylococcus spp. xiv, 2,3,6, 29, 94 streptococcal vulvovaginitis 28–29 Streptococcus spp. 2,3,5, 15, 28, 93, 94 Streptomyces spp. 72 Trichomonads 57 Trichomonas spp. xi,xiii,33, 57–76, 94 axostyle 59 in pregnancy 62 morphology xi,xiii,59

prostate infection 69–72 trichomoniasis 18, 25, 36, 57–76 epidemiology 61–65 microbiology 59–61 of the prostate gland 69–72 patient evaluation and diagnosis 65–69 treatment 69–76 in the pregnant patient 75–76 recommended regimens 75 Ureaplasma urealyticum 17, 70 urinary incontinence 87–88 vaginal ecosystem alteration of 13, 25 healthy xiv–8, 15 bacteria 2 characteristics 3 constituents 2 pathogenic and non-pathogenic bacteria 3 vaginal microflora alteration of 6, 9, 16,17, 30 endogenous 15, 16, 34 healthy 17 transient 15 vaginitis 9. See also bacterial vaginitis atrophic 27, 85–89, 91 clinical presentation 87–88 treatment 88–89 estrogen replacement therapy 88 desquamative 91–94 clinical characteristics 93 clinical presentation and diagnosis 91–93 isolated pathogens 94 treatment 93–94 differential diagnosis 47


group B streptococcal 28 vaginosis 9. See also bacterial vaginosis and cytolytic vaginosis Veillonella spp. 2 vestibulitis 9, 11 vulva hyperplasia 9 vulvadynia 9 vulvar dystrophies 11 vulvar pruritus 12 vulvitis 9–12 differential diagnosis 9 vulvovaginal candidiasis (VVC) ix, xi, 11, 12, 34–52 characteristics 44 chronic 37 clinical presentation and diagnosis 39–47 differential diagnosis 39 epidemiology 37–39 incidence 38 mycology 36–37 pathogenesis 43 recurrent 37, 41–42 factors 41 inhibition of cell-mediated immunity 43 treatment 47–52 available antifungal agents 49 vulvovaginitis. See vulvovaginal candidiasis wet prep ix, xi, 3, 12, 68 whiff test 21 yeast xi, 12, 34, 37, 47 asymptomatic endogenous carriage 34 penile colonization 43

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