Vaginitis: Differential Diagnosis and Management - BPA Pathology

VAGINITISDifferential Diagnosis andManagementSebastian Faro,MD, PhDClinical ProfessorDepartment of Obstetrics, Gynecology, andReproductive SciencesThe University of Texas—Houston HealthSciences CenterAttending PhysicianThe Woman’s Hospital of TexasHouston, TexasBOCA RATON LONDON NEWYORK WASHINGTON, D.C

Published in the USA byThe Parthenon Publishing Group345 Park Avenue SouthNew York, NY 10010, USAThis 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 ofthousands of eBooks please go to www.eBookstore.tandf.co.uk.”Published in the UK byThe Parthenon Publishing Group23–25 Blades CourtDeodar RoadLondon, SW15 2NU, UKCopyright ©2004,The Parthenon Publishing GroupLibrary of Congress Cataloging-in-Publication DataFaro, 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 2003618.1’5–dc222003061739British Library Cataloguing in Publication DataFaro, SebastianVaginitis: differential diagnosis and management1. Vaginitis-Diagnosis 2. Vaginitis-TreatmentI. Title618.1’5ISBN 0-203-50011-3 Master e-book ISBNISBN 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 publishersexcept for the quotation of brief passages for the purpose of reviewComposition by The Parthenon Publishing Group, London, UK

CONTENTSColor illustrations v1. Healthy vaginal ecosystem 12. Vulvitis 103. Bacterial vaginosis 144. Bacterial vaginitis 265. Vulvovaginal candidiasis 356. Trichomoniasis 587. Atrophic vaginitis 868. Desquamative vaginitis 929. Cytolytic vaginosis 96Index 99

COLOR ILLUSTRATIONSFigures 1 and 2 Gram stains of vaginal fluid demonstrating wellestrogenizedsquamous epithelial cells and large gram-positive bacillicharacteristic of Lactobacillus. Note the homogenous appearance of thecytoplasm of the squamous cells, the distinct nucleus, and cell membrane.There is a relative absence of other bacteria. Also note that there are nobacteria adhering to the squamous cells

viFigure 4 Gram stain of vaginal fluid from a patient developing bacterialvaginosis. Note adherent Gram-negative rods to cytoplasmic membranes ofthe squamous epithelial cells. Bacteria in vaginal tend to occur in aggreagates;this is typical of flora dominated by Gardnerella vaginalisFigure 5 Gram stain of vaginal fluid from a patient with developing bacterialvaginosis. Bacteria adhering to squamous epithelial cells. Note individual freefloatingbacteria in the vaginal fluid. The nucleus of the squamous epithelialcells and cell membranes can be identified

viiFigure 6 Gram stain of vaginal fluid from a patient with bacterial vaginosis.Note that the bacteria adhering to the squamous cells have obliterated thenuclei and cell membrane. There are numerous free-floating bacteria in thevaginal fluid. This microplutopaple is typical of the vaginal fluid from apatient with bacterial vaginosisFigure 7 Atrophic smear showing large number of intermediate and basalcells. Reproduced with permission from Brown D. Atrophic andpostirradiation vaginitis. In Horowitz BJ, Mårdh P-A, eds. VaginitisandVaginosis. New York: Wiley-Liss, 1991; 169–79

viiiFigure 8 Cytolytic vaginosis. Note large number of lactobacili anddissolution 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

ixFigure 9 Note erythema of the labia majora and labia minora. The labiamajora are swollen and there is a pustule in the right labiaFigure 10 Wet prep of vaginal discharge from a patient with candidiasis.Note the hyphae among the squamous epithelial cellsFigure 11 Wet prep diluted with saline and viewed under phase contrastmicroscopy. Note that the squamous cells are well estrogenized and the

xrelative absence of white blood cells. The hyphae are characteristic of CandidaablicansFigure 12 Wet prep from a patient with vaginal candidiasis. Note thepresence of budding yeast cells and the absence of hyphae. This patient hadCandida glabrata vaginitisFigure 13 Gram stain of Trichomonas vaginalis. Note the elliptical shape andflagella

xiFigure 14 Wet prep with vaginal fluid from a patient with Trichomonasvaginalis vaginitis. T. vaginalis can assume a spherical shape that is larger thanwhite blood cells; note the variety of T. vaginalis shapes and absence oflactobacilliFigure 15 Phase contract microscopy of Trichomonasvaginalis vaginitis. Onetrichomonad has an elliptical shape and another has assumed an amoeboidcharacteristic

xiiFigure 16 Cytolytic vaginosis. White vaginal discharge mimicking candidalinfection (through colposcope, x6). Reproduced with permission from CibleyLJ, Cibley LJ. Cytolytic vaginosis: a common cause of vaginitis. In HorowitzBJ, Mårdh P-A, eds. Vaginitis andVaginosis. New York: Wiley-Liss, 1991; 181–87Figure 17 Cytolytic vaginosis. Excess lactobacilli with naked squamous cellnuclei (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 ECOSYSTEMINTRODUCTIONThe vaginal ecosystem is a complex biosphere, made up of a variety ofconstituents existing in a delicate equilibrium. The ecosystemcontains many types of bacteria that are constantly secreting andreleasing metabolic products such as acids, carbohydrates, and proteins,and cellular debris from the disruption of dying bacterial cells likenucleic acids, fatty acids, and sugars. The host is also constantlysecreting metabolic products and cellular debris into this ecosystem.This microflora consists of, among other organisms, Gram-positiveand Gram-negative aerobic, facultative and obligate anaerobicbacteria. The most common bacterial species isolated from the vaginaare listed in Table 1. Both non-pathogenic and pathogenic bacteria areamong the numerous bacteria present. However, it is important tounderstand that any bacterium, given the appropriate inoculum sizeand proper environmental conditions, can become pathogenic andcause disease. In a healthy vaginal ecosystem the microflora isdominated by Lactobacillus spp. When the ecosystem becomesdisrupted or unbalanced, the pathogenic bacteria gain dominance andpose a potential threat to the individual’s general health.Although Table 1 represents the bacteria most commonly isolatedfrom the healthy vagina, it is by no means a complete list. Otherbacteria, such as Pseudomonas spp., Staphylococcus aureus and Haemophilusinfluenzae, have also been isolated from the vagina of healthyindividuals.

2 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTTable 1 Bacteria Commonly isolated from a healthy vaginal ecosystemTHE VAGINAL ECOSYSTEMThe vagina is a potentially tubular organ lined by stratified squamousepithelial cells. There are no mucus-secreting cells within the vaginalepithelium; mucus is produced by the periurethral glands, Skene’sglands, and the glands that exit from the medial inferior aspect of thelabia minora, known as Bartholin’s glands. The discharge found withinthe vagina arises from a transudate secreted through the vaginalepithelium and from the cervix. Therefore, the vaginal discharge is acomposite of fluid, cells, and cellular debris that is derived from thevaginal transudate and cervical secretions, as well as fluid secretedfrom the endometrium and fallopian tubes. The average amount ofvaginal discharge a woman of reproductive age not on hormonaltherapy produces on a daily basis is 1–3 g 1 .The vaginal secretions contain a variety of compounds, includingproteins, carbohydrates, urea, and fatty acids. The carbohydrates are amixture of simple and complex sugars. Glucose, maltose,maltotriose, maltotetraose, and free glycogen have all been isolatedfrom vaginal fluid 2 . The proteins in vaginal fluid are derived from atransudate of serum proteins and proteins produced by the uppergenital tract and cervix. The major proteins found in vaginal fluid are

HEALTHY VAGINAL ECOSYSTEM 3albumin and immunoglobulins, and amino acids are also present 3 .These constituents of the vaginal ecosystem provide an excellentculture medium for the endogenous vaginal microflora (Table 1).Since there are a tremendous number of genera and species of bacteriaand other microorganisms that constitute the endogenous flora, manyof which are pathogenic, a mechanism has evolved to regulate theratio of nonpathogenic to pathogenic bacteria, which allows theecosystem to be maintained in a healthy state. The microflora is in thishealthy state when the dominant bacterium is a non-pathogen and theratio of the non-pathogen to pathogen is approximately 200:1. Thebalance is maintained by specific species of Lactobacillus and thesubstances 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 significantamount of time to perform the physician can easily recognize thesecharacteristics. It is important that each obstetrician/gynecologistbecomes very familiar with these characteristics.Typically only one species of Lactobacillus resides in the vagina. In ahealthy state, the species of Lactobacillus that both resides and isdominant in the vagina is a species that produces a significant amountof organic acids, including lactic acid, and secretes hydrogen peroxide(H 2 O 2 ) and a bacteriocin frequently referred to as lactocin.Lactobacillus has evolved as the dominant bacterium in a healthyvaginal 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 ofLactobacillus can be considered ‘good’ species or capable of producingthe necessary compounds to maintain the vaginal ecosystem in abalanced or healthy state. The most common species isolated fromwomen considered to have a healthy vaginal ecosystem are Lactobacilluscrispatus,L. gasseri, L. iners, and L. jensenii 4 .The various bacterial constituents of the endogenous microflora(Table 1) can be divided into two groups, the non-pathogenic andpathogenic bacteria (Table 3). These designations are based on theprobability that a particular bacterium can initiate infection, andaccepting the premise that any bacterium can initiate infection ifpresented with favorable environmental conditions. Lactobacillus cancause infections such as chorioamnionitis and maternal and neonatal

4 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTTable 2 Characteristics of a healthy vaginal ecosystem*wet prep (normal saline dilution of the vaginal discharge), wipe the lateralvaginal wall with a cotton- or Dacrontipped applicator, immerse theapplicator in 2–3 ml of normal saline and shake vigorously. Remove theapplicator and press it to a glass slide to release 1–2 drops of the diluteddischarge, cover with a glass coverslip and view under 40x magnification;WBC, white blood cellsbacteremia 5 . Gardnerella vaginalis has also been demonstrated to causechorioamnionitis as well as septic shock 6 . Bacteria and othermicroorganisms can be introduced into the vaginal ecosystem fromthe patient’s own fecal flora, for example Bacteriodes spp.Microorganisms can also be introduced from the exogenousenvironment through objects introduced into the vagina and by sexualintercourse, for example Chlamydia trachomatis and Neisseria

HEALTHY VAGINAL ECOSYSTEM 5Table 3 Endogenous bacteria of the vaginal ecosystemgonorrhoeae, as well as skin-to-skin contact during sexual activity, forexample human papillomavirus.Other bacteria found in the vaginal ecosystem either do not growat a pH below 4.0, or grow poorly at pH values of 4.0–4.5 7 – 9 .Through the production of organic acids, especially lactic acid,Lactobacillus provides an environment that can be considered hostile tothe growth of other bacteria. Lactobacillus grows very well at a pH ≥ 55 and, through the production of lactic acid, very quickly lowers thepH to below 4.5. However, Lactobacillus does not compete well fornutrients and yields to other bacteria when growing in their midst.When appropriate environmental changes occur within the vagina, thenumber of lactobacilli decrease, the other bacteria become dominant,and an alteration in the vaginal microflora results. The alteration inthe vaginal microflora and ecosystem can cause the patient to becomesymptomatic. With the symptoms depending on the condition thathas evolved, the patient can remain asymptomatic, as is seen withbacterial vaginosis, or when group B Streptococcus or Escherichia colibecome dominant.Lactobacillus appears to control the growth of other bacteria throughat least three mechanisms. Lactobacillus produces lactic acid, tomaintain the vaginal pH between 3.8 and 4.2, H 2 O 2 , and bacteriocinor lactocin. Lactobacillus is not capable of breaking down H 2 O 2 intohydrogen and water because it lacks heme protein catalase and doesnot use the cytochrome oxidase system. This results in the productionof large amounts of H 2 O 2 , which is secreted into the environment.H 2 O 2 has been shown to be toxic to some bacteria 11 – 13 . Thisantibacterial activity is enhanced by the enzyme peroxidase in the

6 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTpresence of the halide ion 14 . Peroxidase enzymes are found in manycells and cellular products: for example, milk and saliva containlactoperoxidase, neutrophils and monocytes containmyeloperoxidase, eosinophils contain eosinophil peroxidase, andhuman cervical mucus contains peroxidase 15−17 . There is little doubtthat Lactobacillus plays a significant role in maintaining the balance ofthe endogenous microflora. In addition to lactic acid, other organicacids, and H 2 O 2 , Lactobacillus produces a bacteriocin that inhibits thegrowth of bacteria 12 . This bacteriocin is of low molecular weight andis 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 pathogenicbacteria that constitute part of the endogenous vaginal microfloraremain suppressed. Thus, the vaginal ecosystem remains in a healthystate and there is no potential threat to the health of the individual.Garner and Dukes 20 were the first to report the near absence ofLactobacillus and its replacement by other endogenous vaginal bacteria.They also reported that Lactobacillus was rarely observed in womenwith Haemophilus vaginalis infection, now known as bacterial vaginosis.The number of lactobacilli present in a healthy vaginal microflora is ≥10 6 cfu/ml of vaginal fluid whereas other bacteria within theendogenous microflora are present in a concentration ≤ 10 3 cfu/ml ofvaginal fluid. When viewing bacteria microscopically, theconcentration required to see the bacteria is ≤ 10 3 cfu/ml of fluid.Therefore, it appears that lactobacilli play a key role in maintainingthe vaginal ecosystem and the microflora in a healthy state. Loss ofLactobacillus dominance can result in bacterial vaginosis or bacterialvaginitis. Once the pathogenic bacteria become dominant the healthof the patient becomes threatened, especially if the patient isundergoing invasive procedures that are performed through the lowergenital tract.PELVIC INFECTIONSThe majority of pelvic infections that occur in the gynecologic andobstetric patient are derived from the patient’s own endogenousvaginal microflora. In fact, excluding sexually transmitted organisms,the incidence of pelvic infections caused by exogenous bacteria is low.

HEALTHY VAGINAL ECOSYSTEM 7The most frequent non-endogenous vaginal bacteria to cause pelvicinfections are Staphylococcus aureus and Listeriamonocytogenes, and thesebacteria are uncommon.Antibiotic prophylaxis is frequently administered to patientsdelivering by Cesarean section, especially if they have labored, andwomen having a hysterectomy. The patient who has labored withruptured membranes for greater than 2 hours is at risk for thedevelopment of postpartum endometritis. The patient scheduled tohave a hysterectomy, especially a vaginal hysterectomy, is at risk forthe development of a postoperative pelvic infection.During labor, bacteria from the vagina ascend into the cervix andcolonize the endocervical epithelium. These bacteria eventuallyadvance to the decidua and the chorionic membranes and amnioticfluid. Infection is established through reproduction, adherence to hostcells, and invasion into deeper tissue. Although antibiotic prophylaxisis given, the amount of bacteria is excessive and they are not all in avulnerable state; therefore, the antibiotic is not effective. If thepatient has a Lactobacillus-dominant flora to begin with, then there is nosignificant threat of infection and the antibiotic administered forprophylaxis is effective.Patients undergoing a vaginal hysterectomy are at risk fordeveloping a postoperative pelvic infection if they have an alteredvaginal microflora. There are several reasons why the vaginalhysterectomy places the patient at risk for development of apostoperative infection: (i) the procedure is performed through acontaminated site, namely the vagina; (ii) if an altered vaginalmicroflora is present the numbers of bacteria are high, i.e. there is alarge inoculum; (iii) the pelvic peritoneum is constantly abraded andtraumatized during the procedure; (iv) dead space is created; (v)necrotic tissue is left behind; and (vi) a foreign body, a suture, is leftin the traumatized and necrotic tissue. These features, combined withthe presence of a high inoculum of virulent bacteria, create conditionsappropriate for infection. Again, administering an antibioticprophylactically will, in most cases, prove ineffective. The reasons forthis are: (i) the inoculum is too large; (ii) the bacteria are not allvulnerable while the antibiotic concentration is high enough to beeffective; (iii) the presence of necrotic tissue and suture lowers therequired inoculum to initiate infection; and (iv) because of decreased

8 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTtissue vascularity at the operative site, antibiotics will not reach thetissue that is colonized in a sufficient concentration to be effective.The best method for preventing postoperative infection is to screenthe patient prior to surgery to determine the status of the endogenousvaginal microflora. If the patient does not have a Lactobacillus-dominantvaginal microflora, then treatment should be initiated to correct thecondition and return the vaginal microflora to a Lactobacillus-dominantstate.REFERENCES1. Moghissi KS.Vaginal fluid constituents. In Beller F, Schumacher GFB,eds. TheBiology of Fluids of the Female Genital Tract. Amsterdam:Elsevier, 1979; 1–302. Sumawong V, Gregoire AT, Johnson WD, Rakoff AE. Identification ofcarbohydrates in vaginal fluid of normal females. Fertil Steril 1952; 13:270–803. Paavonen J. Physiology and ecology of the vagina. Scand J Infect Dis1983; 40 (Suppl):31–54. Vasquez A, Jakobsson T, Ahrne S, Forsum U, Molin G. VaginalLactobacillus flora of healthy Swedish women. /Clin Microbiol 2002;40:2746–95. Cox SM, Phillips LE, Faro S, et alLactobacillemia of amniotic fluidorigin. Obstet Gynecol 1986; 68:134–56. Lee W, Clark SL, Giebel R, et alSeptic shock during pregnancy. Am JObstetGynecol 1988; 159:410–167. Aroutcheva A, Gariti D, Simon M, et al.Defense factors of vaginallactobacilli. Am J Obstet Gynecol 2001; 185:375–98. Simoes JA, Aroutcheva AA, Shott S, Faro S. Effect of metronidazoleon the growth of vaginal lactobacilli in vitro. Infect Dis Obstet Gynecol2001; 9:41–59. Aroutcheva A, Simoes JA, Shott S, Faro S. The inhibitory effect ofclindamycin on Lactobacillus in vitro. Infect Dis Obstet Gynecol 2001; 9:239–4410. Dahiya RS, Speck ML.Hydrogen peroxide formation by lactobacilliand its effect on Staphylococcus aureus. J Dairy Sci 1968; 51:1068–7211. Thompson R, Johnston A. The inhibitory action of saliva on thediphtheria bacillus: hydrogen peroxide, the inhibitory agent producedby salivary streptococci. J Infect Dis 1950; 88:81–5

HEALTHY VAGINAL ECOSYSTEM 912. Wheater DM, Hirsch A, Mattick TR. Possible identity of‘lactobacillin’ with hydrogen peroxide produced by lactobacilli. Nature( London)1952; 170:623–413. Eschenbach DA, Davick PR, Holmes KK, et alPrevalence of hydrogenperoxide producing Lactobacillus species in normal women andwomen with bacterial vaginosis. /Clin Microbiol 1989; 27:251–614. Klebanoff SJ. lodination of bacteria: a bactericidal mechanism. J ExpMed 1967; 126:1063–7815. Klebanoff SJ. Myeloperoxidase-halide-hydrogen peroxide antibacterialsystem. /Bacteriol 1968; 95:2131–816. Klebanoff SJ. Myeloperoxidase-mediated antimicrobial systems andtheir role in leukocyte function. In Schultz J, ed. Biochemistry ofPhagocytic Process. Amsterdam: North-Holland Publishing Company,89–11017. Reite B, Oram JD. Bacterial inhibitors in milk and other biologicalfluids. Nature 1967; 216:328–3018. Aroutcheva AA, Simoes JA, Faro S. Antimicrobial protein producedby vaginal Lactobacillus acidophilus that inhibits Gardnerella vaginalis.Infect Dis Obstet Gynecol2001; 9:33–919. Simoes JA, Aroutcheva A, Heimler I, Shott S, Faro S. Bacteriocinsusceptibility of Gardnerella vaginalis and its relationship to biotype,genotype, and metronidazole susceptibility. Am J Obstet Gynecol 2001;185:1186–9020. Gardner HL, Dukes CD. Haemophilus vaginalis vaginitis. Am J ObstetGynecol 1955; 69:962–76

2.VULVITISOften, conditions that affect the vulva are mistaken for vaginitis,resulting in unnecessary treatments and expense. These treatmentsmay even cause alterations in the endogenous vaginal microflora thatresult in symptomatic vaginosis or vaginitis. Additionally, the variouscreams, ointments, suppositories, and emulsions may cause ahypersensitivity reaction in the tissues of the vulva.Therefore, it is extremely important that the physician establishesand locates the precise anatomical site where the patient’s symptomsare originating. This can easily be achieved by having the patientpoint, with her index finger, to the area that is bothersome. Thepatient with an inflammatory condition of the vulva (vulvitis), forexample vulvadynia, vestibulitis, vulva hyperplasia, or lichen sclerosus(Table 4), is often extremely uncomfortable, has difficulty sitting for aprolonged period, and cannot have sexual intercourse. Therefore shemay not be able function at full capacity. The physician should take adetailed history with regard to onset of first symptoms. This isimportant because when given an opportunity to consider hercondition, the patient often will relate that her symptoms began longbefore the vulvitis became chronic. It is important that the physicianallow the patient ample time to not only describe her condition, butalso explain the factors that impinge on her condition. The physicianmust establish that her symptoms are actually related to a clinicalcondition that can be detected on the vulva or the vagina, or both.The vulvar dystrophies are a group of conditions that are placedtogether based on gross and histopathologic characteristics. Thevulvar dystrophies, or nonneoplastic epithelial disorders, are divided

VULVITIS 11Table 4 Vulvar condition that may be mistaken for viginitisinto three categories: squamous cell hyperplasia, lichen sclerosus, andother dermatoses 1 . Once the vulva is examined and found to be free ofchanges, attention should be given to the vestibule. The urethra,Skene’s glands, Bartholin’s glands, and the epithelium of the vestibuleshould be examined for erythema, induration, and purulent discharge.The examiner should also check each of these areas for pain associatedwith gentle pressure, drainage, blisters, ulcers, or growths. Patientscommonly 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. Theareas most commonly affected are the lower aspect of the medialaspect of the labia minora and posterior fourchette; the etiology ofvestibulitis is unknown.Another condition of the vulva that may be confused withvulvovaginal candidiasis is lichen sclerosus. Patients with lichensclerosus present with itching, soreness, dyspareunia, and dysuria,while the skin of the vulva tends to become pale and, eventually, thearea of involvement is well demarcated and becomes white andsmooth 2 . With lichen sclerosus, the skin also becomes fragile becauseof the development of fissures and erosions. The most commonlyaffected sites are the medial aspect of the labia majora, the labia

12 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTminora, the clitoris (often the clitoris becomes edematous), theposterior fourchette, and the perineum. When these areas aresimultaneously involved, the clinical presentation of thehypopigmented areas takes on a configuration resembling anhourglass. Progression of the disease can result in scarring anddestruction of the normal vulvar anatomy. Agglutination of the labiaand clitoral hood also develops, and the posterior fourchette becomesextremely fragile leading to fissuring and lacerations that areextremely painful. If left untreated, the patient with perianalinvolvement can develop adhesions that, upon defecation, can becomepainful and bleed 2 .Contact dermatitis is another condition that is often misinterpretedas vulvar candidiasis. Contact dermatitis patients often present withitching and eczema, and the eczema may be secondary to atopy or toan exogenous irritant or allergic contact. The skin of the vulvabecomes erythematous and edematous, and excoriations may bepresent. Vesicles can also develop and an exudate may be present. Ifthe condition arises secondary to an irritant the symptoms beginimmediately, but if there was an allergic reaction the symptoms begin24–48 hours after contact with the allergen occurred 3 .Thus, patients presenting with vulvar pruritus, erythema,excoriation, and edema should be considered to have vulvovaginalcandidiasis until proven otherwise. Specimens should be obtainedfrom the vulva and vagina for the detection of yeast and microscopicexamination of the specimens should be performed by wet prep withand without potassium hydroxide. A specimen from each site shouldalso be used to inoculate Nickerson’s or Sabourad’s agar. If microscopicexamination does not reveal the presence of yeast this should not beinterpreted as meaning that yeast are not present. While waiting forconfirmation from the cultures, the physician can prescribe MycologII ® cream, which is a combination of nystatin, an antifungal agent, anda steroid, triamcinolone acetonide, to be applied to the vulva. Thisshould provide some relief until a definite diagnosis can be obtained.The pH of the vaginal discharge should also be obtained. A pH lowerthan 4.5 will, in most instances, rule out a bacterial alteration of thevaginal ecosystem. If this is the case, the microscopic examinationshould reveal the presence of large bacillary forms, which is consistentwith the presence of Lactobacillus.

VULVITIS 13The physician should never prescribe treatment withoutperforming an examination of the vulva and vagina. Only once acorrect diagnosis is established can a definitive management programbe instituted. This approach avoids the unnecessary administration ofnumerous treatment regimens, reduces the cost to the patient, andlessens the likelihood of the patient losing confidence in her physician.REFERENCES1. Kaufman RH, Faro S. Benign Disease of the Vulva and Vagina. St. Louis:Mosby, 1994; 260–822. Neill SM. Vulvar lichen sclerosus. In Black MM, McKay M, BrandePR, eds. Obstetric and Gynecologic Dermatology. Philadelphia: Mosby-Wolfe, 19953. McKay M. Vulvitis and vulvovaginitis: cutaneous considerations. Am JObstet Gynecol1991; 165:1176–82

3.BACTERIAL VAGINOSISINTRODUCTIONIn a pure state, bacterial vaginosis (BV) is a non-inflammatory processand is not an infection. The organisms that constitute BV are allderived from the endogenous microflora, and these bacteria arepresent in a concentration that exceeds 10 6 bacteria/ml of vaginalfluid. In the presence of BV, the concentration of Lactobacillus is lessthan 10 3 bacteria/ml of vaginal fluid. These bacterial concentrationsare 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; inthe gynecologic patient it is associated with endometritis, posthysterectomypelvic infection, and salpingitis. Even though there areno hard data that demonstrate a cause and effect relationship betweenthese conditions and BV, there are data that show a strong correlationbetween BV and some of the aforementioned infections. Although thereis controversy concerning the role of BV in diseases of the genitaltract, there is no doubt that the bacterial constituents that make up BVare almost all significant pathogens capable of causing seriousinfections.EPIDEMIOLOGYAmong women in the reproductive age group, BV is considered themost common alteration of the vaginal ecosystem; 50% of women

BACTERIAL VAGINOSIS 15with BV are asymptomatic 1 . Risk factors shown to be associated withthe development of BV are: sexual activity, multiple partners,frequency of intercourse, and douching 2 – 5 . Additional factors that caninfluence the status of the vaginal microflora are smoking and thepresence of a pessary in the vaginal canal. In a study examining theinfluence of a vaginal pessary on the endogenous vaginal microflora,the presence of a pessary was found to have an adverse effect on themicroflora. The presence of a vaginal pessary was associated with arelative risk of 3.3 (odds ratio, OR 4.37; 95% confidence interval, CI2.15–9.32, p=0.0002) 6 . Bacterial vaginosis was found in 32% ofthose women with a pessary compared with 10% in women withoutone.Bacterial vaginosis is not simply an alteration in the vaginalmicroflora but is the result of changes that occur continuously, likelyon a daily basis. Studies of microflora in a healthy vaginal ecosystemrevealed that there are transient shifts in bacterial dominance inwomen without vaginal infections, and the shifts appear to beassociated with menses 7 – 11 . Schwebke and co-workers 12 performeddaily vaginal cultures of 60 patients over a 6-week period. Theseinvestigators found that 22% of the patients had a Lactobacillusdominantflora (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, multiplesexual partners, and receptive oral sex were associated with anunstable flora.Therefore, while the endogenous vaginal microflora may appear tobe dominated by Lactobacillus, many women actually have a vaginalmicroflora that is transitional; they do not later develop BV butinstead revert to a Lactobacillus-dominant vaginal microflora. Thefactors that cause alterations in the vaginal microflora to continuealong a path that results in BV are not known.MICROBIOLOGYThe microbial and physiologic changes initiated in the vagina thatresult in an alteration in the balance of the vaginal ecosystem and allowBV to develop have not been elucidated. However, there is no doubtthat the one change that must occur is a decrease in the hydrogen ion

16 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTconcentration, or an increase in pH. The pH of a healthy orLactobacillus-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, prefersa pH of 5 when grown on culture media, it cannot compete well atthis pH when placed in the vaginal environment. Because the otherbacteria present, such as Streptococcus spp., Enterococcus spp., Escherichiacoli, and Prevotella spp., are more vigorous competitors thanLactobacillus, it cannot maintain its dominance. Thus, growth ofLactobacillus is inhibited and microbial dominance is assumed byanother genus or multiple genera.It appears that when conditions in the vaginal environment arefavorable for Gardnerella vaginalis, this bacterium assumes dominance.G. vaginalis grows well at a pH of 5 and above, and as it grows itcauses the pH to rise further and the oxygen content of the vaginalenvironment to become depleted. Decreases in the vaginal oxygenconcentration also occur when facultative anaerobes grow. When thevaginal environment becomes oxygen depleted, the facultativeanaerobic bacteria switch to anaerobic metabolism. When the oxygenconcentration reaches a critically minimal level, the obligate anaerobicbacteria begin to grow and eventually take over as the dominantbacteria in the vaginal ecosystem (Figure 3).In order for the vaginal ecosystem to maintain a Lactobacillusdominantmicroflora, the necessary species of Lactobacillus must be ableto produce a significant amount of lactic acid, hydrogen peroxide(H 2 O 2 ), and bacteriocin or lactocin. Thus, the bacterial make-up ofthe vagina undergoes significant changes. When Lactobacillus is thedominant genus, its concentration is ≥ 10 6 bacteria/ml of vaginal fluidand the pathogenic bacterial genera are present in a concentration of ≤10 3 bacteria/ml of vaginal fluid. This balance is challenged by anumber of variables (Table 5).Newton and co-workers 13 demonstrated that African-Americanwomen were more likely than Caucasian women to have an alteredvaginal microflora. This altered vaginal microflora is most likely theresult of behavioral factors, hormonal changes, physiological status ofthe vagina, and hygiene 13 . In addition to the significance of race, theseauthors found that specific species of Lactobacillus affect the growth ofother bacteria.

BACTERIAL VAGINOSIS 17Figure 3 Graphic depiction of the effect of increasing pH and decreasingoxygen concentration on the growth of the endogenous microflora of thevagina. Lines represent growth of A, Gardnerella vaginalis; B, facultativeanaerobes; C, Lactobacillus spp.; and D, obligate anaerobic bacteriaThe number of genera that can be isolated from the lower genitaltract exceeds 17–20. The number depends upon the amount of timespent isolating the bacteria and the use of culture techniques orpolymerase chain reaction (PCR) to detect specific DNA sequences 14 .G. vaginalis appears to play a pivotal role in the development of BV. Inone study, G. vaginalis was isolated from: 87.5% of women with BV,34% of women with a vaginal microflora considered to beintermediate BV (using the Nugent’s scoring system), and 26% ofwomen with healthy vaginal microflora 15 . There are eight biotypes ofG. vaginalis and biotype 5 was isolated most frequently from womenwith a healthy vaginal ecosystem (p=0.0004). Investigators found thatbiotypes 5 and 7 were typically resistant to metronidazole but nospecific biotype was associated with BV. G. vaginalis was also isolatedfrom more than 98% of the women with BV 16 – 18 .The microorganisms that make up the microflora of BV arecomplex and consist of a variety of bacteria, but are dominated byobligate anaerobic bacteria (Table 6).The bacterial make-up of BV is dominated by G. vaginalis Gramnegativeobligate anaerobes as well as Mycoplasma hominis, M. genitalis,

18 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTTable 5 Factors that can cause alternations in the endogenous vaginamicrofloraand Ureaplasmaurealyticum. The bacteria that consistently appear to bepresent in high numbers in women with BV are Gardnerella spp.,obligate anaerobes, and genital mycoplasmata 19 . These same bacteriacan be found in the vaginas of women with a healthy vaginalmicroflora. Thus, BV does not come about because these organismsare introduced into the vagina—they are already present—butbecause there is a shift in the hydrogen ion concentration from an acidpH (pH < 4.5) to a less acidic pH (pH > 5), and these bacteria growas Lactobacillus is suppressed.Thus, BV is an alteration in the endogenous microflora of thevagina and not an infection. However because BV consists,microbiologically, of numerous pathogenic bacteria, this condition hasthe potential to cause significant infectious morbidity in patientsundergoing changes in the reproductive tract. These changes could beintentional, such as pregnancy, or for diagnostic or treatment purposes.DIAGNOSISThe characteristics of BV are quite distinct, thus separating it fromother conditions of the vagina (Table 7). It is important to realize thatwhen BV is present in the absence of other conditions, such astrichomoniasis or cervicitis, there are relatively few white blood cells(WBC) in the discharge. The presence of a significant number ofWBC, i.e. more than 5 per high-power field (hpf), indicates thatthere is an inflammatory process present in addition to BV 20 , 21 .Therefore, the physician must inquire as to the patient’s sexualpractices, frequency of contact, number of contacts, and method ofcontraception. If a barrier method is not part of the patient’s

BACTERIAL VAGINOSIS 19Table 6 Bacteria that constitute bacterial vaginosisAdapted with permission from Hill GB. The microbiology of bacterialvaginosis. Am J Obstet Gynecol 1993; 169:450–4contraceptive regimen then she is at risk for contracting any numberof 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 wouldnot prove to be beneficial because most commercial laboratories willnot process the specimen for anaerobes. If anaerobic bacteriology isperformed, the laboratory personnel will attempt to identify allanaerobic bacteria that are present. If a culture must be obtained, askthe laboratory personnel to document the presence of Gardnerella spp.This is important because the presence of this bacterium taken withthe presence of other characteristics should be enough to establish thediagnosis of BV.If WBC are present and no pathogen can be identified, then aspecimen from the vagina should be obtained to culture for thepossible presence of Trichomonas vaginalis. Cervical specimens shouldalso be obtained for the isolation of Chlamydia trachomatis and Neisseriagonorrhoeae. If the patient’s history suggests that Herpes exposure mayhave occurred, a cervical and labial specimen for Herpes Simplexvirus (HSV) should be obtained. The physician should also considerthe possibility of HSV type I if the patient and her partner practiceorogenital sex. Another consideration is the presence of human

20 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTTable 7 Diagnostic characteristic of vaginal discharge in a patient withbacterial vaginosispapillomavirus (HPV) in the vagina and cervix. If the patient hascondyloma that is not very apparent, a specimen can be collected fromthe vaginal walls, as well as the cervix, for the detection of HPV. Thepatient will often complain of a copious vaginal discharge but thequantity is difficult to establish. One question that can be asked, iftrying to determine whether the quantity of discharge is excessive, iswhether the patient needs to wear a pad on a daily basis.It should not be too difficult to establish if the patient has BV ornot, but relying on pH alone is insufficient. A pH of 5 or higher, apositive whiff test, and the presence of clue cells establish a diagnosisof BV. There may be an associated condition that is indicated by thepresence of WBC and requires further testing to determine thespecific associated condition, e.g. trichomoniasis, chlamydia, orgonorrhea. It is important that the physician perform a thoroughevaluation of both the lower and upper genital tracts when numerousWBC are present in the vaginal discharge, as this could indicate thepresence of pelvic inflammatory disease, even if the patient has nosymptoms of upper genital tract infection.TREATMENTThe treatment of BV is based on the presence of an overgrowth ofobligate anaerobic bacteria. However, the fact that there is a

significant decrease in the hydrogen ion concentration or increase inpH should be taken into consideration. The advocated treatmentregimens all have about the same efficacy, approximately 65–75% 22 .This low success rate is likely because of the failure to re-establish theappropriate pH in the vaginal ecosystem, thus preventing Lactobacillusfrom regaining dominance.The antimicrobial agents of choice are clindamycin andmetronidazole. If the patient’s microflora has not progressed to onethat is dominated by obligate anaerobic bacteria, but is in anintermediate stage or dominated by G. vaginalis, these antibiotictreatments will likely fail since these agents are not active against thisbacterium. Therefore, when examining the vaginal discharge, if cluecells and aggregates of bacteria are seen one should suspect the vaginalmicroflora is in transition and most likely dominated by G. vaginalis.This diagnosis can be reenforced by a positive whiff test or thepresence of a fish-like odor. Successful treatment for this stage of BVdevelopment can be accomplished by administering a first-generationcephalosporin.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 preparationsBACTERIAL VAGINOSIS 21(1)Clindamycin cream 2% one applicator-full at bedtime for 7nights; or(2)Metronidazole gel 0.75% one applicator-full twice a day for 7daysAvailable variations of the intravaginal medications are metronidazolegel dosed for 5 days and clindamycin ovules for 3 days. There is nosignificant advantage in terms of efficacy with the shorter dosageregimens compared with standard regimens. It has been the author’s

22 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTexperience that these shorter dosing regimens tend not to be aseffective (this is anecdotal information).When treating BV, it is important to consider the pH of the vaginalenvironment. A patient treated for BV should be examined 1 weekafter completion of therapy. If the vaginal pH has not returned to thenormal range of 3.8–4.2, there is a good chance that her BV willreturn or a bacterium other than Lactobacillus will become dominant.When examining the vaginal discharge microscopically, the physicianshould focus on the noticeable absence of bacteria. Followingtreatment, it is not uncommon to find that the vaginal dischargeappears relatively healthy. The squamous epithelial cells are wellestrogenized, there are no clue cells, and WBC are scarce, but thereis a noticeable absence of bacteria. If the vagina is checked and the pHis 5 or higher, this should indicate that the vaginal ecosystem has notbeen 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, Acijel ® one applicatorfull twice a day for 14–21 days, or Relagard ® vaginalgel one applicator-full twice a day for 14–21 days. Although there areno published reports addressing this issue, I have found that when thevaginal pH is restored to 4.5 or lower there is a better chance forachieving restoration of a healthy vaginal ecosystem characterized by amicroflora dominated by Lactobacillus.TREATMENT OF CHRONIC, PERSISTENT,OR RECURRENT BACTERICAL VAGINOSISIt is difficult to define recurrent BV, but for practical purposes as faras the patient is concerned, if she has a second episode of BV then it isrecurrent. However, it is probably appropriate to say that if a patienthas four or more episodes of BV within a 12-month period, it couldbe considered recurrent. If the patient experiences only brief periodsof time without BV, for example 1–3 weeks, then it would be fair tolabel her condition as chronic. If the patient has no or only extremelybrief periods without BV symptoms, then the condition could belabeled as persistent BV.Treatment of these conditions requires a comprehensive approach.A detailed history should be repeated with a focus on the use of

BACTERIAL VAGINOSIS 23genital hygiene products, sexual practices, and medications, especiallyantibiotic use and herbal remedies. Patients will often take a dailyantibiotic for acne and fail to mention this because they are only takingone antibiotic a day. However, a single dose of antibiotic can affectthe composition of the vaginal microflora.Patients should refrain from sexual activity because there appears tobe a relationship between the frequency of sexual intercourse and therecurrence of BV. Although there appears to be a similar relationshipbetween the risk factors associated with acquisition of sexuallytransmitted diseases (STDs) and the acquisition of BV, the latter is notconsidered an STD 23 . However, many women report that they haverecurrent episodes of BV only after having sexual intercourse with theirpartner. These are usually women in long-term monogamousrelationships. In those cases, treatment of the male sexual partnerwith oral metronidazole appears to have some benefit.Patients with chronic and/or persistent BV should be treated witha combination of an oral agent, either metronidazole or clindamycin,and an intravaginal acidifying agent. If re-examination reveals anoticeable decrease in the bacteria but the pH has not decreased towithin the normal range, then the intravaginal administration of theacidifying agent should continue. The use of the antimicrobial agentshould be limited because continued administration will result infurther alterations of the vaginal microflora. I will close this discussionwith the fact that at present BV is not considered an infection butrather an alteration of the endogenous microflora. Therefore, it doesnot seem plausible that BV can be successfully corrected with anantimicrobial agent. Successful treatment of BV depends uponrestoring the vaginal ecosystem to a healthy state.REFERENCES1. Hillier S, Holmes KK. Bacterial vaginosis. In Holmes KK, Mardh P,Sparling F, eds. Sexually Transmitted Diseases,2nd edn. New York:McGraw-Hill1989; 547–592. Amsel R, Totten PA, Holmes KK, et al.Nonspecific vaginitis:diagnostic criteria and microbial and epidemiologic associations. Am JMed 1983; 74:14–22

24 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENT3. Barbone F, Austin H, Louv WC, Alexander WJ.A follow-up study ofmethods of contraception, sexual activity, and rates of trichomoniasis,candidiasis and bacterial vaginosis. Am J Obstet Gynecol 1990; 163:510–144. Moi H. Prevalence of bacterial vaginosis and its association with genitalinfections, inflammation, and contraceptive methods in womenattending sexually transmitted disease and primary health clinics. Int JSTD AIDS 1990; 1:86–945. Wolner-Hanssen P, Eschenbach DA, Paavonen J, et alAssociationbetween vaginal douching and acute pelvic inflammatory disease. /AmMed Assoc 1990; 263:1936–416. Alnaif B, Drutz HP. Bacterial vaginosis increases in pessary users. IntUrogynecol J 2000; 11:219–227. Bartlett JG, Onderdonk AB, Drude E, et al.Quantitative bacteriologyof the vaginal flora. /Infect Dis 1977; 136:271–78. Sautter RL, Brown WJ. Sequential vaginal cultures from normalyoung women. /Clin Microbiol 1980; 11:479–849. Johnson SR, Petzold CR, Galask RP. Qualitative and quantitativechanges of the vaginal microbial flora during the menstrual cycle. Am JReprod Immunol 1985; 9:1–510. Priestley CJ, Jones BM, Dahr J, Goodwin L. What is normal vaginalflora? Genitourin Med 1997; 73:23–811. Schwebke JR, Morgan SC, Weiss H. The use of sequential selfobtainedvaginal smears for detecting changes in vaginal flora. /InfectDis 1997; 24:236–912. Schwebke JR, Richey CM, Weiss HL. Correlation of behavior withmicrobiological changes in vaginal flora. J Inf Dis 1999; 180; 1632–613. Newton ER, Piper JM, Shain RN, Perdue ST, Peairs W. Predictors ofthe vaginal microflora. Am J Obstet Gynecol 2001; 184:845–5314. Hillier SL, Krohn MA, Rabe LK, Klebanoff SJ, Eschenbach DA. Thenormal vaginal flora, H 2 O 2 -producing lactobacilli, and bacterialvaginosis in pregnant women. Clin Infect Dis 1993; 16(Suppl 4 4):S273–8115. Aroutcheva AA, Simoes JA, Behbakht K, Faro S. Gardnerella vaginalisisolated from patients with bacterial vaginosis and from patients withhealthy vaginal ecosystems. Clin Inf Dis 2001; 33:1022–716. Catlin BW. Gardnerella vaginalis characteristics, clinical considerations,and controversies. Clin Microbiol Rev 1992; 5:213–3717. Eschenbach DA. History and review of bacterial vaginosis. Am J ObstetGynecol 1993; 169:441–5

BACTERIAL VAGINOSIS 2518. Altrichter T, Heizmann WR. Gardnerella vaginalis: transport,microscopy, testing resistance. Geburtshilfe Frauenheilkunde 1994; 54:606–1119. Hill GB. The microbiology of bacterial vaginosis. Am J Obstet Gynecol1993; 169:450–420. Peipert JF, Ness RB, Soper D, Bass D. Association of lower genitaltract inflammation with objective evidence of endometritis. Infect DisObstet Gynecol 2000; 8:83–721. Steinhandler L, Peipert JF, Heber W, Montagno A, Cruickshank C.Combination of bacterial vaginosis and leukorrhea as a predictor ofcervical chlamydial or gonococcal infection. Obstet Gynecol 2002; 99:603–722. Schmitt C, Sobel JD, Meriwether C. Bacterial vaginosis: treatmentwith clindamycin cream versus oral metronidazole. Obstet Gynecol1992; 79:1020–323. Nilsson U, Hellberg D, Shoubnikova M, Nilsson S, Mardh PA.Sexualbehavior risk factors associated with bacterial vaginosis and Chlamydiatrachomatis infection. Sex Transm Dis 1997; 24:241–6

4.BACTERIAL VAGINITISINTRODUCTIONBacterial vaginitis can be considered a pathologic entity separate frombacterial vaginosis, candidiasis, and trichomoniasis. It can originatefrom the introduction of a bacterium that overgrows the dominantbacterium of the vaginal ecosystem, or an alteration within theecosystem that causes Lactobacillus to lose dominance. In addition, oneor more of the endogenous pathogenic bacteria can gain dominance. Itis possible that when a significant alteration in the vaginal ecosystemoccurs, one or more of the endogenous bacteria can becomedominant and produce symptoms that are recognized as vaginitis.CLINICAL PRESENTATIONThe patient with bacterial vaginitis, regardless of the offendingbacterium, typically presents with a copious purulent vaginaldischarge. There can also be an associated discomfort that isfrequently described as ‘soreness’. The vaginal discharge has a pH of 5or higher, and this is consistent with a decrease in Lactobacillus growthand favorable to the growth of pathogenic bacteria. The vaginalepithelium is erythematous and at times beefy red.It is imperative that the physician rule out other causes of a purulentvaginal discharge, such as trichomoniasis and cervicitis, especiallycervicitis 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 27indicated in patients with purulent vaginal discharge whose behaviorplaces them at risk for contracting a sexually transmitted disease.Evaluation of a patient with purulent vaginal discharge begins withobtaining a detailed history with regard to medications, especiallyantimicrobial agents taken within the last 30 days. It should bedetermined whether the patient practices douching, and if so howoften and which specific douching agent is used. The physician shouldalso obtain a detailed sexual history, determining whether the patientand her partner practice cunnilingus and/or anal intercourse. Thefrequency of sexual intercourse can be significant because semen isalkaline and if the patient is having sexual intercourse with significantfrequency, then it may be the ejaculate that is causing a significantchange in the hydrogen ion concentration. Although some believethere 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 bemeticulous. The external genitalia should be examined for thepresence of discharge, especially discharge originating from theglandular organs of the vestibule and discharge from the vagina. Thenormal amount of vaginal discharge is estimated to be approximately4–6 ml per day 1 . Discharge spilling out from the vagina, causing thepatient to wear a pad on a daily basis, is abnormal. This increase in theamount of discharge may be because of a vaginal, uterine, or fallopiantube infection or an increase in estrogen production.The labia majora, crural folds, and labia minora should be inspectedfor the presence of excoriations, fissures, ulcerations, anderythematous areas with the presence of central pustules. The urethrashould be examined for the presence of purulent discharge. Thisshould be done by visual inspection and then followed with gentlepalpation to determine if there is any expressible discharge.Additionally, Skene’s and Bartholin’s glands should be inspected forthe spontaneous presence of discharge and then gently palpated todetermine if any discharge can be expressed. If discharge is emittedfrom any of these organs, specimens should be sent for both Gram’sstain 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

28 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTindicative of an altered vaginal microflora. A specimen of the vaginaldischarge should then be examined microscopically. The maturity ofsquamous epithelial cells should be noted—that is, do they appearnaviculated (well estrogenized) or are there numerous intermediateand parabasal cells present. The well-estrogenized squamous cell tobasal cell ratio should exceed 10:1. This helps to determine whetheror not the patient has sufficient endogenous estrogen or if atrophicvaginitis exists. The number of white blood cells (WBC) seen under40x magnification should not be greater than 5 per hpf. The presenceof more than five WBC/40x magnification is consistent with aninflammatory state.The color of the vaginal epithelium should also be noted. In ahealthy vaginal ecosystem the epithelium is pink, and if estrogen ispresent in sufficient concentration the wall is rugated. In the absenceof estrogen, the epithelium can appear pale and smooth. In advancedstages of atrophic vaginitis the epithelium can be erythematous. Themajor difference between atrophic vaginitis and bacterial vaginitis isthat when the former is present the number of basal cells far exceedsthe number of naviculated squamous epithelial cells (Figure 7).The endogenous microflora in patients with bacterial vaginitis andatrophic vaginitis will be altered. In both conditions the pH is at orabove 5, Lactobacillus is no longer the dominant bacterium, and thereare numerous WBC. The discharge can be purulent in bothconditions. In atrophic vaginitis a single bacterium can be dominant,as is the case with bacterial vaginitis. The potential pathogenic bacteriaoutgrow Lactobacillus when the pH is 5 or more. If no pathogen, suchas T. vaginalis or Candida, is identified, specimens of the vaginaldischarge should be sent for culture. The specimen should be sent forthe culture and identification of aerobic, facultative, and obligateanaerobic bacteria.STREPTOCOCCAL VULVOVAGINITISInterestingly, the streptococci are commonly found as commensalbacteria in the vagina. It is not uncommon to isolate a and ≥streptococci, as well as group B hemolytic Streptococcus. In fact thelatter can be found to colonize the vagina in up to 25–30% of womenwho are asymptomatic.

BACTERIAL VAGINITIS 29Patients with group B streptococcal (GBS) vaginitis (Streptococcusagalactiae) typically present with erythema and maceration of thevaginal introitus and perianal area. They also have a copious, odorless,watery discharge that is yellow to white. The vaginal epithelium iserythematous 2 . Since the year 2001, the author has treated tenpatients with a diagnosis of GBS vaginitis (unpublished). The patients’symptoms ranged from copious discharge alone to copious dischargeassociated with vaginal soreness. The diagnosis was based on thefollowing:(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 above10:1;d. Lactobacillus was noticeably absent; ande. cocci, typically in chains, were the dominant bacterialmorphotype.Patients are usually treated with oral penicillin, ampicillin, oramoxicillin. However, if the outcome is successful it is usually shortlivedand recurrence is frequent. Improved success has been achievedby combining orally administered penicillin, ampicillin, or amoxicillinwith the intravaginal administration of a vaginal acidifying agent suchas boric acid, 600 mg suppositories twice a day for 14 days, or Acijel ® , one applicator-full twice a day for 3–4 weeks. Honig and coworkers2 treated their two patients with clindamycin and cotrimoxazoleseveral times. These investigators found that duringasymptomatic periods, GBS could not be recovered from the vagina;however, when the symptoms returned the bacterium could easily berecovered from the vagina. They also found that after repeatedcourses of clindamycin therapy the organism became resistant toclindamycin. These investigators prescribed chlorhexidine 5%

30 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTintravaginal gel but this treatment did not prove to be any moreefficacious than the previous treatments.In our unpublished study, vaginal cultures obtained from eachpatient revealed a single bacterial dominance and this was reported asa heavy growth of group (≥ -hemolytic streptococci by commerciallaboratories. Patients were treated with benzathine penicillin, 2.4million units intramuscularly and there was initial resolution but thenrelapse. Neither the oral administration of ampicillin or amoxicillinwas particularly efficacious. One patient responded to two courses ofdoxycyline, 100 mg twice a day for 10 days.Thus, individual antibiotic regimens must be tried as treatment forpatients with GBS vaginitis. No one regimen appears to be effective inthe treatment of all cases of GBS vaginitis.STAPHYLOCOCCAL VAGINITISStaphylococcus can be isolated from the vagina but it is relativelyuncommon. Investigators have reported that Staphylococcus aureus wasisolated from the vagina of 5–15% of women with a healthy vaginalecosystem 3 , 4 . However, S. aureus colonization of the skin is common.Aly and co-workers 5 reported that 67% of asymptomatic womenwere found to harbor S. aureus on their vulva. This is an interestingfinding because while S. aureus is commonly found to colonize thevulvar skin it is unusual to find it in the vagina. This finding impliesthat there is some mechanism in the vagina that inhibits thecolonization and growth of S. aureus.S. aureus did cause a significant problem in the 1980s whennumerous toxic shock syndrome cases were reported. Shands and coworkers6 reported that toxic shock syndrome occurred inmenstruating women who were using tampons and had vaginalcolonization of S. aureus. This was later found to be caused by specificrare strains capable of producing the exotoxin that caused thisdisease.COLIFORM VAGINITISThe vaginal microflora can become altered and then one of thecoliform bacteria might gain dominance. Probably the most common

BACTERIAL VAGINITIS 31coliform is Escherichia coli. Because of the close proximity of therectum, these bacteria can colonize the perineum, the vestibule, andthe vagina. Although this bacterium is commonly isolated from theanatomical sites adjacent to the vagina and is a common cause ofurinary tract infection, it is not a common vaginal isolate. It has beenreported to be present in the vaginas of 12% of women with a healthyvaginal ecosystem 7 . Obtaining a specimen for culture can be ofassistance when examining and evaluating a patient for vaginitis onceall common causes have been ruled out. A report indicating that thevagina is colonized and dominated by one particular bacterium can besignificant. However, if the report states that there are severalbacteria present and the growth of each is light, then the growth is notsignificant. A pH ≥ 5 is also significant, but if the vaginal pH is ≥ 4.5 itis not worth culturing for bacteria. A yeast culture might prove morerewarding.For patients with a variety of coliforms the existence of arectovaginal fistula should be considered. The patient should also beinvestigated for the possible existence of diverticulitis and ulcerativecolitis, since these conditions can result in occult fistula formation andcause constant seeding of the vagina with bacteria from the sigmoidand rectosigmoid colon. Wiseniewski and co-workers 8 described acase of sigmoid colon vaginal fistula in which the patient hassignificant vaginitis caused by contamination with a variety of coliformsoriginating 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 notfrequently seen in the United States.CYTOLYTIC VAGINOSISIn 1982 Cibley and Cibley 9 described a vaginitis that was characterizedby an overgrowth of normal lactobacilli with a profuse vaginaldischarge that tends to be thick or pasty, and a pH less than 4.5(Figure 8). The characteristics of cytolytic vaginosis were initiallydescribed as Döderlein cytolysis and were reported by Bibbo inPapanicolaou smears 10 . The diagnosis of cytolytic vaginosis is based onthe following:

32 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENT(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; andb. 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 tobe an overgrowth of Lactobacillus, whether or not the Lactobacilluspresent is a beneficial species is not known. It may be that the speciesof Lactobacillus that gained dominance adapted to acidic conditions andis not affected by the lactocin produced by the Lactobacillus speciesthat can maintain a healthy vaginal ecosystem. It is interesting to notethat when viewing the vaginal discharge of a patient with cytolyticvaginosis microscopically, the absence of other bacteria is noticeableand the large number of lactobacilli is impressive.TreatmentAt this time, antibiotics do not have a place in the treatment ofcytolytic vaginosis. This is not an infection and the relative absence ofWBC indicates that this is not an inflammatory disease. Since thiscondition is associated with an acid environment, Cibley and Cibley 9recommended sodium bicarbonate douches (30–60 g of sodiumbicarbonate in a liter of warm water) two to three times a week.When the patient notes improvement, douching should be tapered offto once a week and eventually as needed.

SUMMARYBACTERIAL VAGINITIS 33Individuals presenting with complaints of vaginitis, like vaginalburning, soreness, itching, or a combination of symptoms and acopious purulent discharge, should be evaluated in a systematicmanner. Localization of the disease must be established at the vulva,the vestibule and glands of the vestibule, the vagina, the cervix, andthe uterus. The existence of a common pathogen like Trichomonas orCandida, infection of the cervix, and the presence of vaginal warts,must be ruled out. The microscopic examination of the vaginaldischarge should reveal the presence of a dominant bacterium otherthan Lactobacillus. If one sees predominantly small rods or coccalforms, then a vaginal culture could prove beneficial. Treatmentshould be directed at the bacterium identified and broadspectrumantibiotics should not be used. An attempt to correct the vaginalalteration can be put forth with the use of acidifying agents such asboric acid vaginal suppositories, 600 mg each, administered twice aday for 14 days.REFERENCES1. Godley MJ. Quantitation of vaginal discharge in healthy volunteers. BrJ ObstetGynaecol1985; 92:739–422. Honig E. Mouton JW, van der Meijden WI. Can group B streptococcicause symptomatic vaginitis. Infect Dis Obstet Gynecol 1999; 7:206–93. Larsen B, Galask RP. Vaginal microbial flora: composition andinfluences of host physiology. Ann Intern Med 1982; 96:926–304. Guinan ME, Dan BB, Guidotti RJ, et al.Vaginal colonization withStaphylococcusaureus in healthy women: a review of four studies. AnnIntern Med 1982; 96:944–75. Aly R, Britz MB, Maibach HI. Quantitative microbiology of humanvulva. Br JDermatol 1979; 101:445–86. Shands KN, Schmid GP, Dan BB, et alToxic-shock syndrome inmenstruating women. Association with tampon use and Staphylococcusaureus and clinical features in 52 cases. N Engl J Med 1980; 303:1436–427. 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 multivariatestatistical analysis. Am J Obstet Gynecol1986; 154:120−6

34 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENT8. Wisniewski PM, Coonrod T, Thonet MA, Horn AS. Early diagnosis ofdiverticular colovaginal fistula with colposcopy. A case report. /ReprodMed 1988; 33:705–89. 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 1991:181–710. Bibbo M, Weid GL.Microbiology and inflammation of the femalegenital 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 CANDIDIASISINTRODUCTIONVulvovaginal candidiasis (VVC) is probably the most commonlyperceived abnormal condition affecting a woman’s lower genital tract.There is no doubt that this perception has been fueled by theavailability of over-the-counter antifungal products for the treatmentof VVC. Almost every time a woman experiences itching, burning,discomfort, or abnormal discharge of the lower genital tract she willdiagnose herself with a ‘yeast infection’. While approximately 75% ofwomen will experience at least one episode of yeast vulvovaginitis intheir lifetime, about 50% will experience more than one episode and5% will have recurrent episodes 1 . The problem with VVC is that in asymptomatic patient it is difficult to know if it is an infection or anovergrowth of the endogenous yeast present as part of theendogenous vaginal microflora. Approximately 15–20% of women inthe reproductive age group are colonized by yeast; this is referred toas asymptomatic endogenous carriage 2 .Typically, acute symptomatic episodes of VVC are responsive toone of the many antifungal agents available. However, these infectedwomen usually do not have predisposing factors that can be linked totheir recurrent episodes of VVC. For a patient who complains ofvulvovaginal pruritus and burning, has erythema, and has a vaginal pHless than 4.5 but no yeast identified on microscopic examination withpotassium hydroxide (KOH), some physicians recommend that aspecimen be obtained for culture and identification of yeast. Apositive yeast culture is interpreted as the cause of her symptoms.

36 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTHowever, this may not be a valid interpretation of the culture resultssince 15–20% of women are asymptomatic carriers of Candida.Perhaps the culture results should be viewed as any other resultobtained from an area where numerous microorganisms reside; thequantity of yeast recovered should be the determining factor. If theculture returns with scant versus heavy yeast growth, this may not bethe cause of her symptoms. If the patient with scant growth of yeast istreated with an antifungal agent and her symptoms resolve, thediagnosis is definite. If she then returns with her symptoms and thesubsequent culture is positive, the diagnosis is recurrent VVC and sheis treated again, and again, and again. I believe that this scenariocharacterizes the problem. Can we determine which patient is anasymptomatic carrier of Candida, and which patient may have anormal background of Candida and symptoms suggestive ofcandidiasis, but Candida is not the cause of her symptoms?MYCOLOGYThe genera Candida, Torulopsis, and Rhodotorula are all yeast that donot have a sexual stage (do not form ascospores). The principal genusis Candida, which is comprised of approximately 81 species that allproduce pseudohyphae. If Torulopsisglabrata is included in the genusCandida (C. glabrata), then this is an exception as this species onlyproduces budding forms without the development of pseudohyphae 3 .Rhodotorula produces a carotenoid pigment.C. albicans produces B vitamins that stimulate growth ofLactobacillus in vitro, while Lactobacillus has been shown to enhance, aswell as inhibit, the growth of C. albicans 4 – 6 .C.albicans also has beendemonstrated to stimulate the growth of Staphylococcus in vitro 7Members of the Enterobacteriaceae, such as Escherichiacoli, have beenshown to have an inhibitory, although weak, effect on the growth of C.albicans 8 , 9 . Additionally, C. albicans has been shown to produce afactor that can inhibit the growth of Neisseria gonorrhoeae in vitro 10 . Thus,it appears that when colonizing the lower genital tract Candida is ableto compete in this environment, especially at the more acidic pH, byproducing inhibitor compounds that affect the growth of the bacteriafound in this ecosystem.

VULVOVAGINAL CANDIDIASIS 37Candida is able to grow over a wide pH range of 3 to 8. The typicalpH of the vagina in a healthy state is 3.8–4.5, while if the microflorais skewed the pH can range from 4.5 to 6. Therefore, it is notsurprising to find Candida in a variety of situations, for example in thepresence of bacterial vaginosis or vaginitis (BV) or trichomoniasis, aninflammatory vaginitis. Candida reproduces when buds develop fromblastospores. The blastospore can be ovoid, elongated, or spherical.C. albicans is pleomorphic; that is, it can grow as a budding yeast, canproduce pseudohyphae, and when grown in serum can produce truehyphae. The cell wall of Candida serves three important functions: itserves as the outer containment of the cell maintaining its shape; itundergoes metabolic turnover during growth and reproduction; and itserves as the point of contact between the organism and the hostduring infection.The cell wall is a multi-layered polymer of glucan and mannanpolysaccharides containing chitin, protein, and lipid. Although the cellwall is a multi-layered structure it is flexible, allowing the organism toappear as ovoid, budding yeast, pseudohypae, and hyphae. Thispolymorphic appearance can lead to confusion when viewing thepatient’s vaginal discharge through a microscope. If the organism ispresent in its ovoid form, it may be overlooked or not recognized asyeast. Therefore, a culture should be obtained for patients withsymptoms suggestive of VVC.The polymorphism of C. albicans is of interest to mycologists andclinician researchers because it is believed that this capability tochange morphology is related to the organism’s pathogenicity(Table 8).EPIDEMIOLOGYYeast are ubiquitous and found in almost all habitats. In the humanbody, yeast make up part of the microbial ecology of thegastrointestinal and lower genital tracts. Although the microbialecology is complex, bacteria typically outnumber yeast. Yeast can alsobe found in the oral cavity of up to 20% of healthy individuals.Colonization of the rectum occurs in up to 25% of healthyindividuals. Colonization of the oral cavity and rectum has important

38 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTTable 8 Definition of morphologic forms of candida albicansTable 9 Candida species isolated from humansimplications in women with recurrent or chronic vulvovaginalcandidiasis. Candida has been isolated from the vagina in up to 37% ofhealthy, asymptomatic non-pregnant women 11 , 12 . Asymptomaticcarriage of yeast can be a significant problem, since large numbers ofyeast can be isolated from the vaginas of healthy women: for example,concentrations of yeast cells as high as 10 6 and 10 7 yeast cells per mlof vaginal fluid have been isolated from approximately 15% ofasymptomatic women 13 , 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 exactincidence is unknown; however, it is believed that 75% of all womenwill experience one episode of vulvovaginitis caused by Candida 1 . Aspreviously mentioned, it is estimated that 50% of individuals whohave one yeast infection will experience at least one additionalepisode, and approximately 5% will have recurrent infections 15 . C.albicans continues to be the most common cause of vulvovaginitis 16 .There is concern that non-albicans species, specifically C. glabrata, are

VULVOVAGINAL CANDIDIASIS 39increasing in frequency as a cause of VVC. Approximately 50–55% ofcollege women will be treated for confirmed VVC by the time theyare 20 years old, and 75% will have had one confirmed episode intheir lifetime 16 – 18 .Some investigators consider VVC to be a sexually transmitteddisease. Indeed there is no doubt that, in some patients with chronicrecurrent vulvovaginitis, treating the sexual partner does result inresolution of recurrent disease. Candida has been isolated from themale sexual partners of women with vulvovaginal candidiasis 18 , 19 . Thefrequencyof VVC does increase with the onset of sexual activity; therealso appears to be an association between VVC and the practice oforogenital sex 19There has been a great deal of theorizing regarding risks thatpredispose the patient to vulvovaginal yeast infections. Other thandiabetes, immunosuppression, and pregnancy, sufficient data toestablish cause and effect relationships between suspected risk factorsdo not exist. The truth of the matter is, perfectly healthy womendevelop vulvovaginal yeast infections. The basic problem isdetermining who has a true yeast ‘infection’ and who has developedan alteration in their vaginal ecosystem, permitting the endogenousyeast to grow and become symptomatic. Remember, Candida,especially C. albicans, can be grown from the lower genital tract ofhealthy asymptomatic women. The precise proportion of healthywomen who harbor yeast and are asymptomatic is unknown, butstudies indicate the figure may be up to 30%. This creates a problemfor the clinician making a diagnosis and determining treatment.CLINICAL PRESENTATION ANDDIAGNOSISThe patient with symptoms attributed to candidiasis can have any oneof a variety of conditions that mimic VVC (Table 10). It is importantthat when evaluating the patient suspected of having VVCconsideration be given to other possible etiologies, especially whenyeast are not observed in the patient’s vaginal discharge. The physicianshould not automatically come to the diagnosis of VVC but shouldestablish the diagnosis by documenting the presence of yeast in thevagina and vulva.

40 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTTable 10 Differential diagnosis in the patient with vulvovaginitisThe patient with VVC presents with vulvovaginal burning anditching. There is an increase in these symptoms, especially burning,with or shortly after sexual intercourse. The labia becomeerythematous and swollen (Figure 9). Frequently excoriations arepresent and the diabetic patient is at risk of the development ofcellulitis, which can progress to necrotizing fasciitis. Therefore if thelabia are markedly swollen and there is an advancing erythemaextending beyond the labia, secondary bacterial infection should besuspected. The patient should be discouraged from trying to diagnoseherself with a yeast infection. In a study of 365 women previouslydiagnosed with VVC, only 35% were able to correctly diagnoserecurrent VVC 20 .The vaginal discharge should be evaluated as follows:(1)The pH should be determined. Although yeast prefer a moreacidic pH, they can be found at any pH. A pH of 4.5 or less rulesout bacterial vaginosis and bacterial vaginitis, but a pH of 5 ormore does not rule out the possible existence of yeast.(2)An aliquot of the vaginal discharge should be obtained by wipingthe lateral vaginal wall with a cotton- or Dacron-tipped applicator.The applicator should be immersed in 2 ml normal saline andvigorously agitated. The applicator should then be touched to aglass slide so one or two drops of the diluted vaginal discharge ispresent on the slide. Two slides should be prepared andconcentrated KOH should be added to the diluted vaginaldischarge. The KOH will dissolve all non-chitinous material,leaving the yeast intact. The specimens should be covered with aglass cover slip (Figures 10 and 11).(3)The specimens of vaginal discharge should be viewed under 40xmagnification. If budding yeasts cells or hyphal elements areobserved, the diagnosis of VVC is established (Figure 12).(4)A specimen should also be obtained for culture and identificationof yeast. This is important because if the patient does not respondto treatment, knowing that she is colonized by a non-albicansspecies will help in directing further antifungal treatment.

VULVOVAGINAL CANDIDIASIS 41Although cultures are now being touted as the gold standard, theyshould not be used indiscriminately 21 . Following treatment, if thepatient is asymptomatic and no yeast are observed on microscopicexamination of the vaginal discharge, a specimen of the vaginaldischarge should not be cultured (a test of cure culture). It isimportant to remember that approximately 37% of healthyasymptomatic women can have yeast as part of their normalendogenous vaginal microflora 22 .Patients with recurrent or chronic persistent VVC should havedocumentation that they are infected, and a culture should only beobtained to determine if they are infected with a non-albicans species.As mentioned, recurrent VVC affects approximately 5% of patientsand is defined as four or more infections occurring annually. Themajority of patients who experience recurrent VVC are typicallyhealthy and have no obvious or recognizable predisposing factors 23 .Studies trying to determine the relationship between recurrent VVCand the strain of Candida revealed that individuals with early recurrentepisodes—less than 6 months—were likely to have the same strainas the previous infection. Infections recurring more than 6 monthsapart were likely to have a different strain 24 .The source of Candida has not been established. It was believed thatthe rectum served as the reservoir; however, treatment with oralnystatin has not been effective in reducing recurrences, and recurrentVVC occurs in the absence of rectal colonization 25 . The difficulty inmanaging a patient with recurrent vulvovaginitis is determining if sheis experiencing an exacerbation of an existing colonization or hasdeveloped reinfection. Odds 26 demonstrated that to obtain a positiveculture from a vaginal specimen, the concentration of yeast must be atleast 10 3 yeast cells per ml of vaginal fluid in order to develop onecolony on agar medium. Therefore, when a patient who has beentreated subsequently becomes asymptomatic, if microscopicexamination does not reveal the presence of hyphal forms and theculture is negative, she will be considered cured. If she shouldexperience another yeast infection in the following 30–60 days thiswill be considered a reinfection. The difficulty in this case isestablishing if this is an exacerbation of pre-existing candidiasis, ifthere was a change in the vaginal ecosystem that stimulatedovergrowth of endogenous Candida, or if there is a new infection.

42 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTTable 11 Factors associated with recurrent vulvovaginal candidiasisAttempts have been made to establish risk factors that predisposean individual to recurrent VVC (Table 11). The vaginal environmentthat favors the growth of yeast is acidic, with a sufficientconcentration of glucose.Again, the problem associated with recurrent and chronic persistentVVC is that these conditions are frequently found in women who arehealthy. Their vaginal ecosystems are not in a state of significantimbalance because even though they are colonized with Candida andare often symptomatic, there is normal colonization by Lactobacillus.This latter fact alone indicates that the vaginal ecosystem is notimbalanced because in order to support significant growth ofLactobacillus, the ecosystem must be in balance.Most likely, the patient with recurrent VVC is not being reinfectedsince most of these women do not have exogenous riskfactors, e.g. douching (especially with compounds that can alter thevaginal ecosystem like Betadine ® ), multiple sexual partners, or a dietthat may contribute to an increased vaginal glucose concentration.One theory that persists is that women with recurrent and/or chronicVVC have significant rectal colonization. This rectal colonizationprovides a source for repeated vaginal colonization. Odds and Abbottfound that the oral cavities and rectums of women with VVC werecolonized by the same yeast, which was determined by typing 27 . Someinvestigators also found 100% of patients with VVC had rectalcolonization; however, this has not been substantiated by otherinvestigators 25 , 28 , 29 . Treatment regimens that include either oralnystatin or ketoconazole have not been shown to eliminate rectalcolonization.Antibiotic therapy has been associated with vaginal colonization byCandida. It is believed that antibiotics reduce the vaginal bacterial floraand allow the growth of Candida. The possibility exists that whenbacteria like Lactobacillus crispatus or other hydrogen peroxide- and

VULVOVAGINAL CANDIDIASIS 43lactocin-producing lactobacilli are the dominant organisms in thevagina, Candida is suppressed. One study 30 demonstrated thatingesting yogurt, which contains L. acidophilus, daily for 6 monthscould decrease Candida vaginal and rectal colonization and vaginalinfection. However, this was a small study and should be repeatedwith a large number of patients before this can be recommended as partof the therapeutic regimen for treatment of recurrent VVC 30 . Twoclinical studies demonstrated an increase in vaginal yeast colonizationfrom 10 to 30% following 2–3 weeks of tetracycline use 31 , 32 . Animalstudies, specifically in the rat, demonstrated that two organisms,Lactobacillus and Candida, exist in a commensal relationship within thegastrointestinal tract, each colonizing specific sites. Lactobacilluscolonizes the stratified squamous epithelium and Candida colonizes,and attaches to, the secretory mucosal cells 33 . When the animalsreceived tetracycline, the lactobacilli were significantly reduced innumber to levels below detection and the yeast increased in numberto colonize the entire mucosal surface. Following the discontinuationof tetracycline and administration of lactobacilli, the originalmicroflora of the stomach was re-established.This is an extremely interesting area since the vagina is a complexecosystem containing numerous microorganisms living together in avariety of relationships. When a condition of the vagina requirestreatment with antimicrobial agents it is important to remember thatthese agents can have far-reaching effects. There is little doubt that thenon-specific effects of the antimicrobial agents can influence the statusof the microecology, thus giving rise to additional problems.Therefore, when prescribing antimicrobial agents the physician shouldadminister a narrow-spectrum antimicrobial that will have the leastscatter effect, thereby reducing the possible disturbance to theassociated microorganism in the ecosystem.Another potential area that has received significant attention is therole of sexual behavior related to recurrent VVC. Several studies haveshown that the penis is asymptomatically colonized in 5–25% of themale sexual partners of women with symptomatic VVC. Penilecolonization with yeast is four times more prevalent among thesemales than among those whose sexual partners do not haveVVC 26 , 34 – 36 . However the male is often asymptomatic. Sobel 29reported that in 100 women with VVC, three male partners

44 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTdeveloped Candida balanoposthitis. Additionally, 20% of the malepartners developed an acute hypersensitivity reaction, which is asevere itch and redness shortly after intercourse that disappearswithout treatment within 24 hours 29 . However, these findings do notexplain the male who develops erythema of the head and coronalsulcus of the penis associated with persistent chronic itching. Whilethese individuals report significant burning shortly followingintercourse, they do not develop balanoposthitis but requiretreatment. There is no doubt that the male penis can becomecolonized with yeast when exposed to a vagina colonized by asignificant number of yeast. Whether or not the penis becomescolonized and re-inoculates the female most likely depends upon theinoculum size.The local immunity of the lower genital tract may play a vital rolein the pathogenesis of VVC, especially in patients with recurrentdisease. In one study of women with recurrent VVC, immunoglobulinA (IgA) and the secretory component of IgA were found to be absentfrom the patients’ cervicovaginal secretions 37 . These investigatorsfound that IgG was present in the cervicovaginal secretions of 94%and IgA in 73% of the controls, and in women with VVC IgG wasfound in 36% and IgA in 32% (p < 0.001). The secretory componentof IgA was found in cervicovaginal secretions of 13% of women withinfection and 79% of uninfected women (p < 0.001) 37 . Witkinpostulated that women who experience recurrent VVC developed atransient and local inhibition of cell-mediated immunity 38 . VVC ismore frequently found in patients with diabetes mellitus, individualson steroid therapy, individuals taking broad-spectrum antibiotics,pregnant patients, and individuals with immunologic dysfunction. Allindividuals with one or more of these risk factors suffer fromimpairment of their cellmediated immunity. Patients with insulindependentdiabetes have a defect in interlukin-2 (IL-2) synthesis,while patients taking broad-spectrum antibiotics can experiencesuppression of phagocytic function, and pregnant women oftenhave selective inhibition of their cellular immune responses.Therefore, all of these patients may be at an increased risk ofdeveloping recurrent VVC 39 – 41 . Hobbs and coworkers 42demonstrated in vitro a reduced lymphocyte proliferative response toCandida antigens in 65% of 23 women with recurrent VVC. Witkin

VULVOVAGINAL CANDIDIASIS 45and co-workers 43 also showed a decreased lymphocyte proliferativeresponse in patients with recurrent VVC. These investigators alsodemonstrated that serum from patients with recurrent VVC inhibitedthe pr oliferative response to Candida of lymphocytes obtained fromwomen without VVC. Witkin and colleagues 44 confirmed this lack ofproliferative response in lymphocytes in 73% of 65 women withrecurrent VVC. These women did not have predisposing factors andpossessed lymphocytes that did not have the inherent cellular ability toproliferate in vitro in response to Candida antigen stimulation.A healthy endogenous vaginal microflora is probably the mostimportant defense against an overgrowth of Candida. Lactobacillusapparently plays a pivotal role in suppressing or inhibiting Candidaovergrowth 3 . Like other microorganisms, Candida produces substancesthat can inhibit the growth of other microbes. When VVC is present,there is a reduction in the number of lactobacilli present in thecolonized vagina 45 , 46 . The prevention of Candida adhering to vaginalsquamous epithelial cells was observed when the vaginal squamouscells were preincubated with lactobacilli in vitro 47 .Typically VVC does not occur in association with other abnormalconditions or infections. However, there are exceptions because VVChas been observed with BV, trichomoniasis, C. trachomatis, and N.gonorrhoeae. In fact, the presence of an increased number of whiteblood cells (WBC) in the vaginal discharge should alert the physicianto look for an infection, such as trichomoniasis or cervicitis.The following characteristics can be identified in a patient withVVC:(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 dischargePatients complaining of vulvovaginal itching and/or burning, and whohave a white to slate-gray discharge with a pH of less than 4.5 but noevidence of yeast, i.e. no hyphal forms or budding yeast on microscopicexamination of the vaginal discharge, should have a specimen of the

46 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTvaginal 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 theculture returns positive. An additional benefit of the culture, ifpositive, is the identification of the species. If the isolated yeast is aspecies other than C. albicans, then it may be resistant to the typicalantifungals used for treatment. The physician can then institute therapywith Butoconazole ® 2%, Terazol ® , Tioconazole ® , or boric acidvaginal suppositories or capsules (Table 12).The presence of WBC and yeast may indicate the presence of anadditional condition, such as cervicitis. Again, the physician shouldlook for a cervical infection. If the patient has risk factors, thencervical specimens should be obtained f or C. trachomatis and N.gonorrhoeae, and if the Pap smear is abnormal then a specimen shouldbe obtained for human Papillomavirus (HPV). If the vaginal pH is 5 ormore, then T. vaginalis should be considered.The patient may also present with vaginal burning shortly aftersexual intercourse, which may persist for 24 hours. This could befollowed by a mild vulvar pruritus that lasts 1–2 days. The patient’ssexual partner may also complain of penile burning shortly afterintercourse that lasts for a day or two. These patients should beexamined and a specimen for culture and identification of yeast shouldbe obtained. There is little doubt of the value of a vaginal culture,especially in the patient with signs and symptoms of VVC but withoutfungal elements detected in the vaginal discharge. Severalinvestigators have demonstrated the value of a vaginal culture whenevaluating a patient with suspect vaginitis. Handa and Stice 48 cultured40 women with cyclic vulvitis and found 61.5% to be positive foryeast. 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 patientsfrequently have Candida and should be treated vigorously because theyoften will manifest symptoms consistent with VVC. In addition, theirpartners may serve as a source of reinfection. Therefore, theirpartners should be treated with a topical agent such as Mycostatin ®cream. In a study of 4228 women with symptomatic lower genitaltract infection 49 , candidiasis was detected in 3351 cases (79%): C.albicans was identified in 1431 (43%) of these cases, and non-albicans

VULVOVAGINAL CANDIDIASIS 47Table 12 Available antifungal agentsspecies were found in 1920 (57%). These investigators also found thatamong 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 isolatedin patients using oral contraceptive hormones while womenpreviously treated with topical antimicrobial agents were morefrequently infected with non-albicans species. However, theseassociations were not statistically significant. C. albicans was alsoisolated more frequently in women whose partners reportedsymptoms consistent with the presence of penile candidiasis.In summary, the diagnosis and management of VVC can beapproached as follows:(1)Obtain a detailed history regarding the start of symptoms andfactors that aggravate the conditions;(2)Determine if the patient has been treated with oral antibioticswithin the last 14 days;(3)Determine if the patient has recently used intravaginalmedications, home remedies, or has been douching and if sodetermine what agent was used;(4)Determine the anatomic location of her symptoms;(5)Describe the physical findings and location of all abnormalfindings;(6)Obtain a specimen from the vulva for culture and microscopicexamination (differential diagnosis, Table 13);

48 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTTable 13 Differential diagnosis of vaginitis(7)Obtain a specimen from the vagina for culture and microscopicexamination;(8)Determine the vaginal pH. A pH ≥ 5 indicates that the vaginalmicroflora is altered. If yeast are also found, this suggests thattwo conditions are present;(9)The presence of WBC in a patient with a cervix can indicate thepresence of cervicitis; and(10)If no yeast are present, a specimen for culture should beobtained.Interpreting the vaginal discharge with microscopic examination:(1)Squamous cells should be estrogenized. More basal cells thanwell-estrogenized squamous cells, or the appearance of a largenumber of basal cells and intermediately mature estrogenizedsquamous cells instead of well-estrogenized squamous cellssuggests an estrogen deficiency, for example developing orestablished atrophic vaginitis.(2)A pH ≥ 5 5 indicates an alteration in the endogenous vaginalmicroflora. The absence of WBC indicates that Lactobacillus mayno longer be the dominant bacterium. If there are numerousmorphologic bacteria present, look for clue cells. The presence ofclue cells and the absence of a dominant bacterial morphotypeindicates BV.(3)Numerous WBC, i.e. > 5 WBC/high-power field at 40xmagnification, indicate the presence of either an infection or

VULVOVAGINAL CANDIDIASIS 49hypersensitivity 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 cervicitisand obtain specimens for the detection of C. trachomatis and N.gonorrhoeae. If the patient’s Pap smear is abnormal, obtain aspecimen for HPV.(4)Fungal elements will present as either individual elliptical cells,budding cells, elliptical cells with a short germ tube, or hyphalelements. The presence of any of these elements in a patient withvulvovaginal erythema, itching, and/or burning establishes adiagnosis of VVC.Treatment should be initiated if fungal elements are found on themicroscopic examination of the vaginal discharge. Treatment shouldalso be initiated in the patient who has symptoms consistent withVVC, but whose microscopic examination does not confirm thepresence of fungal elements.TREATMENTInitial episodePatients experiencing their initial episode of VVC can be treated withany of the antifungal topical agents (Table 12). The importance ofinitiating treatment is to establish if the patient has a yeast infectionand if the yeast is a hyphal-producing species. If the examiner findsonly budding yeast in the vaginal discharge it is significantly possiblethat the patient will not respond to typical antifungal agents. Thepatient should be examined within 1–2 weeks of completing treatmentto determine if her condition has resolved. There is no need to culturethe individual experiencing her first episode if yeast are documentedon microscopic examination of the vaginal discharge. If the patient hassymptoms and physical findings consistent with VVC, but microscopicexamination of her vaginal discharge does not reveal yeast, then avaginal specimen should be obtained for the culture of yeast.Patients who experience a recurrent episode of VVC but have lessthan four episodes in a year, should be treated with one of the

50 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTantifungal agents listed in Table 12. Again a culture should beobtained to ensure that the patient is colonized with C. albicans andnot a non-albicans species. The presence of a recurrence, although notchronic or persistent yeast vaginitis, can imply that the initialtreatment was not satisfactory. If the patient became asymptomaticafter initial treatment, the number of yeast may have been reduced toa number that was low enough not to initiate symptoms. Whenconditions in the vagina are appropriate for the increased growth ofyeast, the increased number causes symptoms.The patient with a true recurrent yeast infection, i.e. more thanfour infections in a 12-month period, presents a problem similar tothe patient with persistent or chronic VVC. It is important to reviewthe patient’s hygiene because she may be re-inoculating herself frompossible rectal colonization. Another possible source of re-infection orre-inoculation is orogenital sex. If either her or her partner’s oralcavity becomes colonized, they could transmit the yeast to one anothervia fellatio and cunnilingus. Thus, in the patient with recurrent VVCit may be prudent to culture both the oral cavity and the rectum todetermine if yeast is present. Sobel 50 found that oral colonizationoccurred in 20 of 48 women (42%) with recurrent VVC and rectalcolonization occurred in 35 of 48 (73%) of the patients. Sobel alsoreported that 80% of the rectal isolates were identical to the vaginalisolates, and patients with positive oral cultures were usually found tohave positive rectal cultures. In the male sexual partners of womenwith VVC, Sobel also found that 26% had positive penile cultures.None of these patients had positive oral cultures. Seven male partnerswith negative penile cultures were found to have positive oral culturesfor Candida, and these isolates were identical to those from theirfemale partner’s vagina. Although this was a relatively small study andthe investigator did not report on the sexual practices of the patientsin the study, the data does indicate that the male partner can becomecolonized and it is possible that yeast was transmitted via sexualcontact.When attempting to treat a patient with recurrent or chronicVVC, it is not unreasonable to inquire if the patient and her partnerpractice 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 sitesas well as the vagina.Suggested management for the patient with recurrent VVC:(1)obtain a detailed history, including diet, medications, and sexualpractices;(2)thoroughly examine the external genitalia, and note the presenceof 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 ofmore than one infection or abnormal condition;(4)obtain a specimen from the vagina for culture and identificationof yeast; and(5)examine a portion of the vaginal discharge microscopically andrecord the observations accurately.Treatment regimens for recurrent VVC:VULVOVAGINAL CANDIDIASIS 51(1)boric acid vaginal capsules, 600 mg, inserted intravaginally twicea day for 10–14 days;(2)oral nystatin lozenges or pastilles, 400 000 IU q.i.d for 10 days inan attempt to reduce the oral and rectal colonization;(3)re-examine the patient within 1 week after completion oftherapy, determine the pH, and perform both a microscopicexamination of the vaginal discharge and a culture. The culture isneeded to determine if yeast is still present and the identity ofthe yeast. If the patient is asymptomatic, there are no physicalfindings of candidiasis or vaginitis, and the pH is < 4.5, therapycan be considered successful;(4)begin suppressive therapy—fluconazole 150 mg once a month atthe time of menses for 6 months.Alternative suppressive therapies include fluconazole 150 mg once aweek 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 oranal intercourse should be treated as above but they should also be

52 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTadministered nystatin lozenges or pastilles. Evans and co-workers 51successfully treated 28 oral candidiasis patients with 200 000 IU ofnystatin four times a day for 7 days. Of the 45 patients initiallyenrolled in their study, 36 were culture positive for Candida andcompleted follow-up. A total of 28 (78%) patients had a satisfactoryresponse, and 22 (61%) had complete resolution of symptoms andsigns of infection, but only ten (28%) were culture negative. A total of23 (88%) had clinical improvement and three (11.5%) failed therapy.There has been much discussion in the literature regarding theemergence of resistant Candida strains. Resistance of C. albicans hasnot emerged as a significant problem. In a recent study by Bauters andco-workers 52 , 612 women were studied and 39 (6.3%) had clinicalVVC. These investigators found an overgrowth of Candidacolonization in 20% of the women, with C. albicans the mostfrequently isolated species (68.3%), C. glabrata second (16.3%), andC. parapsilosis third in 6.9% of the women. Other species isolatedwere C. humicola (in two women), C. krusei (one), C. lusitaniae (one),Rhodotorula spp. (three), and S. cerevisiae (one). Among the 84 isolatesof C. albicans, 24 were resistant to fluconazole. Among the 20 isolatesof C. glabrata, three were considered resistant to fluconazole 52 .Nyirjesy and colleagues 21 report treatment outcomes for 74 patientsdiagnosed with chronic VVC. They found that 68% of the isolateswere C. albicans and 32% were non-albicans species. They reported thatall 51 of 51 patients were successfully treated with fluconazole butseven patients experienced recurrent disease. Among the non-albicansgroup, two of eight responded to fluconazole, three of six respondedto itraconazole, four of seven responded to clotrimazole, and 11 of 15responded to intravaginal boric acid 21 . Spinillo and co-workers 53evaluated 472 isolates of Candida from women with VVC. Theyisolated 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 mostcommonly isolated followed by C. glabrata and the ratio of almost 10:1 appears to hold steady in most studies. These investigators reportedtesting 100 isolates of C. albicans to a variety of azoles (miconazole,econazole, clotrimazole, ketoconazole, isoconazole) as well as nystatinand 5-fluorocytosine. They found that approximately 20–40% had an

VULVOVAGINAL CANDIDIASIS 53intermediate sensitivity to the azoles, 2% were resistant to nystatin,and 11% had an intermediate sensitivity to 5-fluorocytosine. Amongthe non-albicans species (17–44 isolates were tested) intermediatesensitivity to these same agents ranged from one to 26 isolates.Therefore, when evaluating patients with chronic VVC, culture isimportant not only to demonstrate the presence of Candida but also todetermine the species. Performing sensitivities, at this point in time,appears to be warranted because when the fungus does not respond toone azole there is a high probability that it will not respond to analternative azole.Boric acid vaginal capsules appear to be a good primary choice fortreatment of VVC in patients who do not respond to azole therapy aswell as those with a diagnosis of recurrent disease. It does not appearthat the use of boric acid vaginal capsules provides satisfactory resultswhen therapy is stopped. Guaschino and colleagues 54 demonstratedthat boric acid vaginal therapy was effective both while therapy wasongoing and when maintained for suppressive therapy, but when thetherapy was withdrawn relapses occurred.Patients who fail to respond to boric acid therapy should bereferred to an infectious disease specialist. If this is not rewarding,then I suggest contacting an obstetrician/gynecologists whospecializes in infectious disease.REFERENCES1. Horowitz BJ. Mycotic vulvovaginitis: a broad overview. Am J ObstetGynecol 1991; 165:1188–922. Bingham JS. What to do with the patient with recurrent vulvovaginalcandidiasis. Sex Transm Infect 1999; 75:225–73. Odds FC. Candida and Candidiasis. Baltimore: University Park Press,1997; 8–154. Wilson TE, Goaz PW. The oral yeast Lactobacillus relationship. III.Growth enhancement of Lactobacillus casei by Candida albicans andsaliva. J Dent Res 1960; 39:365–715. Duillot N. Elaboration par Lactobacillus acidophilus d’un produit actifcontre Candida albicans. Ann Inst Pasteur 1958; 95:194–2076. Young G, Krasner RI, Yudofsky PL. Interactions of oral strains ofCandidaalbicans and lactobacilli. J Bacteriol 1956; 72:525–9

54 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENT7. Virtanen I. Observations on the symbiosis of some fungi and bacteria.Ann MedExp Biol Fenn 1951; 29:352–88. Hummel RP, Maley MP, Miskell PW, Altemeier WA.Suppression ofCandidaalbicans by Escherichia coli. J Trauma Injury Infect Crit Care 1975;15:413–189. Hummel RP, Oestreicher EJ, Maley MP, Macmillan BG. Inhibition ofCandidaalbicans by Escherichia coli in vitro and in germfree mouse. J SurgRes 1973; 15:53–810. Hipp SS, Lawton WD, Chen NC, Gaafar HA. Inhibition of Neisseriagonorrhoeae by a factor produced by Candida albicans. Appl Microbiol1974; 27:192–611. Hilton AL, Warnock DW. Vaginal candidiasis and the role of thedigestive tract as a source of infection. Br J Obstet Gynecol 1975; 82:922–612. Sinski JT, Kelley LM, Reed GL. Pagano—Levin Candida testmedium: evaluation using vaginal samples. /Clin Microbiol 1975; 1:206–1113. Lindner JG, Plantema FH, Hoogkamp—Korstanje JA. Quantitativestudies of the vaginal flora of healthy women and of obstetric andgynecological patients. / Med Microbiol 1978:11:233–4114. Barlett JG, Polk BF. Bacterial vaginal flora of the vagina. Quantitativestudy. RevInf Dis 1964; 6(Suppl 1 1):S57–7215. Haefner HK. Current evaluation and management of vulvovaginitis.Clin ObstetGynecol 1999 ;42:184–9516. Sobel JD, Faro S, Force RW, et alVulvovaginal candidiasis:epidemiologic, diagnostic, and therapeutic considerations. Am J ObstetGynecol 1998; 178:203–1117. Geiger AM, Foxman B, Gillespie BW. The epidemiology ofvulvovaginal candidiasis among university students. Am J Public Health1995; 85:1146–818. Sobel JD. Vaginitis. NEngl J Med 1997;337:1896–90319. Horowitz BJ, Edelstein SW, Lippman L. Sexual transmission ofCandida. ObstetGynecol 1987; 69:883–620. Ferris DG, Dekle C, Litaker MS. Women’s use of the over-thecounterantifungal medications for gynecologic symptoms. J Fam Prac1996; 42:595–60021. Nyirjsey P, Seeney SM, Grody MH, Jordan CA, Buckley HR. Chronicfungal vaginitis: the value of cultures. Am J Obstet Gynecol 1995; 173:820–3

VULVOVAGINAL CANDIDIASIS 5522. Anonymous. 1998Guidelines for treatment of sexually transmitteddiseases. Centers for Disease Control and Prevention. MMWR MorbidMortal Wkly Rep 1998; 47(RR-1):1–11123. Sobel JD. Management of recurrent vulvovaginal candidiasis withintermittent ketoconazole prophylaxis. Obstet Gynecol 1985:65:435–4024. O’Conner MI, Sobel JD. Epidemiology of recurrent vulvovaginalcandidiasis: identification and strain differentiation of Candida albicans.J Infect Dis 1986; 154:358–6325. Milne JD, Warnock DW. Effect of simultaneous oral and vaginaltreatment on the rate of cure and relapse in vaginal candidosis. Br JVener Dis 1979; 55:362–526. Odds FC. Genital candidosis. Clin Exp Dermatol 1982; 7:345–5427. Odds FC, Abbott AB. A simple system for the presumptiveidentification of Candida albicans and differentiation of strains withinthe species. Sabouraudia 1980; 18:301–1728. Miles MR, Olsen L, Rogers A. Recurrent vaginal candidiasis.Importance of an intestinal reservoir. J Am Med Assoc 1977; 238:1836–729. Sobel JD. Epidemiology and pathogenesis of recurrent vulvovaginalcandidiasis. Am J Obstet Gynecol 1985; 152:924–3530. Hilton E, Isenbergver HD, Alperstein P, France K, Bornstein MT.Ingestion of yogurt containing Lactobacillus acidophilus as prophylaxis forcandidal vaginitis. Ann Intern Med 1992; 116:353–731. Caruso LJ. Vaginal moniliasis after tetracycline therapy. Am J ObstetGynecol 1964; 90:374–932. Oriel JD, Waterworth PM. Effects of minocycline and tetracycline onthe vaginal yeast flora. /Clin Pathol 1975; 28:403–633. Savage DC. Microbial interference between indigenous yeast andlactobacilli in the rodent stomach. /Bacteriol 1969; 98:1278–8334. Rodin P, Kolator B. Carriage of yeasts on the penis. Br Med J 1976; 1:1123–435. Thin RN, Leighton M, Dixon MJ. How often is genital yeast infectionsexually transmitted ?Br Med J 1977; 2:93–436. Davidson F. Yeasts and circumcision in the male. Br J Vener Dis 1977;53:121–237. Romero-Piffiguer MD, Vucovich PR, Riera CM. Secretory IgA andsecretory component in women affected by recidivant vaginalcandidiasis. Mycopathologia 1985; 91:165–7038. Witkin SS. Immunology of recurrent vaginitis. Am J Reprod Med 1987;15:34–7

56 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENT39. Kaye WA, Adri MN, Soeldner JS, et alAcquired defect ininterleukin-2 production in patients with type 1 diabetes mellitus. NEngl J Med 1986; 315:920–440. Seelig MS. Mechanisms by which antibiotics increase the incidence andseverity of candidiasis and alter the immunological defenses. BacteriolRev 1966; 30:442–5941. Purtilo DT, Hallgren HM, Yunis EJ. Depressed maternal lymphocyteresponse to phytohaemagglutinin in human pregnancy. Lancet 1972; 1:769–7142. Hobbs JR, Brigden D, Davidson F, Kahan M, Oates JK Immunologicalaspects of candidal vaginitis. Proc R Soc Med 1977; 70 [Suppl 4] :11–443. Witkin SS, Yu IR, Ledger WJ. Inhibition of Candida albicans inducedlymphocyte proliferation by lymphocytes and sera from women withrecurrent vaginitis. Am J Obstet Gynecol 1983:147:809–1144. Witkin SS, Hirsch J, Ledger WJ. A macrophage defect in women withrecurrent Candida vaginitis and its reversal in vitro by prostaglandininhibitors. Am JObstet Gynecol 1986; 155:790–545. Auger P, Joly J. Microbial flora associated with Candida albicansvulvovaginitis. Obstet Gynecol 1980; 55:397–40146. Narayanan TK, Rao GR. Beta-indoleethanol and beta-indolelactic acidproduction by candida species: their antibacterial and autoantibioticaction. Antimicrob Agents Chemother 1976; 9:375–8047. Sobel JD, Myers PG, Kaye D, Levison ME. Adherence of Candidaalbicans to human vaginal and buccal epithelial cells. J Infect Dis 1981;143:76–8248. Handa VL, Stice CW. Fungal culture findings in cyclic vulvitis. ObstetGynecol 2000; 96:301–349. Parazzini F, DiCintio E, Chiantera V, Guaschino S. Determinants ofdifferent Candida species infections of the genital tract in women.Sporachrom Study Group. European J Obstet Gynecol Repro Biol 2000;93:141–550. O’Conner MI, Sobel JD. Epidemiology of recurrent vulvovaginalcandidiasis: identification and strain differentiation of Candida albicans.J Infect Dis 1986; 154:358–6351. Evans WK, Shepherd FA, Feld R, Mullis B. Nystatin lozenges: auseful treatment for oral candidiasis in cancer patients. Cur Therap Res1987; 42; 1201–952. Bauters TG, Dhont MA, Temmerman MI, Nelis HJ. Prevalence ofvulvovaginal candidiasis and susceptibility to fluconazole in women.Am J Obstet Gynecol 2002; 187:569–74

VULVOVAGINAL CANDIDIASIS 5753. Spinillo A, Nicola S, Michelone G, et alFrequency and significance ofdrug resistance in vulvovaginal candidiasis. Gynecol Obstet Invest 1994;38:130–354. Guaschino S, De Seta F, Alberico S, et al.Efficacy of maintenancetherapy with topical boric acid in comparison with oral itraconazole inthe treatment of recurrent vulvovaginal candidiasis. Am J ObstetGynecol2001; 184; 598–602

6.TRICHOMONIASISINTRODUCTIONIn 1836, Donné described the protozoan Trichomonas vaginalis 1 . In1936 Hohne demonstrated the relationship between the presence of T.vaginalis in the vagina and symptoms localized to the vagina, such asincreased vaginal discharge. In 1940, Trussell and Plass inoculated thevaginas of healthy volunteers with pure cultures of T. vaginalis andestablished acute symptomatic vaginitis 1 . This fulfilled Koch’spostulates 2 . In 1947, Trussell published a monograph on T. vaginalisdescribing infection of the lower genital tract 3 . Subsequent to thework of Trussell, T. vaginalis has been the subject of intense studybecause of the suspected related infectious complications associatedwith vaginal trichomoniasis, including premature labor, prematurerupture of amniotic membranes (PRAM), postoperative pelvicinfections, and salpingitis.Although effective antimicrobial therapy (metronidazole) has beenavailable in the United States since 1963, urogenital trichomoniasiscontinues to be one of the world’s most prevalent sexuallytransmitted diseases (STD). This is because the patients can have eitherasymptomatic infection or the presence of persistent and chronicrecurring infection. In rare instances, the patient may be allergic tometronidazole. The absence of effective alternatives to be used inthese patients can result in the failure to eradicate the trichomonads.Finally, the emergence of T. vaginalis strains resistant tometronidazole, although rare, has been documented 4 . Trichomonadsthat parasitize humans are unique because each species occupies a

TRICHOMONIASIS 59specific anatomical site in the host. Each species also has a distinctstructure, function, and relationship with its host. T. vaginalis adaptedto the vaginal environment of pregnant women, and infection duringpregnancy is associated with an increase in the severity of symptoms,but the reason for this increase in symptomatic infection has not beendefined. T. vaginalis has been recognized for decades as a significantvaginal pathogen and continues to be a perplexing problem. Thelifecycle of this organism has not been delineated, while thepathophysiology of symptomatic and asymptomatic infection is notunderstood. A significant area yet to be elucidated is the interaction ofT.vaginalis with endogenous microbes of the lower genital tract. Isthere a relationship between T. vaginalis and other microbes withregard 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? Whilevaginitis and vaginosis are the most common problems thegynecologist addresses in the ambulatory setting, the incidence oftrichomoniasis appears to have decreased in the United States andScandinavia 5 . In 1995, the World Health Organization estimated thatthere were 170 million cases of trichomoniasis in the world 6 .MICROBIOLOGYThere are three species of Trichomonas: T. tenax, T. vaginalis, and T.faecalis. These organisms belong to the order Trichomonadida and thefamily Trichomonadidae. T. vaginalis, a common urogenital pathogen,is the most investigated of all the trichomonads. The morphology ofT. vaginalis is influenced by the physiologic conditions of theurogenital organs. The pH, temperature, oxygen concentration,availability of nutrients and ionic concentration of themicroenvironment, and the vaginal ecosystem, are all important fordetermining the structural configuration of the organism. When T.vaginalis is grown in pure culture, the morphology tends to be pearshapedor oval 7 (Figure 13). The organism has five flagella: four aredistinct and can be observed at its anterior end while the fifth is partof the undulating membrane 8 . When environmental conditionsbecome unfavorable, the organism assumes a spherical form. Thisstage is considered to be a pseudocyst; however, some investigators

60 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTbelieve that these are degenerative forms because when theenvironmental conditions that favor survival of the trichomonadsreturn, the pseudocysts do not regenerate into viabletrichomonads 9 , 10 .Trichomonads also have the ability to adhere to squamousepithelial cells lining the vagina via the axostyle that originates at thenucleus and longitudinally traverses the parasite. Axostyles penetratethe posterior aspect of the parasite and terminate in a sharp point thatpermits the parasite to attach to the epithelial cells lining the vagina 11 .When viewing T. vaginalis using light microscopy, it is common tosee granules within the parasite. These granules are intracellularorganelles that have been shown to be catalase negative 11 . Thesestructures produce molecular hydrogen and have been namedhydrogenosomes, and they play an important role in the metabolism ofthe organism 12 . The hydrogenosomes function as mitochondria 13 . Afeature that sets T. vaginalis apart from other trichomonads is thepresence of three parallel rows of hydrogenosomes along the axostyle.In addition to hydrogenosomes, glycogen granules can also beobserved within the parasite. T. vaginalis also contains otherorganelles, such as lysosome-like organelles, for examplephagosomes 14 – 17 .As stated above, the physiologic condition of the vagina influencesthe structural configuration and morphology of T. vaginalis, so it isimportant to recognize that the vaginal ecosystem exists in a delicateand dynamic equilibrium. Indeed, the vaginal ecosystem is extremelycomplex and not very well understood. It appears that this delicatebalance is not solely dependent on host factors, but also is dependentupon the symbiotic or commensal relationship between the host andthe endogenous microbes of the vagina. The interactions between themicrobes, metabolic and immune status of the host, and factors fromthe 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 becomesapparent to the physician when treatment of T.vaginalis vaginitis isunsuccessful.When an organism, such as T. vaginalis, is introduced into thevaginal ecosystem it may develop a symbiotic or commensal

TRICHOMONIASIS 61relationship, where it exists in harmony with a host, or it may notdevelop a foothold and thus be eradicated by the host. It may alsoalter the ecosystem by creating an environment that allows it toflourish. It is generally accepted that 25–50% of women withtrichomoniasis are asymptomatic, and that the trichomonas hasreached such a harmonic existence with the vaginal ecosystem. It is asthough the trichomonads have adapted to the vaginal ecosystem andcan coexist; the relationship of the protozoan with the host when inthe asymptomatic state is therefore symbiotic or commensal. Thenumbers of trichomonads must be maintained below a significantthreshold that will prevent the ecosystem from shifting to a state thatwould be more favorable for the trichomonads, and would permitthem to flourish and become the dominant organism in theecosystem. When a shift in the vaginal environment that favors thesurvival of the trichomonads occurs, trichomonas evolves to anantagonistic state with the lactobacilli and other commensal bacteria.In a healthy vaginal ecosystem, the non-pathogenic bacteria aredominant members of the microflora of the vagina, with lactobacilli asa predominant member. Lactobacilli exert their dominance throughthe production of lactic acid, hydrogen peroxide, and bacteriocin.Through these factors, lactobacilli are able to suppress the growth of allother bacteria within the ecosystem and maintain dominance. Ifconditions that permit T. vaginalis to flourish evolve, growth of thepathogenic bacteria is favored and this results in the suppression ofLactobacillus spp., as well as other non-pathogenic bacteria.T. vaginalis appears capable of assuming different forms within thevagina (Figures 14 and 15). Although the lifecycle of T. vaginalis hasnot been elucidated, the organism has been observed to divide inculture. Both oversized and undersized forms with and withoutflagella have been observed. Forms have also been identified with adividing nucleus and with multiple nuclei. These various forms areconsidered present in response to unfavorable growth conditions anddifferent stages in the lifecycle 11 . These interpretations have beenquestioned and the various forms may represent stages in thedevelopment of mononuclear flagellated organisms 18 , 19 . It is thesevarious forms that may be present in patients who have been treatedbut which go undetected when the vaginal discharge is examinedmicroscopically. Thus, the patient is considered adequately treated

62 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTbut, in reality, the organism has been merely ‘suppressed’. Once theantiparasitic agent is removed from the vaginal environment, theorganism resumes its infection state after a suitable recovery period.Microscopic examination of vaginal fluid from patients on antiparasitictherapy also often fails to reveal the presence of the so-called ‘cystic’form of the organism. When therapy is complete, the cystic form maypersist. If the vaginal fluid is not cultured for trichomonads, thepatient may harbor the parasite, and when conditions favorable to thegrowth of the trichomonads return, so does the infection.T. vaginalis can be cultured in Diamond’s medium, which providesall the nutritional requirements of the obligate parasite 20 – 22 .Themacromolecules that T. vaginalis requires in vivo, especiallypurines, pyrimidines, and lipids, are provided in the vaginalenvironment via phagocytosis of host and bacterial cells 23 , 24 .Diamond’s medium (TYI-33) is a nutrient broth containingtrypticase, yeast extract, iron, fetal bovine serum, and a vitamin–107-Tween 80 complex 25 . Diamond’s medium is commercially availableand suitable for use in the physician’s office to culture T. vaginalis fromthe vagina. The physician can simply swab the vagina, place the swabinto the Diamond’s medium, and swirl the swab vigorously forseveral seconds. The swirling action liberates the trichomonads fromthe swab so it can be removed and discarded. The culture can then beincubated in an ambient air incubator or held at room temperature.Microscopic examination of a drop of culture fluid will reveal thepresence of trichomonads.EPIDEMIOLOGYIt is estimated that there are 170 million cases of vaginaltrichomoniasis in the world each year 26 . It is also estimated that eachyear 3 million cases of vaginal trichomoniasis occur in the UnitedStates alone 26 . While T. vaginalis has not been implicated in uppergenital tract infections to the degree that Chlamydia trachomatis andNeisseria gonorrhoeae have, it has been associated with PID, humanimmunodeficiency virus (HIV) infection, and adverse pregnancyoutcome.Moodley and co-workers 27 found that women with HIV andvaginal trichomoniasis had a significantly higher risk of developing PID

TRICHOMONIASIS 63than HIV-negative women infected with T. vaginalis. Theseinvestigators studied 577 women who complained of vaginal dischargeand 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 thatthere was no association between HIV and PID (p = 0.6) 27 .Interestingly, these investigators found that the prevalence of STDwas high in this study population; however, the only statisticallysignificant sexually transmitted organism was T. vaginalis. Theprevalence of N. gonorrhoeae in all study participants was 12% (p = 0.067), while the prevalence of C. trachomatis (p = 0.8) and T. vaginalisp = 0.03) was 11 and 29% respectively. A 69% prevalence (p = 0.7)of bacterial vaginosis (BV) was also reported. In women not infectedwith HIV, but either complaining of vaginal discharge or diagnosedwith 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 beenviewed 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 birthof a low-birth-weight infant 28 – 30 . Several authors have attempted todemonstrate poor pregnancy outcome in women with T. vaginalisvaginitis. However, Klebanoff and co-workers 31 were unable todemonstrate a beneficial effect—prevention of preterm delivery—oftreating asymptomatic T. vaginalis vaginitis in pregnant women.T. vaginalis is a fastidious protozoan that depends on its host forsurvival; it cannot survive outside the host. The lack of knowledgeabout the T. vaginalis life cycle makes it difficult to understand howthe organism is able to survive in unfavorable conditions. The absenceof a cyst or spore stage should make it difficult for the protozoan tosurvive exposure to desiccation, high temperature, or unfavorablehydrogen ion concentrations. However, when the organism is outsidethe confines of the host, it can survive if the humidity of theenvironment is sufficient to prevent desiccation. The protozoan hasbeen isolated from baths, and poorly chlorinated water in whirlpools,hot tubs, and swimming pools 32 , 33 . Interestingly, studies demonstratethat T. vaginalis can survive in vaginal exudates, outside the vagina, at

64 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENT10°C for up to 48 h 33 . The organism has also survived up to 3 h inurine, and up to 6 h in ejaculated semen 34 . The protozoan has alsobeen found to survive in moist washcloths at a temperature of 35°C 35 , 36 . One-third of washcloths contaminated with T. vaginalis werefound to contain viable trichomonads after up to 3 h, and 10% hadviable protozoans up to 24 h following contamination 36 . In one study,37% of women with vaginal trichomoniasis left contaminated urine ontoilet seats after voiding, and 36% of the samples contained viabletrichomonads. Toilet seats seeded with vaginal exudates containingviable trichomonads were found to have viable organisms up to 45min following deposition of the contaminated fluid 37 , 38 . Although thisevidence suggests that T. vaginalis can exist outside the host for briefperiods, there has not been confirmation that the protozoan can betransmitted via non-sexual contact. Therefore, it is generally acceptedthat transmission and acquisition of T. vaginalis is primarily, and almostexclusively, through sexual intercourse or sexual contact between acontaminated or infected individual and a non-infected individual 37 , 38 .Transmission of T. vaginalis can occur between lesbian couples viamutual masturbation. This occurred in a couple reported to be in amonogamous relationship who did not have sex with males. They alsodid not use sexual instruments, for example penetratinginstruments 40 . This does raise the question of whether a previouspartner was bisexual and transmitted the infection. Infecteddischarge, or discharge containing trichomonads, can be transmitted viaany carrier.Transmission to newborn infants may occur during the birthingprocess as the infant passes through the birth canal. There have beenthree cases of T. vaginalis pneumonia in newborn infants and no otherpathogen was recovered from these infants 41 , 42 .The number of sexual partners that an individual is exposed to isdirectly related to their risk of contracting trichomoniasis. This, inturn, is related to the number of individuals infected with T. vaginaliswithin the pool of contacts. The age group at greatest risk foracquiring trichomoniasis is between 20 and 30 years of age, which isalso the age group that participates in the greatest frequency ofheterogenous sexual activity. However, unlike gonorrhea andchlamydia which tend to decrease in frequency as the population ages,the frequency of trichomoniasis infection tends to increase in women

TRICHOMONIASIS 6530–40 years of age 35 , 43 . The greatest risk factors for acquiringtrichomoniasis are: race, use of contraceptives other than condoms,and a history of STD. African-American women are at a greater riskfor trichomoniasis than Hispanic or Caucasian women. Thisalso appears to be true for N. gonorrhoeae infection 35 , 43 . Individualsnot using contraceptive pills are two times as likely to acquiretrichomoniasis than individuals who use them 44 , 45 .Males appear to serve as asymptomatic carriers and are both animportant vector and reservoir for transmission to their sexualcontacts or partners. It has been hypothesized that the male may besymptomatic and present as though he has non-gonococcal, nonchlamydialurethritis or prostatitis 46 – 48 . Inonestudy T. vaginalis wasisolated from 50 of 447 males evaluated at an STD clinic 49 . Theprotozoan was also isolated from nine (17%) of 52 males who hadsexual contact with women known to have vaginal trichomoniasis.The males usually became symptomatic within 24 h following contactwith an infected sexual partner. A total of 27 of 52 (52%) infected maleshad symptoms of urethritis 49 . A pure trichomonal infection in themale produces a clear-to-slight purulent urethral discharge.PATIENT EVALUATION AND DIAGNOSISTrichomoniasis may be asymptomatic or symptomatic. It is estimatedthat 25–50% of women infected with T. vaginalis are asymptomaticand have a vaginal pH less than 4.5 50 . Interestingly, approximately 33–35% of women with asymptomatic infection or colonization developsymptomatic infection within 6 months 51 . When introduced into thevagina, T. vaginalis has an incubation period of 4–28 days inapproximately 50% of infected individuals 52 . Once in the vaginalenvironment, T. vaginalis can induce an acute infection, a chronicinfection, or establish an asymptomatic state. Once in the vaginalenvironment, the parasite must interact with host factors and theendogenous vaginal microflora. If an asymptomatic state is to beestablished, the organism must develop a symbiotic or perhapscommensal relationship. Therefore, the numbers of trichomonadsmust be kept below a crucial threshold so they will not alter theequilibrium of the vagina, thereby allowing Lactobacillus spp. tomaintain dominance. As long as these conditions are maintained,

66 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTtrichomonads will go unnoticed and undetected. If an infection, likeknown exposure, is suspected, culture of the vaginal discharge shouldreveal the presence of T. vaginalis.Patients with acute T. vaginalis infection typically have a copiousyellow or green to dirty gray discharge. Patients with bothtrichomoniasis and BV often complain of a foul vaginal discharge. Inmany cases they often present with significant vulvar erythema andswelling. Acute infection is often accompanied by the presence ofpetechial hemorrhages on the vaginal epithelium. Approximately 2%of patients with acute cervical-vaginal infection will havepetechial hemorrhages in the vaginal and cervical epithelia 53 . Thepatient’s symptoms tend to worsen during their menses.Patients with chronic infection usually have mild symptoms with ascant discharge, but they can also have a copious discharge. Thesymptoms are usually pruritus and dyspareunia. Since the patient withchronic infection may be asymptomatic, or have mild symptoms, thedisease goes undetected and this group of patients serves as a vectorfor transmission of the disease 54 .T. vaginalis infection is not restricted to the vagina and cervix; itcan also involve the entire urogenital tract. Trichomonas infection cancause a Bartholin’s gland abscess, salpingitis, pyosalpinx,endometritis, and infertility, and is also associated with an increase inHIV transmission 55 – 59 . Because trichomoniasis in the male is usuallyasymptomatic, they serve as an important vector in the transmissionbecause they carry the protozoan and can readily transmit theorganism to a sexual partner. Although usually asymptomatic,infection in the male can be mildly symptomatic or acute. Theasymptomatic carrier is only identified after his sexual contact isinfected, while the male with an acute symptomatic infection usuallydevelops profuse urethritis characterized by a clear to mucopurulentdischarge, dysuria, mild pruritus, or burning immediately followingsexual intercourse 60 . Complications associated with trichomoniasis inwomen are non-gonococcal, non-chlamydial urethritis.The patient with symptomatic vaginal trichomoniasis typicallypresents with a malodorous discharge. The color of the discharge canvary from green to dirty gray and is typically liquid in consistency.The discharge may be frothy or non-frothy, and patients can reportitching, soreness, and dyspareunia. The vaginal epithelium may be

TRICHOMONIASIS 67spotted by petechial hemorrhages, which will appear on the cervix in2% of cases. This is referred to as a ‘strawberry cervix’. Cliniciansshould not rely solely on the clinical presentation because other STDscan present with similar findings, and the frothy discharge is seen inonly 12% of patients with trichomoniasis 35 , 53 , 61 – 63 . Using solelyclinical criteria to establish the diagnosis of trichomoniasis willcorrectly identify only 12% of infected patients 51 .The diagnosis of trichomoniasis vaginitis is usually established byidentifying motile trichomonads on microscopic examination ofvaginal discharge. However, this method is not very accurate anddepends on the observer’s experience. Identification by microscopicexamination of vaginal fluid infected with T. vaginalis has a sensitivitybetween 38 and 82% 64−66 .At the present time, the gold standard for establishing atrichomoniasis diagnosis is a broth culture. This will be the case until apolymerase chain reaction (PCR) test becomes commerciallyavailable. The disadvantage of using broth culture in a clinical settingis that it takes 2–7 days incubation period for the culture to becomepositive 53 , 67 . This delay allows the patient to transmit the disease ifshe is left untreated during the time the culture is incubated.The Papanicolaou stain (Pap smear) does offer a reliable method todiagnose because it is commonly used in gynecology. However, thereis approximately a 48% error rate in diagnosis because of falsepositiveand false-negative reports 68 .To establish a diagnosis of vaginal trichomoniasis, a characterizationof the vaginal discharge should be conducted. The discharge should becharacterized by its color, consistency, and the presence of gas(froth), and should be whiffed before and after mixing with KOH, todetermine if it has an odor. The vaginal pH should be determined andif it is above 4.5, a microscopic examination of the vaginal dischargeshould be performed. A cotton- or Dacron-tipped swab should beused to obtain a specimen from the lateral vagina. The swab shouldthen be placed in 2 ml of saline and agitated vigorously, then removedand discarded. One to two drops of the diluted discharge should thenbe examined under 40x magnification. The observer will noteestrogenized squamous epithelial cells, more than five white bloodcells (WBC) per high-power field (hpf), a variety of bacterialmorphotypes, and the presence of motile (flagellated) ovoid shaped

68 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTprotozoans. If protozoans are not seen then the discharge should becultured.The presence of numerous WBC, a variety of bacterialmorphotypes, a pH above 4.5, and a malodorous or fish-like smellingdischarge indicates the presence of both BV and an accompanyinginfection. The presence of numerous WBC, in fact more than five per40x magnification, is highly suggestive of either an infection or anaccompanying inflammatory process. This finding should be theimpetus for the physician to begin screening for genital tractinfection. The patient’s cervix should be sampled for the presence ofC. trachomatis and N. gonorrhoeae. Other STDs to be considered areHerpes Simplex virus (HSV) and Human Papillomavirus (HPV). Thepresence of WBC in the vaginal discharge, and the failure to detect apathogen when examining the vaginal discharge microscopically,should also lead the physician to obtain a vaginal specimen for theculture of T. vaginalis.One common dilemma confronting all physicians is the presence ofWBC in the vaginal discharge but no detectable pathogen when thedischarge is examined microscopically. Since the most commonmethod of diagnosing vaginal trichomoniasis is by microscopicexamination of an un-dyed specimen of vaginal discharge, thepresence of trichomonads is often undetected. Currently there isno commercially available rapid method of detection that has both ahigh degree of sensitivity and specificity. (Sensitivity is defined as thepercentage of culture-positive specimens identified as positives bymicroscopy or other tests, while specificity is defined as thepercentage of culture-negative specimens identified as negative bymicroscopy or other tests.) Using the characteristics of the vaginaldischarge is not associated with a high degree of sensitivity orspecificity. Approximately 50% of women with a dischargecharacteristic of trichomoniasis are not infected 53 , 69 . The specificityand sensitivity of microscopic examination compared with culture todetermine if the patient has vaginal trichomoniasis has been reportedto range from 96 to 100% and 38 to 82%, respectively 68 , 70 .However, Robertson and co-workers 71 did not confirm the highspecificity with microscopy reported by others. They compared thestandard wet prep with a centrifuged specimen examined under phase

TRICHOMONIASIS 69contrast microscopy with culture and could not confirm ten of 44 wetprep specimens identified as positive by standard light microscopy.In an attempt to enhance the accuracy of establishing the correctdiagnosis of vaginal trichomoniasis, the Gram stain has been used.Cree 72 detected T. vaginalis in only 66% of 249 individuals withculture-proven infection. Cree also reported a false positive rate of7%. However, Sorbrepena 73 was able to identify T. vaginalis in twiceas 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 microscopicexamination of vaginal discharge for the detection of trichomoniasis,the Pap smear was found to be inferior. In this study, 126trichomoniasis infections were diagnosed on Pap smear but could notconfirmed by other methods 73 . Perl studied 1199 patients and found666 to be positive for trichomoniasis on Pap smear but only 37%could be confirmed by culture 68 .New methodology is constantly being developed that will improvethe 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 apractical clinical application is one that can produce reliable resultswithin 5–10 min and is not expensive. If the test cannot yield resultswhile the patient is being evaluated, then the test is not particularlyuseful. Microscopic examination of a diluted specimen of vaginaldischarge (the wet prep) continues to be a fairly reliable method fordiagnosing abnormalities of the lower genital tract with regard to thevaginal ecosystem. One group of investigators 75 found that examiningthe vaginal discharge microscopically at the time a Pap smear isobtained proved to be beneficial in the management of the patient andreduced the need for repeat Pap smears, except for the managementof cellular abnormalities. These investigators also found that thepresence 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 fordiagnosing trichomoniasis is based on the belief that: (1) many

70 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTphysicians do not examine the vaginal discharge microscopically; (2)many physicians lack the experience to perform a thoroughexamination of vaginal discharge; and (3) examination of the vaginaldischarge is too time consuming. A significant amount of informationcan be gained from a thorough evaluation of the vaginal discharge butunfortunately this simple examination is frequently not performed.TREATMENTThe standard treatment for uncomplicated T. vaginalis vaginitis is oralmetronidazole. Oral, or in rare instances parenteral, metronidazole ispreferred to intravaginally administered metronidazole because thetrichomonads commonly infect other sites in the lower genital tract.Successful treatment of the infected woman also depends uponremoving 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 infectedpenile or vaginal discharge from coming in contact with the partner’sgenitalia.Management of the sexual partner is of paramount importance ifthe patient under treatment is to be cured of her infection. All peoplewho have come into contact with the infected patient should betreated, and if possible treatment should occur simultaneously amongall potentially infected individuals. If this cannot be accomplished, thepatient in question should refrain from sexual intercourse until herpartner or partners can be treated. If the woman’s partner takesmetronidazole and the woman is shown to be cured of her infection,but subsequent to having sexual intercourse becomes infected, then itcan be assumed that her partner may have a prostate infection. Ofcourse, this is based on the following: (1) she has not had sexualintercourse with a different partner; (2) he has not had sexualintercourse with a different partner; and (3) he has taken a full courseof therapy. Males who develop trichomoniasis of the prostate glandrequire a prolonged course of metronidazole treatment. Prostateinfection with T. vaginalis was first demonstrated in 1936 in expressedprostatic fluid obtained from husbands of women infected with T.vaginalis 76 . Isolation of trichomonads from men who have had sexualintercourse with women infected with T. vaginalis ranges from 9 to

10% 77 , 78 . Interestingly, in males diagnosed with urethritis but failingto respond to several courses of antibiotics not active against T.vaginalis, 85% were subsequently found to be infected with theprotozoan 79 , 80 . However, one difficulty with these studies was thatthe 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 itis often difficult to document the presence of a protozoan. Severalstudies have demonstrated the presence of T. vaginalis inasymptomatic husbands and the sexual partners of infectedwomen 35 , 81 , 82 . In one investigation, 30 husbands of infected womenwere cultured; 60% of the husbands were found to be positive for T.vaginalis and 61% of the males were asymptomatic 83 . The percentageof male sexual contacts of infected women who subsequently developsymptomatic urethritis and are found to be positive for T. vaginalisranges from 16 to 83% 84 .Sexual partners treated simultaneously may not respond in asimilar manner. The trichomonads present in all infected tissue maynot all be killed, and adequate levels of metronidazole may not beachieved in sufficient concentration in all infected tissues. The maleinfected with T. vaginalis possesses significant problems, for example,treating the infected prostate gland is often difficult and requiresprolonged administration of metronidazole. Infection in the male mayinvolve various sites, like the epididymis, posthitis (infection of theforeskin), balanitis (infection of the glans penis), and may result indraining sinus of the median raphe 37 , 42 , 85 – 89 . Infection in males alsoappears to occur easily. In 1963 Weston and Nicol 90 examined malesexual partners 2 days after being exposed to infected females andrecovered T. vaginalis from 70% of the males. Interestingly, increasingthe time between sampling of the male and exposure correlated witha decrease in recovery rate of the protozoan. Only 30% of theexposed males had positive T. vaginalis cultures when sampled 14 daysafter exposure to an infected female. Thirty days following exposure,only 23% of the males remained positive and subsequent examinationfailed to recover trichomonads. T. vaginalis in males can besummarized thus:(1)symptomatic infection is common;TRICHOMONIASIS 71

72 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENT(2)males exposed to infected females should be consideredcolonized, whether symptomatic or asymptomatic;(3)symptomatic male infection is typically diagnosed as urethritisand these individuals typically have a purulent discharge; and(4)prostatitis is uncommon.Thus, a physician responsible for the health of women shouldremember that all women with documented vaginal trichomoniasisshould be considered a vector for the transmission of T. vaginalis.Finally, when treating a woman for vaginal trichomoniasis it isimperative that her sexual partners be treated, whether they aresymptomatic or not.The only anti-trichomonal agent approved for use in the UnitedStates is metronidazole, which was approved for use in 1963. Anazomycin, a nitroimidazole drug, isolated from a species ofStreptomyces lead to the discovery of synthetic agents that have activityagainst T. vaginalis. Metronidazole was one of these agents and it wassubsequently found to have activity against Giardia lamblia, and canalso be used in the treatment of amebiasis 90−92 . Theanaerobic activityof metronidazole was discovered accidentally: a woman was treatedwith metronidazole for vaginal trichomoniasis and she was also knownto have acute ulcerative gingivitis that simultaneously responded tothe treatment for vaginal trichomoniasis 93 . Davis and co-workers 94confirmed that metronidazole was effective in the treatment ofVincent’s stomatitis and the drug inhibited Fusobacteriumnecrophorum 94 , 95 .Nitroimidazole available in countries other than the United Statesare: nimorazole (Nagogin ® ), tinidazole (Fasigyn ® ), ornidazole,secnidazole, carnidazole, and misonidazole 96 , 97 . Tinidazole is similarto metronidazole in its spectrum of activity against parasites andobligate anaerobic bacteria. The minimum trichomonicidalconcentration is lower than that for metronidazole 98 , 99 . T. vaginalisresistant to metronidazole are usually resistant to tinidazole, but therehave been reports of strains resistant to the former agent but sensitiveto tinidazole 100 , 101 .Metronidazole, when taken orally, is almost completely absorbedby the gastrointestinal tract and approximately 95% of thisantimicrobial agent is bioavailable. The serum half-life is

TRICHOMONIASIS 73Table 14 Adverse effects of metronidazoleapproximately 8.5 h 102 . Peak serum levels are reached 1–3 h afteroral administration. If metronidazole is taken after a meal, absorptionis delayed and peak serum levels are not reached for 3 h 102 , 103 .Metronidazole is metabolized by the liver into at least five differentmetabolites 104 . Approximately 20% of the daily dose is excreted inthe urine and feces. Studies have demonstrated small amounts ofmutagenic derivatives and an acetamide have been found in the urineof patients receiving metronidazole 105 . When metronidazole isadministered vaginally as a cream or suppository, absorption occurswith 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 asopposed to a suppository 106 . Adverse effects associated withmetronidazole are listed in the Table 14.Patients receiving metronidazole therapy should be stronglyadvised not to imbibe alcoholic beverages, or take medicationcontaining alcohol, because they may develop severe abdominal pain(a disulfiram-like reaction) 107 . Individuals taking anticonvulsantmedication or warfarin should be warned that metronidazole couldenhance the action of these medications 108 .The standard regimens for trichomoniasis treatment are based onthe 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 achieveadequate serum and tissue levels. The most expedient and inexpensiveroute is oral. The standard dosing regimens are 2 g administered as asingle 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 canbe taken once so compliance is greater. However, this can causeconsiderable gastric distress. When trichomoniasis is diagnosedaccidentally, perhaps by Pap smear, the patient should be examined

74 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTand the diagnosis confirmed. If the patient is not treated, she mayserve as a vector for T. vaginalis transmission and is likely toexperience acute exacerbations of infection. She is also likely todevelop an abnormal Pap smear in the future 108 . If she is treated butdoes not have trichomoniasis, she is being unnecessarily exposed to anantibiotic. If the exposed male is left untreated, he may infectapproximately 24% of the women with whom he has had sexualcontact 109 .Metronidazole has been effective in the treatment of T. vaginalisand most strains are sensitive to concentrations of less than 1–16 ug/ml 110 – 112 . Under normal anaerobic concentrations most strains of T.vaginalis are sensitive to metronidazole at a concentration of 3 μ g/mlor less, and under aerobic conditions sensitivity occurs at aconcentration of 25 μ g/ml or less 113 .Although T. vaginalis has remained relatively sensitive tometronidazole, resistance to this antimicrobial agent has beenreported 114 . In one study, vaginal fluid was obtained from 911women; T. vaginalis was detected in 82 (9%), and two isolates werefound to have a low-level resistance to metronidazole 115 . Someinvestigators have found patients infected with resistant strains but wereable to treat these patients successfully by increasing the dose ofmetronidazole 116 – 119 . Patients who appear to have intractable orresistant trichomoniasis should be managed by first having theorganism isolated and its sensitivity or resistance to metronidazoledetermined. Isolates that have an aerobic minimal lethal dose (MLD)greater than 50 μ g/ml but lower than 200 μ g/ml will be moderatelysensitive; those with an MLD over 200 μ g/ml will be resistant 116 .Thus, patients with moderate sensitivity to metronidazole may besuccessfully treated with a total daily dose of 2–3.5 g per day for 7–14days. Oral and vaginal administration of metronidazole can becombined for treatment. In cases where higher doses of oralmetronidazole cannot be tolerated, the drug can be givenintravenously. Metronidazole doses exceeding 2 g per day can inducenausea, vomiting, gastrointestinal discomfort, headache, peripheralneuropathy, and seizures that usually appear within 72 h of beginningtreatment (Table 15).Patients who continue to demonstrate a failure to respond tometronidazole, even at higher doses, can be treated with tinidazole.

TRICHOMONIASIS 75Table 15 Recommended treatment regimensAlthough tinidazole is not currently available in the United States, itcan be obtained in Canada; however, it is expected that tinidazole willbecome available in the United States in the near future. Sobel and coworkersreported that tinidazole therapy was successful treatment forrefractory trichomoniasis in 22 of 24 patients 120 .Metronidazole and tinidazole are not themselves active or cytocidalagainst T. vaginalis, but their metabolic products are active agents.Metronidazole enters the protozoan through diffusion and is activatedin the hydrogenosomes of the organism 23 , 121 , 122 . The nitro group isreduced anaerobically by the enzyme pyruvate-ferredoxinoxidoreductase 122 . This reaction yields cytotoxic nitro radical-ionintermediates that break DNA strands of the protozoan 123 . Invitrostudies have demonstrated also that the effect of metronidazole onT. vaginalis is rapid, causing cessation of cell division and motility within1 h, while cell death occurs within 8 h of exposure to the drug 124 .TREATMENT IN THE PREGNANT PATIENTSome investigators have attempted to demonstrate an associationbetween T. vaginalis vaginitis, PRAM, and premature delivery 128 , 129 .However, other investigators failed to show any association betweenT. vaginalis vaginitis and poor pregnancy outcome 31 , 130 , 131 . Thus, thesignificance of T. vaginalis vaginitis in pregnant and non-pregnantwomen, especially those who are to have pelvic surgery, most likelyrests in the fact that these women have an altered vaginal microflora.Whether or not T. vaginalis vaginitis has an adverse effect onpregnancy outcome will most likely remain unresolved because thisprotozoan infection is associated with, and probably is responsible for,the alteration in vaginal flora. The shift in vaginal flora can be skewedtowards a Gram-positive, Gram-negative facultative, or obligateanaerobic bacteriology. Significant increases in the pathogenic vaginalendogenous flora can, and does, result in an increased risk for

76 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTpostpartum endometritis and post-hysterectomy pelvic cellulitis andabscess formation. Screening symptomatic pregnant patients by eitherwet mount or culture is beneficial, whereas when asymptomaticpatients were screened, culture (94.5%) proved to be better than wetmount (70%) 132 . These investigators also found that in the inner-citypopulation in Denver, Colorado, 9.4% of 1175 pregnant women hadT. vaginalis vaginitis. Approximately 18.2% of the 110 infectedwomen complained of symptoms consistent with vaginitis 132 . Bothpregnant and non-pregnant women complaining of symptomsassociated with vaginitis should be thoroughly evaluated. However, atthe individual’s first prenatal visit, in an attempt to enhance the patient’sability to maintain the pregnancy, it is in the patient’s best interest toevaluate the vaginal ecosystem. This can be easily done by thephysician determining the vaginal pH. If the pH is 4.5 or higher, a wetprep should be obtained and examined microscopically. The presenceof WBC (> 5/hpf) should be an indication to determine if T. vaginalisinfection 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 nodifferent than treatment of the non-pregnant patient. Struthers 133published a review of metronidazole use in pregnancy overapproximately four decades and found that the drug did not have ateratogenic 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 whodelivered normal babies and 6564 infants with anomalies. Amongthese women, 1083 received metronidazole in the first trimester. Ofthese, 1020 were normal and 63 had some anomaly. The relative riskof an abnormality being associated with metronidazole was 0.92.Pregnant women can be treated safely for trichomoniasis withmetronidazole in the first, second, and third trimesters. However,when administering any therapeutic agent to a pregnant woman therisk-benefit ratio must be determined. An asymptomatic pregnantwoman who’s Pap smear indicates the presence of T. vaginalis shouldbe evaluated to determine if she indeed has vaginal trichomoniasis. Ifthe patient is proven to harbor T. vaginalis, but is asymptomatic, onemay elect to hold off on therapy until the second trimester, but

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82 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENT77. Sylvestre L, Belanger M, Gallai Z. Urogenital trichomoniasis in themale: review of the literature and report on treatment of 37 patientsby a new nitroimidazole derivative (Flagyl). Can Med Assoc J 1960; 83:2295–978. Kawamura N. Trichomoniasis of the prostate. Jpn J Clin Urol 1973; 27:335–4479. Gallai Z, Sylvestre L. The present status of urogenital trichomoniasis.A general review of the literature. Appl Ther 1966; 8:773–880. Fullilove RE Jr. Trichomonas vaginalis in men. J Med Soc NJ1983; 80:94–681. Wilcox RR. Epidemiological aspects of human trichomoniasis. Br JVener Dis 1960; 36:167–7482. Jennison RF. Incidence of Trichomonas vaginalis in marital partners. Br JVenerDis 1960; 36:163–683. Counts WE, Silva-Inzunza B, Tallman B. Genitourinary complicationsof nongonococcal urethritis and trichomoniasis in males. Urol Int1959; 9:189–20884. Kuberski T. Trichomonas vaginalis associated with nongonococcalurethritis and prostatitis. Sex Transm Dis 1980; 7:135–685. Catterall RD. Diagnosis and treatment of trichomonal urethritis inmen. Br J Med J 1960; 2:113–15 13–1586. Wilson A, Ackers JP. Urine culture for the detection of Trichomonasvaginalis in men. Br J Vener Dis 1980; 56:46–887. Watt L, Jennison RF. Incidence of Trichomonas vaginalis infection of themedian raphae of the penis. Br J Vener Dis 1960; 36:163–688. Soendjojo A, Pindha S. Trichomonas vaginalis infection of the medianraphe of the penis. Sex Transm Dis 1981; 8:255–789. Sowmini CN, Vijayalakshmi K, Chellamuthiah C, SundaramSM.Infections of the median raphe. Report of three cases. Br J VenerDis 1973; 49:469–7490. Dural P, Roiron V, Sibulet H, Borel LJH. Trial of an anti-trichomonalderivative of imidazole (8823 R.P.). Comptes Roehdus Soc Franc Gyn1959; 29:36–991. Powell SJ, MacLeod I, Wilmot AJ, Elsdon-Dew R. Metronidazole inamoebic dysentery and amoebic liver abscess. Lancet 1966; II(7477):1329–3192. Schneider J. Treatment of giardiasis (lambliasis) with metronidazole.Bull SocPathol Exot1961; 54:84–893. Shinn DLS. Metronidazole in acute ulcerative gingivitis. Lancet 1962; I:1191–203

TRICHOMONIASIS 8394. Davies AH, McFadden JA, Squires S. Treatment of Vincet’s stomatitiswith metronidazole. Br Med J 1964; 1:114995. Tally FP, Sutter VL, Finegold SM. Metronidazole versus anaerobes. Invitro data and initial clinical observations. Calif Med 1972; 17:22–696. Miller MW, Howes HL, English AR. Tinidazole, a potent newantiprotozoal agent. Antimicrob Agents Chemother 1969; 9:257–6097. Muller M. Action of clinically utilized 5-nitromidazoles onmicroorganisms. Scand J Infect Dis 1981; 26:31–4198. Howes HL Jr, Lynch JE, Kivlin JL.Tinidazole, a new antiprotozoalagent: Effect on Trichomonas and other protozoa. Antimicrob AgentsChemother 1969; 9:261–699. Forsgren A. Wallin J. Tinidazole—a new preparation for Trichomonasvaginalis infections. I. Laboratory evaluation. Br J Vener Dis 1974; 50:146–7100. Sears SD, O’Hare J. In vitro susceptibility of Trichomonas vaginalis to 50antimicrobial agents. Antimicrob Agents Chemother1988; 32:144–6101. Hamed KA, Studemeister AE. Successful response of metronidazoleresistanttrichomonal vaginitis to tinidazole. A case report. Sex TransmDis 1992; 19:339–40102. Houghton GW, Smith J, Thorne PS, Templeton R. Thepharmacokinetics of oral and intravenous metronidazole in man. /Antimicrob Chemother 1979; 5:621–3103. Levison ME. Microbiological agar diffusion assay for metronidazoleconcentrations in serum. Antimicrob Agents Chemother 1974; 5:466–8104. Stambaugh JE, Feo LG, Manthei RW. The isolation and identificationof the urinary oxidative metabolites of metronidazole in man. JPharmacol Exp Ther 1968; 161:373–81105. Stambaugh JE, Feo LG, Manthei RW. Isolation and identification ofthe major urinary metabolites of metronidazole. Life Sci 1967; 6:1811–19106. Alper MM, Barwin BN, McLean WM, McGilveray IJ, Sved S.Systemic absorption of metronidazole by the vaginal route. ObstetGynecol 1985; 65:781–4107. Winter D, Stanescu C, Sauvard S. The effect of metronidazole on thetoxicity of ethanol. Biochem Pharmacol 1969; 18:1246–8108. Koss IG, Wolinksa WH. Trichomonas vaginalis cervicitis and itsrelationship to cervical cancer. Cancer1959; 12:1 171–93109. Watt L, Jennison RF. Incidence of Trichomonas vaginalis in maritalpartners. BrJ Vener Dis 1960; 36:163–70

84 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENT110. Korner B, Jensen HK. Sensitivity of Trichomonas vaginalis tometronidazole, tinidazole, and nifuratel in vitro. Br J Vener Dis 1976;52:404–8111. McFadzean JA, Pugh IM, Squires SL, Whelan JP. Further observationson strain sensitivity of Trichomonas vaginalis to metronidazole. Br JVener Dis 1969; 45:161–2112. Nielsen R. Trichomonas vaginalis. II. Laboratory investigations intrichomoniasis. Br J Vener Dis 1973; 49:531–5113. Ralph ED, Darwish R, Austin TW, Smith EA, PattisonFL.Susceptibility of Trichomonas vaginalis strains to metronidazole:response to treatment. SexTransm Dis 1983; 10:119–22114. Robinson SC. Trichomonal vaginitis resistant to metronidazole. Can MedAssoc J 1992; 86:665115. Schmid G, Narcisi E, Moreno H, et al.Prevalence of metronidazoleresistantTrichomonas vaginalis in a gynecology clinic. /Reprod Med 2001;46:545–9116. Pereyra AJ, Lansing JD. Urogenital trichomoniasis: treatment withmetronidazole in 2002 incarcerated women. Obstet Gynecol 1964; 24:499–508117. Lossick JG, Muller M, Gorrell TE. In vitro drug susceptibility anddoses of metronidazole required for cure in cases of refractory vaginaltrichomoniasis. J lnfect Dis 1986; 153:948–55118. Forsgren A, Forssman L. Metronidazole-resistant Trichomonasvaginalis. Br JVener Dis 1979; 55:351–3119. Kulda J, Vojtechovska M, Tachezy J, Demes P, Kunzvova E.Metronidazole resistance of Trichomonas vaginalis as a cause oftreatment failure in trichomoniasis—a case report. Br J Vener Dis1982; 58:394–9120. Sobel JD, Nyirjesy P, Brown W. Tinidazole therapy formetronidazole-resistant vaginal trichomoniasis. Clin Infect Dis 2001; 33:1341–6121. Muller M, Lindmark RG. Uptake of metronidazole and its effect onviability in trichomonads and Entamoeba invadens under anaerobic andaerobic conditions. Antimicrob Agents Chemother1976; 9:696–700122. Muller M. Reductive activation of nitroimidazoles in anaerobicmicroorganisms. Bichem Pharmacol 1986; 35:37–41123. Tocher JH, Edwards DI. Evidence for the direct interaction ofreduced metronidazole derivatives with DNA bases. Biochem Pharmacol1994; 48:1089–94

TRICHOMONIASIS 85124. Nielsen MH. In vitro effect of metronidazole on the ultrastructure ofTrichomonas vaginalis donne. Acta Pathol Microbiol Scand Sect B Microbiol1976; 84:93–100125. Caro-Paton T, Carvajal A, Rodriguez Pinilla E, et alIs metronidazoleteratogenic? A meta-analysis. Br J Clin Pharmacol 1997; 44:179–82126. Burtin P, Taddio A, Ariburnu O, Einarson TR, Koren G. Safety ofmetronidazole in pregnancy: a meta-analyis. Am J Obstet Gynecol 1995;172:525–9127. Piper JM, Mitchel EF, Ray WA. Prenatal use of metronidazole andbirth defects: no association. Obstet Gynecol 1993; 82:348–52128. Hardy PH, Hardy JB, Rosenbaum RC, et alPrevalence of six sexuallytransmitted disease agents among pregnant inner-city adolescents andpregnancy outcome. Lancet 1984; 2:333–7129. Minkoff H, Grunebaum AN, Schwarz RH, et al.Risk factors forprematurity and premature rupture of membranes; a prospectivestudy of the vaginal flora in pregnancy. Am J Obstet Gynecol 1984; 150:965–72130. Mason PR, Brown IM. Trichomonas in pregnancy. Lancet 1980; 1025–6131. Ross SM, Van Middelkoop A. Trichomonas infection in pregnancy—does it affect perinatal outcome? S Afr Med J 1983; 63:566–7132. Heine RP, McGregor JA, Jones W, et al Trichomonas vaginalis:diagnosis and clinical characteristics in pregnancy. Infect Dis ObstetGynecol 1994; 1:228–34133. Struthers BJ. Metronidazole appears not to be a human teratogen:review of literature. Infect Dis Obstet Gynecol 1997; 5:326–35134. Rosa FW, Baum C, Shaw M. Pregnancy outcome after first-trimestervaginitis drug therapy. Obstet Gynecol 1987; 69:751–5

7.ATROPHIC VAGINITISINTRODUCTIONVaginal atrophy develops in all women when estrogen depletionoccurs at menopause. However, not all women with vaginal atrophydevelop atrophic vaginitis. The estrogen concentration inperimenopausal women is approximately 120 ng/ml and aftermenopause begins its concentration decreases to approximately 19 ng/ml 1 . The predominant hormone produced by the postmenopausalovary is androstenedione and this hormone is converted in theperipheral fatty tissue to estrogen. Testosterone is also produced inthe ovary and most of this is converted into estradiol in the ovaries.Thus there is an endogenous supply of estrogen as long as thepostmenopausal ovaries continue to function. However, the decreasein estrogen is significant and the vaginal epithelial surface loses itsfolds, or rugae, and thickness, then becomes thin and pale. Thevaginal tissue loses its elasticity and its ability to distend, thus itbecomes shorter and narrower. These changes result in the patientexperiencing dyspareunia and avoiding sexual intercourse.There are noticeable changes in the appearance of vaginal squamousepithelial cells in the absence of sufficient estrogen (Figure 7). Thereis also a lack of mature or naviculated squamous epithelial cells and asignificant increase in intermediate and parabasal cells. Physiologicalchanges within the vaginal ecosystem also occur. The most noticeablechange is a decrease in the available glycogen, creating an insufficientsupply of carbohydrate, which results in a decrease in Lactobacillusgrowth. The decrease in Lactobacillus growth results in a decrease in

ATROPHIC VAGINITIS 87acid production and, in turn, the vaginal pH rises above 5 allowing thenon-lactobacilli to grow. Once non-lactobacilli gain dominance, thevaginal 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 fromvaginal atrophy to atrophic vaginitis. It also appears that women whosmoke enhance the development of atrophic vaginitis 2 . Those womenwhose ovaries produce testosterone and androstenedione, andcontinue to be sexually active appear to experience less severeatrophic changes 3 . Women whose ovaries have become completelynon-functioning are more likely to develop vaginal atrophy 4 .CLINICAL PRESENTATIONPatients often develop vaginal atrophy without knowing the processoccurs. Individuals who have infrequent sexual intercourse will notetightness in their vagina during intercourse. Because of the lack oflubrication, as well as shortness and narrowing of the vagina, thesepatients eventually complain of pain and discomfort. These individualswill often refuse to have sexual intercourse. At this point, the patientmay come to the physician if their husband or sexual partnerencourages them to do so. The development of vaginal spotting,profuse discharge, or vaginal burning is the most likely reason patientsseek a physician’s assistance.The most frequently reported symptoms are:(1)vaginal narrowing and shortness;(2)vaginal spotting or bleeding, especially during or afterintercourse;(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:

88 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENT(1)vaginal epithelium is pale, may observe petechial hemorrhages;(2)severe thinning of the vaginal epithelium results in a deeperythema of the vagina;(3)vaginal walls have lost their rugae and are smooth;(4)fissures are commonly observed on the medial aspect of the labiaminora, posterior fourchette, and vestibule; and(5)synechiae can develop between opposing vaginal walls that havebecome denuded.Patients with vaginal atrophy sometimes develop urinary tractinfections (UTI) as well as urinary in continence 5 – 7 . Thepostmenopausal woman with urinary incontinence should not besubjected to a comprehensive evaluation of the urinary tract as theinitial step in the work-up. The evaluation should begin by obtaining aclean catch urine specimen. If the patient has a copious discharge anevaluation of the vagina should be performed, i.e. physicianinspection, determination of the vaginal pH, and microscopicexamination of the vaginal discharge. Following completion of thepelvic examination, a lubricated tampon (place estrogen cream on thesurface of the tampon) should be inserted into the vagina and thepatient asked to provide a clean catch urine specimen. If the patienthas atrophic vaginitis, and has copious discharge, the urine specimenwill be contaminated by a variety of bacteria from the vagina. Oncethe specimen has been obtained the tampon should be removed.When evaluating the patient with urinary incontinence the presenceof a UTI should be ruled out. If the patient exhibits signs of vaginalatrophy and vaginitis, a trial of estrogen therapy should beadministered. If the patient continues to complain of urinaryincontinence once the vagina has been restored to a healthy state, acomprehensive evaluation of the lower urinary tract should beconducted.TREATMENTThe treatment for vaginal atrophy and atrophic vaginitis is estrogenreplacement, administered either orally or intravaginally. Estrogenadministered in the form of an intravaginal cream results in plasma

ATROPHIC VAGINITIS 89Table 16 Estrogen replacement therapy for treatment of vaginal atrophy andatrophic vaginitisconcentrations of estrone and estradiol similar that obtained withorally administered estrogen 8 , 9 . For this reason, oncologists do notwant patients with breast cancer to use estrogen cream administeredintravaginally. Initially, the absorption of estrogen from the vagina islow because of the decreased vascularity; however, with continuedtreatment both the vascularity of the vagina and estrogen absorptionincrease 10 . Various forms of estrogen that are used for the treatmentof vaginal atrophy and atrophic vaginitis (Table 16).REFERENCES1. Pandit L, Ouslander JG. Postmenopausal vaginal atrophy and atrophicvaginitis. Am J Med Sci 1997; 314:228–312. Kalogeraki A, Tamiolakis D, Relakis K, et alCigarette smoking andvaginal atrophy in postmenopausal women. In Vivo 1996; 10:597–6003. Leiblum S, Bachmann G, Kemmann E, Colburn D, Swartzman L.Vaginal atrophy in the postmenopausal woman. J Am Med Assoc 1983;249:2195–84. Dupont A, Dupont P, Cusan L, et al.Comparative endocrinologicaland clinical effects of percutaneous estradiol and oral conjugatedestrogens as replacement therapy in menopausal women. Maturitas1991; 13:297–3115. Eskin BA. The Menopause: Comprehensive Management, 3rd edn. NewYork: McGraw-Hill Health Professional Division, 1994; 3826. Brown KH, Hammond CB. Urogenital Atrophy. Obstet Gynecol ClinNorth Am 1997; 15:13–327. Smith P. Estrogen and urogenital tract. Acta Obstet Gynecol Scand 1993;72:1–268. Whitehead MI, Minandi J, Kitchen Y, Sharples MJ. Systemicabsorption of estrogen from Premarin vaginal cream. In Cook I, ed.

90 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTThe Role ofEstrogen/Progesterone in the Management of Menopause.Lancaster: MTP Press 1978; 63–719. Englund DE, Johansson ED. Plasma levels of oestrone, oestradiol andgonadotrophins in postmenopausal women after oral and vaginaladministration of conjugated equine oestrogens (Premarin). Br J ObstetGynecol 1978; 85:957–6410. Heimer GM, Englund DE. Effects of vaginally-administered oestriolon postmenopausal urogenital disorders: a cytohormonal study.Maturitas 1992:14:171–911. Englund DE, Victor A, Johanssen EDB. Pharmacokinetics andpharmacodynamic effects of vaginal oestradiol administration fromsilastic rings in post-menopausal women. Marturitas 1981; 3:125–3312. Nash HA, Brache V, Alvarez-Sanchez F, Jackanicz TM, Harmon TM.Estradiol delivery by vaginal rings: potential for hormone replacementtherapy. Maturitas 1997; 26:27–3313. Fraser IS, Ayton R, Murkies Aet alA multicenter Australian trial of lowdose estradiol therapy for symptoms of vaginal atrophy using a vaginalring as delivery system. Maturitas 1995; 22(Suppl):S4114. Henriksson L, Stjernquist M, Boquist L, Cedergren I, Selinus I. A oneyearmulticenter study of efficacy and safety of a continuous, low-dose,estradiolreleasing vaginal ring (Estring) in postmenopausal womenwith symptoms and signs of urogenital aging. Am J Obstet Gynecol 1996;174:85–9215. Henriksson L, Stjernquist M, Boquist L, Alander U, Selinus I. Acomparative multicenter study of the effects of continuous low-doseestradiol released from a new vaginal ring verus estradiol vaginalpessaries in postmenopausal women with symptoms and signs ofurogenital atrophy. Am J Obstet Gynecol 1994; 171:624–3216. Nachtigall LE. Clinical trial of the estradiol vaginal ring in the U.S.Maturitas 1995; 22 (Suppl): S43–717. Barentsen R, van der Weijer PH, Schram JH. Continuous low doseestradiol released from a vaginal ring versus estriol vaginal cream forurogenital atrophy. Eur J Obstet Gynecol Reprod Biol 1997; 71:73–8018. Eierman W. The effect of low dose estradiol in the treatment ofatrophic vaginitis: A double blind controlled study. The urogenitalestrogen deficiency syndrome. Proc Int Workshop, Copenhagen,November 198619. Mettler L, Olsen PG. Long-term treatment of atrophic vaginitis withlow-dose oestradiol vaginal tablets. Maturitas 1991; 14:23–31

ATROPHIC VAGINITIS 9120. Eriksen PS, Rasmussen H. Low-dose 17beta-estradiol vaginal tablets inthe treatment of atrophic vaginitis: A double-blind placebo controlledstudy. Eur JObstet Gynecol Reprod Biol 1992; 44:137–4421. Nilsson K, Heimer G. Low-dose oestradiol in the treatment ofurogenital oestrogen deficiency—a pharmacokinetic andpharmacodynamic study. Maturitas 1992; 15:121–722. Felding C, Mikkelson AL, Clausen HV, Loft A, Larsen LG.Preoperative treatment with oestradiol in women scheduled forvaginal operation for genital prolapse. A randomised, double-blindtrial. Maturitas 1992; 15:241–923. Raz R, Stamm WE. A controlled trial of intravaginal estriol inpostmenopausal women with recurrent urinary tract infections. NEngl J Med 1993; 329:753–624. Rigg LA, Milanes B, Villanueva B, Yen SS. Efficacy of intravaginal andintranasal administration of micronized estradiol-17beta. /ClinEndocrinol Metab 1977; 45:1261–4

8.DESQUAMATIVE VAGINITISINTRODUCTIONDesquamative vaginitis is a condition that resembles atrophicvaginitis, except that the individual does not have estrogen deficiency.The condition was described in 1965 by Gray and Barnes 1 , whotermed it desquamative inflammatory vaginitis because of the largenumbers of white blood cells (WBC) and squamous epithelial cellspresent in the vaginal discharge. In 1968, Gardner 2 described eightcases of vaginitis that resembled atrophic vaginitis, but the patientshad an estrogen deficiency. Lynch 3 , in 1975, suggested thatdesquamative vaginitis is a variety of lichen planus because the patientalso had buccal and gingival plaque similar to that seen in lichen planuspatients. Edwards and Friedrich 4 reported five cases of desquamativevaginitis in patients with oral lesions similar to those seen with lichenplanus, then suggested that desquamative vaginitis is caused by erosivelichen planus.CLINICAL PRESENTATION AND DIAGNOSISDesquamative inflammatory vaginitis presents with erythema of thevaginal epithelium, especially the posterior fornix and portio of thecervix. Typically the areas of erythema are a deep, fiery red with welldefinedborders. Superficial ulcerations and bleeding also accompanythis condition. Occasionally, a gray pseudomembrane develops overthe inflamed tissue, which can be easily removed. A characteristic ofthese ulcerations is the development of a narrow reticulated border at

DESQUAMATIVE VAGINITIS 93Table 17 Clinical characteristics of desquamative inflammatory vaginitisthe periphery of the ulcers and the presence of non-erosive lichenplanus lesions found elsewhere on the skin or mucus membranes(Table 17) 5 .In an attempt to determine the microbiologic etiology, Gardnercultured a variety of pathogens from patients in his case study(Table 18) 2 . He concluded that desquamative inflammatory vaginitiswas not caused by an infection because no common bacterium wasisolated. However, Gardner did not have the ability to culture andidentify obligate anaerobic bacteria. Sobel 6 reported that 51 patientswith desquamative inflammatory vaginitis had a diffuse exudativevaginitis, exfoliation of squamous epithelial cells, and purulentdischarge. Sobel did not find a common bacterium but did note asignificant decrease in Lactobacillus. These patients all had a diffuseexudative purulent vaginal discharge, an increase in the number ofparabasal cells, an elevated vaginal pH, and the presence of a largenumber of Gram-positive cocci 6 . The increase in vaginal pH to 5 ormore is inhibitory to the growth of Lactobacillus and favors growth ofthe non-lactobacilli pathogenic bacteria. The presence of anovergrowth, in some patients, by Gram-positive cocci suggests thatStreptococcus agalactiae might possibly be an etiologic agent.

94 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTTable 18 Pathogens isolated from the vagina of patients with desquamativeinflammatory vaginitis in a study by Gardner 2TREATMENTThe treatment for desquamative inflammatory vaginitis has been theuse of intravaginal corticosteroids: 12.5 mg vaginal suppositoriesinserted twice a day for 2 months 7 . This is followed by theadministration of 12.5 mg vaginal suppositories once a day for 2months and then maintenance therapy of 12.5 mg intravaginalsuppositories one to three times a week 7 . When Sobel treated 51patients with 2% clindamycin intravaginal suppositories, more than95% 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 adecrease in the growth and presence of lactobacilli. The net result isthat bacterial growth within the vagina is reduced and there is a largenumber of WBC. Thus, it appears that the best approach to treatmentis the administration of steroids intravaginally. The steroids need to beadministered for a prolonged period and tapered down once there isnoticeable improvement. The patient will be required to remain on amaintenance dose for a further prolonged period. When vaginalsteroids are discontinued, the patient may experience a relapse. If thisoccurs, steroid therapy should be reinstituted.

REFERENCESDESQUAMATIVE VAGINITIS 951. Gray LA, Barnes ML. Vaginitis in women, diagnosis and treatment.Am J ObstetGynecol1965; 92:125–362. Gardner HL. Desquamative inflammatory vaginitis: a newly definedentity. AmJ Obstet Gynecol 1968; 102:1102–53. Lynch PJ. Desquamative inflammatory vaginitis with oral lichenplanus. In Friedrich EG Jr., Josey WE, eds. Proceedings of the SecondInternational Congress ofthe International Society for the Study of VulvarDisease. Key Biscayne, FL, January 9–11, 19754. Edwards L, Friedrich EG, Jr. Desquamative vaginitis: lichen planus indisguise. Obstet Gynecol 1988; 71:832–65. Pelisse M. The vulvo-vaginal-gingival syndrome. A new form oferosive lichen planus. Int J Dermatol 1989; 28:381–46. Sobel JD. Desquamative inflammatory vaginitis: a new subgroup ofpurulent vaginitis responsive to topical 2% clindamycin therapy. Am JObstet Gynecol 1994; 171:1215–207. Mann MS, Kaufman RH. Erosive lichen planus of the vulva. Clin ObstetGynecol 1991; 34:605–13

9.CYTOLYTIC VAGINOSISINTRODUCTIONCytolytic vaginosis, also referred to as Döderlein cytolysis, appears tobe a common alteration in the vaginal ecosystem 1 . Cytolytic vaginosisis similar in gross appearance to the discharge that is seen with vaginalcandidiasis. When examining a patient with cytolytic vaginosis,physicians often do not see yeast but still treat the patient with an antifungalagent, and the patient’s condition does not resolve.CLINICAL PRESENTATION AND DIAGNOSISThe external genitalia do not undergo any changes with cytolyticvaginosis, unlike with candidiasis. The patient with vaginal candidiasisoften has vulvar involvement, i.e. the labia and crural folds areerythematous, pruritic, and/or burn. However, the patient withcytolytic 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 themenstrual cycle 2 . The microflora of patients with cytolytic vaginosisdoes not shift to a flora dominated by facultative or obligate anaerobesbut is dominated by Lactobacillus. In fact, there appears to be anovergrowth of lactobacilli. The pH of the vagina and the vaginaldischarge remains between 3.5 and 4.5. The hydrogen ionconcentration is maintained by the growth of lactobacilli. Productionby lactobacilli of lactic acid and other organic acids maintains thishydrogen ion concentration and suppresses the growth of other

CYTOLYTIC VAGINOSIS 97Table 19 Characteristics of cytolytic vagionisbacteria 3 . The most common Lactobacillus species found in the vaginaare Lactobacillus crispatus, L. gasseri, L.jensenii, and L. iners 4 .The physical findings of vaginal discharge are quite distinct inpatients with cytolytic vaginosis (Table 19). The most importantdiagnostic aides are microscopic examination of the vaginal dischargeand culture for Trichomonasvaginalis and Candida (Figures 16 and 17).Interestingly, there are relatively few white blood cells (WBC) presentin the vaginal discharge. This is important because it implies that thereis a low probability that the patient has acute cervicitis orendometritis. However, to be complete, if the patient’s history placesher at risk for possible infection with Chlamydia trachomatis andNeisseriagonorrhoeae, specimens for detection of these organisms shouldbe obtained from the endocervix.TREATMENTCibley and Cibley 2 recommend vaginal douching with sodiumbicarbonate, 30–60 g in a liter of water, two to three times a week.Once there appears to be improvement, the douching frequencyshould be tapered off to once a week as needed. However, douchingshould be done with little pressure and preferably in the sitting orstanding position, which helps reduce the possibility of douching

98 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTsolution entering the upper genital tract. Some investigators believethat there is an association between douching and the development ofpelvic infection.The goal of treatment is not to significantly increase the pH sincethis can result in a decrease in Lactobacillus growth and an increase inthe growth of other bacteria. Therefore, it would be detrimental tomaintaining a balanced vaginal ecosystem to raise the pH above 4.5.Perhaps the administration of intravaginal clindamycin cream (2%) ormetronidazole can effectively lower the concentration of Lactobacilluswhile suppressing the growth of obligate anaerobic bacteria.Clindamycin will also have an inhibitory effect on Gram-positivebacteria, except the enterococci. Additionally, clindamycin would nothave a suppressive effect on the Gram-negative facultative bacteria.Therefore, the administration of oral or intravaginal antibiotics shouldnot be for a prolonged period of time in order to avoid selection ofresistant bacteria, which could become the dominant bacteria of thevaginal ecosystem.REFERENCES1. Düderlein A. Die Scheidensekretunter Suchungen. Zentralbl Gynakol1982; 18:10–142. 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; 181–73. Aroutcheva A, Gariti D, Simon M, et al.Defense factors of vaginallactobacilli. Am J Obstet Gynecol 2001; 185:375–94. Vasquez A, Jakobsson T, Ahrne S, Forsum U, Molin G. Vaginallactobacillus flora of healthy Swedish women. /Clin Microbiol 2002; 40:2746–9

INDEXacidifying agents 22, 23amniotic fluid 6antibiotic prophylaxis 6atopy 12bacterial vaginitis 5, 25–33clinical presentation 25–28bacterial vaginosis iv, vi, 5, 13–23,25constituent bacteria 18diagnosis 18–21epidemiology 13–15Haemophilus vaginalis 5microbiology 15–17risk factors 13treatment 21–23bacteriocin 3, 5, 16Bacteriodes spp. 3blastospores 36basal cells viboric acid 22, 29, 33, 45, 52burning 11, 32, 34, 39Candida xi, 33, 34–52, 94, 95balanoposthitis 43Candida albicansand Lactobacillus 36, 42morphologic forms 37cell wall 36resistance 51species isolated from humans 38candidiasis 9, 25, 95.See also vulvovaginal candidiasis(VVC)cellulitis 39, 75cephalosporin 21cervicitis 18, 25, 45Cesarean section 6Chlamydia trachomatis 3, 19, 25, 27,45, 62chorioamnionitis 13chorionic membranes 6clindamycin 21, 23, 29, 98clue cells 21, 22coliform vaginitis 30contact dermatitis 11Corynebacterium spp. 3culture 12, 16, 30, 34, 67, 68cytolytic vaginosis vii, xiii, 30–32,95–98treatment 32, 97–98characteristics 97clinical presentation anddiagnosis 95–97Diamond’s medium 61discharge xiii, xiv–2, 28, 95abnormal 3499

100 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTdiagnostic characteristics andevaluation 19, 27, 40, 67microscopic examination 22, 33,44–45, 49, 88purulent 11, 25, 66, 91dyspareunia 11, 32, 87dysuria 11, 66, 87eczema 11edema 12endometrium xivEnterobacter spp. 2,3Enterococcus spp. 2,3,15epitheliumendocervical 6vaginal xiv, 25, 27vestibular 11erythema 11, 12, 28, 34, 39Escherichia coli 2, 3, 5, 15, 30, 36,94estrogen 27, 85, 88Eubacterium spp. 2fallopian tubes xiv, 27Fusobacterium spp. 2,3,72Gardnerella spp. iv, 3, 15, 17, 18, 21Giardia lamblia 72glandsBartholin’s xiv, 11, 27, 66periurethral xivSkene’s xiv, 11, 27Herpes Simplex virus 19, 67human immunodeficiency virus(HIV) 62, 66human papillomavirus 3, 19, 45, 67hydrogen ion concentrationin bacterial vaginitis 25–27in bacterial vaginosis 15, 17, 21hydrogen peroxide (H 2 O 2 ) 3, 5, 16hypersensitivity 9, 43hysterectomy 6itching 11, 32, 34, 39, 66ketoconazole 42Klebsiella spp. 2labia vii, 39majora 11, 27minora xiv, 11, 27lactic acid 16Lactobacillus iv, vii, xiii, 2,3,12, 13,16, 28, 30–32, 61and Candida albicans 36, 42common species isolated fromwomen 3dominance 5, 6, 8, 15, 21, 25,65in healthy vaginal ecosystem xiv,2, 3inhibition of pathogenic bacteria5lactocin 3, 5, 16leukorrhea 25lichen planus 91lichen sclerosus 9, 11menopause 85metronidazole 17, 21, 23, 69, 72–75adverse effects 73microscopic examination 12, 34, 68Morganella spp. 2,3Mycoplasma 17, 70necrotizing fasciitis 39Neisseria gonorrhoeae 3, 19, 25, 27,36, 45, 62, 97nitroimidazole 72non-pathogenic bacteria 3

INDEX 101Nugent’s score 15, 17nystatin 12, 41, 42Pap smear 45, 67, 69, 73pathogenic bacteria 3pelvic examination 87pelvic infections 6–8, 13pelvic inflammatory disease(PID) 59, 62Peptococcus spp. 2,3Peptostreptococcus spp. 2,3peroxidase 5postpartum endometritis 6, 13premature delivery 13, 75premature rupture of amnioticmembranes 13, 75preterm labor 13Prevotella spp. 2,3,15Proteus spp. 2pruritus 34, 45, 66rectovaginal fistula 30Saccharomyces cerevisiae 45salpingitis 13, 25, 66septic abortion 13squamous cells iv, vi, ix, xiii,xiv, 22,27, 32, 44, 85, 91staphylococcal vaginitis 29Staphylococcus spp. xiv, 2,3,6, 29, 94streptococcal vulvovaginitis 28–29Streptococcus spp. 2,3,5, 15, 28, 93,94Streptomyces spp. 72Trichomonads 57Trichomonas spp. xi,xiii,33, 57–76,94axostyle 59in pregnancy 62morphology xi,xiii,59prostate infection 69–72trichomoniasis 18, 25, 36, 57–76epidemiology 61–65microbiology 59–61of the prostate gland 69–72patient evaluation and diagnosis65–69treatment 69–76in the pregnant patient 75–76recommended regimens 75Ureaplasma urealyticum 17, 70urinary incontinence 87–88vaginal ecosystemalteration of 13, 25healthy xiv–8, 15bacteria 2characteristics 3constituents 2pathogenic and non-pathogenicbacteria 3vaginal microfloraalteration of 6, 9, 16,17, 30endogenous 15, 16, 34healthy 17transient 15vaginitis 9.See also bacterial vaginitisatrophic 27, 85–89, 91clinical presentation 87–88treatment 88–89estrogen replacementtherapy 88desquamative 91–94clinical characteristics 93clinical presentation anddiagnosis 91–93isolated pathogens 94treatment 93–94differential diagnosis 47

102 VAGINITIS: DIFFERENTIAL DIAGNOSIS AND MANAGEMENTgroup B streptococcal 28vaginosis 9.See also bacterial vaginosis andcytolytic vaginosisVeillonella spp. 2vestibulitis 9, 11vulva hyperplasia 9vulvadynia 9vulvar dystrophies 11vulvar pruritus 12vulvitis 9–12differential diagnosis 9vulvovaginal candidiasis (VVC) ix,xi, 11, 12, 34–52characteristics 44chronic 37clinical presentation anddiagnosis 39–47differential diagnosis 39epidemiology 37–39incidence 38mycology 36–37pathogenesis 43recurrent 37, 41–42factors 41inhibition of cell-mediatedimmunity 43treatment 47–52available antifungal agents 49vulvovaginitis. See vulvovaginalcandidiasiswet prep ix, xi, 3, 12, 68whiff test 21yeast xi, 12, 34, 37, 47asymptomatic endogenouscarriage 34penile colonization 43