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A Supplement to Family Practice News®

A Practical Update on Sexually Transmitted Infections: Advances in Diagnosis and Treatment Highlights From a Symposium

COURSE CO-DIRECTORS NORMAL VAGINAL FLORA Jack D. Sobel, MD Jeanne M. Marrazzo, MD, MPH Wayne State University University of Washington Harper Hospital Seattle Detroit DIAGNOSIS AND TREATMENT OF ROUTINE Phillip G. Stubblefield, MD AND RESISTANT Boston University School of Medicine Anne M. Rompalo, MD, ScM Johns Hopkins School of Medicine Jonathan M. Zenilman, MD Baltimore Johns Hopkins School of Medicine Baltimore NEW FINDINGS IN ROUTINE AND RECURRENT VULVOVAGINAL TREATMENT Jack D. Sobel, MD

OVERVIEW OF AND ITS ROLE IN UPPER GENITAL TRACT INFECTION David A. Eschenbach, MD University of Washington Seattle

NONINFECTIOUS VULVOVAGINAL SYMPTOMS AS MANIFESTATIONS OF SYSTEMIC DISEASES Jack D. Sobel, MD 3M_FP_6_17_2003.qxd 6/18/2003 7:18 PM Page 2

® A Practical Update on Sexually Transmitted Infections: Family Practice News Advances in Diagnosis and Treatment Group Publisher/ General Manager Alan J. Imhoff 3INTRODUCTION FROM THE COURSE CO-DIRECTORS Jack D. Sobel, MD Vice President, Medical Education Professor, Chief, Division of Infectious Diseases & Business Development Wayne State University, Harper Hospital Sylvia H. Reitman Detroit Program Manager, Phillip G. Stubblefield, MD Medical Education Professor and Chairman, Obstetrics and Gynecology Jenny R. McMahon Boston University School of Medicine Clinical Editor Director, Obstetrics and Gynecology Geneva Collins Boston Medical Center National Account Manager Jonathan M. Zenilman, MD Kathleen Carlson Professor, Infectious Diseases Division Johns Hopkins School of Medicine Art Director Baltimore Louise A. Lynch

Production Specialist 3NORMAL VAGINAL FLORA Rebecca Slebodnik Jeanne M. Marrazzo, MD, MPH Assistant Professor, Department of Medicine Division of Allergy and Infectious Diseases The presentations from which this University of Washington, Harborview Medical Center supplement was developed took place Seattle at a continuing medical education conference held April 5-6, 2003, in 6DIAGNOSIS AND TREATMENT OF ROUTINE AND Washington, D.C. RESISTANT TRICHOMONIASIS Anne M. Rompalo, MD, ScM This supplement was supported by a Associate Professor restricted grant from Infectious Diseases Division Johns Hopkins School of Medicine Baltimore

8NEW FINDINGS IN ROUTINE AND It was produced by the medical RECURRENT VULVOVAGINAL CANDIDIASIS TREATMENT education and business development Jack D. Sobel, MD department of International Medical News Group. Neither the Editor of 10 OVERVIEW OF BACTERIAL VAGINOSIS AND FAMILY PRACTICE NEWS, the Editorial ITS ROLE IN UPPER GENITAL TRACT INFECTION Advisory Board, nor the reporting staff David A. Eschenbach, MD reviewed or contributed to its content. Professor and Director, Women’s Health The opinions expressed in this Chair, Department of Obstetrics and Gynecology supplement are those of the faculty University of Washington and do not necessarily reflect the Seattle views of the supporter or the Publisher. 12 NONINFECTIOUS VULVOVAGINAL SYMPTOMS AS Copyright 2003 International Medical MANIFESTATIONS OF SYSTEMIC DISEASES News Group, an Elsevier company. All Jack D. Sobel, MD rights reserved. No part of this publication may be reproduced or Faculty Disclosure transmitted in any form, by any means, Faculty/authors must disclose any significant financial interest or relationship with pro- without prior written permission of the prietary entities that may have a direct relationship to the subject matter. They must also Publisher. International Medical News disclose any discussion of investigational or unlabeled uses of products. Group will not assume responsibility for Dr. Eschenbach is a consultant to 3M Pharmaceuticals. Dr. Marrazzo discusses the use damages, loss, or claims of any kind of intravaginal Lactobacillus crispatus capsules for the treatment of bacterial vaginosis. arising from or related to the Dr. Rompalo receives grant/research support from GlaxoSmithKline and is on the speak- information contained in this er’s bureau for GlaxoSmithKline, and Pfizer Inc. Dr. Sobel has received clinical grants publication, including any claims from 3M, Pfizer Inc., and Ortho-McNeil. He discusses the investigational use of flucona- related to the products, drugs, or zole and 17.4% topical flucytosine cream for treating Candida glabrata, and 10% hydro- cortisone for treating erosive lichen planus. Dr. Stubblefield has nothing to disclose. services mentioned herein. Dr. Zenilman receives grant/research support from Osmetech PLC, is a consultant to Merck and Co., and is on the speaker’s bureau for GlaxoSmithKline and Pfizer Inc. 3M_ObGyn_6_17_2003.qxd 6/18/2003 7:30 PM Page 3

Introduction

Jack D. Sobel, MD Phillip G. Stubblefield, MD Jonathan M. Zenilman, MD

The intent of this supplement is to provide a practi- guidelines for trichomoniasis and discusses how to cal update on advances in diagnosis and treatment of document and manage metronidazole-resistant cases. the three most common causes of infectious vagini- In his presentation on BV, Dr. David A. Eschenbach Ttis—diseases that practicing women’s health care explains why empiric treatment of the disease can providers encounter daily—bacterial vaginosis (BV), cause more harm than good. He also summarizes the vulvovaginal candidiasis (VVC), and trichomoniasis. many associations between BV and upper genital We are delighted that some of the leading specialists tract infections. Dr. Jack D. Sobel provides not one in sexually transmitted disease research were able to but two discussions relating to VVC. The first is an provide these insights into the etiology of lower gen- update on management of routine and recurrent ital tract infections, new treatment modalities for VVC. The second discussion is designed to aid them, and the challenges of managing recurrent dis- practicing women’s health care providers in making a ease. Dr. Jeanne M. Marrazzo starts off these pages differential diagnosis of VVC from noninfectious with a discussion of the bacterial flora in the normal causes of vulvovaginitis. The following presentations vaginal environment and how endogenous and exoge- were based on a continuing medical education con- nous elements can disrupt this delicate microbial ference held April 5-6, 2003, in Washington, D.C., ecosystem. Dr. Anne M. Rompalo reviews the revised and jointly sponsored by Boston University School of Centers for Disease Control and Prevention treatment Medicine and OB.GYN. NEWS. Normal Vaginal Flora Jeanne M. Marrazzo, MD, MPH

When a patient comes to a women’s health care provider’s women are spending substantial amounts of money to al- office with a vaginal complaint, the likelihood that she has ter their normal vaginal flora. already tried to self-treat using one or more of the many Wtypes of over-the-counter (OTC) preparations available is Vaginal PH Is a Key Indicator high. In 2002, women in the United States spent $250 mil- Because the other presentations in this supplement center lion on prescription yeast medication, an additional $250 on various pathologic conditions in the , it is im- million on OTC yeast products, $100 million on douch- portant to lay the groundwork here with an explanation of ing preparations, and $60 million on so-called genital cos- what characterizes a normal, healthy vagina. metics (such as deodorants), according to the Consumer A healthy vagina is highly acidic, with a pH less than 4.7. Healthcare Products Association. The vaginal acidity is achieved primarily by lactic acid, which In a discussion of what constitutes normal vaginal flo- is produced by human lactobacilli. The low pH has two ef- ra, it is important to note that what is meant is a vagi- fects. It encourages the growth of acidophilic organisms, pri- nal environment that has not been adulterated by such marily lactobacilli, and it inhibits the growth of other or- products as well as by prescribed medications. OTC ganisms. These other organisms may be either resident douches may contain powerful surfactants and disinfec- commensal flora or exogenous invaders. An elevated vagi- tants. One popular vaginal cream includes a topical anes- nal pH is associated with loss of hydrogen peroxide (H202)- thetic; another contains an antihistamine. A homeopath- producing lactobacilli, presence of bacterial vaginosis (BV) ic vaginal suppository on the market contains nonviable and trichomoniasis, acquisition of , and enhanced Candida organisms along with plant extracts. It is clear transmission of human immunodeficiency virus (HIV). from the impressive sales figures that large numbers of Adequate estrogen is essential for achieving low vaginal

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pH. Estrogen is needed to maintain an adequate squamous helpful in diagnosing the cause of in women. epithelial cell layer of the vaginal mucosa. The cell layer Similarly, Candida is found in 15% to 43% of nonpreg- must be sufficiently thick (ͧ20 cells) to serve as a glyco- nant women, and finding pseudohyphae or yeast cells in gen source for the lactobacilli to produce lactic acid. Al- vaginal fluid via microscopy or culture in the absence of though lactic acid can be produced from glucose even in symptoms does not define vulvovaginal candidiasis (VVC). the absence of lactobacilli, this action alone would not The lactobacilli found in the vagina have specific adher- achieve sufficient vaginal acidity. The presence of lacto- ent properties that let them attach to the vaginal epitheli- bacilli is required to achieve a pH less than 5. um and colonize. Lactobacilli typically found in the gut, Menstrual fluid has a pH similar to that of blood, which when transferred to the vagina, do not thrive. Neither do is in the range of 7.35 to 7.45. Menses in effect introduce the bovine species of lactobacilli that are found in yogurt a pH challenge to the vaginal environment. There are typ- and other OTC products. Lactobacillus crispatus is thought ically a transient increase in pH and changes to the lacto- to be the key player in the vagina, but other species, such bacilli population after exposure to this alkaline fluid.1 as Lactobacillus jensenii and Lactobacillus iners, are being in- 6 Douches and the exogenous products discussed earlier have vestigated as well. Most vaginal lactobacilli produce H202, varying effects on the vaginal environment.2 However, they which interacts with host peroxidases to produce an oxidant typically deplete lactobacilli, espe- that has viricidal and bacteriocidal cially if used repeatedly and in high FIGURE effects. However, some women concentrations. Spermicides, such as have lactobacilli that do not pro- 3 nonoxynol-9, have a similar effect. duce H202. These lactobacilli still Fortunately, many of the antimi- appear to provide benefit, howev- crobial agents more commonly used er: Women with non–H202-pro- to treat , vaginitis, and ducing lactobacilli have been sexually transmitted infections, in- shown to have lower BV prevalence cluding doxycycline, azithromycin, than women with no lactobacilli.7 clotrimazole, and fluconazole, do Lactobacilli appear as large gram- If lactobacilli are so essential to not adversely affect Lactobacillus lev- positive rods when examined via saline- vaginal well-being, an obvious ques- els when used short term. Use of wet preparation microscopy. tion is: Why not recolonize women oral or vaginal metronidazole may who lack these organisms? This is in fact increase the amount of lactobacilli, apparently be- apparently the thinking behind the Lactobacillus products cause of the agent’s targeted effect on the anaerobes. In- found in many health food stores. A study by Hughes and travaginal clindamycin, in contrast, may cause a transient Hillier8 looked at some of these products, such as yogurt-based decrease in lactobacilli, but this effect is not sustained.4 douches and acidophilus powders, and found that not only are these bovine strains of Lactobacillus but they may be con- Host of Organisms Populate taminated with enterococci, E. coli, and other organisms found Vaginal Environment in a cow’s gastrointestinal tract. As mentioned previously, only Lactobacilli should constitute 95% of the flora found in the human strains of lactobacilli appear to have the adherent qual- vagina. Ideally, they should be present at levels of at least ities needed to flourish in the vagina. 105 colony-forming units per milliliter. (See the Figure for This author participated in a still-ongoing study of an in- an example of how lactobacilli appear in normal vaginal flu- travaginal capsule containing human L. crispatus that was id as seen via wet preparation microscopy.) The remaining given to women with BV along with metronidazole.9 The 5% of flora is composed of an array of facultative anaerobes data are still under analysis, but results were mixed. Among (Staphylococcus epidermidis, corynebacteria, groups A and B the insights gained from this study are that the vaginal mi- streptococci, Gardnerella vaginalis, Mobiluncus species), anaer- croenvironment is truly complex and that tinkering with obes (Peptostreptococcus species, Peptococcus species, Eubacterium these regulators can have unanticipated consequences. At- species, Prevotella species), aerobes (Escherichia coli, Staphylo- tempts are now under way to formulate a Lactobacillus prepa- coccus aureus), hominis, , and ration that does not alter the commensal bacteria. fungi (Candida species).5 It should be emphasized that these organisms are normal colonizers and not pathogenic when Aging, Pregnancy, and Other Factors That their numbers are kept in check by a healthy Lactobacillus Change Composition of Vaginal Flora population. This appears to be true even with organisms such The environment of the vagina is very dynamic and is con- as G. vaginalis, the organism associated primarily with BV, stantly responding to both endogenous and exogenous which can be found in approximately half of asymptomatic stimuli. Some of these, such as menstrual fluid, OTC prod- women. This is why doing a routine culture usually is not ucts, and antibiotics, have already been discussed. Hor-

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monal fluctuations and sexual practices can also cause tran- One final observation to make regarding vaginal flora is sient alterations in the balance of flora in the vagina.10 to call attention to an important change in the revised Sex- As women begin menopause and their estrogen levels start ually Transmitted Diseases Treatment Guidelines issued by the to decline, shifts in the vaginal flora become evident. Lacto- Centers for Disease Control and Prevention last year.14 The bacillus levels drop, particularly of guidelines use strong language to TABLE H202-producing lactobacilli. Lev- recommend that vaginal spermi- els of Mobiluncus and other anaerobes Problems in Accurate cides containing nonoxynol-9 not increase. Interestingly, despite the Diagnosis of Vaginitis be used. Not only have several drop in lactobacilli, menopausal and • Failure to do microscopy studies shown these products to be postmenopausal women do not ap- • Poor quality microscopy ineffective in preventing gonor- pear to have increased prevalence of • Insensitivity of wet preparation for rhea, , or HIV, but BV.11 Trichomonas, yeast nonoxynol-9 is now known to be a During pregnancy, the vaginal • Failure to do pH/amine test surfactant that disrupts vaginal cell flora do not differ substantially, save • Inappropriate reliance on vaginal membranes, especially when used bacterial cultures for an increase in Candida.12 Racial frequently or at high concentra- • Mixed infections present, undetected differences in vaginal bacteria, such • Use of over-the-counter products for tions, and can cause microscopic as African American women having self-treatment that obscure diagnosis ulcerations and abrasions that can fewer H202-producing lactobacilli, enhance transmission of disease. may become exaggerated during pregnancy. It is now well known that BV increases the risk REFERENCES of adverse outcomes during pregnancy, but it has also been 1. Eschenbach DA, Thwin SS, Patton DL, et al. Influence of the normal men- strual cycle on vaginal tissue, discharge, and microflora. Clin Infect Dis. shown that the presence of H202-producing lactobacilli alone 2000;30:901-907. is itself predictive of lower likelihood of delivering preterm.13 2. Onderdonk AB, Delaney ML, Hinkson PL, Dubois AM. Quantitative and Sexual intercourse can affect the vaginal environment in qualitative effects of douche preparations on vaginal microflora. Obstet Gy- a number of ways. Semen, like menstrual fluid, is an al- necol. 1992;80(3 pt 1):333-338. kaline agent, with a pH of nearly 7.5. Intercourse is also 3. Richardson BA, Martin HL Jr, Stevens CE, et al. Use of nonoxynol-9 and associated with increased exposure to perineal residents such changes in vaginal lactobacilli. J Infect Dis. 1998;178:441-445. as group B streptococci, E. coli, and enterococci. Use of di- 4. Agnew KJ, Hillier SL. The effect of treatment regimens for vaginitis and cervici- aphragms is known to increase Candida colonization but tis on vaginal colonization by lactobacilli. Sex Transm Dis. 1995;22:269-273. does not appear to affect other flora. Frequent oral sex also 5. Hillier SL. Normal vaginal flora. In: Holmes KK, Marah P-A, Wasserheit J, may affect the vaginal environment; the practice is associ- eds. Sexually Transmitted Diseases. New York: McGraw-Hill; 1999:191-201. 6. Antonio MA, Hawes SE, Hillier SL. The identification of vaginal Lactobacil- ated with increased prevalence of BV and VVC. lus species and the demographic and microbiologic characteristics of women colonized by these species. J Infect Dis. 1999;180:1950-1956. Diagnosing Vaginitis More Accurately 7. Hawes SE, Hillier SL, Benedetti J, et al. Hydrogen peroxide-producing lacto- It is hoped that this discussion of how endogenous and ex- bacilli and acquisition of vaginal infections. J Infect Dis. 1996;174:1058-1063. ogenous factors may disrupt the balance of vaginal flora will 8. Hughes VL, Hillier SL. Microbiologic characteristics of Lactobacillus products aid physicians in diagnosing the root causes of their pa- used for colonization of the vagina. Obstet Gynecol. 1990;75:244-288. tients’ vaginal complaints (Table). The most useful test a 9. Hillier SL et al. A trial of Lactobacillus crispatus as an adjunct to metronida- zole therapy for treatment of bacterial vaginosis. Poster presented at: the an- caregiver can administer, and one that is too frequently nual meeting of the Infectious Diseases Society for Obstetrics and Gynecolo- overlooked, is a vaginal pH test. In addition, measurement gy; August 2002; Banff, Alberta, Canada. of vaginal amines also can be extremely valuable in nar- 10. Schwebke JR, Richey CM, Weiss HL. Correlation of behaviors with micro- rowing the differential diagnosis. An amines test measures biological changes in vaginal flora. J Infect Dis. 1999;180:1632-1636. volatile amines that are the by-products of anaerobic me- 11. Cauci S, Driussi S, De Santo D, et al. Prevalence of bacterial vaginosis and tabolism. Elevated pH and amine values are associated with vaginal flora changes in perimenopausal and postmenopausal women. J Clin Microbiol. 2002;40:2147-2152. both BV and trichomoniasis. 12. Cotch MF, Hillier SL, Gibbs RS, Eschenbach DA. Epidemiology and out- Other common errors physicians may make in misdiag- comes associated with moderate to heavy Candida colonization during preg- nosing vaginitis include insufficient microscopy skills (or nancy. Vaginal Infections and Prematurity Study Group. Am J Obstet Gy- not using a microscope at all to examine vaginal secretions), necol. 1998;178:374-380. not recognizing the poor sensitivity of wet mounts for di- 13. Hillier SL, Krohn MA, Rabe LK, Klebanoff SJ, Eschenbach DA. The nor- agnosing VVC and trichomonal infections, relying on bac- mal vaginal flora, H202-producing lactobacilli, and bacterial vaginosis in pregnant women. Clin Infect Dis. 1993;16:S273-S281. terial cultures for diagnosing vaginitis, and overlooking the 14. Centers for Disease Control and Prevention. Sexually transmitted diseases possibility of mixed infections or that the patient may have treatment guidelines, 2002. MMWR Morb Mortal Wkly Rep. 2002:51 used OTC products that can obscure diagnosis. (RR-6):42-44.

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Diagnosis and Treatment of Routine and Resistant Trichomoniasis Anne M. Rompalo, MD, ScM

According to the World Health Organization (WHO), try to treat partners of exposed women. Men who are ex- trichomoniasis is the most common sexually transmitted periencing no symptoms may balk at having to take med- infection (STI) worldwide. The agency estimated 1999 in- ication. Acidence at 174 million cases, but it acknowledges that data In women, the classic presentation of trichomoniasis is are limited.1 The two regions in which disease rates are a malodorous, diffuse, yellow-green discharge with vulvar highest are South and Southeast Asia, with 76 million new irritation (Figure 1). The discharge and symptoms can cases annually, and sub-Saharan Africa, with 32 million cas- worsen after menses. Left untreated, symptoms can persist es. WHO estimates North America’s incidence at just over for years. Chronic infection can cause desquamation of the 8 million. In the United vaginal epithelium and States, trichomoniasis is sec- FIGURE 1 leukocytic inflammation. ond to chlamydia in estimat- Although the frothy dis- ed annual incidence of STIs. charge accompanied by pru- Trichomoniasis is a para- ritus and burning are the sitic disease caused by the most common symptoms, protozoan Trichomonas vagi- trichomoniasis sometimes is nalis. It is associated with detected in asymptomatic sexual intercourse and is not women. Some of these women generally spread by fomites. Trichomoniasis classically presents with a yellow- may present with the so- It is frequently seen in com- green, malodorous discharge. However, a large called strawberry and percentage of infected women may be asymptomatic. bination with gonorrhea and no discharge. The strawberry bacterial vaginosis (BV). hemorraghea is seen only in Rates are fairly evenly distributed among sexually active about 5% of cases. Its pathogenesis is not well understood. women of all ages. Trichomoniasis is usually diagnosed via microscopy of Trichomoniasis has been characterized for decades, if not vaginal secretions. However, this method has only 60% to longer, as a nuisance disease. However, new evidence sug- 70% sensitivity, at best. When seen on a wet preparation gests that it may be more of a health threat than previously under a microscope, T. vaginalis appears ovoid, about the realized. A study by the Vaginal Infections and Prematu- size of a white blood cell, approximately 10 to 20 µm wide rity Study Group showed that trichomoniasis may be as- (Figure 2). It has four free anterior flagella and a fifth fla- sociated with adverse pregnancy outcomes such as prema- gellum embedded in an undulating membrane that extends ture rupture of the membranes and preterm delivery.2 It around the anterior two-thirds of the cell. Its characteris- has also been associated with increased human immuno- tic jerky movement helps microscopists distinguish it from deficiency (HIV) virus transmission in women.3 an epithelial cell or white blood cell. Culture is the most sensitive commercially available Diagnosing Trichomoniasis via method of diagnosis. However, it is not routinely used be- Wet Preparation and Other Methods cause it takes approximately 2 to 7 days to obtain results. Women are the primary carriers of the disease. Urine is To date, the U.S. Food and Drug Administration (FDA) thought to be toxic to the trichomonad, which is why has not approved any polymerase chain reaction (PCR) tests most men appear to clear the disease rapidly when ex- for T. vaginalis. This author participated in a study to eval- posed. A 1963 study of men who had sex with women uate a new PCR test.5 In this observational study of 337 infected with trichomoniasis showed that 70% of the men women seeking care at an STI clinic, the sensitivity of the were infected within 2 days, but only 47% were infect- PCR test was 84%, compared with 52% for wet prepara- ed 2 weeks later.4 tion and 78% for culture. (Specificity of the PCR test was The majority of men are asymptomatic, but occasional- 94%.) These findings appear to indicate that trichomoni- ly they may present with nongonococcal urethritis—an in- asis may be undertreated using standard algorithms for flammation of the urethra with symptoms akin to chlamy- metronidazole therapy. dial or gonococcal infection. The fact that most men are It should be noted, also, that in addition to T. vaginalis, asymptomatic poses problems when health care providers two related species can infect humans. Trichomonas tenax is

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found in the mouth, and Pentatrichomonas hominis is found not been reinfected should be managed in consultation with in the intestine. When patients who are highly unlikely a specialist. Since therapy is limited for such cases, diagno- to have T. vaginalis, such as an elderly woman in a nurs- sis should be confirmed with culture and sensitivity testing. ing home, have positive urine cultures, contamination of Because very few laboratories do such testing, guidance is the specimen by these other species may be one possible available from the CDC. explanation. However, only T. vaginalis infects the geni- Symptoms of metronidazole-resistant cases of trichomo- tourinary tract. niasis are indistinguishable from routine ones. However, symptoms can persist for months or even years. Unfortu- Treating Trichomoniasis nately for such patients, few alternatives to metronidazole Routine Cases have proved successful. A 1998 study by Nyirjesy et al8 The revised 2002 treatment guidelines from the Centers for found topical paromomycin 6.25% cream to be useful. This Disease Control and Prevention (CDC) recommend metro- medication, however, is associated with a high degree of vul- nidazole 2 g orally as a single dose or 500 mg orally for 7 vovaginal irritation and toxicity and is not widely available. days.6 Randomized controlled trials that have tested these Tinidazole appears to have a good safety profile and bet- regimens have found cure rates as ter patient tolerability than paro- high as 90% to 95%. Treating sex FIGURE 2 momycin. A study by Sobel et al9 partners may result in even higher demonstrated a 92% cure rate in cure rates and is to be encouraged. 24 patients using a regimen of Metronidazole vaginal gel is less ef- oral and vaginal tinidazole for a ficacious than the oral form, with minimum of 14 days. Although cure rates of less than 50%. The the medication has not been ap- vaginal gel does not seem to be able proved by the FDA for this use, it to achieve therapeutic levels in the can sometimes be obtained urethra or perivaginal glands. through a compassionate-use re- The FDA has not approved any quest. Tinidazole is available in therapy other than metronidazole Trichomoniasis, caused by Trichomonas Canada. for treatment of trichomoniasis. vaginalis (shown), is usually diagnosed via In difficult-to-treat cases, not microscopy of vaginal secretions. However, only should sex partners be treat- Difficult-to-Treat Patients this method has only 60% to 70% ed but both patient and partner For routine trichomoniasis infec- sensitivity. Culture is more sensitive but is should be counseled to avoid sex tion, it is unnecessary for either rarely used in the clinical setting. until both are cured. men or women to return for fol- The patient who is allergic to or low-up treatment if they become asymptomatic. But cannot tolerate nitroimidazoles can be desensitized, then what about the returning symptomatic female patient? treated with the therapeutic regimen. Pregnant patients Does she have a new, recurrent, persistent, or resistant in- can be treated with the 2-g oral dose of metronidazole. A fection? Treating the woman’s sex partner during her ini- metaanalysis by Burtin et al10 has shown no teratogenic tial infection may help the caregiver document possible or mutagenic effects from therapeutic dose ranges. Al- cases of resistant disease. though trichomoniasis has been associated with several ad- About 5% of cases of trichomoniasis worldwide are es- verse outcomes of pregnancy, treating asymptomatic in- timated to be resistant to standard metronidazole therapy. fection has not been shown to lessen the association.11 Most cases are of low-level resistance in women and can be HIV-infected patients should be treated the same as HIV- treated with increasing doses of metronidazole. Lossick and negative patients. Kent7 in 1991 published several possible regimens. Dos- ing ranged from 20 g to 40 g, administered over 1 to 2 New on the Horizon: ‘Sick Trich’ weeks. They noted that optimal treatment for men is not Some recent research has reported on an interesting phe- known. The CDC recommends, in cases where initial treat- nomenon that has been named “sick trich,” in which ment with oral metronidazole fails, re-treating patients T. vaginalis itself is infected by a double-stranded (ds) RNA with metronidazole 500 mg twice daily for 7 days.6 If that virus. This causes an upregulation of the synthesis of sur- fails, stepping up to a single 2-g dose of metronidazole dai- face expression of a highly immunogenic protein, p270.12 ly for 3 to 5 days can be tried. High-level metronidazole Infection by this dsRNA virus is also associated with dif- resistance occurs in about 1 in 2,000 to 1 in 3,000 cases. ferential qualitative and quantitative expression of cysteine Patients with laboratory-documented infection who do not proteinases. These proteinases in turn are linked to tricho- respond to the 3- to 5-day treatment regimen and who have Continued on page 15

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New Findings in Routine and Recurrent Vulvovaginal Candidiasis Treatment Jack D. Sobel, MD

The availability of over-the-counter (OTC) medications to that comprise normal vaginal flora, and finding yeast cells treat candidiasis has made it difficult to determine true cur- on cultures of vaginal fluid in the absence of symptoms does rent incidence rates of the disease, because so many women not define VVC. Tself-diagnose and self-treat their infections. However, The pathogenesis of recurrent VVC is typified by two based on data obtained before OTC antifungal medications phases. The first is colonization of the vagina. At this stage, became available, 75% of women have at least one episode the patient is a carrier but is not symptomatic. Host fac- of vulvovaginal candidiasis (VVC) sometime in their lives, tors that enhance susceptibility to Candida colonization in- 40% to 45% have more than one episode, and approxi- clude infection by human immunodeficiency virus (HIV), mately 5% have recurrent VVC.1 uncontrolled diabetes mellitus, and use of corticosteroids, Recurrent VVC is defined as four or more episodes of doc- antibiotics, or hormone replacement therapy. Behavioral umented VVC per year. It is likely that multiple factors factors that may facilitate colonization include frequency contribute to the etiology of recurrent disease. These will of sexual intercourse, orogenital sex, and use of oral con- be discussed in more detail shortly. The majority of recur- traceptives, contraceptive sponges, or an intrauterine de- rent cases are idiopathic, vice. Certain blood serotypes which can be frustrating for FIGURE 1 and African American eth- both patient and clinician. Vulvovaginal Candidiasis (VVC) Incidence nicity are also associated with Women are most likely to by Age, VVC History increased risk of colonization. 1.0 have VVC when they are be- VVC >_4 times in 1 year The second phase in the VVC in past tween 15 and 30 years of age. 0.8 pathogenesis of recurrent In women who have only spo- No history of VVC VVC is the transformation radic VVC, incidence declines 0.6 from colonization to sympto- over the next 20 to 30 years, matic disease. Risk factors for for unknown reasons. It is 0.4 the transformation phase are thought that, perhaps, some 0.2 somewhat different from type of immunity develops Proportion with VVC (Past Year) those for colonization. The 0.0 or that monogamous behavior 18-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64 >_65 major known host factors that may be responsible for the Age in Years facilitate transformation are lower attack rates. In con- Source: Foxman B et al. Sex Transm Dis. 2000;27:230-235. antibiotics use, diabetes, sex- trast, women with recurrent ual activity, and, possibly, VVC do not experience lower incidence until past age 55 carbohydrate excess in the diet. (Figure 1).2 Approximately 25% to 30% of women attribute their Although peak incidence occurs with onset of sexual ac- yeast infections to taking antibiotics. HIV infection is a much tivity, candidiasis is not classified as a sexually transmit- less prominent factor in transformation than it is in colo- ted infection (STI). It is not associated with number of sex- nization. It results in a minor increase in symptomatic dis- ual partners, age of first onset of sexual activity, recent ease. When it does so, the clinical spectrum of the disease change in sexual partners, or other markers seen in classic is identical to that in women without HIV. Recurrent VVC STIs such as chlamydia and gonorrhea. Candida albicans is should not be seen as a sentinel sign of HIV infection. the dominant pathogen in VVC; it is responsible for more Dietary factors such as consuming excessive amounts of than 85% of cases.3 There is no evidence of increasing fre- sugar have been associated anecdotally with recurrent quency of non–C. albicans species, such as Candida glabra- VVC, but an association has now been confirmed by both ta, but if the patient is infected with one of these more un- prospective and retrospective studies. In a recent case-con- usual species, treatment must be altered to fit the pathogen. trol study, Donders et al4 measured glucose metabolism in 62 women without diabetes with recurrent VVC. After in- Pathogenesis of Recurrent VVC gesting 75-g glucose, women with recurrent VVC had a Has Two Phases 15% increase of glucose circulating in their blood, com- As Dr. Marrazzo points out in her discussion elsewhere in pared with the control group, for at least 2 hours. The au- this supplement, Candida are among the many organisms thors suggested that glucose tolerance in women with re-

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current VVC is discretely impaired. It is thought that glu- species, if budding yeast are seen via microscopy, or if the cose may facilitate Candida to vaginal epithelial host is abnormal (e.g., has uncontrolled diabetes, is preg- cells, but this has not been demonstrated. nant, or is immunocompromised).

All ‘Recurrent’ Cases of VVC Treating Recurrent VVC Are Not Candida Ninety percent of the patients who seek treatment for VVC Many of the patients seen by the women’s health care have uncomplicated VVC. These women can be treated provider for recurrent VVC are women who have been re- with short-course therapy with any of the many topical ferred by family practitioners and other nonspecialists. In this azole agents available. Cure rates exceed 90% in this group. author’s experience, approximately three quarters of the pa- Patients with complicated VVC need prolonged thera- tients referred for recurrent VVC do not in fact have the con- py. This approach was validated in a study in which this dition. The most common misdiagnosis is bacterial vaginosis. author participated, comparing a single dose of fluconazole is also frequent- with two sequential doses.6 In this ly misdiagnosed as VVC, a fact FIGURE 2 study, women were categorized as that is not well reported in the having either severe or recurrent herpes literature. What typically candidiasis. The two groups were occurs is that a patient develops separately randomized to receive ei- pruritus, burning, soreness, and ir- ther a single oral 150-mg dose of ritation. Her physician incorrect- fluconazole followed by placebo or ly diagnoses her as having VVC two sequential oral 150-mg doses and prescribes an antifungal of fluconazole 72 hours apart. (Be- cream, and she shows improve- cause fluconazole maintains thera- ment in 4 to 5 days. However, peutic concentrations in vaginal with herpes, she will also get bet- tissue for 72 to 96 hours, the two- Genital herpes is frequently misdiagnosed ter in 4 to 5 days. Most physicians as recurrent vulvovaginal candidiasis, dose treatment was equivalent to 1 expect herpes to manifest as a vesi- especially when it presents with fissures, as week of therapy.) The two-dose cle, a blister, or an ulcer. Howev- seen here, rather than the more classic regimen achieved significantly er, herpes can also appear as a fis- vesicular lesions. higher (P= 0.015) cure rates by day sure, which can be mistaken for 14 in women with severe disease. Candida fissures (Figure 2). When the patient with mis- Logistic regression analysis showed that this benefit may diagnosed herpes experiences subsequent outbreaks, her not apply to women infected with non–C. albicans species. physician may think she has recurrent VVC. Species such as C. glabrata have reduced susceptibility to Other conditions that can be mistaken for VVC include azole agents. The only available agents that appear to be idiopathic vestibulitis syndrome, contact or irritant der- effective against C. glabrata are boric acid and flucytosine. matitis, atrophic vulvovaginitis, physiologic , This physician authored a study of 73 women infected dermatoses such as lichen sclerosus, and, more rarely, with C. glabrata who had failed treatment with azole med- desquamative inflammatory vaginitis. (Some of these con- ications.7 The women were put on a regimen of 600 mg ditions are discussed in more detail in the accompanying of boric acid per day, inserted vaginally, for either 14 or 21 article on vulvovaginal symptoms as manifestations of sys- days. Two thirds of the women were cured, and there was temic diseases.) Thus, the first step in treating recurrent no significant difference in cure rates between the 14-day VVC is to confirm the diagnosis. One cannot make a di- or 21-day regimen. agnosis of VVC on visual inspection alone. If a patient says The patients who were not cured by boric acid were giv- she has used several different antifungal formulations and en 17.4% topical flucytosine cream to use once daily for is not responding to them, she may in fact be communi- 14 days. The flucytosine cream is not available commer- cating that she does not have a Candida infection. cially and must be prepared by a formulating company. It Guidelines have been developed to help physicians des- is very expensive. Of the 30 women who used the flucy- ignate VVC as either uncomplicated or complicated.5 Un- tosine cream, 27 were cured, two failed, and one was lost complicated cases are mild to moderate in degree of sever- to follow-up. ity. Outbreaks are infrequent or sporadic. The pathogen is likely to be C. albicans, and pseudohyphae are seen via mi- Maintenance Therapy for Recurrent VVC croscopy. The host is normal and not pregnant. VVC is con- Numerous studies on treating women with recurrent sidered to be complicated if it is moderate to severe, if it VVC have shown that many women who are cured later recurs four or more times per year, if it is non–C. albicans Continued on page 15

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Overview of Bacterial Vaginosis and Its Role In Upper Genital Tract Infection David A. Eschenbach, MD

Lactobacilli are the dominant microorganisms in normal • Clue cells (squamous epithelial cells covered with bac- vaginal flora, as Dr. Marrazzo discusses elsewhere in this sup- terial rods or cocci, giving them a granular border) are plement. In women with bacterial vaginosis (BV), both present via wet preparation microscopy of vaginal fluid. Lprevalence and concentrations of Gardnerella vaginalis and anaerobic bacteria are increased and lactobacilli are de- The importance of doing a pH test cannot be overem- creased. This author participated in a 2002 study that phasized. A normal pH reading tells the practitioner that the demonstrated that, in women with normal flora, lactobacilli patient has either normal flora or candidiasis; an elevated pH are present in concentrations of about 108 colony-forming reading indicates possible BV, trichomoniasis, or cervicitis. units (CFU)/mL and BV flora are present in concentrations Research has shown that microscopy by the average prac- of about 107 CFU/mL.1 In contrast, the vaginal flora of ticing physician in the United States is not very accurate.4 women with BV show lacto- For practitioners who do not bacilli at 106 CFU/mL con- FIGURE 1 feel confident of their mi- centrations and BV flora at 108 Prevalence/Concentration of Vaginal Flora croscopy skills, a DNA hy- 9 to 10 CFU/mL (Figure 1). Prevalence: 90% ~50% 15% ~95% bridization test is available, Factors known to predis- 8-9 as well as alternative office- 8 10 pose women to BV are (1) Concentration: 10 based tests that measure pH (CFU/mL) lack of lactobacilli or lack of and amines. These tests may 7 hydrogen peroxide (H2O2)- 10 be expensive, but they are producing lactobacilli, (2) better than an unskilled mi- new sexual partner, (3) lesbian 10 6 croscopist in detecting BV. partner with BV, (4) douch- Recommended treatment ing, (5) antibiotic treatment, Lactobacillus BV Flora Lactobacillus BV Flora for BV, according to the lat- (6) coexisting sexually trans- Normal Flora Bacterial Vaginosis (BV) est revision of the Centers for CFU = colony-forming units mitted infection (STI) such as Adapted from Marrazzo JM et al. J Infect Dis. 2002;185:1307-13. Disease Control and Preven- trichomoniasis, and (7) Afri- tion guidelines, is to use can American ethnicity. metronidazole 500 mg twice BV is not considered an STI in the classic sense of daily orally for 7 days, metronidazole gel 0.75% intra- chlamydia or gonorrhea, and treating male partners does vaginally (5-g applicator) once daily for 5 days, or clin- not appear to help prevent recurrence in women. Howev- damycin cream 2% intravaginally (5-g applicator) for er, research done on lesbian partners seems to indicate that 7 days.5 Alternative regimens for BV—metronidazole 2 g BV is transmitted through insertive sex toys and receptive orally in a single dose, clindamycin 300 mg orally twice oral-anal sex.1 This implies that something is being trans- daily for 7 days, or clindamycin ovules 100 g intravaginally mitted sexually, whether it is a phage that kills lactobacilli for 3 days—have lower efficacy against BV. or some other microorganism that has yet to be identified. Research done in 1955 when Gardner and Dukes2 first Dangers of Treating BV Empirically characterized BV showed that introducing G. vaginalis into Dr. Sobel emphasizes the importance of confirming a di- the vagina usually does not produce BV, but introducing agnosis of vulvovaginal candidiasis before treating it in his flora from women with BV into the vagina of someone presentation on that subject in this supplement. The same without BV will induce BV symptoms 73% of the time. is equally true for BV (Figure 2). Medications used im- properly can upset the delicate balance of flora in the nor- Recognizing and Treating BV mal vagina and actually introduce disease in a population Diagnosis of BV is made clinically using Amsel criteria.3 that is otherwise normal. This author participated in a Three of the following four criteria must be met: dose-finding study for clindamycin cream that evaluated • Vaginal fluid has pH ͧ4.7; changes in the vaginal flora.6 In this study, quantitative • Discharge has a homogenous appearance; vaginal cultures for facultative and anaerobic bacteria and • A positive amine odor is evident when potassium hy- genital were performed on women with droxide is added to vaginal fluid (“whiff” test); clinical signs of BV who were treated with various con-

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centrations of clindamycin cream or placebo. The cultures ing exogenous matter into the vagina, whether medications were obtained at baseline and approximately 1 week and or pathogens, is not like putting something on the skin. In 1 month after completion of therapy. In patients treated women, there is direct communication from the vagina with active medication, concentrations of lactobacilli in- through the cervix into the and abdominal cavity. creased and concentrations of other bacteria species de- In women with lactobacilli-dominant flora, most of the creased overall, which was desirable. However, concen- harmful organisms are nonpathogenic or are neutralized be- trations of undesirable Enterococcus species and Escherichia fore they can do harm. This is evidently not the case in coli increased, apparently filling the microbial void left by women with abnormal flora. the drop in other bacteria. These Work by Watts et al11 and New- two organisms are not particular- FIGURE 2 ton et al12 showed that women ly sensitive to clindamycin cream. with BV have a twofold increase in A study from the Netherlands that postpartum —a six- examined changes in vaginal flo- fold increase if they have a cesarean ra after administration of clin- delivery—compared to women damycin cream to women at high with normal flora. A study by Lars- risk of spontaneous preterm birth son et al13 showed that PID fol- showed that using the antimicro- lowing abortion was reduced three- bial agent on women with normal fold by metronidazole therapy in flora was actually harmful.7 Six- women who had BV. teen women in the study who had Bacterial vaginosis typically presents with a The etiology of PID, which in- normal flora at baseline had inter- homogenous, skim milk–like discharge. cludes endometritis, , mediate flora after clindamycin Diagnosis should not be based on pelvic peritonitis, and related in- treatment. appearance alone but in conjunction with fections, is assumed to occur by the pH and amines tests and wet preparation ascent of microorganisms from the microscopy of vaginal fluid. Treating Recurrent BV vagina into the upper genital tract. A study by Sobel et al8 showed that PID has been considered primari- treatment of BV with oral metronidazole or topical clin- ly a sexually transmitted disease caused in large part by gon- damycin yields high success rates initially, but within 90 days orrhea and chlamydia; however, work by Hillier et al14 symptoms have returned in a substantial portion of women. found BV-associated microorganisms present in women What are the options, then, for women with recurring BV? with PID. A number of new approaches are being tested. Several studies conducted in the 1990s have shown that In her discussion on vaginal flora, Dr. Marrazzo discuss- women with BV have three to four times the risk of post- es an ongoing study in which she is involved that is look- hysterectomy cuff cellulitis than women with normal flo- ing at ways to recolonize the of women with BV ra. Evidence for pretreating women with BV prior to sur- with strains of human Lactobacillus crispatus. Dr. Sobel has gical procedures such as hysterectomy is strong, but the studied using metronidazole gel twice weekly to prevent optimal time to begin therapy has not yet been determined. recurrent BV.9 Studies that have looked at BV in patients undergoing in vitro fertilization have found that women with BV have BV and Upper Genital Tract Infection the same conception rates as women with normal flora but As will be discussed in more detail below, BV is associat- a higher pregnancy-loss rate in the first trimester. It ed with increased risk of postpartum endometritis follow- should be noted that the rate of BV or intermediate flora ing either cesarean or vaginal delivery, postcesarean wound in women undergoing in vitro fertilization is approximately infection, postabortion pelvic inflammatory disease (PID), 35% to 40%. This relatively high rate is probably due to postabdominal hysterectomy cuff cellulitis, and preterm the antibiotics patients receive as part of their treatment. delivery. A number of studies have documented an association be- BV has some qualities that make it more likely to invade tween BV and preterm delivery. However, a large study the upper genital tract than other microorganisms. It has of nearly 2,000 women by Carey et al15 found that the ability to produce sialidase, which appears to impair the metronidazole therapy did not have any impact on pre- body’s local immunoglobulin A.10 It is important for venting preterm delivery. This finding does not mean that ob.gyns. to recognize that the cervical mucus does not pro- BV does not cause preterm delivery, only that this an- vide an impermeable barrier and that there is probably a timicrobial regimen given at this time in the pregnancy constant, low-level travel of microorganisms from the vagi- did not work. na to the uterus, fallopian tubes, and abdomen. Introduc- Continued on page 16

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Noninfectious Vulvovaginal Symptoms as Manifestations of Systemic Diseases Jack D. Sobel, MD

Every women’s health care provider learns in medical Lastly, before inserting the speculum, the physician school that the three most common causes of infectious should inspect the entire vulvar and vestibular region thor- vaginitis are, in order of prevalence, bacterial vaginosis oughly. Fissures, lesions, and ulcerations that may lie hid- E(BV), vulvovaginal candidiasis (VVC), and trichomoniasis. den behind skinfolds or obscured by pubic hair will not What is often overlooked, however, is just how frequent- be discovered in a cursory check. ly women who present with vulvovaginal symptoms do not have any of the above diseases. Contact Dermatitis and Irritant Dermatitis In an unpublished study in which this author participat- Among noninfectious causes of vaginitis (Table), the ed, several thousand women at a Midwestern university com- most common are contact dermatitis or chemical der- pleted a daily questionnaire about their vulvovaginal symp- matitis, resulting from exposure to soaps, deodorants, per- toms for 2 months. An interesting finding from this survey fumes, or other products that provoke an allergic or irri- was that approximately one third of respondents described tant reaction. Questioning the patient about use of transient vulvovaginal symptoms that disappeared after 1 to exogenous agents, including spermicides, lubricants, panty 3 days. Women sometimes self-treated with a variety of over- liners, and feminine hygiene products, or about wearing the-counter medications, and most of the time their symp- synthetic or tight-fitting clothing will usually help the toms did not result in a visit to a practitioner. It is impor- physician decide whether the woman’s vaginal symptoms tant for women’s health care providers may be due to chemical dermatitis or to understand how common mild to TABLE an allergic reaction. moderate vulvovaginal symptoms are, Noninfectious Causes of especially in a younger population. Vulvovaginal Symptoms This discussion will focus initially • Irritant/chemical Atrophic vaginitis, or, more specifi- on patients who present with vulvo- cally, atrophic vestibular disease, is • Contact dermatitis/allergic vaginitis but who have normal vagi- underdiagnosed and understudied, • Atrophic (estrogen) nal pH, which effectively rules out particularly in premenopausal women. Postmenopausal BV and trichomoniasis, and who test Postpartum Up to 40% of postmenopausal women negative for Candida via wet prepara- experience symptoms of atrophic • Vulvar dermatosis tion microscopy or culture. Lichen sclerosus, lichen simplex vaginitis, which is caused by a decrease in circulating estrogen. In pre- • Systemic dermatosis Full Dermatologic Eczema, atopic dermatitis menopausal women, estrogen produc- History Is Essential Psoriasis tion can be interrupted by radiation Before the women’s health care provider • Collagen vascular disease therapy, chemotherapy, immunologic begins the clinical examination of the disorders, and oophorectomy. Postpar- • Idiopathic vulvovestibulitis patient, he or she must take a complete syndrome tum estrogen declines may also cause history. Knowing whether a patient has vaginal atrophy. dermatologic disorders, allergies, oral In atrophic vaginal disease, the vagi- pathology, or chronic disease may aid the practitioner in mak- nal epithelium becomes thin and atrophic from lack of es- ing a diagnosis. If a patient says, for example, that she has trogen, with markedly reduced secretions. This may result systemic lupus erythematosus or Sjögren’s syndrome, fore- in . The woman may experience pruritus or most on the physician’s mind should be whether the condi- burning, accompanied by a watery discharge. tion might have vulvar or vaginal manifestations. An ex- amination of the patient’s skin also may reveal important Other Vulvar Dermatoses: Case Studies clues. Eczematous lesions in the antecubital region, for ex- Behçet’s Syndrome ample, may be an indication that a patient has eczema, which A patient was referred to this physician because of recur- may be an explanation for her vulvar pruritus. Inspecting the rent genital ulceration. Upon physical examination, a mouth and oral cavity may uncover chronic mucocutaneous large, deep ulcer on her vulva was apparent. Questioned candidiasis, Behçet’s syndrome, oral lichen planus, or other about her history of oral diseases, she mentioned that she conditions that also manifest in the genitalia. experienced recurrent ulcers in her mouth. She was subse-

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quently diagnosed as having Behçet’s syndrome, a chron- Atopic dermatitis is managed with topical corticosteroids ic inflammatory disorder of unknown etiology character- or one of the newer nonsteroidal immunomodulatory agents. ized by deep, painful, penetrating, and recurring oral and genital ulcers. The ulcers can be either single or multiple, Erosive Lichen Planus do not form a vesicle, and last for weeks. They can occur The usual expression of lichen planus is cutaneous. Occa- on the vulva or in the vagina. sionally, the condition affects solely the mucosal membranes There are no laboratory tests for confirming Behçet’s syn- of the mouth and genitalia. In the mouth, the lesions are drome; diagnosis must be made clinically. Fortunately, it erosive and typically present on the buccal and gingival sur- is relatively uncommon in the United States. Prevalence faces, surrounded by a white area (Figure 2A on page 14). is highest in Japan, the Middle East, and certain Mediter- Oral lichen planus causes soreness in the mouth and some- ranean regions. Management depends on the frequency and times the pharynx and esophagus. There may be gingival severity of recurrences. Patients are irritation as well. typically treated with intralesional FIGURE 1 In the genital area, the vestibule corticosteroids as palliative therapy. is far more likely to be the site of in- These do not prevent recurrences. volvement than the vagina. The ero- Thalidomide is sometimes used for sive lesions are similar to those seen systemic treatment. in the mouth (Figure 2B on page 14). There are no obvious, well- Recurrent Erythema Multiforme demarcated ulcers but instead a fo- A patient was referred as having re- cal, multifocal, or diffuse erosion. current VVC because every few The condition typically causes severe weeks she would experience rawness dyspareunia. and soreness, accompanied by edema, If the patient has florid lichen in her labia that had an erosive com- planus of the mouth, diagnosis of ponent (Figure 1). When ques- This patient was referred for recurrent genital involvement is straightfor- tioned, she acknowledged that she vulvovaginal candidiasis because she ward. However, occasionally a pa- also had soreness in her pharynx. Ex- experienced soreness, erythema, and tient will present with vaginal or amination of her palate revealed the edema every few weeks. When ques- vulvar symptoms with no prior di- typical finding of recurrent erythe- tioned about pain anywhere else, she agnosis of skin or oral involvement. acknowledged that these recurrences ma multiforme. Recurrent erythema were frequently accompanied by sore- In these cases, diagnosis is much multiforme is sometimes drug in- ness in her pharynx. Inspection of her more difficult. Biopsy is not essen- duced, but it is most commonly as- mouth revealed oral lesions of recur- tial to diagnosis, but, if done, should sociated with virus rent erythema multiforme. reveal loss of surface epithelium and infection. It is usually treated with deeper inflammatory infiltrate. acyclovir, along with corticosteroids during the acute phase. Typically, patients with erosive lichen planus have pu- rulent discharge. A Gram stain or wet preparation exam- Psoriasis and Atopic Dermatitis ination of the discharge would likely reveal vast numbers With Vulvar Involvement of both polymorphonuclear neutrophil (PMN) leukocytes Another patient presented with and ery- and mononuclear cells. thematous focal lesions that were lateral to the vagina and Both oral and genital manifestations of erosive lichen vulva, with a silvery sheen. These types of lesions are char- planus are extremely difficult to treat. For the women’s acteristic of psoriasis. Psoriatic involvement of the vulva health care provider, management of the disease depends is quite common. When examining the patient, the prac- on whether the erosive involvement is in the vagina or the titioner can look for signs of psoriasis elsewhere, such as vestibule. For the vagina, potent topical corticosteroids are knees and other extensor surfaces. Diagnosis can be con- required, but until the recent introduction of a clobetasol firmed by biopsy. Cases are typically managed by derma- gel, such products were not commercially available for in- tologists using topical corticosteroids and systemic agents. travaginal use. Corticosteroids designed for rectal use are Similarly, atopic dermatitis can also present with pruri- not strong enough. This physician has had success in treat- tus vulvae. Once again, the practitioner can look for signs ing patients by having creams containing from 10% to of eczematous lesions elsewhere on the body. A patient was 15% hydrocortisone formulated. The vagina typically re- referred to the author for recurrent VVC because she had sponds dramatically, provided the patient has adequate pruritus and irritation. However, she had lesions in the per- vaginal estrogenization. Topical estrogen may be required ineal area that were typical of severe atopic dermatitis. for optimal healing effect.

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Erosive lichen planus of the vestibule is far more prob- addition to its antimicrobial capabilities. Later work by An- lematic to treat. Patients typically cannot tolerate topical dersen et al3 has shown that 60% to 70% of patients get corticosteroids on the raw, eroded skin surface. The typi- better with corticosteroid suppositories. The fact that DIV cal approach is to begin management with very-low-dose responds to corticosteroids argues against its having an in- corticosteroids, accompanied by topical estrogen, and to try fectious etiology. to increase the corticosteroid’s strength as the patient heals. Lichen Sclerosus Desquamative Inflammatory Vaginitis A patient presented with hypopigmented skin changes lat- Occasionally, women will present with a vaginitis that is pu- eral to the labia, along with telangiectasia, atrophy, and loss rulent, but they have no evidence of lichen planus in either of labia minora. This agglutination of the labia minora, typ- the mouth or the genitalia. Typically, these are post- ically accompanied by erythematous atrophy or vestibular menopausal women already on hor- erosion, is typical of lichen sclerosus. mone replacement therapy (HRT). FIGURES 2A, 2B In advanced disease, the They complain of a chronic discharge, may be ablated, and there is scarring which is greenish yellow, as well as and fibrosis of the surrounding tissue. burning, pruritus, and pain in the The vulvar component responds to vagina, vestibule, or vulva. They ex- corticosteroid treatment. However, perience not only dyspareunia but also erosion and inflammation in the postcoital burning. A test of the vagi- vestibule do less well with cortico- nal discharge will indicate pH above steroids. Because many of the women 6.0, and wet preparation microscopy who present with lichen sclerosus are will show numerous PMNs and A postmenopausal, they are often on mononuclear and parabasal cells. Bac- HRT. Treating them with cortico- teriologist Herman Gardner first de- steroids gives them two risk factors for scribed this syndrome several decades candidiasis. Therefore, the physician ago, naming it desquamative inflam- must ascertain whether exacerbation of matory vaginitis (DIV).1 He termed it pruritus is due to the natural history “desquamative” because of the eroded of lichen sclerosus or possible super- appearance of the vagina and the large imposed VVC infection. number of parabasal cells representing Graft vs. Host Disease a desquamation of the epithelium. B An inspection of the vagina may re- Patients who have received bone mar- veal anular erythematous lesions. Oral erosive lichen planus may pre- row grafts or other types of transplants They may give the vagina a spotted sent (A) with diffuse erosive lesions frequently develop vulvovaginal symp- appearance, similar to the strawberry on the buccal surface, accompa- toms. Because they are on long-term cervix. Sometimes the erosions are nied by gingival symptoms and immunosuppressive therapy, they are soreness in the esophagus and much more diffuse. pharynx. In the genital area (B), often treated empirically for VVC. Al- Distinguishing DIV from erosive involvement usually centers on the though the most common sites for lichen planus can be difficult. In fact, vestibule, not the vagina. Lesions graft vs. host disease are the skin, gut, many patients first diagnosed with are similar to those seen in the and liver, vulvovaginal manifestations DIV are later rediagnosed as having mouth. can occur. The disease may present as the latter disease. It is possible that erosions that resemble lichen sclerosus they are the same entity and that patients with DIV are or lichen planus. These patients are managed by treating women who have no oral, skin, or vulvar manifestations of the graft vs. host disease in consultation with an oncologist. the disease. This author participated in a study in which DIV was REFERENCES treated with 2% clindamycin suppositories, resulting in 1. Gardner HL. Desquamative inflammatory vaginitis: A newly defined entity. clinical improvement in more than 95% of patients.2 Be- Am J Obstet Gynecol. 1968;102:1102-1105. cause the patients did not get better with topical metro- 2. Sobel JD. Desquamative inflammatory vaginitis: A new subgroup of puru- lent vaginitis responsive to topical 2% clindamycin therapy. Am J Obstet Gy- nidazole or systemic antibiotics, it was thought that DIV necol. 1994;171:1215-1220. may be caused by a clindamycin-specific microorganism, 3. Anderson M, Kutzner S, Kaufman RH. Treatment of vulvovaginal lichen such as Mycoplasma genitalium. However, it is now known planus with vaginal hydrocortisone suppositories. Obstet Gynecol. that topical clindamycin has an antiinflammatory effect in 2002;100:359-362.

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Diagnosis and Treatment of Routine and Prematurity Study Group. Sex Transm Dis. 1997;24: 353-360. Resistant Trichomoniasis 3. Laga M, Manoka A, Kivuvu M, et al. Nonulcerative sexually transmitted diseases as risk factors for HIV-1 transmission in women: Results from a co- Continued from page 7 hort study. AIDS. 1993; 95-102. 4. Weston TET, Nicol GS. Natural history of trichomonal infection in males. monal adherence to the vaginal epithelium, cytotoxicity, Br J Venerol Dis. 1963;39:251-257. and degradation of basement membrane components. 5. Wendel KA, Erbelding EJ, Gaydos CA, Rompalo AM. Trichomonas vaginalis This author participated in a cross-sectional study in an polymerase chain reaction compared with standard diagnostic and therapeu- STI clinic to determine the prevalence and clinical signif- tic protocols for detection and treatment of vaginal trichomoniasis. Clin In- fect Dis. 2002;35:576-580. icance of the dsRNA virus–infected T. vaginalis.13 The 6. Centers for Disease Control and Prevention. Sexually transmitted diseases dsRNA virus was isolated in 21 of the 28 cases of trich- treatment guidelines, 2002. MMWR Morb Mortal Wkly Rep. 2002:51(RR- omoniasis (22 women and 6 men). The virus was not as- 6):44-45. sociated with the presence of discharge, dysuria, or geni- 7. Lossick JG, Kent HL. Trichomoniasis: Trends in diagnosis and manage- tal pruritus, irritation, or odor. Women were more ment. Am J Obstet Gynecol. 1991;165:1217-1222. commonly infected than men (86% vs. 33%). Patients with 8. Nyirjesy P, Sobel JD, Weitz MV, Leaman DJ, Gelone SP. Difficult-to-treat trichomoniasis: Results with paromomycin cream. Clin Infect Dis. the dsRNA-infected Trichomonas were significantly older 1998;26:986-988. than patients without it (median age, 38 years vs. 23 years; 9. Sobel JD, Nyirjesy P, Brown W. Tinidazole therapy for metronidazole- P=0.003). However, it should be emphasized that this was resistant vaginal trichomoniasis. Clin Infect Dis. 2001;33:1341-1346. a small study, with few male subjects. Although this new 10. Burtin P, Taddio A, Ariburnu O, Einarson TR, Koren G. Safety of dsRNA virus may have important implications for viru- metronidazole in pregnancy: A meta-analysis. Am J Obstet Gynecol. 1995;172:525-529. lence and pathogenesis of T. vaginalis, much more data are 11. Klebanoff MA, Carey JC, Hauth JC, et al. Failure of metronidazole to pre- needed before conclusions can be made on its significance. vent preterm delivery among pregnant women with asymptomatic Tricho- monas vaginalis infection. N Engl J Med. 2001;345:487-493. REFERENCES 12. Khoshnan A, Alderete JF. Trichomonas vaginalis with a double-stranded 1. World Health Organization Department of HIV/AIDS. Global prevalence RNA virus has upregulated levels of phenotypically variable immunogen and incidence of selected curable sexually transmitted infections. 2001. mRNA. J Virol. 1994;68:4035-4038. Available at: http://www.who.int/docstore/hiv/GRSTI/006.htm. Accessed 13. Wendel KA, Rompalo AM, Erbelding EJ, Chang TH, Alderete JF. Dou- April 27, 2003. ble-stranded RNA viral infection of Trichomonas vaginalis infecting patients 2. Cotch MF, Pastorek JG, Nugent RP, et al. Trichomonas vaginalis associated attending a sexually transmitted diseases clinic. J Infect Dis. with low birth weight and pre-term delivery. The Vaginal Infections and 2002;186:558-561.

New Findings in Routine and Recurrent maintenance prophylactic therapy of 284 women with re- Vulvovaginal Candidiasis Treatment current VVC. Initial findings are discussed here, although Continued from page 9 the study has not yet been published. Patients were initially given three doses of fluconazole relapse. Even in women without recurrent vaginitis, the 72 hours apart to induce clinical remission. At day 14, all offending Candida species can be cultured again approx- patients were asymptomatic and 95% had negative cul- imately 4 weeks after successful treatment (i.e., success- tures. However, polymerase chain reaction analysis showed ful treatment defined as having an early posttreatment neg- that the women were still colonized with the microorgan- ative culture as well as cessation of symptoms). This is isms; there were simply too few of them to be detected by rarely due to reinfection. Instead, the organisms appear to culture. The women then began fluconazole 150 mg or have learned how to adapt. Such organisms are now be- placebo once a week as maintenance therapy for 6 months. ing referred to as adaptive strains of C. albicans that are After they concluded the maintenance therapy, they were genetically selected to adapt to fluconazole. The existence observed for an additional 6 months. of such strains may explain why so many women experi- During the 6-month maintenance period, 128 of the 142 ence recurrent VVC. women taking fluconazole remained in remission, compared Not only are the women who have recurrent disease more with only 51 of 142 women taking placebo. At the end of likely to become colonized after initial treatment, they are 12 months, approximately 40% of the women who had also more likely to develop symptoms. They appear less able been on fluconazole had relapsed. However, a 60% cure rate to tolerate the organism in their vaginas than women with in this difficult-to-treat population is worth noting. uncomplicated disease. Thus, a study was done to see if Serial cultures performed throughout the study did not maintenance therapy could prevent these women from be- show emergence of resistance to fluconazole or emergence coming colonized. This was a randomized, double-blind, of non–C. albicans species. Fluconazole appeared to be ex- multicenter study comparing fluconazole with placebo as Continued on page 16

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New Findings in Routine and Recurrent 3. Sobel JD. Treatment of vaginal Candida infections. Expert Opin Pharmacother. Vulvovaginal Candidiasis Treatment 2002;3:1059-1065. Continued from page 15 4. Donders GG, Prenen H, Verbeke G, Reybrouck R. Impaired tolerance for glucose in women with recurrent vaginal candidiasis. Am J Obstet Gynecol. 2002;187:989-993. tremely safe, with no discontinuations due to adverse ef- 5. Sobel JD, Faro S, Force RW, et al. Vulvovaginal candidiasis: Epidemiologic, fects. In conclusion, fluconazole appears to be a safe and rea- diagnostic, and therapeutic considerations. Am J Obstet Gynecol. sonable means of managing, if not curing, recurrent VVC. 1998;178:203-211. 6. Sobel JD, Kapernick PS, Zervos M, et al. Treatment of complicated Candida REFERENCES vaginitis: Comparison of single and sequential doses of fluconazole. 1. Centers for Disease Control and Prevention. 1998 treatment guidelines for Am J Obstet Gynecol. 2001;185:363-369. sexually transmitted diseases. MMWR Morb Mortal Wkly Rep. 1998:47(RR- 7. Sobel JD. Therapy of vaginitis due to Candida glabrata: Use of topical boric 1):75-79. acid and flucytosine. Am J Obstet Gynecol. 2003. In press. 2. Foxman B, Barlow R, D’Arcy H, Gillespie B, Sobel JD. Candida vaginitis: Self-reported incidence and associated costs. Sex Transm Dis. 2000;27:230-235.

Overview of Bacterial Vaginosis and 5. Centers for Disease Control and Prevention. Sexually transmitted diseases Its Role In Upper Genital Tract Infection treatment guidelines, 2002. MMWR Morb Mortal Wkly Rep. 2002:51 (RR- 6):42-44. Continued from page 11 6. Hillier S, Krohn MA, Watts DH, Wolner-Hanssen P, Eschenbach D. Mi- crobiologic efficacy of intravaginal clindamycin cream for the treatment of BV and HIV bacterial vaginosis. Obstet Gynecol. 1990;76:407-413. Several cohort studies have shown that women with BV have 7. Vermeulen GM, van Zwet AA, Bruinse HW. Changes in the vaginal flora after 2% clindamycin vaginal cream in women at high risk of spontaneous higher acquisition rates of human immunodeficiency virus preterm birth. Br J Obstet Gynecol. 2001;108:697-700. (HIV) than women with normal flora. The elevated pH and 8. Sobel JD, Schmitt C, Merriwether C. Long-term follow-up of patients with decreased number of H2O2-producing lactobacilli in the bacterial vaginosis treated with oral metronidazole and topical clindamycin. vagina that characterize BV may be two possible mechanisms J Infect Dis. 1993;167:783-784. by which BV may aid in HIV seroconversion. BV is also as- 9. Sobel JD, Leaman D. Suppressive maintenance therapy of recurrent bacteri- al vaginosis utilizing 0.75% metronidazole vaginal gel. Presented at: the sociated with lowered levels of secretory leukocyte protease Second International Meeting of Bacterial Vaginosis; September 6, 1998; inhibitors, both of which are believed to contribute to HIV Aspen, Colo. resistance. BV is associated with increased levels of inter- 10. Cauci S, Driussi S, Monte R, et al. Immunoglobulin A response against leukin 1-β cytokines, which are known to upregulate HIV Gardnerella vaginalis hemolysin and sialidase activity in bacterial vaginosis. replication. Lastly, G. vaginalis and Mycoplasma hominus both Am J Obstet Gynecol. 1998;178:511-515. 11. Watts DH, Krohn MA, Hillier SL, Eschenbach DA. Bacterial vaginosis as a have been shown to stimulate HIV expression in vitro. risk factor for post-cesarean endometritis. Obstet Gynecol. 1990;75:52-58. 12. Newton ER, Prihoda TJ, Gibbs RS. A clinical and microbiologic analysis of REFERENCES risk factors for puerperal endometritis. Obstet Gynecol. 1990;75:402-406. 1. Marrazzo JM, Koutsky LA, Eschenbach DA, et al. Characterization of vagi- 13. Larsson PG, Platz-Christensen JJ, Thejls H, Forsum U, Pahlson C. Inci- nal flora and bacterial vaginosis in women who have sex with women. J In- dence of pelvic inflammatory diseases after first-trimester legal abortion in fect Dis. 2002;185:1307-1313. women with bacterial vaginosis after treatment with metronidazole: A dou- 2. Gardner HL, Dukes CD. Haemophilus vaginalis vaginitis: A newly defined ble-blind randomized study. Am J Obstet Gynecol. 1992;166:100-103. specific infection previously classified “non-specific vaginitis.” Am J Obstet 14. Hillier SL, Kiviat NB, Hawes SE, et al. Role of bacterial vaginosis–associat- Gynecol. 1955:69:962-967. ed microorganisms in endometritis. Am J Obstet Gynecol. 1996;175:435-441. 3. Amsel R, Totten PA, Spiegel CA, et al. Nonspecific vaginitis: Diagnostic 15. Carey JC, Klebanoff MA, Hauth JC, et al. Metronidazole to prevent criteria and microbial and epidemiologic associations. Am J Med. preterm delivery in pregnant women with asymptomatic bacterial vagi- 1983;74:14-22. nosis. National Institute of Child Health and Human Development Net- 4. Ferris DG, Hendrich J, Payne PM, et al. Office laboratory diagnosis of work of Maternal-Fetal Medicine Units. N Engl J Med. 2000;342:534-540. vaginitis: Clinician-performed tests compared with a rapid nucleic acid hy- bridization test. J Fam Pract. 1995;41:575-581.

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