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A Supplement to

Ob.Gyn. News

A Clinical Update In Treatment of Bacterial Vaginosis


H IGHLIGHTS
I NTRODUCTION
Jack D. Sobel, MD, Chair Professor & Chief Division of Infectious Diseases Wayne State University, Detroit
OF A

C LINICAL R OUNDTABLE

P RIMARY C ARE P ERSPECTIVE IN T REATING B ACTERIAL VAGINOSIS


Daron G. Ferris, MD Professor of Family Medicine and Obstetrics and Gynecology Medical College of Georgia, Augusta

M ISDIAGNOSIS

OF

VAGINAL I NFECTIONS

Paul Nyirjesy, MD Associate Professor of Obstetrics and Gynecology Drexel University College of Medicine, Philadelphia

B ACTERIAL VAGINOSIS

AND

C ERVICAL I NFLAMMATION

Jane R. Schwebke, MD Professor of Medicine University of Alabama at Birmingham, School of Medicine

C ERVICAL C YTOKINE R ESPONSE IN P REGNANT W OMEN T REATED FOR B ACTERIAL VAGINOSIS


Sharon L. Hillier, PhD Professor Obstetrics, Gynecology and Reproductive Sciences Magee Womens Hospital of the University of Pittsburgh Medical Center, Pittsburgh

R ECENT F INDINGS IN THE T REATMENT R ECURRENT B ACTERIAL VAGINOSIS


Jack D. Sobel, MD

OF

C HALLENGES FOR THE N URSE P RACTITIONER /P HYSICIAN A SSISTANT IN M ANAGING PATIENTS WITH VAGINITIS
Mimi Secor, MS, FNP CEO President NPACE Natick, Mass.

Jointly sponsored by Excerpta Medica, Inc., and OB.GYN. NEWS.

Ob.Gyn. News
Alan J. Imhoff

Group Publisher/ General Manager

A Clinical Update In Treatment of Bacterial Vaginosis


H IGHLIGHTS 4
OF A

Vice President, Medical Education & Business Development

C LINICAL R OUNDTABLE

Sylvia H. Reitman
Clinical Editor

Geneva Collins
Program Manager, Medical Education

INTRODUCTION Jack D. Sobel, MD, Chair


Professor & Chief Division of Infectious Diseases Wayne State University Detroit

Sara M. Hagan
National Account Manager

Kathy Carlson
Art Director

PRIMARY CARE PERSPECTIVE IN TREATING BACTERIAL VAGINOSIS Daron G. Ferris, MD


Professor of Family Medicine and Obstetrics and Gynecology Medical College of Georgia Augusta

Louise A. Lynch
Production Specialist

Rebecca Slebodnik
The roundtable discussion from which this supplement was developed took place on January 9, 2004, in Costa Rica. It was supported by a restricted educational grant from

MISDIAGNOSIS OF VAGINAL INFECTIONS Paul Nyirjesy, MD


Associate Professor of Obstetrics and Gynecology Drexel University College of Medicine Philadelphia

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The supplement was produced by the medical education department of International Medical News Group. Neither the Editor of OB.GYN. NEWS, the Editorial Advisory Board, nor the reporting staff contributed to its content. Copyright 2004 International Medical News Group, an Elsevier company. All rights reserved. No part of this publication may be reproduced or transmitted in any form, by any means, without prior written permission of the Publisher. The opinions expressed in this supplement are those of the presenters and do not necessarily reflect the views of the supporter or the Publisher. International Medical News Group will not assume responsibility for damages, loss, or claims of any kind arising from or related to the information contained in this publication, including any claims related to the products, drugs, or services mentioned herein.

BACTERIAL VAGINOSIS AND CERVICAL INFLAMMATION Jane R. Schwebke, MD


Professor of Medicine University of Alabama at Birmingham, School of Medicine

10

CERVICAL CYTOKINE RESPONSE IN PREGNANT WOMEN TREATED FOR BACTERIAL VAGINOSIS Sharon L. Hillier, PhD
Professor Obstetrics, Gynecology and Reproductive Sciences Magee Womens Hospital of the University of Pittsburgh Medical Center Pittsburgh

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RECENT FINDINGS IN THE TREATMENT RECURRENT BACTERIAL VAGINOSIS Jack D. Sobel, MD

OF

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CHALLENGES FOR THE NURSE PRACTITIONER/PHYSICIAN ASSISTANT MANAGING PATIENTS WITH VAGINITIS Mimi Secor, MS, FNP
CEO President NPACE Natick, Mass.

IN

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Cover illustration: Agnes Audras/ PhotoAlto/PictureQuest

CME POST-TEST

AND

EVALUATION

Accreditation This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Excerpta Medica, Inc., and OB.GYN. NEWS. Excerpta Medica is accredited by the ACCME to provide continuing medical education for physicians. Excerpta Medica designates this educational activity for a maximum of 1.25 category 1 credits toward the AMA Physicians Recognition Award. Each physician should claim only those credits that he/she actually spent in the educational activity. The American Medical Association has determined that non-US licensed physicians who participate in this activity are eligible for AMA/Physicians Recognition Award category 1 credit. Term of Approval: April 2004 March 2005 Target Audience This activity has been developed for obstetricians/ gynecologists, family practice physicians, nurse practitioners, and other health care professionals who are involved in the diagnosis and treatment of bacterial vaginosis. Educational Needs Bacterial vaginosis (BV), once thought to be an infection that caused symptomatic vaginitis and discomfort to women, but was not harmful outside the vaginal microenvironment, is now known to be associated with many adverse sequelae, including increased risk of preterm birth, premature rupture of membranes, pelvic inflammatory disease, mucopurulent cervicitis, postoperative infections, and spontaneous abortion. Clinicians who treat patients with the condition need to keep abreast of recent advancements in BV research, such as studies that demonstrate that proinflammatory cytokines are elevated in the cervical secretions of women with BV and trials that evaluate maintenance suppressive therapy for treatment of recurrent BV.

Learning Objectives After reading and studying the presentations in this supplement, participants should be prepared to: List the criteria for diagnosing BV and how to distinguish it from vulvovaginal candidiasis and other conditions involving symptomatic vaginal discharge. Summarize recent research that examined cervical cytokine response in BV and the implications of these findings for treatment of mucopurulent cervicitis. Describe the conflicting data surrounding treatment of pregnant women with BV to prevent preterm birth and other complications. Identify two novel therapeutic regimens that are being evaluated to treat recurrent BV. Faculty Disclosure Faculty/authors must disclose any significant financial interest or relationship with proprietary entities that may have a direct relationship to the subject matter. They must also disclose any discussion of investigational or unlabeled uses of products. Dr Ferris has received funding for clinical grants from 3M Pharmaceuticals. He is a consultant to and has received honoraria for CME presentations from 3M. Dr Hillier has received funding for clinical grants from 3M, Pfizer Inc., and Johnson & Johnson. She is a consultant to 3M, Cytokine PharmaSciences, Inc., Rostam Ltd., and Wyeth. She discusses the unlabeled use of metronidazole gel for the treatment of bacterial vaginosis in pregnancy. Dr Nyirjesy has received clinical grants from 3M and Pfizer. He is a consultant to 3M and Personal Products Company. Dr Schwebke has received funding for clinical grants from 3M, Personal Care Products, Pfizer, and Rostam. She is a consultant to 3M and Rostam. Ms Secor is a consultant to 3M. She discusses the unlabeled use of metronidazole vaginal gel 0.75% for suppressive therapy of chronic bacterial vaginosis. Dr Sobel has received funding for clinical grants from 3M, Merck & Co., Inc., and Pfizer. He discusses the unlabeled use of metronidazole gel for maintenance therapy of bacterial vaginosis.

Introduction

aginitis has been estimated to be responsible for more than 10 million physician office visits per year,1 yet proper diagnosis and successful treatment remain a challenge for many clinicians. Bacterial vaginosis (BV), in particular, is a poorly understood phenomenon despite the fact that it is the most common cause of infectious vaginitis in the United States. Although its precise etiology remains a mystery, BV is now recognized as a complex process that represents a profound shift in the microbial flora of the vagina. It has been linked to numerous adverse sequelae, from preterm birth to pelvic inflammatory disease. In these pages, readers will find guidance from five distinguished colleagues and this author designed to

aid them in managing patients with either acute or chronic symptoms: an overview on making a differential diagnosis for common causes of vaginitis, separate research updates on the possible links between BV and cervicitis, primary care physician and nurse practitioner perspectives on treating women with vaginitis, and insight into the latest theories on the etiology of recurrent BV, including some novel therapies being explored. The following presentations were based on a roundtable discussion that took place on January 9, 2004, at Playa Herradura, Costa Rica. Jack D. Sobel, MD
Reference
1. Kent HL. Epidemiology of vaginitis. Am J Obstet Gynecol. 1991;165:1168-1176.

Primary Care Perspective in Treating Bacterial Vaginosis


Daron G. Ferris, MD

acterial vaginosis (BV) represents a transformation of the normal vaginal ecosystem into a polymicrobial syndrome that is clinically diagnosed by the presence of three of four characteristics. The first characteristic is one of which the patient herself is often aware and which may be the reason for her visit to the practitioners office: a thin, homogenous, vaginal discharge. The discharge is uniformly adherent, coating the vaginal walls, and may have either a yogurt-like or pasty consistency. A second defining characteristic of BV is elevated pH levels. A normal, healthy vagina has a pH <4.5. The importance of pH testing has been discussed elsewhere (see article by Paul Nyirjesy, MD, page 6), but it cannot be emphasized enough that a pH test is one of the most sensitive tests for diagnosis of BV. Although Amsel criteria state that BV has a pH >4.5, other guidelines use a cutoff of pH >4.7.1,2 How it is defined in daily clinical practice will probably be determined by the type of pH paper used; scaling guides vary. When performing a pH test, clinicians should be careful to sample only the vaginal side walls and to avoid the cervical os or posterior fornix, where there may be pooling of cervical secretions, which have a more alkaline pH than that of normal vaginal fluid. The presence of menstrual blood or semen will also elevate vaginal pH levels. A third characteristic of BV is a fishy odor, indicating the presence of amines. Sometimes the odor is evident during the vaginal examination, and testing for it by adding 10% potassium hydroxide to vaginal fluid is unnecessary. A fourth characteristic is the presence of clue cells (squa-

mous epithelial cells covered with bacterial rods or cocci, giving them a granular border) when the vaginal discharge is examined by wet-preparation microscopy. However, normal cells can sometimes be misdiagnosed as clue cells. These so-called pseudo-clue cells have intracellular vacuoles that may resemble bacteria adhering to the cell surface. The key in distinguishing them from genuine clue cells is to look carefully at the cellular borders. On real clue cells, the borders will appear stippled or rough, because of bacteria clinging to them. More important, the clinician should note the background bacteria. If there are not plentiful lactobacillilarge, grampositive rod-shaped organismsthe suspicion for BV is raised. Polymorphonuclear leukocytes are not associated with BV infection but, if seen, could be a sign of mixed infection or cervicitis. Treatment for BV The Centers for Disease Control and Prevention (CDC) 2002 treatment guidelines for sexually transmitted diseases recommend using one of three regimens to treat BV: oral metronidazole (500 mg twice daily for 7 days), metronidazole vaginal gel (one applicator full intravaginally daily for 5 days), or clindamycin cream (one applicator full intravaginally daily for 7 days) for treatment of BV.3 The guidelines provide alternative therapies but describe them as less efficacious. The first alternative, 2 g oral metronidazole given in a single dose, may be a reasonable approach if patient noncompliance is a concern (Table on page 5). Patients prescribed metronidazole should be counseled to
A Clinical Update in Treatment of Bacterial Vaginosis

TABLE.

Treatment Guidelines for BV*

Recommended Regimens (equal efficacy) Oral metronidazole 500 mg twice daily for 7 days Metronidazole vaginal gel 0.75% intravaginally for 5 days Clindamycin cream 2% intravaginally for 7 days Alternative Treatment (less efficacious) Oral metronidazole 2 g single dose Oral clindamycin 300 mg twice daily for 7 days Clindamycin vaginal ovules intravaginally for 3 days
* Bacterial vaginosis; for nonpregnant women. Source: Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2002. MMWR Morb Mortal Wkly Rep. 2002;51(RR-6):42-44.

gel than if they used oral medication. This was true whether compliance was recorded via paper diary or PDA. However, the vast majority (95% of PDA entries and 93% of paper diary entries) of noncompliant patients were shown to be not truthful when answering the question After you took each dose of medicine, did you enter the date and time on the patient diary? Thus, it can be construed that self-reports of compliance may be overestimated. Conclusion The physician should be aware not only of the presenting symptoms of BV but also of the tests available for making the differential diagnosis and of the limitations of these tests. Although the recommended therapies for BV are generally efficacious, treatment failures do occur, and referral to a specialist may be appropriate for confusing cases. Proper diagnosis leads to greater patient satisfaction and fewer visits to health care providers. It reduces the use of inappropriate medications and minimizes the potential for serious sequelae to develop from untreated disease. It saves money. In other words, it leads to better health care. Further Comments Dr Schwebke: Dr Ferris has described noncompliance in taking prescribed medications, but patient noncompliance regarding follow-up visits can be an issue as well, particularly in a population that is seeking treatment at a sexually transmitted infection clinic. The patients simply do not return for evaluation, so it is difficult to determine treatment efficacy. The idea of treat the cervicitis and the BV will resolve may have been based on empiric experience that patients do not return once they receive treatment for cervicitis. But if this experience is based on a high-risk population, the logic is flawed, because these patients usually do not come back regardless of their symptom status. Dr Sobel: I agree that studies in patients with BV are a challenge because of the high dropout rate. This has been especially true in our long-term maintenance therapy trials, in which we put women on 10-day treatment therapy, followed by 3 months maintenance therapy, and then sought to evaluate them 6 months later (see article by Jack D. Sobel, MD, page 12). References
1. Amsel R, Totten PA, Spiegel CA, et al. Nonspecific vaginitis: Diagnostic criteria and microbial and epidemiologic associations. Am J Med. 1983;74: 14-22. 2. Thomason JL, Gelbart SM, Anderson RJ, et al. Statistical evaluation of diagnostic criteria for bacterial vaginosis. Am J Obstet Gynecol. 1990;162:155-160. 3. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2002. MMWR Morb Mortal Wkly Rep. 2002;51(RR-6):42-44. 4. Ferris DG, Litaker MS, Woodward L, Mathis D, Hendrich J. Treatment of bacterial vaginosis: A comparison of oral metronidazole, metronidazole vaginal gel, and clindamycin vaginal cream. J Fam Pract. 1995;41:443-449. 5. Bartley JB, Ferris DG, Allmond LM, et al. Personal digital assistants used to document compliance of bacterial vaginosis treatment. Presented at: 17th FIGO World Congress of Gynecology and Obstetrics; November 2-7, 2003; Santiago, Chile.

avoid consuming any alcohol within 24 hours of taking the medication or they may experience disulfiram-like reactions such as nausea and vomiting. Patients given clindamycin cream should be advised that the product has an oil base that may weaken barrier contraceptive methods such as condoms and diaphragms. The CDC states that a follow-up visit is unnecessary if symptoms resolve. When treating patients with recurrent BV, however, clinicians should request that they return for an evaluation. Lack of cure could indicate refractory disease, not recurrent episodes. It is common for women to develop a subsequent yeast infection after treatment for BV (30% do, according to one study4). A patient may mistake this for BV recurrence. If the physician does not examine her but merely prescribes more antimicrobial therapy after a telephone consultation, this action is likely to overlook her symptoms. Patient Compliance for BV Therapy When a patients BV symptoms do not resolve after treatment or if they return within a few months, it may not be an issue of recurrence or refractory disease at all, but simply that the patient failed to take her medication as prescribed. Patient compliance with some at-home therapies is notoriously difficult to measure. Patient diaries are unreliable all too often they are completed at the last minute, just before patients return for their follow-up visits to hand them in. One study took a novel approach to measure compliance by issuing patients personal digital assistant (PDA) hand-held devices to record when they took their medication.5 In this study, 125 women were given a paper diary and a PDA to record information. Women were trained in PDA use and even tested for competency in entering data in them. The PDA had the ability to time- and date-stamp each entry, although the study participants did not know this. The women were not told it was a compliance study; they thought it was a study comparing the efficacy of metronidazole gel to that of oral metronidazole. The findings showed that women were much more likely to comply with therapy if they used vaginal metronidazole
A Clinical Update in Treatment of Bacterial Vaginosis

Misdiagnosis of Vaginal Infections


P a u l N y i r j e s y, M D

he three most frequently diagnosed infectious causes of vaginitis are bacterial vaginosis (BV), vulvovaginal candidiasis (VVC), and trichomoniasis. Because these three infections are so prevalent in female patients, it is easy for clinicians to overlook other possible causes of vaginitis in women. However, the differential diagnosis for chronic vulvovaginal symptoms is actually quite broad, as will be discussed in more detail. BV is believed to be the most common cause of vaginitis. It is not considered a sexually transmitted infection (STI), in that BV infection has been described in virginal women, but it is sexually associated. It results from an imbalance in the vaginal flora, leading to an overgrowth of anaerobic bacteria, mycoplasmas, and Gardnerella vaginalis, although its precise etiology is not well understood (see article by Jack D. Sobel, MD, page 12). The primary symptoms of BV are abnormal discharge and odor; vulvovaginal itching and irritation are relatively rare. VVC is believed to be less common than BV, but it is much better known among the lay population. Up to 75% of women will have VVC sometime during their lifetime, and 40% to 50% will have two or more episodes.1 The most common cause of VVC is infection by Candida albicans. As with BV, there is a sexual association with the condition, but it is not an STI. The primary symptoms of VVC are itching, burning, irritation, dyspareunia, and abnormal discharge. Trichomoniasis, caused by the protozoan Trichomonas vaginalis, affects 5 million people in the United States annually.2 It is an STI, and asymptomatic men and women represent the major reservoir of transmission. The primary symptoms are itching, burning, dysuria, dyspareunia, abnormal discharge, and odor. As noted earlier, these three infectious entities may predominate, but they are not the only possible causes of chronic vulvovaginal symptoms. At one chronic vaginitis clinic, for example, VVC was responsible for 27% of cases, followed by vulvar vestibulitis (18%), irritant dermatitis (17%), BV (11%), and atrophic vaginitis (6%).3 An additional 6% of patients experienced a physiologic discharge that did not appear to be abnormal. The remaining 15% experienced symptoms due to a variety of other causes, such as desquamative inflammatory vaginitis, erosive lichen planus, and lichen sclerosus. Self-Diagnosis and Treatment Issues In 1990, Sobel4 detailed a number of potential pitfalls that could lead to misdiagnosis of vaginitis. These missteps included: Patient self-diagnoses and treats her condition Diagnosis is made by telephone consultation Patient is seen, but no pelvic examination is performed Patient is examined, but vulva and vestibule are not checked adequately Laboratory diagnostic tests are not performed

Escherichia coli, Enterococcus species, G. vaginalis, and other normal flora are treated as pathogens Shotgun therapy is used Topical steroids are overprescribed Papanicolaou smear results are used to make diagnosis Potential of topical therapy to exacerbate symptoms is not recognized It is notable that Sobel listed the chief hazard as patient self-diagnosis and treatment, given that his review was written before antifungal agents for treatment of VVC were available over the counter (OTC). Subsequent data have since borne out that the accuracy of patient self-diagnosis is problematic. The first OTC antifungal agent, clotrimazole, came on the market in 1990. Many other medications have since joined it. Arguments in favor of deregulating these products included convenience, the ability for women to initiate therapy quickly, the feeling of empowerment patients gained by being able to self-treat, and reduction of health care costs. Lipsky et al5 estimated in a 2000 study that the 15% decline in physician visits for vaginitis that may be attributable to OTC products has resulted in $45 million in direct cost savings and $18.75 million in indirect cost savings annually. If women are self-treating, a logical question to ask is, how accurate is their self-diagnosis? Chaponis et al6 addressed that question in a 1993 study in which 54 women who thought they had VVC were examined. Only 59% were found to have the condition. The investigators then examined 100 women who had a prior history of VVC and found that accuracy of self-diagnosis rose to 82% in this population. However, the 82% statistic may not be truly representative of findings. According to the study methodology, women who thought they had VVC were told to phone a call center, where they were screened regarding their suspected infection. If the women answered the questions appropriately, they were told to come in for an examination. But the study does not note how many women called the center who did not answer the questions correctly and thus were not examined. Ferris et al7 approached the question in a different way. In their 1996 study, they presented hypothetical case scenarios of genitourinary infections (acute cystitis, BV, pelvic inflammatory disease [PID], trichomoniasis, and VVC) to 552 women. Only 28% could identify VVC infection from the classic symptoms and only 4% recognized BV. A retrospective study in which this author participated examined the issue of self-treatment.3 A total of 105 women referred to a chronic vaginitis center by gynecologists were interviewed about their use of OTC antifungal products and alternative medicines during the preceding year. Seventythree percent of the women had used OTC antifungal agents in the past year. More than 40% had used alternative therapies such as acidophilus supplements orally or vaginally, yogurt orally or vaginally, vinegar douches, or boric acid suppositories. Yet, when examined, only 28% had VVC. Fifteen
A Clinical Update in Treatment of Bacterial Vaginosis

percent had irritant dermatitis and 17% had vulTABLE. Bacterial Vaginosis and Associated var vestibulitis, both of which could be exacerbatMorbidities: Implications of Misdiagnosis ed by topical therapies. Ferris et al8 returned to the self-diagnosis issue Pregnancy Nonpregnant women with a five-center prospective study. Women who Prematurity Cervicitis were about to purchase OTC antifungal products at area pharmacies were given brochures offering them Premature rupture of Pelvic inflammatory disease a free evaluation within 24 hours to see if they remembranes Urinary tract infection ally had VVC. Ninety-five women enrolled over 2 Preterm labor Postoperative infection years. Thirty-four percent were found to have VVC Intraamniotic fluid infection Cervical dysplasia alone, 19% had BV, 21% had mixed infections, 2% Postpartum endometritis Human immunodeficiency had trichomoniasis, and 11% had vaginitis from othvirus susceptibility er causes. The rest were normal. Thus, self-treatment with antifungals alone would have been inappropriate treatment for nearly two thirds of these sponsible for an inaccurate diagnosis of vaginal symptoms. women. However, as noted by the authors, difficulties enMisdiagnosis causes a delay in initiating proper treatment and countered in getting patients to come in for evaluation uncan contribute to unnecessary medication costs. derscore the fact that self-diagnosis and self-treatment are well BV, which may be the most commonly missed diagnosis, accepted by the general population and are clearly here to stay. is associated with several serious sequelae, including cerviciA 2002 study by Allen-Davis et al9 looked at the accuracy of telephone diagnosis of vaginal symptoms. Of 485 tis, PID, postoperative infection, cervical dysplasia, and suswomen who were diagnosed over the telephone by registered ceptibility to human immunodeficiency virus (Table). In nurses, 52% were seen within 24 hours for evaluation. Stapregnant women, it is associated with premature labor and tistical analysis showed very poor agreement between teledelivery, premature rupture of membranes, and postpartum phone diagnosis and practitioner diagnosis of BV, VVC, and endometritis. Thus, women who have BV but are not accutrichomoniasis. rately diagnosed risk prolonged exposure to pathogens that can lead to serious adverse events. Clinician Diagnosis Issues A number of tools and techniques are available to help clinConclusion icians make a differential diagnosis of BV, VVC, or trichoThe estimated cost savings of nearly $64 million for self-treatmoniasis, including the use of pH paper to test vaginal acidment of VVC put forth by Lipsky et al5 may in fact be more than offset by medical costs due to the misuse of OTC antiity, the so-called whiff test for BV (adding 10% potassium fungal products, although this issue has not been studied adhydroxide to vaginal fluid to test for amine odor), and wetequately. The reasons for deficiencies in accurately diagnospreparation microscopy of vaginal discharge to look for the ing vaginitis are extensive, ranging from decisions made at clue cells of BV, the motile trichomonads of trichomoniasis, home to evaluations made in the practitioners office. Imor the pseudohyphae and yeast cells of VVC. provements in technology, especially the development of home However, a study by Wiesenfeld and Macio10 that reviewed the records of 52 women referred to a tertiary care vaginitis tests, may bridge the gap between the perceived risks and percenter showed that many of these standard tests were rarely ceived benefits of self-treatment. if ever performed by the referring physician. Whiff and vaginal pH tests were performed in only 3% of cases, and 42% Further Comments Dr Sobel: Why do you think there has been a lack of diof physicians used no microscopy at all to evaluate vaginitis. agnostic tests for these infectious agents in the past 20 In 54% of cases in which medication was prescribed, inadeyears? quate evaluation was evident, the authors concluded. Dr Nyirjesy: Lack of reimbursement may be one factor. Even when microscopy is done by skilled investigators, such Rapid diagnostic test kits have been developed that meaas in the research setting, the sensitivity of diagnosis is only sure vaginal pH and amines to test for BV, but physicians about 50% for VVC and 50% to 70% for trichomoniasis.11, 12 Other diagnostic tests, such as Gram stain of vaginal smear are not using them because they are not being reimbursed and culturing for Candida species or T. vaginalis, are not perfor the full cost of the test by health insurers. Dr Sobel: Several home diagnostic tests are in various stages formed routinely in clinical practice. A DNA probe test is of development. I have participated in advisory commitavailable that can identify Candida species, G. vaginalis, and tee meetings for some of these products and have argued T. vaginalis nucleic acid in vaginal fluid specimens, but it is in favor of practitioner-controlled tests. Several tests are expensive, results are not immediate, and it is likely more suitbeing developed that will tell a woman her vaginal pH. able for a laboratory than a practitioners office setting. What she does with this information is uncertain, but ideImplications of Misdiagnosis ally it would reduce inappropriate use of OTC antifungal Misdiagnosis is encountered on many levels. The patient, the agents. Continued on page 15 health care provider, or the method of test used may be reA Clinical Update in Treatment of Bacterial Vaginosis

Bacterial Vaginosis and Cervical Inflammation


Jane R. Schwebke, MD

Does Treating Cervicitis Cure Concurrent BV? Many years ago, it was thought that treating cervicitis in women with concurrent BV (by prescribing doxycycline or a similar antibiotic) would resolve the BV. The rationale behind this was that the secretions exuded from the cervix made the vagina more alkaline, favoring the growth of anaerobic vaginal flora. Curing the cervicitis would thus restore the normal balance of vaginal flora. This theory was tested in a small pilot study in Chicago-area STI clinics.8 One group of women received doxycycline alone for cervicitis and BV; the other group used doxycycline plus metronidazole gel. In the doxycycline-only group, 95% of women still had BV at 4 weeks posttreatment, compared with only 14% of the combination therapy group, a difference that Etiology of Cervicitis was highly significant (P <0.001). Interestingly, 47% of the The primary causes of mucopurulent cervicitis are believed doxycycline group still had evidence of cervical inflammation to be chlamydia, followed by Neisseria gonorrhoeae, and, to a at 4-week follow-up, yet only 14% of the lesser extent, herpes simplex virus (HSV), women using combination therapy did. but in as many as half the cases, the IMAGE. Swab Test For decades, BV was considered a noninpathogen is unknown. Two decades ago, flammatory condition, in that PMNs are not chlamydia was estimated to cause 40% to visible when vaginal discharge is examined 50% of mucopurulent cervicitis cases in the by wet-preparation microscopy. (For more United States,3 but because of the recent implementation of screening programs that on BV and inflammatory response, see arhave led to more widespread diagnosis and ticle by Sharon L. Hillier, PhD, page 10.) treatment of the infection, this percentage Findings from the Chicago study raised the is probably much lower today. Similarly, possibility that BV may be a contributor to older estimates of gonorrhea infection as a cervical inflammation. A second study was cause of 7% to 18% of cervicitis cases initiated to test that theory. would likely be revised downward.4 HSV is thought to contribute to only 3% to 5% of Does Treating BV Resolve Mucopurulent discharge from infections.4 Thus, this raises the likelihood Concurrent Cervicitis? cervix appears green or that the percentage of mucopurulent cerIn a randomized double-blind trial at a yellow on a swab. vicitis cases of unknown etiology may be inBirmingham, Alabama STI clinic, women creasing. with diagnosed BV and cervicitis received Image credit: Claire E. Stevens, A small portion of such cases might be doxycycline plus ofloxacin for their cerRonald E. Roddy. (See References, p. 9, for full source credit.) explained by false negatives of chlamydia vicitis.9 Half the group also received metronidazole gel and the other half a tests (although this is less likely with nuplacebo gel. A total of 71 women received cleic acid amplification testing). Another therapy; 61 patients were evaluated 2 weeks later, and 51 pafraction may be due to oral contraceptive use, since these tients completed the study by returning for the 4-week evalagents sometimes initiate inflammatory changes in the cervix. uation. At enrollment, nine of the women were diagnosed with A third explanation may be a condition often referred to as gonorrhea and eight women with chlamydia. Thus, 24% of chronic cervicitis, in which there are copious secretions from the study population had an identifiable pathogen for their the cervix that, when examined under the microscope, show cervicitis. predominately lymphocytes and monocytes, not PMNs, inAt both 2- and 4-week follow-up visits, women who redicating that this is not mucopus. ceived metronidazole gel were significantly more likely to have However, because so many cases of mucopurulent cerviciresolution of BV (P = 0.003 and P = 0.001, respectively) than tis cannot be explained by chlamydia, gonorrhea, or HSV inwomen who used placebo gel, which is not surprising. More fection, it is now suspected that unrecognized pathogens may noteworthy is that women who received metronidazole gel play a role. A strong association of bacterial vaginosis (BV) were also significantly more likely at 4-week follow-up to have and cervicitis has been made in several studies.5,6 Paavonen et al7 found that up to 50% of women seeking treatment for resolution of their cervical inflammation than women using

esearch into the etiology and treatment of mucopurulent cervicitis has been hampered by the lack of a universally accepted definition of the condition. In the research setting, an increased number of polymorphonuclear (PMN) leukocytes per field on endocervical Gram stain (eg, 10 or 30 PMNs at magnification of 1,000) has been used to define cervicitis,1,2 but this method has been shown to have a low positive predictive value for common infectious causes such as Chlamydia trachomatis, and there is no standard criterion. In the clinical setting, visualization of mucopurulent discharge exuding from the cervical os (or greenish-yellow mucopus on an endocervical swab sample) is usually sufficient (Image). Cervical edema, erythema, and friability can be used to support the diagnosis.

cervicitis at sexually transmitted infection (STI) clinics have coexisting BV.

A Clinical Update in Treatment of Bacterial Vaginosis

the greenish-yellow coloration can be hard to discernI would suggest they take a sample of the cervical secretion and examine it under the Resolution of Metronidazole Gel microscope, comparing it to a vaginal mucus Cervicitis n/N* (%) Placebo P Value specimen. If there are more white blood cells Subjects with in the cervical sample, that is likely the source resolution of BV of the discharge. 1st follow-up 20/20 (100) 4/7 (57) 0.01 Dr Ferris: There has been some recent speculation 2nd follow-up 18/19 (95) 3/5 (60) 0.10 that genital tract mycoplasmas, including Mycoplasma genitalium, Mycoplasma hominis, and UreSubjects without aplasma urealyticum, may play a role in mucoresolution of BV purulent cervicitis. Do you think it would be 1st follow-up 9/12 (75) 18/22 (82) 0.7 useful for the clinician to culture for pathogens 2nd follow-up 6/8 (75) 12/19 (63) 0.7 other than chlamydia or gonorrhea? Or to treat empirically for such infections? *n = number of patients cured; N = number in treatment group. Bacterial vaginosis. Dr Schwebke: I think the role of Mycoplasma and Ureaplasma species in cervicitis remains conSource: Schwebke JR, Weiss HL. Sex Transm Dis. 2002;29:59-64. troversial. A lot of investigation has been done on these organisms because they are so ubiquithe placebo gel (89% vs 63%, respectively, P = 0.03). Betous, but I do not think there is evidence yet that they are cause it was recognized that not all women who used the causative agents. So I would not recommend testing for or metronidazole gel would experience resolution of their BV treating these organisms until more is known. (cure rates are estimated at 70% to 80%10), results were furReferences ther stratified by that criterion. Investigators found that 1. Brunham RC, Paavonen J, Stevens CE, et al. Mucopurulent cervicitisthe women whose BV resolved were more likely to experience resignored counterpart in women of urethritis in men. N Engl J Med. 1984;311: olution of their cervicitis than did women whose BV persisted. 1-6. However, the difference was not statistically significant, be2. Nugent RP, Hillier SL. Mucopurulent cervicitis as a predictor of chlamydial infection and adverse pregnancy outcome. The Investigators of the Johns cause of the small numbers of subjects (Table).
TABLE.

Resolution of Cervicitis by Treatment Group

Conclusion

Hopkins Study of Cervicitis and Adverse Pregnancy Outcome. Sex Transm Dis. 1992;19:198-202. 3. Paavonen J, Stamm WE. Sexually transmitted diseases. Lower genital tract infections in women. Infect Dis Clin North Am. 1987;1:179-198. 4. Holmes KK, Stamm WE. Lower genital tract infection syndromes in women. In: Holmes KK, Marah PA, Wasserheit J, eds. Sexually Transmitted Diseases. New York: McGraw-Hill; 1999:761-781. 5. Paavonen J, Critchlow CW, DeRouen T, et al. Etiology of cervical inflammation. Am J Obstet Gynecol. 1986;154:556-564. 6. Moi H. Prevalence of bacterial vaginosis and its association with genital infections, inflammation, and contraceptive methods in women attending sexually transmitted disease and primary health clinics. Int J STD AIDS. 1990;1:86-94. 7. Paavonen J, Roberts PL, Stevens CE, et al. Randomized treatment of mucopurulent cervicitis with doxycycline or amoxicillin. Am J Obstet Gynecol. 1989;161:128-135. 8. Schwebke JR, Schulien MB, Zajackowski ME. A pilot study to evaluate the appropriate management of patients with coexistent bacterial vaginosis and cervicitis. Infect Dis Obstet Gynecol. 1995;3:119-122. 9. Schwebke JR, Weiss HL. Interrelationships of bacterial vaginosis and cervical inflammation. Sex Transm Dis. 2002;29:59-64. 10. Joesoef MR, Schmid GP, Hillier SL. Bacterial vaginosis: Review of treatment options and potential clinical indications for therapy. Clin Infect Dis. 1999;28:S57-S65.

The findings of these two studies suggest that there is an association between BV and cervicitis, but they do not answer the question of whether BV causes cervicitis. Other possible explanations for the efficacy of metronidazole gel are: (1) it has nonspecific antiinflammatory properties that are responsible for reducing cervical inflammation or (2) it eradicates a specific component of the largely anaerobic mix of flora of BV that is also pathogenic in cervical tissue. Further Comments Dr Ferris: Dr Schwebke has stated that cervicitis can be diagnosed by presence of cervical mucopus, but are there other guidelines for nonspecialists, for whom making a differential diagnosis may be difficult? Dr Schwebke: When my students insert the speculum in a patient and see discharge throughout the vagina, I instruct them to take their time and look carefully: Is discharge simply coating the cervix because it is vaginal discharge that is on all the walls, or is it truly emanating from the cervix? Sometimes it is helpful to remove the vaginal discharge and use a large swab to sample endocervical secretions. If the discharge appears green or yellow, it is mucopurulent. Ms Secor: For clinicians who are having a hard time making a diagnosis even after taking a swab specimensometimes

Source for image on page 8: Reprinted, with permission, from: Celum CL, Marrazzo J, Ocbamichael N, Meegan A, Stamm WE. The Practitioners Handbook for the Management of Sexually Transmitted Diseases. 3rd ed. Seattle STD/HIV Prevention Training Center, University of Washington; 2002.

A Clinical Update in Treatment of Bacterial Vaginosis

Cervical Cytokine Response in Pregnant Women Treated for Bacterial Vaginosis


S h a r o n L . H i l l i e r, P h D

acterial vaginosis (BV) has been linked with several adverse sequelae in pregnant women, including preterm labor, preterm delivery, chorioamnionitis, postpartum endometritis, and post-cesarean delivery wound infections. Treatment trials have evaluated the use of oral and vaginal metronidazole and oral and vaginal clindamycin for prevention of preterm birth in women with BV, but the results of these studies have differed substantially. A large trial by Carey et al,1 for example, showed that two doses of 2 g oral metronidazole did not reduce the incidence of preterm birth, but a recent meta-analysis of data by Leitich et al2 found a significant reduction in the incidence of preterm delivery in high-risk patients treated for 7 days or longer with oral metronidazole. After several trials using topical clindamycin either failed to demonstrate a decrease in preterm delivery rates or showed an increase in adverse events such as preterm birth and perinatal infections, the Centers for Disease Control and Prevention (CDC) 2002 treatment guidelines for sexually transmitted diseases recommended against its use during pregnancy. 3 However, a recent trial by Ugwumadu et al4 showed that women with BV who were treated with oral clindamycin in the second trimester had marked reductions in the incidence of late miscarriage and preterm delivery. Thus, both route of drug administration and duration of therapy appear to affect BV treatment benefits and risks. These contradictory findings have led to much confusion among clinicians with respect to defining what constitutes the best care for pregnant women with BV. The CDC guidelines recommend testing and treating symptomatic pregnant women for BV, adding that current evidence does not support routine screening and treatment for asymptomatic pregnant women with BV. The CDC notes that treatment of BV in asymptomatic pregnant women who are at high risk for preterm delivery might prevent adverse pregnancy outcomes. However, it should be recognized that most women with BV who are pregnant have not previously delivered preterm infants. The regimens recommended in the CDC treatment guidelines for pregnant women are oral metronidazole 250 mg three times daily for 7 days or oral clindamycin 300 mg twice daily for 7 days. Data on metronidazole vaginal gel in pregnant women were too limited for the CDC to make recommendations on its use.
BV as an Inflammatory Condition

BV is still a poorly understood phenomenon (see article by Jack D. Sobel, MD, page 12), and the mechanisms by which it may cause obstetric complications are unclear. One hypothesis is that the pathogenic organisms that characterize BV migrate from the vagina into the upper reproductive tract. There is a substantial body of data to support this hypothesis. BV has been linked with chorioamnion infection, and organisms found in the vagina can be recovered from the amniotic fluid of women

with intact membranes. However, most women who deliver preterm or have other pregnancy complications related to BV have no evidence of upper genital tract invasion. Therefore, other mechanisms by which lower genital tract infection increases the risk of preterm birth should be investigated. A second hypothesis is that BV causes inflammatory changes at the cervix that lead to preterm delivery. Women with BV have been found to have increased concentrations of bacterial endotoxin in their vaginal fluid. These endotoxins have been associated with increased levels of proinflammatory cytokines in cervical mucus, including interleukin (IL)-1, IL1, IL-1, and IL-8.5, 6 Inflammation has traditionally been measured by the presence of polymorphonuclear (PMN) leukocytes; BV was previously considered a noninflammatory condition because PMNs were not always evident in microscopic analysis of vaginal fluid of women with the condition. Further, BV does not cause erythema or other evidence of inflammation of the vaginal epithelium. However, the upregulation of proinflammatory cytokines by BV suggests that the condition is associated with inflammatory response in the cervix at the immunologic level. Recently, Yudin et al7 conducted a study to evaluate the clinical and cervical cytokine response to treatment of BV with oral or vaginal metronidazole in pregnant women. The purpose of the study was twofold. The first goal was to investigate the use of either metronidazole vaginal gel or oral metronidazole at the 500-mg twice-daily dose level in pregnant women with BV. Although the tested regimens (one applicator full daily for 5 days for the metronidazole gel and 500 mg twice daily for 7 days for the oral metronidazole) are recommended therapies for nonpregnant women, neither has been well studied in a gravid population. The second goal was to compare levels of three cervical cytokines (IL-1, IL-6, and IL-8) before and after treatment and to observe any differences between systemic and topical therapy. The hypothesis was that the cervical cytokine abnormalities observed in women with BV are attributable to alterations in the vaginal flora and that resolution of BV, whether due to oral or vaginal metronidazole, would resolve the proinflammatory changes in the cervix. A total of 102 pregnant women were randomized to receive either oral or vaginal metronidazole and were evaluated 1 month posttreatment for resolution of BV. Cytokine profiles were compared before and after treatment. The investigators found both therapies to be equally efficacious in resolving BV. Proinflammatory cytokine levels in women cured of BV were substantially lower than those in women who failed to respond to therapy. The similarity in cytokine response between the oral and vaginal groups suggests that the women did not have upper genital tract infections but that the cytokine changes were due to the disturbance of vaginal flora. These findings suggest that proinflammatory changes
A Clinical Update in Treatment of Bacterial Vaginosis

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TABLE.

Effect of BV* Treatment on Cervical Inflammation in Pregnancy

sidered as a possible inducer of broad macrolide resistance in vaginal flora.


Conclusion

Pregnant women with BV have increased levels of interleukin (IL)-1, IL-6, and IL-8 Treatment and cure of BV results in decreased levels of cytokines, suggesting that increased cytokine levels seen in pregnant women with BV are directly attributable to changes in flora Resolution of cervical cytokines is similar whether BV is treated orally or intravaginally
*Bacterial vaginosis. Source: Yudin MH, et al. Obstet Gynecol. 2003;102:527-534.

BV has traditionally been considered a noninflammatory condition, but recent research clearly indicates that inflammatory changes are occurring at the molecular level. Treatment and cure of BV in pregnancy results in the normalization of vaginal flora and positive alterations in proinflammatory cytokine response in cervical mucus.
Further Comments
Dr Nyirjesy: Even though the study by Yudin and colleagues7

are occurring in the cervical mucus of women with BV and that BV should be considered an inflammatory condition of the cervix (Table). Many pregnant women with BV are at low risk for preterm birth and are offered treatment to relieve symptoms. The study by Yudin et al7 suggests that both vaginal metronidazole gel and the 500-mg twice-daily dosage of oral metronidazole provide effective resolution of signs and symptoms of BV during pregnancy.
BV and the Issue of Macrolide Resistance

As noted previously, topical clindamycin has not been found to be effective in preventing preterm birth and other adverse sequelae in pregnant women. A recent study on macrolide resistance may offer an explanation as to why this is so. The category of antibiotics known as macrolides, which include erythromycin, clindamycin, and azithromycin, have been used widely in the treatment of reproductive tract infections because of their broad-spectrum activity against a number of pathogens. They are also used to prevent early-onset group B streptococcal sepsis in neonates. Of increasing concern in the medical community is the emergence of erythromycin- and clindamycin-resistant bacteria. Up to 20% of group B streptococci are now recognized as being resistant to clindamycin and/or erythromycin. Treatment for BV with either metronidazole or clindamycin is recognized as generally being 70% to 80% effective.8 One aspect that has not been evaluated until recently is whether the emergence of resistant bacterial strains affects therapeutic efficacy. Beigi et al9 conducted a randomized open-label clinical trial of treatment for BV designed to evaluate antimicrobial response to metronidazole vaginal gel and vaginal clindamycin ovules. Although the presence of macrolideresistant anaerobes at baseline did not predict treatment failure, use of vaginal clindamycin was associated with a significant increase in the prevalence of clindamycin-resistant anaerobic bacteria for up to 3 months. Metronidazole resistance was rare at baseline and following treatment. Given the broad use of macrolides for treatment of reproductive tract infections and intrapartum prophylaxis for prevention of postnatal group B streptococcal sepsis, the use of short-course clindamycin for treatment of BV should be conA Clinical Update in Treatment of Bacterial Vaginosis

found similar responses between oral and topical therapies, does that really exclude the possibility of upper genital tract infection? Isnt it possible that local treatment of the vagina may also cause changes in the upper tract? In terms of treating BV in pregnancy, it may be that the studies showing no benefit with treatment were treating too late, after the cascade of events leading to preterm birth had begun. Do you think that the timing of treatment of BV is important if you are trying to prevent adverse outcomes? Dr Hillier: It is likely that preterm delivery caused by infection occurs through several mechanisms. Two of the proposed mechanisms are invasion of the upper genital tract and changes in the immune response at the cervix. The Yudin et al7 study was interpreted as demonstrating that increased levels of proinflammatory cytokines seen at the cervix were due to vaginal flora shifts rather than upper tract infection because it is unlikely that topical administration of metronidazole could achieve drug levels in the upper tract sufficient to clear infection of the chorioamnion or amniotic fluid. In nonpregnant women, it may be possible for drugs delivered intravaginally to achieve therapeutic levels in the upper genital tract. A number of questions regarding the timing, correct dosage, and route of administration need to be answered before routine treatment of asymptomatic BV in pregnancy becomes the standard of care. Some experts have argued that routine screening early in pregnancy should be the standard care for prevention of preterm delivery, whereas others have argued that this would present a logistic nightmare for clinicians because of the recurrent nature of BV. Infection-related preterm delivery occurs primarily prior to 32 weeks gestation. Thus, screening women who have previously delivered preterm at the first prenatal visit for BV, with monthly assessments thereafter, makes sense, although this strategy has not been evaluated in well-designed clinical trials. Screening for BV does not need to be cumbersome. Simple assessment of vaginal pH should allow the clinician to determine whether additional evaluation is needed.
References
1. Carey JC, Klebanoff MA, Hauth JC, et al. Metronidazole to prevent preterm delivery in pregnant women with asymptomatic bacterial vaginosis. National Institute of Child Health and Human Development Network of MaternalFetal Medicine Units. N Engl J Med. 2000;342:534-540.

Continued on page 15

11

Recent Findings in the Treatment of Recurrent Bacterial Vaginosis


Jack D. Sobel, MD

here is no universally accepted definition of recurrent bacterial vaginosis (BV) among the specialists who study and treat the condition. For the purposes of this article, it will be defined as three or more confirmed attacks per year. Presence of BV may be confirmed clinically by using Amsel criteria (three of the four criteria must be met: pH of vaginal fluid is >4.5, discharge has a homogenous appearance, positive amine odor is evident when potassium hydroxide is added to the vaginal fluid, clue cells are visible by wetpreparation microscopy of vaginal fluid) or by Gram stain of vaginal smears, a technique used more frequently in the research setting. A few studies have attempted to estimate the incidence of recurrent BV. Hay1 states that BV recurs in 20% to 30% of women within 1 month of treatment. It is presumed that he was referring to women who met Gram stain criteria for BV 30 days posttreatment; it is doubtful that he was referring to symptomatic recurrence in so short a time. More than two decades ago, Blackwell and Barlow2 reported a 30% recurrence rate within 3 months. Hillier and Holmes3 have suggested that up to 80% of women will experience a recurrence within 9 months. Recurrence rates will obviously vary according to the population studied. In a 1993 long-term follow-up study of women treated with either oral metronidazole or clindamycin cream, approximately 70% of women had recurrence of BV within 90 days, but it should be noted that these women were invited to participate in the study because they had intractable BV (Figure).4
Pathogenesis of BV Is Unknown

FIGURE.

Recurrent Nature of BV*

Cure Rates After Therapy With Oral Metronidazole or Clindamycin Cream


80 70 60 50 40 30 20 10 0

% of Patients Cured

5-8

28

Day

60

90

*Bacterial vaginosis. Source: Sobel JD, et al. J Infect Dis. 1993;167:783-784.

antimicrobial resistance, and (4) persistence of, or reinfection by, the precipitating trigger or pathogen.
Many Therapies Being Explored

The precise pathogenesis of BV is unclear. Many factors are associated with an increased risk of BV, including changing sexual partners, having a lesbian partner with BV, douching, using an intrauterine device, taking antibiotics, having a coexisting sexually transmitted infection, and African American ethnicity. A decrease in lactobacilli concentration and an overgrowth of anaerobic and facultatively anaerobic organisms, including Gardnerella vaginalis and Mobiluncus, Ureaplasma, Prevotella, and Mycoplasma species, are known to produce the symptoms of BV, but the precise triggering mechanism is not understood. One hypothesis is that the loss of protective hydrogen peroxide (H2O2)-producing lactobacilli allows the overgrowth to occur. A second hypothesis is that the overgrowth of bacteria crowds out the lactobacilli, so their loss is a secondary phenomenon, not a primary one. Because the pathogenesis of acute BV is unclear, it is predictable that even less is understood about recurrent BV. A number of hypotheses exist as to why BV symptoms return, including: (1) failure of beneficial H2O2-producing lactobacilli to recolonize the vagina, (2) failure of vaginal acidification to be restored, (3) failure to reduce the numbers of G. vaginalis and other harmful bacteria in the vagina, perhaps because of

The Centers for Disease Control and Prevention (CDC) 2002 treatment guidelines for sexually transmitted diseases recommend oral metronidazole (500 mg twice daily for 7 days), metronidazole vaginal gel (one applicator full intravaginally daily for 5 days), or clindamycin cream (one applicator full intravaginally daily for 7 days) for treatment of BV.5 The three regimens are described as equally efficacious. The guidelines do not address therapy for recurrent BV. Several strategies have been described in the literature, but none has been tested in large-scale clinical trials, and data are lacking to recommend one approach over another. One empiric option is for the clinician to prescribe the same medication tried previously but for a longer duration than that recommended by the CDC guidelines (typically 10 to 14 days).6 Another therapeutic approach is to switch classes of medication (eg, if a patient has been treated repeatedly with metronidazole, the clinician can switch to clindamycin). It is thought that this may be effective because the different agents have different spectra of activity against the various bacteria populating the vagina. Still other techniques include prescribing combination therapy or treating the sexual partner. Every clinician likely has anecdotal evidence of a patient whose recurrent BV resolved after changing sexual partners, yet most of the studies that have examined treatment of the male partner have shown no benefit. Using condoms for barrier protection has also been recommended as a possible means of breaking the cycle of reinfection. Exogenous acidification of the vagina was tried for many years but was ultimately shown to be ineffecA Clinical Update in Treatment of Bacterial Vaginosis

12

tive. Recent research into two other therapeutic approaches will be discussed in more detail.
Replacement of Lactobacilli

Conclusion

Because lactobacilli are responsible for creating the lactic acid that makes a healthy vagina acidic and able to keep bacteria growth in check, it has been hypothesized that recolonizing the vagina with the organisms might be effective in preventing recurrence of BV. A 1996 placebo-controlled study by Parent et al7 investigated the efficacy of a vaginal tablet containing Lactobacillus acidophilus and estriol as BV therapy in 32 women for 6 days. At 28 days posttreatment, 77% of the women taking the active medication were cured vs 25% of those on placebo. Although the study was very small, results were encouraging. A large, two-center study was conducted more recently by Hillier et al8 using vaginal capsules containing Lactobacillus crispatus (the species of lactobacilli now thought to be most important in the healthy vaginal environment) in conjunction with a 2-g single dose of oral metronidazole. Ninety percent of the women had had BV at least once previously in the past year. Results have not been published, but it appears from preliminary data that the majority of women with recurrent BV were successfully recolonized with exogenous L. crispatus, and if this occurred, they were significantly less likely to have a relapse than women treated with placebo. However, women who used the L. crispatus vaginal capsules who failed to become colonized had increased rates of BV recurrence compared to women treated with placebo. The authors believe this unexpected result may have been caused by exogenous material in the capsules unrelated to lactobacilli that facilitated the growth of undesirable organisms. Clinical testing of a reformulated product containing L. crispatus is ongoing.
Maintenance Suppressive Therapy

The pathogenesis of BV is poorly understood, which hampers efforts to treat recurrent disease. Numerous therapeutic options are under investigation but management of this common condition remains a major challenge.
Further Comments

It is likely that there are many women with chronic BV who are not receiving treatment, because of clinicians inability to document proven relapses, misdiagnosis of symptoms, or other factors. Lack of a clear definition of what constitutes recurrent BV hinders our ability to find and treat these women. Dr Schwebke: Regarding combination therapy, I am involved in a study that is examining the efficacy of azithromycin in combination with oral metronidazole to treat recurrent BV. It is thought that this might be beneficial because many Mobiluncus organisms are resistant to metronidazole. However, results are not known yet. Dr Hillier: During our treatment trial of metronidazole plus L. crispatus capsules, we had an opportunity to evaluate behaviors that occurred more frequently in women whose BV recurred. We provided condoms to all study participants and counseled them to use them with each act of intercourse. We found that women who did not use condoms during the first month of follow-up were significantly more likely to have recurrent BV 30 days after treatment.
Dr Ferris:

References
1. Hay PE. Recurrent bacterial vaginosis. Dermatol Clin. 1998;16:769-773. 2. Blackwell A, Barlow D. Clinic diagnosis of anaerobic vaginosis (non-specific vaginitis). A practical guide. Br J Vener Dis. 1982;58:387-393. 3. Hillier SL, Holmes KK. Bacterial vaginosis. In: Holmes KK, Marah P-A, Wasserheit J, eds. Sexually Transmitted Diseases. New York: McGraw-Hill; 1999. 4. Sobel JD, Schmitt C, Meriwether C. Long-term follow-up of patients with bacterial vaginosis treated with oral metronidazole and topical clindamycin. J Infect Dis. 1993;167:783-784. 5. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2002. MMWR Morb Mortal Wkly Rep. 2002;51(RR-6):42-44. 6. Sobel JD. Bacterial vaginosis. Annu Rev Med. 2000;51:349-356. 7. Parent D, Bossens M, Bayot D, et al. Therapy of bacterial vaginosis using exogenously-applied Lactobacilli acidophili and a low dose of estriol: A placebocontrolled multicentric clinical trial. Arzneimittelforschung. 1996;46:68-73. 8. Hillier SL, Wiesenfeld HC, Murray P. A trial of Lactobacillus crispatus as an adjunct to metronidazole therapy for treatment of bacterial vaginosis. Poster presented at: Annual Meeting of the Infectious Disease Society for Obstetrics and Gynecology; August 8-10, 2002, Banff, Alberta, Canada. 9. Pulkkinen P, Saranen M, Kaaja R. Metronidazole combined with nystatin (vagitories) in the prevention of bacterial vaginosis after initial treatment with oral metronidazole. Gynecol Obstet Invest. 1993;36:181-184. 10. Sobel JD, Leaman D. Suppressive maintenance therapy of recurrent bacterial vaginosis utilizing 0.75% metronidazole vaginal gel. Presented at: Second International Meeting of Bacterial Vaginosis; September 6, 1998; Aspen, Colo. 11. Sobel JD. Preliminary analysis of a placebo-controlled trial indicates a substantial protective effect of twice-weekly metronidazole vaginal gel in excess of 70% and associated with significantly enhanced overall cure rate. Presented at: Fourth World Conference on Vaginitis; January 10-13, 2004; Playa Herradura, Costa Rica.

A placebo-controlled study of 66 women with BV conducted more than a decade ago examined the efficacy of a combination of intravaginal metronidazole and nystatin as prophylactic therapy after initial treatment with 2 g oral metronidazole.9 The prophylactic regimen was used for 3 days following menstruation for six menstrual cycles. The study exhibited such high cure rates at 6 months100% of women using the active medication and 76% of women using placebothat it must be regarded with a degree of skepticism. A pilot study examining metronidazole vaginal gel as suppressive maintenance therapy was conducted more recently.10 Women were treated initially with open-label 10-day therapy of metronidazole vaginal gel. After clinical remission was established, the women began a maintenance regimen of twice-weekly metronidazole vaginal gel or placebo for 3 months. They were then followed for six more months. During the maintenance phase, one of six patients using metronidazole vaginal gel had clinical recurrence, compared to four of six women using the placebo. However, the protective benefit appeared to dissipate shortly thereafter. Based on these results, a large multicenter study involving more than 160 women was launched.11 The data are still being analyzed and findings have not yet been published.
A Clinical Update in Treatment of Bacterial Vaginosis

13

Challenges for the Nurse Practitioner/Physician Assistant in Managing Patients With Vaginitis
M i m i S e c o r, M S , F N P

ne of the more significant trends in the US health care workforce in the past decade has been the growth of advanced-practice clinicians, who are expected to number more than 380,000 in 2005.1 Chief among these in providing primary care services are nurse practitioners (NPs), of which there were about 103,000 in 2000,2 and physician assistants (PAs), who number approximately half that.3 One recent workforce overview suggests that only 10% of health care is actually provided by physicians today.4 NPs and PAs are the firstand, in many cases, the only point-of-care clinicians whom women see when seeking care for vulvovaginal complaints. Studies have shown that NPs and PAs are more likely to care for underserved and low-income patients, including minority patients and Medicaid recipients, and to practice in rural communities than are primary care physicians.5 Some of these patient characteristics are also associated with populations at increased risk for sexually transmitted infections. The NP/PA as Patient Educator NPs and PAs play a key role not only in diagnosing and managing vaginitis but also in educating patients about optimal vaginal health. The annual womens health examination or problem visit is an opportunity to screen for bacterial vaginosis (BV) and other possible infectious causes of vaginitis in women of reproductive age and to impart information regarding behaviors that may increase their risk of infection or exacerbate existing symptoms. Patients may feel more comfortable discussing vulvovaginal complaints with an NP or PA, who is perhaps perceived as being more approachable than a physician. (NPs are more likely to be female, and many female patients self-select female providers for womens health care.6) In questioning patients about their sexual history, a proactive approach, with open-ended questions that encourage more detailed responses, is helpful. How the clinician frames a question can be important. For example, Has there been any change in your vaginal discharge? may elicit more information than Are you having any abnormal discharge? Often a patient will not volunteer information about vaginal symptoms or attempts at self-treatment without prompting. Due to embarrassment or stigma about discussing sexual habits, it may not occur to her to mention a symptom such as vaginal odor unless the clinician asks directly, Have you noticed odor after intercourse or during your menstrual period? As part of this patient education effort, clinicians should encourage women not to self-diagnose vaginal problems, as studies have shown high inaccuracy rates among the lay population (see article by Paul Nyirjesy, MD, page 6), and that use of over-the-counter antifungal agents and other alternative therapies may complicate diagnosis and treatment. Pa-

tients also should be counseled on the negative effects of douching on the balance of flora in the vagina, depleting the healthy lactobacilli that keep the growth of undesirable bacteria in check. Managing the Patient With Chronic Vaginitis Because of the sheer volume of patients they see, NPs and PAs may manage a considerable number of women with chronic vaginitis, including recurrent BV. Like physicians, they feel frustrated when their patients return again and again for the same problems and stymied by the lack of evidence-based medicine to help guide them. They may not have access to the latest research insights, such as the recent findings indicating that BV may play a role in cervicitis (see article by Jane R. Schwebke, MD, page 8) or initiate an inflammatory response at the cytokine level (see article by Sharon L. Hillier, PhD, page 10), or that BV may increase the risk of acquiring human immunodeficiency virus infection. One hopes that as such findings become better known, it will lead to an increase in screening for BV when the clinician finds evidence of cervical inflammation during an examination. Health care providers may feel that it is easier, as they are expected to see growing numbers of patients daily, to stick with familiar routines than to incorporate new technology, such as rapid diagnostic point-of-care tests (eg, pH and amines tests and DNA probe tests that may help in the diagnosis of BV and other types of infection), into daily practice. That said, it is this practitioners observation that NPs and PAs are often more likely to embrace diagnostic tests such as pH paper to test vaginal acidity than are physicians during routine pelvic examinations. Many have taken advanced microscopy classes and may be more skilled than their physician counterparts at reading wet-preparation slides of vaginal discharge. Several strategies to manage patients with recurrent BV are reviewed elsewhere (see article by Jack D. Sobel, MD, page 12), including lengthening duration of initial therapy, using suppressive maintenance therapy, and using barrier methods such as condoms during treatment to prevent reinfection. Because menstrual fluid raises the pH of the vagina and can reduce the lactobacilli population,7 another empiric approach is to use oral contraceptives to reduce menses, but this has not been studied in trials. One prospective study has shown a decreased risk of BV acquisition with use of oral contraceptives or medroxyprogesterone.8 Conclusion Patients benefit from a comprehensive approach to screening forand diagnosis and treatment ofvaginitis. As frontline care providers, NPs and PAs are in a unique position to provide patient education and prevention strategies as well as manage disease appropriately.
A Clinical Update in Treatment of Bacterial Vaginosis

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References
1. Cooper RA, Laud P, Dietrich CL. Current and projected workforce of nonphysician clinicians. JAMA. 1998;280:788-794. 2. American College of Nurse Practitioners. Facts about nurse practitioners. Available at: http://www.nurse.org/acnp/facts/index.shtml. Accessed February 2, 2004. 3. American Academy of Physician Assistants. Information update: Projected number of people in clinical practice as PAs as of January 1, 2004. Available at: http://www.aapa.org/research/03-04num-clin-prac.pdf. Accessed February 2, 2004. 4. Sheldon GF. Great expectations: The 21st century health workforce. Am J Surg. 2003;185:35-41.

5. Grumbach K, Hart GL, Mertz E, Coffman J, Palazzo L. Who is caring for the underserved? A comparison of primary care physicians and nonphysician clinicians in California and Washington. Ann Fam Med. 2003;1:97-104. 6. Zuckerman M, Navizedeh N, Feldman J, McCalla S, Minkoff H. Determinants of womens choice of obstetrician/gynecologist. J Womens Health Gend Based Med. 2002;11:175-180. 7. Eschenbach DA, Thwin SS, Patton DL, et al. Influence of the normal menstrual cycle on vaginal tissue, discharge, and microflora. Clin Infect Dis. 2000;30:901-907. 8. Baeten JM, Nyange PM, Richardson BA, et al. Hormonal contraception and risk of sexually transmitted disease acquisition: Results from a prospective study. Am J Obstet Gynecol. 2001;185:380-385.

Misdiagnosis of Vaginal Infections


Continued from page 7 References
1. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2002. MMWR Morb Mortal Wkly Rep. 2002;51 (RR-6):42-44. 2. Cates W. Estimates of the incidence and prevalence of sexually transmitted diseases in the United States. Sex Transm Dis Suppl. 1999;26:52-57. 3. Nyirjesy P, Weitz MV, Grody MH, Lorber B. Over-the-counter and alternative medicines in the treatment of chronic vaginal symptoms. Obstet Gynecol. 1997;90:50-53. 4. Sobel JD. Vaginal infections in adult women. Med Clin North Am. 1990;74:1573-1602. 5. Lipsky MS, Waters T, Sharp LK. Impact of vaginal antifungal products on utilization of health care services: Evidence from physician visits. J Am Board Fam Pract. 2000;13:178-182. 6. Chaponis RJ, Bresnick PA, Weiss RR, Edwards LD. Candida vaginitis: Signs and symptoms aid womens self-recognition. J Clin Res Drug Dev. 1993;7:17-23.

7. Ferris DG, Dekle C, Litaker MS. Womens use of over-the-counter antifungal medications for gynecologic symptoms. J Fam Pract. 1996;42:595-600. 8. Ferris DG, Nyirjesy P, Sobel JD, et al. Over-the-counter antifungal drug misuse associated with patient-diagnosed vulvovaginal candidiasis. Obstet Gynecol. 2002;99:419-425. 9. Allen-Davis JT, Beck A, Parker R, Ellis JL, Polley D. Assessment of vulvovaginal complaints: Accuracy of telephone triage and in-office diagnosis. Obstet Gynecol. 2002;99:18-22. 10. Wiesenfeld HC, Macio I. The infrequent use of office-based diagnostic tests for vaginitis. Am J Obstet Gynecol. 1999;181:39-41. 11. Bergman JJ, Berg AO, Schneeweis R, Heidrich FE. Clinical comparison of microscopic and culture techniques in the diagnosis of Candida vaginitis. J Fam Pract. 1984;18:549-552. 12. Krieger JN, Tam MR, Stevens CE, et al. Diagnosis of trichomoniasis: Comparison of conventional wet-mount examination with cytologic studies, cultures, and monoclonal antibody staining of direct specimens. JAMA. 1988;259:1223-1238.

Cervical Cytokine Response


Continued from page 11
2. Leitich H, Brunbauer M, Bodner-Adler B, et al. Antibiotic treatment of bacterial vaginosis in pregnancy: A meta-analysis. Am J Obstet Gynecol. 2003;188:752758. 3. Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2002. MMWR Morb Mortal Wkly Rep. 2002;51(RR-6):42-44. 4. Ugwumadu A, Manyonda I, Reid F, Hay P. Effect of early oral clindamycin on late miscarriage and preterm delivery in asymptomatic women with abnormal vaginal flora and bacterial vaginosis: A randomised controlled trial. Lancet. 2003;361:983-988. 5. Platz-Christensen JJ, Mattsby-Baltzer I, Thomsen P, Wiqvist N. Endotoxin and interleukin-1 alpha in the cervical mucus and vaginal fluid of pregnant women with bacterial vaginosis. Am J Obstet Gynecol. 1993;169:1161-1166.

6. Mattsby-Baltzer I, Platz-Christensen JJ, Hosseini N, Rosen P. IL-1beta, IL-6, TNF-alpha, fetal fibronectin, and endotoxin in the lower genital tract of pregnant women with bacterial vaginosis. Acta Obstet Gynecol Scand. 1998;77:701706. 7. Yudin MH, Landers DV, Meyn L, Hillier SL. Clinical and cervical cytokine response to treatment with oral or vaginal metronidazole for bacterial vaginosis during pregnancy: A randomized trial. Obstet Gynecol. 2003;102:527-534. 8. Joesoef MR, Schmid GP, Hillier SL. Bacterial vaginosis: Review of treatment options and potential clinical indications for therapy. Clin Infect Dis. 1999;28:S57-S65. 9. Beigi RH, Austin MN, Macio IS, et al. High prevalence of clindamycin-resistant anaerobic gram negative rods after treatment with intravaginal clindamycin for bacterial vaginosis. Abstract presented at: Annual meeting of the Infectious Disease Society for Obstetrics and Gynecology; August 7-9, 2003; Hyannis, Mass.

A Clinical Update in Treatment of Bacterial Vaginosis

15

Ob.Gyn. News
Release Date: April 2004 Expiration Date: March 2005

A Clinical Update in Treatment of Bacterial Vaginosis CME Post-Test and Evaluation


Estimated Time to Complete This Activity: 1.25 hours
CONTINUING EDUCATION INSTRUCTIONS: There is no fee to participate in this activity. Please forward the Test Answer Sheet and Evaluation form to: Excerpta Medica/Elsevier, Office of Continuing Medical Education, Department BV, 105 Raider Blvd. Suite 101, Hillsborough, N.J. 08844-1528. FAX: (908) 874-5633. Responses for AMA/Physicians Recognition Award credit must be submitted by March 2005.
INSTRUCTIONS: For each question or incomplete statement, one answer or completion is correct. Circle the most appropriate response. Seven of 10 correct responses are required for credit.

1. Which organism is believed to be the primary cause of mucopurulent cervicitis, when a pathogen is identified? a. Trichomonas vaginalis b. Chlamydia trachomatis c. Neisseria gonorrhoeae d. Herpes simplex virus 2. What is the estimated cure rate of women with bacterial vaginosis (BV) treated with either metronidazole or clindamycin? a. 45% to 50% b. 55% to 65% c. 70% to 80% d. 80% to 90% 3. Which of the following statements regarding a differential diagnosis of common vaginitis symptoms is true? a. Vulvovaginal itching is rare in BV but common in vulvovaginal candidiasis (VVC). b. VVC and BV can be diagnosed by wet-preparation microscopy, but trichomoniasis requires lab culture. c. BV is characterized by copious quantities of polymorphonuclear leukocytes when vaginal discharge is examined under the microscope; VVC is characterized by pseudohyphae. d. All of the above statements are true. 4. Which of the following statements best describes the results of a pilot study using metronidazole vaginal gel as suppressive maintenance therapy for recurrent BV? a. Metronidazole vaginal gel given four times weekly as suppressive therapy was found to be significantly more effective than a twiceweekly dose. b. Women using metronidazole vaginal gel had a significant reduction in BV recurrence compared to women using placebo not only during the maintenance phase but for 12 months after cessation of therapy. c. Metronidazole vaginal gel was found to cause irritant dermatitis in more than 50% of women at the twice-weekly dose level, so dosage was reduced to once per week for the latter half of the maintenance phase. d. Five out of six patients using metronidazole vaginal gel had no BV recurrence during the maintenance phase, vs only two of six women using placebo. 5. In a 1996 study by Ferris et al, what percentage of women could correctly identify VVC from a description of classic symptoms? a. 28% b. 52% c. 59% d. 82%

6. The 2002 sexually transmitted diseases treatment guidelines from the Centers for Disease Control and Prevention recommend two regimens for treating BV in pregnant women. Which of the following is one of them? a. Oral metronidazole 500 mg twice daily for 7 days b. Oral clindamycin 300 mg twice daily for 7 days c. Metronidazole vaginal gel, one applicator full daily for 7 days d. Clindamycin cream, one applicator full daily for 7 days 7. In a study by Yudin et al regarding treatment of pregnant women with BV, how did topical therapy compare to systemic therapy? a. Both medications were equally efficacious in resolving BV and had similar effects on cytokine response levels. b. Oral therapy was significantly superior to topical therapy in all endpoints evaluated. c. Both medications were equally efficacious in clinical resolution of BV, but only oral therapy significantly altered cytokine response levels. d. Topical therapy was superior to oral therapy, but patient compliance was thought to be a confounding factor. 8. One study has shown that ________________ may decrease risk of BV acquisition. a. douching b. consumption of yogurt supplemented with live Lactobacillus acidophilus cultures c. oral contraceptive use d. all of the above 9. In a study of women in Alabama with concurrent cervicitis and BV, women who received _____________________ were significantly more likely to have resolution of their cervical inflammation than the placebo group. a. metronidazole vaginal gel b. oral clindamycin c. doxycycline and ofloxacin d. doxycycline, ofloxacin, and metronidazole vaginal gel 10. In a study by Beigi et al evaluating topical therapies for BV, vaginal clindamycin ovules were _______________. a. more effective than metronidazole vaginal gel in resolving BV b. well tolerated for long-term maintenance therapy of recurrent BV c. associated with an increase in clindamycin-resistant bacteria d. preferred by patients to clindamycin cream

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