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Clinical Expert Series

Management of Persistent Vaginitis


Paul Nyirjesy,

MD

With vaginitis remaining a common condition that leads women to seek care, it is not surprising
that some women develop chronic vulvovaginal problems that are difficult to diagnose and
treat. With a differential diagnosis that encompasses vulvar disorders and infectious and
noninfectious causes of vaginitis, accurate diagnosis is the cornerstone of choosing effective
therapy. Evaluation should include a symptom-specific history, careful vulvar and vaginal
examination, and office-based tests (vaginal pH, amine test, saline and 10% potassium hydroxide
microscopy). Ancillary tests, especially yeast culture with speciation, are frequently crucial to
obtaining a correct diagnosis. A heavy but normal physiologic discharge can be determined by
excluding other causes. With vulvovaginal candidiasis, differentiating between Candida albicans
and non-albicans Candida infection has important treatment ramifications. Most patients with C
albicans infections can be successfully treated with maintenance antifungal therapy, usually with
fluconazole. Although many non-albicans Candida, particularly Candida glabrata, may at times
be innocent bystanders, vaginal boric acid therapy is an effective first choice for many true nonalbicans Candida infections. Recurrent bacterial vaginosis, a difficult therapeutic challenge, can
often be controlled with maintenance therapy. Multiple options, especially high-dose tinidazole,
have been used for metronidazole-resistant trichomoniasis. With the aging of the U.S. population, atrophic vaginitis and desquamative inflammatory vaginitis, both associated with hypoestrogenism, are encountered frequently in women with persistent vaginitis.
(Obstet Gynecol 2014;0:112)
DOI: 10.1097/AOG.0000000000000551

aginal complaints are considered one of the most


common reasons that women seek the care of
a health care provider.1 Although the word vaginitis
is used as a diagnostic term by patients and health care
providers alike, it is a nonspecific term encompassing
a broad range of conditions that cause vulvovaginal
symptoms and affect women in virtually every age
group. After a standard evaluation, it is estimated that
70% of episodes of vaginitis in premenopausal women
are caused by bacterial vaginosis, vulvovaginal candi-

From the Department of Obstetrics and Gynecology, Drexel University School of


Medicine, Philadelphia, Pennsylvania.
Continuing medical education for this article is available at http://links.lww.
com/AOG/A573.
Corresponding author: Paul Nyirjesy, MD, 245 North 15th Street, New
College Building, 16th Floor, Philadelphia, PA 19102; e-mail: pnyirjes@
drexelmed.edu.
Financial Disclosure
Dr. Nyirjesy has been a consultant for Novadigm, Viamet Pharmaceuticals,
Symbiomix, Cepheid, and Hologics. He has received research grants from
Novadigm, Viamet Pharmaceuticals, Symbiomix, and BectonDickinson.
2014 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/14

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diasis, and trichomoniasis.2 Furthermore, as the population in the United States ages, an increasing
number of women may develop symptomatic atrophic vaginitis. For most women, episodes of vaginitis
will resolve without any difficulty or long-term
sequelae.
On the other hand, many women with vulvovaginal symptoms remain undiagnosed or either fail to
improve or recur after treatment. Although persistent
vaginitis is seldom life-threatening, it leads to morbidities of discomfort and pain, days lost from school or
work, and impaired sexual functioning and self-image.
Because women with chronic or recurrent symptoms
are a therapeutic challenge for health care providers,
their problems may be ignored or trivialized and may
last for months or years. As a result, they often selfmedicate with various over-the-counter and alternative medicines; sometimes these treatments in turn
exacerbate symptoms and make the overall problem
worse.3 This article describes a systematic approach to
diagnosis and management, which can lead to complete cure or at least significant symptom resolution
for the vast majority of affected women.

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Copyright American College of Obstetricians and Gynecologists

EVALUATION OF PATIENTS WITH


PERSISTENT VAGINITIS
Although most women with chronic vaginitis believe
that they have recurrent yeast infections,3 the differential diagnosis encompasses a broad array of vulvar
and vaginal conditions, including infectious, inflammatory, dermatologic, and neuropathic pain conditions. In one prospective survey of 200 patients
evaluated at a tertiary care vaginitis center, 62%
of whom had had symptoms for more than 1 year,
Nyirjesy and colleagues4 found that the most common
diagnoses were contact dermatitis (21%), recurrent
vulvovaginal candidiasis (21%), atrophic vaginitis
(15%), localized provoked vestibulodynia (13%), and
physiologic discharge (9%); 18% had two or more
concurrent diagnoses. Although these results may be
different in other practice populations, they serve to
underscore the broad differential diagnosis. It may
seem daunting to evaluate a woman who has seen
multiple health care providers and tried many therapies over the years without improvement, but being
aware of possible causes creates a framework for evaluation and management. This review focuses on the
etiology and treatment of those entities that cause primarily vaginal symptoms, but health care providers
should note that many women with persistent vaginitis have chronic vulvar diseases, recently discussed
by the American College of Obstetricians and Gynecologists.5 Conversely, even women with obvious vulvar diseases such as lichen sclerosus can also have
vaginal processes such as candidiasis or atrophic vaginitis, which complicate management and prevent
overall improvement. Thus, accurate diagnosis is the
cornerstone of effective therapy. Because selfdiagnosis and telephone diagnosis are frequently inaccurate, they should be avoided wherever possible,
particularly in women with chronic symptoms.6
Obtaining an appropriate history is the first step
to proper diagnosis. When doing so, it is helpful to
review patient symptoms in detail with a structured
interview, which we routinely administer in our
tertiary care vaginitis center. Patient symptoms can
be broadly grouped into those of discharge, odor,
itching, burning, irritation, or combinations thereof.
Patients who report an abnormal discharge are asked
about quantity, color, viscosity, and relationship to the
menstrual cycle. Those reporting an abnormal odor
are asked to describe it in more detail. With symptoms such as itching, burning or irritation, we try to
distinguish among acute episodes, chronic discomfort,
and acute exacerbations of chronic discomfort. Asking patients whether symptoms are located mainly in

Nyirjesy

Management of Persistent Vaginitis

the vulva, vestibule, or vagina can be helpful. Furthermore, asking about chronic dyspareunia and
whether it is with intromission as opposed to thrusting
is quite important, because women with localized
provoked vestibulodynia have pain with penetration
but few daily symptoms.
Because patients have frequently received many
different forms of treatment, we review what types of
treatments have been administered (antifungals, antibiotics, corticosteroids, estrogen), the mode of administration (oral, topical, both), the length of therapy for
each course (episodic or maintenance), and the
response to each type of therapy (complete, partial,
nonexistent). For example, if a woman reliably
improves after each course of antifungal therapy only
to recur later, she is much more likely to have
vulvovaginal candidiasis than someone who describes
no improvement, even short term. With contact
dermatitis commonly found in this population, questions about soaps, feminine hygiene products, douching, and use of over-the-counter antifungal and
numbing agents containing sensitizers such as benzocaine are important for identifying and removing
possible irritants. In this population in which selftreatment is common, knowing the timing of the last
dose of any treatment is important, because any recent
medication hampers the clinicians ability to do a thorough evaluation. Finally, a sexual history may lead to
testing for sexually transmitted infections. Although
this type of review may seem time-consuming, it only
takes a few minutes and provides a concise picture of
what symptoms are bothering the patient.
A general physical examination may yield a diagnosis before doing a pelvic examination. For example,
finding erosive lichen planus in the mouth or hidradenitis suppurativa in the axillae makes it easier to
recognize it on the vulva. Pelvic examination should
begin with inspection of the vulva, including separating all the skin folds to look for abnormalities such as
redness, erosions, fissures, ulcers, masses, atrophy, or
alterations in the vulvar architecture such as periclitoral scarring or resorption of the labia minora.
Examination of the vestibule should also include
palpation with a swab to look for tenderness, a sign
of possible vestibulodynia. Similarly, vaginal evaluation should start with inspection to look for evidence
of inflammation, erosions, and even synechiae before
obtaining samples. Finally, because cervicitis can
cause an abnormal irritating discharge, the cervix
itself should be examined to assess for any mucopurulent discharge or areas of contact bleeding.
Practice guidelines by both the American College
of Obstetricians and Gynecologists6 and the Centers

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Copyright American College of Obstetricians and Gynecologists

for Disease Control and Prevention7 stress the importance of in-office testing for vaginal pH, amines, and
both saline and 10% potassium hydroxide microscopy. Frequently underused, vaginal pH testing in
particular can be used to drive the entire diagnostic
process. Figure 1 describes the pH-based algorithm
that we use in practice.8 Saline microscopy can aid
in diagnosing bacterial vaginosis and trichomoniasis.
In addition, by assessing for increased white blood
cells and abnormal cytology such as parabasal cells,
saline microscopy tests for atrophic vaginitis and desquamative inflammatory vaginitis.
As shown in Table 1, these easily available tests
can frequently diagnose common forms of vaginitis.
However, office testing has poor performance characteristics, and ancillary tests are frequently indicated. Of
those, yeast cultures with speciation of the organism
play an integral part in diagnosing, treating, and ruling
out vulvovaginal candidiasis. If Trichomonas vaginalis
infection is suspected but not proven, the gold standard
test remains either culture or the more easily available
polymerase chain reaction (PCR) with the U.S. Food
and Drug Administrationcleared APTIMA T vaginalis
assay. We perform this latter test in all of our patients at
risk for a sexually transmitted infection, those with
many white blood cells on microscopy, and those in
whom evaluation is consistent with recurrent bacterial
vaginosis. The findings of vesicles, fissures, or ulcers
should routinely lead to PCR tests for herpes simplex
virus and possibly type-specific immune globulin G
antibody testing. Polymerase chain reaction testing
for Neisseria gonorrhoeae and Chlamydia trachomatis and
bacterial cultures looking specifically for group A strep-

tococci or Staphylococcus aureus should be considered in


women with many white blood cells on saline microscopy. Although these latter two organisms may be
commensals, they are also occasional causes of purulent vaginitis. Routine bacterial cultures are otherwise
unhelpful and can be misleading, because normal vaginal flora such as Escherichia coli, Gardnerella vaginalis,
enterococci, and group B streptococci are frequently
found.9 For other tests for vaginal infections (ie,
point-of-care enzymatic, antigen and DNA tests for
candida, Gardnerella, and trichomoniasis, PCR testing
for yeast and bacterial vaginosis), there is currently
little evidence that they are superior to current gold
standards, and in the case of PCR testing for yeast
and bacterial vaginosis, they are more costly than current modalities. Finally, vulvar biopsies, and, less commonly, vaginal biopsies, should be considered for focal
abnormalities, particularly if the etiology is unclear.

NORMAL VAGINAL PHYSIOLOGY


AND DISCHARGE
With physiologic discharge occurring as the final
diagnosis in 9% of the patients referred to our tertiary
care program,4 understanding the normal vaginal
environment is important. During a womans reproductive years, estrogen plays a key role in maintaining
the normal vaginal environment. Before puberty, the
vagina is thinned and has a high pH; culture of the
vagina demonstrates a variety of organisms, including
skin and fecal flora and lactobacilli. Under the influence of estrogen, the vaginal epithelium thickens.
Lactobacilli become the dominant flora, which lowers
the pH of the vagina to less than 4.7. Vaginal

Fig. 1. A pH-based framework for


diagnosing the most common causes of
vaginitis. Reprinted with kind permission from Springer Science+Business
Media: Nyirjesy P, Sobel JD. Advances
in diagnosing vaginitis: development of
a new algorithm. Curr Infect Dis Rep
2005;7:45862, Figure 2.
Nyirjesy. Management of Persistent Vaginitis. Obstet Gynecol 2014.

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Management of Persistent Vaginitis

Copyright American College of Obstetricians and Gynecologists

Table 1. Testing for Causes of Vaginitis


Vaginal
pH

Saline or 10% Potassium Hydroxide


Microscopy

Normal

,4.7

Negative

Clinical diagnosis

Vulvovaginal candidiasis

,4.7

Unremarkable, 6white blood cells, bacillary


flora
Hyphae, blastospores

Negative

Bacterial vaginosis

$4.7

Clue cells, coccobacillary flora

Positive

Trichomoniasis

Varies

Trichomonads

Variable

Atrophic vaginitis
Desquamative inflammatory
vaginitis

$4.7
$4.7

Parabasal cells, decreased mixed flora


Parabasal cells, increased white blood cells,
mixed flora

Negative
Negative

Yeast culture with


speciation
Gram stain (Nugent
score)
Trichomonas
vaginalis PCR
Maturation index
Clinical diagnosis

Condition

Amines

Current Gold
Standard

PCR, polymerase chain reaction.

discharge usually becomes heavier. Hormonal influences will change a discharge, with women noting
a clear mucus midcycle to a thick white discharge at
other times. Because many women and health care
providers are taught that a thick white discharge is
most frequently caused by vulvovaginal candidiasis,
and despite evidence that the symptom of discharge
is nonspecific,2 complaints of a thick white discharge
often lead to repeated use of unnecessary antifungal
therapy and raise fears of recurrent infection.
Diagnosing a discharge as physiologic can only be
done by excluding potential causes, which will be
discussed later. Furthermore, an abnormal discharge
may sometimes be the result of occult urinary incontinence, which can be diagnosed by having a patient
take phenazopyridine for 12 days and looking for
a change in the color of the discharge. Even more
uncommonly, a heavy discharge coming from the
upper genital tract may be the result of an endometrial
polyp or fallopian tube malignancy; when suspected,
pelvic ultrasonography or sonohysterography should
be considered. In our experience, when a discharge is
physiologic, some patients require multiple visits with
normal evaluations to be fully reassured.

VULVOVAGINAL CANDIDIASIS
With the proliferation of over-the-counter antifungal
drugs, the annual market has been estimated at $275
million, and these medications number in the top 10 of
all over-the-counter medications sold in the United
States.10 The associated annual costs of vulvovaginal
candidiasis in the United States in 1995, including medical and treatment expenses, travel costs, and time
missed from work, were estimated to be $1.8 billion.11
Approximately 75% of women will develop symptomatic vulvovaginal candidiasis at least once in their lives,

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Management of Persistent Vaginitis

50% of women will experience sporadic recurrences,


and perhaps 810% will suffer from four or more episodes every year, the current definition of recurrent
disease.11
Although most people believe that a thick white
discharge is the hallmark symptom of yeast infections,
a womans perception of her discharge correlates
quite poorly with vulvovaginal candidiasis, which typically causes itching, irritation, soreness, burning,
external dysuria, or dyspareunia.4,12 Although findings may be minimal, examination may reveal vulvar
redness, swelling, fissures, or excoriations; vaginal
signs are usually limited to erythema or occasionally
thrush.12 Office microscopy (Table 1), the first line in
diagnosis, only has a sensitivity of approximately
50%13 and, depending on the health care provider,
may have high false-positive rates.14 Thus, yeast cultures with speciation should be obtained to confirm
the diagnosis, certainly in women with recurrent infection and possibly in those in whom candidiasis is suspected but not proven. Repeated sampling through
patient vaginal self-culture for yeast may further aid
in diagnosis; in a study at a Dutch dermatology clinic,
four weekly self-obtained cultures for yeast increased
the number of positives from 59 at baseline to 111 in
441 women with suspected recurrent candidiasis,
almost doubling the rate of diagnosis.15
To develop a symptomatic infection, the prerequisite is colonization with Candida species, a common event for almost every woman. Vaginal
colonization occurs through multiple routes, including
local transport from the perineum and perianal areas,
digital introduction, or sexual transmission. Candida
colonization, usually with Candida albicans, is present
in normal healthy women, up to 30% at any single
time and 70% if followed longitudinally for 1 year;

OBSTETRICS & GYNECOLOGY

Copyright American College of Obstetricians and Gynecologists

for most, this is a transient asymptomatic event.16


After colonization, candida may be a commensal
organism, but some women develop a symptomatic
infection that goes away easily with standard antifungal therapy, perhaps with sporadic recurrence. In an
even smaller group, as many 5%, there is a more complicated course with either failure to respond to treatment and the development of chronic infection17 or
relatively rapid relapse after successful antifungal therapy and eventual recurrent disease.11
The transition from asymptomatic colonization to
symptomatic infection may be the result of intrinsic
host, environmental, behavioral, or organism-related
factors. Of these, diabetes, antibiotic and estrogen use,
immunosuppression, and behavioral factors are familiar to most health care providers. Diabetics may be
more prone to developing infections caused by Candida
glabrata18; glycosuria may be one mechanism contributing to both colonization and symptomatic infection.19
With antibiotic use, symptomatic episodes seem to
occur mainly in women with preexisting colonization.20 In menopausal women, exogenous estrogen
use increases the risk of both candidal colonization
and infection.21 In our experience, systemic immunosuppression is rare in women with vulvovaginal candidiasis, although topical and systemic corticosteroid use
may be more common. Sexual activity, particularly
orogenital sex,22 and using contraception with oral contraceptives, an intrauterine device, or a diaphragm with
spermicide have all been associated with increased
infection.23 Although up to 20% of male partners of
women with recurrent infections may harbor candida
strains on their penises, actual transmission is thought
to be uncommon, and treatment of the male partner to
prevent vulvovaginal candidiasis is not recommended.7
In at least half of women with recurrent vulvovaginal candidiasis, there are no clear risk factors.
Women with recurrent infections have increased
vaginal Candida species colonization rates.24 As
reviewed by Fidel,25 most affected women seem to
exhibit altered local immunoregulatory mechanisms,
which result in increased susceptibility to infection. In
the past, it was felt that these women had a decreased
immune response, but, more recently, it has been suggested that symptomatic candidiasis is the result of an
increased sensitivity to yeast, leading to an inflammatory response to yeast colonization, which in turn
causes symptoms.25 Finally, other host factors, including genetic factors, may be at play.23 Whatever the
cause, most women with recurrent disease develop
a pattern in which the infection clears with antifungal
therapy only to recur within a few weeks to months,
usually with the same strain of yeast.

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In most women with vulvovaginal candidiasis,


C albicans remains by far the most common cause of
infection.23 As reviewed by Sobel,26 adherence of
yeast cells to vaginal epithelium causes colonization,
and subsequent germination promotes subsequent
vaginitis. Virulence factors produced by Candida species, including secreted aspartate proteinases, proteases, phospholipases, and mycotoxins, may inhibit
phagocytic activity and suppress the local immune
system.26 In tertiary care vaginitis programs, approximately 30% of women will be infected by other species of yeast, with C glabrata and Candida parapsilosis
being the most common.27
Most treatment guidelines distinguish between
uncomplicated and complicated vulvovaginal candidiasis.6,7 In general, women with uncomplicated infections
are otherwise healthy women with mild-to-moderate
symptoms resulting from sporadic episodes of infections
caused by C albicans; other women, including those with
recurrent vulvovaginal candidiasis and those with nonalbicans Candida infections, should be considered complicated and are more likely to fail standard antifungal
therapy. Furthermore, with many women asymptomatically colonized with yeast, when a woman with persistent vaginitis has a positive yeast culture, it can be
difficult to distinguish between one who truly has vulvovaginal candidiasis as opposed to one who is asymptomatically colonized with yeast and has a separate
cause for the symptoms. An effective approach to
resolve the question is to treat her and see if successful
treatment, determined by a negative follow-up culture,
is associated with a relief of symptoms. With C albicans
infections, its eradication results in a relief of symptoms
in up to 90% of cases.27 However, with C glabrata, perhaps 54% of women have no improvement of symptoms after successful eradication, and with C parapsilosis,
40% have a similar result.28
For uncomplicated disease, there are many available treatments, ranging from oral to topical, prescription to over-the-counter, and 1-day to 7-day
regimens. Although each has its own advantages and
disadvantages, they all have similar efficacy for C
albicans infections with an expected cure rate of 80
90% in uncomplicated patients.7 However, these regimens are clearly inadequate in women with complicated
disease with failure rates of 35% within just 1 month
of treatment.29 Most experts agree that management
begins by obtaining a positive yeast culture with speciation of the organism to confirm the diagnosis and
identify the pathogen and then using that information
to aggressively treat the infection.
For infections resulting from C albicans, the
approach that is commonly used is maintenance

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Management of Persistent Vaginitis

Copyright American College of Obstetricians and Gynecologists

antifungal therapy, in which patients are treated with


a prolonged (usually 6-month) regimen. This
approach gives almost all women a prolonged period
of symptom relief. The initial regimen used was 100
mg ketoconazole daily for 6 months, but it is no longer recommended because of the risk of liver toxicity.6 The advent of fluconazole in the early 1990s led
to the replacement of ketoconazole by fluconazole as
maintenance. In a study of maintenance fluconazole
for recurrent vulvovaginal candidiasis,30 women were
initially given three doses of 150 mg fluconazole, 3
days apart, to induce a negative culture. They were
then randomized to weekly 150 mg fluconazole or
placebo for 6 months (treatment phase), and then followed for an additional 6 months (observation phase).
Of the 343 patients who were studied for efficacy, the
proportions of women who remained disease-free at 6,
9, and 12 months in the fluconazole group were 91,
73, and 42.9% compared with 36, 28, and 22%,
respectively, in the placebo group (P,.001). Only
one patient discontinued treatment because of an
adverse event (headache) attributable to fluconazole,
and only one had a mild elevation in aminotransferase
levels. Thus, maintenance fluconazole therapy is
a well-tolerated and effective approach to treating
recurrent C albicans infections (Table 2). Although
unstudied, alternate doses of fluconazole (100 or 200
mg) are also recommended,6,7 because they may be
more easily accepted by prescription plans.
For women who recur after maintenance therapy
(approximately 50%), many health care providers
restart maintenance if the pathogen remains C albicans.
Although resistance to fluconazole seems to be fortunately rare, a recent report by Marchaim31 of clinically fluconazole-resistant C albicans vulvovaginal
candidiasis, possibly induced by long-term use of

fluconazole, raises new concerns and underscores


the need to bring the patients on maintenance therapy
back to make sure that they have a negative culture
and are responding to treatment appropriately.
There are some situations such as pregnancy,
allergy, gastrointestinal discomfort, headaches, or
cost, which prevent the use of fluconazole. Although
alternate topical maintenance regimens with clotrimazole have been described and shown to be effective,
those specific formulations are no longer commercially available. Current guidelines7 suggest using topical regimens intermittently. Regimens of miconazole
2% cream or clotrimazole 1% cream, used daily for 14
days, then twice a week for 6 months, have been used
successfully in our practice (unpublished observation).
Although clinical and in vitro resistance to C
albicans is rare, the same cannot be said for non-albicans
Candida species.32 Vaginal boric acid at 600 mg,
administered daily in a gelatin capsule for 14 days,
is recommended as initial therapy and cures up to
70% of C glabrata infections (Table 2).7,32 Apart from
occasionally causing local irritation and an abnormal
discharge, it is inexpensive and well-tolerated. The
second line of therapy, flucytosine compounded into
a 15.5% vaginal cream, given 5 g daily for 14 days, has
been shown to be effective32 but has become prohibitively expensive. Limited experience with topical amphotericin B as a 50-mg suppository offers another
option for C glabrata infections.33 Finally, with C
parapsilosis, one case series described successful mycologic cure in 17 of 19 patients receiving 200 mg fluconazole twice a week for a month and six of six patients
receiving 600-mg daily boric acid vaginal capsules twice
daily for 2 weeks.34 For other non-albicans Candida
infections, evidence is limited to case reports or small
case series, but the approaches used for C glabrata or

Table 2. Initial Treatment Options for Women With Chronic Vaginitis


Condition

Treatments

Normal
Vulvovaginal candidiasis Candida albicans
Non-albicans Candida
Bacterial vaginosis
Trichomoniasis
Atrophic vaginitis (vaginal treatments)

Desquamative inflammatory vaginitis

Source

None indicated
Fluconazole 150 mg orally every 3 d33, then once/wk36 mo
Boric acid 600-mg capsules vaginally per d32 wk
Metronidazole 0.75% vaginal gel 5 g/d310 d, then twice/wk34 mo
Tinidazole 2 g/d daily for 5 d
Estradiol 0.01% vaginal cream 24 g/d daily for 12 wk,
then 1 g 13 times/wk
Conjugated estrogen (0.625 mg/g) cream 0.5 g twice/wk
Estradiol (0.010 mg) tablet/d32 wk, then twice/wk
Estradiol (2 mg) ring every 3 mo
Clindamycin 2% vaginal cream, 5 g/d34 wk
Hydrocortisone 10% vaginal cream, 3 g/d34 wk

Sobel30
Sobel32
Sobel43
CDC7
NAMS51

Sobel58

CDC, Centers for Disease Control and Prevention; NAMS, North American Menopause Society.

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Management of Persistent Vaginitis

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Copyright American College of Obstetricians and Gynecologists

C parapsilosis are likely to be effective. As noted earlier, there may be less of a need to treat non-albicans
Candida infections, particularly those resulting from C
glabrata, because the yeast may be an innocent
bystander in at least 50% of cases.28

BACTERIAL VAGINOSIS
Affecting approximately 30% of women, bacterial
vaginosis is considered the most common form of
vaginitis.2 Associated sociodemographic factors
include a younger age, being non-Hispanic black or
Mexican American, having less than a high school
education, living at or near the federal poverty level,
and douching.35 Bacterial vaginosis is marked by a disturbance in the vaginal microflora with a lack of the
normal hydrogen peroxide-producing lactobacilli and
an overgrowth of primarily anaerobic organisms. Initially thought to be caused by G vaginalis, more recent
studies using standard culture and DNA-based technologies have shown that a broad range of bacteria,
including Atopobium vaginae, Bacteroides species,
Peptostreptococcus species, Fusobacterium species, Prevotella species, Mobiluncus species, bacterial vaginosisassociated bacteria, bacterial vaginosis-associated
bacteria-2, bacterial vaginosis-associated bacteria-3,
Megasphaera species, Eggerthella species, Megasphaera
type 1, Leptotrichia species and many others, are
found in vaginal samples of infected women.36 This
disturbed vaginal flora is a risk factor for many infectious morbidities, including urinary tract infections;
increased risk of infection after gynecologic surgery;
cervicitis; pelvic inflammatory disease; and an
increased susceptibility to human immunodeficiency
virus, gonococcal, chlamydial, trichomonal, and genital herpes infections in nonpregnant women as well
as spontaneous abortion, preterm birth, and postpartum endometritis in pregnant women.6
Although at least 50% of infected women have no
symptoms, the most common complaints are of an
abnormal vaginal discharge and a fishy odor. Usually,
the vulvovaginal examination will be normal apart from
a discharge described as watery and gray. Diagnosis
relies on finding three of four Amsels criteria (abnormal gray discharge, high vaginal pH, positive amine
test, and greater than 20% clue cells on saline microscopy). A vaginal Gram stain, known as the Nugent
score, where the presence or absence of different bacterial morphotypes is scored, is considered the gold
standard.6 Compared with the Nugent score and much
easier to perform in an office setting, Amsels criteria
have a sensitivity of 92%.37 Culture for G vaginalis is not
recommended because of a lack of specificity.6,7
Although commercial laboratories now offer

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PCR-based modalities to diagnose bacterial vaginosis


using various criteria, there is no evidence of clear clinical superiority of these expensive tests over Amsels
and Nugent criteria nor have they been shown to help
in guiding therapy.
Metronidazole (oral or topical), tinidazole (oral),
and clindamycin (oral or topical) are all recommended as initial treatments.6,7 They offer equivalent efficacy and can be distinguished from each other on the
basis of cost, mode of administration, and adverse
events. If patients fail an initial course of treatment,
they can often be cured with a second course of the
same therapy.7
After treatment, a single recurrence or more may
occur in up to 58% of women within 12 months.38 In
a cohort of 130 Australian women treated with a 7-day
course of oral metronidazole, Bradshaw and colleagues
found that the risk factors for recurrence were a history
of bacterial vaginosis, having a regular sex partner
throughout the study, or having a female sex partner,
and that hormonal contraception had a protective
effect. In a molecular analysis of uncultivated organisms, they also found that women with both A vaginae
and G vaginalis present initially had a much higher rate
of recurrence at 1 year than those in whom G vaginalis
alone was present (83% compared with 38%, P,.001).39
Recent controversies about the role of the sexual
partner and the possible development of vaginal
biofilms as a result of G vaginalis infection have fueled
new discussion of why women get bacterial vaginosis
and why some women recur. After the early report by
Gardner and Dukes40 describing G vaginalis as a possible cause of bacterial vaginosis, later research suggested that it was instead caused by complex changes
in vaginal flora and G vaginalis was ignored until
recently. Biofilms are a type of slime produced by
bacteria, which coats certain surfaces and within
which bacteria hide from and are protected from the
effects of antibiotics; the best known example is the
biofilm that occurs on infected foreign bodies such as
central venous catheters. As reviewed by Verstraelen
and Swidsinski,41 recent studies have found that 90%
of women with and 10% without bacterial vaginosis
have a complex polymicrobial biofilm, which can be
demonstrated on electron microscopy of vaginal biopsies. In women with disease, the biofilm consists primarily of G vaginalis and sometimes with A vaginae.
With standard antibiotic regimens, the bacterial load
may be decreased but the biofilm may not be eliminated, thus setting the stage for recurrence after treatment. These data suggest that it is not the mere
presence of G vaginalis that causes bacterial vaginosis,
but rather biofilm-associated G vaginalis.

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Gardner and Dukes40 had also hypothesized that


bacterial vaginosis was sexually transmitted, but this
theory was later discounted. However, as summarized
by Muzny and Schwebke,42 data in favor of sexual
transmission include evidence that bacterial vaginosis
can be transmitted between female sexual partners,
the data implicating the male partner from the Bradshaw study and the finding of similar flora in the male
partners of women with bacterial vaginosis. The finding of polymicrobial G vaginalisdominant biofilm in
men has added further fuel to the debate.41
Thus, bacterial vaginosis and its recurrence could
be the result of one or several mechanisms: reinfection through sexual activity, failure to reestablish
normal lactobacillus-dominant flora, or persistence
of a vaginal biofilm. Based on these various theories,
a variety of potential treatment interventions make
sense. To date, treatment of partner studies, despite
serious limitations,42 and recolonization with lactobacillus supplements, have shown no benefit and are not
recommended.6,7 In an attempt to prevent reinfection,
we routinely recommend consistent condom use for
36 months, although data supporting this recommendation are lacking. In women who have sex with
women, the cleaning of shared sex toys between uses
is encouraged, but routine screening or treatment of
the female partner is not.7
For now, the best approach seems to be maintenance therapy. To date, the only controlled study
consisted of metronidazole gel twice weekly for 4
months after an initial 10-day course of therapy
(Table 2).43 In this study of 127 evaluable women,
infection recurred in 26% of metronidazole gel and
59% of placebo patients (P5.001). However, a 51%
recurrence rate within 3 months and 59% rate of vulvovaginal candidiasis because of prolonged antibiotic
therapy demonstrate the need for more effective therapy. Thus, an alternate regimen of 500 mg metronidazole or tinidazole twice a day for 7 days followed by
21 days of 600 mg boric acid daily followed by an
additional twice weekly metronidazole gel regimen
for 16 weeks was studied in 77 episodes of recurrent
bacterial vaginosis.44 Cumulative cure at 12, 16, and
28 weeks from the initial visit was 87, 78, and 65%,
respectively, with a failure rate of 50% by 36 weeks of
follow-up. Although these results represent the most
promising ones to date, it remains difficult to truly
cure women with recurrent bacterial vaginosis.

TRICHOMONIASIS
Considered the third most common cause of infectious vaginitis,2 trichomoniasis is a surprisingly
uncommon diagnosis at our tertiary care vaginitis

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center and is found in fewer than 1% of the women


referred to us (unpublished observation). Although up
to 50% of infected women may be asymptomatic,45
symptomatic women will complain of an abnormal
discharge (clear to yellowgreen and frothy), dyspareunia, vulvovaginal soreness and itching, and pain on
urination. Physical findings include vulvovaginal erythema, discharge, and occasionally punctate hemorrhages of the vaginal mucosa and cervix. Most
uncomplicated cases will be cured with treatment with
either oral metronidazole or tinidazole along with
treatment of the sexual partner.6,7 However, not all
patients with trichomoniasis are straightforward. As
noted in a review of 45 cases seen in a specialty vaginitis clinic, the most common issues pertaining to
trichomoniasis in women with persistent vaginitis
are missed diagnosis (31%) and metronidazoleresistant infection (33%); other cases were incident
cases occurring in women being treated for other conditions.46 Occasionally, health care providers may
also encounter women with allergic reactions to
nitroimidazoles.
With a sensitivity of 6070%, saline microscopy
alone is simply not a good enough test to reliably
diagnose trichomoniasis. Other tests, such as the
U.S. Food and Drug Administrationcleared OSOM
Trichomonas Rapid Antigen Test may provide a rapid
(less than 10 minutes) result in the office.7 However, if
T vaginalis infection is suspected but not proven, culture or PCR is recommended. The mainstay of therapy has been metronidazole and, more recently,
tinidazole. Although hypersensitivity reactions have
been rare, patients who are allergic to nitroimidazoles
represent a therapeutic challenge. Fortunately, oral or
parenteral desensitization to metronidazole followed
by treatment has been shown to be highly effective
in a study of 15 patients treated and cured with such
an approach.47 Thus, a patient with this uncommon
clinical scenario should be managed in conjunction
with an allergist.
Treatment failure can be related to noncompliance, reinfection, and metronidazole resistance, the
latter estimated at anywhere between 1.7 and 10.1%.48
Thus, if a patient returns with ongoing trichomoniasis
after treatment, health care providers should check to
make sure that the treatment was taken and that reinfection did not occur. With resistance, the in vitro
mechanisms are the result of both aerobic and anaerobic pathways. Because in vitro resistance correlates
poorly with clinical outcome, metronidazole-resistant
trichomoniasis is primarily a clinical diagnosis. With
a resistant infection, Centers for Disease Control and
Prevention guidelines recommend obtaining cultures

OBSTETRICS & GYNECOLOGY

Copyright American College of Obstetricians and Gynecologists

for resistance testing and can offer management recommendations (telephone: 404-718-4141; web site: http://
www.cdc.gov/std). A longer course of metronidazole,
500 mg orally twice daily for 7 days, then, if necessary,
2 g metronidazole or tinidazole orally daily for 5 days
is recommended as initial therapy (Table 2).7 Beyond
that, the most extensive experience is with high-dose
tinidazole. In a series of 33 patients who failed courses
of high-dose metronidazole, 92% were cured with highdose tinidazole, 1 g two or three times a day orally
along with 500 mg a day vaginally for 14 days.49
Apart from nitroimidazoles, the medical literature
is peppered with other medications used in resistant
trichomonas cases, mostly to no avail. However,
experience with paromomycin, an aminoglycoside
agent active against protozoa including T vaginalis, suggests that it may be one option in problematic women.
Used as a 5% cream, 5 g vaginally nightly, paromomycin had a 58% cure rate, but vestibular and vulvar
ulceration is a side effect that limits its use.49 Recently,
the combination of high-dose (1 g three times a day)
tinidazole and paromomycin cream nightly for 14 days
was used successfully in two women with clinical resistance to high-dose tinidazole.50 To minimize the risk of
ulceration, patients are instructed to apply a barrier
such as petrolatum to the vestibule.

VULVOVAGINAL ATROPHY
As one might expect, symptomatic vulvovaginal
atrophy, ie, atrophic vaginitis, is believed to be the
most common cause of vulvovaginal symptoms in
menopausal women.51 As summarized by the North
American Menopause Society, most women with vulvovaginal atrophy may not relate their symptoms to
menopausal changes. Furthermore, in 469 women
with chronic vaginitis, it was diagnosed not only in
women older than 50 years (48%) but also in younger
women (5%).52 Thus, recognition and treatment of
atrophy are part of any discussion of chronic vaginitis.
The main complaints are those of dryness, itching, burning, dyspareunia, and external dysuria.
Despite the sensation of dryness, affected women
may sometimes note a heavier discharge, yellow or
watery, and even blood-tinged. Findings include
atrophy of the labia majora or minora, vestibular
and vaginal pallor, a loss of rugal folds, vaginal
erythema or even petechiae, contact bleeding, and
a yellow watery discharge. Laboratory findings are
summarized in Table 1. Importantly, the degree of
atrophic changes as measured by findings and maturation index does not correlate with symptoms.51
Expert consensus opinion51 recommends nonhormonal vaginal lubricants and moisturizers as well as

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continued sexual activity as initial therapy for women


with vulvovaginal atrophy. However, very few controlled studies have been done to assess their effect.
For most women, low-dose vaginal estrogen, used
commonly in our practice, can provide adequate
symptom relief (Table 2). Intravaginal dihydroepiandrosterone or hyaluronic acid may be considered as
possible alternatives to estrogen, although published
experience is very limited.51,53 For those women preferring systemic therapy, systemic estrogen (with or
without progesterone) or ospemifene may be considered. The nuances and controversies surrounding
treatment of vulvovaginal atrophy have recently been
reviewed.51 Finally, it should be noted that more than
50% of women older than 50 years with chronic vaginitis may have causes that are separate from atrophic
vaginitis with desquamative inflammatory vaginitis
(15%) and lichen sclerosus (14%) being the most
common.52

DESQUAMATIVE INFLAMMATORY VAGINITIS


First described by Gray and Barnes in 1965,54 desquamative inflammatory vaginitis is a condition that is
unfamiliar to most health care providers yet is found
in up to 8% of women with persistent vaginitis.4 Initially thought of as a possible bacterial overgrowth of
an atrophic vagina55 or even a variant of lichen planus,56 the cause remains unknown. In a minority of
women, it may be the result of a local toxin-induced
inflammatory reaction to S aureus infection57 or even
group A streptococcal infection.
The typical patient with desquamative inflammatory vaginitis is hypoestrogenic (on continuous lowdose birth control pills, postpartum and breastfeeding,
or perimenopausal or postmenopausal) and notices the
onset of an abnormal discharge, usually described as
yellow or brown, along with burning and severe
dyspareunia. Unlike vulvovaginal atrophy, examination reveals severe introital and vaginal erythema and
a copious vaginal discharge. The presence of white
blood cells on saline microscopy can distinguish it from
atrophy. Because some patients with severe atrophic
vaginitis may have white blood cells on microscopy,
a lack of response to topical estrogen may also serve to
distinguish between the two conditions. When we
suspect desquamative inflammatory vaginitis, we routinely perform vaginal bacterial cultures, looking for
group A streptococci or S aureus, and PCR for
T vaginalis.
Because the cause remains unknown, various
treatment regimens have been proposed. The most
extensive published experience was from Wayne
State University, where they studied 98 women

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treated in a nonrandomized fashion with either 2%


clindamycin vaginal cream (5 g) or 10% hydrocortisone compounded vaginal cream (35 g) daily for 46
weeks.58 After initial treatment, 86% of women were
fully controlled with the remainder partially
improved. However, with longer follow-up at 1 year,
26% of treated women were cured, 58% required
some sort of maintenance therapy, and 16% were only
partially controlled with ongoing treatment. No conclusions could be made in terms of the relative efficacy of either drug. Anecdotally, because of the
potential role of hypoestrogenism in triggering desquamative inflammatory vaginitis, most experts will
use exogenous estrogen after initial treatment to
decrease the chance of recurrence.
Box 1. Possible Pitfalls in the Treatment of
Women With Chronic Vaginitis

Evaluation
Accepting patient self-diagnosis or telephone diagnosis
Failure to:
 get appropriate problem-focused history
 inspect vulva, vestibule, vagina, and cervix
 perform vaginal pH, amine test, and saline and
potassium hydroxide microscopy
 obtain yeast culture with speciation, and, when
appropriate, other ancillary laboratory tests*
 realize that one patient may have multiple causes for
her symptoms
Depending on inappropriate criteria to diagnose or
exclude vulvovaginal infections (eg, Pap test for bacterial
vaginosis)

Management
Assuming that positive cultures or PCR for group B
streptococci, Gardnerella vaginalis, enterococcus and
Escherichia coli represent true infection
Treating for vulvovaginal candidiasis or bacterial vaginosis presumptively
Too short a course of treatment for patients with
refractory or recurrent infections
Not bringing the patient back after therapy to assess her
response
Forgetting that treatment with topical creams or ointments can cause symptoms similar to what the patient
had in the past
*Trichomonas vaginalis polymerase chain reaction (PCR) or
culture, bacterial culture, Neisseria gonorrhoeae and
Candida trachomatis PCR, herpes simplex virus PCR and
type-specific immune globulin G antibodies, vulvar or
vaginal biopsies.

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FINAL CONCERNS
Because women with chronic vaginitis are often
desperate to try some sort of treatment to help their
symptoms, it is easy to fall into many traps, summarized in Box 1. Some of these pitfalls such as selfdiagnosis and telephone diagnosis are at times
unavoidable. However, by acknowledging they exist
and steering clear of them when possible, most health
care providers should be able to help the vast majority
of women with chronic vaginitis achieve significant
control of their symptoms, a gratifying outcome for
patient and health care provider alike. There remain
unresolved issues with each of the conditions discussed that will require ongoing research in this
often-neglected area of medicine.
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