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Abstract
Bacterial vaginosis (BV), candidiasis, and trichomoniasis account for more than
90% of vaginal infections. BV typically is associated with a decrease in
commensal, protective lactobacilli and a proliferation of other flora. Mobiluncus is
pathognomonic but found in only 20% of cases. Presence of 3 of 4 criteria
indicates BV: a homogenous noninflammatory discharge (not many WBCs); pH
>4.5; clue cells (bacteria attached to borders of epithelial cells, > 20 % of
epithelial cells); and a positive whiff test. New intravaginal BV preparations cause
less-adverse systemic effects than oral regimens. Trichomonas vaginalis, a
protozoan, appears to be sexually transmitted and causes up to 25% of vaginitis
cases. Diagnosis is made by observation of a foul, frothy discharge; pH >4.5
(present in 70% of cases); punctate cervical microhemorrhages (25% of cases);
and motile trichomonads on wet mount (50%-75% of cases). Recommended
treatment is a single 2g dose of oral metronidazole. Treatment failure is usually
due to nontreatment of the male partner. Candidiasis typically presents as a thick,
"curdled" white discharge or vulvar pruritus, with a hyperemic vagina and an
erythematous and/or excoriated vulva. Vaginal pH is usually in the normal range
of 3.8-4.2 in uncomplicated candidiasis. Microscopic examination of the
discharge reveals hyphae or budding yeast in 50%-70% of cases. While the most
common offender isCandida albicans, Candida tropicalis and Candida
glabrata have become increasingly prevalent. Approximately 15% of C
albicans organisms are resistant to clotrimazole and miconazole. Recurrent
infections may be treated with fluconazole 150mg weekly for up to 12
consecutive weeks.
Introduction
Vaginal discharge and the associated vulvar itching are the most common
reasons for a woman to seek gynecological care. While these may seem minor
complaints to the provider, the patient may feel intensely anxious over the
possibility of an underlying sexually transmitted disease (STD) or even cancer.
The initial episode provides the best opportunity for effective resolution of
symptoms. Hence, appropriate treatment needs to be based upon correct and
complete diagnosis, for which an understanding of the pathophysiology of the
discharge is essential.
Not all vaginal discharges result from an infective etiology. Atrophic vaginitis,
physiologic leukorrhea, and local irritants cause a number of cases. Of the
infective etiologies, bacterial vaginosis (BV) and yeast (candidiasis) are by far the
most common. Add the occasional case of trichomoniasis, and the list covers
more than 90% of the cases of vaginal infections.
[1]
Not infrequently, multiple
etiologies exist.
Diagnosis and elimination of the cause of the problem rely heavily on an accurate
and thorough history and physical examination.
[2]
The history should investigate
the patient's duration of symptoms, her sexual activity, whether the discharge
smells foul after intercourse, current medical conditions, medications,
contraceptive methods, prior similar episodes, and a history of STDs.
[3]
In the
search for a noninfective cause of the vaginosis, ask the woman if she has
changed detergents/fabric softeners or uses scented hygiene products or
douches. Also ascertain whether the woman has any signs of complications or
systemic infection: abdominal or pelvic pain suggesting pelvic inflammatory
disease, dysuria suggesting urinary tract infection, and fever.
Physical Exam
Using a good light source and a vaginal speculum, inspect the vulva, vaginal
walls, and cervix for the presence of lesions, erythema, and excoriations. The
discharge should be observed for color, consistency, odor, and whether it is
vaginal or emanating from the cervix. Using either a dipstick or paper roll,
measure the pH of secretions from the vaginal sidewall (not from the posterior
fornix, which may be contaminated with cervical mucus). Separate slides of the
discharge should then be made with 10% KOH (potassium hydroxide) and with
normal saline, then secured with cover slips and examined for flagellated
protozoa, hyphae or budding yeast, or other organisms under the microscope.
Slides should be wafted for the release of volatile amines (a fishy or musty odor)
upon adding the alkaline KOH solution, since this is a sign of bacterial vaginosis.
Bacterial Vaginosis
BV is a polymicrobial, primarily anaerobic, infection associated with sometimes
fishy-smelling increased vaginal discharge (Fig. 1), but not accompanied by
leukorrhea, vulvar burning, or pruritis. Infection with BV can have significant
sequelae, however. It has been associated with an increased risk of septic
abortion, premature rupture of amniotic membranes, preterm labor, preterm
delivery, post-Cesarean endomyometritis, and post-hysterectomy pelvic
cellulitis.
[4-11]
Figure 1. The characteristic milky or creamy vaginal discharge of bacterial vaginosis is associated with a high vaginal pH and a fishy odor. Figure courtesy of James A. McGregor, MD,
University of Colorado Health Sciences Center.
Its presence represents a change in the vaginal ecosystem, specifically a
decrease in lactobacilli, which is part of the normal flora; a proliferation of
pathogenic inhabitants of the vagina; and an elevation of pH (>4.5). Despite
exhaustive basic research, it is unclear whether the decline in lactobacilli,
proliferation of pathogens, or rise in pH initiates the cascade. While BV was
originally described by Curtis in 1911, it gained notoriety only in 1955 after
Gardner and Dukes described the offending organism asHaemophilus vaginalis;
the organism has since been renamed Gardnerella vaginalis in honor of its
discoverer.
[1]
The current term, bacterial vaginosis, rather than vaginitis, indicates
lack of an inflammatory reaction (absence of WBCs in the discharge) and is much
more reflective of the true polymicrobial nature of this condition.
Although the majority of pathogens causing BV are derived from the endogenous
flora, one genus--Mobiluncus--is unique to patients with BV; it has never been
found in patients without vaginosis.Mobiluncus are comma-shaped, gram-
variable or gram-negative, anaerobic rods with tapered ends that utilize subpolar
flagella for a tumbling motility. G vaginalis is found in nearly 100% of women with
symptomatic BV.
[12]
In fact, G vaginalis may be the organism primarily responsible
for the premature rupture of membranes in women with BV. The organism has
phospholipase A2 activity, which initiates labor.
[13]
Other factors may also play a
role in early labor, however, as G vaginalis is also found in many normal women
with uncomplicated pregnancies.
Whether BV is sexually transmitted remains unsettled. The majority of
observations, such as those listed below, suggests that BV is probably not
sexually transmitted.
1. Urethral colonization rates of Gardnerella and Mobiluncus species among male partners of women with BV have been observed to be no higher than those
for partners of normal women.
[14]
2. The incidence of BV has not been documented to rise with increasing number of lifetime sexual partners.
[14]
3. Cotreating the male partner has not been shown to reduce the recurrence risk in females (hence the basis for the current recommendation not to cotreat the
male partner).
[14,15]
However, one contrary piece of evidence, suggesting a sexually transmitted
aspect, is that condom use is associated with a decreased incidence of BV
among the female partners. Hence, if a patient experiences recurrences of BV,
there is some basis to treat the partner.
[16]
Bacterial vaginosis identified on wet mount (Fig. 2) represents the most common
vaginal infection identified in women with inflammation or altered flora on
Papanicolaou smear.
[17]
Figure 2. On wet preparation of vaginal fluid, absence of WBCs and stippling of epithelial cells support a diagnosis of bacterial vaginosis. From Infect Med 9(1):50, 1992. Copyright
1992, SCP Communications, Inc.
Diagnosis. The diagnosis of BV requires the presence of at least 3 of the
following 4 criteria (Table I):
[18]
1. A homogenous noninflammatory discharge (not many WBCs).
2. Vaginal pH >4.5.
3. Clue cells (bacteria attached to the borders of epithelial cells, >20 % of epithelial cells; Fig. 3).
4. Whiff test positive for fishy or musty odor when alkaline KOH solution added to smear.
Figure 3. Pap smear showing clue cells consistent with bacterial vaginosis. Courtesy of Abner P. Korn, MD. Copyright 1996, SCP Communications, Inc.
Applying these diagnostic criteria will result in correctly diagnosing BV more than
90% of the time with a false-positive rate of less than 10%.
[18,19]
Note that neither
Papanicolaou smear nor culture are diagnostic in and of themselves. The
Papanicolaou smear may indicate a coccobacillary shift of flora, but this report
should prompt patient evaluation for the formal diagnostic criteria rather than
empiric treatment. Culture is not helpful since the flora of BV are largely derived
from the normal commensal flora.
Treatment. For years, oral metronidazole has been the primary indicated
regimen. While very effective, this regimen is fraught with such serious side
effects as convulsive seizures and peripheral neuropathy, causing many patients
to discontinue their treatment prior to completion of the 7-day regimen. Other
systemic options include oral clindamycin. More recently, the advent of
intravaginal preparations has afforded topical options that cause less-adverse
systemic effects.
[20]
The amount of drug absorbed and delivered is also much
less. For example, metronidazole requires an oral dose of 500mg, while only
37.5mg of metronidazole intravaginal gel is needed to achieve therapeutic
vaginal tissue levels.
[21,22]
Similarly, oral and intravaginal preparations of
clindamycin achieve equal efficacy, although a lower dose is delivered
intravaginally.
[20,23]
While the regimens listed in Table II have been shown to provide 90% or better
efficacy, the single 2g dose of metronidazole affords only 70% efficacy and leads
to more gastrointestinal adverse effects than clindamycin.
[24-27]
The oral
clindamycin regimen is associated with a higher incidence of diarrhea than oral
metronidazole.
[28]
A decade ago, ampicillin had traditionally been endorsed as
first-line therapy for BV in pregnancy; however, this finding was based more on
safety concerns than on efficacy. Given the more recent data suggesting that BV
is associated with worse obstetric outcomes,
[4,9-11]
more efficacious therapy is
justified. Oral metronidazole alone, or in combination with oral erythromycin, has
been shown to reduce adverse obstetric sequelae in high-risk patients with
BV.
[29,30]
Clindamycin cream, while effectively treating the BV, was associated by
Amsel's criteria with worse obstetric outcomes.
[31,32]
This paradox may be
explained by clindamycin reducing the endogenous lactobacillus population or by
the overgrowth of Escherichia coli andEnterococcus.
[23,33]
Despite common
opinion, exhaustive studies have not shown metronidazole to be teratogenic. It is
mutagenic in bacteria and carcinogenic in rodents, but no human data have
demonstrated adverse outcomes when subjected to analytic scrutiny. However,
several sources, albeit without evidence-based data, state that metronidazole is
contraindicated in the first trimester of pregnancy.
[15,28]
Trichomonas vaginalis
The trichomonad parasite is a flagellated protozoan that causes up to 25% of vaginitis cases. While trichomonas infection is asymptomatic up to 50% of the time,
[34]
when
clinical signs are present they include irritation and soreness of the vulva, perineum, and thighs, with dyspareunia and dysuria. Typically, the trichomonas infection is
accompanied by a copious, greenish-yellow frothy discharge (Fig. 4a). Unlike bacterial vaginosis, it seems that trichomonas is primarily a sexually transmitted infection.
Figure 4a. Bubbly discharge of vaginal fluid growing the parasite Trichomonas vaginalis. Figure courtesy of James A. McGregor, MD, University of Colorado Health
Sciences Center.
Diagnosis. The diagnosis is made by observation of the following features (Table I):
A foul-smelling frothy discharge (present in 35% of cases
Vaginal pH >4.5 (70% of cases)
Punctate cervical microhemorrhages (25%)
[34]
Motile trichomonads on wet mount (50%-75%)
[35]
Papanicolaou smear is quoted to be 70% sensitive in identifying trichomonads
[28]
(Fig. 4b). But the resemblance of leukocytes to nonmotile parasites can lead to
overdiagnosis of trichomonas when a Pap smear is used to confirm a suspected infection. Cultures are not generally indicated because wet mount and clinical diagnostic
criteria are sufficiently accurate (except for recalcitrant infections or when rare instances of metronidazole resistance are suspected).
Figure 4b. Pap smear is reported to be 70% sensitive in showing Trichomonas vaginalisinfection. Courtesy of Abner P. Korn, MD. Copyright 1996, SCP
Communications, Inc.
Treatment. The current primary treatment recommendation is a single 2g dose of oral metronidazole (Table II). For those who cannot tolerate this single large dose,
500mg bid for 7 days is equally efficacious if the patient completes her regimen. The male partner(s) must also receive treatment. The most common cause of treatment
failure in a woman is failure to treat the partner(s). Actual metronidazole resistance is decidedly rare. There is no consensus as to the best treatment of this condition.
Many authorities recommend high-dose (2g or more) metronidazole daily for several consecutive days.
[15]
This regimen may be supplemented with intravaginal
metronidazole suppositories (500mg bid). The 0.75% metronidazole gel is only 50% effective in treating trichomoniasis. Alternatively, the patient may be admitted for
intravenous metronidazole 500mg every 8 hours.
[36,37]
Clotrimazole, another nitro-imidazole compound similar to metronidazole, has been reported to attain nearly a 50%
cure rate when given as an intravaginal cream.
[38]
Neither of these latter 2 regimens is endorsed by the US Food and Drug Administration (FDA) for this indication.
While classically contraindicated in the first trimester of pregnancy, the 2g single dose of metronidazole may be given thereafter in pregnancy. In the interim, clotrimazole
has some (approximately 50%) efficacy, although has not been approved by the FDA for this use.
[38]
4 of 8
Candidiasis
Candida, a commensal organism, is found in small population densities in the
vaginal ecosystems of nearly one third of healthy women. Symptomatic infection
arises, however, when proliferation causes a shift from colonization to frank
adherence and infection. The most common offender is Calbicans; however,
other species of Candida, such as tropicalisand glabrata, have become
increasingly prevalent, currently representing one third of
isolates.
[39]
Vaginal candidiasisoccurs more commonly after antibiotic treatment
and among women taking oral contraceptives.
[40-42]
Yet unless a patient has a
history of antibiotic-associated candidiasis, it is not recommended to routinely
prescribe antifungal therapy for every woman with candidiasis preceded by a
course of antibiotics.
Diagnosis. The patient typically presents with a thick, "curdled" white discharge
or vulvar pruritus (Table I). The vagina has no "itch" receptors, hence, pruritus
ensues only after the fungus has spread distally onto the vulva (Fig. 5). The
discharge is usually neither malodorous nor off-white unless a mixed infection is
present. The vagina often appears hyperemic; the vulva can be erythematous
and/or excoriated. Vaginal pH is usually normal in cases of uncomplicated
candidiasis. Microscopy of the discharge with 10% KOH will often reveal hyphae
or budding yeast in 50%-70% of cases
[43,44]
(Fig. 6). C albicans organisms are
easiest to identify, as they have long hyphae with blastospores along their length
and a terminal cluster of chlamydiaspores (Fig. 7). The "atypical" species of
yeast, however, may only have features of budding yeast (resembling small
snowmen), which are easily obscured within surrounding cellular debris. Hence, if
a patient presents with classic symptoms of candidiasis and her thorough
evaluation is otherwise negative (normal pH, no motile trichomonads, no clue
cells, no excessive leukocytes), it is not unreasonable to offer the patient an
antifungal agent as a therapeutic trial. Fungal cultures are not recommended
initially.
[39]
The presence of fungal elements on Papanicolaou smear is not
necessarily indicative of infection; because it could simply represent colonization,
treatment is not recommended on the basis of this finding alone.
[45]
Figure 5. Vaginal mucosa can be covered with numerous white, thrushlike patches in vulvovaginal candidiasis. From The AIDS Reader, 1(5):155, 1991, courtesy of Jeffrey Laurence,
MD. Reproduced from Kaufman RH: Common causes of vaginitis. Hosp Med 22:23-44, 1986.
Figure 6. Pseudohyphae and blastoconidia (yeast cells) on wet mount (KOH preparation) are consistent with Candida albicans. Copyright 1992, SCP Communications, Inc.
Figure 7. Both pseudohyphae and blastoconidia (yeast cells) stain purple on Gram's stain preparation of clinical material from patient with candidiasis. Copyright 1992, SCP
Communications, Inc.
Patients often experience recurrent yeast infections. This complaint demands
thorough attention. It is important to assess for underlying hygiene issues, such
as frequent douching and constrictive synthetic undergarments that retain
moisture in vaginal secretions. Also rule out other conditions that have been
closely associated with candidal infections (eg, diabetes and
immunocompromise). Finally, rule out other pathogens and mixed infections.
Culture, to confirm and speciate yeast, may play a role in this setting.
Treatment. In the treatment guidelines released in 1993 by the Centers for
Disease Control and Prevention, myriad imidazoles and triazoles were endorsed
for treatment of vaginal candidiasis.
[15]
Notably, each regimen was an intravaginal
preparation. In July 1994, the FDA approved oral fluconazole for vaginal
candidiasis (Table II). Most albicans species are susceptible to commonly
prescribed imidazoles (eg, clotrimazole, miconazole). However, approximately
15% of albicans organisms are resistant; albicans strains are frequently more
susceptible in vitro to triazoles (eg, fluconazole, terconazole) than to
imidazoles.
[46]
However, in comparing regimens, it must be noted that in vitro
susceptibility testing does not correlate well with clinical efficacy, and study
designs of various therapies are widely varied and hence not readily comparable.
Another cause of treatment failures, besides resistance, relates to the reservoir of
yeast which 15% of healthy women harbor in their gastrointestinal
tract.
[47]
Obviously, intravaginal therapies fail to target the source of infection in
these individuals. Of orally available agents (fluconazole, ketoconazole, and
itraconazole), only fluconazole is currently approved by the FDA for this use.
Fluconazole has much less hepatotoxicity than ketoconazole. Recurrent
infections may be treated with weekly administration of fluconazole 150mg for up
to 12 consecutive weeks.
[47]
Alternatively, boric acid (600mg in #1 size gelatin
capsules inserted bid per vagina for 10 days) is quite effective against most
strains of Candida.
[39]
While candidial vaginitis is not considered a sexually
transmitted disease, women may infect the glans penis of their partners.
Cotreatment of the male partner is usually not indicated, except in cases of fungal
balanitis or in an uncircumcised male who harbors a penile reservoir.
Table 1. Vaginal Infections: Diagnostic Clues
Clinical Signs
Discharge
Characteristics
Vaginal
pH Microbiology
Sexually
Transmitted?
Bacterial
Vaginosis
Vaginal discharge NOT
accompanied by
leukorrhea, vulvar
burning, or pruritis.
Color: off-white
Consistency:
creamy
Consistency:
creamy
Odor: whiff test
positive for fishy
or musty odor
when alkaline
KOH solution
added to smear.
>4.5 Polymicrobial; mostly normal
flora, but can include comma-
shaped, gram-variable
anaerobicMobiluncusrods
,Gardnerella vaginalis, or clue
cells (> 20 % of the epithelial
cells), but few WBCs. Pap smear
may indicate coccobacillary shift
of flora.
Probably not.
Trichomonads Irritation and soreness
of the vulva, perineum,
and thighs, with
dyspareunia and
dysuria. Punctate
cervical
microhemorrhages
visible in 25% of cases.
Asymptomatic up to
50% of the time.
Color: greenish-
yellow
Consistency:
Frothy
Odor: foul-
smelling
> 4.5
(70% of
cases)
Flagellated protozoa visible on
wet mount (50%-75%); Pap
smear sensitive for trichomonads
(70%).
Yes
Candida Vulvar pruritus,
indicating spread of
fungus distally onto the
vulva. Hyperemic
vagina, erythematous or
excoriated vulva.
Color: white; off-
white if mixed
infection present
Consistency:
"curdled"
Odor: not
Normal
range
of 3.8-
4.2
Hyphae or budding yeast visible
in 50%-70% of cases. Fungal
elements on Pap smear could
indicate colonization, not
infection. Culture can confirm
and speciate yeast.
Patients may
infect the
glans penis of
their partners.
malodorous
unless a mixed
infection is
present
Table 2. Current Treatment Recommendations for Bacterial Vaginosis,
Trichomonas, and Candida
Bacterial Vaginosis
o Metronidazole 500mg PO bid for 7 days
o Clindamycin 300mg PO bid for 7 days
o Metronidazole gel 0.75% bid per vagina for 5 days
o Clindamycin cream 2% per vagina for 7 nights
Trichomonas
o Metronidazole 2g PO, single dose
o Metronidazole 500mg PO for 7 days
o Metronidazole 2g or more daily for several consecutive days, supplemented with intravaginal metronidazole suppositories (500mg bid)
o Metronidazole 500mg IV q8h*
o Clotrimazole,* single 500mg tablet or cream used once intravaginally at night
Candida**
o Intravaginal imidazoles and triazoles (eg, clotrimazole given as single 500mg tablet or cream used once intravaginally at night, miconazole
given as 200mg suppository inserted intravaginally once daily at bedtime for 3 consecutive days)
o Fluconazole 150mg PO for up to 12 consecutive weeks for recurrent infections
o Boric acid 600mg in #1 gelatin capsule per vagina bid for 10 days
* Not endorsed by the US Food and Drug Administration for this indication.
** Cotreatment of the male partner usually not indicated, except in cases of fungal balanitis or in an uncircumcised male with a penile reservoir.