4/4/06njm

**Q. My patient with bacterial vaginosis is allergic to metronidazole.
What else can I use?**

A. First make sure it is bacterial vaginosis, and then consider one of
these other regimens.

**Quick Answer**

**Two most effective regimens**

Metronidazole, administered either orally or intravaginally

[Clindamycin](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/60665&drug=true),
administered either orally or intravaginally

**Other less effective therapies**

Triple-sulfa creams

[Erythromycin](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/94465&drug=true)

[Tetracycline](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_L_Z/258546&drug=true)

[Acetic
acid](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/6099&drug=true)
gel

Povidone-iodine vaginal douches

[Ampicillin](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/17350&drug=true)

[Amoxicillin](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/15870&drug=true)

**Now some Background**

1.) First let us make sure it is bacterial vaginosis (BV) (see
**Diagnosis** below).

2.) Next, let's review the big picture about therapy (see **Therapy**
below).

BV resolves spontaneously in up to one-third of nonpregnant and pregnant
women. Treatment is indicated in women with symptomatic infection and
those with asymptomatic infection prior to abortion or hysterectomy;
asymptomatic pregnant women with previous preterm births may also
benefit, but screening and treatment of these women is controversial. It
is not necessary to treat sexual partners.

3.) Lastly, we need to remember that every symptom that the patient
thinks is related to BV, may not be BV. Vulvovaginal symptoms are
extremely common, accounting for over 10 million office visits per year,
as well as frequent self-diagnosis and therapy. As an example, a random
telephone survey in the United States found that 8 percent of white
women and 18 percent of African American women reported an episode of
vaginal symptoms of any severity in the previous year (1995). A
healthcare professional was consulted in 55 and 83 percent of the cases,
respectively. Most women purchased an over-the-counter antifungal
preparation to treat their symptoms, whether or not they saw a
physician.

The etiology of vaginal complaints includes infection of the vagina,
cervix, and upper genital tract, and a number of noninfectious causes
such as chemicals or irritants (eg, spermicides or douching), hormone
deficiency, and rarely systemic diseases. Variations in vaginal
discharge may also occur during the normal menstrual cycle. Since the
symptoms of vaginitis are nonspecific, neither self-diagnosis nor
diagnosis by a physician is reliable without laboratory or histological
confirmation of a specific disorder. Regrettably, the management of
vaginitis remains largely empirical, although this practice should be
avoided because of frequent misdiagnosis and inappropriate therapy.

The three most common infectious causes of vaginitis: bacterial
vaginosis, candida vulvovaginitis, and trichomoniasis, which account for
at least 90 percent of vaginitis. Women with vulvovaginal disease
unrelated to infection should also be considered.

As this patient is allergic to our best therapy, it is even more
important than ever to consider other etiologies. (see **Differential
Diagnosis** below)

**#1**

**DIAGNOSIS** --- The general diagnostic approach to women with vaginal
complaints is reviewed separately.

The diagnosis of BV is clinical; criteria have been established that are
simple and useful in office practice. Three of the four criteria (ie,
Amstel criteria) listed below are necessary for diagnosis, although the
first three findings are sometimes present in patients with
trichomoniasis

-Homogeneous, grayish-white discharge

-Vaginal pH greater than 4.5

-Positive whiff-amine test, defined as the presence of a fishy odor when
10 percent KOH is added to vaginal discharge samples

-Clue cells on saline wet mount

The presence of clue cells is the single most reliable predictor of BV.
Clue cells are vaginal epithelial cells studded with adherent
coccobacilli that are best appreciated at the edge of the cell. At least
20 percent of the epithelial cells on wet mount should be clue cells.
The sensitivity of Amstel criteria for diagnosis is over 90 percent,
which is as good as gram stain.

Gram staining of vaginal secretions is also a reliable method for the
diagnosis of BV, but is mostly performed in research studies because it
is more cumbersome than Amstel criteria. If clinical criteria are used
to define infection, then the sensitivity reported for gram stain ranges
from 62 to 100 percent.

Vaginal culture has no role in the diagnosis because there are no
bacteria that are specific for BV. Although cultures for G. vaginalis
are positive in almost all cases, the organism may be detected in 50 to
60 percent of healthy asymptomatic women.

DNA probes for G. vaginalis are expensive and suffer from the same
limitations as culture, but provide fairly quick answers and may be
useful to practitioners unable to perform microscopy. In one study, for
example, the combination of a positive DNA probe (concentration of G.
vaginalis ![](media/image1.png){width="8.333333333333333e-2in"
height="9.236111111111112e-2in"}10(7) CFU/mL) and vaginal pH greater
than 4.5 had a sensitivity and specificity of 95 and 99 percent,
respectively, compared with diagnosis based upon clinical criteria.

Diagnostic cards (eg, Femcard) have become available commercially,
providing a useful and rapid role in confirming the diagnosis of BV.
These are especially useful for practitioners not able to perform
microscopy. The test detects the presence of elevated vaginal pH and
increased amine with a sensitivity of 87 percent and a specificity of 92
percent.

**#2**

**THERAPY** --- BV resolves spontaneously in up to one-third of
nonpregnant and pregnant women. Treatment is indicated in women with
symptomatic infection and those with asymptomatic infection prior to
abortion or hysterectomy; asymptomatic pregnant women with previous
preterm births may also benefit, but screening and treatment of these
women is controversial. It is not necessary to treat sexual partners.

**Options** ---
[Metronidazole](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_L_Z/166085&drug=true)
or clindamycin administered either orally or intravaginally will result
in a high rate of clinical cure (70 to 80 percent at four weeks of
follow-up). Oral medication is more convenient, but associated with a
higher rate of systemic side effects than vaginal administration.

-Metronidazole is the most successful therapy. Most studies using
multiple divided-dose oral regimens for one week achieved early rates of
clinical cure in excess of 90 percent, and cure rates of approximately
80 percent at four weeks.

The recommended oral regimen is 500 mg twice daily for seven days.
Topical vaginal therapy with 0.75 percent
[metronidazole](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_L_Z/166085&drug=true)
gel (5 g once daily for five days) is as effective as oral
metronidazole. The choice of oral versus topical therapy depends upon
patient preference.

Single-dose therapy with 2 g of
[metronidazole](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_L_Z/166085&drug=true)
achieves a similar immediate rate of clinical response, with a higher
relapse rate in some, but not all studies, and is considered an
alternative, slightly less effective regimen.

Side effects of
[metronidazole](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_L_Z/166085&drug=true)
include a metallic taste, nausea (in 10 percent of patients), transient
neutropenia (7.5 percent), a disulfiram-like effect with alcohol,
interaction with
[warfarin](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_L_Z/280743&drug=true),
and peripheral neuropathy. Allergy to metronidazole is uncommon; it
manifests as rash, urticaria, pruritus, and rarely, anaphylaxis, which
can be successfully treated by oral desensitization.

-Topical vaginal therapy with 2 percent
[clindamycin](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/60665&drug=true)
cream (5 g of cream containing 100 mg of clindamycin phosphate) appears
to be effective as a one, three, or seven day regimen, \[but is less
effective than the metronidazole regimens; nevertheless, topical
clindamycin cream is a reasonable therapeutic choice. Alternative
regimens that have lower efficacy for eradicating bacterial vaginosis
include oral clindamycin (300 mg twice daily for seven days) or
clindamycin ovules (100 mg intravaginally once daily for three days),
but these regimens have not been studied extensively.

Intravaginal
[clindamycin](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/60665&drug=true)
therapy has been associated with an increased prevalence of clindamycin
resistant anaerobic bacteria in the vagina posttreatment (17 percent of
bacterial isolates before versus 53 percent of isolates after therapy).
This effect persisted in most women for at least 90 days after
clindamycin treatment. In contrast, increased resistance to
[metronidazole](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_L_Z/166085&drug=true)
was not observed in women treated with that drug. Further investigation
is required to determine the clinical implications of these findings.

Pseudomembranous colitis has been reported with both oral and topical
[clindamycin](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/60665&drug=true).
Clindamycin cream should not be used with condoms, which may be
weakened.

Triple-sulfa creams,
[erythromycin](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/94465&drug=true),
[tetracycline](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_L_Z/258546&drug=true),
[acetic
acid](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/6099&drug=true)
gel, and povidone-iodine vaginal douches are significantly less
effective therapies. There are only mediocre cure rates with
[ampicillin](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/17350&drug=true)
(mean, 66 percent) and
[amoxicillin](http://www.uptodateonline.com/utd/content/topic.do?topicKey=Drug_A_K/15870&drug=true).

**#3**

**Differential diagnosis**

**OUTCOME** --- A literature review concluded that initial office
evaluation (history and physical examination, vaginal pH, wet mount
microscopy, whiff test) correctly diagnosed 60 percent of Candida
vaginitis, 70 percent of Trichomonas vaginitis, and 90 percent of
bacterial vaginosis
\[[7](http://www.uptodateonline.com/utd/content/abstract.do?topicKey=gen_gyne/4886&refNum=7)\].
If the initial evaluation is nondiagnostic, then obtaining a culture for
Candida is a reasonable approach. Testing for Trichomonas using culture
on Diamond\'s medium or one of the rapid diagnostic tests for
Trichomonas should also be performed if pH is \>4.5 in this setting.
Failure to reach a diagnosis at the time of the first evaluation should
be followed by repetition of the afore-mentioned studies at a second
visit, preferably when the patient is symptomatic.

See the myriad Causes of Vaginitis listed table below. There are links
to the Diagnostic approach to vaginitis, UpToDate and the Approach to
sexually transmitted diseases, UpToDate in the Resources below.

**Causes of Vaginitis**

<http://www.uptodateonline.com/utd/content/image.do?imageKey=prim_pix/causes98.gif>

(this Table is available to Indian Health and tribal staff)

**Resources**

Guidelines for the treatment of sexually transmitted diseases. MMWR Morb
Mortal Wkly Rep 2002; 51(RR-6):1.

<http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5106a1.htm>

**Bacterial vagniosis, UpToDate**

<http://www.uptodateonline.com/utd/content/topic.do?topicKey=gen_gyne/27221&type=A&selectedTitle=1~19>

**Diagnostic approach to vaginitis, UpToDate**

<http://www.uptodateonline.com/utd/content/topic.do?topicKey=gen_gyne/4886&type=A&selectedTitle=2~19>

**Approach to sexually transmitted diseases, UpToDate**

<http://www.uptodateonline.com/utd/content/topic.do?topicKey=stds/8727&type=A&selectedTitle=3~19>

**Other Background**

**Bacterial Vaginosis**

Guidelines for the treatment of sexually transmitted diseases. MMWR Morb
Mortal Wkly Rep 2002; 51(RR-6):1.

BV is a clinical syndrome resulting from replacement of the normal
H~2~O~2~-producing *Lactobacillus* sp. in the vagina with high
concentrations of anaerobic bacteria (e.g., *Prevotella* sp. and
*Mobiluncus* sp.), *G. vaginalis*, and *Mycoplasma hominis*. BV is the
most prevalent cause of vaginal discharge or malodor; however, up to 50%
of women with BV may not report symptoms of BV. The cause of the
microbial alteration is not fully understood. BV is associated with
having multiple sex partners, douching, and lack of vaginal
lactobacilli; it is unclear whether BV results from acquisition of a
sexually transmitted pathogen. Women who have never been sexually active
are rarely affected. Treatment of the male sex partner has not been
beneficial in preventing the recurrence of BV.

**Diagnostic Considerations**

BV can be diagnosed by the use of clinical or Gram-stain criteria.
Clinical criteria require three of the following symptoms or signs:

-   a homogeneous, white, noninflammatory discharge that smoothly coats
    the vaginal walls;

-   the presence of clue cells on microscopic examination;

-   a pH of vaginal fluid \>4.5; and

-   a fishy odor of vaginal discharge before or after addition of 10%
    KOH (i.e., the whiff test).

When a Gram stain is used, determining the relative concentration of the
bacterial morphotypes characteristic of the altered flora of BV is an
acceptable laboratory method for diagnosing BV. Culture of *G.
vaginalis* is not recommended as a diagnostic tool because it is not
specific. However, a DNA probe based test for high concentrations of *G.
vaginalis* (Affirm^™^ VP III, manufactured by Becton Dickinson, Sparks,
Maryland) may have clinical utility. Cervical Pap tests have limited
clinical utility for the diagnosis of BV because of low sensitivity.
Other commercially available tests that may be useful for the diagnosis
of BV include a card test for the detection of elevated pH and
trimethylamine (FemExam^®^ test card, manufactured by Cooper Surgical,
Shelton, Connecticut) and prolineaminopeptidase (Pip Activity
TestCard^™^, manufactured by Litmus Concepts, Inc., Santa Clara,
California).

**Treatment**

The established benefits of therapy for BV in non-pregnant women are to
a) relieve vaginal symptoms and signs of infection and b) reduce the
risk for infectious complications after abortion or hysterectomy. Other
potential benefits include the reduction of other infectious
complications (e.g., HIV and other STDs). All women who have symptomatic
disease require treatment.

BV during pregnancy is associated with adverse pregnancy outcomes,
including premature rupture of the membranes, preterm labor, preterm
birth, and postpartum endometritis. The established benefit of therapy
for BV in pregnant women is to relieve vaginal symptoms and signs of
infection. Additional potential benefits of therapy include a) reducing
the risk for infectious complications associated with BV during
pregnancy and b) reducing the risk for other infections (e.g., other
STDs or HIV). The results of several investigations indicate that
treatment of pregnant women who have BV and who are at high risk for
preterm delivery (i.e., those who previously delivered a premature
infant) may reduce the risk for prematurity (*52\--54*). Therefore,
high-risk pregnant women who have asymptomatic BV may be evaluated for
treatment.

The bacterial flora that characterizes BV have been recovered from the
endometria and salpinges of women who have PID. BV has been associated
with endometritis, PID, and vaginal cuff cellulitis after invasive
procedures, including endometrial biopsy, hysterectomy,
hysterosalpingography, placement of an IUD, cesarean section, and
uterine curettage. The results of two randomized controlled trials
indicated that treatment of BV with metronidazole substantially reduced
postabortion PID (*55,56*). Three trials that evaluated the use of
anaerobic antimicrobial coverage (metronidazole) for routine operative
prophylaxis before abortion and seven trials that evaluated this
additional coverage for women undergoing hysterectomy found a
substantial reduction (range: 10%\--75%) in post-operative infectious
complications (*57\--66*). Because of the increased risk for
postoperative infectious complications associated with BV, some
specialists recommend that before performing surgical abortion or
hysterectomy, providers screen and treat women with BV in addition to
providing routine prophylaxis. However, more information is needed
before recommending treatment of asymptomatic BV before other invasive
procedures.

***Recommended Regimens***

**Metronidazole** 500 mg orally twice a day for 7 days,

**OR**

**Metronidazole gel** 0.75%, one full applicator (5 g) intravaginally,
once a day for 5 days,

**OR**

**Clindamycin** cream 2%, one full applicator (5 g) intravaginally at
bedtime for 7 days.

**NOTE:** Patients should be advised to avoid consuming alcohol during
treatment with metronidazole and for 24 hours thereafter. Clindamycin
cream and ovules are oil-based and might weaken latex condoms and
diaphragms. Refer to condom product labeling for additional information.

The recommended metronidazole regimens are equally efficacious. The
vaginal clindamycin cream appears less efficacious than the
metronidazole regimens. The alternative regimens have lower efficacy for
BV.

***Alternative Regimens***

**Metronidazole** 2 g orally in a single dose,

**OR**

**Clindamycin** 300 mg orally twice a day for 7 days,

**OR**

**Clindamycin ovules** 100 g intravaginally once at bedtime for 3 days.

One randomized trial evaluating the clinical equivalency of intravaginal
metronidazole gel 0.75% once daily versus twice daily found similar cure
rates 1 month after therapy (*67*). One randomized trial that evaluated
the equivalency of clindamycin cream and clindamycin ovules found that
cure rates did not differ significantly (*68*). Metronidazole 2 g
single-dose therapy is an alternative regimen because of its lower
efficacy for treatment of BV. Although FDA has approved metronidazole
750-mg extended release tablets once daily for 7 days, no data have been
published on the clinical equivalency of this regimen with other
regimens.

Studies are currently underway to evaluate the efficacy of vaginal
lactobacilli suppositories in addition to oral metronidazole for the
treatment of BV. No data support the use of non-vaginal lactobacilli or
douching for the treatment of BV.

**Follow-Up**

Follow-up visits are unnecessary if symptoms resolve. Because recurrence
of BV is not unusual, women should be advised to return for additional
therapy if symptoms recur. Another recommended treatment regimen may be
used to treat recurrent disease. No long-term maintenance regimen with
any therapeutic agent is recommended.

**Management of Sex Partners**

The results of clinical trials indicate that a woman\'s response to
therapy and the likelihood of relapse or recurrence are not affected by
treatment of her sex partner(s) (*69\--71*). Therefore, routine
treatment of sex partners is not recommended.

**Special Considerations**

***Allergy or Intolerance to the Recommended Therapy***

Clindamycin cream or oral clindamycin is preferred in case of allergy or
intolerance to metronidazole. Metronidazole gel can be considered for
patients who do not tolerate systemic metronidazole, but patients
allergic to oral metronidazole should not be administered metronidazole
vaginally.

***Pregnancy***

All symptomatic pregnant women should be tested and treated. BV has been
associated with adverse pregnancy outcomes (e.g., premature rupture of
the membranes, chorioamnionitis, preterm labor, preterm birth,
postpartum endometritis, and post-cesarean wound infection). Some
specialists prefer using systemic therapy to treat possible subclinical
upper genital tract infections among women at low risk for preterm
delivery (i.e., those who have no history of delivering an infant before
term). Existing data do not support the use of topical agents during
pregnancy. Evidence from three trials suggests an increase in adverse
events (e.g., prematurity and neonatal infections), particularly in
newborns, after use of clindamycin cream (*72\--74*). Multiple studies
and meta-analyses have not demonstrated a consistent association between
metronidazole use during pregnancy and teratogenic or mutagenic effects
in newborns (*75\--77*).

***Recommended Regimens***

**Metronidazole** 250 mg orally three times a day for 7 days

**OR**

**Clindamycin** 300 mg orally twice a day for 7 days.

Because treatment of BV in asymptomatic pregnant women at high risk for
preterm delivery (i.e., those who have previously delivered a premature
infant) with a recommended regimen has reduced preterm delivery in three
of four randomized controlled trials (*52\--54,78*), some specialists
recommend the screening and treatment of these women. However, the
optimal treatment regimens have not been established. The screening (if
conducted) and treatment should be performed at the first prenatal
visit.

The two trials that examined the use of metronidazole during pregnancy
used the 250-mg regimen; the recommended regimen for BV in nonpregnant
women is 500 mg twice daily. Some specialists also recommend this higher
dose for treatment of pregnant women. In one published study, women with
BV were treated at 19 weeks with a regimen of an initial dose of 2 g,
followed by a 2-g dose 2 days later; the regimen was repeated 4 weeks
later (*78*). This regimen was not effective in reducing preterm birth
in any group of women.

Data are conflicting regarding whether treatment of asymptomatic
pregnant women who are at low risk for preterm delivery reduces adverse
outcomes of pregnancy. Several unpublished trials have evaluated
screening and treatment for BV among asymptomatic low-risk pregnant
women in the first or early second trimester. One trial, using oral
clindamycin, demonstrated a reduction in spontaneous preterm birth;
another indicated a reduction in postpartum infectious complications
(*79*).

***Follow-Up of Pregnant Women***

Treatment of BV in asymptomatic pregnant women who are at high risk for
preterm delivery might prevent adverse pregnancy outcomes. Therefore, a
follow-up evaluation 1 month after completion of treatment should be
considered to evaluate whether therapy was effective.

***HIV Infection***

Patients who have BV and also are infected with HIV should receive the
same treatment regimen as those who are HIV-negative.