INTRODUCTION — Bacterial vaginosis (BV) is the most common cause of vaginal discharge in women of childbearing age, accounting for 40 to 50 percent of cases [1-3]. In the United States, the National Health and Nutrition Examination Survey, which included results from self-collected vaginal swabs from over 3700 women, estimated the prevalence of BV was 29 percent in the general population of women aged 14 to 49 years and 50 percent in African-American women [4]. BV is also common worldwide among women of reproductive age, with variations according to the population studied.
The absence of inflammation is the basis of the term "vaginosis" rather than "vaginitis."
PATHOGENESIS AND MICROBIOLOGY — BV represents a complex change in the vaginal flora characterized by a reduction in concentration of the normally dominant hydrogen-peroxide producing lactobacilli and an increase in concentration of other organisms, especially anaerobic gram negative rods [5-8]. The major bacteria detected are Gardnerella vaginalis, Prevotella species, Porphyromonas species, Bacteroides species, Peptostreptococcus species, Mycoplasma hominis, Ureaplasma urealyticum, and Mobiluncus species [5]. Fusobacterium species and Atopobium vaginae are also common. The mechanism by which the floral imbalance occurs and the role of sexual activity in the pathogenesis of BV are not clear.
Hydrogen-peroxide producing lactobacilli appear to be important in preventing overgrowth of the anaerobes normally present in the vaginal flora. With the loss of lactobacilli, pH rises and massive overgrowth of vaginal anaerobes occurs. These anaerobes produce large amounts of proteolytic carboxylase enzymes, which break down vaginal peptides into a variety of amines that are volatile, malodorous, and associated with increased vaginal transudation and squamous epithelial cell exfoliation, resulting in the typical clinical features observed in patients with BV. (See 'Clinical features' below.). The rise in pH also facilitates adherence of G. vaginalis to the exfoliating epithelial cells.
The difference in vaginal flora between women with and without BV was illustrated in a study that used broad range DNA probes to determine the vaginal flora of 27 women with BV and 46 controls [9]. Overall, 35 bacterial phylotypes were identified in women with BV, including 16 which were newly recognized. Women with BV had a mean of 12.6 phylotypes (range 9 to 17) per sample compared to 3.3 phylotypes (range 1 to 6) per sample in women without BV. The organisms newly identified by PCR include fastidious bacteria termed “BV associated bacterium (BVAB) 1, 2 and 3” in the Clostridiales order, which appear to be specific indicators of BV [10].
Some data suggest that G. vaginalis is the key player in the pathogenesis of BV and the development of a biofilm may be an essential component of this process, in addition to the gradual overgrowth of resident anaerobic vaginal flora. A study of microbiota on the epithelial surfaces of vaginal biopsy specimens from women with BV showed that a biofilm adhered to part or all of the epithelium, and Gardnerella vaginalis comprised 90 percent of bacteria in the biofilm, while Atopobium vaginae accounted for most of the remainder [11]. Subsequent desquamation of these epithelial cells would result in the classic clue cells diagnostic of the disorder. (See 'Diagnosis' below.) In contrast to BV, adherent biofilms were not observed on the epithelium of most healthy controls; instead, unstructured accumulations of bacteria within secretions were loosely attached to specimen surfaces.
RISK FACTORS — Sexual activity is a risk factor for BV, and most experts believe that BV does not occur in women who have never had vaginal intercourse [12,13]. Epidemiologic studies are strongly supportive of sexual transmission of BV pathogens. There is a high occurrence of BV and concordance of flora in women who have sex with women, further suggesting sexual transmission is important in this setting [14-16]. It is not clear, however, whether one type of sexual activity may be more important in the pathogenesis of infection than another. As an example, oral-genital sex may be a more important risk factor than penile intromission into the vagina. (See "Medical care of women who have sex with women".)
Among sexually active women, additional risk factors for acquisition of BV include multiple or new sexual partners, douching, and cigarette smoking [1,2,17-21]. Douching, but not other personal hygienic behaviors, appears to be casually associated with BV [22].
Although some degree of genetic susceptibility to BV is likely, no association between a gene polymorphism and BV has been established [23].
CLINICAL FEATURES — Approximately 50 to 75 percent of women with BV are asymptomatic [12,24,25]. Those with symptoms present with an unpleasant, "fishy smelling" discharge that is more noticeable after coitus. The discharge is off-white, thin, and homogeneous.
Dysuria and dyspareunia rarely occur, while pruritus and vaginal inflammation (erythema, edema) are typically absent. BV can be associated with cervicitis (endocervical mucopurulent discharge or easily induced bleeding), with or without concomitant chlamydial or gonococcal infection [26]. (See "Acute cervicitis".)
DIAGNOSIS — The general diagnostic approach to women with vaginal discharge is reviewed separately. (See "Evaluation of women with symptoms of vaginitis".)
Using microscopy — The diagnosis of BV is based on the presence of characteristic clinical findings and results from laboratory testing; criteria have been established that are simple and useful in office practice where microscopy is available [24]. Three of the four criteria (ie, Amsel criteria) listed below are necessary for diagnosis, although the first three findings are sometimes present in patients with trichomoniasis (table 1).
The presence of clue cells diagnosed by experienced microscopists is the single most reliable predictor of BV [27]. Clue cells are vaginal epithelial cells studded with adherent coccobacilli that are best appreciated at the edge of the cell (picture 1A-B). In women with BV, at least 20 percent of the epithelial cells on wet mount should be clue cells.
Gram’s stain of vaginal secretions is a reliable method for the diagnosis of BV (figure 1A-B and table 2) [28], but is mostly performed in research studies because it is more cumbersome to use in clinical practice than Amsel criteria [29-31]. Using Gram’s stain as the standard for diagnosing BV, the sensitivity of Amsel criteria for diagnosis of BV is over 90 percent and specificity is 77 percent [32]. If clinical criteria are used to define infection, then the sensitivity reported for Gram’s stain ranges from 62 to 100 percent [33].
The Papanicolaou smear is not reliable for diagnosis of BV (sensitivity 49 percent, specificity 93 percent) [34]. There is no information on the sensitivity and specificity of liquid based methods. If the cytology smear suggests BV (ie, shift in flora from predominantly lactobacilli to predominantly coccobacilli with or without clue cells), women should undergo standard diagnostic testing (vaginal examination, vaginal pH, whiff-amine test, wet mount) and treatment, if appropriate.
Without microscopy — Vaginal culture has no role in diagnosis because there are no bacteria that are diagnostic of BV. Although cultures for G. vaginalis are positive in almost all women with symptomatic infection, the organism is detected in up to 50 to 60 percent of healthy asymptomatic women; thus, its presence alone is not diagnostic.
DNA probes for G. vaginalis are expensive and suffer from the same limitation as culture, but provide fairly quick results 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 ≥107 CFU/mL) and vaginal pH >4.5 had a sensitivity and specificity of 95 and 99 percent, respectively, for diagnosis of BV when clinical criteria were used as the diagnostic standard [35]. Not all studies have reproduced these encouraging results, and over-diagnosis is possible.
Diagnostic cards (eg, Femcard, QuickVue, Pip Activity TestCard) are rapid tests for confirming the clinical suspicion of BV. These cards are particularly useful for practitioners not able to perform microscopy. One group reported these tests detected the presence of elevated vaginal pH and increased amines with sensitivity and specificity of 87 and 92 percent, respectively [36], although others have reported lower values [37].
PCR-based tests are being investigated for molecular diagnosis of BV, mostly based upon molecular quantification of G. vaginalis and Atopobium vaginae [38]. These tests are expensive and of questionable advantage [39].
Differential diagnosis — BV is usually suspected because of high vaginal pH (>4.5). Other causes of increased pH include trichomoniasis, atrophic vaginitis, and desquamative inflammatory vaginitis. These four entities are easily distinguishable by clinical and microscopy features.
CONSEQUENCES
TREATMENT — BV resolves spontaneously in up to one-third of nonpregnant and one-half of pregnant women [57-60]. Treatment is indicated for relief of symptoms in women with symptomatic infection and to prevent postoperative infection in those with asymptomatic infection prior to abortion or hysterectomy (see 'Gynecologic procedures' below).
Treatment of BV may also reduce the risk of acquiring STDs, including HIV [48,61]. For this reason, some experts support the concept of treating all women with BV regardless of presence or absence of symptoms.
Asymptomatic pregnant women with previous preterm births may also benefit, but screening and treatment of these women is controversial (see 'Pregnant women' below).
Nonpregnant women
Options — Metronidazole or clindamycin administered either orally or intravaginally result in a high rate of clinical cure (70 to 80 percent at four weeks of follow-up) (table 3) [62-65]. Oral medication is more convenient, but associated with a higher rate of systemic side effects, than vaginal administration. Tinidazole is a reasonable oral alternative.
Metronidazole — Metronidazole is the most successful therapy. The oral regimen we recommend is 500 mg twice daily for seven days [66].
There is little evidence of benefit from prolonging therapy greater than seven days. Most comparative studies using multiple divided-dose oral regimens for one week achieved early rates of clinical cure in excess of 90 percent, and cure rates (by Amsel criteria) of approximately 80 percent at four weeks [63,65,67-71]. A randomized trial showed that short-term cure rates were significantly higher when the initial course of metronidazole therapy was 14 days rather than 7 days; however, long-term cure rates (21 days after completion of therapy) were similar for both treatment regimens [20].
Topical vaginal therapy with 0.75 percent metronidazole gel (5 g once daily for five days) is as effective as oral metronidazole [68,69,72]. The choice of oral versus topical therapy depends upon patient preference. The 2 g oral single dose therapy has lower efficacy [73] and is no longer recommended for treatment of BV.
Side effects of metronidazole include a metallic taste, nausea (in 10 percent of patients), transient neutropenia (7.5 percent), a disulfiram-like effect with alcohol, interaction with warfarin, 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 [74].
Clindamycin — The efficacy of clindamycin has been demonstrated in multiple randomized trials, both comparative and placebo controlled [63,75-78]. Topical vaginal therapy with 2 percent clindamycin cream (5 g of cream containing 100 mg of clindamycin phosphate) is recommended as a seven day regimen, but may be less effective than the metronidazole regimens; nevertheless, topical clindamycin cream is a reasonable therapeutic choice [66].
Alternative regimens include oral clindamycin (300 mg twice daily for seven days) or clindamycin ovules (100 mg intravaginally once daily for three days) [66,79]. A one-day or single application of clindamycin as a bioadhesive is another option (Clindesse). These regimens have not been studied extensively and may have lower efficacy for eradicating BV.
Intravaginal clindamycin 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) [80]. This effect persisted in most women for at least 90 days after clindamycin treatment. In contrast, increased resistance to metronidazole was not observed in women treated with that drug. Further investigation is required to determine the clinical implications of these findings.
Clindamycin cream should not be used concurrently with latex condoms, which may be weakened.
Pseudomembranous colitis has been reported with both oral and topical clindamycin.
Tinidazole — Tinidazole is a second generation nitroimidazole. It has a longer half-life than metronidazole (12 to 14 hours versus 6 to 7 hours) and fewer side effects [81]. Randomized trials in the United States and elsewhere have shown that it is at least as effective as metronidazole, but not superior [82-86]. If used, we suggest 1 g orally once daily for five days, as efficacy is slightly higher and side effects are slightly less frequent than with shorter course therapy (tinidazole 2 g orally daily for two days) [82].
Less effective and ineffective therapies — Triple-sulfa creams, erythromycin, tetracycline, ampicillin, amoxicillin, acetic acid gel, ascorbic acid, azithromycin, and povidone-iodine vaginal douches are significantly less effective than metronidazole and clindamycin and should not be used [20,87-92]. Cure rates with ampicillin and amoxicillin are mediocre.
Probiotics — Probiotics have been used alone and as adjunctive therapy to antibiotics for treatment of BV and prevention of relapse. Systemic reviews of trials of probiotics for treatment of BV have not found sufficient evidence for or against efficacy [93,94]. Although some trials have reported very promising results, we feel the results should be reproduced in more well-designed and larger trials before use of this therapy is considered. In addition, further investigation is needed to determine the optimum route of administration (oral or vaginal), which strains or combination of strains are most effective (eg, Lactobacillus rhamnosus GR-1, Lactobacillus reuteri RC-14, Lactobacillus acidophilus), and the dose and duration of use.
Follow-up — Follow-up is unnecessary if symptoms resolve [66].
Sexual partners — It is not necessary to treat male sexual partners of affected women, as there is no strong evidence that the woman's response to therapy and risk of relapse are influenced by treatment of her male sex partner(s) [66,95]. However, these data are limited and larger trials should be performed.
Sexual intercourse appears to play a role in disease activity. Some studies have reported reduced rates of recurrence when male sexual partners used condoms routinely during coitus or when women remained abstinent [20,96-99].
Women with BV who have sex with women should be encouraged to inform their sexual partner(s) regarding the need for screening, diagnosis, and treatment. (See "Medical care of women who have sex with women".)
Relapse and recurrent infection — Approximately 30 percent of patients with initial responses to therapy have a recurrence of symptoms within three months [67] and more than 50 percent experience a recurrence within 12 months [96]. The explanation for this high rate of recurrence is unclear. Reinfection is possible, but recurrence more likely reflects a failure to eradicate the offending organisms or to reestablish the normal protective vaginal flora dominated by lactobacillus.
We suggest symptomatic relapse be treated initially with a seven-day course of oral or vaginal metronidazole or clindamycin. The treatment regimen may be the same as or different from the initial or previous treatment regimen [66].
After initial induction therapy, most women with a history of recurrent infection benefit from suppressive therapy to maintain an asymptomatic state. We feel any patient with more than three documented episodes of BV in the previous 12 months should be offered a long-term maintenance regimen consisting of maintenance metronidazole gel. Long-term clindamycin regimens, oral or topical, are not advised because of toxicity and lack of documented efficacy. Accordingly, if any of the aforementioned antimicrobials fail, we prescribe metronidazole gel 0.75 percent or an oral nitroimidazole for 7 to 10 days followed by twice weekly dosing of gel for four to six months [66]. In one multicenter prospective trial of this metronidazole gel regimen, recurrent BV occurred in 25.5 percent of patients on suppressive therapy versus 59.1 percent of those receiving placebo [100]. Secondary vaginal candidiasis was a common side effect.
Results can be improved by adding vaginal boric acid to the oral nitroimidazole induction therapy [101]. Metronidazole or tinidazole is taken orally for 7 days; vaginal boric acid 600 mg is begun at the same time and continued for 21 days. Patients are seen for follow-up a day or two after their last boric acid dose; if they are in remission, we immediately begin metronidazole gel twice weekly for four to six months as suppressive therapy. Therapy is then discontinued. Boric acid can cause death if consumed orally; patients should be told to store boric acid in a secure place that is inaccessible to children.
As discussed above, no study has demonstrated reduced rates of recurrence in women whose partners were treated with metronidazole. However, some studies have reported reduced rates of recurrence when sexual partners used condoms routinely with coitus or the patient remained abstinent [20,96-99]. For this reason, some experts suggest these behavioral interventions for women with recurrent infection.
A single trial has reported that use of condoms and combination metronidazole/nystatin ovule therapy may reduce the frequency of recurrent infection [97]. The higher efficacy of the ovule may be due to the higher content of metronidazole (500 mg) compared with the gel (37.5 mg).
Exogenous lactobacillus recolonization with 30 days of oral probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 in addition to 7 days of metronidazole therapy has been suggested, but there is minimal evidence of the efficacy of this approach [65,102]. These results should be reproduced in other trials before use of this therapy is considered.
Vaginal acidifying agents, although popular and widely used, have no role in the treatment of acute or chronic BV, as they have never been shown to enhance cure rates. Douching should be avoided.
Asymptomatic infection — Treatment of asymptomatic BV is typically avoided since patients often spontaneously improve over a period of several months and any antibacterial therapy is often followed by symptomatic vaginal yeast infection. This practice is supported by a double-blind, placebo controlled trial of 54 women with asymptomatic BV who were randomly assigned to receive intravaginal metronidazole or placebo gel [59]. There was no difference in the proportion of women in either group who noticed improvement in vaginal odor or discharge. In addition, 6 of 28 women receiving metronidazole developed symptomatic vaginal candidiasis compared with no women taking placebo.
However, some experts now recommend treatment of asymptomatic BV because affected women are more susceptible to acquiring other STDs (including HIV and increased expression of herpes simplex virus).
Treatment is indicated for asymptomatic women who are scheduled for certain gynecologic procedures (see below). Treatment of asymptomatic infection in pregnant women is more complex and is discussed in detail below (see 'Pregnant women' below).
Gynecologic procedures — Evidence linking asymptomatic BV with gynecologic complications has caused this issue to be reassessed, especially with the availability of topical therapy. It is reasonable to treat asymptomatic BV prior to hysterectomy and before pregnancy termination to prevent postprocedure infection (cuff infection after hysterectomy, endometritis after abortion). Reported reductions in postoperative infectious complications range from 10 to 75 percent [103-109].
Pregnant women
Symptomatic BV infection — All women with symptomatic BV should be treated to relieve bothersome symptoms. Oral treatment is effective and has not been associated with adverse fetal or obstetrical effects [110-115]. The therapeutic options include [66]:
Some clinicians avoid use of metronidazole in the first trimester because it crosses the placenta, and thus has a potential for teratogenicity. However, meta-analysis has not found any relationship between metronidazole exposure during the first trimester of pregnancy and birth defects [116] and the Centers for Disease Control and Prevention no longer discourage the use of metronidazole in the first trimester [117]. An additional concern is that the drug is mutagenic in bacteria and carcinogenic in mice, but there is no evidence of harm in humans.
As mentioned above, topical therapy is as effective as oral therapy in the treatment of nonpregnant women with BV. In contrast, some experts avoid topical therapy in pregnant women because they believe oral treatment is more effective against potential subclinical upper genital tract infection [118-120].
Asymptomatic BV infection — As many as one-third of pregnant women in the United States have BV [40]. Of concern, a meta-analysis has reported a statistically significant increased risk of preterm birth in these women; the pooled odds ratio for prematurity was 2.19 (95% CI, 1.54-3.12) [121]. The increased risk of preterm birth attributable to BV appears to be linked to preterm labor due to chorioamnionitis [41,122]. Other complications of BV are endometritis after cesarean delivery (55 versus 17 percent in uninfected controls) [123] and after vaginal birth (8 versus 1.5 percent in uninfected controls), and possibly an increased risk of miscarriage [121,124].
Despite the association between BV and preterm birth, screening and treatment of asymptomatic BV during pregnancy is controversial. Meta-analyses of randomized trials performed in general obstetric populations have not consistently found that treatment of asymptomatic infection reduces the incidence of preterm labor or delivery [110,125], but this may not apply to women at high risk for preterm birth or those treated early in pregnancy.
Based upon these data, routinely screening and treating all pregnant women with asymptomatic BV to prevent preterm birth and its consequences is not recommended. It is not possible to define specific features characterizing a subgroup of women who might respond favorably to a screening and treatment protocol. Defining these features is an active area of investigation.
As illustrated above, there may be benefits to early screening and treatment of asymptomatic pregnant women who have a history of a previous preterm delivery, but there are insufficient data to recommend this as a routine practice [112,121,129-131]. Further definition of high risk subgroups is under investigation. As an example, women with polymorphisms of genes regulating cytokine production (eg, tumor necrosis factor variants) have a greater proinflammatory immune response to infectious stimuli, such as BV [132]. Enhanced induction of cytokines in these women could then lead to preterm labor or rupture of membranes. Other aspects of host response (eg, low levels of IgA to Gardnerella vaginalis) or the specific types of BV associated bacteria involved (eg, bacteria that produce high levels of sialidase or protease) may also play a role in placing some women with BV at high risk of preterm birth. (See "Risk factors for preterm labor and delivery", section on 'Infection' and "Risk factors for preterm labor and delivery", section on 'Genetic factors'.)
When treatment of BV is initiated, the optimal choice of antibiotic, timing of therapy, duration of use, and harms of therapy are also controversial. The first trials demonstrated a reduction in preterm birth in high risk women treated with oral metronidazole or oral metronidazole and erythromycin (table 4) [118-120]. However, in two studies, metronidazole use in pregnancy appeared to increase the risk of preterm birth [127,133]. This association requires further investigation and confirmation before avoiding metronidazole for treatment of BV in pregnancy. Other trials suggest that oral clindamycin given early in pregnancy is an effective therapy [128] and that topical clindamycin given in the second half of pregnancy is less effective and even associated with an increase in low birth weight and neonatal infection [134]. Therefore, we use oral therapy when treatment is indicated, and consider both metronidazole and clindamycin acceptable choices.
Breastfeeding women — The American Academy of Pediatrics (AAP) considers clindamycin use compatible with breastfeeding [135]. However, clindamycin has the potential to cause adverse effects on the breastfed infant's gastrointestinal flora so the infant should be monitored for diarrhea, candidiasis (thrush, diaper rash) or, rarely, blood in the stool indicating possible antibiotic-associated colitis [136]. Infant side effects are less likely with vaginal than oral use since only about 30 percent of a vaginal dose is absorbed.
The AAP considers use of oral metronidazole and tinidazole of concern in nursing women [135]. There are no human data supporting an association between metronidazole and cancer; however, an association with carcinogenesis in rodents has been demonstrated [137]. Outcomes data of maternal metronidazole use did not show a significant increase in adverse events compared to use of other antimicrobials, although a cohort study found a nonsignificant trend toward more loose stools and more candidal colonization in metronidazole-exposed infants. Since the relative infant dose of metronidazole is high (29 percent) with maternal administration of the 2 g one-time dose, the AAP recommends that mothers receiving this dose express and discard their milk for 24 hours. (See "Principles of medication use during lactation".)
Use of vaginal metronidazole has not been studied during breastfeeding. After vaginal administration, plasma levels are less than 2 percent of those after a 500 mg oral dose, so vaginal use of metronidazole during breastfeeding is unlikely to be of concern [137].
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SUMMARY AND RECOMMENDATIONS
Diagnosis
The presence of clue cells is the single most reliable predictor of BV. Vaginal culture is not useful. (See 'Diagnosis' above.)
Treatment of nonpregnant women
Treatment of pregnant women
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