INTRODUCTION — Bacterial vaginosis (BV) is the most common cause of abnormal vaginal discharge in reproductive-age females. Treatment is aimed at relieving symptoms, although many individuals are asymptomatic. Of those with symptoms, abnormal vaginal discharge and fishy odor are typical. Individuals with three or more documented BV episodes in one year are defined as having recurrent BV.
This topic will present the treatment options for patients with recurrent BV. Related topics on the diagnosis and initial treatment of BV, as well as the approach to the patients with vaginitis or cervicitis, are presented separately.
●(See "Acute cervicitis".)
In this topic, when discussing study results, we will use the terms "woman/en" or "patient(s)" as they are used in the studies presented. However, we encourage the reader to consider the specific counseling and treatment needs of transgender and gender-expansive individuals.
DEFINITION AND POSSIBLE MECHANISMS — Recurrent BV is defined as three or more confirmed symptomatic BV episodes in one year . Patients with confirmed recurrent BV who are asymptomatic are not treated unless they are undergoing gynecologic surgery that involves the vagina. Content related to the presentation, diagnosis, and initial management of BV is presented separately.
Multiple etiologies likely contribute to the high rates of BV recurrence. Hypothesized causes include [1-5]:
●Inadequate treatment – Medication misuse or early discontinuation may result in a persistent vaginal reservoir of organisms, particularly given that biofilm presence may be a key part of BV development and persistence . A biofilm consists of a matrix of extracellular polymeric substances that often hosts microorganisms ; in the case of recurrent vaginal infections, the presence of Gardnerella vaginalis is consistent with the possibility of a biofilm reservoir for these agents. (See "Bacterial vaginosis: Clinical manifestations and diagnosis", section on 'Pathogenesis and microbiology'.)
●Reinfection – Reinfection through sexual transmission from both male and female sex partners is a suspected source of recurrent BV, in part based on studies reporting reduced recurrence rates with condom use. Although this mechanism has not been directly confirmed, there are strong epidemiologic data to support it [8-12].
•(See 'Condoms or abstinence' below.)
●Infection relapse – Relapse despite adequate drug therapy may result from failure to eradicate the offending organisms or failure to reestablish the normal protective vaginal microbiota dominated by lactobacillus.
•Impact of biofilm – Infections involving biofilms can be more difficult to eradicate . This mechanism may explain the persistence of pathogenic bacteria, as documented by 16S rRNA sequencing and polymerase chain reaction (PCR) testing, in patients with documented infection who are treated with seven days of oral metronidazole therapy . Biofilm disruption and concomitant destruction of common BV-associated bacteria (ie, G. vaginalis) is under investigation as a potential BV therapy and is a presumed mechanism of action for agents like boric acid [14,15]. (See "Bacterial vaginosis: Clinical manifestations and diagnosis", section on 'Pathogenesis and microbiology'.)
•Impact of polymicrobial infection – One study of 28 patients reported that an increase in diverse, low-abundance taxa was associated with BV recurrence after initial treatment with oral metronidazole (500 mg twice a day for seven days total) . It is not known if the bacterial diversity was an independent contributor to treatment resistance or a reflection of an established bacterial community, possibly facilitated by biofilm-forming taxa.
●Antimicrobial resistance – While antimicrobial resistance of BV-associated bacteria might explain recurrent infection, and presence of some bacteria species have been predictive of relapse [5,17], such resistance has not been systematically studied or documented, although available evidence is sparse [4,18]. PCR and molecular techniques have identified BV pathogens that have not been successfully grown in culture, and thus the drug susceptibility and sensitivities of these organisms are not yet known .
Despite these limitations, patient-based studies provide evidence of progressive antimicrobial resistance:
-One study of G. vaginalis isolates from 80 females reported progressive decrease in percentage of drug-susceptible isolates with increasing rounds of antibiotic treatment . Pretreatment metronidazole susceptibility ranged from 88 to 100 percent and progressively decreased over four rounds of antibiotic exposure to 0 percent (percent of drug susceptible isolates: 76 to 82 percent after one round, 53 to 82 percent after second round, 36 percent after third round, and 0 percent after fourth round).
-A study evaluating 41 patients with recurrent BV reported that core bacterial species did not change in abundance between vaginal specimens obtained before and after metronidazole treatment, which suggests drug resistance or tolerance .
●Genetics – Limited data suggest that host characteristics, including Toll-like receptor status, might contribute to likelihood of BV and perhaps impact risk of recurrent BV; this preliminary information requires further study [21,22].
APPROACH TO TREATMENT SELECTION — Treatment selection is driven by patient preference, medication cost and availability, and prior agents used. As trials directly comparing the extended metronidazole and vaginal boric acid regimens, both approaches are equally reasonable. We generally use the extended metronidazole regimen first because it is well tolerated, easy to use, and avoids the toxicity risks of vaginal boric acid (algorithm 1).
In addition, we apply the following thinking:
●When possible, we treat recurrent BV using a different drug or regimen from what was used from prior therapy given that some patients may have multiple recurrences or recur on maintenance therapy.
●If there are no therapeutic options that have not yet been tried, then we use the drug and/or regimen that resulted in the best past response for the patient.
TREATMENT OPTIONS — There is no single data-driven approach to the management of recurrent BV. The approaches below are based on available supporting data and the author's experience (algorithm 1) .
Treatment — The extended metronidazole regimen is generally well tolerated, easy to use, and has a lower toxicity profile compared with boric acid-containing regimens.
●Induction – For initial treatment, we suggest treatment with oral pills or vaginal gel. The choice of initial oral pill or vaginal gel is based upon prior patient response, drug availability, and patient preferences for oral versus intravaginal therapy. In our practice, we typically use oral pills but vaginal therapy is reasonable.
•Intravaginal therapy – Intravaginal metronidazole 0.75% gel is given as a 5-gram dose twice daily for seven days.
●Maintenance – For maintenance therapy, we use metronidazole 0.75% gel, 5-gram dose, placed intravaginally twice a week for four to six months [1,24]. We use maintenance therapy as prophylaxis against symptom recurrence and, in some cases, to increase chance of cure . Patients who remain in remission may elect to continue maintenance therapy for a longer duration. As the optimal duration of maintenance is not known, we use shared decision-making with the patient to determine length of treatment. (See 'Assessment of response' below.)
●Recurrent symptoms – Patients who develop BV symptoms despite maintenance therapy are again tested to confirm BV. Documented BV infection is typically a result of reinfection by a sex partner or relapse of infection. We use discuss the patient's symptoms in relation to sexual activity patterns in attempt to determine the likely cause.
•Reinfection by sexual contact – BV symptoms that return during or following use of maintenance therapy may be a result of reinfection by a sex partner. If reinfection from sexual activity is likely based on patient history, then patients are retreated with primary treatment and condom use is strongly encouraged. (See 'Condoms or abstinence' below.)
•Relapse of infection – Patients with confirmed recurrence that is likely relapse (ie, not reinfection from a sex partner) next try the extended vaginal boric acid regimen. (See 'Vaginal boric acid regimen' below.)
Supporting data — One multicenter prospective trial of 112 patients that compared the extended metronidazole gel maintenance regimen with placebo reported recurrent BV in 26 versus 59 percent of patients, respectively . Secondary vaginal candidiasis was a common side effect. However, BV symptoms may return when maintenance therapy is stopped [25,26].
Vaginal boric acid regimen — For this approach an oral nitroimidazole is used in combination with vaginal boric acid followed by the option of suppressive treatment with vaginal metronidazole gel for patients who achieve remission (algorithm 1) [24,27-29]. While solo boric acid has been used to reduce vaginal odor, it does not eradicate infection and we do not advise solo use .
●Maintenance – Boric acid 600 mg inserted in the vagina at bedtime for a total of 30 days . While the oral nitroimidazole is stopped after seven days, the vaginal boric acid is continued for 30 days of total treatment.
Other boric acid doses and/or durations of treatment may be adequate but have not yet been studied. Boric acid should never be taken orally. (See 'Critical warning on boric acid use' below.)
●Reassessment – One to two days after finishing the vaginal boric acid, patients are evaluated for evidence of remission based on Amsel criteria or similar.
-Remission – Those who achieve remission have the options of stopping treatment or continuing with maintenance therapy.
-No remission – Patients who do not achieve remission are retested to confirm BV, evaluated for likely cause of infection (eg, relapse, reinfection, and/or coinfection), and treated again, preferably with a different regimen. If remission is achieved with retreatment, maintenance therapy is advised to suppress symptoms.
●Suppression – Patients who are in remission based on Amsel criteria or similar have the option of immediately beginning metronidazole 0.75% gel 5 gram vaginally twice weekly for four to six months as suppressive therapy [24,27,28]. Therapy is then discontinued once treatment has been completed. Choice for suppression is based on shared decision-making with the patient. Some patients prefer to use a lower-intensity maintenance therapy rather than repeat the entire treatment regimen should BV recur.
Supporting data — Six-month cure rates of 65 to 70 percent have been reported in small observational studies [27,28].
●In an observational study of 93 patients with recurrent BV treated with an oral nitroimidazole and vaginal boric acid, 99 percent (92 out of 93) were asymptomatic with ≤2 Amsel criteria at the first follow-up visit (mean 32 days) . By six months from treatment, 70 percent (48 out of 69) remained in remission while 30 percent (21 out of 69) had relapsed. During the maintenance phase, five patients declined to participate, and 18 were lost to follow-up.
●A retrospective chart review of 58 women treated with an oral nitroimidazole and vaginal boric acid for recurrent BV reported initial cure rates of 88 to 92 percent at 7 to 12 weeks of follow-up followed by cumulative cure rates of 87, 78, and 65 percent at 12, 16, and 28 weeks, respectively . By 36 weeks of follow-up, the failure rate had risen to 50 percent.
Obtaining boric acid — Boric acid vaginal suppositories use can be prescribed through a compounding pharmacy or purchased over-the-counter. Use of a compounding pharmacy may be more costly compared with over-the-counter options. Studies directly comparing these sources have not been done.
Critical warning on boric acid use — 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. Boric acid should not be used by individuals who are pregnant or attempting conception. Sexual partners of patients treated with vaginal boric acid have reported skin irritation after exposure . The magnitude and duration of risk for skin irritation from the time of boric acid use is not known. We also counsel patients to avoid receptive oral sex while using vaginal boric acid so that their partners are not orally exposed to the drug.
Risk-reducing strategies — Adjunct approaches to reduce the risk of BV recurrence include condom use, sexual abstinence, and hormonal contraceptives. Risk of harm is low but duration of maintenance is not known. These approaches are not for primary treatment of infection.
Condoms or abstinence — Some studies have reported reduced rates of recurrence when sexual partners used condoms routinely with coitus or the patient remained abstinent [3,31-35]. For this reason, some experts suggest these behavioral interventions for those with recurrent infection. However, direct prospective trial data supporting these interventions are lacking.
In a trial studying female BV recurrence after male partner treatment with metronidazole or placebo, condom use at the last sexual encounter (as reported by both sex partners) was associated with lower recurrence rates of BV in univariate analysis (47 versus 83 to 84 percent) . The trend remained in multivariate analysis but was no longer statistically significant. Correct and consistent use of either external or internal condoms also reduces chance of pregnancy and risk of sexually transmitted infections (STIs) [36,37].
Hormonal contraception — Use of hormonal contraception has been associated with reductions in BV, although most supporting data are observational . Hormonal contraception may help prevent BV recurrence but is not a treatment.
●In a retrospective study of 682 women using a variety of contraceptives who underwent 16S rRNA gene analysis of vaginal fluid, those using combined estrogen-progestin oral contraceptives were 70 percent less likely to have BV-associated bacterial colonization and were nearly twice as likely to have H2O2-producing lactobacillus species compared with those using condoms .
●A meta-analysis of 55 studies (mainly observational) reported that hormonal contraceptive use was associated with reduced odds of prevalent BV (pooled effect size by random effects 0.68, 95% CI 0.63-0.73) . Combined estrogen-progestin and progestin-only contraceptives were associated with both reduced BV prevalence and incidence.
Combination prophylactic therapy — In a trial of Kenyan HIV-seronegative sex workers treated with either combination metronidazole plus fluconazole or placebo, dosed monthly, women receiving combination treatment had fewer episodes of BV infection . In a different trial of Kenyan HIV-seronegative women comparing combination treatment (metronidazole and miconazole) with placebo, treatment was associated with a reduced proportion of visits with BV over a 12-month period (21 percent in treatment group versus 32.5 percent in placebo group) . In both trials, there was no impact on infection with vulvovaginal candidiasis or trichomoniasis. More trial data are needed before these therapies can be applied to a broad population.
For patients with recurrent BV, an observational study of a multidose vaginal regimen that combined high-dose metronidazole with miconazole reported short-term remission in 68 percent of patients . This combination is not commercially available.
ASSESSMENT OF RESPONSE — We typically reevaluate patients in 4- to 16-week intervals and use a symptom-based approach to assess patient response .
●Asymptomatic – Patients who are asymptomatic at the end of suppressive therapy have the option of continuing the suppressive medication or stopping it . In general, we continue the suppressive medication as patients often prefer using a lower intensity maintenance treatment rather than waiting for symptom recurrence and need for higher intensity retreatment. However, it is reasonable to stop suppressive therapy for asymptomatic individuals and observe. If BV recurs, we repeat treatment followed by a course of suppressive therapy.
●Symptomatic – Symptomatic individuals are reevaluated to confirm BV and retreated for confirmed BV recurrence. For patients who developed BV symptoms while on suppressive therapy with metronidazole gel, we generally proceed with the triple-therapy protocol above or, for those already on the triple-phase regimen, we use extended vaginal boric acid following antibiotic treatment.
INVESTIGATIONAL INTRAVAGINAL THERAPIES
Lactobacillus crispatus — Intravaginal treatment with Lactobacillus crispatus is a promising therapy to follow the initial course of metronidazole 0.75% vaginal gel for five days . In a phase 2b trial comparing vaginal L. crispatus CTV-05 (LACTIN-V) with placebo in 228 women diagnosed with BV, patients receiving LACTIN-V had fewer BV recurrences at 12 and 24 weeks of follow-up (recurrence rate 12 weeks: 30 versus 45 percent; 24 weeks: 39 versus 54 percent) . Treatment with LACTIN-V also resulted in higher rates of detectable vaginal L. crispatus compared with placebo (12 weeks: 79 versus 6 percent; 24 weeks: 48 versus 2 percent). All patients initially received seven days of vaginal metronidazole followed by 11 weeks of either therapy or placebo. Adverse event rates were similar between the two groups; no serious adverse events were attributable to either therapy. This approach is promising both for eliminating BV and for restoring Lactobacillus colonization. However, limitations include that 30 percent of patients experienced recurrence during active treatment, and outcomes were not studied beyond three months. In addition, the product is not commercially available, and these results should not be extrapolated to other probiotic remedies.
Boric acid with EDTA — TOL-463 is a boric-acid based anti-infective enhanced with EDTA (ethylenediaminetetraacetic acid) that targets vaginal bacterial and fungal biofilms. In a study of 106 individuals (53 with BV, 36 with vulvovaginal candidiasis, and 17 with both infections), BV test of cure rates performed at days 9 to 12 were 59 percent for vaginal insert and 50 percent for gel . Long-term follow-up was not obtained. A phase 2 study is in process .
Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 — Exogenous lactobacillus recolonization with 30 days of oral probiotic Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14 in addition to seven days of metronidazole therapy has been suggested, but there is minimal evidence of the efficacy of this approach [47,48]. These results should be reproduced in other trials before use of this therapy is considered.
Microbiome transplant — Vaginal microbiome transplant has been investigated in small pilot studies, without control groups, as a potential treatment for patients with recurrent BV infection [49,50]. More data are needed before this approach becomes a standard therapy.
INEFFECTIVE THERAPIES — The following treatments have not been shown to treat recurrent BV.
●Clindamycin for long-term suppression – While initial symptomatic relapse can be treated with a seven-day course of oral or vaginal clindamycin, long-term clindamycin regimens, oral or topical, are not advised because of toxicity (oral) and lack of documented efficacy (topical) . In our experience, clindamycin therapy is frequently associated with vaginal yeast coinfections compared with metronidazole gel. Clindamycin should not be used in women with a history of C. difficile infection.
●Vaginal acidifying agents – 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.
●Probiotics – In a randomized trial, probiotics were not more effective than placebo for prevention of relapse. (See "Bacterial vaginosis: Initial treatment", section on 'Probiotics and other therapies'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Bacterial vaginosis".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Bacterial vaginosis (The Basics)")
●Beyond the Basics topics (see "Patient education: Bacterial vaginosis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Definition – Recurrent bacterial vaginosis (BV) is defined as three or more confirmed symptomatic BV episodes in one year. Patients with confirmed BV who are asymptomatic do not require treatment unless they are undergoing gynecologic surgery that involves the vagina.
•(See 'Definition and possible mechanisms' above.)
●Mechanisms – Possible mechanisms of recurrent BV include inadequate treatment, reinfection, infection relapse, and drug resistance. (See 'Definition and possible mechanisms' above.)
●Approach to treatment selection – Treatment selection is driven by patient preferences, patient response to any prior treatments, and medication cost and availability. The approaches below are based mainly on author experience as there are limited available data. Other approaches may be acceptable.
•When possible, we treat recurrent BV using a different drug or regimen from what was used from prior therapy given that some patients may have multiple recurrences or recur on maintenance therapy.
•If there are no therapeutic options that have not yet been tried, then we use the drug and/or regimen that resulted in the best past response for the patient.
•Otherwise, we proceed with the treatments in the order presented below.
●Treatment regimens – There is no single data-driven approach to the management of recurrent BV. The approaches below are based on available supporting data and the author's experience (algorithm 1).
•Extended metronidazole regimen – For patients with recurrent BV, we suggest maintenance intravaginal metronidazole gel after induction nitroimidazole therapy rather than induction therapy alone (Grade 2C).
-Induction – The choice of oral pill or vaginal gel for induction is based upon patient preferences, prior patient response, and drug availability. Patients often prefer oral to vaginal therapy but both are effective. (See 'Extended metronidazole regimen' above.)
Intravaginal metronidazole 0.75% gel given as a 5-gram dose twice daily for seven days.
-Maintenance – Maintenance therapy is started immediately after finishing induction treatment.
Metronidazole 0.75% gel, 5-gram dose, placed vaginally twice a week for four to six months.
•Extended vaginal boric acid regimen
-Induction – For this approach, the patient starts an oral nitroimidazole and vaginal boric acid at the same time. (See 'Protocol' above.)
-Maintenance – Vaginal boric acid 600 mg daily (typically at night). After seven days, the nitroimidazole is stopped while the vaginal boric acid is continued for a total of 30 days. Boric acid should never be used orally. (See 'Critical warning on boric acid use' above.)
-Suppression – Patients who achieve remission based on Amsel criteria or similar have the options of stopping treatment or immediately beginning metronidazole 0.75% gel, 5 gram vaginally twice weekly for four to six months as suppressive therapy. The decision to start suppression is based on shared decision-making with the patient. (See 'Protocol' above.)
●Critical warning on boric acid use – 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. Boric acid should not be used by individuals who are pregnant or attempting conception. (See 'Critical warning on boric acid use' above.)
●Risk-reducing strategies – Although supporting data are limited, condom use, sexual abstinence, and hormonal contraceptive use have been associated with reduced risk of BV recurrence. For all, risk of harm is low, but duration of maintenance is not known. (See 'Risk-reducing strategies' above.)
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