Characterization and Treatment of Recurrent Bacterial Vaginosis

Abstract

Bacterial vaginosis (BV) is a common but treatable condition, with a number of effective available treatments, including oral and intravaginal metronidazole and clindamycin and oral tinidazole. However, as many as 50% of women with BV experience recurrence within 1 year of treatment for incident disease. Some reasons for recurrence include the persistence of residual infection, resistance, and possibly reinfection from either male or female partners. Persistence may occur due to the formation of a biofilm that protects BV-causing bacteria from antimicrobial therapy. Poor adherence to treatment among patients with genitourinary infections may lead to resistance. However, the underlying mechanisms of recurrent etiology of BV are not known. Recommended treatment for recurrent BV consists of an extended course of metronidazole treatment (500 mg twice daily for 10–14 days); if ineffective, metronidazole vaginal gel 0.75% for 10 days, followed by two times per week for 3–6 months, is an alternate treatment regimen. Past studies of clindamycin and tinidazole in the treatment of recurrent BV have focused on patients with evidence of metronidazole resistance. Secnidazole may be an attractive new option due to one-time dosing. Initial studies on biofilm disruption, use of probiotics and prebiotics, and botanical treatments have shown some promise, but must be studied further before use in the clinic. Despite limitations, antimicrobial therapy will remain the mainstay of treatment for recurrent BV for the foreseeable future.

Introduction

Bacterial vaginosis (BV) affects ∼30% of women in the United States.¹ Although symptoms of BV may be mild and not bothersome for most women, those with recurrent BV report a moderate-to-severe impact on their self-esteem, sex life, and overall quality of life.² The healthy microbiota of the lower genital tract in women predominantly consists of Lactobacillus spp., providing a key line of defense against potential pathogens.³ BV is characterized by a shift in the vaginal microbiota from aerobic lactobacilli to anaerobic bacteria, including Gardnerella vaginalis, Atopobium vaginae, Mobiluncus spp., Bacteroides spp., and Prevotella spp.^4
–6 Previously, G. vaginalis was considered to be the sole bacterium causing BV, but its presence in many women without BV suggests that the presence of G. vaginalis alone is not sufficient to warrant treatment. However, some evidence suggests that a polymicrobial biofilm dominated by G. vaginalis may contribute to the etiology of BV.⁵ Ultimately, BV is not caused by the mere presence of these bacteria, but rather by their unrestrained increase in number, often reaching cell counts that are 100- to 1,000-fold above the normal bacterial levels of the vagina.³

Amsel's criteria are widely used to diagnose BV. A diagnosis of BV is considered when at least three out of four of the following criteria are present^7,8: (1) a homogeneous, milk-like vaginal discharge that coats the vaginal walls; (2) vaginal pH >4.5; (3) a fishy odor released with the addition of 10% potassium hydroxide (KOH) to a sample of the discharge (KOH whiff test); and (4) presence of clue cells (epithelial cells coated with bacteria such that they appear heavily stippled with indistinct borders). The Nugent score is a standardized Gram-stain laboratory test for assessment of vaginal smears that can also be used for diagnosis.⁹ Often employed in research settings, the Nugent score is also used in the interpretation of vaginal swab test results in the clinic and for reporting of these results.¹⁰

The most recent Centers for Disease Control and Prevention (CDC) guidelines recommend treatment of BV with oral metronidazole, vaginal metronidazole gel, or vaginal clindamycin cream; alternative antibacterial treatments are also noted (Table 1).^8,11 Clinical cure rates in pivotal clinical trials (defined as return to normal vaginal discharge and resolution of Amsel's criteria) with these recommended treatments range from 36% to 61%.^12,13 The CDC guidelines were last updated in 2015 and do not yet include the recently approved secnidazole, which is administered as a single dose of 2 g oral granules. Beyond treatment with antimicrobials, it is recommended that women refrain from sexual activity during treatment or use condoms consistently and correctly, and to refrain from douching since douching may increase the risk of relapse.⁸

Table 1.

Recommendations for Treatment of Bacterial Vaginosis^8,1 ¹

Recommended treatments
Metronidazole 500 mg orally bid for 7 days
Metronidazole gel 0.75% intravaginally qd for 5 days
Clindamycin cream 2% intravaginally for 7 days
Alternative treatments
Metronidazole 2 g orally as a single dose or two doses separated by 48 hours
Clindamycin 300 mg orally bid for 7 days
Tinidazole 1 g orally qd for 5 days
Tinidazole 2 g orally qd for 2 days
Clindamycin 100 mg ovules intravaginally at bedtime for 3 days
Secnidazole 2 g single dose orally^a

Secnidazole has been approved by the FDA for the treatment of BV, but has not yet been incorporated into CDC guidelines.

bid, twice daily; BV, bacterial vaginosis; CDC, Centers for Disease Control and Prevention; FDA, U.S. Food and Drug Administration; qd, once daily.

Of note, cure has been defined in multiple ways, including clinical cure and bacteriological cure, with assessment at different time points after the treatment. This is especially true in older studies conducted before the U.S. Food and Drug Administration (FDA) issued guidances to standardize BV trials.^14,15 Thus, reported cure rates (including in this review) may be based on different assessments across studies.^14,15 Despite the availability of these treatments, more than half of women experience recurrence of symptoms and/or reemergence of abnormal vaginal flora usually within 1 year of treatment.^16,17 In addition, poor understanding of the etiology of BV recurrence makes treatment of recurrent BV challenging.^18,19

Epidemiology and Consequences of Recurrent BV

The National Health and Nutrition Examination Survey data from 2001 to 2004 identified a number of risk factors for BV, including education less than high school level, income below the poverty line, African American or Mexican American ethnicity, and douching.¹ In addition, other risk factors are associated with recurrent BV, including poor adherence to treatment, trichomoniasis, longer duration of the menstrual cycle, less than 3 days of menstruation, dysmenorrhea, inconsistent condom use, and intrauterine device use.^20

–24 Ethnic differences in the vaginal microbiome may explain the prevalence of BV in African American women that is as high as 50%.²⁵ Douching is associated with both BV and recurrent BV,^26

–29 suggesting that the disruption of vaginal microbial populations may be a causative factor. Use of hormonal contraceptives appears to be protective against BV.^16,30
–32 A decrease in the frequency of withdrawal bleeding associated with some hormonal contraceptives may lead to a reduction in volume and presence of hemoglobin in the genital tract.³² In addition, estrogen-containing contraceptives may increase the glycogen content of epithelial cells in the vagina.³² Glycogen is metabolized to lactic acid by both epithelial cells and Lactobacillus, resulting in acidification of the vagina. Finally, estrogen and progesterone act as immune modulators in the genital tract and regulate immunoglobulins, secretory leukocyte protease inhibitors, cytokines, and defensins, and help in the recruitment of immune cells.³² However, to date, no randomized clinical trials have investigated the effectiveness of oral contraceptives in the prevention of recurrent BV.

The sequelae of BV can be serious, including increased risk of sexually transmitted diseases, such as HIV^33,34 and pelvic inflammatory disease (and associated subsequent infertility), and adverse outcomes of pregnancy, including miscarriage, preterm delivery, low-birth-weight infants, chorioamnionitis, and reduced quality of life.^2,35
–37 Women who reported a higher number of recurrences tended to report a greater negative impact of BV on quality of life.²

Etiology of Recurrence

While there is no universally accepted definition of recurrent BV, a few studies have defined it as three or more confirmed episodes (clinically diagnosed by Amsel's criteria or microscopically) in 12 months.¹⁸ It is not clear whether BV becomes recurrent due to residual infection, resistance, or reinfection.^21,34

Residual infection is implicated as a cause of recurrence due to persistence of infection following treatment. G. vaginalis resistance to metronidazole has been demonstrated,³⁸ as has resistance to clindamycin, although there is no direct relationship between microbiological resistance and clinical resistance.³⁹ There are a number of possible mechanisms for antimicrobial resistance, including failure to achieve inhibitory concentrations (most likely due to a lack of adherence), reduced drug activation, drug inactivation, prevention of entry or efflux, and altered bacterial DNA repair.⁴⁰ Of note, a meta-analysis in 29,291 subjects found that adherence to antibiotic therapy was only 41% for patients with genitourinary infections, substantially lower than for antibiotic use overall.⁴¹ The presence of different clades of G. vaginalis could be associated with microbiological resistance and BV recurrence. G. vaginalis clades 1 and 3 have been associated with BV but not with normal vaginal microbial populations, whereas clades 3 and 4 exhibit a high frequency of metronidazole resistance in vitro.³⁸ Furthermore, in a recent study in women with BV, clade 1 G. vaginalis decreased immediately after high-dose intravaginal metronidazole treatment and increased posttreatment only in those with recurrent BV, whereas clade 2 decreased in patients who had a sustained response but not in those with recurrent BV.⁴²

BV-associated bacteria, primarily G. vaginalis and A. vaginae, are associated with the formation of a biofilm in the vagina.^43,44 A biofilm forms when bacteria attach to a surface and form a slimy extracellular matrix accompanied by an altered bacterial phenotype and gene transcription.^45,46 A recent study indicated that expression of a gene coding for the sialidase enzyme may be key for biofilm formation. Sialidases facilitate the destruction of the protective mucus layer on the vaginal wall through hydrolysis of sialic acid on the glycans of mucous membranes and allow bacteria to adhere on the epithelium.⁴⁷ These biofilms can cause a decrease in susceptibility to antimicrobial agents and facilitate development of resistance, as well as provide a safe haven for other pathogens.^19,46,48 Known mechanisms of biofilm resistance include slow or incomplete penetration of antimicrobials, physiological changes in the biofilm microenvironment, phenotypic changes in biofilm cells (similar to spore formation), cell-to-cell signaling between biofilm microorganisms, expression of solute pumps that can remove antimicrobials, and the presence of “persister” cells that can survive antimicrobial concentrations well above minimal inhibitory concentrations.⁴⁹ As a result, the formation of a biofilm may be a key for recurrent BV, and disruption of biofilms may be required for successful treatment.¹⁹

The presence and persistence of pathogens is also associated with recurrent BV. Most research to date has been focused on G. vaginalis, but studies have also found associations of other bacteria, including A. vaginae, Mobiluncus spp., Bacteroides spp., Prevotella spp., Clostridiales spp., and Leptotrichia/Sneathia spp.^4,5,50 A recent study found that higher concentrations of Megasphaera phylotype 2 and BV-associated bacteria at initial diagnosis, as well as higher concentrations of G. vaginalis posttreatment, were associated with recurrent disease.⁵¹ A. vaginae is frequently present with G. vaginalis in patients with recurrent BV, with 83% of patients with both bacteria reporting recurrent BV, compared with 38% of those with only G. vaginalis. ⁵² Additionally, persistence of Mobiluncus curtisii is significantly associated with BV recurrence.⁵³

Although BV is not considered to be a sexually transmitted disease, having a regular sexual partner,^16,30 having a female sexual partner with confirmed BV,⁵⁴ multiple sexual partners,^23,54 and inconsistent condom use for penile/vaginal sex³⁰ are associated with recurrent BV. A trial to determine the effect of male sexual partner treatment is currently recruiting.⁵⁵ However, current treatment guidelines do not recommend treatment of male sex partners based on the results of six randomized, controlled trials that showed no consistent benefit.^8,56

Treatment of Recurrent BV

Treatments that have been tested in the context of recurrent BV are summarized in Table 2.^{11,57

–70} Although this is not a systematic review, an extensive literature search was conducted to identify both antimicrobial and alternative treatments of recurrent BV; however, we acknowledge the potential for bias in such an approach. Key studies, systematic reviews, and meta-analyses identified during our review process discussing these treatments are covered in detail below.

Table 2.

Tested Treatments for Recurrent Bacterial Vaginosis

Treatment	Outcome
Metronidazole 500 mg bid for 10–14 days¹¹	Standard therapy, but not supported by data in recurrent BV
Metronidazole vaginal gel (0.75%) for 3–6 months⁵⁷	Recurrence rate 25.5% vs. placebo 59.1% (p = 0.001) after 16 weeks of therapy
Secnidazole 2 g single dose⁵⁸	53.3% clinical responder rate with secnidazole vs. placebo 19.3% (p < 0.001) in patients with a mean of three episodes in prior 12 months
Metronidazole 750 mg/miconazole 200 mg for five nights each month for 12 months⁵⁹	BV observed at 21.2% of follow-up visits with metronidazole/miconazole vs. placebo 32.5% (p = 0.005)
Dequalinium chloride 10 mg tablets for 6 days⁶⁰	Recurrence occurred in 13.5% of patients vs. 9.2% with clindamycin 2% vaginal cream; 70% of patients had prior BV
Clindamycin vaginal cream 2% for 7 days⁶⁰	Recurrence occurred in 9.2% vs. dequalinium chloride 10 mg; 70% of patients had prior BV
Octenidine for 7 days⁶¹	Relapse occurred in 66.6% (recurrence in 33.4%)
Lactic acid vaginal gel 5 g for 7 days⁶²	Recurrence rate 6.7% over 56 days vs. 14.3% with metronidazole 500 mg bid for 7 days and 3.6% with metronidazole + lactic acid
Acetic acid vaginal gel 0.94% 2.5 g⁶³	Recurrence rate 51%
Ascorbic acid 250 mg intravaginal tablet for six nights/month⁶⁴	Recurrence rate 16.2% vs. placebo 32.4% (p < 0.05)
Lactobacillus rhamnosus, Lactobacillus acidophilus, and Streptococcus thermophilus probiotic capsule for 7 days on, 7 days off, and 7 days on⁶⁵	Recurrence rate 15.8% vs. placebo 45.0% (p < 0.001) after 2 months and 10.6% vs. 27.7% after 11 months (p = 0.04)
Prebiotic gel with APP-14⁶⁶	Recurrence rate 11% at day 84 vs. placebo 19%
Lactobacillus gasseri, Lactobacillus fermentum, and Lactobacillus plantarum were administered twice daily for 10 days after 7 days of oral metronidazole⁶⁷	No significant difference in recurrence vs. metronidazole alone
Vaginal capsules of Lactobacillus crispatus ⁶⁸	Recurrence rate 20.5% vs. placebo 41%
Vitamin D 50,000 IU at weeks 1, 2, 3, 4, 8, 12, 16, 20, and 24 after metronidazole therapy⁶⁹	Recurrence rate 65% vs. placebo 48%
Vaginal gel containing metronidazole 0.75% and Myrtus communis 2% for five nights⁷⁰	No recurrence vs. metronidazole gel 0.75% alone 30% at 3 weeks follow-up

Antibacterials

In women with documented recurrent BV, extending the course of metronidazole treatment (500 mg twice daily for 10–14 days) may prevent further recurrences.¹¹ Alternatively, metronidazole vaginal gel 0.75% therapy for 10 days followed by two times per week for 3–6 months has also been recommended. Recurrence rates with twice-weekly metronidazole gel therapy for 16 weeks in women with recurrent BV were found to be 25.5% versus 59.1% with placebo (p = 0.001) at the end of the 16-week treatment period.⁵⁷

In 2017, a single oral dose of secnidazole 2 g was approved for the treatment of incident BV after FDA priority review in the United States.⁷¹ A randomized, phase 2 study of single-dose treatment of secnidazole 1 or 2 g oral granules in 215 women with BV showed a significantly higher clinical cure rate compared with placebo with both doses (51.6% and 67.7% vs. 17.7%, respectively, p < 0.001 for each comparison). Microbiological cure rates were also significantly higher (23.4% [p = 0.007] and 40.3% [p < 0.001] vs. 6.5%, respectively).⁷² In a phase 3, randomized, double-blind, placebo-controlled study in 189 women randomized 2:1 to a single dose of secnidazole 2 g or placebo, secnidazole was shown to be superior to placebo, with 53.3% and 19.3% of the patients (p < 0.001) achieving clinical cure, respectively.⁵⁸ This trial included subjects with a history of BV; ∼30% of those treated with secnidazole who were clinical responders reported four or more occurrences of BV in the last 12 months. An earlier, ex-U.S. phase 3 clinical study found secnidazole was at least as effective as a multiple-dose regimen of metronidazole with respect to clinical and bacteriological cure rates at day 28 (60.1% and 59.5%, respectively).⁷³ Other preliminary studies suggested secnidazole efficacy is similar to that of metronidazole.^58,71,74,75 Oral secnidazole has not been evaluated for the treatment of recurrent BV. However, the single-dose administration and the lack of an alcohol interaction make it an attractive therapeutic option, especially for those patients with lower medication adherence.

Other approaches have also been studied in restricted settings or have been proposed. In a randomized, placebo-controlled trial, compounded suppositories containing metronidazole 750 mg with miconazole 200 mg were used by women for five consecutive nights each month for 12 months. BV was observed at 21.2% of the follow-up visits with the metronidazole/miconazole combination compared with 32.5% with placebo (p = 0.005).⁵⁹ Recently, an intravaginal ring designed to release metronidazole over 4–7 days and lactic acid over 28 days for prophylaxis and treatment of BV has been proposed.⁷⁵ Finally, treatment of recurrent BV with the bacteriostatic compound dequalinium chloride as 10 mg vaginal tablets for 6 days was shown to be as effective as clindamycin vaginal cream for 7 days in a randomized, single-blind study (70% of women had recurrent BV at baseline), with similar recurrence rates.⁶⁰

Biofilm disruption

While treatment with antimicrobials can effectively eliminate bacteria, they do not eliminate biofilms in which bacteria persist in a carrier state.^61,76,77 Persistence of biofilms in otherwise successful antimicrobial treatment appears to be an important mechanism of BV recurrence. Hence, biofilm targeting may be an attractive approach to treat recurrent BV disease. A study by Reichman et al. suggested that the addition of daily intravaginal boric acid to weekly metronidazole for 4 months may reduce recurrence rates.⁷⁸ However, the uncontrolled study design did not allow for the contribution of boric acid to be properly evaluated. A randomized, placebo-controlled study of intravaginal boric acid (600 mg) and metronidazole (10%) intravaginal cream for 10 days is ongoing and may provide the insight on the effect of boric acid for the treatment of symptomatic BV.⁷⁹

Octenidine, a local antiseptic that has been found to be effective in treating several biofilm-associated infections, has demonstrated initial cure rates as high as 87.5%, but the relapse rate at 6 months was also high as resistance developed in 66.6% of the patients.⁶¹ There is also an interest in using DNAse, retrocyclin, chitosan gels, subtilosin, and lauramide arginine ethyl ester to disrupt biofilms, but none of these has been evaluated in humans.^80

–83 Overall, the use of antiseptics and disinfectants for treatment of BV has been poorly studied, and there is insufficient evidence to warrant their use.⁸⁴

Vaginal acidification

BV is characterized by a vaginal pH of more than 4.5.⁷ Therefore, it has been proposed that maintenance of an acidic vaginal pH <4.5 to prevent overgrowth of undesired bacteria and allow regrowth of Lactobacillus spp. may be an alternative therapeutic approach. Treatment of women with a lactic acid vaginal gel as an adjunct to metronidazole treatment has been associated with a lower rate of recurrence of BV than metronidazole alone.⁶² In a study of 90 women randomized to treatment with lactic acid vaginal gel 5 g, oral metronidazole 500 mg twice daily, or both together for 7 days, two patients given lactic acid gel, four patients in the metronidazole arm, and one patient in the combination arm had recurrence of BV within 15–56 days.⁶² Wilson et al. evaluated the efficacy of acetic acid vaginal gel in 49 women with frequent recurrence of BV.⁶³ Half of the women had no further recurrence. Moreover, acetic acid vaginal gel prolonged the time to recurrence of the BV disease compared with the time to their previous recurrence (4.8 months vs. 2.1 months, p = 0.003). In an uncontrolled study, 58 women applied hydrogen peroxide 3% each evening for a week to normalize pH to <4.5.⁸⁵ Vaginal pH was normalized in 98% of participants and normal vaginal flora was restored in 100% of the participants; 89% of the primary BV symptoms were eliminated within 3 months of the end of treatment. Anaerobic pathogenic flora and clue cells were also eliminated from vaginal smears in 100% of patients. A systematic review, however, found no benefit to hydrogen peroxide douches.⁸⁶ Vitamin C suppositories have also been used to reduce intravaginal pH. In a randomized, double-blind, placebo-controlled study, women with a history of BV recurrence who had been successfully treated with metronidazole or clindamycin were randomized to ascorbic acid tablets 250 mg or placebo.⁶⁴ One tablet was inserted into the vagina for six nights per month after menses for 6 months. After 6 months, the rate of recurrence was 16.2% in the vitamin C group compared with 32.4% in the placebo group (p < 0.05). Nevertheless, as there have been studies of vaginal acidification on symptomatic BV with negative or variable results, more well-designed studies of the effect of vaginal acidification on recurrent BV are needed to better understand if this is a viable treatment option.⁴⁴

Prebiotics/probiotics

Since a decrease in the normal vaginal lactobacilli and proliferation of anaerobic species is observed in BV,^4
–6 one approach to prevention and treatment of recurrent BV may be to restore the normal vaginal microbiota. While some systematic reviews have suggested a potential benefit to this approach, these have been based on a relatively small number of trials with heterogeneity among study designs, and thus should be interpreted with caution.^87
–89 A recent meta-analysis of probiotics in combination with metronidazole showed no significant benefit compared with metronidazole alone for the treatment of BV.⁹⁰ There is a clear need for good-quality randomized controlled trials. Some of the most intriguing trials conducted to date are described below.

McLean and Rosenstein identified strains of lactobacilli that demonstrated good inhibitory activity against BV-associated bacterial species in vitro, created a highly acidic intravaginal pH <4, produced hydrogen peroxide, and were strongly adherent to vaginal epithelial cells, potentially allowing for disruption of biofilms.⁹¹ Although not clinically tested, two Lactobacillus acidophilus strains were identified as potential probiotics for vaginal recolonization. Other potential probiotics were also studied clinically. One hundred and twenty Chinese women with a history of recurrent BV were randomized to receive daily vaginal prophylaxis with a capsule containing Lactobacillus rhamnosus, L. acidophilus, and Streptococcus thermophilus or placebo for 7 days on, then 7 days off, and lastly 7 days on. BV recurrence rates after 2 months were 15.8% with the probiotic compared with 45.0% for placebo (p < 0.001), and after 11 months the rates were 10.6% versus 27.7% (p = 0.04).⁶⁵ The incidence of G. vaginalis colonization was also lower with capsules compared with placebo (3.5% vs. 18.3%, respectively, p = 0.02). Coste et al. took a slightly different approach to restoring the normal vaginal biota through the application of a prebiotic gel that promoted growth of Lactobacillus crispatus, Lactobacillus vaginalis, and Lactobacillus jensenii without promoting growth of Candida albicans, Escherichia coli, or G. vaginalis. ⁶⁶ All patients in this study who were randomized to the prebiotic gel had a normal Nugent score after 16 days of treatment, whereas 24% of those treated with placebo had scores equal to or greater than intermediate. At follow-up on day 84, 11% of the treatment group and 19% of the placebo group experienced a recurrent episode of BV.

The efficacy of oral probiotics has also been evaluated in a few clinical studies. An oral probiotic containing a mixture of Lactobacillus gasseri, Lactobacillus fermentum, and Lactobacillus plantarum was administered twice daily for 10 days after 7 days of oral metronidazole in a randomized, placebo-controlled trial.⁶⁷ This large study, which included 578 women, found no significant difference in clinical BV recurrence between arms, but the average time to relapse was 47.3 days in the placebo group compared with 71.4 days in the probiotic group. Laue et al. assessed oral probiotic treatment using a yogurt formulated with strains of L. crispatus, L. gasseri, L. jensenii, and L. rhamnosus isolated from healthy pregnant women and selected based on their acidification capacity, production of hydrogen peroxide, glycogen utilization, bile salt tolerance, and inhibition of pathogens.⁹² This was a small, single-center, randomized, placebo-controlled trial of the probiotic taken for 4 weeks along with metronidazole 500 mg twice daily for 7 days. Recovery from BV and BV symptoms was significantly different in favor of probiotic treatment as assessed by Amsel's criteria but not Nugent criteria at week 4. However, recurrence was not assessed over a longer period. In another prospective, multicenter, double-blind, randomized trial of women with at least two documented episodes of BV in the previous year, Bohbot et al. compared the effect of vaginal capsules of L. crispatus and placebo after treatment with metronidazole 1 g/day for 7 days.⁶⁸ Fewer women treated with L. crispatus reported BV recurrence compared with placebo (20.5% vs. 41%; p < 0.05), and time to recurrence was increased by 28% in the L. crispatus group (3.75 months) compared with placebo (2.93 months).⁶⁸ Restoration of normal vaginal flora with prebiotics and/or probiotics in addition to pharmacotherapy present an attractive approach to improve response rates and reduce BV recurrence. However, more clinical evidence is required to determine correct formulation and dosing.

Vitamin-based treatment

BV has been reported to be associated with vitamin D insufficiency.⁶⁹ Inadequate vitamin D levels may also be a source of racial differences in the incidence of BV. However, in a 24-week, randomized, double-blind, placebo-controlled study in 118 women, vitamin D 50,000 IU taken at weeks 1, 2, 3, 4, 8, 12, 16, 20, and 24 after metronidazole therapy resulted in a higher rate of BV recurrence (65%) compared with placebo (48%). Hence, vitamin D supplementation did not reduce BV recurrence.

Herbal treatments

Herbal or botanical treatments have also been used to treat BV. Myrtus communis is an extract of the common myrtle with antibacterial and antifungal properties.⁷⁰ In combination with metronidazole, M. communis was studied for the prevention of recurrent BV. Recently, Masoudi et al. investigated the effect of an application of a vaginal gel containing metronidazole 0.75% and M. communis 2% for five nights on the recurrence of BV in a double-blind, randomized clinical trial. No recurrence was observed in the metronidazole and M. communis-treated patients compared with recurrence of BV in 30% of the patients treated with metronidazole alone in a relatively short follow-up of 3 weeks.⁷⁰ Hence, M. communis may be used as an adjunct to metronidazole in the prevention of BV recurrence. However, further studies with a longer follow-up period and a larger sample size are needed.

Challenges in the Management of Patients with Recurrent BV

Currently, effective treatment for recurrent BV is lacking. Although a few of the approaches discussed in this review show some promise, a greater understanding of the etiology of BV and its recurrence is required to further improve outcomes.¹⁹

Women have a high level of dissatisfaction with current pharmacotherapy for BV. In fact, most of them have resorted to self-help remedies and lifestyle modifications at some point to prevent further recurrences, although with little benefit and increased risk of exacerbating recurrence.⁹³ Self-help remedies include douching, bathing in cider vinegar diluted with water, garlic suppositories, over-the-counter pH-balancing vaginal gel, yogurt, probiotics, and vitamins. Lifestyle approaches include changes in sexual practices and hygiene, changes in clothing choices, and attempts to improve general health and well-being.⁹³ However, some of these approaches, such as excessive cleansing and use of douches, are established risk factors that actually exacerbate BV or may lead to recurrence of BV. Since numerous factors contribute to the recurrence of BV, it is important to record patient history (to consider any of the abovementioned measures) when determining a course of treatment for recurrent BV.

Development of antimicrobial resistance is a major challenge in treating any infection. Poor medication adherence is an important cause of resistance since it may lead to drug levels that are too low to prevent bacterial replication but high enough to exert a selection pressure, leading to treatment failure, emergence of resistant bacteria, and loss of therapeutic options.⁹⁴ Reasons for nonadherence to BV treatments include gastrointestinal complaints, duration of therapy, lifestyle restrictions (such as refraining from intercourse with intravaginal treatments), symptomatic improvement, bad taste, and messy application.^21,93,95,96

The alcohol avoidance required during and immediately following nitroimidazole (metronidazole and tinidazole) therapy⁸ may also be challenging for some women with BV. A study of BV in adolescent girls (11–18 years of age) who attended sexually transmitted disease clinics in Baltimore, Maryland, found high rates of alcohol use in this patient population, highlighting the need to counsel teens who may need BV treatment.²¹ A review of the literature also found a high prevalence of alcohol use among female sex workers worldwide. Underlying reasons for high alcohol use among sex workers may include: dealing with an impoverished lifestyle, coping with stresses and fears related to work (potential for arrest, violence, disease, etc.), boosting one's confidence, allowing for relaxation, and/or overcoming aversion to clients.²⁴ Intravaginal boric acid or hydrogen peroxide may be considered in such populations to control BV.

Currently available therapy for recurrent BV necessitates repeated or long-term treatment that may increase health care costs. Oral metronidazole is an inexpensive generic treatment in the United States, but this medication may not be suitable for women with recurrent BV who refuse to avoid alcohol, have already failed oral metronidazole treatment, or have experienced side effects. In the United Kingdom, oral metronidazole is the least expensive treatment available, followed by intravaginal metronidazole 0.75%, oral tinidazole, and clindamycin 2% intravaginal cream.⁹⁷ Over-the-counter remedies such as prebiotics and herbal treatments are often cost prohibitive for women of low socioeconomic status, and evidence for their effectiveness is limited.^87
–89 Any assessment of the cost implications of recurrent BV should include effects on loss of work productivity, time off from work for physician appointments, and decreased access to care, as well as the direct costs of the medication.

Conclusions

Although BV is a readily treatable condition, it is associated with a high rate of recurrence. The exact mechanism of recurrence is not fully understood, but may be related to the formation of biofilms that protect BV-associated bacteria and allow them to persist, even with efficacious treatments. To date, interventional strategies to target BV-associated bacteria and biofilms and to restore the normal vaginal microbiome are at an early stage. Thus, there is an unmet need for improved treatment regimens to prevent and treat BV recurrence. Further research to understand mechanisms of recurrent BV and effective and safe prophylaxis and treatment is warranted.

Footnotes

Acknowledgments

The authors are responsible for all content and editorial decisions, and received no honoraria related to the development of this article. Both authors contributed to the research, writing, and reviewing of all drafts of this article and approved the final version. Editorial support in the preparation of this article was provided by Phase Five Communications, funded by Symbiomix Therapeutics, LLC.

Author Disclosure Statement

B.M.F. has received research funding from IPSEN Innovation and has been a speaker/consultant for AMAG Pharmaceuticals, Inc., Duchesnay, Lupin Pharmaceuticals, JDS Therapeutics, and TherapeuticsMD. S.R. has no competing financial interests to disclose.

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