Bacterial vaginosis (BV) is the most common cause of vaginitis among reproductive aged women, commonly presenting with vaginal discharge and odor (1). BV is characterized by a decline in abundance of Lactobacillus, a healthy vaginal bacteria (2, 3), and a simultaneous overgrowth of pathogenic bacteria, such as Gardnerella vaginalis, Atopobium vaginae, Megasphaera spp., Prevotella spp. and Sneathia spp. Point-of-care diagnosis of BV can be made by noting at least three of four Amsel criteria, which include thin, white discharge, clue cells on microscopy, a vaginal pH > 4.5, and a fishy odor with application of potassium hydroxide (4). Laboratory based molecular tests, which identify DNA from a subset of BV-associated species, have recently been FDA approved (5). Research studies often use the Nugent score of bacterial morphotypes on vaginal fluid Gram stain for diagnosis (6).

In the United States, the estimated prevalence of BV is 29%–49% (7, 8). Despite this high prevalence, an effective long-term cure for BV remains elusive for many women. There is a high recurrence rate of BV following antibiotics (9–11), the only approved therapeutic regimen, and many women struggle with recurrent BV [defined as ≥3 episodes in a 12 month period (11)]. Such high recurrence may be due to persistence of the infection, re-exposure to BV-associated organisms, or a failure of lactobacilli to recolonize the vagina. Lack of adequate treatment for BV is a significant public health issue both because of the impact of symptoms on quality of life, and because women with BV are at increased risk for preterm birth (12, 13), sexually transmitted infections (STIs) including HIV(14, 15), and pelvic inflammatory disease(16). Additionally, women with BV are at increased risk for post-operative complications such as vaginal cuff cellulitis (17).

Various studies have found racial differences in BV prevalence (18). It is important to highlight that race is not a biologic factor, suggesting that there are environmental or situational factors linked to the lived experience of a racial or ethnic group, including racism (19), that may contribute to differences in BV prevalence. While differences in BV prevalence may exist across race or ethnicity (20), there is no known difference in treatment efficacy.

The failure of antibiotics to provide a long-term cure for BV has led many women and clinicians to consider alternative therapies. The focus of this review is to discuss the evidence for potential non-antibiotic therapeutic and preventive options for BV, including those currently under investigation and those more informally used (Table 1).

Antibiotics are the first line treatment for BV. The recommended therapeutic regimens include oral or intravaginal metronidazole and intravaginal clindamycin. These treatments have similar efficacy and are effective for short-term resolution of the infection (22). Recurrent bacterial vaginosis is a common drawback to current treatment options. Within 6–12 months of finishing antibiotic therapy, 50%–80% of women will experience a bacterial vaginosis recurrence (9–11). Proposed reasons for this treatment failure include reinfection via sexual partners, antimicrobial resistance, biofilm, and failure to reestablish a health-optimal vaginal microbiota. A more comprehensive review of the nuances of current antibiotic treatment regimens can be found in two review papers by Muzny et al. (42, 43).

There is a debate in the field as to whether BV can be transmitted sexually via male or female partners; however, studies have shown that treating male partners with antibiotics does not affect bacterial vaginosis reoccurrence in female partners (44–46). No studies have evaluated treatment of female partners in female-female partnerships.

Antibiotic resistance and biofilm persistence are other proposed reasons for long-term treatment failure. One study found that out of 50 strains of Gardnerella vaginalis, the majority were resistant to both metronidazole and clindamycin (47). Another study found increased antimicrobial resistance to clindamycin among anaerobic isolates following previous treatment (48). Although there is a paucity of data, a recent review discusses the studies that have attempted to examine antibiotic resistance in BV (49). In an analysis of available in vivo data, they indicate there is increasingly convincing evidence of antimicrobial resistance in BV and a need to address this in clinical management (49). Persistent polymicrobial biofilm, which has been more often identified in people with recurrent BV compared to healthy people or those with a single episode, may play a part in antimicrobial resistance (50). Bacterial biofilm reduces antimicrobial penetrance and even after clinically successful bacterial vaginosis antibiotic therapy, biofilm persists (51).

Failure of antimicrobial Lactobacillus to recolonize the vagina following antibiotic therapy may be another reason for high BV recurrence. Among the Lactobacillus species most commonly found in the vagina, Lactobacillus crispatus is most correlated with a stable, lactobacilli-rich vaginal microbiome, while Lactobacillus iners correlates with vaginal microbiome instability (52, 53). Although antibiotic therapy reduces the quantity of Gardnerella vaginalis and other BV-associated species, the post-antibiotic treatment microbiota are usually dominated by L. iners rather than the species considered more beneficial (L. crispatus, L. jensenii) (54, 55). The failure to restore a non-iners Lactobacillus rich microbial community is a possible reason that antibiotics have failed to provide a long-term cure to recurrent BV.

Probiotics are live microorganisms that can be ingested through diet or supplements, or can be administered vaginally. Probiotics containing Lactobacillus are often used and marketed for the management of BV and may be beneficial in preventing recurrent BV through recolonization of the vaginal microbiota. Lactobacillus species have been shown to have antimicrobial effects against BV-associated species (53, 56, 57). Their use has been studied as both a treatment for BV as well as to prevent recurrence of BV after antibiotic therapy.

Studies of probiotics vary widely in species included in the product, study methodology, and final outcomes. The majority of studies used species of Lactobacillus that are prominent in the gut, not vagina (58). A wide variety of Lactobacillus strains exist, and their abundance differs between the gut and vagina (59, 60). Lactobacillus crispatus, L. iners, L. gasseri and L. jensenii are the species most commonly found in the vaginal tract (60, 61). Even among these strains, there is variability, with L. crispatus associated with a protective effect on vaginal health while L. iners is associated with a more unstable vaginal microbiome (52, 53). Despite this wide variability in environmental abundance and effect of strains, the majority of oral probiotics marketed for vaginal health contain Lactobacillus strains that are more commonly found in the gut than vagina (58), and very few contain L. crispatus.

The mechanism of action of oral probiotics, which are more commonly used, is unknown. It is possible that oral probiotics may reach the vaginal microbiome through the gastrointestinal tract. Two studies have demonstrated that bacterial species may be shared between intestinal and vaginal tracts (62, 63) and a cross-sectional study found that co-colonization of the rectum and vagina by hydrogen peroxide-producing lactobacilli was associated with lower prevalence of BV (63). A randomized controlled trial (N = 544) found that people with BV taking oral probiotics experienced a higher rate of restitution to Lactobacillus-rich vaginal microbiota at six weeks than in the placebo group (61.5% vs. 26.9%) (28). This research did not compare the effect of oral probiotics to existing antibiotic therapies. A comprehensive systemic review assessed randomized control trials using oral and vaginal probiotics for BV treatment (64). They identified four trials meeting their inclusion criteria and found no conclusive evidence that probiotics are comparable to or enhance the effectiveness of antibiotics. They did report a suggestible beneficial outcome of combined use of probiotics and antibiotics. Three out of the four identified studies used vaginal, rather than oral, probiotics.

Unlike oral probiotics, vaginal probiotics have the advantage of direct administration. Many trials are underpowered to determine whether probiotics are equivalent to existing therapies. Even among five randomized controlled trials that include more than 80 participants (and thus, approach reasonable power), results vary. Two placebo-controlled studies comparing antibiotic therapy and antibiotics plus vaginal probiotics found comparable cure rates (29) and recurrence (30) of BV between the two arms. Another study (N = 100) found that, when administered following antibiotic therapy, vaginal probiotics did not significantly impact BV cure rate, but they did prolong time without BV recurrence (64.9% vs. 46.2%) (31). Similar results were found in a study (N = 115) examining the effect of probiotics vs. antibiotic treatment; the probiotic arm had a higher 30-day cure rate than the antibiotic arm (96% vs. 70%), and among clinically cured participants, the probiotic arm had a lower BV recurrence rate (32). Finally, a randomized controlled trial (N = 190) demonstrated that vaginal probiotics significantly improved vaginal microbiota restoration following antibiotic treatment (25)—an outcome associated with decreased risk for BV recurrence. Even among these large-scale randomized controlled trials, the effectiveness of probiotics remains inconclusive. This is likely due to the variability of Lactobacillus species used across studies.

Two randomized studies have examined the effect of L. crispatus on BV recurrence after antibiotic treatment. In a phase III randomized clinical trial (N = 98), women with recurrent BV previously treated with metronidazole were given two treatments of vaginally administered L. crispatus, also known as Physioflor (34). The administration of L. crispatus significantly reduced the incidence of BV recurrence (20%) compared to those in the placebo group (41%). Of note, this study had a considerable amount of missing data, with only 78 participants' data included in their analysis, which introduces significant bias. A more robust, phase IIb randomized, placebo-controlled study examined the role of an intravaginally applied L. crispatus live biotherapeutic product, also known as Lactin-V, in managing recurrent BV among 228 women (33). Lactin-V was administered to women within 48 h of finishing a course of metronidazole, daily for 5 days and then twice weekly for 10 weeks. They found that at 12 weeks, women administered Lactin-V had a significantly lower incidence of BV recurrence (30%) than those who received placebo (45%). A secondary outcome demonstrated that at 24 weeks after antibiotic treatment, L. crispatus was detected in 48% of women who had received Lactin-V and 2% of women who received placebo. This well conducted study demonstrated that among women with recurrent BV, the vaginal administration of L. crispatus significantly reduces BV recurrence (33).

There is insufficient evidence to recommend commercially available probiotics at this time.

Vaginal microbiome transplantation (VMT) is a novel therapeutic option currently under investigation for prevention of recurrent BV. In VMT, women receive vaginal fluid collected from healthy donors. Similar to fecal microbiome transplantation, which can successfully treat recurrent C. difficile infections (65), VMT introduces an exogenous bacterial community to help restore eubiosis. Unlike probiotics, which introduce isolated species of bacteria into the vaginal microbiota, VMT transfers a whole microbiome.

A 2019 case series was the first to assess the effectiveness of VMT (23). The study enrolled five women with recurrent BV who had previously undergone multiple antibiotic regimens. Following an intravaginal antibiotic treatment, the women received transplanted vaginal fluids from donors. Two out of the five women had full remission of BV after one transplant, and two more after multiple transplants, for the duration of follow up (5–21 months) with no adverse effects. The fifth woman had partial remission. This study demonstrated that VMT can change the composition of vaginal microbiota. The four women for whom VMT was successful had vaginal microbiota dominated by L. crispatus for the duration of follow up. L. gasseri dominated the microbiota of the patient with unsuccessful VMT. This finding supports the hypothesis that L. crispatus may be the most beneficial species of Lactobacillus for restoring healthy vaginal microbiota.

This is a promising outcome, suggestive that VMT has potential to restore healthy vaginal microbiota and treat recurrent BV. However, there was no control group and some of the women required multiple VMTs to achieve full remission. Additionally, donors must be screened appropriately and thoroughly to minimize potential risks to recipients. Further research is needed before this approach can be adopted clinically. At the time of this review, per clinicaltrials.gov there are two ongoing randomized trials of VMT, one in Israel and one in the United States. This procedure should not be performed outside of clinical trials.

Lactobacilli produce lactic acid, which helps maintain a low, acidic, vaginal pH (66). BV-associated anaerobic bacteria grow poorly in acidic environments, which has led many to hypothesize that lactic acid could provide protective effects against vaginal infections (67). BV is characterized by loss of lactobacilli and the lactic acid they produce, leading to an increase in vaginal pH, which may allow the anaerobic overgrowth that is the hallmark of this syndrome (68, 69). The administration of lactic acid, and other pH modulators, therefore, may hold potential in the management of BV (2).

Studies of pH modulating agents including lactic acid, mucoadhesive vaginal gel, and acetic acid in women with BV have mostly been small, with sample sizes of less than 100. Results from these studies have varied: effects range from no benefit (70, 71) to providing a clinical cure (72, 73). A literature review concluded that lactic-acid containing agents do not significantly affect vaginal microbiota (74). A randomized controlled trial (N = 409) which compared lactic acid gel to oral metronidazole for clinical cure of BV found that lactic acid was less effective than metronidazole at resolving BV symptoms (47% vs. 70%) in a two-week span. For those in the study whose symptoms cleared in the initial 2 weeks, both lactic acid and metronidazole had correspondingly high recurrence rates at 70% and 71% (24).

Vaginally administered vitamin C has also been demonstrated to decrease vaginal pH (75–77). When used after antibiotic treatment, vitamin C helps maintain an acidic vaginal environment, allowing more time for restoration of healthy vaginal microbiota (75). A randomized controlled trial (N = 277) demonstrated that vitamin C, applied for 6 days intravaginally, had a higher clinical cure rate for BV than placebo (44% vs. 22%) (78). A subsequent randomized controlled trial (N = 142) found that intravaginal vitamin C significantly decreased BV recurrence rate for up to 6 months compared to placebo (16% vs. 32%) (79). However, in this trial, there was no difference in vaginal pH between people who did vs. did not receive vaginal Vitamin C during treatment, suggesting that any mechanism of effect was not related to lowering of pH. Of note, the formulation used in these studies is a silicone-coated tablet that slowly releases the ascorbic acid, which is not available in the United States.

There is no reliable evidence that pH modulators alone are effective at treating BV or that they are more effective than existing antibiotic treatments. In vitro experiments continue to provide biologic plausibility for elevated pH as a permissive mechanism to allow growth of BV-associated organisms, but it is not yet clear whether a pH altering product can counter that in vivo. Thus, pH modulating products should not be recommended at this time.

One hypothesized reason for high rates of recurrence of BV is the presence of a polymicrobial biofilm (80–85). Biofilms are composed of microbial cells and an extracellular matrix that can provide bacterial protection, and are generally associated with decreased efficacy of antimicrobial agents (86). Fluorescence in-situ hybridization (FISH) studies using vaginal biopsies demonstrate an adherent layer of bacteria in many people with BV (84). However, there is still some debate about whether this is a true biofilm, as no studies have yet demonstrated the presence of an extracellular matrix.

There are a variety of agents that are purported to target biofilms. Thymbra capitata, an essential oil, has antimicrobial effects on Gardnerella spp. (87) and BV-associated polymicrobial biofilms in vitro (88). Although not yet studied in vivo, it may hold promise in BV management. Dequalinium chloride (DQC) is a quaternary ammonium compound that has antimicrobial activity against vaginal pathogens such as Gardnerella (89, 90) and it can partially disrupt in vitro Gardnerella biofilms on plastic culture plates (91). A randomized non-inferiority trial (N = 321) demonstrated DQC can also successfully treat BV clinically, with cure rates similar to vaginally administered clindamycin 25 days after treatment (74.8%vs. 74.8%) (92), however it is not available commercially in the United States.

PM-477, a genetically engineered endolysin, is asserted to destroy Gardnerella biofilms in vitro. Preclinical data demonstrates that PM-477 effectively inhibits Gardnerella biofilm growth and that it is not prone to resistance development, unlike metronidazole and clindamycin (93). PM-477 may also be effective at disrupting polymicrobial biofilms which include organisms other than Gardnerella (94). This agent has not yet been studied in vivo.

Boric acid is a chemical that, while not FDA-approved, is commonly used by women attempting to manage persistent BV (26). In vitro it inhibits biofilm formation by Staphylococcus aureus and Pseudomonas auruginosa (95). However, it did not decrease the viability of S. aureus in an existing biofilm (96). A retrospective chart review examined clinical use of boric acid for recurrent vulvovaginal candidiasis and BV in 272 patients. They found that long term use of boric acid was well tolerated, had high reported satisfaction by patients, and few adverse effects (97). A recent study (N = 105) found that boric acid, used in conjunction with antibiotic therapies, resulted in a 69% six month cure for women with recurrent BV (98). A randomized trial of two formulations of TOL-463, a boric-acid based therapy, in 106 participants demonstrated 50%–59% efficacy in early clinical cure (9–12 days) of BV (99). These results are promising and, if studied in the setting of recurrent BV, may have potential in clinical management. Despite its relatively widespread use in BV management, there is limited research on boric acid in the treatment of vaginitis and no studies have examined boric acid alone in the setting of recurrent BV. Additionally, boric acid is used as a pesticide, and although the EPA has found that it is not a carcinogen, the long-term safety of its topical use in humans is unexplored (100).

Astodrimer Sodium, also referred to as Astodrimer 1% Vaginal gel, is a polyanionic dendrimer that prevents formation of bacterial biofilms through blocking bacterial adhesion (27). Randomized, placebo-controlled studies have demonstrated greater clinical cure rates for BV compared to placebo (46.2% vs. 11.5%) (101) and comparable to current antibiotic treatments (102). A recent randomized control trial (N = 864) demonstrated that Astodrimer, when applied every other day for 16 weeks following antibiotic therapy, was associated with a 20% reduction in recurrent BV compared to placebo during 16-week follow up (27). This product is not commercially available in the United States, but is sold over the counter in the United Kingdom (Betafem), Europe (Betadine BV) and also in Australia, New Zealand, Southeast Asia and South Africa.

Of the products discussed, Astodrimer and dequalinium chloride have the most evidence of benefit in BV, however neither are available in the United States.

It is well known that smoking has adverse effects on the body, including increased risk for infections (103). A cohort study of 956 women found smoking to be a significant risk factor for BV (adjusted odds ratio of 3.0) (41) and various other studies have found smoking to be an independent factor related to BV incidence (7, 104, 105). A small cross sectional study (N = 20) found that vaginal microbial communities of smokers were more likely to be Lactobacillus depleted while nonsmokers were more likely to have L. crispatus dominated microbiota (106). Another study identified that women who smoke have higher concentrations of biogenic amines, which may promote non-Lactobacillus species and increase vaginal pH (107). Smoking is a modifiable risk factor of BV and is an important lifestyle change to consider in its management (Figure 1).

Both hormonal and non-hormonal contraceptives may play a role in BV occurrence. A large scale cross sectional study (N = 16,314) found that BV is more common in women using the non-hormonal copper intrauterine device (IUD) (14.8%) than women with hormonal IUDs (9.7%) and women who are not IUD users (11.1%) (109). Another large study (N = 2,585), as a secondary analysis, found that copper IUDs increased women's risk of BV 1.28 fold compared to other non-hormonal methods (110). A well-powered systematic review and meta-analysis found that hormonal contraceptive use, regardless of type, is associated with reduced prevalence, incidence, and recurrence of BV (40).

Various studies have examined condom use in relation to BV occurrence and prevalence. A systematic review and meta-analysis found that condom use was protective against BV, with an estimated relative risk of 0.8 (39). A case-crossover study among 871 women found that consistent condom use was protective against BV (111). Existing research suggests that copper IUDs may increase risk of BV, while condoms and hormonal forms of contraception may decrease risk of BV (Figure 1).

Contraceptive choice is very individual, however if a person with recurrent BV is interested in a hormonal contraceptive method rather than a copper IUD, this may reduce the risk for BV. Additionally, using condoms—at least during antibiotic therapy for BV—may be beneficial.

In today's health care climate, many now turn to the internet for answers to their medical questions. Online forums and articles describe several “home remedies” to cure BV. In the following section we discuss several remedies often mentioned online (Table 2). Unfortunately, there are few rigorous studies on these therapies, making it difficult to draw conclusions about their potential efficacy.

Bacterial vaginosis is a common medical diagnosis that significantly impacts women's quality of life and reproductive health. Antibiotics, the only approved treatment for BV, have high recurrence rates, negative side effects, and after antibiotic treatment, there is limited recolonization of the vaginal microbiota with beneficial Lactobacillus species. Despite high prevalence of BV worldwide and the inability of antibiotics to provide a long-term cure, few effective alternative treatment options exist. There are various studies underway attempting to identify novel approaches, with possible solutions ranging from diet and lifestyle changes to biofilm disruption, pH modulation and vaginal microbiome transplantation. Still, much of this research is either underpowered or concentrated on in vitro models. Considering the lack of science-based answers, clinicians and patients alike are attempting to find solutions on their own. It is important that medical research continues to prioritize BV management and that both clinicians and patients have the resources to be informed on the safety and efficacy of the products that many are already using.