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. Author manuscript; available in PMC: 2026 Feb 1.
Published in final edited form as: Curr Opin Infect Dis. 2025 Nov 27;39(1):67–74. doi: 10.1097/QCO.0000000000001172

Advances in treating bacterial vaginosis: recognizing sexual transmission and pipeline of therapies

Eun Sol Kim 1,*, Andreea Waltmann 2,3,*, Joseph A Duncan 2,3,4,5, Indriati Hood-Pishchany 1,6
PMCID: PMC12839515  NIHMSID: NIHMS2139634  PMID: 41452092

Abstract

Purpose of review:

Bacterial vaginosis (BV) is a common vaginal dysbiosis linked to increased risk of HIV, other STIs, and adverse obstetric outcomes. Standard antibiotic therapy often induces symptom remission, but recurrence rates exceed 50% within six months. The purpose of this review is to discuss recent clinical trials that demonstrate improved outcomes when compared to treatment according to current management guidelines and outline potential future therapies.

Recent findings:

Strong evidence supporting transmission of bacteria associated with the dysbiotic state of BV between sexual partners has accumulated over time. A recent clinical study (StepUp) demonstrated overwhelming evidence that treating male partners with combined oral and topical antibiotics significantly reduces BV recurrence in their female partners, highlighting the role of sexual transmission. Recent guideline updates reflect these advances: the American College of Obstetricians and Gynecologists now advises partner therapy for recurrent BV, signaling a shift toward partner-inclusive management strategies. In parallel, live biotherapeutic products (LBPs) and vaginal microbiota transplantation (VMT) show promise in restoring a stable, Lactobacillus crispatus–dominant microbiome. Novel approaches targeting metabolic vulnerabilities of BV-associated bacteria, such as L. iners, and non-antibiotic agents like metastable iron sulfides are in early development.

Summary:

Several advances in managing recurrent BV have shown promise in improving care of this condition. They represent a shift toward microbiome-informed, durable, and woman-controlled therapies. Strategies combining these along with continued development of promising novel approaches to treatment will be needed to optimize care of patients and reduce global BV burden.

Keywords: bacterial vaginosis, male partner treatment, sexual transmission, recurrence, reinfection prevention, vaginal microbiome, penile microbiome, Lactobacillus

Introduction

Bacterial vaginosis (BV) is a highly prevalent vaginal microbiome disorder linked to adverse sexual and reproductive health outcomes [1]. Despite standard antimicrobial treatment, recurrence rates exceed 50% within six months [2], underscoring the need to better understand the drivers of recurrence. An evolving model of BV is emerging in which treatment failure and recurrence are driven not by failure to eradicate BV-associated bacteria, but by reintroduction from sexual partners as well as failure to stably restore a healthy vaginal microbial community. While a Lactobacillus-dominated microbiome has long been understood as an optimal health state, there is mounting evidence that an L. iners-dominated microbiome, which predominates after BV treatment [3], represents an intermediate, sub-optimal state. L. crispatus is emerging as the predominant health-associated species across populations. While L. crispatus-dominant communities are often highly skewed, with a relative abundance of 90% or greater, there is an increasing appreciation that these are nonetheless polymorphic communities, where the coexistence of multiple L. crispatus strains or other low-abundance taxa may contribute to community stability [4,5]. This review highlights recent advances in the understanding of sexual transmission in BV recurrence, as well as novel therapeutic directions prompted by the evolving ecological model of BV.

Sexual transmission in BV

Evidence for sexual transmission before the StepUp Trial

Before the landmark StepUp trial [6], evidence from epidemiological, clinical, and microbiological studies implicated sexual activity as a primary driver of BV acquisition and recurrence. The earliest evidence suggesting the sexual transmissibility of the condition, initially termed “Haemophilus vaginalis vaginitis,” focused heavily on male partners. Studies performed in the 1950s by Gardner and Dukes isolated the vaginitis-associated bacteria from the urethras of 96% of the male partners of affected women [7].

In epidemiological studies conducted over time, BV recurrence has been linked to ongoing exposure to a regular sexual partner. For example, a randomized male circumcision trial in Rakai, Uganda, showed that male circumcision reduced the risk of BV in female partners by 18% (adjusted PRR 0.82) and severe BV by 69% (PRR 0.31) [8]. Microbiological studies have established that the male genital tract serves as a reservoir for BV-associated bacteria, with studies confirming that the highly diverse and heterogeneous pre-circumcision penile coronal sulcus microbiota frequently harbored bacteria associated with BV, and that circumcision significantly reduced their load and prevalence [9–12]. Furthermore, specific bacteria, notably Leptotrichia/Sneathia spp., were significantly associated with idiopathic non-gonococcal urethritis (NGU) in heterosexual men and their presence correlated with a history of sexually transmitted pathogens, supporting the notion of sexual acquisition [13]. Crucially, deep sequencing studies confirmed direct transmission through concordance of BV-associated organisms between sexual partners, including strain-level concordance [9–11]. Despite the wealth of data supporting sexual transmission of BV, before 2023, multiple clinical trials failed to provide convincing evidence that partner treatment could reduce BV recurrence [2,14].

The StepUp Trial

The StepUp randomized controlled trial (RCT) directly addressed the limitations of previous studies by targeting both internal (urethral) and external (cutaneous) reservoirs of BV-associated bacteria in men [6]. The open-label, multicenter trial recruited couples in which the woman had symptomatic BV (defined by Amsel criteria and a Nugent score of 4 to 10) and was in a monogamous relationship with a male partner. Women in both arms received standard first-line antimicrobial treatment, typically oral metronidazole (400 mg twice daily for 7 days), or alternative intravaginal treatments if oral metronidazole was contraindicated. Male partners in the intervention group received concurrent combined oral and topical antimicrobial treatment for 7 days: oral metronidazole (400 mg tablets twice daily) plus topical 2% clindamycin cream applied to the penile skin (twice daily). Male partners in the control group received no treatment. The trial was stopped early by the independent data and safety monitoring board at an interim analysis in October 2023 due to the inferiority of standard care (treating the woman only). The primary efficacy outcome was recurrence of BV within 12 weeks. The addition of combined oral and topical antimicrobial therapy for male partners significantly lowered the rate of BV recurrence within 12 weeks compared to the control group (35% vs 63%, respectively). The hazard ratio was 0.37 (95% CI, 0.22–0.61; p < 0.0001), demonstrating substantial efficacy for partner treatment. By successfully targeting BV-associated organisms in both the urethra and on the penile skin, the trial provided definitive evidence that the male genital tract serves as a significant reservoir of BV bacteria, causing recurrence.

Implications and Challenges

BV profoundly affects women’s daily lives, causing odor, discharge, and discomfort, leading to shame, stigma, and diminished quality of life. BV is also associated with other serious health consequences, such as an increased risk of HIV and other STI acquisition, and adverse obstetric outcomes. The success of partner treatment has the potential to shift the perspective of BV away from being viewed exclusively as a “women’s condition”. Involving partners can ensure BV becomes a shared responsibility and may help reduce stigma and broaden funding opportunities.

Reflecting this paradigm shift, the American College of Obstetricians and Gynecologists (ACOG) issued updated guidance in October 2025 [15] recommending concurrent partner therapy for recurrent BV, using oral metronidazole and topical clindamycin for male partners. This marks the first formal endorsement of partner treatment in U.S. guidelines and underscores BV’s recognition as sexually transmissible, though at this time these medications are not labeled for this use by US FDA. However, evidence for benefit in same-sex partnerships is lacking. Further, although there are demonstrable benefits to circumcision for male partners, including reduced risk of HIV and other STI acquisition, there is no strong evidence that partner treatment for BV-associated bacteria in men provides a direct health benefit. This may limit the use of strategies like expedited partner therapy, contact tracing, or even partner treatment referral that have been successfully deployed for traditional bacterial STI. Global applicability and integration into routine care will require further research and stakeholder engagement.

Definitional Tensions in the Classification of Bacterial Vaginosis as an STI

BV has historically been excluded from the conventional classification of STIs. The fundamental debate surrounding BV’s classification stems from its classification as a dysbiosis caused by a consortium of microbes, rather than an infection caused by a single, universally present pathogen [1]. Despite robust epidemiological and molecular evidence demonstrating the occurrence and clinical relevance of sexual exchange of BV-associated bacteria, this distinction has persisted. The World Health Organization continues to classify BV as one of the most common causes of abnormal vaginal discharge that is not considered an STI [16]. Historically, BV was excluded from STI definitions because classification emphasized etiology rather than transmission, although exchange of BV-associated bacteria between partners is well documented. If future studies define a consistent, synergistic consortium capable of both transmission and disease induction, BV would fulfill the functional criteria of an STI. In that sense, BV may exemplify polymicrobial pathogenesis [17], where disease arises from interactions within a microbial consortium, akin to periodontitis. The current terminology may therefore be scientifically inadequate to describe a sexually transmissible condition with major public health implications.

Therapeutic pipeline for bacterial vaginosis

Despite the recent breakthrough in heterosexual partner treatment, recurrence remained high in the StepUp trial at 35%, and it is not yet known whether this approach achieves long-term remission [6]. Moreover, partner treatment may not be feasible or effective in all settings, underscoring the challenges of long-term management and prevention of (recurrent) BV. Many adjunctive and alternative therapies, including boric acid, dequalinium chloride, and astodrimer sodium, among others, have been used clinically or experimentally with mixed results [18]. This review highlights a few recent advances, as these therapies have been comprehensively reviewed elsewhere [18]. Although major gaps persist, advances in understanding the ecology of the vaginal microbiome and the critical role of lactobacilli, and especially L. crispatus, in vaginal health are spurring novel therapeutic strategies. Durable, woman-controlled, and specific therapies should both eradicate BV-associated bacteria and re-establish a stable, non-L. iners, Lactobacillus-dominant community. Current approved therapies do not address microbiome restoration, but ongoing clinical trials of live biotherapeutic products and vaginal microbiota transplantation aim to address this gap and reduce recurrence [19,20]. In parallel, molecular microbiology approaches are identifying new targets for ecological engineering [21–24].

Live Biotherapeutic Products (LBPs)

Probiotics have gained increasing popularity, and while most products are marketed for gut health, there is a relatively long history of products marketed for vaginal or genitourinary health [25,26]. However, probiotics are not classified as drugs and make up part of a lightly regulated industry of health supplements. In contrast, with growing appreciation of the role of the microbiome in health, the FDA introduced a new class of biologic drugs in 2012 termed live biotherapeutic products (LBPs). An LBP is a product that “1) contains live microorganisms, such as bacteria; 2) is applicable to the prevention, treatment, or cure of a disease or condition of human beings; and 3) is not a vaccine” [27].

Lactobacilli dominate the healthy vagina, though the precise mechanisms underlying their beneficial effects remain unclear. L. crispatus is the most strongly associated with health across populations. The first LBP evaluated for vaginal health was developed using a strain of L. crispatus, CTV-05 (LACTIN-V), and intended for the prevention of recurrent BV [19,28–30]. Women receiving LACTIN-V had lower BV recurrence after 11 weeks of daily therapy (30% vs 45%) [19]. A follow-up phase 2 trial in young South African women at high risk of HIV acquisition showed that LACTIN-V treatment increased L. crispatus colonization and suppressed endocervical HIV-target cells and genital tract inflammation biomarkers associated with HIV susceptibility [29]. The LACTIN-V group achieved higher rates of L. crispatus dominance (41% vs 0% in placebo, p = 0.0088) and attenuated the expansion of activated endocervical CD4+ HIV target cells (median change 1.06 vs 1.89; p = 0.016). Together, these findings suggest that beyond preventing BV, LACTIN-V may offer protective benefits against STI/HIV risk, although further studies are needed to confirm direct effects on HIV incidence.

With growing evidence that L. crispatus-dominant communities are composed of multiple strains, the Vaginal live Biotherapeutic RANdomized Trial (VIBRANT) evaluated two novel, multi-strain L. crispatus LBPs [31]. Both formulations had excellent safety and tolerability. Across all active arms, at least one strain was detected during the first 5 weeks of follow-up, and 49% of participants with early colonization remained colonized with LBP strains at 12 weeks, despite receiving only short (3- or 7-day) initial treatments [31]. Taken together, the emerging evidence supports LBPs as a promising adjunct for BV management, though their current use is limited to clinical trials because these products are not currently approved for use to treat BV by US FDA.

Vaginal Microbiome Transplantation (VMT)

Building on the recognition that health-associated, Lactobacillus-dominant microbiota function as true communities, vaginal microbiome transplantation (VMT) has emerged as an approach to transfer an entire microbial ecosystem from a healthy donor. Adapted from fecal microbiome transplantation in the gut, the goal is to replace a disrupted or suboptimal vaginal microbiome by transferring vaginal fluid from a healthy donor with a Lactobacillus-dominant microbiome [32,33].

The first proof-of-concept clinical trial demonstrated that VMT achieved complete restoration of a Lactobacillus-dominant vaginal microbiota in four out of five women with antibiotic-refractory recurrent BV, with long-term maintenance and no adverse events reported [32]. Wrønding et al. (2024) reported engraftment in 50% of recipients following pretreatment with antiseptic, and the women who achieved conversion maintained eubiosis for several months [34]. More recently, a striking case described donor-derived L. crispatus that not only engrafted successfully but also remained stable throughout pregnancy, culminating in a full-term delivery after the recipient had experienced multiple prior pregnancy losses [35]. A recent pilot Phase 1 randomized trial demonstrated that VMT after antibiotic treatment led to the establishment of a L. crispatus-dominance in 75% of recipients at four weeks post-transplantation [36].

These studies highlight the potential of VMT, but several important limitations must be addressed before VMT can become a broadly adopted therapy. These include standardization for donor selection criteria, processing and storage of donated fluid, dosing schedule, and administration route [33]. Furthermore, variability in engraftment among recipients highlights a need to better define the factors that drive clinical outcomes. Larger RCTs with extended follow-up, harmonized safety protocols, quantitative engraftment and durability metrics, and clarity on patient selection will strengthen confidence in VMT’s efficacy and safety, which will be critical to address.

Antibiotic-sparing approaches to reduce BV-associated bacteria

Metabolic and ecological investigations are uncovering microbial metabolic interactions that shape vaginal community stability. Among these, several emerging strategies target dysbiosis through distinct chemical, metabolic, and biological mechanisms. Recent studies have introduced metastable iron sulfides (mFeS), particularly D-Fe₃S₄, as promising non-antibiotic agents against BV, with potent activity against metronidazole-resistant Gardnerella vaginalis, one of the key species associated with BV [21,37]. These agents act via multiple mechanisms, including metabolic disruption and inhibition of biofilm formation [37].

Bacteriophage endolysins are under investigation as antibiotic alternatives due to their taxonomic selectivity, efficient biofilm penetration, and high barrier to resistance. An engineered, domain-swapped endolysin derived from a Gardnerella prophage gene, PM-477 and the single amino acid variant derivative BNT331-EL, both developed by BioNTech, exhibit genus-selective killing of Gardnerella strains [22]. BNT331-EL has also demonstrated efficacy in disrupting Gardnerella-dominant biofilm in ex vivo vaginal samples [38]. These findings underscore the potential of phage-derived precision antimicrobials as a targeted strategy for managing BV.

Species-specific modulation of the metabolic environment targeting L. iners

Frequent BV recurrence has been linked to shifts in the vaginal microbiota toward L. iners dominance [3]. Unlike other vaginal Lactobacillus species, L. iners frequently coexists with Gardnerella and often persists during dysbiosis and after antibiotic treatment, suggesting it may represent a transitional, less protective community state [3,39]. L. iners expression of cytolysins, such as inerolysin, has further raised concerns about its potential contribution to epithelial disruption and BV recurrence [40]. Recent work has highlighted metabolic specialization in L. iners that differentiates this species from other vaginal Lactobacilli, potentially offering therapeutic targets to disrupt L. iners-dominated microbiota in favor of L. crispatus [39]. L. iners occupies a metabolically narrow ecological niche, showing both species and strain-specific nutrient dependencies[23,24,41]. For example, L. iners is a cysteine auxotroph, distinguishing it from other vaginal Lactobacillus species [24]. Like other vaginal Lactobacilli, it is a fatty acid auxotroph, but it is unique in its lack of key genes for detoxifying or exporting excess oleic acid. In synthetic vaginal communities, combining oleic acid with metronidazole treatment promotes L. crispatus expansion [23]. Leveraging these metabolic constraints may offer a therapeutic strategy to suppress L. iners growth while promoting L. crispatus dominance, thereby supporting durable restoration of vaginal health. Together, these advances redefine L. iners as a BV-promoting and potentially targetable species within the vaginal ecosystem due to its metabolic specialization.

Therapeutic outlook and research needs

Recent advances are reshaping therapeutic strategies to restore and sustain a healthy vaginal microbiome resistant to recurrent BV. Moving beyond antibiotics and probiotics, new microbiome-informed and metabolically targeted approaches aim to re-establish Lactobacillus dominance while preserving ecological balance. While LBPs offer defined, strain-based interventions, VMT provides a broader community-level approach. Additional trials are needed in diverse global populations (including countries with a high burden of BV and populations such as LGBT-QIA+ individuals who have a vagina) and to evaluate different partner treatment regimens globally. Integrated research combining analysis of the metabolome, proteome, virome, and host-microbiome interactions is necessary to fully understand BV pathophysiology and understand which microbial and functional interactions drive beneficial effects.

Mechanistic insights are guiding the development of microbiota-sparing treatments. Recognition of L. iners as a metabolically restricted but resilient species highlights the need for species-specific modulation strategies. Finally, a critical barrier to both mechanistic understanding and therapeutic development is the lack of robust, well-validated models for empiric studies and preclinical testing. Recent developments in organotypic models are promising, but incorporation of diverse, representative microbial consortia into these models has been limited to date [42]. Continued clinical and translational efforts will be essential to transform these advances into durable, safe, and accessible solutions for women’s health.

Conclusion

BV remains a highly prevalent condition with substantial sexual and reproductive health consequences, yet current therapies are insufficient to prevent frequent recurrence. Accumulating epidemiologic, microbiologic, and now randomized trial evidence demonstrates that sexual exchange of BV-associated bacteria plays a central role in recurrence, prompting updated guidelines that incorporate partner treatment. At the same time, an ecological understanding of BV highlights that durable remission depends not only on suppression of BV-associated bacteria but also on restoration of a stable Lactobacillus-dominant community, particularly L. crispatus. These insights fueled the development of new therapeutic strategies, including partner treatment, live biotherapeutic products (LBPs), vaginal microbiota transplantation (VMT), precision antimicrobials, and metabolically targeted approaches designed to promote resilient microbial ecosystems (Figure 1). Nonetheless, important questions remain, including heterogeneous treatment response and limited understanding of strain-level interactions. Continued mechanistic studies and clinical trials will be essential for achieving sustained BV cure and require integrating partner-inclusive care with strategies that restore and maintain a protective vaginal microbiome.

Figure 1.

Figure 1.

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Therapeutic development pipeline for bacterial vaginosis (BV), integrating current and emerging strategies informed by ecological and transmission-based models of BV pathogenesis. Partner treatment, supported by the StepUp trial, targets reinoculation from male genital reservoirs and has demonstrated efficacy in reducing recurrence. Live Biotherapeutic Products (LBPs), including single- and multi-strain Lactobacillus crispatus formulations, aim to restore a stable, health-associated vaginal microbiota. Vaginal Microbiota Transplantation (VMT) offers a community-level approach to reestablish eubiosis, though standardization and engraftment variability remain challenges. Novel metabolic and ecological interventions, including species-specific targeting of L. iners via cysteine deprivation and oleic acid sensitivity, and non-antibiotic agents like metastable iron sulfides, represent early-phase strategies to suppress BV-associated bacteria while preserving beneficial lactobacilli. Together, these approaches reflect a shift toward microbiome-informed, durable, and woman-controlled therapies.

Key Points.

  • Bacterial vaginosis (BV) is a condition characterized by disruption of the normal vaginal microbiota, marked by loss of Lactobacillus-dominant flora and overgrowth of a diverse polymicrobial community.

  • Antibiotic therapy for BV can temporarily reduce symptoms, but recurrence remains high, affecting more than half of women within six months.

  • Sexual transmission contributes to recurrence; partner treatment with systemic and topical antibiotics significantly lowers reinfection risk. ACOG now recommends partner treatment for recurrent BV, aligning clinical practice with emerging evidence.

  • Unlike the use of antimicrobials alone, microbiome-based strategies, including live biotherapeutic products derived from L. crispatus strains, or transplanted vaginal microbiota, can enhance restoration of protective, stable vaginal microbiota and reduce recurrence.

  • The current early therapeutic pipeline for BV therapy includes novel metabolic therapies directed against BV-associated bacteria and L. iners.

Financial Support and Sponsorship

The authors were supported by the National Institutes of Health, National Center for Advancing Translational Sciences, and National Institute of Allergy and Infectious Disease through Grant Award Number K12TR004416 and R01AI176997 as well as the Bill and Melinda Gates Foundation through grant INV-072197. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Bill and Melinda Gates Foundation.

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