1. Introduction

Vaginitis is frequently cited as the most common gynecological diagnosis in primary care, affecting most women at least once in their lifetime [1, 2]. It is associated with vaginal symptoms such as pruritis, irritation, soreness, and variable discharge [3]. Vaginitis is mostly caused by microbial infections, the most common being bacterial vaginosis (BV) which accounts for 40–50% of vaginitis cases, while vulvovaginal candidiasis (VVC) are found in 20–25% of cases and trichomoniasis vaginalis (TV) accounts for 15–20% of cases [3].

Vulvovaginal candidiasis affects up to 75% of women [4]. It is commonly caused by Candida (C.) albicans (up to 90%) but an increase in non-albicans Candida (NAC) species have been reported, which is often a therapeutic challenge [5, 6]. VVC is diagnosed by microscopy and cultures from symptomatic women and is often treated with topical azoles or oral fluconazole (cure 80–90%). Approximately, 5–9% of infected women will experience recurrent vulvovaginal candidiasis (RVVC) [7, 8], defined as three or more episodes within 12 months [9]. Maintenance fluconazole is often necessary in RVVC, but relapses are common with a rate of 30–50% over six months [4]. In addition, fluconazole-resistant C. albicans, which can develop under the selective pressure of prolonged fluconazole treatment [10], is an emerging problem [11].

Bacterial vaginosis is the most frequent type of vaginitis, characterized by a vaginal overgrowth of anaerobic bacteria that forms a biofilm on the epithelial cells [12]. Gram staining (Nugent score) and Amsel’s criteria are two common diagnostic methods in BV [13]. The standard treatment for BV is antibiotics such as oral metronidazole or clindamycin with a cure rate of 80–90%; however, a recurrence rate of 75–80% has been reported three to six months after treatment [14, 15].

Trichomoniasis is caused by the protozoa Trichomonas vaginalis (TV), accounting for 15–20% of vaginitis cases [16]. TV can be diagnosed microscopically, but a higher sensitivity is found in nucleic acid amplification tests (NAAT) and cultures [17]. It is treated with 5-nitroimidazoles, with cure rates of 84–100%, but reinfections are common as 17% experienced reinfection within 3 months in one study [4, 18].

An increase in resistant species or selection of NAC species in VVC is linked to excessive exposure to antimycotic drugs, and high recurrences of BV are thought to be caused by antibiotic resistance due to polymicrobial biofilm and acquired resistance genes [19]. In TV infections, resistance also plays a role with metronidazole resistance varying from 4% in the US to 17% in Papua New Guinea [20, 21].

Intravaginal boric acid (BA) is a nonpharmaceutical antiseptic agent first shown to be effective in treating mycotic vaginitis in 1974 by Swate and Weed [22]. It has been used to treat VVC, BV, and TV, especially in case of recurrences [23, 24]. Unlike antibiotics and antimycotics, BA affects a broad spectrum of biologic processes in microbes, including inhibition of NAD-dependent enzymes in mitochondria and inhibition of hyphal growth [25], and in vitro studies have recently shown BA inhibition of biofilm production in bacteria and fungus [26, 27]. One in vitro study has shown that BA is microbicidal against TV independent of pH [28]. These mechanisms make resistance development more unlikely against BA as compared to conventional therapies [25].

The emergence of resistance and selection of species with low susceptibility to conventional therapy as well as the potentially lower risk of systemic adverse effects would theoretically make BA an ideal treatment option for vaginitis.

This review aims to summarize the efficacy of BA in patients with VVC, BV, and TV, compared to conventional therapies, to investigate whether BA is superior to other treatment options or has a lower recurrence rate, and lastly to make clinical recommendations for the use of BA in acute and recurrent microbial vaginitis.

2. Methods

2.2. Inclusion and Exclusion Criteria

Inclusion criteria included randomized and nonrandomized clinical trials, observational and interventional studies, including case series and case reports assessing BA for the treatment of microbial vaginitis. Case reports and case series were included since only case reports described trichomoniasis treated with BA. Exclusion criteria included in vitro studies, animal studies, non-English language articles, reviews, guidelines, and expert opinions. Articles without a BA treatment outcome were also excluded. The reference lists were manually checked for further eligible studies. A PRISMA flow diagram (Figure 1) provides additional details of the literature search and exclusions.

3. Results

4. Discussion

BA is an old anti-infective agent which may still be useful in some situations even though it may be difficult to obtain in some countries (Table 4). BA capsules can be prescribed as a magistral formulation.

It has been found to be equally effective as fluconazole and itraconazole as monotherapy in selected studies [37–39] and significantly superior to nystatin, as well as fluconazole in C. glabrata infections [39, 43]. Fifteen articles and twelve case series/reports investigated the use of BA in VVC infections with a microbial cure rate average of 76% (range 40–100%) as compared with a 61% average (range 25–100) when using antimycotic medication (Table 2). When specifically summarizing microbial cure rates in NAC infections, BA had a microbial cure rate average of 72% (range 40–100%) [5, 36, 39–42, 44], as compared to a 56% fluconazole (range 25–89%) [5, 36, 39, 41, 44], and 54% nonfluconazole azole (range 38–100%) cure rate, respectively [5, 40, 41, 44]. Lower cure rates to antimycotic treatments were expected in NAC species, which are known to be less sensitive to azoles [4, 71].

For acute VVC and VVC due to C. albicans with mild symptoms, primarily local treatment should be administered, and for severe symptoms of VVC, oral azole antifungals should be applied [72]. However, C. albicans infections have also recently demonstrated increasing fluconazole resistance [71] which has been found to be associated with low doses of weekly fluconazole therapy (P = 0.03) [11].

In order to prevent fluconazole resistance in fluconazole susceptible Candida species or the selection of Candida species with initial fluconazole resistance (e.g., C. glabrata and C. krusei), and considering the relatively low adverse effect rate of 7.3% in treated patients as shown in this systematic review, we recommend the use of intravaginal BA treatment for recurrent infections and NAC infections (Table 5). Sobel et al. recommend vaginal application of 600 mg BA suppositories for 14 days of C. glabrata, while others recommend topical flucytosine [42]. Furthermore, topical applied treatment has a lower risk of systemic adverse events and drug-drug interaction.

BA has seemingly been used to treat BV for years [43] but only four articles were found to investigate the effect of BA in BV either in combination with nitroimidazole or in cases with a concomitant BV and VCC infections [33, 46–48]. Therefore, it is difficult to evaluate the individual effect of BA, and further studies are needed. Two studies added BA to a nitroimidazole regimen, which seemed effective when evaluating early remission rates at 30 days and 7 weeks (99 and 92%, respectively) [46, 47]. It was not possible to differentiate between relapse and reinfections in RBV. BA was also used as maintenance therapy [33] in BV patients in another study which also seemed to be beneficial to RBV patients although the only available outcome was self-reported satisfaction (77% satisfaction). An advantage of BA is also the antimycotic effect that decreased the risk of secondary VVC infections. When treatment failure on conventional therapy occurs, BA might be useful in these patients in combination with nitroimidazole. However, the current evidence is very limited.

BA for the treatment of trichomoniasis was only described in eleven individuals with 5-nitroimidazole intolerance (n = 6) or resistance (n = 5) (Table 3). Optimal treatment regimen for BA monotherapy is unclear in TV patients, but based on these case reports, it appears to require up to several months of high dose intravaginal BA to clear a TV infection. BA monotherapy was unsuccessful in one individual with a regimen of 600 mg daily for 90 days [62], while 600 mg twice daily resulted in cure in three individuals [65, 66, 68]. Thus, a dose-dependent response looks reasonable, as proposed by Thorley and Ross [24]. When bearing in mind that TV infections are normally treated with systemic antibiotics, it is apparent that a topical antiseptic agent such as BA has its limitations. However, these cases suggest BA as an alternative treatment option in rare cases of persistent TV infections due to resistance to nitroimidazole or for patients with nitroimidazole allergy or intolerance, drug-drug interactions, or other contraindications. Combinational therapy of BA and another drug could potentially prove more useful than BA monotherapy, as seven out of eight individuals described in this review were cured with a combination of BA and other drugs, but this should be further investigated.

It is noticeable that five studies and one case report mention the use of a maintenance BA therapy in patients with recurrent BV and VVC [11, 33, 35, 37, 41, 59]. Maintenance BA was equally effective as compared to oral itraconazole maintenance therapy [33] and retrospective data on maintenance use of BA in RVVC and RBV up to more than three years resulted in high patient satisfaction (77%) with few adverse events [33]. These findings indicate that BA could be beneficial as a maintenance therapy in RVVC and RBV, but more studies are needed.

BA is known for its antibacterial, antifungal, and antiviral activities and its antiseptic and astringent characteristics, poisoning is rare, and it is generally of low oral toxicity after acute oral ingestion in humans [73]. However, while it has been shown to be beneficial for multiple processes at low doses, including bone mineralization and wound healing [25], the safety profile of BA is controversial due to its toxic properties at high doses [25]. The long-term effects of intravaginal BA are unclear, and it is questionable if vaginal absorption could pose a problem. The number of adverse events in the included studies was low, temporary, and mild. However, it is possible that rare but serious side effects exist. Topical administration of BA 600 mg appears safe, but treatment regimens vary greatly depending on the type of vaginitis, and while 14 days of BA 600 mg daily in VVC patients seem efficient, a few cases of TV infections required up to 60 days of 1200 mg per day. Extended regimens of BA in BV and TV patients could thus prove more successful, but studies that assess the long-term effects and adverse effects are warranted. Given uncertainties use of BA in pregnancy and lactating woman should be avoided [74].

BA therapy has limitations. Due to its daily topical application, it is less convenient to use than oral medications. The topical application makes it less suitable for deep seated infections such as TV and will likely result in prolonged treatment duration. When it comes to availability, BA can be difficult to obtain in some countries and prices can be higher than conventional therapy. There are no studies on the safety of BA in pregnancy and during lactation and it should therefore not be used during these circumstances. Only four RCTs were included and the remaining studies had either inconsistent results, intermediate (B), or low level of evidence (C) as well as small sample sizes. Thus, heterogeneity did not allow a meta-analysis to be performed. It was especially difficult to conclude on BV and TV because of the limited data available.

In conclusion, the authors suggest considering the use of intravaginal BA 600 mg daily for 14 days as the first choice for VVC due to C. glabrata and azole-resistant VVC and as the second choice for RVVC when fluconazole has been used for a minimum of six months. Suggested dosage is BA 600 mg daily for 14 days followed by BA twice weekly with monthly clinical status, albeit that data are sparse regarding the length of the maintenance therapy. More studies are needed on this matter.

BA may be used for resistant BV infections in the same dosage as for VVC and RVVC. The authors, however, do not recommend the use of BA for acute symptomatic BV as there is a lack of evidence and other well-documented regimens. Regarding nitroimidazole-resistant TV infections, we suggest 600 mg twice daily, although there may be limited effects of a topical agent in this case and the optimal dose as well as the optimal time of duration is not known (Table 5).

Additional Points

Key Message. Rising microbial resistance to pharmacological treatments of microbial vaginitis calls for other treatment options. The old antisepticum boric acid is a well-tolerated and effective treatment alternative in mycotic vaginitis. Its promising effect on nonmycotic microbial vaginitis needs further investigation.

Conflicts of Interest

MLM has no conflicts of interest. DMLS was paid as a consultant for advisory board meeting by Novartis, AbbVie, Janssen, Sanofi, Leo Pharma, UCB and received speaker’s honoraria and/or received grants from the following companies: Abbvie, Galderma, Astellas, Novartis, UCB, Jamjoom Pharma, and Leo Pharma during the last 3 years. CDP has received grants from the European Society for Sexual Medicine and Nordic Society for Gynecology and Obstetrics and has received the speaker’s honoraria from the following companies: Astellas, Bayer and Boehringer Ingelheim during the last 3 years.