REGISTRO DOI: 10.5281/zenodo.11663513
João Lucas Peres dos Santos1; Ana Kamila Rodrigues Alves1; Ernesto Barros Amorim Costa1; Ana Thécia Fonseca Dias1; Júlia Rodrigues Santos1; Antonio Carlos Oliveira de Sousa1; Lívia Maria Ribeiro Rodrigues1; Pedro Henrique do Nascimento Castro1; Sabrina Amorim Correia1; Guilherme Pertinni de Morais Gouveia2
INTRODUCTION: The recommended treatment of Bacterial Vaginosis (BV) is based on antibiotic therapy, however, given the increase in evidence against its isolated use, the literature shows different therapeutic options, such as treatment based on probiotic strains. Thus, based on the premise that the use of probiotics as an adjuvant therapy to antibiotic therapy is beneficial, there is a need to demonstrate the combined use of these therapies in the management of this clinical condition. AIM: Therefore, the objective was to analyze the clinical effectiveness of joint therapy of probiotics with antibiotics compared to monotherapy in the treatment of bacterial vaginosis (bv): a systematic review. METHOD: Systematic review (SR) based on the flowchart of the PRISMA. Free access articles were included, regardless of language and period of publication, through the Medline/Pubmed, NCBI, Scielo, PEDro, Cochrane, LILACS, ScienceDirect and OpenGray databases. RESULTS: Based on the research carried out, it was possible to identify that the use of vaginal probiotic capsules L. rhamnosus DSM 14870 and L. gasseri DSM 14869 together with traditional antibiotic therapy resulted in the colonization of the vagina by the strains contained in the capsules, but had no significant effect on the rate BV cure or relapse prevention. On the other hand, exogenous application of lactobacillus to vaginal capsules L. casei rhamnosus showed restoration of the vaginal flora after treatment with antibiotics, showing a reduction in the Nugent score by at least 5 degrees. CONCLUSION: The treatment of BV using antibiotic therapy together with probiotic therapy did not have a significant effect on the cure rate of BV or on the prevention of relapses, but resulted in the colonization of the vagina by the strains contained in the capsules.
Keywords: Bacterial Vaginosis, Women’s Health, Antibiotics, Probiotics.
INTRODUCTION
Bacterial vaginosis is defined as a disorder of vaginal flora constitution, characterized by a sudden substitution of Lactobacillus with anaerobic bacteria such as Gardenerella vaginalis, Atopobiumvaginae, Ureaplasma urealyticum, Mycoplasmahominis, and various uncultivated fastidious bacteria (Chen, 2021). Lactobacillus is the most commonly isolated microorganism from the healthy human vagina, encompassing Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus iners, and Lactobacillus jensenii (Chee, Chew and Than, 2020; Sudha, Yelikar and Deshpande, 2012; Wang, He and Zheng, 2019).
The etiology of bacterial vaginosis remains unknown; however, its implications for women’s health are significant, involving obstetric complications and increased risks of sexualty transmitted and urogenital infections (Ellington and Saccomano, 2020). It can manifest in two forms: asymptomatic or symptomatic, characterized by increased vaginal discharge. Diagnosis relies on clinical criteria like Amsel’s and/or Gram staining based on the Nugent score, considered a reference examination (Abou Chacra, Fenollar and Diop, 2022; LI, 2019; Wang, He and Zheng 2019).
International guidelines advocate for the treatment of bacterial vaginosis using antibiotics such as metronidazole and clindamycin, administered orally or intravaginally (Faught and Reyes, 2019). However, this therapy has exhibited adverse effects on vaginal flora, especially concerning lactobacilli. Studies indicate that antibiotic therapy is ineffective in completely eliminating the characteristic vaginal biofilm of bacterial vaginosis, leading to recurrent infections (Bradshaw, 2021).
With increasing evidence against the use of isolated antibiotic treatments, parallel therapeutic approaches gain traction, such as probiotic-based treatments (Dobrohotova, 2021; Russo, Karadja and Seta, 2018; Elsharkawy, 2019). Probiotics are natural organisms in the vagina, capable of adhering to the vaginal mucosa and creating a protective biofilm against harmful agents, binding the strain to the pathogen and enabling bacterial elimination (Rostok, 2019). In cases of bacterial vaginosis, common probiotics used in the treatment include: L. reuteri RC14, L. fermentum. L. gasseri, L. rhamnosus GR-1, L. brevis, L. acidophilus, L. crispatus, and L. plantarum; administration routes comprise intravaginal and oral, where intavaginal administration ensures direct microbiota rebalancing, while oral administration serves as an indirect alternative for vaginal flora benefit (Oliveira, 2020).
Considering the premise that antibiotic therapy is more indicated in bacterial vaginosis treatment, and the recent emergence of probiotics as an adjunct therapy to antibiotic treatment (Sgibnev and Kremleva, 2019), there is a need to highlight, through a meta-analysis, the combined use of these therapies in treating this clinical condition. It’s essential to emphasize that this study represents a systematic review, as there have been no systematic reviews with this research approach to date. Therefore, the objective was to analyze the clinical effectiveness of joint therapy of probiotics with antibiotics compared to monotherapy in the treatment of bacterial vaginosis (bv): a systematic review.
METHOD
Study Design
Systematic Review (SR) based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) flowchart, encompassing primary experimental or quasi-experimental quantitative articles. Interventions from randomized clinical trials were assessed for their efficacy. This review is registered on the PROSPERO platform as CRD42023426980.
Inclusion Criteria
Articles available in all languages, regardless of publication date, as this is the first review addressing the subject. A total of 1,305 articles were searched from February to April 2023, through databases including the Medical Literature Analysis and Retrieval System Online (Medline), National Center for Biotechnology Information (NCBI), Scientific Electronic Library Online (Scielo), Physiotherapy Evidence Database (PEDro), Cochrane Library (Cochrane), Latin American and Caribbean Health Sciences Literature (LILACS), ScienceDirect, and OpenGrey. These articles encompass crucial information for healthcare professionals on the repercussions of using antibiotics alone or in combination with probiotics in treating bacterial vaginosis.
Exclusion Criteria
Articles were excluded if their titles did not contain the terms “bacterial vaginosis”, “antibiotic”, “probiotic”, “lactobacillus”, “placebo”, “treatment”, and their synonyms. Additionally, studies with incomplete abstracts or lacking well-defined methods and conclusions were excluded, as were works that did not clearly present the research’s guiding question and duplicate articles.
PICO Strategy and Search
The PICO strategy (P – population; I – intervention; C – comparison; O- outcomes) guided the formulation of the guiding question for the SR and served as the basis for developing search strategies using Medical Subject Headings (MeSH) descriptors and the boolean operators AND and OR, as depicted in Table 1. Thus, the delimited research question was: “Are there sufficient evidences that identify and compare the effectiveness of combining probiotics with antibiotic therapy in treating bacterial vaginosis compared to the isolated use of antibiotics?”.
In it, the first element of the strategy (P) consists of women with bacterial vaginosis; the second element (I) Use of probiotics in combination with antibiotics; (C) Isolated use of antibiotics; and the fourth element (O) Time of pain, efficiency, and response time. The searches were conducted using the following search strategy: (lactobacil OR probiotic) AND (bacterial vaginosis*) AND (antibiotic*).
Article Selection
The systematic review manager “StArt” was used to automatically exclude duplicated articles. Subsequently, title analysis was performed, followed by abstract reading to identify those to be fully evaluated independently (bliding) by three assessors. In case of disagreements, a fourth assessor was required for a final consensus. The necessary data were extracted using an instrument with identification data (authors and years), population, and repercussions generated by thoracic binding in transmaculins.
Assessment of Methodological Quality and Study Bias Risk
To assess the methodological quality of the studies, the Risk of Bias 2 instrument (Rob 2.0) was used. This tool enables judging the methodological quality of five categories of studies: qualitative research, randomized clinical trials, non-randomized studies, quantitative descriptive studies, and mixed methods studies (Hong, 2018).
Regarding the assessment of bias risk in selected studies, the PEDro instrument was used, based on a list composed of 11 items containing eligibility criteria, blinding of subject distribution, precision measures of variability, among other criteria.
This tool was developed to classify the information present in each study and allows for the assessment of methodological quality through scoring. Each item in the table represents one point, excluding only the first item in the final summation, ranging from 0 to 10 points. Scores were defined as high risk of bias (if scores up to 3 points), moderate risk (When scvored 4 to 5 points), or low risk bias (when scored 6 points or more).
Results Analysis
Following complete reading, data from the studies included in this SR were analyzed and presented descriptively in a table containing study identification (authors and year), study type, population, objectives, results, and conclusion.
RESULTS
From the searches conducted in the databases, a total of 1,305 articles were found, with five duplicates, and ultimately, two articles were selected. Regarding the exclusion criteria, articles that diverged from the central theme of this review were disregarded, resulting in the exclusion of (1,299) after title and abstract reading.
Bias Risk Assessment
The selected studies demonstrated homogeneity concerning bias risk, evaluated through the Risk of Bias (ROB 2) tools from Cochrane and PEDro. As depicted in Figure 2, both selected studies exhibited low risk across all meansured items by the ROB 2 tool, as they detailed processes such as randomization, participant recruitment, intervention deviations, measured data, and resultant outcomes. On the PEDro scale, Petricevic and Witt (2008) scored nine, and Marcotte (2019) scored eight, both scores deemed satisfactory by the authors of this review.
Characteristics of Selected Studies
The analyzed studies exhibited well-structured research methodology in the sample assessed, with a heterogeneous sample size of 134 individuals in total. The included groups had participants aged between 18 to 45 years, with an average weight of 59.6 kg and an average height of 164.6 cm, with no significant differences between the groups.
Participant allocation in the studies was based on the criteria such as the presence or absence of bacterial vaginosis, alongside classification according to Amsel criteria and Gram staining, adhering to the Nugent score. Women scoring less than 3 were classified as healthy, while those scoring 7 or higher diagnosed with bacterial vaginosis.
The articles used were conducted in two countries: Austria and South Africa. A total of 107 patients received vaginal probiotic capsules as adjunctive treatment for BV; 95 received capsules of L. casei rhamnosus, and 12 received capsules of both L. rhamnosus and L. gasseri. Marcotte (2019) used isolated treatment with cefixine (400 mg), doxycycline (100 mg), metronidazole (2 g) as the control group, whereas Petricevic and Witt (2008) employed a three-arm methodology, comparing the intervention group both is isolated treatment with clindamycin (600 g) and isolated treatment with L. casei rhamnosus.
Marcotte (2019) research analyzed the effects of using L. Rhamnosus and L. gasseri capsules in treating BV associated with traditional antibiotic therapy. The supplementation with vaginal probiotic capsules resulted in vagina colonization by the strains contained in the capsules but did not significantly affect the cure rate of BV or prevent relapses. The study highlights that using probiotic capsules as adjunctive therapy to enhance antibiotic treatment requires further investigation, possibly employing an alternative antibiotic regimen in a larger cohort.
In their study, Petricevic and Witt (2008) aimed to demonstrate the effect of adding vaginal capsules containing L. casei rhamnosus to the standard treatment for BV, which solely uses antibiotics. Petricevic and Witt (2008) concluded that the restorating of vaginal flora after antibiotic treatment for BV can be significantly enhanced by exogenously applied live lactobacilli. The addition of probiotics restored normal flora in 83% of women in the intervention group. In the control group, 35% of women had normal vaginal flora at the study’s conclusion. The decision to use Lcr35 as a test preparation was based on the multiple beneficial effects of L. casei rhamnosus. In addition to its proven positive role as a probiotics, it is one of the four lactobacilli frequently isolated from the vagina, producing protein substances with antimicrobial activity, such as lactocin 160, eliminating microorganisms associated with BV while preserving healthy vaginal microflora. The research highlights that the local application of Lcr35 after antibiotic treatment of BV significantly improved vaginal flora, as demonstrated after based on Nugent scores, a scoring system commonly regarded as an objective and suitable method for evaluating vaginal flora. Table 3 highlights the details of the analyzed studies according to authors, year, and country; objective; study design; sample; intervention; and results.
The administration of antibiotics and probiotic capsules was conducted in different doses and specifications for each study, lacking a well-defined standard. Concerning the study by Marcotte (2019), healthy women self-administered vaginal probiotic capsules once a day for 30 days, followed by once a week until day 190. All women with BV took a combination of three antibiotics orally for vaginal discharge syndrome in accordance with South African guidelines, namely, cefixime (400 mg), doxycycline (100 mg twice a day for 7 days), and metronidazole (2 g). In the study by Petricevic and Witt (2008), the sample comprised all women treated orally for BV with a standard antibiotic regimen, specifically, 2300 mg of clindamycin for 7 days. The participants assigned to the intervention group also received a vaginal Lactobacillus capsule (Gynophilus; Laboratoires Lyocentre, Aurillac Cedex, France) for 7 days following antibiotic treatment. Each capsule contained at least 109 colony-forming units for live L. casei rhamnosus (Lcr35), 5.59mg of lactose, and 3.41 mg of magnesium stearate. Women in the control group did not receive Lcr35.
The protocols used for treating women in the sample included vaginal probiotics and antibiotics, as well as standard antibiotic therapy and vaginal capsules administered orally. The description and outcomes of the interventions are outlined below in Table 3.
Marcotte (2019) conducted a study in women with and without BV to determine whether vaginal probiotics would lead to vaginal colonization with lactobacilli. The groups received interventions in the form of probiotic capsules (group 1), standard antibiotics for the condition (group 3), and both therapies administered together in group 2. It was observed that vaginal colonization with Lactobacilli was higher in group 2 compared to group 1 after one month of follow-up. Additionally, the study highlighted that both group 1 and group 2 showed favorable outcomes for a higher number of vaginal samples positive for a lactobacilli when compared to group 3. No significant difference in the Frequency of isolation of any lactobacillus was observed between groups 1 and 2, suggesting that colonization with administered strains is not significantly associated with the cure and prevention of BV relapses.
Similarly, Petricevic and Witt (2008) sought to demonstrate the effectiveness of administering lactobacilli as enhancers in restoring vaginal flora after traditional antibiotic treatment for BV. The groups received treatment through oral antibiotic therapy, and only the intervention group received capsules containing lactobacillus (Lcr35) during the antibiotic treatment period. It was observed that participants in the intervention group decreased by up to 8 degrees (60%) in Nugent socres, indicating superior improvement in BV compared to the control group (14%). Futhermore, the study points to a restoration of vaginal flora in 83% against 35% of women in the intervention and control groups, respectively, highlighting significant positive results with the administration of lactobacilli.
DISCUSSION
This systematic review aims to verify the clinical efficacy of combined therapy (antibiotics + probiotics) compared to antibiotic monotherapy in treating BV. Two randomized clinical trials, involving a total of 134 women, were evaluated.
The standard treatment for bacterial vaginosis (BV) involves the use of nitrimidazoles (metronidazole and tinidazole), cefixime or certriaxone, clindamycin, and doxycycline. The analyzed studies emphasize the inclusion of lactobacilli in pharmacological treatment, administered orally or intravaginally. The intervention is based on symptom reduction, decreased recurrence rates, and microflora reconstruction. To reduce the prevalence and recurrence of this vaginal infection, in addition to the associated risk of sexually transmitted infections, the vaginal microbiome must be maintained normally, with sufficient populations of Lactobacillus to protect against harmful agents. The dominance of Lactobacillus in the human vaginal microbiome is assumed to benefit women by reducing the risk of diseases. The results indicate considerable variability in BV cure rates When comparing antibiotic monotherapy with antibiotic therapy associated with lactobacilli, owing to substantial differences in samples, treatment duration, and strain types used (Barreno, 2021; Chen, 2021; MA, 2023; Marcotte, 2019. Petricevic and Witt, 2008).
The therapy combining metronidazole with clindamycin proved to be effective in BV therapy by promoting the restorating of vaginal microflora similar to probiotics. Although metronidazole is widely used as the first-line treatment for BV, clindamycin was better tolerated by the examined women. Moreover, clindamycin was found to be more effective in reducing vaginal discharge. However, monotherapy of BV using clindamycin is correlated with significant indicators of antimicrobial resistance among vaginal anaerobic bacteria (Afifirad, 2022; Bradshaw, 2021; Petricevic and Witt, 2008).
Petricevic and Witt (2018) studies highlighted the restoration of vaginal flora after antibiotic treatment for BV, which could be significantly enhanced by the exogenous application of live lactobacilli, allowing more effective restoration of vaginal flora. This finding supports Tomás (2021) and Ling (2012), in which the authors indicate that combination therapy has beneficial effects on flora, albeit with limited scientific knowledge. However, Wang (2019) and Chetwin (2019) identified that the possible reason for variability in BV cure rates with such treatment lies in the heterogeneity of the vaginal microbiome profiles in Caucasian, Black, and Indigenous women.
Another factor explaining the improvement observed in study participants receiving probiotics in their treatment is the potential of Lactobacillus to synthesize bacteriostatic and bactericidal protein substances, thereby maintaining a low hydrogen potential (pH <4.5) to preserve the balance of the vaginal microbiome, minimizing the incidence of urogenital infections (Watkins, 2019). This factor is also addressed in the research by Donders (2017), where the authors discuss that bacterial vaginosis and other infections like aerobic vaginitis and human papilomavirus are directly associated with an increased vaginal pH caused by a lack of natural Lactobacillus. A promising treatment for this condition involves exogenous applications of probiotics to ensure maintenance of vaginal pH below 5.0 (Bertuccini, 2017; Mionooei, 2023; MA, 2017; Pérez, 2017; Happel, 2020).
The analysis of the intervention Applied to South African participants mostly of Black ethnicity, indicated that supplementing antibiotic therapy with vaginal probiotic capsules resulted in vaginal colonization by Lactobacillus strains (L. rhamnosus DSM 14870 and L. gasseri DSM 14869) contained in the capsules. However, this supplementation did not have any significant effect on the cure rate of BV or on preventing relapses. These findings align with the research of Wang, Zheng and He (2019), where the authors claim that the composition of the vaginal flora is conditioned by genetic factors, which lead the vaginal microbiome of Black women to a déficit of lactobacilli. This explains the good colonization by the strains applied in the study by Marcotte (2019). However, the same authors discuss that BV in Black women is resistant to probiotic therapy, thus explaining the non-significant cure and relapse rates in the target population of the analyzed study.
The probiotics used for supplementation in the analyzed studies were L. casei rhamnosus, L. rhamnosus and L. gasseri. Without achieving a significant effect in increasing the cure rate of BV or preventing relapses, it’s evident that the action of Lactobacillus supplementation is equivalent to isolated antibiotic therapy in vaginal pathologies. That is, although the application of lactobacilli is beneficial, the association of such therapies doesn’t strengthen the treatment already recommended. The beneficial potential of the analyzed Lactobacillus is addressed by Ehrstrom (2010) in the study Where the authors describe the intervention based on topical monotherapy of L. gasseri in patients with BV and vulvovaginal candidiasis compared to Clindamycin antibiotic treatment. In the study, the intervention group showed improvement in their clinical condition, decreased relapses, increased and maintained colonization of vaginal lactobacilli up to 6 months post-intervention, even though there wasn’t a significant increase in symptom improvement or cure rate when compared to the control group. Similar results are presented by Eriksson (2005) in their clinical trial comparing the effect of L. casei rhamnosus, L. rhamnosus with antibiotic monotherapies.
CONCLUSION
The research shows that although the therapy for BV from traditional antibiotic therapy adjuvant with probiotic therapy has no significant effect on the cure rate of BV or in preventing relapses, the use of vaginal probiotic capsules resulted in the colonization of the vagina by the strains contained in the capsules. The restoration of the vaginal microbiome from the combination of antibiotic therapy with probiotic therapy is one of the new possible directions to be pursued for the treatment of BV. However, the development of innovative treatment strategies that effectively and safely address initial episodes of BV and prevent rapid recurrence requires further in-depth investigation.
Furthermore, this research demonstrates the need for more studies that seek to elucidate the safety and impact on the quality of life of patients using probiotics in addition to standard antibiotic therapy for BV. There is also a clear need for studies exploring other strains of probiotics, considering the wide range of lactobacilli that could potentially be used in the treatment of BV.
REFERENCES
ABOU CHACRA, L.; FENOLLAR, F.; DIOP, K. Bacterial Vaginosis: What Do We Currently Know? Frontiers in Cellular and Infection MicrobiologyFrontiers Media S.A., , 18 jan. 2022.
AFIFIRAD, R. et al. Effects of Pro/Prebiotics Alone over Pro/Prebiotics Combined with Conventional Antibiotic Therapy to Treat Bacterial Vaginosis: A Systematic Review. International journal of clinical practiceNLM (Medline), , 2022.
BERTUCCINI, L. et al. Effects of Lactobacillus rhamnosus and Lactobacillus acidophilus on bacterial vaginal pathogens. International Journal of Immunopathology and Pharmacology, v. 30, n. 2, p. 163–167, 1 jun. 2017.
BRADSHAW, C. S. et al. High Recurrence Rates of Bacterial Vaginosis over the Course of 12 Months after Oral Metronidazole Therapy and Factors Associated with Recurrence. [s.l: s.n.]. Disponível em: <https://academic.oup.com/jid/article/193/11/1478/885098>.
BRADSHAW, C. S. et al. Efficacy of oral metronidazole with vaginal clindamycin or vaginal probiotic for bacterial vaginosis: Randomized placebo-controlled double-blind trial. PLoS ONE, v. 7, n. 4, 3 abr. 2012.
CHEE, W. J. Y.; CHEW, S. Y.; THAN, L. T. L. Vaginal microbiota and the potential of Lactobacillus derivatives in maintaining vaginal health. Microbial Cell FactoriesBioMed Central Ltd, , 1 dez. 2020.
CHEN, R. et al. Probiotics are a good choice for the treatment of bacterial vaginosis: a meta-analysis of randomized controlled trials. Reproductive HealthBioMed Central Ltd, , 1 dez. 2022.
CHEN, X. et al. The Female Vaginal Microbiome in Health and Bacterial Vaginosis. Frontiers in Cellular and Infection MicrobiologyFrontiers Media S.A., , 7 abr. 2021.
CHETWIN, E. et al. Antimicrobial and inflammatory properties of South African clinical Lactobacillus isolates and vaginal probiotics. Scientific Reports, v. 9, n. 1, 1 dez. 2019.
DOBROHOTOVA, Y. E. et al. [The efficiency of probiotics in the prevention of recurrent lower urinary tract infections and bacterial vaginosis]. Urologiia (Moscow, Russia: 1999), n. 4, p. 30–34, 1 set. 2021.
DONDERS, G. G. G. et al. Aerobic vaginitis: no longer a stranger. Research in Microbiology, v. 168, n. 9–10, p. 845–858, 1 nov. 2017.
EHRSTRÖM, S. et al. Lactic acid bacteria colonization and clinical outcome after probiotic supplementation in conventionally treated bacterial vaginosis and vulvovaginal candidiasis. Microbes and Infection, v. 12, n. 10, p. 691–699, set. 2010a.
EHRSTRÖM, S. et al. Lactic acid bacteria colonization and clinical outcome after probiotic supplementation in conventionally treated bacterial vaginosis and vulvovaginal candidiasis. Microbes and Infection, v. 12, n. 10, p. 691–699, set. 2010b.
ELLINGTON, K.; SACCOMANO, S. J. Recurrent bacterial vaginosis. The Nurse Practitioner, out. 2020.
ELSHARKAWY, I. et al. Continuous versus interrupted use of vaginal probiotics plus vaginal clindamycin cream for bacterial vaginosis: a randomized controlled study. Journal of Maternal-Fetal and Neonatal Medicine, v. 34, n. 1, p. 58–65, 2 jan. 2021.
ERIKSSON, K. et al. A double-blind treatment study of bacterial vaginosis with normal vaginal lactobacilli after an open treatment with vaginal clindamycin ovules. Acta Dermato-Venereologica, v. 85, n. 1, p. 42–46, 2005.
FAMULARO, G. et al. Microecology, bacterial vaginosis and probiotics: Perspectives for bacteriotherapy. Medical Hypotheses, v. 56, n. 4, p. 421–430, 2001.
FAUGHT, B. M.; REYES, S. Characterization and Treatment of Recurrent Bacterial Vaginosis. Journal of Women’s Health, v. 28, n. 9, p. 1218–1226, 1 set. 2019.
HAPPEL, A. U. et al. Exploring potential of vaginal Lactobacillus isolates from South African women for enhancing treatment for bacterial vaginosis. PLoS Pathogens, v. 16, n. 6, 1 jun. 2020.
KOVACHEV, S.; VATCHEVA-DOBREVSKI, R. [Efficacy of combined 5-nitroimidazole and probiotic therapy of vaginosis bacterial: randomized open trial]. Akusherstvo I Ginekologiia, v. 52, n. 3, p. 19–26, 2013.
LI, C. et al. Probiotics for the treatment of women with bacterial vaginosis: A systematic review and meta-analysis of randomized clinical trials. European Journal of PharmacologyElsevier B.V., , 1 dez. 2019.
LING, Z. et al. The Restoration of the Vaginal Microbiota After Treatment for Bacterial Vaginosis with Metronidazole or Probiotics. Microbial Ecology, v. 65, n. 3, p. 773–780, 1 abr. 2013.
MA, L. et al. Probiotics administered intravaginally as a complementary therapy combined with antibiotics for the treatment of bacterial vaginosis: A systematic review protocol. BMJ OpenBMJ Publishing Group, , 1 out. 2017.
MA, S. et al. Antibiotics therapy combined with probiotics administered intravaginally for the treatment of bacterial vaginosis: A systematic review and meta-analysis. Open Medicine, v. 18, n. 1, 13 set. 2023.
MARCOTTE, H. et al. An exploratory pilot study evaluating the supplementation of standard antibiotic therapy with probiotic lactobacilli in south African women with bacterial vaginosis. BMC Infectious Diseases, v. 19, n. 1, 18 set. 2019.
MINOOEI, F. et al. Mesh and layered electrospun fiber architectures as vehicles for Lactobacillus acidophilus and Lactobacillus crispatus intended for vaginal delivery. Biomaterials Advances, v. 154, p. 213614, 1 nov. 2023.
MUÑOZ-BARRENO, A. et al. Comparative effectiveness of treatments for bacterial vaginosis: A network meta-analysis. Antibiotics, v. 10, n. 8, 1 ago. 2021.
MUR PÉREZ, A. M. et al. Uso de probióticos en las vaginosis bacterianas. Semergen, v. 43, n. 5, p. 394–398, 1 jul. 2017.
PAGE, M. J. et al. A declaração PRISMA 2020: diretriz atualizada para relatar revisões sistemáticas. Epidemiologia e Serviços de Saúde, v. 31, n. 2, 1 jun. 2022.
PARMA, M. et al. Probiotics in the prevention of recurrences of bacterial vaginosis. Alternative Therapies in Health and Medicine, v. 20 Suppl 1, p. 52–57, 2014.
PETRICEVIC, L; WITT, A. (2008). The role of Lactobacillus casei rhamnosusLcr35 in restoring the normal vaginal flora after antibiotic treatment of bacterial vaginosis. BJOG: An International Journal of Obstetrics & Gynaecology, 115(11), 1369–1374.
RATNA SUDHA, M.; YELIKAR, K. A.; DESHPANDE, S. Clinical Study of Bacillus coagulans Unique IS-2 (ATCC PTA-11748) in the Treatment of Patients with Bacterial Vaginosis. Indian Journal of Microbiology, v. 52, n. 3, p. 396–399, 1 set. 2012.
Risk of Bias 2 (RoB 2) tool. Disponível em: <https://methods.cochrane.org/risk-bias-2>.
ROSTOK, M. et al. Potential vaginal probiotics: Safety, tolerability and preliminary effectiveness. Beneficial Microbes, v. 10, n. 4, p. 385–393, 2019.
RUSSO, R.; KARADJA, E.; DE SETA, F. Evidence-based mixture containing Lactobacillus strains and lactoferrin to prevent recurrent bacterial vaginosis: A double blind, placebo controlled, randomized clinical trial. Beneficial Microbes, v. 10, n. 1, p. 19–26, 2019.
SGIBNEV, A.; KREMLEVA, E. Probiotics in addition to metronidazole for treatment of Trichomonas vaginalis in the presence of BV: a randomized, placebo-controlled, double-blind study. European Journal of Clinical Microbiology and Infectious Diseases, v. 39, n. 2, p. 345–351, 1 fev. 2020.
TOMÁS, M. et al. Bacterial vaginosis: Standard treatments and alternative strategies. International Journal of PharmaceuticsElsevier B.V., , 25 set. 2020.
WANG, Z.; HE, Y.; ZHENG, Y. Probiotics for the treatment of bacterial vaginosis: A meta-analysis. International Journal of Environmental Research and Public HealthMDPI AG, , 2 out. 2019.
WATKINS, J. A. et al. Acceptability of and treatment preferences for recurrent bacterial vaginosis—Topical lactic acid gel or oral metronidazole antibiotic: Qualitative findings from the VITA trial. PLoS ONE, v. 14, n. 11, 1 nov. 2019.