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Intermittent Lactobacilli-containing Vaginal Probiotic or Metronidazole Use to Prevent Bacterial Vaginosis Recurrence: A Pilot Study Incorporating Microscopy and Sequencing.

ABSTRACT: Bacterial vaginosis (BV) is associated with HIV acquisition and adverse pregnancy outcomes. Recurrence after metronidazole treatment is high. HIV-negative, non-pregnant Rwandan BV patients were randomized to four groups (n = 17/group) after seven-day oral metronidazole treatment: behavioral counseling only (control), or counseling plus intermittent use of oral metronidazole, Ecologic Femi+ vaginal capsule (containing multiple Lactobacillus and one Bifidobacterium species), or Gynophilus LP vaginal tablet (L. rhamnosus 35) for two months. Vaginal microbiota assessments at all visits included Gram stain Nugent scoring and 16S rRNA gene qPCR and HiSeq sequencing. All interventions were safe. BV (Nugent 7-10) incidence was 10.18 per person-year at risk in the control group, and lower in the metronidazole (1.41/person-year; p = 0.004), Ecologic Femi+ (3.58/person-year; p = 0.043), and Gynophilus LP groups (5.36/person-year; p = 0.220). In mixed effects models adjusted for hormonal contraception/pregnancy, sexual risk-taking, and age, metronidazole and Ecologic Femi+ users, each compared to controls, had higher Lactobacillus and lower BV-anaerobes estimated concentrations and/or relative abundances, and were less likely to have a dysbiotic vaginal microbiota type by sequencing. Inter-individual variability was high and effects disappeared soon after intervention cessation. Lactobacilli-based vaginal probiotics warrant further evaluation because, in contrast to antibiotics, they are not expected to negatively affect gut microbiota or cause antimicrobial resistance.

SUBMITTER: van de Wijgert JHHM

PROVIDER: S-EPMC7054572 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTo determine if oral metronidazole (MTZ-400 mg bid) with 2% vaginal clindamycin-cream (Clind) or a Lactobacillus acidophilus vaginal-probiotic containing oestriol (Prob) reduces 6-month bacterial vaginosis (BV) recurrence.MethodsDouble-blind placebo-controlled parallel-group single-site study with balanced randomization (1:1:1) conducted at Melbourne Sexual Health Centre, Australia. Participants with symptomatic BV [Nugent Score (NS) = 7-10 or ≥3 Amsel's criteria and NS = 4-10], were randomly allocated to MTZ-Clind, MTZ-Prob or MTZ-Placebo and assessed at 1,2,3 and 6 months. MTZ and Clind were administered for 7 days and Prob and Placebo for 12 days. Primary outcome was BV recurrence (NS of 7-10) on self-collected vaginal-swabs over 6-months. Cumulative BV recurrence rates were compared between groups by Chi-squared statistics. Kaplan-Meier, log rank and Cox regression analyses were used to compare time until and risk of BV recurrence between groups.Results450 18-50 year old females were randomized and 408 (91%), equally distributed between groups, provided ≥1 NS post-randomization and were included in analyses; 42 (9%) participants with no post-randomization data were excluded. Six-month retention rates were 78% (n = 351). One-month BV recurrence (NS 7-10) rates were 3.6% (5/140), 6.8% (9/133) and 9.6% (13/135) in the MTZ-Clind, MTZ-Prob and MTZ-Placebo groups respectively, p = 0.13. Hazard ratios (HR) for BV recurrence at one-month, adjusted for adherence to vaginal therapy, were 0.43 (95%CI 0.15-1.22) and 0.75 (95% CI 0.32-1.76) in the MTZ-Clind and MTZ-Prob groups compared to MTZ-Plac respectively. Cumulative 6-month BV recurrence was 28.2%; (95%CI 24.0-32.7%) with no difference between groups, p = 0.82; HRs for 6-month BV recurrence for MTZ-Clind and MTZ-Prob compared to MTZ-Plac, adjusted for adherence to vaginal therapy were 1.09(95% CI = 0.70-1.70) and 1.03(95% CI = 0.65-1.63), respectively. No serious adverse events occurred.ConclusionCombining the recommended first line therapies of oral metronidazole and vaginal clindamycin, or oral metronidazole with an extended-course of a commercially available vaginal-L.acidophilus probiotic, does not reduce BV recurrence.Trial registrationANZCTR.org.au ACTRN12607000350426.

Project description:BACKGROUND:The aim of this study was to investigate the colonisation by lactobacilli and clinical outcome in women with bacterial vaginosis (BV) and recurrent vulvovaginal candidiasis (R-VVC) receiving antibiotic or anti-fungal treatment in combination with the probiotic EcoVag® capsules. METHODS:A total of 40 Scandinavian women diagnosed with BV or VVC on the basis of Amsel's criteria or clinical symptoms were consecutively recruited in two pilot open label clinical trials. In trial I, women with BV were treated with clindamycin and metronidazole followed by vaginal EcoVag® capsules, containing Lactobacillus rhamnosus DSM 14870 and Lactobacillus gasseri DSM 14869, for 5 consecutive days after each antibiotic treatment. In trial II, women were recruited in three groups as follows: women with BV receiving clindamycin and metronidazole treatment together with a prolonged administration of EcoVag® (10 consecutive days after each antibiotic treatment followed by weekly administration of capsules for next four months), women with R-VVC receiving extended fluconazole and EcoVag® treatment, and women receiving extended fluconazole treatments only. The difference in frequency of isolation of EcoVag® strains or other lactobacilli between groups was compared by Fisher's exact test. RESULTS:The 6-month cure rate for BV was 50 % in trial I while both the 6- and 12-month cure rates were 67 % in trial II. The 6- and 12-month cure rates for VVC were 100 % and 89 % in women receiving fluconazole and EcoVag®, and 100 % and 70 % in women receiving fluconazole only. The frequency of isolation of any Lactobacillus species during the course of the study was associated with cure of BV in trial I and II, whereas the frequency of isolation of EcoVag® strains was significantly associated with the cure of BV in trial II only. As previously observed, a change in sexual partner was associated with relapse of BV with an Odds ratio of 77 (95 % CI: 2.665 to 2225). CONCLUSIONS:The study suggests that the treatment with antibiotics or anti-fungal medication in combination with EcoVag® capsules provide long-term cure against BV and R-VVC as compared to previous reports. TRIAL REGISTRATION:ClinicalTrials.gov NCT02295579 . Registered November 20, 2014.

Project description:Bacterial vaginosis (BV) is an abnormal condition caused by the change of microbiota in the vagina. One of the most common bacteria found in the case of BV is Gardnerella vaginalis, which is categorised as anaerobic facultative bacteria. Currently, the available treatment for BV is the use of antibiotics, such as metronidazole (MTZ), in topical and oral dosage forms. The limitation of the currently available treatment is that multiple administration is required and thus, the patient needs to apply the drug frequently to maintain the drug efficacy. To address these limitations, this research proposed prolonged delivery of MTZ in the form of intravaginal devices made from biodegradable and biocompatible polymers. Semi-solid extrusion (SSE) 3D printing was used to prepare the intravaginal devices. The ratio of high and low molecular weight poly(caprolactone) (PCL) was varied to evaluate the effect of polymer composition on the drug release. The versatility of SSE 3D printer was used to print the intravaginal devices into two different shapes (meshes and discs) and containing two different polymer layers made from PCL and a copolymer of methyl vinyl ether and maleic anhydride (Gantrez™-AN119), which provided mucoadhesive properties. Indeed, this layer made from Gantrez™-AN119 increased ca. 5 times the mucoadhesive properties of the final 3D-printed devices (from 0.52 to 2.57 N). Furthermore, MTZ was homogenously dispersed within the polymer matrix as evidenced by scanning electron microscopy analysis. Additionally, in vitro drug release, and antibacterial activity of the MTZ-loaded intravaginal devices were evaluated. Disc formulations were able to sustain the release of MTZ for 72 h for formulations containing 70/30 and 60/40 ratio of high molecular weight/low molecular weight PCL. On the other hand, the discs containing a 50/50 ratio of high molecular weight/low molecular weight PCL showed up to 9 days of release. However, no significant differences in the MTZ release from the MTZ-loaded meshes (60/40 and 50/50 ratio of high molecular weight/low molecular weight PCL) were found after 24 h. The results showed that the different ratios of high and low molecular weight PCL did not significantly affect the MTZ release. However, the shape of the devices did influence the release of MTZ, showing that larger surface area of the meshes provided a faster MTZ release. Moreover, MTZ loaded 3D-printed discs (5% w/w) were capable of inhibiting the growth of Gardnerella vaginalis. These materials showed clear antimicrobial properties, exhibiting a zone of inhibition of 19.0 ± 1.3 mm. Based on these findings, the manufactured represent a valuable alternative approach to the current available treatment, as they were able to provide sustained release of MTZ, reducing the frequency of administration and thus improving patient compliance.

Project description:Bacterial vaginosis (BV) is a prevalent multifactorial disease of women in their reproductive years characterized by a shift from the Lactobacillus species-dominated microbial community toward a taxonomically diverse anaerobic community. For unknown reasons, some women do not respond to therapy. In our recent clinical study, among 37 women diagnosed with BV, 31 were successfully treated with metronidazole, while 6 still had BV after treatment. To discover possible reasons for the lack of response in those patients, we performed a metatranscriptome analysis of their vaginal microbiota, comparing them to the patients who responded. Seven of 8 clustered regularly interspaced short palindromic repeat (CRISPR)-associated (Cas) genes of Gardnerella vaginalis were highly upregulated in nonresponding patients. Cas genes, in addition to protecting against phages, might be involved in DNA repair, thus mitigating the bactericidal effect of DNA-damaging agents such as metronidazole. In the second part of our study, we analyzed the vaginal metatranscriptomes of four patients over 3 months and showed high in vivo expression of genes for pore-forming toxins in L. iners and of genes encoding enzymes for the production of hydrogen peroxide and d-lactate in L. crispatusIMPORTANCE Bacterial vaginosis is a serious issue for women in their reproductive years. Although it can usually be cured by antibiotics, the recurrence rate is very high, and some women do not respond to antibiotic therapy. The reasons for that are not known. Therefore, we undertook a study to detect the activity of the complete microbiota in the vaginal fluid of women who responded to antibiotic therapy and compared it to the activity of the microbiota in women who did not respond. We found that one of the most important pathogens in bacterial vaginosis, Gardnerella vaginalis, has activated genes that can repair the DNA damage caused by the antibiotic in those women that do not respond to therapy. Suppressing these genes might be a possibility to improve the antibiotic therapy of bacterial vaginosis.

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Intermittent Lactobacilli-containing Vaginal Probiotic or Metronidazole Use to Prevent Bacterial Vaginosis Recurrence: A Pilot Study Incorporating Microscopy and Sequencing.

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