The use of 3 selected lactobacillary strains in vaginal probiotic gel for the treatment of acute Candida vaginitis: a proof-of-concept study.

In vitro studies suggest that certain probiotic bacterial strains have potential activity against opportunistic infections such as Candida. There are few in vivo trials using probiotics as a single treatment for acute Candida vulvovaginitis (CV). In this open-label, proof-of-concept study, selected Lactobacillus strains were tested in women with acute Candida vaginitis. Twenty women diagnosed with proven, symptomatic CV were instructed to administer a vaginal probiotic gel with L. plantarum YUN-V2.0, L. pentosus YUN-V1.0 and L. rhamnosus YUN-S1.0 for 10 consecutive days. Vaginal rinsing fluid, vaginal culture swab and vaginal smear for fresh wet-mount microscopy were collected before and 7, 14 and 28 days after start of treatment. On average, participating women were 39 years old and had an history of 5 vaginal infections of which 95% was CV. Nine women (45%) completed the study without the need of rescue medication. Women who needed rescue treatment experienced twice as much Candida infections in the past. A negative correlation was found between the clinical composite score and the time to use rescue medication (R2 = 0.127). Seventy-four per cent of participants found the study gel comfortable to use, and 42% of all women would use the tested gel again for this indication. Forty-five per cent of women were treated successfully for acute CV with a novel vaginal gel containing 3 selected Lactobacillus strains. Patients needing rescue treatment were suffering from more severe and long-standing disease. These results warrant for further testing of this new product, especially of its potential in cases with mild to moderate severity, as an adjuvant to antimycotics or as a preventive measure in women with recurrent vulvovaginal candidosis.

Treatment Attitudes for Belgian Women With Persistent Trichomonas vaginalis Infection in the VlaResT Study.

BACKGROUND: Because of its increasing prevalence worldwide, its sexual transmissibility and its facilitation of human immunodeficiency virus transmission, Trichomonas vaginalis (TV) infection constitutes an important public health concern. THE AIM OF THE STUDY: While searching for possible resistant TV cases, adequacy of management of TV-infected women was assessed. METHODS: Cervical cytology between July 2007 and July 2014 was tested with TV polymerase chain reaction, and 304 women expressed repeatedly positive results, 718 in total. For each of these positive results, a questionnaire about treatment decisions was sent to the 182 Belgian physicians treating these women. RESULTS: From the 346 returned questionnaires by their physician it was evident that 58.1% of women with repeatedly positive TV had received no treatment. TV was overlooked in 31.5%, and in 17.6% the test result was seen but ignored. Upon seeing the positive result, 23.9% of physicians decided that this finding was not important enough to institute treatment, and/or requested confirmatory tests. Adequate treatment was prescribed in 38.4%. Retreatment after failed therapy was given in only 29.3% of the cases. And 60% of the partners of women with persistent TV infection were not traced, nor treated. CONCLUSION: Most of the repeatedly positive TV infection may not be due to antibiotics resistance. The low awareness, poor attention, failure of contact tracing, and low rates of proper treatment provided by treating physicians question the adequacy of the current management of TV infection and requires renewed education campaigns and increased surveillance.

Abnormal vaginal microbioma is associated with severity of localized provoked vulvodynia. Role of aerobic vaginitis and Candida in the pathogenesis of vulvodynia.

Localized provoked vulvodynia (LPV) causes introital dyspareunia in up to 14% of premenopausal women. Vaginal infections like candidosis may play a initiating role. The aim of this study was to test a possible association of vaginal microbiota alternations such as Candida vaginitis (CV), aerobic vaginitis (AV) and bacterial vaginosis (BV) with severity of vulvodynia and painful intercourse. In an observational study, Q-tip touch test (score 1 (no pain) to 10 (worst possible pain)) was performed on seven vestibular locations in 231 LPV patients presenting in the Vulvovaginal Disease Clinics in Tienen, Leuven and Antwerp, Belgium. Severity of pain upon attempting sexual intercourse was recorded in a similar scale. Both scales were compared to results from fresh wet mount phase contrast microscopy on vaginal fluid smears tested for abnormal vaginal flora (AVF), BV, AV and CV according the standardized microscopy method (Femicare). Fisher's exact test was used. Average age was 31.3 ± 11.6 years, and 58.8% (n = 132) had secondary vestibulodynia. There was an inverse relation between the presence of Candida in the vaginal smears and pain score (p = 0.03). There was no relation of pain score, nor Q-tip score with BV. LPV patients with Q-tip score above 7 at 5 and/or 7 o'clock or at 1 and/or 11 o'clock had more often AV than women with lower pain scores (30 vs 14.5%, p = 0.01, and 39 vs 14.7%, p < 0.005, respectively). Detailed study of the vaginal microflora in patients demonstrates that the most severe patients suffer more from AV and less from Candida. These abnormalities need to be actively looked for and corrected before considering surgery or other therapies.

Sexual behaviour and extra-genital colonisation in women treated for recurrent Candida vulvo-vaginitis.

OBJECTIVE: This study analyses a relation between sexual habits and the presence of Candida in extra-genital locations as well as a potential effect on therapy response. MATERIAL AND METHODS: Candida cultures were obtained from mouth, nose, anus, urine and perineum of 117 women enrolled in a RVVC treatment trial (ReCiDiF). Sexual behaviour and carriage rates of extra-genital Candida of women responding well to treatment were compared to that of non-responders. RESULTS: Most respondents were heterosexual. All but one practiced vaginal sex. Regular receptive oral sex was not related to multiple site colonisation with Candida (OR = 1.27; CI95% 0.36-4.48), nor to non-response to therapy (OR = 1.3; CI 95% 0.41-4.73). Also, masturbation was not related to response to therapy (OR 0.8; CI95% 0.31-1.84), nor was anal sex (OR = 0.54; CI95% 0.11-2.72). CONCLUSION: Neither oral nor casual anal sex, nor masturbation can be held responsible for the association of the multiple site/anal colonisation with Candida and inferior response to fluconazole maintenance therapy. Changing sexual behaviour during fluconazole maintenance treatment for RVVC in otherwise healthy women should not be advocated. Also, treatment of asymptomatic sexual partners of women with RVVC is not recommended.

Non-response to fluconazole maintenance treatment (ReCiDiF regimen) for recurrent vulvovaginal candidosis is not related to impaired glucose metabolism.

Is non-response to maintenance treatment for recurrent vulvovaginal candidosis (RCVV) related to the impaired glucose metabolism? In the ReCiDiF trial, women with RCVV were given a degressive regimen with fluconazole according to their clinical, microscopic and mycologic response. Data obtained from optimal, suboptimal and non-reponding patients were used for secondary analysis of medical history, physical status and family history for potential glucose impairment. Results were presented in means and percentages. Pearson chi-square, Fisher exact, Mann-Whitney U, Kruskal-Wallis and Spearman's correlation coefficient was calculated. P<.05 were interpreted as statistically significant. Sociodemographic characteristics and family and personal history of diabetes were not different between optimal, suboptimal and non-responders. The average HbA1c concentration was 5.1±0.3% in optimal, 5.0±0.4% in sub-optimal, and 5.1±0.3% in non-responding patients (P=1.0). There are no statistical differences between optimal, sub-optimal and non-respondents to treatment in all deciles of HbA1c among patients with recurrent candidosis (P=1.0). There was no difference among groups in fasting glucose concentration, nor after 30 min, 60 min or 120 min during the oral glucose tolerance test (OGTT) (P=.6). Area under the OGTT curve did not differ within groups (P=.8), nor was the deviation from the normal cut-off value any different (P=.8). Glucose concentration in vaginal rinsing fluid showed no correlation with responsiveness to treatment (P=.7). Glucose metabolism, BMI, personal or family history of diabetes are not related to non-response to maintenance treatment with fluconazole for patients with RVVC.

Mycoplasma/Ureaplasma infection in pregnancy: to screen or not to screen.

Mycoplasmata have been linked to pregnancy complications and neonatal risk. While formerly a limited number of species could be discovered by cultures, molecular biology nowadays discovers both lower quantities and more diverse species, making us realize that mycoplasmata are ubiquitous in the vaginal milieu and do not always pose a danger for pregnant women. As the meaning of mycoplasmata in pregnancy is not clear to many clinicians, we summarized the current knowledge about the meaning of different kinds of mycoplasmata in pregnancy and discuss the potential benefits and disadvantages of treatment. Currently, there is no general rule to screen and treat for mycoplasmata in pregnancy. New techniques seem to indicate that Ureaplasma parvum (Up), which now can be distinguished from U. urealyticum (Uu), may pose an increased risk for preterm birth and bronchopulmonary disease in the preterm neonate. Mycoplasma hominis (Mh) is related to early miscarriages and midtrimester abortions, especially in the presence of abnormal vaginal flora. Mycoplasma genitalium (Mg) is now recognized as a sexually transmitted infection (STI) that is involved in the causation of cervicitis, pelvic inflammatory disease (PID) in non-pregnant, and preterm birth and miscarriages in pregnant women, irrespective of the presence of concurrent other STIs, like Chlamydia or gonorrhoea. Proper studies to test for efficacy and improved pregnancy outcome are scarce and inconclusive. Azythromycin is the standard treatment now, although, for Mg, this may not be sufficient. The role of clarithromycin in clinical practice still has to be established. There is a stringent need for new studies based on molecular diagnostic techniques and randomized treatment protocols with promising and safe antimicrobials.

Lab-Based Retrospective 10-Year Analysis Shows Seasonal Variation of Vaginal Candida Infection Rates in Belgium.

Candida vulvovaginitis is a frequent condition, and although several risk factors are known, its behavior is still enigmatic. The seasonal influence of climate conditions and living habits on its prevalence was studied. In a retrospective lab-based cohort over 10 years, we studied the prevalence of Candida in 12,941 vaginal cultures taken from women attending a vulvovaginitis clinic. The prevalence of non-albicans and albicans species were compared per month to detect differences in positivity rates in summer versus winter months. Chi-square and chi-square for trend were used. Of the 2109 (16.3%) Candida spp. positive swabs, 201 (1.0%) revealed non-albicans species, varying between 1.0% and 2.0% per month, but without significant monthly differences. Over the 10 years, compared to other months, vaginal Candida was more frequent in June (19.0%, p = 0.008) and less frequent in December (14.5%, p = 0.04). The Candida prevalence was 15.5% in summer (June/July/August) versus 14.0% in the winter (Dec/Jan/Feb, p = 0.04). Change in temperature, dietary habits, and bodily adaptations due to increased amount of sunlight were discussed as potential pathophysiological mechanisms to explain the excess of Candida in summertime. Further confirmatory research would be beneficial. Women at risk for Candida vulvovaginitis should pay more attention to living habits in summertime to avoid recurrences.

Vaginal pH and microbiota during fluconazole maintenance treatment for recurrent vulvovaginal candidosis (RVVC).

BACKGROUND: It is commonly stated that Candida in the vagina prefers a low pH to develop infection. However, mixed infections of Candida with bacterial vaginosis (BV) and aerobic vaginitis (AV) are rather common and may challenge the rule that Candida should only be looked for in low vaginal pH settings. In this study we tested whether the vaginal pH in acute vaginal candidosis is lower than in women successfully treated to prevent Candida recurrences. METHODS: Vaginal pH and microscopy findings of vaginal microbiota were recorded during 12 visits over 1.5 years in 117 patients medically monitored during a degressive fluconazole maintenance regimen for proven recurrent vulvovaginal candidosis (ReCiDiF trial). The fluctuation of the mean pH of and microscopic findings of the vaginal smears were studied before, during and after the treatment. RESULTS: The mean vaginal pH of women with acute infection before or after ending maintenance treatment was (4.7±0.8 and 4.8 ±1.0, respectively, p>0.05). During maintenance treatment with fluconazole, the pH dropped significantly to 4.5±0.8 (p=0.01). Depression of Lactobacilli spp. (increased lactobacillary grades) was more frequent during the acute, pre-treatment period (30.0%) than during the treatment period (23.1%, p=0.03). Aerobic vaginitis type flora was also more prevalent pre-treatment than during treatment (30.0% vs 22.2%, OR=0.7 (95%CI 0.5-0.9), p=0.01). DISCUSSION: In women with RVVC, acute vaginal Candida infection is associated with an increased pH, and disturbed vaginal bacterial microbiota. During fluconazole maintenance treatment, the pH drops to normal levels and the lactobacillary grade improves. CONDENSATION: Acute Candida vulvovaginitis can be associated with a disturbance of the vaginal microbiota. In patients with recurrent vulvovaginal candidosis, decrease of pH, and increase of Lactobacilli spp. were observed during fluconazole maintenance treatment. This pH drop was seen in all response groups. This contradicts the common belief that active vaginal Candida infection is related to low pH.

The Dwindling Microbiota of Aerobic Vaginitis, an Inflammatory State Enriched in Pathobionts with Limited TLR Stimulation.

While bacterial vaginosis (BV) is a well-known type of vaginal dysbiosis, aerobic vaginitis (AV) is an inflammatory condition that remains understudied and under-recognised. It predisposes women to serious complications including urogenital infections and pregnancy problems. Here, we investigated the bacterial community in AV to explore its possible role in AV pathogenesis. We collected vaginal lavage fluid samples of women (n = 58) classified by wet-mount microscopy as suffering from AV or BV and included an asymptomatic reference group without signs of AV or BV. AV samples showed reduced absolute abundances of bacteria in general and specifically of lactobacilli by qPCR, but 16S rRNA gene sequencing and amplicon sequence variant analysis revealed that Lactobacillus remained the dominant taxon in 25% of the AV samples studied. The other AV samples showed high relative abundances of Streptococcus agalactiae and, unexpectedly, the anaerobes Gardnerella vaginalis and Prevotella bivia in more than half of the AV samples studied. Yet, despite increased relative abundance of these potential pathogens or pathobionts in the AV bacterial communities, the AV samples only slightly stimulated Toll-like receptor 4 and showed reduced activation of Toll-like receptor 2/6, receptors of two pathways central to mucosal immunity. Our findings indicate that the reduced total bacterial abundance with associated enrichment in certain pathobionts in AV might be mainly a consequence of the inflammatory conditions and/or altered hormonal regulation rather than bacteria being a major cause of the inflammation.

Pharmacotherapy for the treatment of vaginal atrophy.

INTRODUCTION: Despite its frequency, recognition and therapy of vulvovaginal atrophy (VVA) remain suboptimal. Wet mount microscopy, or vaginal pH as a proxy, allows VVA diagnosis in menopause, but also in young contraception users, after breast cancer, or postpartum. Intravaginal low dose estrogen product is the main therapy. Ultra-low-dose vaginal estriol is safe and sufficient in most cases, even in breast cancer patients, while hyaluronic acid can help women who cannot or do not want to use hormones. AREAS COVERED: The authors provide an overview of the current pharmaceutical treatment for vulvovaginal atrophy and provide their expert opinions on its future treatment. EXPERT OPINION: The basis of good treatment is a correct and complete diagnosis, using a microscope to study the maturity index of the vaginal fluid. Minimal dose of estriol intravaginally with or without lactobacilli is elegant, cheap and can safely be used after breast cancer and history of thromboembolic disease. Laser therapy requires validation and safety data, as is can potentially cause vaginal fibrosis and stenosis, and safer and cheaper alternatives are available.

Is multiple-site colonization with Candida spp. related to inadequate response to individualized fluconazole maintenance therapy in women with recurrent Candida vulvovaginitis?

OBJECTIVE: Although most women on fluconazole maintenance therapy for recurrent vulvovaginal candidosis experience a substantial improvement in quality of life, some do not respond to therapy. Is candidal colonization of extragenital sites related to suboptimal response to maintenance therapy? PATIENTS AND METHODS: Women included in a multicenter follow-up study (ReCiDiF) were evaluated for clinical signs and presence of yeasts in nose, mouth, anus, perineum, and urine. Candida was diagnosed by positive microscopy, confirmed by positive culture or polymerase chain reaction. After treatment, women were divided into groups according to their response to a fluconazole maintenance regimen (optimal, suboptimal, and nonresponders). RESULTS: The most frequent extravaginal Candida spp. were detected in urine (79.5%), perineum (78.6%), and anus (56.4%). Carriers of Candida in the mouth were more likely to have it in the anus (OR 3.2; 95% CI 1.4-7.7). Colonization in anus (OR 3.3; 95% CI 1.3-8.1) or in multiple extravaginal sites (OR 3.0; CI95% 1.2-7.4) was related to nonresponse to therapy. Candidal carriage in the anus did not increase anal and perianal symptoms. CONCLUSION: Women with anal carriage and multiple-site candidal colonization are less likely to respond to individualized decreasing dose fluconazole therapy.

Short- and long-term influence of the levonorgestrel-releasing intrauterine system (Mirena®) on vaginal microbiota and Candida.

BACKGROUND: Recurrent vulvovaginal infections are a frequent complaint in young women in need of contraception. However, the influence of the contraceptive method on the course of the disease is not well known. AIM: To investigate the influence of the levonorgestrel-releasing intrauterine-system (LNG-IUS) on the vaginal microflora. METHODS: Short-term (3 months) and long-term (1 to 5 years) changes of vaginal microbiota were compared with pre-insertion values in 252 women presenting for LNG-IUS insertion. Detailed microscopy on vaginal fluid was used to define lactobacillary grades (LBGs), bacterial vaginosis (BV), aerobic vaginitis (AV) and the presence of Candida. Cultures for enteric aerobic bacteria and Candida were used to back up the microscopy findings. Fisher's test was used to compare vaginal microbiome changes pre- and post-insertion. RESULTS: Compared to the pre-insertion period, we found a temporary worsening in LBGs and increased rates of BV and AV after 3 months of LNG-IUS. After 1 and 5 years, however, these changes were reversed, with a complete restoration to pre-insertion levels. Candida increased significantly after long-term carriage of LNG-IUS compared to the period before insertion [OR 2.0 (CL951.1-3.5), P=0.017]. CONCLUSIONS: Short-term use of LNG-IUS temporarily decreases lactobacillary dominance, and increases LBG, AV and BV, but after 1 to 5 years these characteristics return to pre-insertion levels, reducing the risk of complications to baseline levels. Candida colonization, on the other hand, is twice as high after 1 to 5 years of LNG-IUS use, making it less indicated for long-term use in patients with or at risk for recurrent vulvovaginal candidosis.

Aerobic vaginitis: no longer a stranger.

Aerobic vaginitis (AV) is the name given in 2002 to a vaginal infectious entity which was not recognized as such before. It is characterized by abnormal (dysbiotic) vaginal microflora containing aerobic, enteric bacteria, variable levels of vaginal inflammation and deficient epithelial maturation. Although AV and bacterial vaginosis (BV) share some characteristics, such as a diminished number or absence of lactobacilli, increased discharge (fishy smelling in BV, while in severe forms of AV, a foul, rather rotten smell may be present) and increased pH (often more pronounced in AV), there are also striking differences between the two. There is no inflammation in women with BV, whereas the vagina of women with AV often appears red and edematous, and may even display small erosions or ulcerations. The color of the discharge in BV is usually whitish or gray and of a watery consistency, whereas in AV it is yellow to green and rather thick and mucoid. Women with BV do not have dyspareunia, while some women with severe AV do. Finally, the microscopic appearance differs in various aspects, such as the presence of leucocytes and parabasal or immature epithelial cells in AV and the absence of the granular aspect of the microflora, typical of BV. Despite all these differences, the distinction between AV and BV was not recognized in many former studies, leading to incomplete and imprecise diagnostic workouts and erroneous management of patients in both clinical and research settings. The prevalence of AV ranges between 7 and 12%, and is therefore less prevalent than BV. Although still largely undiagnosed, many researchers and clinicians increasingly take it into account as a cause of symptomatic vaginitis. AV can co-occur with other entities, such as BV and candidiasis. It can be associated with dyspareunia, sexually transmitted infections (such as human papilloma virus, human immunodeficiency virus, Trichomonas vaginalis and Chlamydia trachomatis), chorioamnionitis, fetal infection, preterm birth and cervical dysplasia. Many other possible pathological associations are currently under investigation. The diagnosis of AV is made using wet mount microscopy, ideally using phase contrast. An AV score is calculated, according to: lactobacillary grade, presence of inflammation, proportion of toxic leucocytes, characteristics of the microflora and presence of immature epithelial cells. To circumvent the hurdle of microscopic investigation, some groups have begun to develop nucleic-acid-based and enzymatic diagnostic tests, but the detailed information obtained with phase contrast microscopy is irreplaceable. The best treatment is not yet fully determined, but it must be tailored according to the microscopic findings and the patient's needs. There is a role for local estrogen therapy, corticosteroids, antimicrobials and probiotics. Further research will reveal more precise data on diagnosis, pathogenesis, management and prevention.