A molecular view on the interference established between vaginal Lactobacilli and pathogenic Candida species: Challenges and opportunities for the development of new therapies.

Vaginal infectious diseases caused by viruses and bacteria have been linked to the occurrence of dysbiosis, that is, a reduction in the abundance of the normally dominating vaginal Lactobacillus species. Mucosal infections in the vagina and/or vulva caused by Candida species, usually known as vulvovaginal candidiasis (or VVC), are among the leading causes of diseases in the vaginal tract. The existence of a clear link between the occurrence of dysbiosis and the development of VVC is still unclear, although multiple observations point in that direction. Based on the idea that vaginal health is linked to a microbiota dominated by lactobacilli, several probiotics have been used in management of VVC, either alone or in combination with antifungals, having obtained different degrees of success. In most cases, the undertaken trials resorted to lactobacilli species other than those indigenous to the vaginal tract, although in vitro these vaginal species were shown to reduce growth, viability and virulence of Candida. In this paper we overview the role of lactobacilli and Candida in the vaginal micro- and myco-biomes, while discussing the results obtained in what concerns the establishment of interference mechanisms in vivo and the environmental factors that could determine that. We also overview the molecular mechanisms by which lactobacilli species have been shown to inhibit pathophysiology of Candida, including the description of the genes and pathways determining their ability to thrive in the presence of each other. In a time where concerns are increasing with the emergence of antifungal resistance and the slow pace of discovery of new antifungals, a thorough understanding of the molecular mechanisms underneath the anti-Candida effect prompted by vaginal lactobacilli is of utmost importance to assure a knowledge-based design of what can be a new generation of pharmaceuticals, eventually focusing therapeutic targets other than the usual ones.

Vaginal Epithelial Cell Membrane-Based Phototherapeutic Decoy Confers a "Three-in-One" Strategy to Treat against Intravaginal Infection of Candida albicans.

Phototherapy is an effective strategy to control Candida albicans (C. albicans) infection without raising the concern of drug resistance. Despite its effectiveness, a higher dose of phototherapeutic power is required for C. albicans elimination compared to bacteria that have to be used, which is readily accompanied by off-target heat and toxic singlet oxygen to damage normal cells, thus limiting its usefulness for antifungal applications. Here to overcome this, we develop a "three-in-one" biomimetic nanoplatform consisting of an oxygen-dissolved perfluorocarbon camouflaged by a photosensitizer-loaded vaginal epithelial cell membrane. With a cell membrane coating, the nanoplatform is capable of specifically binding with C. albicans at the superficial or deep vaginal epithelium, thereby centering the phototherapeutic agents on C. albicans. Meanwhile, the cell membrane coating endows the nanoplatform to competitively protect healthy cells from candidalysin-medicated cytotoxicity. Upon candidalysin sequestration, pore-forming on the surface of the nanoplatform accelerates release of the preloaded photosensitizer and oxygen, resulting in enhanced phototherapeutic power for improved anti-C. albicans efficacy under near-infrared irradiation. In an intravaginal C. albicans-infected murine model, treatment with the nanoplatform leads to a significantly decreased C. albicans burden, particularly when leveraging candidalysin for further elevated phototherapy and C. albicans inhibition. Also, the same trends hold true when using the nanoplatform to treat the clinical C. albicans isolates. Overall, this biomimetic nanoplatform can target and bind with C. albicans and simultaneously neutralize the candidalysin and then transform such toxins that are always considered a positive part in driving C. albicans infection with the power of enhancing phototherapy for improved anti-C. albicans efficacy.

Lived experience of medical management in recurrent vulvovaginal candidiasis: a qualitative study of an uncertain journey.

BACKGROUND: Recurrent vulvovaginal candidiasis (RVVC) is experienced by up to 10% of pre-menopausal women globally, yet there is limited research exploring the perspective of women living with this challenging condition. METHODS: Semi-structured interviews with Australian women experiencing RVVC were conducted between April-July 2021. Interviews were transcribed verbatim, and qualitative interpretative phenomenological analysis (IPA) was conducted. RESULTS: Ten RVVC patients were interviewed. IPA revealed an uncertain journey living with RVVC for all participants ranging from initial symptoms and difficulties in obtaining a diagnosis, the trial and error of symptom management, to the overall debilitating impact of living with a personal and intimate health condition. Four key themes were identified: Theme 1 outlined challenges and delays in diagnosis and clinically appropriate management. Theme 2 found that health care professional (HCP) knowledge limitations impacted RVVC management. Theme 3 illustrated the consequences of a lack of HCP support leading to self-referral and self-education. Theme 4 details the significant emotional and psycho-social repercussions of RVVC. CONCLUSIONS: This debilitating, life-long disease has a prolonged effect on women both physically and psychologically. Living with RVVC seems an uncertain journey that, to a large degree, women feel they must navigate alone. While resilience and self-empowerment were noted, better support through evidence-based treatment options, educated and evidence-informed HCPs and a sympathetic social support network is needed to decrease the disease burden. Future clinical management guidelines and patient support need to consider the findings of this study.

Probiotic lactobacilli in formulas and hygiene products for the health of the urogenital tract.

Lactobacilli are the predominant microorganisms of the healthy human vagina. A novel alternative for the prevention and treatment of female urogenital tract infections (UGTI) is the inclusion of these microorganisms as active pharmaceutical ingredients in probiotic formulas, and more recently in female hygienic products. Probiotics are defined as "live microorganisms that, when administered in adequate amounts, confer a health benefit on the host." A list of requirements must be considered during the development of probiotic product/formula for the female urogenital tract (UGT). This review aims to resume the requirements, probiotic characteristics, and clinical trial applied to determine the effect of probiotic and potentially probiotic strains on different woman's physiological and pathological conditions, and in preterm birth prevention. A revision of female hygienic products available in the world market is included, together with novel studies applying nanotechnology for Lactobacillus incorporation in hygienic products. Further studies and well-designed clinical trials are urgently required to complement the current knowledge and applications of probiotics in the female UGT. The use of probiotic formulas and products will improve and restore the ecological equilibrium of the UGT microbiome to prevent and treat UGTI in women under different conditions.

Guideline: Vulvovaginal candidosis (AWMF 015/072, level S2k).

Approximately 70-75% of women will have vulvovaginal candidosis (VVC) at least once in their lifetime. In premenopausal, pregnant, asymptomatic and healthy women and women with acute VVC, Candida albicans is the predominant species. The diagnosis of VVC should be based on clinical symptoms and microscopic detection of pseudohyphae. Symptoms alone do not allow reliable differentiation of the causes of vaginitis. In recurrent or complicated cases, diagnostics should involve fungal culture with species identification. Serological determination of antibody titres has no role in VVC. Before the induction of therapy, VVC should always be medically confirmed. Acute VVC can be treated with local imidazoles, polyenes or ciclopirox olamine, using vaginal tablets, ovules or creams. Triazoles can also be prescribed orally, together with antifungal creams, for the treatment of the vulva. Commonly available antimycotics are generally well tolerated, and the different regimens show similarly good results. Antiseptics are potentially effective but act against the physiological vaginal flora. Neither a woman with asymptomatic colonisation nor an asymptomatic sexual partner should be treated. Women with chronic recurrent Candida albicans vulvovaginitis should undergo dose-reducing maintenance therapy with oral triazoles. Unnecessary antimycotic therapies should always be avoided, and non-albicans vaginitis should be treated with alternative antifungal agents. In the last 6 weeks of pregnancy, women should receive antifungal treatment to reduce the risk of vertical transmission, oral thrush and diaper dermatitis of the newborn. Local treatment is preferred during pregnancy.

Preclinical approaches in vulvovaginal candidiasis treatment with mucoadhesive thermoresponsive systems containing propolis.

Vulvovaginal candidiasis (VVC) is a common vaginitis that affects women, especially in childbearing age, caused by Candida albicans in almost 80% of cases. Considering the limited drug arsenal available and the increasing fungal resistance profile, the search for new therapeutic sources with low toxicity and easy administration should be supported. Propolis has been used as a traditional medicine for multiple diseases, considering its particular composition and pharmaceutical properties that permits its wide applicability; it has also emerged as a potential antifungal agent. Thus, this study performed an in vitro and in vivo investigation into the efficacy of a new mucoadhesive thermoresponsive platform for propolis delivery (MTS-PRPe) in a preclinical murine model of VVC treatment caused by C. albicans. The methodologies involved chemical analysis, an assessment of the rheological and mucoadhesive properties of propolis formulations, in vitro and in vivo antifungal evaluations, histological evaluations and electron microscopy of the vaginal mucosa. The results demonstrated the antifungal activity of propolis extract and MTS-PRP against the standard strain and a fluconazole-resistant clinical isolate of C. albicans, in both in vitro and in vivo assays. These results were similar and even better, depending on the propolis concentration, when compared to nystatin. Thus, the formulation containing propolis exhibited good performance against C. albicans in a vulvovaginal candidiasis experimental model, representing a promising opportunity for the treatment of this infection.

Identification of sulfur components enhancing the anti-Candida effect of Lactobacillus rhamnosus Lcr35.

GYNOPHILUS (Lcr REGENERANS) is a live biotherapeutic product (LBP) aimed at restoring the vaginal microbiome and contains the live biotherapeutic microorganism Lactobacillus rhamnosus Lcr35. In this study, the LBP formulation and manufacturing process significantly enhanced the anti-Candida activity of L. rhamnosus Lcr35, with a complete loss of viability of the yeast after 48 h of coincubation. Sodium thiosulfate (STS), one excipient of the product, was used as a potentiator of the anti-Candida spp. activity of Lactobacilli. This contact-independent phenomenon induced fungal cell disturbances, as observed by electron microscopy observations. Nonverbal sensory experiments showed clear odor dissimilarities between cocultures of L. rhamnosus Lcr35 and C. albicans in the presence and absence of STS, suggesting an impact of odor-active metabolites. A volatolomic approach allowed the identification of six odor-active compounds, including one sulfur compound that was identified as S-methyl thioacetate (MTA). MTA was associated with the antifungal effect of Lcr35, and its functional link was established in vitro. We show for the first time that the LBP GYNOPHILUS, which is a highly active product in the reduction of vulvovaginal candidiasis, requires the presence of a sulfur compound to fully achieve its antifungal effect.

Improving the Diagnosis of Vulvovaginitis: Perspectives to Align Practice, Guidelines, and Awareness.

Vulvovaginitis is a frequent reason for women to see a health care provider and has been linked to adverse reproductive and psychosocial consequences. Accurate diagnosis is a cornerstone of effective treatment, yet misdiagnosis of this condition approaches 50%, raising the risk of recurrence. The past 3 decades have seen few improvements over the traditional means of diagnosing the 3 main causes of vaginitis: bacterial vaginosis, Candida infections, and trichomoniasis. Newer molecular tests, which are both more sensitive and specific, have introduced the potential to transform the diagnosis of vaginitis-ensuring more accurate diagnoses and timely interventions, while reducing health care costs and enhancing patients' quality of life. Clinical approaches and professional guidelines should be updated to reflect advances in molecular testing and improve the diagnosis and management of acute and recurrent vulvovaginitis.

Impact of a lactobacilli-containing gel on vulvovaginal candidosis and the vaginal microbiome.

Vulvovaginal candidosis (VVC) is a common condition with severe symptoms and high recurrence rates. Probiotic lactobacilli are explored as alternatives to azole treatments. Although the vaginal microbiota is generally not depleted in lactobacilli during VVC, studies indicate that the functionality and antimicrobial activity of the lactobacilli is impaired. We selected three strains from the Lactobacillus genus complex (L. rhamnosus GG, L. pentosus KCA1 and L. plantarum WCFS1) based on in vitro evaluation and formulated them in a gel for vaginal application. This gel was evaluated in 20 patients suffering from acute VVC, who were followed for four weeks including a 10-day treatment period. The microbiome was assessed through 16S rRNA (bacteria) and internal transcribed spacer (ITS; fungi) amplicon sequencing, supplemented with quantitative PCR, culture and microscopy for Candida evaluation. 45% of women did not require rescue medication (3×200 mg fluconazole), implying an improvement of their symptoms. These women showed similar end concentrations of fungi as women treated with fluconazole. Moreover, fluconazole appeared to reduce numbers of endogenous lactobacilli. Our study points towards important aspects for future selection of lactobacilli for probiotic use in VVC and the need to investigate possible negative influences of azoles on the vaginal bacterial community.

Vaginosis bacteriana y candidiasis vaginal: análisis de una nueva alternativa terapéutica / Bacterial vaginosis and vaginal candidiasis: analysis of a new therapeutic alternative

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Prospective trial for the clinical efficacy of anogenital skin care with miconazole nitrate-containing soap for diaper candidiasis.

Anogenital skin care for the elderly remains an umbrella term concerning protective and non-interventional regimens, particularly for ordinary diaper users. Our recent investigation has demonstrated the preventive effect of daily anogenital washing with miconazole nitrate-containing soap to the development of diaper candidiasis. We extended this work to cover our hypothesis as to whether the miconazole soap has a therapeutic benefit in genital candidiasis. The study outline includes: (i) the enrollment of 21 bedridden inpatients (84 ± 9 years; eight men and 13 women) who were diagnosed clinically and mycologically with genital candidiasis, and who had never received topical and/or systemic antifungal agents; (ii) administration of anogenital washing with 0.75% miconazole-containing soap once daily for 4 weeks; and (iii) assessment of clinical symptoms and detection of Candida materials by culture and microscopic examination. As assessed by clinical symptom scoring for incontinence-associated dermatitis (IAD), the ratio of patients with severe to moderate symptoms dramatically decreased by 2 weeks and 10 of 21 patients became symptom-free at 4 weeks. The IAD clinical severity score was significantly decreased at 4 weeks. Compared with the baseline positivity, both microscopic and cultured Candida-positive rates were significantly decreased at 4 weeks after washing. All culture-detected fungi were Candida albicans. Severe adverse events did not occur in all participants. Individual medical and risk factors had no significant correlation with clinical severity and duration of candidiasis on variance analysis. In conclusion, topical washing with miconazole soap is a safe and reliable non-medical approach for soothing diaper-associated genital candidiasis in bedridden inpatients in whom it is difficult to perform prompt medical examination.

Blue light therapy to treat candida vaginitis with comparisons of three wavelengths: an in vitro study.

Anti-fungal blue light (ABL) therapies have been widely studied to treat various microbial infections in the literature. The blue light with wavelengths ranging from 400 to 470 nm has been reported to be effective to inhibit various kinds of bacteria and fungi. The existing studies usually report the viability rates of the pathogens under the irradiation of the blue light with different dosage parameters. However, to the best of our knowledge, there is still no work especially focusing on studying the effect of ABL therapies on treating candida vaginitis, where it is important to study the viability of both the Candida albicans (C. albicans) and the human vaginal epithelial cells. It is the purpose of this work to conduct ABL experiments on both of these two cells, analyze the effects, and determine the best ABL wavelength out of three candidates, i.e., 405-nm, 415-nm, and 450-nm wavelength. The viability rates of the C. albicans and the human vaginal epithelial cells irradiated by the three blue LED light sources were measured, whose irradiance (power density) were all set to 50 mW/cm2. The dynamic viability models of the C. albicans and the epithelial cells were built based on the experimental data. Moreover, in this work, we also built a functional relationship between the viability of these two types of cells, by which we further compared the effects of the blue light irradiation on both the C. albicans and vaginal epithelial cells. The experimental data showed that when an approximately 80% inhibiting rate of the C. albicans was achieved, the survival rates of the epithelial cells were 0.6700, 0.7748, and 0.6027, respectively for the treatment by the 405-nm, 415-nm, and 450-nm wavelength light. On the other hand, by simulating the functional relationship between the viability of the two types of cells, the survival rates of the epithelial cells became 0.5783, 0.6898, and 0.1918 respectively using the 405-nm, 415-nm and 450-nm wavelength light, when the C. albicans was completely inhibited. Therefore, both the experimental data and the model simulation results have demonstrated that the 415-nm light has a more effective anti-fungal result with less damage to the epithelial cells than the 405-nm and 450-nm light.

A Combination of Polybacterial MV140 and Candida albicans V132 as a Potential Novel Trained Immunity-Based Vaccine for Genitourinary Tract Infections.

Recurrent urinary tract infections (RUTIs) and recurrent vulvovaginal candidiasis (RVVCs) represent major healthcare problems with high socio-economic impact worldwide. Antibiotic and antifungal prophylaxis remain the gold standard treatments for RUTIs and RVVCs, contributing to the massive rise of antimicrobial resistance, microbiota alterations and co-infections. Therefore, the development of novel vaccine strategies for these infections are sorely needed. The sublingual heat-inactivated polyvalent bacterial vaccine MV140 shows clinical efficacy for the prevention of RUTIs and promotes Th1/Th17 and IL-10 immune responses. V132 is a sublingual preparation of heat-inactivated Candida albicans developed against RVVCs. A vaccine formulation combining both MV140 and V132 might well represent a suitable approach for concomitant genitourinary tract infections (GUTIs), but detailed mechanistic preclinical studies are still needed. Herein, we showed that the combination of MV140 and V132 imprints human dendritic cells (DCs) with the capacity to polarize potent IFN-γ- and IL-17A-producing T cells and FOXP3+ regulatory T (Treg) cells. MV140/V132 activates mitogen-activated protein kinases (MAPK)-, nuclear factor-κB (NF-κB)- and mammalian target of rapamycin (mTOR)-mediated signaling pathways in human DCs. MV140/V132 also promotes metabolic and epigenetic reprogramming in human DCs, which are key molecular mechanisms involved in the induction of innate trained immunity. Splenocytes from mice sublingually immunized with MV140/V132 display enhanced proliferative responses of CD4+ T cells not only upon in vitro stimulation with the related antigens contained in the vaccine formulation but also upon stimulation with phytohaemagglutinin. Additionally, in vivo sublingual immunization with MV140/V132 induces the generation of IgG and IgA antibodies against all the components contained in the vaccine formulation. We uncover immunological mechanisms underlying the potential mode of action of a combination of MV140 and V132 as a novel promising trained immunity-based vaccine (TIbV) for GUTIs.

Lactobacilli-containing vaginal probiotics to cure or prevent bacterial or fungal vaginal dysbiosis: a systematic review and recommendations for future trial designs.

BACKGROUND: Vaginal probiotics claiming to cure and/or prevent bacterial and/or fungal vaginal dysbiosis are available on the market but, until recently, did not have to be approved as drugs for human use. OBJECTIVES: We evaluated the impact of vaginal probiotics on bacterial vaginosis (BV) and vulvovaginal candidiasis (VVC) cure and/or recurrence, as well as vaginal microbiota (VMB) composition and vaginal detection of probiotic strains. SEARCH STRATEGY: We performed a systematic literature search in MEDLINE and Embase up to 15 January 2019. SELECTION CRITERIA: There were no restrictions in probiotic strains/formulations, study populations, and designs. BV had to be diagnosed by Nugent or Ison-Hay Gram stain scoring, VVC by culture, wet mount or PCR, and VMB composition/detection by molecular techniques. DATA COLLECTION AND ANALYSIS: The authors independently extracted data. MAIN RESULTS: All 22 vaginal probiotics evaluated in the 34 eligible studies contained Lactobacillus strains, and some contained additional active ingredients. The probiotics hold promise for BV cure and prevention, but much less so for VVC cure and prevention. No major safety concerns were reported in any of the studies. Vaginal detection of probiotic strains never lasted long beyond the dosing period, suggesting that they did not colonise the vagina. However, findings are not definitive because heterogeneity was high and the quality of most studies suboptimal. CONCLUSIONS: Availability of vaginal probiotics for vaginal health indications will likely decline in 2020 because of regulatory changes. We urge the field to invest in clinical evidence-based product development and to conduct future trials more rigorously. TWEETABLE ABSTRACT: Lactobacilli-containing vaginal probiotics hold promise for bacterial vaginosis cure and prevention, but not for vulvovaginal candidiasis.

Migrañas, candidiasis y acné. La solución única / Migraines, candidiasis and acne. One solution

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Probiotics for oral and vulvovaginal candidiasis: A review.

Dermatologists commonly prescribe medications such as antibiotics and corticosteroids that can increase the risk for candidiasis. Though conventional antifungals are often effective against candidiasis, they are not without side effects and species of Candida are gaining resistance. Probiotics help treat conditions such as post-antibiotic diarrhea and infectious diarrhea, and thus have the potential to help with Candida infections, as well. For this reason, we provide an overview of therapies prescribed in dermatology that may increase the risk for candidiasis, and we review the literature on whether probiotics are useful in the treatment and prevention of oral and vulvovaginal candidiasis to help dermatologists treating the condition be better informed about their supplemental use with conventional antifungals.

Probiotics and vaginal microecology: fact or fancy?

BACKGROUND: Probiotics are live microorganisms that, when administered in adequate amounts, should confer a health benefit to the host. Media sources tend to present probiotics as an appealing health promotion method able to prevent or treat a wide variety of clinical conditions. In obstetrics and gynaecology, Lactobacilli species are mainly used to restore the physiologic vaginal microbiota in order to treat bacterial vaginosis and vulvovaginal candidiasis (VVC) and prevent preterm birth. DISCUSSION: Several RCTs investigated the potential benefits of probiotics in gynaecological and obstetrics conditions. For all potential indications, recent specific meta-analyses have been published. Considering vulvovaginal candidiasis in non-pregnant women, probiotics slightly improved the short-term clinical and mycological cure, and reduced the 1-month relapse. However, no important impact of probiotic use was observed on long-term clinical or mycological cure. Similarly, the addition of probiotics to metronidazole for the treatment of bacterial vaginosis was not shown to provide any additional benefit. In obstetrics, using probiotics during pregnancy neither decreased nor increased the risk of preterm birth before 34 weeks or before 37 weeks. Similarly, no benefits emerged for gestational diabetes, preterm premature rupture of membrane, and small and large for gestational age infants. CONCLUSION: Despite increasing marketing of probiotics for the treatment of vulvovaginal candidiasis and prevention of preterm birth robust evidence demonstrating a beneficial effect is scarce. Moreover, there was considerable heterogeneity among the different studies in terms of route of administration, strain/s of probiotic adopted, and length of probiotic use. Before recommending the systematic use of probiotics to treat bacterial vaginosis and VVC and prevent preterm birth, high-quality research is needed. Professional medical associations should issue recommendations defining if, when, and how probiotics should be used for gynaecological disorders.

Alternative and complementary therapies for vulvovaginal candidiasis.

When it comes to women's health, treating vaginal infections makes up a high proportion of the gynecological services. Among the forms of vaginitis, vulvovaginal candidiasis (VVC) is considered the second most common. Demand for new treatment alternatives is increasingly relevant, especially for therapies with fewer side effects, better tolerability, and lower cost, while still offering improved quality of life in terms of disease prevention. This study intended to investigate the alternative therapies described for the adjuvant treatment of vulvovaginitis caused by Candida species, including alternative and complementary treatment methods used by women. This literature review is based on articles written in English and Portuguese in the PubMed, Google Scholar, and SciELO databases. This study was conducted for the most part using the Brazilian Government's Capes Periodicals Portal, which directs to Google Scholar and PubMed. Since the 1980s, there has been growing interest in alternative therapies in Brazil, a trend which also began in other Western countries in the second half of the twentieth century. Some alternative treatments include substances with antifungal activity, some substances help restore the balance of the vaginal microbiota, while others have an inhibitory activity on microbial virulence factors. The proper use of therapeutic alternatives can effectively contribute to the treatment of VVC, but it should be remembered that some chemical products, such as boric acid or vinegar, and even natural products such as propolis, garlic, and tea tree may have undesirable side effects, having not been tested by well-designed clinical studies. Even so, alternative therapies in the treatment of VVC do have support in the scientific literature.