Randomised clinical trial in women with Recurrent Vulvovaginal Candidiasis: Efficacy of probiotics and lactoferrin as maintenance treatment.

BACKGROUND: Vulvovaginal candidiasis (VVC) is a recurrent vaginal condition in childbearing women. OBJECTIVES: The aim of this study was to assess the efficacy of an oral formulation containing Lactobacillus acidophilus GLA-14, Lactobacillus rhamnosus HN001 and bovine lactoferrin on symptoms and recurrence of VVC as adjuvant therapy to topical clotrimazole. PATIENTS/METHODS: Forty-eight women positive for C. albicans, symptoms of VVC and documented history of recurrences were randomised into 2 groups receiving verum or placebo (2 capsules/day for 5 days followed by 1 capsule/day for additional 10 days) as adjuvant treatment to clotrimazole (induction phase) followed by a maintenance cycle of 6 months (1 capsule/day verum or placebo for 10 consecutive days each month). Symptoms, overall cure rate and recurrence rate were assessed. RESULTS: After clotrimazole therapy, a significant improvement of symptoms was shown in both groups. However, only women treated with probiotics and lactoferrin showed a significant improvement of itching and discharge at 3 and 6 months. During the six-month follow-up, recurrences were significantly less in the intervention group vs placebo (33.3% vs 91.7% after 3 months and 29.2% vs 100% after 6 months). CONCLUSIONS: The results show that the investigated lactobacilli mixture in combination with lactoferrin represents a safe and effective adjuvant approach for reducing symptoms and recurrences of RVVC.

Development, characterization, and in vitro-in vivo evaluation of polymeric nanoparticles containing miconazole and farnesol for treatment of vulvovaginal candidiasis.

Vulvovaginal candidiasis (VVC) is caused mainly by the opportunistic fungus Candida albicans, and its yeast to hyphae transition is considered a major virulence factor. Farnesol is a molecule that inhibits yeast to hyphae transition. The increased incidence of VVC has influenced a need for developing new therapeutic strategies. The objective was to develop a mucoadhesive nanostructured system composed of miconazole and farnesol co-encapsulated within chitosan nanoparticles. The miconazole presented a minimal inhibitory concentration (MIC) of 1 µg/ml against C. albicans. The farnesol was capable of inhibiting yeast to hyphae transition at levels greater or equal to 300 µM. The combination of miconazole and farnesol showed no change in miconazole MIC. Chitosan nanoparticles containing miconazole and farnesol were prepared by ionic gelation and showed favorable characteristics for use on mucous membranes. They showed size variation and polydispersion index (PDI) after 30 days, but the efficiency of drug encapsulation was maintained. Regarding toxicity in cultured fibroblasts (BALB/c 3T3) the nanoparticles were considered nontoxic. The nanoparticles showed antifungal activity against the C. albicans strain used with MICs of 2.5 µg/ml and 2 µg/ml for nanoparticles containing miconazole or miconazole/farnesol, respectively. Nanoparticles containing farnesol inhibited yeast to hyphae transition at concentrations greater than or equal to 240 µM. The in vivo antifungal activity was assessed in the murine model for VVC. The results suggested that chitosan nanoparticles containing miconazole and farnesol were effective at inhibiting fungal proliferation. Additionally, chitosan nanoparticles containing farnesol were capable of decreasing the pathogenicity of infection, demonstrated through the absence of inflammation.

Current treatment options for vulvovaginal candidiasis caused by azole-resistant Candida species.

INTRODUCTION: Clinicians are increasingly challenged by patients with refractory vulvovaginal candidiasis (VVC) caused by azole-resistant Candida species. Fluconazole resistant C.albicans is a growing and perplexing problem following years of indiscriminate drug prescription and unnecessary drug exposure and for which there are few therapeutic alternatives. Regrettably, although the azole class of drugs has expanded, new classes of antifungal drugs have not been forthcoming, limiting effective treatment options in patients with azole resistant Candida vaginitis. AREAS COVERED: This review covers published data on epidemiology, pathophysiology and treatment options for women with azole-resistant refractory VVC. EXPERT OPINION: Fluconazole resistant C.albicans adds to the challenge of azole resistant non-albicans Candida spp. Both issues follow years of indiscriminate drug prescription and unnecessary fluconazole exposure. Although an understanding of azole resistance in yeast has been established, this knowledge has not translated into useful therapeutic advantage. Treatment options for such women with refractory symptoms are extremely limited. New therapeutic options and strategies are urgently needed to meet this challenge of azole drug resistance.

Pulsatilla decoction inhibits Candida albicans proliferation and adhesion in a mouse model of vulvovaginal candidiasis via the Dectin-1 signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Pulsatilla decoction (PD) is a classical prescription in Traditional Chinese Medicine (TCM) and has been reported to have inhibitory effects on Candida albicans proliferation. STUDY AIM: To investigate the therapeutic effects of PD in the treatment of Vulvovaginal candidiasis (VVC) and elucidate the potential mechanism. MATERIALS AND METHODS: Female BALB/c mice (N = 90) were randomized to six treatment groups, including the Control group, Model group, three PD groups and Fluconazole group which served as a positive control (20 mg/kg weekly). The three PD groups (low dose group, medium dose group and high dose group) were given a daily intragastric gavage of PD at doses of 5, 10 and 20 g/kg, respectively. Five animals from each group were euthanized on Day 4, Day 7 and Day 14 after treatment. Colony forming unit (CFU) was measured by the serial dilution method. The degree of infection was assessed by Gram staining, Periodic acid schiff (PAS) staining, Hematoxylin and eosin (H&E) staining and Scanning electron microscopy (SEM). The serum inflammation levels were determined by a Luminex assay. Gene and protein expression levels of components of the Dectin-1 signaling pathway were determined by Real-time PCR, Western-blot and immunohistochemistry, respectively. RESULTS: The administration of PD significantly decreased the fungal load from Day 7 post-infection onwards and decreased the number of visible microorganisms based on findings from Gram staining, PAS staining and SEM. H&E staining indicated that the impaired histological profiles were improved in all three PD groups. PD led to a significantly lower level of IL-23 in the serum; the levels of IL-10 and TNF-α were also decreased, although the differences were not significant. Furthermore, a substantial downregulation of Dectin-1, CARD9 and NF-κB mRNA levels and Dectin-1, Syk, CARD9 and NF-κB protein levels was observed after the administration of PD. CONCLUSION: This study suggests that PD exerts inhibitory effects on C. albicans proliferation, adhesion and inflammation and simultaneously downregulates the expression levels of important genes and proteins associated with the Dectin-1 pathway, highlighting the potential application of PD to improve the clinical management of VVC.

Saccharomyces cerevisiae-based probiotic as novel anti-fungal and anti-inflammatory agent for therapy of vaginal candidiasis.

Previously we demonstrated that the treatment with live Saccharomyces cerevisiae exerts beneficial therapeutic effects against vaginal candidiasis. Here, we address potential mechanisms particularly examining the probiotic capacity to modulate both fungus and host-related factors. We show that the S. cerevisiae-based probiotic markedly affects the expression of virulence traits of Candida albicans such as aspartyl proteinases (SAPs) as well as hyphae-associated proteins Hwp1 and Ece1 in the vaginal cavity. On the host side, the probiotic suppression of the influx of neutrophils caused by the fungus into the vaginas of the mice is likely related to: (1) lower production of interleukin-8; and (2) inhibition of SAPs expression. However, these neutrophils displayed reactive oxygen species hyperproduction and increased killing activity as compared to the neutrophils of placebo-treated mice. There was no evidence of any cytotoxic effect by the probiotic, either when used in vivo on vaginal epithelial cell and organ architecture, or in in vitro in human vaginal epithelium. Inactivated yeast cells did not affect any of the factors above. In summary, the data suggest that the beneficial effect exerted by this S. cerevisiae-based probiotic is the result of its interference with the expression of fungus virulence factors coupled with the modulation of the inflammatory response of the host.

Gardnerella, Trichomonas and Candida in cervical smears of 58,904 immigrants participating in the Dutch national cervical screening program.

OBJECTIVE: To report the prevalence of Gardnerella, Trichomonas and Candida in the cervical smears of 9 immigrant groups participating in the Dutch national cervical screening program. STUDY DESIGN: Cervical smears were taken from 58,904 immigrant participants and 498,405 Dutch participants. As part of the routine screening process, all smears were screened for the overgrowth of Gardnerella (i.e. smears with an abundance of clue cells) and for the presence of Trichomonas and Candida. The smears were screened by 6 laboratories, all of which use the Dutch KOPAC coding system. The odds ratio and confidence interval were calculated for the 9 immigrant groups and compared to Dutch participants. RESULTS: Immigrants from Suriname, Turkey and the Dutch Antilles have a 2-5 times higher prevalence of Gardnerella and Trichomonas when compared to native Dutch women. Interestingly, the prevalence of Trichomonas in cervical smears of Moroccan immigrants is twice as high, yet the prevalence of Gardnerella is 3 times lower than in native Dutch women. CONCLUSIONS: Immigrants with a high prevalence of Gardnerella also have a high prevalence of Trichomonas. In the context of the increased risk of squamous abnormalities in smears with Gardnerella, such slides should be screened with extra care.

[Treatment of atrophic and irritative vulvovaginal symptoms with an anhydrous lipogel and its complementary effect with vaginal estrogenic therapy: new evidences]. / Trattamento dei disturbi trofici e irritativi vulvovaginali con un lipogel anidro e suo effetto complementare alla terapia estrogenica per via vaginale: nuovi approfondimenti.

It is sometimes difficult to treat vulvovaginal itching and dryness, which represent frustrating symptoms for both patients and doctors. In case that the etiological agent is Candida albicans, effective antimycotic therapies are available; however, itching is often caused by aspecific allergic-irritative factors, which are difficult to be defined. In these cases, patients are invited to limit local irritative factors; nevertheless, this advice is not always taken and sometimes it turns out to be insufficient. Besides behavioral suggestions, a therapeutic support would be useful; medical doctors habitually prescribe local symptomatic treatments which, however, do not target numerous causes of irritative vulvovaginal symptomatology, though they are formulated for vulvovaginal application. If there is estrogenic deficit, the best therapeutic approach is based on topical estrogenic therapy, which is sometimes ineffective on vulvar symptoms. Frequently, it is necessary to choose a complementary therapeutic tool for vaginal application in order to alleviate itching, burning, erythema, dryness. The aim of this study was to evaluate the efficacy of an innovative anhydrous lipogel containing vitamin E and boswellic acids. Results of this study, performed on 34-58-year-old patients, confirmed the efficacy of the lipogel on irritative vulvovaginal symptoms. In postmenopausal women, the lipogel is a useful synergistic complement to topical hormonal therapy.

Protective activity of geranium oil and its component, geraniol, in combination with vaginal washing against vaginal candidiasis in mice.

In order to evaluate an effective administration method of essential oils for vaginal candidiasis, efficacy of vaginal application of essential oils against murine experimental candidiasis was investigated. The effect on vaginal inflammation and Candida growth form was also studied. Vaginal candidiasis was established by intravaginal infection of C. albicans to estradiol-treated mice. These mice intravaginally received essential oils such as geranium and tea tree singly or in combination with vaginal washing. Vaginal administration of clotrimazole significantly decreased the number of viable C. albicans cells in the vaginal cavity by itself. In contrast, these essential oils did not lower the cell number. When application of geranium oil or geraniol was combined with vaginal washing, the cell number was decreased significantly. The myeloperoxidase activity assay exhibited the possibility that essential oils worked not only to reduce the viable cell number of C. albicans, but also to improve vaginal inflammation. The smear of vaginal washing suspension suggested that more yeast-form cells appeared in vaginal smears of these oil-treated mice than in control mice. In vitro study showed that a very low concentration (25 microg/ml) of geranium oil and geraniol inhibited mycelial growth, but not yeast growth. Based on these findings, it is estimated that vaginal application of geranium oil or its main component, geraniol, suppressed Candida cell growth in the vagina and its local inflammation when combined with vaginal washing.

Vaginitis: making sense of over-the-counter treatment options.

BACKGROUND: The FDA approved over-the-counter (OTC) use of vaginal antifungals in 1990. Subsequently, a plethora of OTC products have become available to women on drugstore shelves. OBJECTIVES: The purpose of this study was to determine the availability of OTC products marketed for the treatment of vaginitis and to determine if their efficacy had been confirmed by published prospective randomized control trials (RCTs). MATERIALS AND METHODS: The authors chose four retail locations frequented by women seeking vaginitis treatment. All products deemed a viable treatment option were purchased. Results. All intravaginal imidazoles purchased, regardless of treatment duration or active ingredient, were found to be of proven efficacy. We were unable to find an RCT confirming the effectiveness of vaginal anti-itch creams and homeopathic treatments for vaginitis. CONCLUSION: 45% of products available to women in the feminine hygiene section of the stores surveyed could not be confirmed to be effective for treating infectious vaginitis.

Evaluation of carvacrol and eugenol as prophylaxis and treatment of vaginal candidiasis in an immunosuppressed rat model.

OBJECTIVES: Anticandidal activity of carvacrol and eugenol, the major phenolic components of oregano and clove essential oils, respectively, were tested in vivo. METHODS: Efficacy evaluation of carvacrol and eugenol in the prophylaxis and treatment of experimental vaginal candidiasis was performed in immunosuppressed rats. The anticandidal activity was analysed by microbiological and histological techniques and was compared with that of nystatin. RESULTS: Microbiologically, prophylactic treatment with carvacrol eradicated the vaginal fungal burden of infected rats, whereas eugenol reduced the number of colony counts of Candida albicans in vaginas of infected rats by 98.9% 10 days after inoculation. Therapeutic treatment for 7 consecutive days with carvacrol was able to eradicate the vaginal candidal burden in 7/9 of the infected rats and reduced the number of colony counts of C. albicans in vaginas of the two remaining rats by 98%. Treatment with eugenol completely cured 2/9 of the infected animals, but the 7/9 still infected showed an 84% reduction of colony counts of C. albicans in their vaginas. Histologically, in all treated rats, no Candida organisms were found in the lumina of the vagina; this was in contrast to control groups in which many yeasts, strongly stained with periodic acid-Schiff, were observed. The results obtained with nystatin used at 10-fold minimal inhibitory concentration confirm the validity of this model. CONCLUSIONS: Carvacrol and eugenol could be considered as promising products in the treatment of vaginal candidiasis. This work is a preliminary contribution to the development of a new generation of efficient and natural antifungal agents for curative treatment and prophylaxis.

The importance of diagnostic work-up in the management of candidal vulvovaginitis. A prospective study.

OBJECTIVE: To assess the accuracy of the diagnostic work-up in identifying vaginal candidal infection, and to determine the safety, efficacy and speed of action of clotrimazole vaginal tablets. PARTICIPANTS: Two hundred and twenty-three patients with symptoms and signs of candidal infection, a presence of vaginal pH < or = 4.5 and positive 10% KOH examination. METHODS: After vaginal culture was taken, the eligible patients were treated with clotrimazole 200 mg vaginal tabs (manufactured by Teva or Agis). RESULTS: Cultures grew Candida albicans in 189 cases (85%), and Candida non-albicans in five (2.2%); 29 patients (13%) did not have any candidal infection. Of the 189 C. albicans-positive patients, 174 were reassessed for effects of clotrimazole treatment by self-reports and objective measures. Ninety-four percent of the patients reported improvement after treatment, rated moderate to high by 87%. The physician evaluation was similar: some improvement in 96%, and moderate or high improvement in 91%. At the second examination, 7.5% of the treated patients still had a positive culture for Candida albicans, and they remained positive on KOH microscopic examination, although vaginal pH was significantly higher. Maximal improvement was recorded three to four days after starting treatment. CONCLUSION: It is important that the diagnostic work-up for suspected candidal infections consist of at least vaginal pH measurement and microscopy study with KOH. We encourage the use of vaginal cultures, especially in recurrent cases. Clotrimazole is a safe and effective treatment.

Topical antiseptics as an alternative in the treatment of acute vulvovaginal candidosis.

The aim of this prospective, multicenter, randomized, case-control study was to investigate the efficacy of a nonspecific mucosal antiseptic (octenidine dihydrochloride, phenoxyethanol) with proven antifungal effects, in patients with acute symptomatic vaginal candidosis, in comparison with a specific topical antifungal agent (clotrimazole), particularly in respect to non-Candida albicans yeasts. A total of 491 patients from 29 gynecological practices, who had new clinical vaginal mycosis, not treated with antifungal agents in the last 12 months, were included in the study. The diagnosis in each case was confirmed by microscopy or positive culture. The majority of the vaginal mycoses were infections with C. albicans (72%). In 28% of patients a non- Candida species (mainly C. glabrata) contributed to the infection. Except for vaginal discharge, the success of treatment was between 71% and 91% for both clinical and subjective parameters. The control preparation was significantly better than the treatment in the test group. Mycological cure rate on the basis of cultures was 78% in the test group and 87% in the control group. These results were also significantly different. The relatively high proportion of C. glabrata isolates in this study tended to be more successfully treated by the antiseptic (to 72%) than by the administration of clotrimazole (59%). Even though therapeutic success with clotrimazole was overall significantly better than with the test preparation, the success of treatment with the antiseptic used was within the range between 70% and 90% described for topical antifungal agents. Both the good efficacy of the topical antiseptic and the increased prevalence of non-Candida albicans species causing vaginal infections mean that the use of an antiseptic may be considered a suitable alternative therapeutic concept to an appropriate topical antifungal agent in the treatment of acute vaginal candidosis.

[Prerequisites for effective therapy of chronic recurrent vaginal candidiasis]. / Voraussetzungen für eine effektive Therapie chronisch rezidivierender Vaginalcandidosen.

67 women with chronic recurrent or persistent vaginal candidosis between 5-79 years of age were seen in our outdoor department. In 34 cases, yeasts could be isolated in a vaginal swab taken at the first consultation. On average the patients reported 5 episodes per year during the last years. Typical symptoms consisted of pruritus vulvae, local inflammation and a curdy vaginal discharge. Nearly all of the women had received local or systemic antimycotic treatment for several times. In 53% (18 patients), C. albicans had been isolated, in 29% (10 patients) C. glabrata and in 9% (3 patients) C. krusei. While candidosis due to C. albicans and C. krusei was frequently associated with distressing complaints, infections with C. glabrata caused only very few symptoms. Independent of the species, severe and persistent infections were characterized by long term persisting specific IgM-antibody-titers and remarkable lack of IgG-antibodies. The laboratory parameters of WBC, CRP and immunelectrophoresis were normal. The minimum inhibitory concentrations (MIC) of 60 Candida strains against fluconacole were determined by microdilution assay. The MIC for C. albicans (n = 35) were between 0.78 and 3.125 micrograms/ml, for C. glabrata (n = 20) between 8 and 32 micrograms/ml and for C. krusei (n = 5) between 25 and 128 micrograms/ml. In 7 cases, local antimycotic treatment was sufficient. Correlating to the sensitivity, 18 women were treated with 100-800 mg fluconacole/d for 10-20 days. In 13 of them, clearance of symptoms and yeasts was achieved. The treatment of fluconacole-resistant strains with itraconazole (100-200 ml/d for 10-20 days) together with local application of nystatin (2 x 1 Mio. IE for 10 days) was without any effect. Three women with C. albicans, C. glabrata and C. krusei infection received a candidin-vaccination (0.005 BE/ml-500 BE/ml). In all of these cases, production of IgM-antibodies was induced. However, the clinical symptoms could not be influenced. Only in two cases it was not possible to reach a clearance of symptoms and yeasts. The results show the benefit of a precise differentiation before therapy. Serologic controls of antibody titers seem to be useful tools to control the efficacy of treatment.

Effect of fenticonazole in vaginal candidiasis: a double-blind clinical trial versus clotrimazole.

Fenticonazole is an imidazole derivative which possesses a broad spectrum antimycotic activity, including activity against Candida albicans. Its therapeutic activity and tolerability have been evaluated, in a double-blind clinical trial versus clotrimazole, in 54 patients affected by mycologically confirmed symptomatic vaginal candidiasis. Both drugs were administered intravaginally as a cream once a day for 7 days. Assessment was by laboratory mycological investigations and symptomatic evaluation. Patients 'cured' at the end of the trial were re-evaluated after 4-6 weeks for possible relapses. Both treatments resulted in a progressive, statistically significant reduction in vaginal symptoms (itching and discharge) and in elimination of Candida in more than 95% of patients. When 'cured' patients were reassessed 4-6 weeks after therapy, relapses occurred in four patients after fenticonazole treatment, but in none following clotrimazole treatment. This apparent difference between treatments is far from being statistically significant and, therefore, may have been a chance occurrence. It should also be noted that patients from the fenticonazole group had a previous history of significantly more frequent episodes of candidiasis suggesting that they may have been at greater risk of re-infection than patients from the control group. The tolerance of both treatments was excellent since no local or systemic signs or symptoms of toxicity were reported. An equally high efficacy and safety for both drugs in the elimination of symptoms and objective evidence of vaginal candidiasis is indicated.