Vulvovaginal candidiasis: An overview of mycological, clinical, and immunological aspects.

AIM: To provide an overview of clinical, immunological, and mycological aspects of vulvovaginal candidiasis (VVC). METHODS: A literature search was conducted to find relevant articles about different aspects of VVC. Related data from retrieved articles were summarized in different headings. RESULTS: VVC has a global distribution and Candida albicans is the leading cause of infection except for specific patient groups like postmenopausal, diabetic, or immunocompromised women. VVC has a range of clinical presentations, accordingly, its diagnosis should be based on clinical examination coupled with laboratory investigations. The best therapeutic regimen depends on the patient's conditions and the causative agent. Moreover, factors like drug resistance of the causative agents and different mutations in the immunity-related genes could affect the treatment outcome. CONCLUSION: As a globally distributed disease, VVC needs further attention, especially in areas related to the treatment failure and recurrence of the disease.

A Fungal Immunotherapeutic Vaccine (NDV-3A) for Treatment of Recurrent Vulvovaginal Candidiasis-A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial.

Background: Recurrent vulvovaginal candidiasis (RVVC) is a problematic form of mucosal Candida infection, characterized by repeated episodes per year. Candida albicans is the most common cause of RVVC. Currently, there are no immunotherapeutic treatments for RVVC. Methods: This exploratory randomized, double-blind, placebo-controlled trial evaluated an immunotherapeutic vaccine (NDV-3A) containing a recombinant C. albicans adhesin/invasin protein for prevention of RVVC. Results: The study in 188 women with RVVC (n = 178 evaluable) showed that 1 intramuscular dose of NDV-3A was safe and generated rapid and robust B- and T-cell immune responses. Post hoc exploratory analyses revealed a statistically significant increase in the percentage of symptom-free patients at 12 months after vaccination (42% vaccinated vs 22% placebo; P = .03) and a doubling in median time to first symptomatic episode (210 days vaccinated vs 105 days placebo) for the subset of patients aged <40 years (n = 137). The analysis of evaluable patients, which combined patients aged <40 years (77%) and ≥40 years (23%), trended toward a positive impact of NDV-3A versus placebo (P = .099). Conclusions: In this unprecedented study of the effectiveness of a fungal vaccine in humans, NDV-3A administered to women with RVVC was safe and highly immunogenic and reduced the frequency of symptomatic episodes of vulvovaginal candidiasis for up to 12 months in women aged <40 years. These results support further development of NDV-3A vaccine and provide guidance for meaningful clinical endpoints for immunotherapeutic management of RVVC. Clinical Trials Registration: NCT01926028.

High-dose vaginal metronidazole for recurrent bacterial vaginosis--a pilot study.

OBJECTIVE: The purpose of this study was to evaluate high-dose intravaginal metronidazole, with or without miconazole, in enhancing cure rates in women with recurrent BV. MATERIALS AND METHODS: A total of 43 women with symptomatic recurrent BV were enrolled in a 4-arm study comparing 500 mg versus 750 mg of metronidazole, with or without miconazole, intravaginally for 7 days. Test of cure by saline wet mount and 10% potassium chloride microscopy, pH, Gram stain for Nugent score, and yeast culture were performed 3 times after treatment: 3 to 7 days, 30 to 35 days, and 60 to 70 days. RESULTS: Overall cure rate for the entire group was 92.6% at visit 2, 62.1% at visit 3, and 51.4% at visit 4. At visit 2, there was no difference in cure rates among patients who received metronidazole 750 mg ± miconazole daily (90.5%) compared with metronidazole 500 mg ± miconazole daily (85%). At visit 3, there was a significant improvement in cure rates among patients who received metronidazole 750 mg ± miconazole daily (78.9%) compared with metronidazole 500 mg ± miconazole daily (44.4%) (p < .05). At visit 4, a significant difference in clinical cure rates persisted among patients who received metronidazole 750 mg ± miconazole daily (68.4%) compared with of metronidazole 500 mg ± miconazole daily (33.3%; p < .05). Poor responses (Nugent score > 4 or pH > 4.4) at the first visit alter treatment-predicted recurrence. The addition of miconazole did not enhance BV response rates. CONCLUSIONS: Cure rates for BV were high in this refractory cohort and seemed dose dependent.

Fluconazole-resistant Candida albicans vulvovaginitis.

OBJECTIVE: As a result of high recurrence rates of Candida albicans vaginitis, successful suppressive fluconazole is widely used, and drug resistance is considered rare. We report increased occurrence of secondary fluconazole resistance, analysis of risk factors thereof, and describe management of fluconazole-refractory vaginitis. METHODS: Patients referred to the Vaginitis Clinic at Wayne State University with clinically refractory fluconazole-resistant (minimum inhibitory concentration [MIC] 2 micrograms/mL or greater) C albicans vaginitis from 2000 to 2010 were enrolled. Patients completed a questionnaire pertaining to demographics, comorbidities, behavioral characteristics, exposure to antimicrobials and antifungals, fluconazole consumption in defined daily doses in the previous 6 months, management received, and outcomes. With patients not located, data were extracted from charts. Susceptibilities to antifungals were determined by broth microdilution. RESULTS: Twenty-five women with fluconazole-resistant recurrent C albicans vaginitis were identified, and 16 returned filled questionnaires. Study cohort consisted mainly of married, insured white women with more than 12 years of formal education and average or above average socioeconomic status. Median fluconazole MIC was 8 micrograms/mL (range 2-128 micrograms/mL). Risk factors for mycologic failure included increased fluconazole consumption (P=.03) with 16 of 25 women exposed to low-dose weekly fluconazole maintenance therapy. All patients were clinically controlled successfully, although treatment was difficult and often prolonged. CONCLUSION: Fluconazole-resistant C albicans vaginitis was previously considered rare. We report 25 cases over an 11-year period, indicating an emerging problem. All patients had fluconazole consumption in the previous 6 months. Management of fluconazole refractory disease is extremely difficult with limited options, and new therapeutic modalities are needed.

Effect of pH on in vitro susceptibility of Candida glabrata and Candida albicans to 11 antifungal agents and implications for clinical use.

The treatment of vulvovaginal candidiasis (VVC) due to Candida glabrata is challenging, with limited therapeutic options. Unexplained disappointing clinical efficacy has been reported with systemic and topical azole antifungal agents in spite of in vitro susceptibility. Given that the vaginal pH of patients with VVC is unchanged at 4 to 4.5, we studied the effect of pH on the in vitro activity of 11 antifungal agents against 40 C. glabrata isolates and compared activity against 15 fluconazole-sensitive and 10 reduced-fluconazole-susceptibility C. albicans strains. In vitro susceptibility to flucytosine, fluconazole, voriconazole, posaconazole, itraconazole, ketoconazole, clotrimazole, miconazole, ciclopirox olamine, amphotericin B, and caspofungin was determined using the CLSI method for yeast susceptibility testing. Test media were buffered to pHs of 7, 6, 5, and 4. Under conditions of reduced pH, C. glabrata isolates remained susceptible to caspofungin and flucytosine; however, there was a dramatic increase in the MIC(90) for amphotericin B and every azole drug tested. Although susceptible to other azole drugs tested at pH 7, C. albicans strains with reduced fluconazole susceptibility also demonstrated reduced susceptibility to amphotericin B and all azoles at pH 4. In contrast, fluconazole-sensitive C. albicans isolates remained susceptible at low pH to azoles, in keeping with clinical observations. In selecting agents for treatment of recurrent C. glabrata vaginitis, clinicians should recognize the limitations of in vitro susceptibility testing utilizing pH 7.0.

Genital malodor in women: a modern reappraisal.

Genital malodor is a common distressing complaint that brings a woman to her physician's office. Vaginal infections, primarily bacterial vaginosis and trichomoniasis, still remain the commonest causes and are relatively easy to diagnose and treat. However, in approximately one third of women who present with malodor, no cause is identified. Although data on the management of vaginal discharge are extensive, the management of genital odor beyond common vaginal infections remains poorly studied. This presents a frustrating situation for both the patient and her physician. Often, patients resort to home remedies and over-the-counter preparations, which, while providing short-term relief for some women, almost never address the cause and, in some cases, can exacerbate symptoms. In this review, we have attempted to consolidate the known and documented causes of genital malodor including the nonvaginal causes and provide case studies that will help clinicians understand the possible settings for the various causes. We also provide an algorithm for the management of this symptom beyond vaginal infections.

Reduced fluconazole susceptibility of Candida albicans isolates in women with recurrent vulvovaginal candidiasis: effects of long-term fluconazole therapy.

Fluconazole resistance and resultant failure to control Candida vaginitis (vulvovaginal candidiasis) remains extremely uncommon; however, long-term clinically relevant decrease in fluconazole susceptibility undoubtedly occurs and accompanies prolonged fluconazole chemoprophylaxis. Accordingly, in patients with refractory vaginitis or breakthrough infections due to Candida albicans, in vitro susceptibility testing is essential to optimally manage vaginitis.

Tinidazole for bacterial vaginosis.

Tinidazole has been used for bacterial vaginosis (BV) outside the USA for almost four decades. Tinidazole has recently been resurrected and FDA approved for trichomoniasis and BV in the USA and is being restudied as an alternative to metronidazole for BV. In vitro antimicrobial activity and pharmacokinetics studies indicate that when compared directly with metronidazole, tinidazole has minor but possibly relevant antimicrobial as well as pharmacokinetic advantages. Clinical comparisons have been infrequent, although the limited head-to-head studies indicate minimal therapeutic advantage with tinidazole. Perhaps the more relevant differences relate to the enhanced tolerance and reduced toxicity of tinidazole. Currently, studies are still ongoing directly comparing the clinical efficacy of metronidazole and tinidazole. These studies should establish the role of tinidazole in the treatment of BV; however, cure rates are unlikely to be significantly different.

Tinidazole for the treatment of vaginal infections.

Tinidazole has been used for vaginal infection worldwide but not in the US for > 40 years. Recently, tinidazole has been re-introduced and approved by the FDA for trichomoniasis and restudied as an alternative to metronidazole for bacterial vaginosis. In vitro antimicrobial activity and pharmacokinetics studies indicate that tinidazole has minor but possibly relevant antimicrobial as well as pharmacokinetic advantages when compared directly with metronidazole. Clinical comparison has been infrequent although the limited head-to-head studies indicate minimal therapeutic advantage with tinidazole. Perhaps the more relevant differences relate to the enhanced tolerance and reduced toxicity of tinidazole. Ongoing, as yet incomplete, studies directly comparing the clinical efficacy of metronidazole and tinidazole for bacterial vaginosis should clarify the status of tinidazole; however, cure rates are unlikely to be significantly different. Although uncommon, high-level trichomonal metronidazole resistance can be reliably cured by using tinidazole, which is an invaluable advantage.

Anidulafungin: a novel echinocandin.

Until recently, the treatment available for serious fungal infections was composed of amphotericin B and azoles, and each class demonstrated significant limitations. Echinocandins are a new class of drugs that have shown promising results in treating a variety of fungal infections. Of these, anidulafungin is a novel echinocandin that appears to have several advantages over existing antifungals. It is unique because it slowly degrades in humans, undergoing a process of biotransformation rather than being metabolized. It has potent in vitro activity against Aspergillus and Candida species, including those resistant to fluconazole or amphotericin B. Results of several clinical trials indicate that anidulafungin is effective in treating esophageal candidiasis, including azole-refractory disease. The results of a recent study comparing fluconazole versus anidulafungin demonstrated the superiority of anidulafungin in the treatment of candidemia and invasive candidiasis (IC). Studies evaluating the concomitant use of anidulafungin and either amphotericin B, voriconazole, or cyclosporine did not demonstrate significant drug-drug interactions or adverse events. To date, anidulafungin appears to have an excellent safety profile. On the basis of early clinical experience, it appears that anidulafungin will be a valuable asset in the management of serious and difficult-to-treat fungal infections.

Design of clinical trials of empiric antifungal therapy in patients with persistent febrile neutropenia: considerations and critiques.

Febrile neutropenic patients who receive antibiotics are at risk for fungal infections. This risk increases greatly with the length and severity of neutropenia. Because diagnostic tests for fungal infections lack sensitivity and specificity and because established fungal infections are associated with poor outcomes, empiric antifungal therapy is frequently given to patients with fever that persists despite antibacterial therapy. Early trials of empiric amphotericin B showed reductions in the number of invasive fungal infections and in related morbidity and mortality. However, as a result of infusion-related and renal adverse effects of amphotericin B, newer agents, such as lipid formulations of amphotericin B, extended-spectrum azoles, and echinocandins, have been developed. Although these alternatives have been associated with decreased toxicity, improved efficacy has not been clearly demonstrated. Although empiric antifungal therapy can prevent undetected breakthrough infections and morbidity associated with many fungal infections, its shortcomings include overtreatment, toxicity, and increased costs of unnecessary treatment. Recent studies have highlighted several questions in trial design and data interpretation. For example, what is the appropriate study design? Who should be enrolled in studies of empiric antifungal therapy? How should successful therapy be defined? These issues are reviewed to determine whether new antifungal agents should be evaluated for empiric use in patients with fever and neutropenia.

Vaginitis due to Candida krusei: epidemiology, clinical aspects, and therapy.

Twelve women with vaginal Candida krusei infection were evaluated. In vitro antifungal susceptibility testing and molecular typing were performed. Patients infected with C. krusei frequently had refractory vulvovaginal signs and symptoms that were otherwise indistinguishable from vaginitis due to other yeasts. Patients were 32-63 years old and had previously received multiple courses of antimycotic agents, including fluconazole and miconazole. The most active azole in vitro was clotrimazole, with a 90% minimum inhibitory concentration of 0.25 microg/mL. Four of 6 patients treated with boric acid had clinical and mycological cure. Two dominant genotypes of C. krusei were identified via contour-clamped homogenous electrical field analysis. No major genotypic change was observed in successive isolates from the same patient in most cases, suggesting that these refractory cases were relapses. C. krusei is a rare but important cause of refractory vaginitis and is unique because of its intrinsic resistance to fluconazole.