Oral versus intra-vaginal imidazole and triazole anti-fungal treatment of uncomplicated vulvovaginal candidiasis (thrush).

BACKGROUND: Anti-fungals are available for oral and intra-vaginal treatment of uncomplicated vulvovaginal candidiasis. OBJECTIVES: The primary objective of this review is to assess the relative effectiveness (clinical cure) of oral versus intra-vaginal anti-fungals for the treatment of uncomplicated vulvovaginal candidiasis. Secondary objectives include the assessment of the relative effectiveness in terms of mycological cure, in addition to safety, side effects, treatment preference, time to first relief of symptoms, and costs. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and two trials registers on 29 August 2019 together with reference checking and citation searching. SELECTION CRITERIA: We included randomised controlled trials published in any language comparing at least one oral anti-fungal with one intra-vaginal anti-fungal in women (aged 16 years or over) with a mycological diagnosis (positive culture, microscopy for yeast, or both) of uncomplicated vulvovaginal candidiasis. We excluded trials if they solely involved participants who were HIV positive, immunocompromised, pregnant, breast feeding or diabetic. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as recommended by Cochrane. MAIN RESULTS: This review includes 26 trials (5007 participants). Eight anti-fungals are represented. All but three trials included participants with acute vulvovaginal candidiasis. Trials were conducted in Europe: UK (3), Croatia (2). Finland (2), the Netherlands (2), Germany (1), Italy (1), Sweden (1) and one trial across multiple European countries, USA (7) Thailand (2), Iran (2), Japan (1) and Africa (Nigeria) (1). The duration of follow-up varied between trials. The overall risk of bias of the included trials was high. There was probably little or no difference shown between oral and intra-vaginal anti-fungal treatment for clinical cure at short-term follow-up (OR 1.14, 95% CI 0.91 to 1.43; 13 trials; 1859 participants; moderate-certainty evidence) and long-term follow-up (OR 1.07, 95% CI 0.77 to 1.50; 9 trials; 1042 participants; moderate-certainty evidence). The evidence suggests that if the rate of clinical cure at short-term follow-up with intra-vaginal treatment is 77%, the rate with oral treatment would be between 75% and 83%; if the rate of clinical cure at long term follow-up with intra-vaginal treatment is 84%, the rate with oral treatment would be between 80% and 89%. Oral treatment probably improves mycological cure over intra-vaginal treatment at short term (OR 1.24, 95% CI 1.03 to 1.50: 19 trials; 3057 participants; moderate-certainty evidence) and long-term follow-up (OR 1.29, 95% CI 1.05 to 1.60; 13 trials; 1661 participants; moderate-certainty evidence). The evidence suggests that if the rate of mycological cure at short-term follow-up with intra-vaginal treatment is 80%, the rate with oral treatment would be between 80% and 85%; if the rate of mycological cure at long-term follow-up with intra-vaginal treatment is 66%, the rate with oral treatment would be between 67% and 76%. In terms of patient safety, there is a low risk of participants withdrawing from the studies due to adverse drug effects for either treatment (23 trials; 4637 participants; high-certainty evidence). Due to the low certainty of evidence, it is undetermined whether oral treatments reduced the number of side effects compared with intra-vaginal treatments (OR 1.04, 95% CI 0.84 to 1.29; 16 trials; 3155 participants; low-certainty evidence). The evidence suggests that if the rate of side effects with intra-vaginal treatment is 12%, the rate with oral treatment would be between 10% and 15%. We noted that the type of side effects differed, with intra-vaginal treatments being more often associated with local reactions, and oral treatments being more often associated with systemic effects including gastro-intestinal symptoms and headaches. Oral treatment appeared to be the favoured treatment preference over intra-vaginal treatment or no preference (12 trials; 2206 participants), however the data were poorly reported and the certainty of the evidence was low. There was little or no difference in time to first relief of symptoms between oral and intra-vaginal treatments: four trials favoured the oral treatment, four favoured intra-vaginal, one study reported no difference and one was unclear. The measurements varied between the 10 trials (1910 participants) and the certainty of the evidence was low. Costs were not reported in any of the trials. AUTHORS' CONCLUSIONS: Oral anti-fungal treatment probably improves short- and long-term mycological cure over intra-vaginal treatment for uncomplicated vaginal candidiasis. Oral treatment was the favoured treatment preference by participants, though the certainty of this evidence is low. The decision to prescribe or recommend an anti-fungal for oral or intra-vaginal administration should take into consideration safety in terms of withdrawals and side effects, as well as cost and treatment preference. Unless there is a previous history of adverse reaction to one route of administration or contraindications, women who are purchasing their own treatment should be given full information about the characteristics and costs of treatment to make their own decision. If health services are paying the treatment cost, decision-makers should consider whether the higher cost of some oral anti-fungals is worth the gain in convenience, if this is the patient's preference.

Fungal Lanosterol 14α-demethylase: A target for next-generation antifungal design.

The cytochrome P450 enzyme lanosterol 14α-demethylase (LDM) is the target of the azole antifungals used widely in medicine and agriculture as prophylaxis or treatments of infections or diseases caused by fungal pathogens. These drugs and agrochemicals contain an imidazole, triazole or tetrazole substituent, with one of the nitrogens in the azole ring coordinating as the sixth axial ligand to the LDM heme iron. Structural studies show that this membrane bound enzyme contains a relatively rigid ligand binding pocket comprised of a deeply buried heme-containing active site together with a substrate entry channel and putative product exit channel that reach to the membrane. Within the ligand binding pocket the azole antifungals have additional affinity determining interactions with hydrophobic side-chains, the polypeptide backbone and via water-mediated hydrogen bond networks. This review will describe the tools that can be used to identify and characterise the next generation of antifungals targeting LDM, with the goal of obtaining highly potent broad-spectrum fungicides that will be able to avoid target and drug efflux mediated antifungal resistance.

Eficacia terapéutica del voriconazol en candidiasis vulvovaginal crónica por Candida glabrata / Efficacy of voriconazole treatment in chronic vulvovaginal candidosis due to Candida glabrata

Antecedentes. La vulvovaginitis candidiásica es una infección frecuente en mujeres jóvenes que se acompaña de alta morbilidad y elevados gastos sanitarios. Objetivos. Las candidiasis vaginales causadas por Candida glabrata constituyen un reto terapéutico dada la resistencia adquirida por muchas cepas de esta especie a los antifúngicos azólicos. Métodos. En este trabajo presentamos 2 casos de candidiasis vaginal complicada por Candida glabrata resistentes a fluconazol y tratadas con voriconazol. Resultados. Las 2 pacientes mejoraron tras la administración de voriconazol, 400mg/12h el primer día y posteriormente 200mg/12h durante 14 días, con desaparición de la sintomatología y la negativización de los cultivos. Conclusiones. En conclusión, los resultados obtenidos nos llevan a sugerir el uso del voriconazol como alternativa terapéutica en este tipo de candidiasis que, aunque no comprometen la vida, llevan asociada una elevada morbilidad(AU)

Background. Vulvovaginal candidosis is a common infection in young women, and it is associated with high morbidity and high health costs. Aims. Vulvovaginal candidosis caused by Candida glabrata is a therapeutic challenge due to the acquired resistance of many strains of this species to azole antifungals. Methods. We present two cases of vaginal candidosis complicated by fluconazole-resistant Candida glabrata, and treated with voriconazole. Results. Both patients improved after administration of voriconazole, 400mg/12h the first day and then 200mg every 12h for 14 days. Their symptoms disappeared and cultures became negative. Conclusions. These results suggest voriconazole can be used as a therapeutic alternative for this type of candidosis which, although not life threatening, is associated with a high morbidity(AU)

Impact of education and an antifungal stewardship program for candidiasis at a Thai tertiary care center.

BACKGROUND: We evaluated the impact of education and an antifungal stewardship program for candidiasis on prescribing practices, antifungal consumption, Candida species infections, and estimated costs at a Thai tertiary care hospital. METHODS: A hospital-wide, quasi-experimental study was conducted for 1.5 years before the intervention and 1.5 years after the implementation of an antifungal stewardship program. Inpatient antifungal prescriptions were prospectively observed, and patients' demographic, clinical, and administrative-cost data were collected. Interventions included education, introduction of an antifungal hepatic and/or renal dose adjustment tool, antifungal prescription forms, and prescription-control strategies. RESULTS: After the intervention, there was a 59% reduction in antifungal prescriptions (from 194 to 80 prescriptions per 1,000 hospitalizations; P<.001). Inappropriate antifungal use decreased (from 71% to 24%; P<.001), a sustained reduction in antifungal use was observed (r=0.83; P<.001), and fluconazole use decreased (from 242 to 117 defined daily doses per 1,000 patient-days; P<.001). Reductions in the incidence of infection with Candida glabrata (r=0.69; P<.001) and Candida krusei (r=0.71; P<.001) were observed, whereas the incidence of infection with Candida albicans (r=-0.81; P<.001) increased. Total cost savings were US$31,615 during the 18-month postintervention period. CONCLUSIONS: Implementation of an antifungal stewardship program was associated with appropriate antifungal drug use, improved resource utilization, and cost savings.

Current concepts in systemic and topical therapy for superficial mycoses.

There presently exists a wide selection of choices in the treatment of superficial mycoses. The main categories of broad-spectrum agents are the allylamines and imidazoles, which have been tried and proven over more than 2 decades of usage with good safety. Nystatin and griseofulvin have even longer experience of about 5 decades but have niche usage for yeasts and dermatophytes, respectively. Although no new therapeutic groups have appeared, extensive development of vehicles and delivery systems has enhanced therapeutic results and increased patient compliance.

Systematic review of topical treatments for fungal infections of the skin and nails of the feet.

OBJECTIVE: To identify and synthesise the evidence for efficacy and cost effectiveness of topical treatments for superficial fungal infections of the skin and nails of the feet. DESIGN: Systematic review. INTERVENTIONS: Topical treatments for superficial fungal infections. MAIN OUTCOME MEASURES: Cure confirmed by culture and microscopy for skin and by culture for nails in patients with clinically diagnosed fungal infections. RESULTS: Of 126 trials identified in 121 papers, 72 (57.1%) met the inclusion criteria. Placebo controlled trials yielded pooled relative risks of failure to cure skin infections: allylamines (0.30, 95% confidence interval 0.24 to 0.38); azoles (0.54, 0.42 to 0.68); undecenoic acid (0.28, 0. 11 to 0.74); and tolnaftate (0.46, 0.17 to 1.22). Although meta-analysis of 11 trials comparing allylamines and azoles showed a relative risk of failure to cure of 0.88 (0.78 to 0.99) in favour of allylamines, there was evidence of language bias. Seven reports in English favoured allylamines (0.79, 0.69 to 0.91), but four reports in foreign languages showed no difference between the two drugs (1. 01, 0.90 to 1.13). Neither trial of nail infections showed significant differences between alternative topical treatments. CONCLUSIONS: Allylamines, azoles, and undecenoic acid were efficacious in placebo controlled trials. There are sufficient comparative trials to judge relative efficacy only between allylamines and azoles. Allylamines cure slightly more infections than azoles but are much more expensive than azoles. The most cost effective strategy is first to treat with azoles or undecenoic acid and to use allylamines only if that fails.