Oral Antifungal Agents Research Articles

Spotlight on tavaborole for the treatment of onychomycosis.

Onychomycosis is a fungal nail plate infection that has been increasing in prevalence. A variety of oral and topical anti-fungal agents are currently available but their use is limited by their adverse effect profile, drug–drug interactions, and limited efficacy. Therefore, there is a great need for newer anti-fungal agents. Tavaborole is one of these newer agents and was approved by the US Food and Drug Administration in July 2014 for the topical treatment of mild to moderate toenail onychomycosis. Tavaborole is a novel, boron-based anti-fungal agent with greater nail plate penetration than its predecessors, due to its smaller molecular weight. It has proven through several Phase II and III trials that it can be a safe and effective topical agent for the treatment of mild to moderate toenail onychomycosis without the need for debridement. In this paper, we review the landscape of topical and systemic treatment of onychomycosis, with particular attention to the pharmacokinetics, safety, and efficacy of topical tavaborole.

Routes of drug delivery into the nail apparatus: Implications for the efficacy of topical nail solutions in onychomycosis

The route of antifungal drug entry into the nail plate and the underlying nail bed plays an important role in determining the efficacy of therapy. Oral antifungal agents reach the nail bed and nail plate by being ingested and achieving antifungal levels in the blood stream that are well in excess of the minimum inhibitory concentration. The reticular circulation at the distal end of the digit enables the drug to reach the nail bed, the proximal matrix and the lateral nail folds. The drug then diffuses into the proximal, ventral and lateral nail plate. The primary route of drug delivery for topical lacquers is transungual, with drug applied to the dorsal aspect of the nail plate and penetrating to the underlying nail bed. The new topical agents approved in the US for the treatment of onychomycosis are solutions with lower viscosity and increased nail penetration characteristics; therefore, these agents penetrate through the transungual route, but also through the space between the nail plate and the nail bed. This subungual route is an important method of drug delivery and is able to in part circumvent the thickness of the nail plate.

Laser Therapy for Onychomycosis: Fact or Fiction?

Onychomycosis is a common fungal infection, afflicting some 10% of the adult population in industrialized countries. Aside from cosmetic concerns, onychomycosis can be the cause of toe and foot pain, as well as the underlying etiology for serious secondary bacterial infections and traumatic ulcerations. In select populations, such as diabetics, the latter conditions may even result in loss of all or part of the lower extremity. Thus, a simple, cost-effective and safe treatment for onychomycosis is highly desirable. Although both topical and oral systemic antifungal agents are available for this purpose, they are not always effective, carry some medical risks, are associated with potentially significant drug-drug interactions, and may be unacceptable to patient and healthcare provider alike. Physical modalities, such as laser therapy, therefore appear appealing. The question is whether laser treatment is sufficiently efficacious and safe to warrant the current high cost per treatment. The readily available literature on this controversy will be reviewed herein.

The Rise and Fall of Oral Ketoconazole.

Ketoconazole was the first broad-spectrum oral antifungal agent available to treat systemic and superficial mycoses. Evidence of hepatotoxicity associated with its use emerged within the first few years of its approval. Growing evidence of serious side effects including endocrine dysregulation, several drug interactions, and death led to the review of oral ketoconazole in 2011. This article chronicles the use of oral ketoconazole from its introduction to its near replacement in medicine. Due to its hepatotoxic side effects, oral ketoconazole was withdrawn from the European and Australian markets in 2013. The United States imposed strict relabeling requirements and restrictions for prescription, with Canada issuing a risk communication echoing these concerns. Today, oral ketoconazole is only indicated for endemic mycoses, where alternatives are not available or feasible. Meanwhile, topical ketoconazole is effective, safe, and widely prescribed for superficial mycoses, particularly as the first-line treatment for tinea versicolor.

Recent advances in topical formulation carriers of antifungal agents.

Fungal infections are amongst the most commonly encountered diseases affecting the skin. Treatment approaches include both topical and oral antifungal agents. The topical route is generally preferred due to the possible side effects of oral medication. Advances in the field of formulation may soon render outdated conventional products such as creams, ointments and gels. Several carrier systems loaded with antifungal drugs have demonstrated promising results in the treatment of skin fungal infections. Examples of these newer carriers include micelles, lipidic systems such as solid lipid nanoparticles and nanostructured lipid carriers, microemulsions and vesicular systems such as liposomes, niosomes, transfersomes, ethosomes, and penetration enhancer vesicles.

Amorolfine vs. ciclopirox - lacquers for the treatment of onychomycosis.

Amorolfine 5% and ciclopirox 8% nail lacquers are commonly used in topical treatment of onychomycosis. These formulations may be used alone or in combination with oral antifungal agents. Amorolfine and ciclopirox are valuable therapeutic options, however, their usage in monotherapy should be limited. Proper amorolfine and ciclopirox penetration through the nail plate is provided by transungual drug delivery systems. Although amorolfine and ciclopirox have a different mode of action, they both exhibit a broad antifungal activity. The use of antifungal nail lacquers in combination with oral agents, such as terbinafine and itraconazole, improves efficacy of antifungal therapy.

Trichophyton species of Arthroderma benhamiae - a new infectious agent in dermatology.

In Germany, infections due to the zoophilic dermatophyte Trichophyton (T.) species of Arthroderma benhamiae are being more frequently diagnosed. The source of infection of this emerging pathogen overlaps with that of the zoophilic species T. interdigitale. The most common source are guinea pigs. T. species of Arthroderma benhamiae causes inflammatory dermatophytosis in children and adolescents. In addition to tinea capitis, it may cause both tinea corporis, tinea manus and frequently tinea faciei. In Germany, T. species of Arthroderma benhamiae is a frequent zoophilic dermatophyte, which in regions is probably more frequent than Microsporum canis. The mycological identification of the isolates with their yellow stained colonies is based on their macroscopic and microscopic features. However, some exhibit colony features consistent with those of T. interdigitale. These strains only can be identified unambiguously by means of molecular techniques. Using detection methods such as PCR-ELISA or real-time PCR, the dermatophyte can be identified directly from clinical material. Sequencing of the internal transcribed spacer region (ITS) of the ribosomal DNA has been approved as culture confirmation test for T. species of Arthroderma benhamiae. In addition, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI TOF MS) is useful. Widespread dermatophytosis due to T. species of Arthroderma benhamiae, in particular of tinea capitis, requires oral antifungal agents. Terbinafine is most effective, alternatives are fluconazole and itraconazole.

A retrospective descriptive study of oral azole antifungal agents in patients with patch test–negative head and neck predominant atopic dermatitis

Head and neck dermatitis is a subtype of atopic dermatitis driven by Malassezia yeast. We sought to evaluate the response of these patients to systemic azole antifungals. We queried the electronic medical records from our institution for patients that were referred for allergy patch testing, were ultimately given the diagnosis of head and neck dermatitis, and were treated with oral azole antifungals over a 2-year period. Twenty-four patients met inclusion criteria and were analyzed. Most patients noted their characteristic flare beginning during their teenage, young adult, or adult years. All were noted to have some involvement of the head and neck, and 17 responded to treatment. The mean time taking an azole antifungal medication was 8 months, with a mean overall follow-up of 10 months. This was a retrospective descriptive study, from a single institution, of a limited number of patients, and did not use a validated scoring system. Itraconazole and other azole antifungals were an effective treatment for more than two-thirds of adult patients with head and neck predominant atopic dermatitis.

The value of antifungal therapy in allergic fungal rhinosinusitis

Background: Allergic fungal rhinosinusitis (AFS) is considered to part of the disease spectrum of chronic rhinosinusitis, which affects between five to fifteen per cent of the population. Currently, there is uncertainty relating to the pathological process and therefore optimal management of AFS. Studies assessing antifungal use have shown mixed results. The aim of this review is to assess the effect of antifungals on patients with AFS. Methods: A systematic review of the literature to include all published trials searching Pubmed, Medline (Ovid), CINAHL (EBSCO) and the Cochrane central register of controlled trials (CENTRAL) databases. Results: Sixteen studies (two systematic reviews, two meta-analysis, four randomised controlled trials, five prospective cohort studies and three retrospective studies) were included in this review. There was found to be no overall benefit of topical or oral antifungals upon endoscopic findings or patient reported outcome measures in AFS. There were no statistically significant differences in adverse effect profiles between treatment and control groups. Conclusion: There is limited evidence to support the use of topical or oral antifungal agents in patients with AFS. Future research recommendations include large multicentre randomised trials with better matched patient groups and appropriate dosage and timing of antifungals.

The value of antifungal therapy in allergic fungal rhinosinusitis

Allergic fungal rhinosinusitis (AFS) is considered to part of the disease spectrum of chronic rhinosinusitis, which affects between five to fifteen per cent of the population. Currently, there is uncertainty relating to the pathological process and therefore optimal management of AFS. Studies assessing antifungal use have shown mixed results. The aim of this review is to assess the effect of antifungals on patients with AFS. A systematic review of the literature to include all published trials searching Pubmed, Medline (Ovid), CINAHL (EBSCO) and the Cochrane central register of controlled trials (CENTRAL) databases. Sixteen studies (two systematic reviews, two meta-analysis, four randomised controlled trials, five prospective cohort studies and three retrospective studies) were included in this review. There was found to be no overall benefit of topical or oral antifungals upon endoscopic findings or patient reported outcome measures in AFS. There were no statistically significant differences in adverse effect profiles between treatment and control groups. There is limited evidence to support the use of topical or oral antifungal agents in patients with AFS. Future research recommendations include large multicentre randomised trials with better matched patient groups and appropriate dosage and timing of antifungals.

Effect of Itraconazole on Therapeutic Efficacy of Rosiglitazone in Healthy Albino Rats

The most of drug-drug interaction between oral hypoglycemic agents and antifungal agents was reported in healthy rats, rabbits and diabetic rats. The aim of this study was evaluated the effect of itraconazole on therapeutic efficacy of rosiglitazone in healthy albino rats. The blood was withdrawn from the retro-orbital plexuses of rats at different time intervals at 0hr, 1, 2, 4, 8, 12, 18 and 24 hour and blood glucose was estimated by GOD-POD enzymatic method and values are expressed in mg/dl. The results indicate itraconazole enhances the onset, peak effect and duration action of rosiglitazone in healthy rats during concomitant administration of these drugs. In conclusion, the dose and frequency of administration of itraconazole and rosiglitazone should be readjusted while giving simultaneously.

Use of Oral Fluconazole During Pregnancy and the Risk of Birth Defects

Whether common doses of oral fluconazole used in treating fungal infections of the skin or mucous membranes increase the risk of specific birth defects remains a concern. The teratogenic potential of oral azole antifungal agents is important because pregnant women are at increased risk for vaginal candidiasis, the most common clinical indication for these drugs. This registry-based, nationwide cohort study evaluated the association between first-trimester oral fluconazole exposure and the risk of major birth defects. Using a nationwide cohort of all live-born infants born between 1996 and 2011, data were obtained on prescriptions for oral fluconazole, itraconazole, and ketoconazole that were filled by the cohort women during their pregnancies. Unexposed women were those who did not fill prescriptions for oral azole antifungal agents during the first trimester. The 15 specific birth defects previously associated with azole antifungal agents were craniosynostosis, cleft palate, cleft lip with or without cleft palate, other craniofacial defects, middle ear defects, limb defects, limb reduction defects, polydactyly, syndactyly, diaphragmatic hernia, heart defects, tetralogy of Fallot (TOF), pulmonary artery hypoplasia, ventricular septal defects, and hypoplastic left heart. Chromosomal aberrations, genetic syndromes, birth defect syndromes with known causes, congenital viral infections associated with malformations, and minor defects were excluded. Prevalence odds ratios (ORs) with 95% confidence intervals (CIs) were estimated by logistic regression for each exposure category and each birth defect outcome. Primary analyses included any exposure to fluconazole or exposure to different fluconazole doses and the outcome of either birth defects overall or birth defects linked with azole antifungal agents. Categories of cumulative doses during the first trimester were 150, 300, and 350 to 6000 mg, based on the standard treatment of vaginal candidiasis. Secondary analyses included exposure to itraconazole and ketoconazole and the outcome of birth defects overall. A total of 976,300 live-born infants were included in the study. No significantly increased risk of birth defects overall was observed among 7352 pregnancies exposed to any fluconazole, as compared with 968,236 unexposed pregnancies (adjusted prevalence OR, 1.06; 95% CI, 0.92–1.21); evaluation of exposure using the cumulative doses did not change this result. No significantly increased risk was found for 14 of the defects, with the only exception being TOF. Based on 7 exposed pregnancies, the risk of TOF was 3 times higher (prevalence 0.10%) than that among 287 unexposed pregnancies (prevalence, 0.03%; adjusted prevalence OR, 3.16; 95% CI, 1.49–6.71). Similar results were observed when the 15 birth defects were evaluated according to cumulative fluconazole dose. No significantly increased risk of birth defects overall was observed among the 687 and 72 pregnancies exposed to itraconazole and ketoconazole, respectively, and no clustering of malformations was observed. Exposure to any oral fluconazole or to the described cumulative doses during the first trimester of pregnancy was not associated with significantly increased risks of birth defects overall, nor was exposure to oral itraconazole or ketoconazole. The only birth defect at higher risk was TOF, but the absolute risk was small. However, this association should be confirmed in future studies.

Risk of oral antifungal agent‐induced liver injury in Taiwanese

Oral antifungal agent-induced liver injury is a common safety concern that may lead to patients' hesitation in treating fungal infections such as onychomycosis. This study evaluated risk of drug-induced liver injury (DILI) caused by oral antifungal agents in Taiwanese populations. A population-based study was conducted by analyzing who used oral antifungal agents from 2002 to 2008 from the Taiwan National Health Insurance Database. A comparison control group was randomly extracted from the remainder of the original cohort. Of the 90,847 oral antifungal agents users, 52 patients had DILI. Twenty-eight DILI cases used ketoconazole, 12 fluconazole, eight griseofulvin, three itraconazole and two terbinafine. The incidence rates (IR) of DILI per 10,000 persons were 31.6, 4.9, 4.3, 3.6 and 1.6 for fluconazole, ketoconazole, griseofulvin, itraconazole and terbinafine, respectively. Longer exposure duration increased the risk of DILI, with IR for exposure duration ≥ 60 defined daily dose (DDD) of 170.9, 62.5, and 36.1 per 10,000 persons for ketoconazole, itraconazole and terbinafine, respectively. Patients taking antifungal agents had higher incidences of developing DILI compared with those in the control group after adjusting for age, gender and co-morbidities (relative risk 2.38, P < 0.001). All of the six patients with fatal DILI used fluconazole. Old age and fluconazole increased the risk of oral antifungal-induced fatal DILI. Oral antifungal agents are associated with low incidence of acute liver injury, but which may be fatal, especially for the elderly. Longer treatment duration may increase the risk of antifungal agent-induced liver injury, especially ketoconazole.

Allergic Bronchopulmonary Aspergillosis in Asthma: Epidemiological, Clinical and Therapeutic Issues

Allergic bronchopulmonary aspergillosis (ABPA) is a complex pulmonary disorder caused by immunologic reactions to antigens released by Aspergillus fumigatus, a ubiquitous fungi colonizing the tracheobronchial tree of asthmatic patients. The clinical presentation is usually poorly controlled asthma, recurrent pulmonary opacities and bronchiectasis. The prevalence of ABPA in asthma clinics may be as high as 13% with a global burden of almost 5 million patients. A. fumigatus-specific IgE level is the most sensitive test in diagnosis of ABPA, and all asthmatic patients should be routinely screened with A. fumigatus-specific IgE levels for early diagnosis. The goals of managing ABPA include control of asthma, prevention and treatment of acute exacerbations, and preventing the development or progression of bronchiectasis. Glucocorticoids are the treatment of choice with itraconazole reserved for those with recurrent exacerbations and glucocorticoid-dependent disease. There is a dire need for newer treatment approaches including oral antifungal agents and immunomodulatory therapy.

Efficacy and safety of probiotics in the treatment of Candida‐associated stomatitis

This study aimed at evaluating the short-term efficacy and safety of probiotics as an aid in the treatment of Candida-associated stomatitis in a randomised controlled trial. A total of 65 patients were randomly assigned to receive oral local antifungal agents alone (gargle 2% sodium bicarbonate solution for 30s, wait 10min and then apply 2% nystatin paste) or these agents plus local probiotics (the mixture of Bifidobacterium longum, Lactobacillus bulgaricus and Streptococcus thermophilus) three times per day for 4weeks. Parameters related to hyperaemia, visual analogue scale scores, culture of resting saliva and a lingual dorsum swab and adverse reactions were assessed or recorded in the beginning, middle and end of treatment. Although the baseline characteristics of the participants were similar, both groups showed a significant reduction in pain level and hyperaemia on the tongue mucosa (P=0.000) after 4-week application. However, despite the reduction in hyperaemia in the probiotic group, these improvements did not display statistically significant differences. The detection rate of Candida spp. was 100% before treatment and 8.21% in the experimental group and 34.6% in the control group after treatment. The detection rate of Candida spp. decreased (P=0.000) in both groups and was significantly lower in the probiotic group than the control group (P=0.038). Other analysed micro-organisms, including the decreased detection rate for Lactobacillus spp. (P=0.049) and the increased detection rate for Staphylococcus epidermidis (P=0.019), did not display consistent change trends in the probiotics group. Compared with conventional antifungal therapies for oral candidiasis, the inclusion of locally administered probiotics helped improve certain clinical conditions and reduced the prevalence of Candida spp., although the impact of probiotics on oral bacterial species remains to be further studied.

Allergic bronchopulmonary aspergillosis: review of literature and proposal of new diagnostic and classification criteria

Allergic bronchopulmonary aspergillosis (ABPA) is an immunological pulmonary disorder caused by hypersensitivity to Aspergillus fumigatus, manifesting with poorly controlled asthma, recurrent pulmonary infiltrates and bronchiectasis. There are estimated to be in excess of four million patients affected world-wide. The importance of recognizing ABPA relates to the improvement of patient symptoms, and delay in development or prevention of bronchiectasis, one manifestation of permanent lung damage in ABPA. Environmental factors may not be the only pathogenetic factors because not all asthmatics develop ABPA despite being exposed to the same environment. Allergic bronchopulmonary aspergillosis is probably a polygenic disorder, which does not remit completely once expressed, although long-term remissions do occur. In a genetically predisposed individual, inhaled conidia of A. fumigatus germinate into hyphae with release of antigens that activate the innate and adaptive immune responses (Th2 CD4(+) T cell responses) of the lung. The International Society for Human and Animal Mycology (ISHAM) has constituted a working group on ABPA complicating asthma (www.abpaworkinggroup.org), which convened an international conference to summarize the current state of knowledge, and formulate consensus-based guidelines for diagnosis and therapy. New diagnosis and staging criteria for ABPA are proposed. Although a small number of randomized controlled trials have been conducted, long-term management remains poorly studied. Primary therapy consists of oral corticosteroids to control exacerbations, itraconazole as a steroid-sparing agent and optimized asthma therapy. Uncertainties surround the prevention and management of bronchiectasis, chronic pulmonary aspergillosis and aspergilloma as complications, concurrent rhinosinusitis and environmental control. There is need for new oral antifungal agents and immunomodulatory therapy.

An intertriginous lesion on the foot of a 74-year-old man

A 74-year-old man presented with an 8-year history of an intertriginous lesion on his right foot. He had been treated with several topical and oral antifungal agents, with no improvement. The rest of his medical history was unremarkable. On physical examination, maceration and eroded erythema were seen at the base of the fourth toe. This involved the web space, which was hard on palpation. On the dorsa of the foot, there was a cutaneous retraction with superficial ulceration, and adherences between the fourth and fifth toes (Fig. 1). The rest of the examination was unremarkable. A biopsy of the lesion was taken and sent for histopathological study.

Phase 2 Study of Pemetrexed and Itraconazole as Second-Line Therapy for Metastatic Nonsquamous Non–Small-Cell Lung Cancer

Preclinical studies have suggested that the oral antifungal agent itraconazole specifically inhibits proliferation, migration, and tube formation of endothelial cells. Itraconazole has potent antiangiogenic activity and enhances the efficacy of cytotoxic chemotherapy in multiple primary xenograft lung cancer models. On the basis of these data, we performed an exploratory clinical study, assessing the efficacy of itraconazole with cytotoxic chemotherapy in the treatment of patients with advanced lung cancer. The study enrolled patients with progressive nonsquamous non-small-cell lung cancer after one prior cytotoxic therapy for metastatic disease, randomized 2:1 to intravenous administration of pemetrexed 500 mg/m2 on day 1, with or without itraconazole 200 mg orally daily, on a 21-day cycle. Outcome measures included percent progression-free at 3 months, progression-free survival, overall survival, and observed toxicity. A total of 23 patients were enrolled; the study was stopped early because of increasing use of pemetrexed in the first-line setting. At 3 months, 67% of the patients on itraconazole plus pemetrexed were progression-free versus 29% on the control arm of pemetrexed alone (p = 0.11). Median progression-free survivals were 5.5 months (itraconazole) versus 2.8 months (control) (hazard ratio = 0.399, p = 0.089). Overall survival was longer in patients receiving itraconazole (median 32 months) versus control (8 months) (hazard ratio = 0.194, p = 0.012). There were no evident differences in toxicity between the study arms. Itraconazole is well tolerated in combination with pemetrexed. Consistent with our preclinical data, daily itraconazole administration is associated with trends suggestive of improved disease control in patients receiving chemotherapy for advanced lung cancer.

Does the use of oral nonabsorbable antifungal prophylaxis reduce the incidence of fungal colonization and/or systemic infection in preterm infants?

Invasive fungal infection is a significant cause of mortality and morbidity in preterm infants. Oral nonabsorbable agents are used prophylactically, but the literature regarding their effectiveness has not been systematically reviewed. To determine if oral nonabsorbable antifungal prophylaxis reduces the incidence of fungal colonization and/or systemic infection in preterm infants. The literature was reviewed using the methodology for systematic reviews for the Consensus on Resuscitation Science adapted from the American Heart Association's International Liaison Committee on Resuscitation. Five studies were reviewed. Three level of evidence 1 studies and two level of evidence 3/4 studies provided evidence that the prophylactic use of oral nonabsorbable antifungal agents can reduce the incidence of fungal colonization and/or systemic fungal infection in preterm infants. Prophylactic oral nonabsorbable antifungal medications are an acceptable approach to reduce colonization and invasive fungal infection in preterm infants in units with high baseline colonization rates.

Pharmacoeconomic assessment of therapy for invasive aspergillosis

Invasive aspergillosis (IA) is a major cause of morbidity and mortality in immunocompromised hosts. Economic expenditures prompted by this invasive fungal infection (IFI) are significant. Although, the duration and associated costs of hospitalization comprise the largest proportion of costs in large surveillance studies, the newer oral antifungal agents may impact significantly on these costs. A review of the pharmacoeconomic (PE) studies is provided focussing on primary therapy, salvage therapy, empiric therapy and prophylaxis for IA. PE evaluations have demonstrated the cost effectiveness and dominance of voriconazole for targeted primary treatment of IA compared with other available agents. Differences in the drug choice and analytic methodology of the PE analyses of empiric antifungal strategy hamper definitive conclusions about the agents employed as empiric antifungal that may be directed at suspected IA although both caspofungin and voriconazole appear to be cost effective and dominant over liposomal amphotericin B (LAmB), whereas LAmB is more costly than conventional amphotericin B. Posaconazole is the most cost-effective agent for antifungal prophylaxis against IFI and IA.