SciCombinator

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Concept: Athlete's foot

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Recent estimates suggest that >300 million people are afflicted by serious fungal infections worldwide. Current antifungal drugs are static and toxic and/or have a narrow spectrum of activity. Thus, there is an urgent need for the development of new antifungal drugs. The fungal sphingolipid glucosylceramide (GlcCer) is critical in promoting virulence of a variety of human-pathogenic fungi. In this study, we screened a synthetic drug library for compounds that target the synthesis of fungal, but not mammalian, GlcCer and found two compounds [N'-(3-bromo-4-hydroxybenzylidene)-2-methylbenzohydrazide (BHBM) and its derivative, 3-bromo-N'-(3-bromo-4-hydroxybenzylidene) benzohydrazide (D0)] that were highly effective in vitro and in vivo against several pathogenic fungi. BHBM and D0 were well tolerated in animals and are highly synergistic or additive to current antifungals. BHBM and D0 significantly affected fungal cell morphology and resulted in the accumulation of intracellular vesicles. Deep-sequencing analysis of drug-resistant mutants revealed that four protein products, encoded by genes APL5, COS111, MKK1, and STE2, which are involved in vesicular transport and cell cycle progression, are targeted by BHBM.

Concepts: Bacteria, Chromosome, Fungus, Cell cycle, In vitro, Antifungal drug, Athlete's foot, Griseofulvin

167

BACKGROUND: Incorporation of the solubilizing excipient, sulfobutylether-beta-cyclodextrin (SBECD), in the intravenous (IV) formulation of voriconazole has resulted in the recommendation that this formulation be used with caution in patients with creatinine clearances (Clcr) < 50 mL/min. This study evaluated the safety of IV voriconazole compared with two other IV antifungals not containing SBECD in patients with compromised renal function. METHODS: A total of 128 patients aged 11--93 years who had a baseline Clcr < 50 mL/min between January 1, 2007 and December 31, 2010 were identified from a database of a university-affiliated inpatient healthcare system; of these, 55 patients received caspofungin, 54 patients received fluconazole, and 19 patients received voriconazole. Changes in serum creatinine (Scr) and Clcr levels while on therapy were compared with baseline values and between groups. RESULTS: The groups had similar characteristics apart from the larger proportion of females that received fluconazole. Baseline Scr was higher in those receiving caspofungin, but maximal increases of Scr and decreases in Clcr were greatest for the fluconazole group. Acute kidney injury (AKI), assessed by RIFLE criteria, was more frequent in the fluconazole vs. the caspofungin group (p < 0.01); incidence of AKI in the voriconazole group was not significantly different than found in the other two groups. The infecting organism was a predictor of AKI and formulation with SBECD was not. CONCLUSIONS: Treatment of fungal infections in patients with compromised renal function with an SBECD-containing antifungal agent was not associated with AKI in clinical practice. Since the infecting organism was associated with AKI, decision on which antifungal to use should be determined by susceptibilities to the organism and not the incorporation of SBECD in the IV formulation.

Concepts: Renal failure, Renal physiology, Blood urea nitrogen, Antifungals, Candidiasis, Antifungal drug, Athlete's foot, Griseofulvin

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F901318 is an antifungal agent with a novel mechanism of action and potent activity against Aspergillus spp. An understanding of the pharmacodynamics (PD) of F901318 is required for selection of effective regimens for study in phase II and III clinical trials. Neutropenic murine and rabbit models of invasive pulmonary aspergillosis were used. The primary PD endpoint was serum galactomannan. The relationships between drug exposure and the impacts of dose fractionation on galactomannan, survival, and histopathology were determined. The results were benchmarked against a clinically relevant exposure of posaconazole. In the murine model, administration of a total daily dose of 24 mg/kg of body weight produced consistently better responses with increasingly fractionated regimens. The ratio of the minimum total plasma concentration/MIC (Cmin/MIC) was the PD index that best linked drug exposure with observed effect. An average Cmin (mg/liter) and Cmin/MIC of 0.3 and 9.1, respectively, resulted in antifungal effects equivalent to the effect of posaconazole at the upper boundary of its expected human exposures. This pattern was confirmed in a rabbit model, where Cmin and Cmin/MIC targets of 0.1 and 3.3, respectively, produced effects previously reported for expected human exposures of isavuconazole. These targets were independent of triazole susceptibility. The pattern of maximal effect evident with these drug exposure targets was also apparent when survival and histopathological clearance were used as study endpoints. F901318 exhibits time-dependent antifungal activity. The PD targets can now be used to select regimens for phase II and III clinical trials.IMPORTANCE Invasive fungal infections are common and often lethal. There are relatively few antifungal agents licensed for clinical use. Antifungal drug toxicity and the emergence of drug resistance make the treatment of these infections very challenging. F901318 is the first in a new class of antifungal agents called the orotomides. This class has a novel mechanism of action that involves the inhibition of the fungal enzyme dihydroorotate dehydrogenase. F901318 is being developed for clinical use. A deep understanding of the relationship between dosages, drug concentrations in the body, and the antifungal effect is fundamental to the identification of the regimens to administer to patients with invasive fungal infections. This study provides the necessary information to ensure that the right dose of F901318 is used the first time. Such an approach considerably reduces the risks in drug development programs and ensures that patients with few therapeutic options can receive potentially life-saving antifungal therapy at the earliest opportunity.

Concepts: Pharmacology, Clinical trial, Aspergillosis, Aspergillus, Antifungals, Antifungal drug, Athlete's foot, Griseofulvin

28

Because of the low prevalence of onychomycosis in children, little is known about the efficacy and safety of systemic antifungals in this population. PubMed and Embase databases and the references of related publications were searched in March 2012 for clinical trials (CTs), retrospective analyses (RAs), and case reports (CRs) on the use of systemic antifungals for onychomycosis in children (<18 years). Twenty-six studies (5 CTs, 3 RAs, and 18 CRs) were published between 1976 and 2011. Most of these studies reported the use of systemic terbinafine and itraconazole for the treatment of onychomycosis in children. Therapy with systemic antifungals alone in children age 1 to 17 years resulted in a complete cure rate of 70.8% (n = 151), whereas combined systemic and topical antifungal therapy in one infant and 19 children age 8 and older resulted in a complete cure rate of 80.0% (n = 20). The efficacy and safety profiles of terbinafine, itraconazole, griseofulvin, and fluconazole in children were similar to those previously reported for adults. In conclusion, based on the little information available on onychomycosis in children, systemic antifungal therapies in children are safe and cure rates are similar to the rates achieved in adults.

Concepts: Medicine, Therapy, Antifungals, Antifungal drug, Onychomycosis, Athlete's foot, Fluconazole, Griseofulvin

28

Trichophyton rubrum var. raubitschekii is a rare anthropophilic dermatophyte isolated around the world from tinea corporis, tinea cruris, tinea pedis and tinea unguium. In this study, the isolation rate of T. rubrum var. raubitschekii was studied in 200 cases of tinea pedis and tinea unguium in Japan. The 200 clinical isolates were shown to be of downy type as their colonies on Sabouraud’s dextrose agar were white to cream, suede-like to downy, with a yellow-brown to wine-red reverse, and they produced few macroconidia. The type strain of T. rubrum var. raubitschekii (CBS 100084) and one clinical isolate (KMU 8337; isolated at Kanazawa) of downy type tested positive for urease, but the reference strain of T. rubrum (CBS 392.58) and the remaining 199 clinical isolates tested negative. Further epidemiological investigations are required to study human cases of infection with the granular type of T. rubrum and T. rubrum var. raubitschekii in Japan.

Concepts: Biology, Trichophyton rubrum, Onychomycosis, Athlete's foot, Dermatophyte, Fungal diseases, Terbinafine, Mycosis-related cutaneous conditions

28

Trichophyton rubrum is a worldwide agent responsible for chronic cases of dermatophytosis which have high rates of resistance to antifungal drugs. Attention has been drawn to the antimicrobial activity of aromatic compounds because of their promising biological properties. Therefore, we investigated the antifungal activity of eugenol against 14 strains of T. rubrum which involved determining its minimum inhibitory concentration (MIC) and effects on mycelial growth (dry weight), conidial germination and morphogenesis. The effects of eugenol on the cell wall (sorbitol protect effect) and the cell membrane (release of intracellular material, complex with ergosterol, ergosterol synthesis) were investigated. Eugenol inhibited the growth of 50% of T. rubrum strains employed in this study at an MIC = 256 μg/ml, as well as mycelial growth and conidia germination. It also caused abnormalities in the morphology of the dermatophyte in that we found wide, short, twisted hyphae and decreased conidiogenesis. The results of these studies on the mechanisms of action suggested that eugenol exerts antifungal effects on the cell wall and cell membrane of T. rubrum. Eugenol act on cell membrane by a mechanism that seems to involve the inhibition of ergosterol biosynthesis. The lower ergosterol content interferes with the integrity and functionality of the cell membrane. Finally, our studies support the potential use of the eugenol as an antifungal agent against T. rubrum.

Concepts: Cell membrane, Ergosterol, Antifungal drug, Trichophyton rubrum, Onychomycosis, Athlete's foot, Ketoconazole, Miconazole

27

A novel model of infected nail plate for testing the efficacy of topical antifungal formulations has been developed. This model utilized keratin film made of human hair keratin as a nail plate model. Subsequent to infection by T. rubrum, the common causative agent of onychomycosis, keratin films as infected nail plate models were treated with selected topical formulations, i.e., cream, gel and nail lacquer. Bovine hoof was compared to keratin film. In contrast to the common antifungal susceptibility test, the antifungal drugs tested were applied as ready-to-use formulations because the vehicle may modify and control the drug action both in vitro and in vivo. Extrapolating the potency of an antifungal drug from an in vitro susceptibility test only would not be representative of the in vivo situation since these drugs are applied as ready-to-use formulations, e.g., as a nail lacquer. Although terbinafine has been acknowledged to be the most effective antifungal agent against T. rubrum, its antifungal efficacy was improved by its incorporation into an optimal formulation. Different gels proved superior to cream. Therefore, this study is able to discriminate between efficacies of different topical antifungal formulations based on their activities against T. rubrum.

Concepts: Antifungals, Keratin, Antifungal drug, Onychomycosis, Athlete's foot, Griseofulvin, Ketoconazole, Ringworm

27

Candida species are responsible for many opportunistic fungal infections. Fluconazole is a well-tolerated antifungal drug, commonly used in the treatment of Candidiasis. However, with fluconazole resistance ever increasing, rapid detection and antifungal susceptibility testing of Candida is imperative for proper patient treatment. Presented herein is a cost-effective, simple, and rapid chromogenic agar dilution method for simultaneous Candida species identification and fluconazole susceptibility testing. The results obtained by X-Plate Technology were in absolute concordance with standard microbroth dilution assays. Analysis of 1383 clinical patient samples with suspected vulvovaginal Candidiasis revealed that this technology was able to detect and speciate the Candida isolate and determine the fluconazole susceptibility. The prevalence and susceptibility profiles of the clinical isolates using this method were highly similar to published reports using the microbroth dilution method.

Concepts: Opportunistic infection, Antifungals, Candidiasis, Antifungal drug, Athlete's foot, Fluconazole, Griseofulvin, Ketoconazole

27

Superficial fungal infections due to dermatophytes are common over the world and their frequency is constantly increasing. The aim of our study was to discuss fungal infections with frequency of occurrence, clinical stages and aetiology in patients admitted to dermatological ward and microbiological laboratory of the specialist hospital in Krakow. Investigations performed between 1995 and 2010 included the group of 5333 individuals. Dermatophyte infections, confirmed by culture, were revealed in 1007 subjects (18.9%), i.e. in 553 males and 454 females. The most frequent clinical forms of infections were tinea unguium and tinea pedis, caused mainly by Trichophyton rubrum and by Trichophyton mentagrophytes. Tinea corporis, tinea manuum, tinea capitis and tinea cruris constituted a small percentage of infections and the main aetiological factors of these dermatomycoses were also T. rubrum and T. mentagrophytes. Between 1995 and 2000 there were stated small differences in the number of isolated strains of dermatophytes in comparison with the number of examined patients. Since 2006 there has been observed a decrease in number of patients in our hospital with suspected fungal infections, but per cent of positive cultures has remained unchanged in comparison with earlier period.

Concepts: Trichophyton rubrum, Onychomycosis, Athlete's foot, Dermatophyte, Fungal diseases, Terbinafine, Mycosis-related cutaneous conditions, Dermatophytosis

27

Onychomycosis is a common fungal nail infection in adults that is difficult to treat. The in vitro antifungal activity of efinaconazole, a novel triazole antifungal, was evaluated in recent clinical isolates of T. rubrum, T. mentagrophytes and C. albicans, common causative onychomycosis pathogens. In a comprehensive survey of 1493 isolates, efinaconazole minimum inhibitory concentrations (MIC) against T. rubrum and T. mentagrophytes ranged from ≤0.002 to 0.06 μg/ml, with 90% of isolates inhibited (MIC(90)) at 0.008 and 0.015 μg/ml, respectively. Efinaconazole MICs against 105 C. albicans isolates ranged from ≤0.0005 to >0.25 μg/ml, with 50% of isolates inhibited (MIC(50)) by 0.001 and 0.004 μg/ml at 24 and 48 hours, respectively. Efinaconazole potency against these organisms was similar or greater compared to antifungal drugs currently used in onychomycosis, including amorolfine, ciclopirox, itraconazole and terbinafine. In 13 T. rubrum toenail isolates from onychomycosis patients who were treated daily with topical efinaconazole for 48 weeks, there were no apparent increases in susceptibility, suggesting low potential for dermatophytes to develop resistance to efinaconazole. The activity of efinaconazole was further evaluated in other 8 dermatophyte, 15 nondermatophyte and 10 yeast species (109 isolates total from research repositories). Efinaconazole was active against Trichophyton, Microsporum, Epidermophyton, Acremonium, Fusarium, Paecilomyces, Pseudallescheria, Scopulariopsis, Aspergillus, Cryptococcus, Trichosporon and Candida, and compared favorably to other antifungal drugs. In conclusion, efinaconazole is a potent antifungal with broad spectrum of activity that may have clinical applications in onychomycosis and other mycoses.

Concepts: Fungus, Yeast, Antifungals, Ascomycota, Antifungal drug, Onychomycosis, Athlete's foot, Ketoconazole