Recent Approaches to Antifungal Therapy for Invasive Mycoses

Mathew, Bijoy P.; Nath, Mala

doi:10.1002/cmdc.200800353

Cited by 83 publications

(58 citation statements)

References 140 publications

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“…Drug interactions are often related to subtherapeutic concentrations caused by the specific metabolic pathway of triazoles. In particular, ITC is both an inhibitor and a substrate of cytochrome P450 3A4 (CYP3A4) (47) and of the P-glycoprotein transporter system (23,32), and PSC is an inhibitor of CYP3A4 and is metabolized by glucuronization (40,47). VRC is a substrate and inhibitor of CYP2C19, CYP2C8/9, and CYP3A4 (23,47).…”

Section: Discussionmentioning

confidence: 99%

Development, Validation, and Routine Application of a High-Performance Liquid Chromatography Method Coupled with a Single Mass Detector for Quantification of Itraconazole, Voriconazole, and Posaconazole in Human Plasma

Baietto

D’Avolio

Ventimiglia

et al. 2010

Antimicrob Agents Chemother

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We have developed and validated a high-performance liquid chromatography method coupled with a mass detector to quantify itraconazole, voriconazole, and posaconazole using quinoxaline as the internal standard. The method involves protein precipitation with acetonitrile. Mean accuracy (percent deviation from the true value) and precision (relative standard deviation percentage) were less than 15%. Mean recovery was more than 80% for all drugs quantified. The lower limit of quantification was 0.031 g/ml for itraconazole and posaconazole and 0.039 g/ml for voriconazole. The calibration range tested was from 0.031 to 8 g/ml for itraconazole and posaconazole and from 0.039 to 10 g/ml for voriconazole.The incidence of mycoses has continued to increase over the past 2 decades, especially in immunocompromised patients. Notwithstanding the fact that in the last decades new antifungal agents have been approved, there is still a therapeutic need for azole compounds, such as itraconazole (ITC), posaconazole (PSC), and voriconazole (VRC), which inhibit 14a-demethylase, a key enzyme in the ergosterol biosynthesis of yeasts and molds (40).Antifungal prophylaxis, empirical therapy, and treatment of established fungal infections in the hematology patient population may be associated with significant toxicity or drug interactions, leading to subtherapeutic antifungal drug concentrations and poorer clinical outcomes (47). For example, a relationship between plasma concentrations and antifungal efficacy was shown for ITC (19), and the ratio between the area under the concentration-time curve (AUC) and MIC was identified to be predictive for the treatment efficacy of voriconazole and posaconazole, as well (1, 2). Antifungal therapeutic drug monitoring (TDM) could be an important tool in clinical practice if compliance is poor, the therapeutic window is narrow, or drug interactions and toxicity are common adverse effects. Therefore, quantification of drug in plasma samples is an important issue in clinical practice to improve efficacy and to decrease toxicity.Many methods to individually quantify ITZ (6,7,9,17,18,26,[31][32][33][34]37,45,46), PSC (8,35,39), and VRC (11,20,24,25,28,29,36,38) in human plasma have been published. Only one method described the quantification of the three triazoles plus fluconazole, ITC metabolite, and ketokonazole in human plasma using a solid-phase extraction procedure.The aim of this study was to develop and validate a high-performance liquid chromatography-mass spectrometry (HPLC-MS) method useful in routine TDM for quantitation of ITC, PSC, and VRC in human plasma using a protein precipitation extraction procedure and direct injection in an HPLC system. MATERIALS AND METHODSChemicals. ITC and dimethyl diquinoxaline (QX), used as the internal standard (IS), were purchased from Sigma Aldrich (St. Louis, MO), and PSC and VRC were purchased from Sequoia Research (Pangbourne, United Kingdom). Acetonitrile (HPLC grade) and methanol (HPLC grade) were purchased from J.T. Baker (Deventer, Holland). Formic aci...

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Section: Discussionmentioning

confidence: 99%

Development, Validation, and Routine Application of a High-Performance Liquid Chromatography Method Coupled with a Single Mass Detector for Quantification of Itraconazole, Voriconazole, and Posaconazole in Human Plasma

Baietto

D’Avolio

Ventimiglia

et al. 2010

Antimicrob Agents Chemother

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“…However, clinical therapies that have been developed to target either fungal or bacterial infections have generally failed to consider that fungi and bacteria often coinfect, forming mixed communities that have virulence and resistance properties significantly different from those of the single-species communities (366,397). An understanding of the functioning of BFIs in human health is therefore an emerging and important challenge for medical researchers, particularly given the development of strains that are resistant to drug therapies (127,243,290,292).…”

Section: Roles In Host Health and Diseasementioning

confidence: 99%

Bacterial-Fungal Interactions: Hyphens between Agricultural, Clinical, Environmental, and Food Microbiologists

Frey‐Klett

Burlinson

Deveau

et al. 2011

Microbiol Mol Biol Rev

700

531

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SUMMARY Bacteria and fungi can form a range of physical associations that depend on various modes of molecular communication for their development and functioning. These bacterial-fungal interactions often result in changes to the pathogenicity or the nutritional influence of one or both partners toward plants or animals (including humans). They can also result in unique contributions to biogeochemical cycles and biotechnological processes. Thus, the interactions between bacteria and fungi are of central importance to numerous biological questions in agriculture, forestry, environmental science, food production, and medicine. Here we present a structured review of bacterial-fungal interactions, illustrated by examples sourced from many diverse scientific fields. We consider the general and specific properties of these interactions, providing a global perspective across this emerging multidisciplinary research area. We show that in many cases, parallels can be drawn between different scenarios in which bacterial-fungal interactions are important. Finally, we discuss how new avenues of investigation may enhance our ability to combat, manipulate, or exploit bacterial-fungal complexes for the economic and practical benefit of humanity as well as reshape our current understanding of bacterial and fungal ecology.

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“…Despite recent advances in prevention and diagnosis, the incidence of fungal infections continues to rise, particularly due to the increase in the number of immunocompromised patients (3)(4)(5)(6). Available clinical antifungal agents include echinocandins, polyenes, and azoles.…”

mentioning

confidence: 99%

Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14α-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity

Hargrove

Garvey

Hoekstra

et al. 2017

Antimicrob Agents Chemother

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Within the past few decades, the incidence and complexity of human fungal infections have increased, and therefore, the need for safer and more efficient, broad-spectrum antifungal agents is high. In the study described here, we characterized the new tetrazole-based drug candidate VT-1598 as an inhibitor of sterol 14␣-demethylase (CYP51B) from the filamentous fungus Aspergillus fumigatus. VT-1598 displayed a high affinity of binding to the enzyme in solution (dissociation constant, 13 Ϯ 1 nM) and in the reconstituted enzymatic reaction was revealed to have an inhibitory potency stronger than the potencies of all other simultaneously tested antifungal drugs, including fluconazole, voriconazole, ketoconazole, and posaconazole. The X-ray structure of the VT-1598/A. fumigatus CYP51 complex was determined and depicts the distinctive binding mode of the inhibitor in the enzyme active site, suggesting the molecular basis of the improved drug potency and broadspectrum antifungal activity. These data show the formation of an optimized hydrogen bond between the phenoxymethyl oxygen of VT-1598 and the imidazole ring nitrogen of His374, the CYP51 residue that is highly conserved across fungal pathogens and fungus specific. Comparative structural analysis of A. fumigatus CYP51/voriconazole and Candida albicans CYP51/VT-1161 complexes supports the role of H bonding in fungal CYP51/inhibitor complexes and emphasizes the importance of an optimal distance between this interaction and the inhibitor-heme iron interaction. Cellular experiments using two A. fumigatus strains (strains 32820 and 1022) displayed a direct correlation between the effects of the drugs on CYP51B activity and fungal growth inhibition, indicating the noteworthy anti-A. fumigatus potency of VT-1598 and confirming its promise as a broad-spectrum antifungal agent.

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Recent Approaches to Antifungal Therapy for Invasive Mycoses

Cited by 83 publications

References 140 publications

Development, Validation, and Routine Application of a High-Performance Liquid Chromatography Method Coupled with a Single Mass Detector for Quantification of Itraconazole, Voriconazole, and Posaconazole in Human Plasma

Development, Validation, and Routine Application of a High-Performance Liquid Chromatography Method Coupled with a Single Mass Detector for Quantification of Itraconazole, Voriconazole, and Posaconazole in Human Plasma

Bacterial-Fungal Interactions: Hyphens between Agricultural, Clinical, Environmental, and Food Microbiologists

Crystal Structure of the New Investigational Drug Candidate VT-1598 in Complex with Aspergillus fumigatus Sterol 14α-Demethylase Provides Insights into Its Broad-Spectrum Antifungal Activity

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