Current Options in Antifungal Pharmacotherapy

Mohr, John; Johnson, Melissa D.; Cooper, Travis Warren; Lewis, James S.; Ostrosky‐Zeichner, Luis

doi:10.1592/phco.28.5.614

Cited by 71 publications

(30 citation statements)

References 243 publications

(280 reference statements)

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“…Along with the immunocompromised population, the incidence of invasive aspergillosis is constantly growing, but therapy remains problematic. The sterol binding polyene amphotericin B and the ergosterol biosynthesis inhibitor itraconazole have long been the drugs of choice for treatment of this infection, but because of their higher efficacy and lower toxicity, new triazoles, such as voriconazole or posaconazole, are supplanting these drugs (28,33). Additionally, a novel class of antifungal agents called the echinocandins provides further options for treatment.…”

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confidence: 99%

Contribution of Galactofuranose to the Virulence of the Opportunistic Pathogen Aspergillus fumigatus

et al. 2008

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The filamentous fungus Aspergillus fumigatus is responsible for a lethal disease called invasive aspergillosis that affects immunocompromised patients. This disease, like other human fungal diseases, is generally treated by compounds targeting the primary fungal cell membrane sterol. Recently, glucan synthesis inhibitors were added to the limited antifungal arsenal and encouraged the search for novel targets in cell wall biosynthesis. Although galactomannan is a major component of the A. fumigatus cell wall and extracellular matrix, the biosynthesis and role of galactomannan are currently unknown. By a targeted gene deletion approach, we demonstrate that UDP-galactopyranose mutase, a key enzyme of galactofuranose metabolism, controls the biosynthesis of galactomannan and galactofuranose containing glycoconjugates. The glfA deletion mutant generated in this study is devoid of galactofuranose and displays attenuated virulence in a low-dose mouse model of invasive aspergillosis that likely reflects the impaired growth of the mutant at mammalian body temperature. Furthermore, the absence of galactofuranose results in a thinner cell wall that correlates with an increased susceptibility to several antifungal agents. The UDP-galactopyranose mutase thus appears to be an appealing adjunct therapeutic target in combination with other drugs against A. fumigatus. Its absence from mammalian cells indeed offers a considerable advantage to achieve therapeutic selectivity.

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confidence: 99%

Contribution of Galactofuranose to the Virulence of the Opportunistic Pathogen Aspergillus fumigatus

et al. 2008

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“…Prophylaxis using antifungal drugs has markedly reduced the occurrence of these infections (8,19,23,24); however, mortality for aspergillosis remains high (17). Most clinically deployed antifungal drugs target ergosterol, a membrane sterol present in plants and fungi (19), leaving a great need for drugs with alternative mechanisms of action. In vitro demonstration that lactoferrin inhibits the growth Aspergillus fumigatus conidia by iron deprivation (25) and the topical use of the iron chelator ciclopirox for superficial fungal infections (11) suggest that inhibition of fungal iron acquisition may provide an alternative drug target.…”

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confidence: 99%

Antifungal Activities of Natural and Synthetic Iron Chelators Alone and in Combination with Azole and Polyene Antibiotics against Aspergillus fumigatus

Zarember¹,

Cruz²,

Huang

et al. 2009

Antimicrob Agents Chemother

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Antifungal effects of iron chelators (lactoferrin, deferoxamine, deferiprone, and ciclopirox) were tested alone and in combination with antifungal drugs against Aspergillus fumigatus B5233 conidia. Lactoferrin, ciclopirox, and deferiprone inhibited whereas deferoxamine enhanced fungal growth. Antifungal synergy against conidia was observed for combinations of ketoconazole with ciclopirox or deferiprone, lactoferrin with amphotericin B, and fluconazole with deferiprone. Iron chelation alone or combined with antifungal drugs may be useful for prevention and treatment of mycosis.Invasive aspergillosis in neutropenic and immunocompromised patients is a serious therapeutic challenge (2,4,7,16). Prophylaxis using antifungal drugs has markedly reduced the occurrence of these infections (8,19,23,24); however, mortality for aspergillosis remains high (17). Most clinically deployed antifungal drugs target ergosterol, a membrane sterol present in plants and fungi (19), leaving a great need for drugs with alternative mechanisms of action. In vitro demonstration that lactoferrin inhibits the growth Aspergillus fumigatus conidia by iron deprivation (25) and the topical use of the iron chelator ciclopirox for superficial fungal infections (11) suggest that inhibition of fungal iron acquisition may provide an alternative drug target. Furthermore, transfusional siderosis and iron overload in malignancy and liver and stem cell transplantation are associated with an increased risk of aspergillosis (1,3,15).To assay the effects of iron chelators and antifungal drugs on the growth of Aspergillus fumigatus strain B5233 (provided by June Kwon-Chung, NIAID), conidia (10 5 ) were cultured in 90 l RPMI 1640 without phenol red, buffered with 25 mM HEPES (pH 7.2), in the presence of drugs or buffer (final volume, 100 l).After 16 h at 37°C in a humidified 5% CO 2 incubator, 100 l of RPMI with 5 M 5-chloromethylfluorescein diacetate (Invitrogen) was added, followed by incubation for 30 min, and fluorescence measured as described previously (5, 25). As shown in Fig. 1, lactoferrin (partially saturated native human; Sigma Chemicals, St. Louis, MO) was most potent on a molar basis, requiring only 105 Ϯ 9 nM to reduce untreated control growth by 50% (50% inhibitory concentration [IC 50 ]), followed by ciclopirox (6-cyclohexyl-1-hydroxy-4-methyl-2(1H)-pyridinone; Toronto Research Chemicals, North York, Ontario, Canada) (IC 50 ϭ 4.22 Ϯ 0.18 M) and deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one; Toronto Research Chemicals) (IC 50 ϭ 1.29 Ϯ 0.2 mM). Deferoxamine mesylate (Sigma) promoted A. fumigatus growth, as has been reported for Rhizopus (6, 9).Analysis of the combined effects of different drugs is clinically important since synergistic combinations of drugs may be more efficacious and less toxic than single agents (14,20,21). Checkerboard assays of the three active iron chelators alone and in combination with itraconazole, fluconazole, ketoconazole (Sigma), or amphotericin B (Toronto Research Chemicals) were performed. The respective IC 50 s (Ϯ...

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“…Inhibition of this enzyme prevents the conversion of lanosterol to AmB amphotericin B, 5-FC flucytosine, IV intravenously, PO orally, q every ergosterol, leading to the accumulation of methyl sterols and ultimately resulting in disruption of fungal cell growth and replication [8,22,23]. Each of the four triazole antifungals (fluconazole, voriconazole, itraconazole, and posaconazole) have differing affinities for the 14-α-demethylase enzyme, leading to differing potencies against Candida species and differences in fungistatic and fungicidal activity against various mycoses [22].…”

Section: Triazolesmentioning

confidence: 99%

Antifungal Dosing in Critically Ill Patients

Bergman

Tyagi

Ronald

2010

Curr Fungal Infect Rep

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This article reviews appropriate dosing for antifungals and emphasizes factors specific to the critically ill patient, along with drug pharmacokinetics and pharmacodynamics. The rationale for doses of the echinocandins (caspofungin, micafungin, anidulafungin), triazoles (fluconazole, voriconazole, itraconazole, posaconazole), amphotericin B (including lipid formulations), and flucytosine are discussed.

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Current Options in Antifungal Pharmacotherapy

Cited by 71 publications

References 243 publications

Contribution of Galactofuranose to the Virulence of the Opportunistic Pathogen Aspergillus fumigatus

Contribution of Galactofuranose to the Virulence of the Opportunistic Pathogen Aspergillus fumigatus

Antifungal Activities of Natural and Synthetic Iron Chelators Alone and in Combination with Azole and Polyene Antibiotics against Aspergillus fumigatus

Antifungal Dosing in Critically Ill Patients

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