Oral Azole Drugs as Systemic Antifungal Therapy

Como, Jackson A.; Dismukes, William E.

doi:10.1056/nejm199401273300407

Cited by 526 publications

(39 citation statements)

References 111 publications

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“…The newer azole class of antifungal agents, particularly triazoles, has proven to be useful in treating many different systemic mycosis caused by yeasts and molds [13,14]. Little is known, however, about their effect against disseminated T. beigelii infection.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of Amphotericin B and Azoles Alone and in Combination against Disseminated Trichosporonosis in Neutropenic Mice

Kamberi

Hashimoto²,

Tashiro³

et al. 1997

Chemotherapy

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The activities of amphotericin B, miconazole, fluconazole, and itraconazole against Trichosporon beigelii were assessed in a mouse model of disseminated infection. Cyclophosphamide plus prednisolone-immunosuppressed ICR mice, intravenously challenged with a lethal inoculum of (6 × 10⁶ CFU/mouse), were assigned to receive 7 days of therapy with amphotericin B (0.5 or 2 mg/kg/day), miconazole (10 or 40 mg/kg/day), fluconazole (10 or 40 mg/kg/day), or itraconazole (10 and 40 mg/kg/day). The efficacy of a combination of amphotericin B (1 mg/kg/day) with fluconazole (10 mg/kg/day) or itraconazole (20 mg/kg/day) with that of each agent alone was also compared. Both amphotericin B and azoles improved survival and reduced the fungal counts in kidneys of infected mice in a dose-dependent pattern. In general, fluconazole was superior to amphotericin B and the other azoles, whereas the latter two drugs were as effective as amphotericin B. The activity of amphotericin B combined with fluconazole appeared to be superior to that of each agent alone, especially in reducing the organ fungal burden. The other combination (amphotericin B plus itraconazole) had a weaker effect, but no antagonism was observed. In conclusion, azoles may be an alternative to amphotericin B for the treatment of T. beigelii infection. Furthermore, their combination with amphotericin B may improve the poor outcome seen in profoundly neutropenic patients with disseminated trichosporonosis.

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Section: Introductionmentioning

confidence: 99%

Efficacy of Amphotericin B and Azoles Alone and in Combination against Disseminated Trichosporonosis in Neutropenic Mice

Kamberi

Hashimoto²,

Tashiro³

et al. 1997

Chemotherapy

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“…If not swiftly and appropriately treated, these fungal infections can progress to serious illness and rapidly become fatal (2,6). The azole class of drugs is still the most commonly prescribed treatment for many fungal infections because the drugs are relatively cheap to produce, are generally nontoxic to humans, and are usually more effective for controlling an infection than other classes of antifungals (5,7).…”

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confidence: 99%

“…Specifically, azoles enter the fungal cell and inhibit the fungal cytochrome P450-dependent enzyme, lanosterol 14␣-demethylase, encoded by the cyp51A and cyp51B genes in A. fumigatus (7,8). Disruption of the ergosterol biosynthesis pathway leads to increased membrane permeability and instability in the fungal cell, which is deleterious to cell growth and replication (6,9). The intrinsic resistance of A. fumigatus to FLC is possibly due to the differential FLC binding affinity to the Cyp51A and Cyp51B proteins (8,10).…”

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Azole Drug Import into the Pathogenic Fungus Aspergillus fumigatus

Esquivel

Smith

Zavřel

et al. 2015

Antimicrob Agents Chemother

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The fungal pathogen Aspergillus fumigatus causes serious illness and often death when it invades tissues, especially in immunocompromised individuals. The azole class of drugs is the most commonly prescribed treatment for many fungal infections and acts on the ergosterol biosynthesis pathway. One common mechanism of acquired azole drug resistance in fungi is the prevention of drug accumulation to toxic levels in the cell. While drug efflux is a well-known resistance strategy, reduced azole import would be another strategy to maintain low intracellular azole levels. Recently, azole uptake in Candida albicans and other yeasts was analyzed using [ 3 H]fluconazole. Defective drug import was suggested to be a potential mechanism of drug resistance in several pathogenic fungi, including Cryptococcus neoformans, Candida krusei, and Saccharomyces cerevisiae. We have adapted and developed an assay to measure azole accumulation in A. fumigatus using radioactively labeled azole drugs, based on previous work done with C. albicans. We used this assay to study the differences in azole uptake in A. fumigatus isolates under a variety of drug treatment conditions, with different morphologies and with a select mutant strain with deficiencies in the sterol uptake and biosynthesis pathway. We conclude that azole drugs are specifically selected and imported into the fungal cell by a pH-and ATPindependent facilitated diffusion mechanism, not by passive diffusion. This method of drug transport is likely to be conserved across most fungal species.T he fungal pathogen Aspergillus fumigatus is one of the most common and ubiquitous environmental molds. Aspergillus infections represent a significant human health burden. Aspergillus causes serious illnesses, ranging from sinus infections to invasive or chronic aspergillosis in immunocompromised individuals (1-3). Infection can be fatal when Aspergillus colonizes or invades tissues, such as the lungs and blood vessels (2). The patients most at risk for these infections are those with prior lung conditions such as asthma, tuberculosis, chronic obstructive pulmonary disease (COPD), or cystic fibrosis, as well as bone marrow transplant patients and people living with HIV, AIDS, or other immune deficiencies (1-4). Aspergillus infections greatly affect the quality of life, cause dramatically lengthened hospital stays, and cost the United States more than 1 billion dollars each year (3, 5). In recent years, there has been a significant rise in the number of fungal infections due to the growing subpopulation of individuals with weakened immune health (3).If not swiftly and appropriately treated, these fungal infections can progress to serious illness and rapidly become fatal (2, 6). The azole class of drugs is still the most commonly prescribed treatment for many fungal infections because the drugs are relatively cheap to produce, are generally nontoxic to humans, and are usually more effective for controlling an infection than other classes of antifungals (5, 7). Although A. fumigatus has an intri...

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“…Also, due to the rise of serum creatinine, the use of amphotericin B had to be discontinued. The therapy was continued with oral fluconazole which is easily absorbed into the cerebrospinal fluid from the blood [14]. Fluconazole is the most effective new oral antifungal medication for cryptococcosis.…”

Section: Discussionmentioning

confidence: 99%

Cryptococcosis during Systemic Glucocorticosteroid Treatment

Lauerma

Jeskanen²,

Rantanen³

et al. 1999

Dermatology

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Cryptococcosis is an opportunistic infection caused by a fungus, Cryptococcus neoformans. It is usually seen in immunocompromised patients with AIDS, leukaemia, lymphoma, sarcoidosis or immunosuppressive treatments. We describe a patient who was treated with systemic glucocorticosteroids for 4 years because of lung sarcoidosis. During the last year of treatment, a papular eruption developed which later became ulcerative. In a histopathological examination of a skin biopsy, there was granulomatous inflammation, and the disease was treated as sarcoidosis without success. After 1 year’s unsuccessful treatment, another skin biopsy and skin fungal culture revealed C. neoformans. Cryptococcal antigen was found in blood and cerebrospinal fluid, too. The patient was successfully treated first with an amphotericin-B-flucytosine combination and later with fluconazole.

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Oral Azole Drugs as Systemic Antifungal Therapy

Cited by 526 publications

References 111 publications

Efficacy of Amphotericin B and Azoles Alone and in Combination against Disseminated Trichosporonosis in Neutropenic Mice

Efficacy of Amphotericin B and Azoles Alone and in Combination against Disseminated Trichosporonosis in Neutropenic Mice

Azole Drug Import into the Pathogenic Fungus Aspergillus fumigatus

Cryptococcosis during Systemic Glucocorticosteroid Treatment

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