Antifungal drugs and rational use of antifungals in treating invasive aspergillosis: the role of the hospital pharmacist

Bauters, Tieneke; Buyle, Franky; Peleman, Renaat; Robays, Hugo

doi:10.1007/s11096-004-1735-0

Cited by 7 publications

(5 citation statements)

References 22 publications

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“…The saprophytic fungus Aspergillus fumigatus is a serious health hazard in hospitals (Latge, 1999(Latge, , 2001. A. fumigatus is responsible for >90% of invasive aspergilloses (IA), with mostly fatal outcomes in immunocompromised patients suffering from AIDS, tuberculosis, cancer, or bone marrow/organ transplants (Latge, 1999;Bauters et al, 2005). The true incidence of A. fumigatus infections is underestimated because of the inherent diffi culty of positive diagnosis (Latge, 1999).…”

Section: Introductionmentioning

confidence: 99%

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The mitochondrial protein Bak is pivotal for gliotoxin-induced apoptosis and a critical host factor of Aspergillus fumigatus virulence in mice

Pardo

Urban²,

Gálvez

et al. 2006

The Journal of Cell Biology

100

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Aspergillus fumigatus infections cause high levels of morbidity and mortality in immunocompromised patients. Gliotoxin (GT), a secondary metabolite, is cytotoxic for mammalian cells, but the molecular basis and biological relevance of this toxicity remain speculative. We show that GT induces apoptotic cell death by activating the proapoptotic Bcl-2 family member Bak, but not Bax, to elicit the generation of reactive oxygen species, the mitochondrial release of apoptogenic factors, and caspase-3 activation. Activation of Bak by GT is direct, as GT triggers in vitro a dose-dependent release of cytochrome c from purified mitochondria isolated from wild-type and Bax- but not Bak-deficient cells. Resistance to A. fumigatus of mice lacking Bak compared to wild-type mice demonstrates the in vivo relevance of this GT-induced apoptotic pathway involving Bak and suggests a correlation between GT production and virulence. The elucidation of the molecular basis opens new strategies for the development of therapeutic regimens to combat A. fumigatus and related fungal infections.

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Section: Introductionmentioning

confidence: 99%

“…Thus, anti-A. fumigatus therapy remains inadequate and, as a consequence, high morbidity and mortality from IA prevails (Latge, 1999;Bauters et al, 2005). One reason for this is our poor under standing of the pathobiology of A. fumigatus.…”

Section: Introductionmentioning

confidence: 99%

The mitochondrial protein Bak is pivotal for gliotoxin-induced apoptosis and a critical host factor of Aspergillus fumigatus virulence in mice

Pardo

Urban²,

Gálvez

et al. 2006

The Journal of Cell Biology

100

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“…The most common species causing disease in patients is Aspergillus fumigatus (90%), followed by Aspergillus flavus, Aspergillus niger, and Aspergillus terreus (6,8). In the meantime, besides amphotericin B (AMB), several other drugs are available as treatments for invasive aspergillosis, such as voriconazole (VRZ), posaconazole (POS), and caspofungin (1,9,23,24). POS was recently approved for use for the treatment of patients with invasive infections that are refractory to other antifungal agents (17).…”

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confidence: 99%

Posaconazole Enhances the Activity of Amphotericin B against Aspergillus Hyphae In Vitro

Perkhofer

Lugger

Dierich

et al. 2007

Antimicrob Agents Chemother

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The MICs and fractional inhibitory concentrations of posaconazole (POS) and voriconazole (VRZ), alone and in combination with amphotericin B (AMB), for the conidia and hyphae of 100 Aspergillus isolates were evaluated. POS-AMB had more synergistic activity against hyphae (75% of isolates) than VRZ-AMB (37%) and significantly more synergistic activity against hyphae than against conidia (12%).Filamentous fungal pathogens are recognized as major and increasing sources of infection in immunocompromised hosts (6,18). The most common species causing disease in patients is Aspergillus fumigatus (90%), followed by Aspergillus flavus, Aspergillus niger, and Aspergillus terreus (6,8). In the meantime, besides amphotericin B (AMB), several other drugs are available as treatments for invasive aspergillosis, such as voriconazole (VRZ), posaconazole (POS), and caspofungin (1,9,23,24). POS was recently approved for use for the treatment of patients with invasive infections that are refractory to other antifungal agents (17). The high rate of mortality from mold infections and the relatively limited efficacies of the current agents have produced a significant interest in the use of polyene-and azole-based combinations for these difficult-to-treat infections (3,5,11,19). The present study evaluated the antifungal activity of either POS or VRZ, alone and in combination with AMB, against the conidia and hyphae of Aspergillus spp. in vitro.We tested 25 clinical isolates each of A. fumigatus, A. terreus, A. flavus, and A. niger from patients with invasive aspergillosis. The MICs of AMB (Sigma Aldrich, Vienna, Austria), VRZ (kindly provided by Pfizer, Vienna, Austria), and POS (kindly provided by Schering-Plough Research Institute, Kenilworth, NJ) for Aspergillus spp. were tested according to the guidelines described in the CLSI (formerly the NCCLS) M38-A document (15). The MICs for hyphae were tested by the method of . For all drugs the endpoints were read at 100% inhibition of conidia germination and hyphal growth after 48 h of incubation at 35°C. The endpoints read at 80% resulted in similar MIC data (not shown). Drug combinations were assessed by a checkerboard method. The synergy tests were evaluated by using the MIC endpoints of each drug. The fractional inhibitory concentration (FIC) of each drug for an individual isolate was calculated as the ratio of the concentration of the drug in combination that achieves the MIC endpoint to the MIC of the drug alone obtained by use of that endpoint. FIC index values were interpreted as follows: FIC Յ0.5, synergistic; FIC Ն1 to Յ4, indifferent; and FIC Ͼ4, antagonistic (3). Also, the metabolic activity of drug-treated hyphae was determined by their ability to reduce the tetrazolium compound 3-(4,5-dimethl-2-thiazol)-2,5-diphenyl-2H-tetrazolium bromide (MTT), as described elsewhere (13). Duplicate testing was performed on separate days. The results of the in vitro tests were compared by the log-rank test. Significance was defined as a P value of Ͻ0.05.The MIC ranges for conidia and hyphae...

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“…Antifungal therapies are particularly complicated to administer, often requiring premedication for infusion‐related toxicities and monitoring and management of adverse events and drug interactions (Fromtling & Castaner 1996, Hann & Prentice 2001, Rapp 2004, Bauters et al. 2005).…”

Section: Introductionmentioning

confidence: 99%

A multi‐centre comparison of nursing staff time required for the preparation and administration of liposomal amphotericin B and amphotericin B deoxycholate vs. voriconazole

Flynn

Marciniak

Barbabietola

et al. 2009

Journal of Clinical Nursing

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Antifungal drugs and rational use of antifungals in treating invasive aspergillosis: the role of the hospital pharmacist

Abstract: Invasive fungal infections will remain a frequent and important complication of modern medicine. Considering the clinical and financial outcome of invasive fungal infections, the role of the hospital pharmacist can be a paramount to the treatment.

Cited by 7 publications

References 22 publications

The mitochondrial protein Bak is pivotal for gliotoxin-induced apoptosis and a critical host factor of Aspergillus fumigatus virulence in mice

The mitochondrial protein Bak is pivotal for gliotoxin-induced apoptosis and a critical host factor of Aspergillus fumigatus virulence in mice

Posaconazole Enhances the Activity of Amphotericin B against Aspergillus Hyphae In Vitro

A multi‐centre comparison of nursing staff time required for the preparation and administration of liposomal amphotericin B and amphotericin B deoxycholate vs. voriconazole

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