Caspofungin Inhibits
            <i>Rhizopus oryzae</i>
            1,3-β-
            <scp>d</scp>
            -Glucan Synthase, Lowers Burden in Brain Measured by Quantitative PCR, and Improves Survival at a Low but Not a High Dose during Murine Disseminated Zygomycosis

Ibrahim, Ashraf S.; Bowman, Joel; Avanessian, Valentina; Brown, K; Spellberg, Brad; Edwards, John E.; Douglas, Cameron M.

doi:10.1128/aac.49.2.721-727.2005

Cited by 192 publications

(168 citation statements)

References 37 publications

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“…However, the protective benefit of POS against R. oryzae was inoculum dependent. These results are similar to those recently found by Ibrahim et al (5). Those investigators found that caspofungin improved the survival of mice with diabetic ketoacidosis infected with a small inoculum but not with a large inoculum of R. oryzae.…”

Section: Discussionsupporting

confidence: 82%

Posaconazole Prophylaxis in Experimental Systemic Zygomycosis

Barchiesi¹,

Spreghini²,

Santinelli³

et al. 2007

Antimicrob Agents Chemother

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Three isolates of zygomycetes belonging to two different genera (Rhizopus oryzae and Absidia corymbifera) were used to produce a systemic infection in neutropenic mice. On days ؊2 and ؊1 and at 2 h prior to infection, the mice received either posaconazole (POS) at doses ranging from 20 to 80 mg/kg of body weight/day or amphotericin B (AMB) at 1 mg/kg/day. Antifungal drug efficacy was assessed by determination of the prolongation of survival, determination of the percentage of infected organs (brain, lung, spleen, and kidney), and histological examination for the number of infection foci and their sizes in brain and kidney tissues. AMB significantly prolonged the survival of mice infected with all isolates. POS significantly prolonged the survival of mice infected with zygomycetes. Cultured organs from mice infected with R. oryzae were all positive, while treated mice challenged with A. corymbifera generally showed lower percentages of infected organs compared with the percentages for the controls. Zygomycete isolates established an active infection (the presence of hyphae) in the brains and the kidneys of all controls. In mice challenged with R. oryzae, both antifungal drugs were effective at reducing the number and the size of infection foci in the kidneys. Only AMB reduced the numbers, but not the sizes, of infection foci in the brain. Finally, both drugs significantly reduced the numbers and the sizes of infection foci in both tissues of mice infected with A. corymbifera. Our data suggest that prophylaxis with POS has some potential to prevent zygomycosis. Zygomycosis is a rare but highly aggressive filamentous fungal infection (4). The clinical manifestations of zygomycosis include primary rhinocerebral, pulmonary, gastrointestinal, cutaneous or subcutaneous, and allergic disease and disseminated disease (4, 6, 7, 13). The zygomycetes most commonly identified as etiologic agents of human diseases are Rhizopus species, Rhizomucor species, Mucor species, and Absidia species (13). The invasive forms of zygomycosis cause angioinvasion, followed by progressive, necrotic, and generally fatal infections in immunocompromised hosts, such as diabetic patients with ketoacidosis, neutropenic patients, patients taking corticosteroids, and subjects with burns or iron overload (4,6,7,12,13). The standard therapy for these life-threatening infections consists of removal of the predisposing factors, widespread surgical debridement, and high doses of intravenous amphotericin B (AMB) (13). Nevertheless, even with aggressive therapy, the rate of mortality is often above 50% (4, 6). It is clear that new strategies for the treatment of zygomycosis are urgently needed.Posaconazole (POS) is a new broad-spectrum triazole with activity against many filamentous fungal pathogens, including zygomycetes (3,8,11,13,14). Experimental infection models and clinical data showed that POS might be useful for the treatment of zygomycosis (3,11,14). No data on the effects of POS prophylaxis against these infections are available. Therefore, in th...

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Section: Discussionsupporting

confidence: 82%

Posaconazole Prophylaxis in Experimental Systemic Zygomycosis

Barchiesi¹,

Spreghini²,

Santinelli³

et al. 2007

Antimicrob Agents Chemother

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“…20,88,89 However, Rhizopus oryzae expresses the target enzyme of echinocandins, 1,3-D-glucan synthase, and caspofungin has shown some efficacy in an animal model of infection but with an unexplained inverse-dose response relationship: low doses were more effective in reducing mortality than high doses. 90 This inverse dose-response relationship may be similar to the paradoxical effect previously described with caspofungin against Candida albicans. 91 No clinical data are available with echinocandin monotherapy in mucormycosis and occurrence of mucormycosis has been documented in HM currently receiving or recently exposed to caspofungin.…”

Section: Echinocandinssupporting

confidence: 59%

Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3)

et al. 2012

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“…The primary efficacy endpoint was time to moribundity. In some experiments, as a secondary endpoint, fungal burden in the lungs and brains (primary and secondary target organs) was determined 48 hours after infection by quantitative PCR assay, as we previously described (58). Values were expressed as log10 spore equivalent/g tissue.…”

Section: Interaction Of Fungi With Endothelial or Cho Cellsmentioning

confidence: 99%

CotH3 mediates fungal invasion of host cells during mucormycosis

Gebremariam¹,

Liu²,

Luo³

et al. 2013

J. Clin. Invest.

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199

294

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Angioinvasion is a hallmark of mucormycosis. Previously, we identified endothelial cell glucose-regulated protein 78 (GRP78) as a receptor for Mucorales that mediates host cell invasion. Here we determined that spore coat protein homologs (CotH) of Mucorales act as fungal ligands for GRP78. CotH proteins were widely present in Mucorales and absent from noninvasive pathogens. Heterologous expression of CotH3 and CotH2 in Saccharomyces cerevisiae conferred the ability to invade host cells via binding to GRP78. Homology modeling and computational docking studies indicated structurally compatible interactions between GRP78 and both CotH3 and CotH2. A mutant of Rhizopus oryzae, the most common cause of mucormycosis, with reduced CotH expression was impaired for invading and damaging endothelial cells and CHO cells overexpressing GRP78. This strain also exhibited reduced virulence in a diabetic ketoacidotic (DKA) mouse model of mucormycosis. Treatment with anti-CotH Abs abolished the ability of R. oryzae to invade host cells and protected DKA mice from mucormycosis. The presence of CotH in Mucorales explained the specific susceptibility of DKA patients, who have increased GRP78 levels, to mucormycosis. Together, these data indicate that CotH3 and CotH2 function as invasins that interact with host cell GRP78 to mediate pathogenic host-cell interactions and identify CotH as a promising therapeutic target for mucormycosis.

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Caspofungin Inhibits Rhizopus oryzae 1,3-β- d -Glucan Synthase, Lowers Burden in Brain Measured by Quantitative PCR, and Improves Survival at a Low but Not a High Dose during Murine Disseminated Zygomycosis

Cited by 192 publications

References 37 publications

Posaconazole Prophylaxis in Experimental Systemic Zygomycosis

Posaconazole Prophylaxis in Experimental Systemic Zygomycosis

Diagnosis and treatment of mucormycosis in patients with hematological malignancies: guidelines from the 3rd European Conference on Infections in Leukemia (ECIL 3)

CotH3 mediates fungal invasion of host cells during mucormycosis

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