Antifungal Activities of Posaconazole and Granulocyte-Macrophage Colony-Stimulating Factor Ex Vivo and in Mice with Disseminated Infection Due to
            <i>Scedosporium prolificans</i>

Simitsopoulou, Maria; Gil-Lamaignere, Cristina; Avramidis, Nicholaos; Maloukou, Avgi; Lekkas, S.; Havlova, E.; Kourounaki, L.; Loebenberg, David; Roilides, Emmanuel

doi:10.1128/aac.48.10.3801-3805.2004

Cited by 37 publications

(25 citation statements)

References 49 publications

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“…In most of the previous experimental studies with POS, this drug was administered once a day (6,9,20), but in human therapy this drug is administered twice a day to optimize its pharmacodynamics (10). In our model, the administration of POS twice a day proved to be more effective at prolonging survival and reducing the tissue burden than the once-a-day regimen and correlated with higher POS levels in serum.…”

Section: Discussionmentioning

confidence: 75%

Correlation of In Vitro Activity, Serum Levels, and In Vivo Efficacy of Posaconazole against Rhizopus microsporus in a Murine Disseminated Infection

Rodríguez

Pastor

Salas

et al. 2009

Antimicrob Agents Chemother

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A broth microdilution method was used to evaluate the in vitro activities of seven antifungal agents against 15 clinical strains of Rhizopus microsporus. Amphotericin B (AMB) and posaconazole (POS) were the most active drugs. In a model of disseminated R. microsporus infection in immunosuppressed mice, we studied the efficacy of POS administered once or twice daily against four of the strains previously tested in vitro and compared it with that of liposomal AMB (LAMB). LAMB was the most effective treatment for the two strains with intermediate susceptibility to POS. For the two POS-susceptible strains, LAMB and POS at 20 mg/kg of body weight twice a day orally showed similar efficacies. The in vivo efficacy of POS administered twice a day orally correlated with the in vitro susceptibility data and the serum drug concentrations.Zygomycosis is a frequently lethal invasive infection that occurs predominantly in immunocompromised patients (4), a population with a very poor prognosis and a high mortality rate (8). The clinical manifestations include rhino-orbito-cerebral, cutaneous, pulmonary, gastrointestinal, and disseminated infections (4). In a recent study in which a large number of clinical isolates of zygomycetes from different regions of the United States were molecularly identified, it was demonstrated that Rhizopus oryzae and Rhizopus microsporus were the most common species (3). Traditionally, amphotericin B (AMB) and, more recently, its lipid formulations are the front-line agents for the treatment of zygomycosis (4). Specifically, liposomal amphotericin B (LAMB) is less nephrotoxic than AMB and has better central nervous system penetration than AMB and the other lipid formulations (21). Posaconazole (POS) is a broad-spectrum triazole antifungal with a large volume of distribution into tissues (12). This drug has shown good in vitro activity against zygomycetes (1, 2) and has been used successfully as salvage therapy in some case reports and clinical trials of disseminated zygomycosis (8,22,23). However, its effectiveness remains controversial, since in experimental studies it has shown poor activity against R. oryzae, the main species causing zygomycosis (6, 9, 17). Several in vitro studies have shown that POS also exhibits significant activity against R. microsporus, another relevant clinical species (1, 2, 11), and a few clinical (14) and experimental (6) studies seem to demonstrate in vivo efficacy as well.In this study, after confirming the significant in vitro activity of POS and AMB, we evaluated the efficacy of POS against four strains of R. microsporus in a murine model of disseminated infection. Considering that antifungal susceptibility can differ substantially among different strains of a given species, which could explain the variable percentages of success demonstrated by POS and AMB in clinical trials (8,18, 23), we tested multiple strains exhibiting various in vitro responses to obtain more-robust results. MATERIALS AND METHODSThe in vitro antifungal susceptibilities of 15 clinical strains...

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Section: Discussionmentioning

confidence: 75%

Correlation of In Vitro Activity, Serum Levels, and In Vivo Efficacy of Posaconazole against Rhizopus microsporus in a Murine Disseminated Infection

Rodríguez

Pastor

Salas

et al. 2009

Antimicrob Agents Chemother

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“…However, when posaconazole and GM-CSF were administered to mice with invasive infection due to S. prolificans, they had selective beneficial effects on the burdens in certain organs but offered no additional benefit to survival (403).…”

Section: Immunotherapymentioning

confidence: 99%

Infections Caused byScedosporiumspp

et al. 2008

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SUMMARY Scedosporium spp. are increasingly recognized as causes of resistant life-threatening infections in immunocompromised patients. Scedosporium spp. also cause a wide spectrum of conditions, including mycetoma, saprobic involvement and colonization of the airways, sinopulmonary infections, extrapulmonary localized infections, and disseminated infections. Invasive scedosporium infections are also associated with central nervous infection following near-drowning accidents. The most common sites of infection are the lungs, sinuses, bones, joints, eyes, and brain. Scedosporium apiospermum and Scedosporium prolificans are the two principal medically important species of this genus. Pseudallescheria boydii, the teleomorph of S. apiospermum, is recognized by the presence of cleistothecia. Recent advances in molecular taxonomy have advanced the understanding of the genus Scedosporium and have demonstrated a wider range of species than heretofore recognized. Studies of the pathogenesis of and immune response to Scedosporium spp. underscore the importance of innate host defenses in protection against these organisms. Microbiological diagnosis of Scedosporium spp. currently depends upon culture and morphological characterization. Molecular tools for clinical microbiological detection of Scedosporium spp. are currently investigational. Infections caused by S. apiospermum and P. boydii in patients and animals may respond to antifungal triazoles. By comparison, infections caused by S. prolificans seldom respond to medical therapy alone. Surgery and reversal of immunosuppression may be the only effective therapeutic options for infections caused by S. prolificans.

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“…S. prolificans was studied in a murine model, and the combination of micafungin with either voriconazole or amphotericin B was associated with improved survival, though the triple combination of all three agents was not more effective (637). Posaconazole with granulocyte-macrophage colony-stimulating factor (GM-CSF) against S. prolificans did not improve survival in one study (698), though liposomal amphotericin B with G-CSF did improve survival in a murine model (560).…”

Section: Animal Models Of Infectionmentioning

confidence: 99%

Melanized Fungi in Human Disease

2010

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SUMMARY Melanized or dematiaceous fungi are associated with a wide variety of infectious syndromes. Many are soil organisms and are generally distributed worldwide, though certain species appear to have restricted geographic ranges. Though they are uncommon causes of disease, melanized fungi have been increasingly recognized as important pathogens, with most reports occurring in the past 20 years. The spectrum of diseases with which they are associated has also broadened and includes allergic disease, superficial and deep local infections, pneumonia, brain abscess, and disseminated infection. For some infections in immunocompetent individuals, such as allergic fungal sinusitis and brain abscess, they are among the most common etiologic fungi. Melanin is a likely virulence factor for these fungi. Diagnosis relies on careful microscopic and pathological examination, as well as clinical assessment of the patient, as these fungi are often considered contaminants. Therapy varies depending upon the clinical syndrome. Local infection may be cured with excision alone, while systemic disease is often refractory to therapy. Triazoles such as voriconazole, posaconazole, and itraconazole have the most consistent in vitro activity. Further studies are needed to better understand the pathogenesis and optimal treatment of these uncommon infections.

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Antifungal Activities of Posaconazole and Granulocyte-Macrophage Colony-Stimulating Factor Ex Vivo and in Mice with Disseminated Infection Due to Scedosporium prolificans

Abstract: Invasive infection due toWhile the combination of POS and GM-CSF showed enhanced activity ex vivo, it did not increase the activities of the two agents against this highly refractory filamentous fungus in mice.

Cited by 37 publications

References 49 publications

Correlation of In Vitro Activity, Serum Levels, and In Vivo Efficacy of Posaconazole against Rhizopus microsporus in a Murine Disseminated Infection

Correlation of In Vitro Activity, Serum Levels, and In Vivo Efficacy of Posaconazole against Rhizopus microsporus in a Murine Disseminated Infection

Infections Caused byScedosporiumspp

Melanized Fungi in Human Disease

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