John Perfect

..In this post hoc analysis of a large, open-label, multicenter study, we evaluated efficacy and safety of posaconazole, a new extended-spectrum triazole, as salvage therapy for IFIs in SOT recipients...

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..neoformans, the future of research in this area will require a certain critical mass of investigators to help share in the developmental costs which continue to occur...

..Despite widespread use of amphotericin B aerosols, there are still few studies on how to validate their effectiveness or optimize pharmacokinetics...

..Voriconazole is an effective and well-tolerated treatment for refractory or less-common invasive fungal infections...

..In an area with little guidance for therapy, the CLEAR data indicate that ABLC can be an effective broad-spectrum treatment choice for several invasive and refractory non-Aspergillus mould infections...

..This article collates and analyzes both new and old knowledge about the pathogen to help frame the meaning of human cryptococcosis as it starts to evolve in the new millennium...

..C. neoformans has now become a primary model to study molecular fungal pathogenesis with the goal of identifying drug targets or vaccine strategies...

..However, significant progress has been made, and with careful use of the clinical tools available it is possible to make a successful impact on infection outcomes...

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..Chronic necrotizing aspergillosis, aspergilloma, and allergic bronchopulmonary aspergillosis have variable management strategies and better short-term outcomes...

..However, if the diagnosis is made early, if clinicians adhere to the basic principles of these guidelines, and if the underlying disease is controlled, then cryptococcosis can be managed successfully in the vast majority of patients...

..If patients are intolerant of or refractory to conventional therapy, effective alternatives include a lipid formulation of amphotericin B or an echinocandin...

..Caspofungin is effective against both invasive aspergillosis and invasive candidiasis...

..neoformans with a potential for synergistic behavior with azoles...

..Caspofungin and voriconazole show good activity against most Candida species and may be good alternatives for patients with Candida glabrata and Candida krusei infections and for those with relapsing infections...

..The fluconazole-FK506 combination demonstrated the most obvious advantage over single-drug therapy by clearing conidia and protecting skin from damage at low drug concentrations...

..A mean serum creatinine level decrease of 0.02 mg/dL occurred. ABLC was an effective treatment for cryptococcal infection in immunocompromised patients...

..These studies in C. neoformans and previous studies in other pathogenic fungi support the view of the trehalose pathway as a selective fungicidal target for use in antifungal development...

..neoformans infection. Compounds that specifically target only ICL1 are unlikely to cripple C. neoformans growth in vivo...

..Additional research is needed to define the best therapeutic strategy for these patients during transplantation...

..To determine the true institutional cost of treating invasive fungal infections in light of recent advances in diagnostic techniques and antifungal therapies for both treatment and prophylaxis of these infections...

..neoformans...

..albicans mutants, against other Candida species, or when combined with different azoles. We propose that calcineurin is part of a membrane stress survival pathway that could be targeted for therapy...

..Additionally, the calcineurin pathway elements cnaA and crzA play a major role in proper chitin and glucan incorporation into the A. fumigatus cell wall...

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..In summary, these highly successful pharmaceutical agents may find an even broader clinical application in combating infectious diseases...

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..Despite the fatal outcome for our patient, we encourage other clinicians to try unique medical approaches for this historically life-threatening infection when adjunctive surgery is impossible...

..Our findings demonstrate the utility of even partial-genome microarrays for delineating regulatory cascades that contribute to microbial pathogenesis...

..In addition, the importance of CrzA to the production of disease is critical, and thus CrzA is an attractive fungus-specific antifungal target for the treatment of invasive aspergillosis...

..gattii in the invertebrate and mammalian hosts. These results highlight the central importance of this pathway in the virulence composites of both pathogenic cryptococcal species...

..Taken together, our data suggest a mechanistic role for A. fumigatus calcineurin signaling in the chitin biosynthetic response observed during paradoxical growth in the presence of high-dose caspofungin treatment...

..Our findings indicate that the genes required for C. neoformans survival in CSF ex vivo are necessary for survival and infection in this unique host environment...

..neoformans possesses a robust antioxidant system, composed of functionally overlapping and compensatory components that provide protection against endogenous and exogenous oxidative stresses...

..These studies reveal the first virulence difference between congenic a and alpha strains in the most common pathogenic variety and suggest an explanation for the prevalence of alpha strains in clinical isolates...

..Finally, we discuss the implications of newer antifungal agents and diagnostic adjuncts in the design of future clinical trials to evaluate prophylaxis and early prevention strategies...

..Recent advances in antifungal therapy and their direct application to specific diseases provide important new approaches to this complex and often seriously ill patient population...

..This has implications for the emergence of other microbial pathogens and inbreeding in host range expansion in the fungal and other kingdoms...

..Finally, therapeutic drug monitoring of select antifungals (notably posaconazole and voriconazole) may play an increasing role due to significant interpatient variability in serum concentrations after standard doses...

..Our studies highlight a role for sexual recombination in the evolution of a human fungal pathogen and provide a robust genetic platform to establish the molecular determinants of virulence...

..Crz1 is a proposed downstream target of calcineurin based on studies of Saccharomyces cerevisiae. However, the in vitro phenotypes of C. albicans crz1/crz1 and calcineurin mutants differ and Crz1 is not required for virulence...

..fumigatus and provides evidence that CbpA may serve as a feedback inhibitor in some aspects of calcineurin functions...

..In half the cases, there was a latent period of several months. These infections can be difficult to treat because C glabrata is often resistant to the antifungal agents commonly used to treat Candida albicans...

..These findings provide evidence that C. neoformans subverts host defense mechanisms involving surfactant, establishing a novel virulence paradigm that may be targeted for therapy...

..In this unselected review, caspofungin performed similarly as in clinical trials, and clinicians should consider caspofungin as first-line therapy for invasive candidiasis, particularly non-albicans species...

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..However, further evaluation of their performance for determining the MICs of azoles, particularly for C. glabrata, is warranted...

..Other echinocandin and triazole antifungals are under development in attempts to provide improved effective therapy for fungal pneumonia...

..Quantification of 1,3-beta-d-glucan revealed decreased amounts in the calcineurin A (DeltacnaA) mutant. Calcineurin can be an excellent adjunct therapeutic target in combination with other cell wall inhibitors against A. fumigatus...

..Further analysis of these genes and their peptide products may identify important roles for secondary metabolites produced by NRPS in Aspergillus physiology, ecology, and fungal pathogenicity...

..Our findings reveal that calcineurin appears to play a globally conserved role in the virulence of several pathogenic fungi and yet plays specialized roles in each and can be an excellent target for therapeutic intervention...

..This result suggests that gliotoxin is not required for virulence in an immunosuppressed host with an invasive pulmonary infection...

..We also review the treatments and outcomes of 28 reported cases of osteomyelitis or septic arthritis caused by Scedosporium species in immunocompetent patients...

..Omeprazole did not significantly affect the C(max), T(max) or AUC(0-8) of itraconazole or hydroxyitraconazole when administered as IOS...

..29; 95% CI, 0.15-0.56). Voriconazole is likely to be a better treatment choice for A. terreus infection than is a polyene...

..The administration of an optimal fungicidal therapy early in the course of the illness and control of the underlying disease are vital to prevent complications and mortality from these tenacious mycoses...

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..neoformans can compensate for the loss of the Cu,Zn SOD in vivo...

..However, more clinical data are needed to define its role as primary therapy for invasive aspergillosis, and its role in combination antifungal therapy...

..This review will focus primarily on recent liposomal amphotericin B experience and attempt to put its use into perspective considering other available antifungal agents...

..Our findings suggest a potential role for combination therapy with calcineurin pathway inhibitors and existing antifungal agents to augment activity against A. fumigatus...

..The optimal management of Candida infective endocarditis (IE) is unknown...

..In contrast, the inhalation of antifungal aerosols, such as amphotericin B, is rapidly becoming a viable prophylactic option...

..The patient may be best served by removal of the urinary catheter, if possible, rather than by instillation of bladder irrigation with amphotericin B...

..We evaluated 16 patients with Candida IE nested within a cohort of 2,022 patients with IE. Prosthetic valve IE was more common in patients with Candida (50% vs 17%); mortality was 37% for patients with Candida...

..Clinical antifungal drug resistance must be controlled by improving a series of antifungal therapeutic strategies...

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..Evidence-based studies using these new agents are accumulating, and they are assuming important roles in the pharmacotherapy of invasive fungal infections in seriously ill and complex patients...

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..albicans, azole resistance is associated with increased expression of CDR1...

..Current treatments provide limited benefit. Posaconazole is an extended-spectrum triazole with in vitro and in vivo activity against Aspergillus species...

..neoformans with environmental predators such as free-living nematodes and amoebae and suggest that C. elegans can be used as a simple model host in which C. neoformans pathogenesis can be readily studied...

..To describe the safety and efficacy of voriconazole in children treated within the compassionate release program...

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..Taken together, the results reveal specific metabolic adaptations of C. neoformans during pulmonary infection and indicate a role for ACS1 and SNF1 in virulence...

..These data suggest that cryptococcal PLB1 may act as a virulence factor by enhancing the ability to survive macrophage antifungal defenses, possibly by facilitating fungal eicosanoid production...

..This study identifies App1 as a novel regulator of virulence for C. neoformans, and it highlights that internalization of fungal cells by AMs increases the dissemination of C. neoformans when the host cellular response is impaired...

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..It is our hypothesis that beginning to understand the genetic regulation of C. neoformans during infection through this proposal will be a powerful tool to find targets to interrupt pathogenesis. ..

..This program emphasizes a focus on a single pathogen with a basic but broad-spectrum and highly interactive genomic approach to scientific investigations which can be extrapolated to other fungi. ..

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