Browsing by Author "Sobel, Jack D"

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    Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of america.
    (Clin Infect Dis, 2010-02-01) Perfect, John R; Dismukes, William E; Dromer, Francoise; Goldman, David L; Graybill, John R; Hamill, Richard J; Harrison, Thomas S; Larsen, Robert A; Lortholary, Olivier; Nguyen, Minh-Hong; Pappas, Peter G; Powderly, William G; Singh, Nina; Sobel, Jack D; Sorrell, Tania C
    Cryptococcosis is a global invasive mycosis associated with significant morbidity and mortality. These guidelines for its management have been built on the previous Infectious Diseases Society of America guidelines from 2000 and include new sections. There is a discussion of the management of cryptococcal meningoencephalitis in 3 risk groups: (1) human immunodeficiency virus (HIV)-infected individuals, (2) organ transplant recipients, and (3) non-HIV-infected and nontransplant hosts. There are specific recommendations for other unique risk populations, such as children, pregnant women, persons in resource-limited environments, and those with Cryptococcus gattii infection. Recommendations for management also include other sites of infection, including strategies for pulmonary cryptococcosis. Emphasis has been placed on potential complications in management of cryptococcal infection, including increased intracranial pressure, immune reconstitution inflammatory syndrome (IRIS), drug resistance, and cryptococcomas. Three key management principles have been articulated: (1) induction therapy for meningoencephalitis using fungicidal regimens, such as a polyene and flucytosine, followed by suppressive regimens using fluconazole; (2) importance of early recognition and treatment of increased intracranial pressure and/or IRIS; and (3) the use of lipid formulations of amphotericin B regimens in patients with renal impairment. Cryptococcosis remains a challenging management issue, with little new drug development or recent definitive studies. 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.
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    Prevalent mutator genotype identified in fungal pathogen Candida glabrata promotes multi-drug resistance.
    (Nature communications, 2016-03) Healey, Kelley R; Zhao, Yanan; Perez, Winder B; Lockhart, Shawn R; Sobel, Jack D; Farmakiotis, Dimitrios; Kontoyiannis, Dimitrios P; Sanglard, Dominique; Taj-Aldeen, Saad J; Alexander, Barbara D; Jimenez-Ortigosa, Cristina; Shor, Erika; Perlin, David S
    The fungal pathogen Candida glabrata has emerged as a major health threat since it readily acquires resistance to multiple drug classes, including triazoles and/or echinocandins. Thus far, cellular mechanisms promoting the emergence of resistance to multiple drug classes have not been described in this organism. Here we demonstrate that a mutator phenotype caused by a mismatch repair defect is prevalent in C. glabrata clinical isolates. Strains carrying alterations in mismatch repair gene MSH2 exhibit a higher propensity to breakthrough antifungal treatment in vitro and in mouse models of colonization, and are recovered at a high rate (55% of all C. glabrata recovered) from patients. This genetic mechanism promotes the acquisition of resistance to multiple antifungals, at least partially explaining the elevated rates of triazole and multi-drug resistance associated with C. glabrata. We anticipate that identifying MSH2 defects in infecting strains may influence the management of patients on antifungal drug therapy.