Characterization and regulation of the trehalose synthesis pathway and its importance in the pathogenicity of Cryptococcus neoformans.

The disaccharide trehalose has been found to play diverse roles, from energy source to stress protectant, and this sugar is found in organisms as diverse as bacteria, fungi, plants, and invertebrates but not in mammals. Recent studies in the pathobiology of Cryptococcus neoformans identified the presence of a functioning trehalose pathway during infection and suggested its importance for C. neoformans survival in the host.

Candida glabrata fungemia in transplant patients receiving voriconazole after fluconazole.

The clinical impact of voriconazole resistance in Candida glabrata is not well described. Five hematopoietic stem cell transplant recipients that developed breakthrough Candida glabrata bloodstream infections while receiving voriconazole are described and the clinical management and susceptibility profiles of their isolates are reported. All patients were markedly immunosuppressed, and in all cases, voriconazole use was preceded by prolonged fluconazole exposure (median 60 days); median voriconazole exposure prior to candidemia was 48 days.

In vitro interactions between antifungals and immunosuppressants against Aspergillus fumigatus isolates from transplant and nontransplant patients.

We performed in vitro antifungal checkerboard testing on 12 Aspergillus fumigatus clinical isolates (6 transplant recipients and 6 nontransplant patients) with three antifungal agents (amphotericin B, voriconazole, and caspofungin) and three immunosuppressants (FK506, cyclosporine, and rapamycin). We were not able to detect a difference in calcineurin inhibitor antifungal activity against isolates from transplant recipients and nontransplant patients.

Value of an inhalational model of invasive aspergillosis.

Animal models of invasive aspergillosis have been used for virulence studies and antifungal efficacy evaluations but results have been inconsistent. In an attempt to reproduce human infection, many Aspergillus animal models have utilized a 'pulmonary route' for delivery of conidia, largely through intranasal instillation. However, several radiolabeled particle studies have shown that aerosol delivery is preferable to intranasal instillation to create a more homogenous delivery to the lungs.

NADH cytochrome b5 reductase and cytochrome b5 catalyze the microsomal reduction of xenobiotic hydroxylamines and amidoximes in humans.

Hydroxylamine metabolites, implicated in dose-dependent and idiosyncratic toxicity from arylamine drugs, and amidoximes, used as pro-drugs, are metabolized by an as yet incompletely characterized NADH-dependent microsomal reductase system. We hypothesized that NADH cytochrome b5 reductase and cytochrome b5 were responsible for this enzymatic activity in humans. Purified human soluble NADH cytochrome b5 reductase and cytochrome b5, expressed in Escherichia coli, efficiently catalyzed the reduction of sulfamethoxazole hydroxylamine, dapsone hydroxylamine, and benzamidoxime, with apparent Km values similar to those found in human liver microsomes and specific activities (Vmax) 74 to 235 times higher than in microsomes.

Thiopurine methyltransferase activity in red blood cells of dogs.

Thiopurine methyltransferase (TPMT) is an important enzyme in the metabolism of thiopurine medications such as azathioprine. In humans, activity varies widely among individuals, primarily because of genetic polymorphisms. Low TPMT activity increases the risk of myelosuppression from azathioprine and 6-mercaptopurine, whereas high TPMT activity is associated with poor drug efficacy.

Risk of fungemia due to Rhodotorula and antifungal susceptibility testing of Rhodotorula isolates.

Rhodotorula infections occur among patients with immunosuppression and/or central venous catheters. Using standardized methods (NCCLS M27-A), we determined the antifungal susceptibilities of 10 Rhodotorula bloodstream infection isolates. Patient information was collected for clinical correlation.

Scedosporium prolificans osteomyelitis in an immunocompetent child treated with voriconazole and caspofungin, as well as locally applied polyhexamethylene biguanide.

Scedosporium species are increasingly isolated from immunocompromised and immunocompetent patients. Unfortunately, Scedosporium infections are generally resistant to amphotericin B, and Scedosporium prolificans strains are particularly resistant to the antifungal agents now in use. We report here on an immunocompetent child with S.

Inhibition by atovaquone of CYP2C9-mediated sulphamethoxazole hydroxylamine formation.

Objective: To determine whether the antiprotozoal drug atovaquone inhibits the cytochrome P(450) (CYP)2C9-mediated metabolism of sulphamethoxazole (SMX) to its potentially harmful hydroxylamine metabolite (SMX-HA) in vitro.

Methods: Generation of SMX-HA from SMX was measured directly using high-performance liquid chromatography in human liver microsomes or expressed CYP2C9*1, with or without preincubation with reduced nicotinamide adenine dinucleotide phosphate, and the inhibition constant (K(i)) for atovaquone was determined. To determine the effect of protein binding in vitro, in some experiments, atovaquone was pre-incubated with serum proteins, followed by filtration.