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Peripheral blood eosinophilia as a clue to the diagnosis of an occult Coccidioides infection.
Simons CM, Stratton CW, Kim AS
(2011) Hum Pathol 42: 449-53
MeSH Terms: Aged, Antifungal Agents, Antigens, Fungal, Coccidioides, Coccidioidomycosis, DNA, Fungal, Eosinophilia, Fluconazole, Humans, Lung Diseases, Fungal, Male, Radiography, Thoracic, Treatment Outcome
Show Abstract · Added May 28, 2014
A marked peripheral blood eosinophilia is an uncommon finding in a complete blood count (CBC). According to Wardlaw and Kay (Eosinophils and Their Disorders. In: Beutler E, Lichtman MA, Coller BS, Kipps TJ, Seligsohn U, editors. Williams Hematology. 6(th) ed. New York: McGraw-Hill, 2001. p. 790-93), the most common causes are infection by helminthic parasites, atopic disease, and, less commonly, primary hypereosinophilic syndromes. Therefore, when eosinophilia is seen in a CBC, it can provide an important clue to the correct diagnosis. We present a case of a patient with a finding of pulmonary nodules in the setting of cancer and a CBC finding of profound peripheral blood eosinophilia. As a result of the high level of clinical suspicion for Coccidioides infection due in part to the eosinophilia, adequate steps were taken in the clinical laboratory not only to correctly diagnosis the patient, but also to protect the laboratory staff from work-related exposure to this easily aerosolizable infectious agent.
Copyright © 2011 Elsevier Inc. All rights reserved.
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13 MeSH Terms
Fluconazole prophylaxis for prevention of invasive fungal infections in targeted highest risk preterm infants limits drug exposure.
Weitkamp JH, Ozdas A, LaFleur B, Potts AL
(2008) J Perinatol 28: 405-11
MeSH Terms: Antifungal Agents, Fluconazole, Humans, Infant, Newborn, Infant, Premature, Infant, Premature, Diseases, Infant, Very Low Birth Weight, Medical Order Entry Systems, Retrospective Studies, Risk Factors
Show Abstract · Added February 27, 2014
OBJECTIVE - Previous reports suggest a benefit of fluconazole prophylaxis in extremely low birth weight (ELBW) infants <1000 g. Our aim was to evaluate if limiting fluconazole prophylaxis to targeted highest risk infants effectively prevents invasive fungal infections, has no undesired side effects and limits unnecessary drug exposure.
STUDY DESIGN - This nonrandomized retrospective pre-post intervention study compared two groups of infants: (1) Infants <26 weeks gestation and/or <750 g birth weight, requiring central vascular access and admitted to the Monroe Carell Jr Children's Hospital at Vanderbilt neonatal intensive care unit (NICU) prior to 5 days of age, who received fluconazole prophylaxis and (2) a matched control group from the year prior to prophylaxis. This target population was selected for fluconazole prophylaxis based on prior infection control data from our institution and a number needed to treat of <15 to prevent one episode of fungemia. Following implementation and integration through the institution's computerized physician order entry (CPOE) system, provider adherence to the protocol was assessed during the prophylaxis period.
RESULT - A total of 86 patients were included in the study, 44 in the no-prophylaxis group and 42 in the prophylaxis group. In the targeted prophylaxis group, no invasive fungal infections were observed as compared to nine infants with invasive infections in the no-prophylaxis group (P=0.004). No significant adverse effects were recorded. Targeting the highest risk infants reduced the number of infants <1000 g requiring prophylaxis from 80 to 42 (48% reduction) with no preventable infection missed. Provider compliance was 91% following implementation of this protocol through the CPOE system using a standardized order set.
CONCLUSION - Targeting the highest risk infants for fluconazole prophylaxis through CPOE can effectively prevent invasive fungal infections and limit drug exposure with no unwanted side effects.
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10 MeSH Terms
Fluconazole binding and sterol demethylation in three CYP51 isoforms indicate differences in active site topology.
Bellamine A, Lepesheva GI, Waterman MR
(2004) J Lipid Res 45: 2000-7
MeSH Terms: Amino Acid Sequence, Antifungal Agents, Binding Sites, Catalytic Domain, Cytochrome P-450 Enzyme System, DNA Primers, Fluconazole, Fungal Proteins, Humans, Inhibitory Concentration 50, Models, Chemical, Models, Molecular, Molecular Sequence Data, Mutagenesis, Site-Directed, Mutation, Mycobacterium tuberculosis, Oxidoreductases, Protein Binding, Protein Conformation, Protein Isoforms, Sequence Homology, Amino Acid, Species Specificity, Spectrophotometry, Sterol 14-Demethylase, Sterols, Time Factors
Show Abstract · Added February 12, 2015
14alpha-Demethylase (CYP51) is a key enzyme in all sterol biosynthetic pathways (animals, fungi, plants, protists, and some bacteria), catalyzing the removal of the C-14 methyl group following cyclization of squalene. Based on mutations found in CYP51 genes from Candida albicans azole-resistant isolates obtained after fluconazole treatment of fungal infections, and using site-directed mutagenesis, we have found that fluconazole binding and substrate metabolism vary among three different CYP51 isoforms: human, fungal, and mycobacterial. In C. albicans, the Y132H mutant from isolates shows no effect on fluconazole binding, whereas the F145L mutant results in a 5-fold increase in its IC(50) for fluconazole, suggesting that F145 (conserved only in fungal 14alpha-demethylases) interacts with this azole. In C. albicans, F145L accounts, in part, for the difference in fluconazole sensitivity reported between mammals and fungi, providing a basis for treatment of fungal infections. The C. albicans Y132H and human Y145H CYP51 mutants show essentially no effect on substrate metabolism, but the Mycobacterium tuberculosis F89H CYP51 mutant loses both its substrate binding and metabolism. Because these three residues align in the three isoforms, the results indicate that their active sites contain important structural differences, and further emphasize that fluconazole and substrate binding are uncoupled properties.
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26 MeSH Terms
Cryptococcosis in human immunodeficiency virus-negative patients in the era of effective azole therapy.
Pappas PG, Perfect JR, Cloud GA, Larsen RA, Pankey GA, Lancaster DJ, Henderson H, Kauffman CA, Haas DW, Saccente M, Hamill RJ, Holloway MS, Warren RM, Dismukes WE
(2001) Clin Infect Dis 33: 690-9
MeSH Terms: Adolescent, Adult, Aged, Aged, 80 and over, Antifungal Agents, Azoles, Child, Child, Preschool, Cryptococcosis, Cryptococcus neoformans, Female, Fluconazole, HIV Seronegativity, Humans, Infant, Male, Middle Aged, Multivariate Analysis, Predictive Value of Tests, Prognosis, Risk Factors, Treatment Outcome, United States
Show Abstract · Added March 13, 2015
We conducted a case study of human immunodeficiency virus (HIV)-negative patients with cryptococcosis at 15 United States medical centers from 1990 through 1996 to understand the demographics, therapeutic approach, and factors associated with poor prognosis in this population. Of 306 patients with cryptococcosis, there were 109 with pulmonary involvement, 157 with central nervous system (CNS) involvement, and 40 with involvement at other sites. Seventy-nine percent had a significant underlying condition. Patients with pulmonary disease were usually treated initially with fluconazole (63%); patients with CNS disease generally received amphotericin B (92%). Fluconazole was administered to approximately two-thirds of patients with CNS disease for consolidation therapy. Therapy was successful for 74% of patients. Significant predictors of mortality in multivariate analysis included age > or =60 years, hematologic malignancy, and organ failure. Overall mortality was 30%, and mortality attributable to cryptococcosis was 12%. Cryptococcosis continues to be an important infection in HIV-negative patients and is associated with substantial overall and cause-specific mortality.
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23 MeSH Terms
Crystal structure of cytochrome P450 14alpha -sterol demethylase (CYP51) from Mycobacterium tuberculosis in complex with azole inhibitors.
Podust LM, Poulos TL, Waterman MR
(2001) Proc Natl Acad Sci U S A 98: 3068-73
MeSH Terms: Amino Acid Sequence, Antifungal Agents, Candida albicans, Crystallography, X-Ray, Cytochrome P-450 Enzyme Inhibitors, Cytochrome P-450 Enzyme System, Drug Resistance, Microbial, Enzyme Inhibitors, Fluconazole, Imidazoles, Molecular Sequence Data, Mycobacterium tuberculosis, Oxidoreductases, Peptide Mapping, Protein Structure, Tertiary, Sterol 14-Demethylase, Substrate Specificity
Show Abstract · Added February 12, 2015
Cytochrome P450 14alpha-sterol demethylases (CYP51) are essential enzymes in sterol biosynthesis in eukaryotes. CYP51 removes the 14alpha-methyl group from sterol precursors such as lanosterol, obtusifoliol, dihydrolanosterol, and 24(28)-methylene-24,25-dihydrolanosterol. Inhibitors of CYP51 include triazole antifungal agents fluconazole and itraconazole, drugs used in treatment of topical and systemic mycoses. The 2.1- and 2.2-A crystal structures reported here for 4-phenylimidazole- and fluconazole-bound CYP51 from Mycobacterium tuberculosis (MTCYP51) are the first structures of an authentic P450 drug target. MTCYP51 exhibits the P450 fold with the exception of two striking differences-a bent I helix and an open conformation of BC loop-that define an active site-access channel running along the heme plane perpendicular to the direction observed for the substrate entry in P450BM3. Although a channel analogous to that in P450BM3 is evident also in MTCYP51, it is not open at the surface. The presence of two different channels, with one being open to the surface, suggests the possibility of conformationally regulated substrate-in/product-out openings in CYP51. Mapping mutations identified in Candida albicans azole-resistant isolates indicates that azole resistance in fungi develops in protein regions involved in orchestrating passage of CYP51 through different conformational stages along the catalytic cycle rather than in residues directly contacting fluconazole. These new structures provide a basis for rational design of new, more efficacious antifungal agents as well as insight into the molecular mechanism of P450 catalysis.
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17 MeSH Terms