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    ABSTRACT: IntroductionIntravenous (IV) voriconazole is not recommended in patients with creatinine clearance <50 ml/min to avoid potentially toxic accumulation of sulfobutylether-ß-cyclodextrin (SBECD). The purpose of this study was to evaluate the pharmacokinetics of SBECD, voriconazole, and voriconazole N-oxide in critically ill patients undergoing continuous renal replacement therapy (CRRT) and to determine if CRRT removes SBECD sufficiently to allow for the use of IV voriconazole without significant risk of SBECD accumulation.Methods This prospective, open-label pharmacokinetic study enrolled patients >18 years old receiving IV voriconazole for a known or suspected invasive fungal infection while undergoing CRRT. Serial blood and effluent samples were collected on days 1, 3, 5, 7, and every 3 to 5 days thereafter. SBECD, voriconazole, and voriconazole N-oxide plasma and effluent concentrations were measured by liquid chromatography-tandem mass spectrometry. Pharmacokinetic, pharmacodynamic, and pharmacogenetic analyses were conducted.ResultsTen patients (mean¿±¿standard deviation (SD)) 53¿±¿11 years old, 50% male, 81¿±¿14 kg, with Acute Physiologic and Chronic Health Evaluation II (APACHE II) scores of 31.5¿±¿3.8 were evaluated. All patients underwent continuous veno-venous hemofiltration (CVVH) with a median predilution replacement fluid rate of 36 (interquartile range (IQR) 32 to 37) ml/kg/hr and total ultrafiltration rate of 38 (IQR 34 to 39) ml/kg/hr. Mean¿±¿SD voriconazole and SBECD dosages administered were 8.1¿±¿2.1 mg/kg/day and 129¿±¿33 mg/kg/day, respectively. Voriconazole plasma trough concentrations were >1 mg/L in all patients with CVVH accounting for only 15% of the total body clearance. CVVH accounted for 86% of the total body clearance of SBECD with the majority of the dose being recovered in the effluent. Minimal increases in dose normalized SBECD area under the concentration-time curve from 0 to 12 hours (AUC0¿12) (4484¿±¿4368 to 4553¿±¿2880 mg*hr/L; P¿=¿0.97) were observed after study day 1.ConclusionsCVVH effectively removed SBECD at a rate similar to the ultrafiltration rate. Voriconazole clearance by CVVH was not clinically significant. Standard dosages of IV voriconazole can be utilized in patients undergoing CVVH without significant risk of SBECD accumulation.Trial registrationClinicalTrials.gov NCT01101386. Registered April 6 2010.
    Critical care (London, England) 02/2015; 19(1):32. DOI:10.1186/s13054-015-0753-8 · 5.04 Impact Factor
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    ABSTRACT: The clinical feature of invasive pulmonary aspergillosis (IPA) in immunocompromised patients is well studied in the past decades. While the manifestations of IPA in immunocompetent patients remain unclear. The purpose of this study was to determine the clinical and radiological manifestations of invasive pulmonary aspergillosis (IPA) in patients without immunosuppression, as well as the reasons for the misdiagnosis of IPA. We retrieved and retrospectively reviewed the records of 102 patients from whom surgical lung specimens of chronic inflammatory granulomas were harvested. 26 patients were eventually diagnosed with pulmonary aspergillosis on Grocott methenamine silver staining. We investigated these patients in detail. We found that the rate of misdiagnosis before the lung surgery was as high as 73%. The most common symptom was hemoptysis, and the main feature in radiology was nodule or mass lesion. Air crescent sign or Halo sign were not common in our study. The atypical radiological manifestations and non-specific clinical findings make the diagnosis of IPA difficult and lead to a high misdiagnosis rate.
    International Journal of Clinical and Experimental Medicine 01/2014; 7(12):5075-82. · 1.42 Impact Factor
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    ABSTRACT: Fungal infections remain a threat due to the lack of broad-spectrum fungal vaccines and protective antigens. Recent studies showed that attenuated Blastomyces dermatitidis confers protection via T cell recognition of an unknown but conserved antigen. Using transgenic CD4+ T cells recognizing this antigen, we identify an amino acid determinant within the chaperone calnexin that is conserved across diverse fungal ascomycetes. Calnexin, typically an ER protein, also localizes to the surface of yeast, hyphae, and spores. T cell epitope mapping unveiled a 13-residue sequence conserved across Ascomycota. Infection with divergent ascomycetes, including dimorphic fungi, opportunistic molds, and the agent causing white nose syndrome in bats, induces expansion of calnexin-specific CD4+ T cells. Vaccine delivery of calnexin in glucan particles induces fungal antigen-specific CD4+ T cell expansion and resistance to lethal challenge with multiple fungal pathogens. Thus, the immunogenicity and conservation of calnexin make this fungal protein a promising vaccine target.
    Cell Host & Microbe 03/2015; · 12.19 Impact Factor

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