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Browsing by Subject "Fluconazole"
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Item Fluconazole impacts the extracellular matrix of fluconazole-susceptible and -resistant Candida albicans and Candida glabrata biofilms(Taylor & Francis Open, 2018-06-04) Panariello, Beatriz Helena Dias; Klein, Marlise I.; Mima, Ewerton Garcia De Oliveira; Pavarina, Ana Cláudia; Cariology, Operative Dentistry and Dental Public Health, School of DentistryBackground: Fluconazole (FLZ) is a drug commonly used for the treatment of Candida infections. However, β-glucans in the extracellular matrices (ECMs) hinder FLZ penetration into Candida biofilms, while extracellular DNA (eDNA) contributes to the biofilm architecture and resistance. Methods: This study characterized biofilms of FLZ-sensitive (S) and -resistant (R) Candida albicans and Candida glabrata in the presence or absence of FLZ focusing on the ECM traits. Biofilms of C. albicans American Type Culture Collection (ATCC) 90028 (CaS), C. albicans ATCC 96901 (CaR), C. glabrata ATCC 2001 (CgS), and C. glabrata ATCC 200918 (CgR) were grown in RPMI medium with or without FLZ at 5× the minimum inhibitory concentration (37°C/48 h). Biofilms were assessed by colony-forming unit (CFU)/mL, biomass, and ECM components (alkali-soluble polysaccharides [ASP], water-soluble polysaccharides [WSP], eDNA, and proteins). Scanning electron microscopy (SEM) was also performed. Data were analyzed by parametric and nonparametric tests (α = 0.05). Results: In biofilms, FLZ reduced the CFU/mL of all strains (p < 0.001), except for CaS (p = 0.937). However, the ASP quantity in CaS was significantly reduced by FLZ (p = 0.034), while the drug had no effect on the ASP levels in other strains (p > 0.05). Total biomasses and WSP were significantly reduced by FLZ in the ECM of all yeasts (p < 0.001), but levels of eDNA and proteins were unaffected (p > 0.05). FLZ affected the cell morphology and biofilm structure by hindering hyphae formation in CaS and CaR biofilms, by decreasing the number of cells in CgS and CgR biofilms, and by yielding sparsely spaced cell agglomerates on the substrate. Conclusion: FLZ impacts biofilms of C. albicans and C. glabrata as evident by reduced biomass. This reduced biomass coincided with lowered cell numbers and quantity of WSPs. Hyphal production by C. albicans was also reduced.Item Physiologically-Based Pharmacokinetic Modeling Characterizes the CYP3A-Mediated Drug-Drug Interaction Between Fluconazole and Sildenafil in Infants(Wiley, 2021) Salerno, Sara N.; Edginton, Andrea; Gerhart, Jacqueline G.; Laughon, Matthew M.; Ambalavanan, Namasivayam; Sokol, Gregory M.; Hornik, Chi D.; Stewart, Dan; Mills, Mary; Martz, Karen; Gonzalez, Daniel; Pediatrics, School of MedicinePhysiologically-based pharmacokinetic (PBPK) modeling can potentially predict pediatric drug-drug interactions (DDIs) when clinical DDI data are limited. In infants for whom treatment of pulmonary hypertension and prevention or treatment of invasive candidiasis are indicated, sildenafil with fluconazole may be given concurrently. To account for developmental changes in cytochrome P450 (CYP) 3A, we determined and incorporated fluconazole inhibition constants (KI ) for CYP3A4, CYP3A5, and CYP3A7 into a PBPK model developed for sildenafil and its active metabolite, N-desmethylsildenafil. Pharmacokinetic (PK) data in preterm infants receiving sildenafil with and without fluconazole were used for model development and evaluation. The simulated PK parameters were comparable to observed values. Following fluconazole co-administration, differences in the fold change for simulated steady-state area under the plasma concentration vs. time curve from 0 to 24 hours (AUCss,0-24 ) were observed between virtual adults and infants (2.11-fold vs. 2.82-fold change). When given in combination with treatment doses of fluconazole (12 mg/kg i.v. daily), reducing the sildenafil dose by ~ 60% resulted in a geometric mean ratio of 1.01 for simulated AUCss,0-24 relative to virtual infants receiving sildenafil alone. This study highlights the feasibility of PBPK modeling to predict DDIs in infants and the need to include CYP3A7 parameters.Item RAPD-PCR DNA fingerprinting on sequential isolates of Histoplasma capsulatum from AIDS patients failing fluconazole therapy(1998) Connolly, Patricia Anne