A5036942082- Antibiotic Resistance in Bacteria
- Antibiotics Pharmacokinetics and Efficacy
- Pneumonia and Respiratory Infections
- Vibrio bacteria research studies
- Bacterial biofilms and quorum sensing
- Malaria Research and Control
- Cancer therapeutics and mechanisms
- Pharmaceutical and Antibiotic Environmental Impacts
- Phenothiazines and Benzothiazines Synthesis and Activities
- Asthma and respiratory diseases
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Monoclonal and Polyclonal Antibodies Research
- Central Venous Catheters and Hemodialysis
- Pancreatic and Hepatic Oncology Research
- Diabetes Treatment and Management
- Allergic Rhinitis and Sensitization
- Helicobacter pylori-related gastroenterology studies
- Bacterial Genetics and Biotechnology
- Galectins and Cancer Biology
- Pharmacogenetics and Drug Metabolism
- T-cell and B-cell Immunology
- Pancreatic function and diabetes
- Antimicrobial Resistance in Staphylococcus
- Radiopharmaceutical Chemistry and Applications
- Adolescent and Pediatric Healthcare
Exelixis (United States)
2021-2023
AstraZeneca (United States)
2020-2022
University at Buffalo, State University of New York
2008-2017
Center for Excellence in Education
2017
Colistin is increasingly being utilized against Gram-negative pathogens, including Pseudomonas aeruginosa, resistant to all other antibiotics. Since limited data exist regarding killing by colistin at different initial inocula (CFUo), we evaluated of aeruginosa several CFUo and developed a mechanism-based mathematical model accommodating range CFUo. In vitro time-kill experiments were performed using >or=8 concentrations up 64 x the MIC P. PAO1 two clinical isolates 10(6), 10(8), 10(9)...
Bacterial resistance is among the most serious threats to human health globally, and many bacterial isolates have emerged that are resistant all antibiotics in monotherapy. Aminoglycosides often used combination therapies against severe infections by multidrug-resistant bacteria. However, models quantifying different antibacterial effects of aminoglycosides lacking. While mode aminoglycoside action on protein synthesis has been studied, their disruptive outer membrane Gram-negative bacteria...
ABSTRACT Evidence is mounting in support of the inoculum effect (i.e., slow killing at large initial inocula [CFUo]) for numerous antimicrobials against a variety pathogens. Our objectives were to (i) determine impact CFUo Pseudomonas aeruginosa on ceftazidime activity and (ii) develop validate pharmacokinetic/pharmacodynamic (PKPD) mathematical model accommodating range CFUo. Time-kill experiments using seven concentrations up 128 mg/liter (MIC, 2 mg/liter) performed duplicate P. PAO1 five...
ABSTRACT Quantitative modeling of combination therapy can describe the effects each antibiotic against multiple bacterial populations. Our aim was to develop an efficient experimental and strategy that evaluates different synergy mechanisms using a rapidly killing peptide (nisin) combined with amikacin or linezolid as probe drugs. Serial viable counts over 48 h were obtained in time-kill experiments all three antibiotics monotherapy methicillin-resistant Staphylococcus aureus USA300 strain...
Abstract Objectives Colistin is an ‘old’ drug, which being increasingly utilized due to limited therapeutic options. However, resistance emergence during monotherapy concerning. Here, our objective was optimize colistin combinations against Pseudomonas aeruginosa by profiling the time course of synergistic killing and prevention resistance. Methods Hollow-fibre infection models over 10 days simulated clinically relevant dosage regimens doripenem two heteroresistant P. strains (MIC 1 mg/L)...
Polymyxin B is being increasingly utilized as a last resort against resistant Gram-negative bacteria. We examined the pharmacodynamics of novel dosing strategies for polymyxin combinations to maximize efficacy and minimize emergence resistance drug exposure Acinetobacter baumannii. The together with doripenem were evaluated in time–kill experiments over 48 h 108 cfu/mL two polymyxin-heteroresistant A. baumannii isolates (ATCC 19606 N16870). Pharmacokinetic/pharmacodynamic relationships...
ABSTRACT Increasing evidence suggests that colistin monotherapy is suboptimal at currently recommended doses. We hypothesized front-loading provides an improved dosing strategy for polymyxin antibiotics to maximize killing and minimize total exposure. Here, we utilized in vitro pharmacodynamic model examine the impact of front-loaded regimens against a high bacterial density (10 8 CFU/ml) Pseudomonas aeruginosa . The pharmacokinetics were simulated patients with hepatic (half-life [ t 1/2 ]...
Objective Immune complexes (ICs) play a critical role in the pathology of autoimmune diseases. The aim this study was to generate and characterise first-in-class anti-FcγRIIA antibody (Ab) VIB9600 (previously known as MEDI9600) that blocks IgG immune complex-mediated cellular activation for clinical development. Methods humanised optimised from IV.3 Ab. Binding affinity specificity were determined by Biacore ELISA. Confocal microscopy, Flow Cytometry-based assays binding competition used...
ABSTRACT The in vitro pharmacodynamics of colistin against Pseudomonas aeruginosa PAO1 wild-type and isogenic knockout strains phoP pmrA were evaluated. Colistin killing at subinhibitory concentrations was greater the mutants than wild type within first 8 h: concentration that results 50% maximal effect (EC 50 ) mutant (0.413 mg/liter) less (0.718 ( P < 0.05). An pharmacodynamic model simulating human regimens displayed initial followed by regrowth gradual type.
Abstract Tezepelumab is a human monoclonal antibody that blocks thymic stromal lymphopoietin, an epithelial cytokine involved in asthma pathogenesis. In the phase 2b PATHWAY study (ClinicalTrials.gov identifier: NCT02054130), tezepelumab significantly reduced exacerbations adults with severe, uncontrolled asthma. We used pharmacokinetic (PK) and pharmacodynamic (PD) modeling to guide dose selection for 3 trials patients severe PK data from 7 clinical studies were develop population model....
Abstract Purpose In the phase 3 CheckMate 9ER trial, intravenous nivolumab (240 mg every 2 weeks) plus oral cabozantinib (40 mg/day) improved progression-free survival (PFS) versus sunitinib as first-line therapy for advanced renal cell carcinoma (RCC). To support dosing with combination, this exposure–response analysis characterized relationship of exposure clinical endpoints. Methods Dose modification was allowed (holds and reductions) to manage adverse events (AEs). The population...
Development of spontaneous mutations in Pseudomonas aeruginosa has been associated with antibiotic failure, leading to high rates morbidity and mortality. Our objective was evaluate the pharmacodynamics polymyxin B combinations against rapidly evolving P. mutator strains characterize time course bacterial killing resistance via mechanism-based mathematical models. Polymyxin or doripenem alone combination were evaluated six strains: wild-type PAO1, mismatch repair (MMR)-deficient (mutS mutL)...
The impact of quorum sensing on polymyxin and azithromycin pharmacodynamics was assessed in Pseudomonas aeruginosa PAO1 an isogenic rhlR/lasR double knockout. For B, greater killing against the knockout than observed at 108 CFU/ml (polymyxin B half-maximal effective concentration [EC50], 5.61 versus 12.5 mg/liter, respectively; P < 0.005). Polymyxin combined with (256 mg/liter) synergistic each strain, significantly reducing respective EC50 compared to those monotherapy (P 0.005), is a...
Ertapenem provides broad-spectrum activity against many pathogens, and its use is relevant for the prophylaxis treatment of infections in morbidly obese patients undergoing surgery. However, pharmacokinetics tissue penetration these are not well defined. We assessed population target attainment ertapenem plasma, subcutaneous tissue, peritoneal fluid patients. Six female (body mass index, 43.7 to 55.9 kg/m2) received 1,000 mg as 15-min infusions at 0 26 h. On day 2, unbound concentrations...
Monte Carlo simulations (MCS) present a powerful tool to evaluate candidate regimens by determining the probability of target attainment. Although these assessments have traditionally incorporated variability in pharmacokinetic (PK) parameters and MICs, consideration interstrain pharmacodynamic (PD) has been neglected. A population PK/PD model was developed for doripenem using murine thigh infection data based on 20 bacterial strains. PK were fit linear two-compartment with first-order input...
The interplay between polymyxin B pharmacodynamics and pathogenicity was examined in Pseudomonas aeruginosa PAO1 isogenic DNA repair-deficient mutators (mutM mutS strains). Against mutators, initial killing concentration dependent, with >99.9% bacterial reduction at 2 h followed by regrowth resistance. pre- versus postexposed strains were inoculated real time into Galleria mellonella waxworms, resulting increased median survival times from 20 to 23 (P < 0.001). Emergence of resistance P....
<b>Background:</b> Tezepelumab, a human anti-thymic stromal lymphopoietin monoclonal antibody, has demonstrated efficacy and safety in placebo-controlled phase 2b dose-ranging study (Corren J et al. NEJM 2017;377:936-46) adults with severe uncontrolled asthma. <b>Objective:</b> To characterize the exposure-response (ER) relationship for tezepelumab to determine optimal dose 3 studies. <b>Methods:</b> Population pharmacokinetics were characterized using pooled data from 7 clinical ER models...
In the USA, cabozantinib was approved for treatment of patients aged ≥ 12 years with radioiodine-refractory differentiated thyroid cancer (DTC) who progressed on prior vascular endothelial growth factor (VEGFR)-targeted therapy based Phase 3 COSMIC-311 trial, which evaluated 60 mg/day versus placebo. Approved dosing is adults and pediatric body surface area (BSA) 1.2 m2, 40 BSA < m2. This report describes a population pharmacokinetic (PopPK) exposure–response analysis COSMIC-311. A PopPK...