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Pharmacokinetic-Pharmacodynamic Target Attainment Analyses To Determine Optimal Dosing of Ceftazidime-Avibactam for the Treatment of Acute Pulmonary Exacerbations in Patients with Cystic Fibrosis.
Bensman, Timothy J; Wang, Joshua; Jayne, Jordanna; Fukushima, Lynn; Rao, Adupa P; D'Argenio, David Z; Beringer, Paul M.
Afiliação
  • Bensman TJ; Biomedical Simulations Resource, Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, California, USA.
  • Wang J; Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, California, USA.
  • Jayne J; Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, California, USA.
  • Fukushima L; Division of Pulmonary and Critical Care Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • Rao AP; Division of Pulmonary and Critical Care Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
  • D'Argenio DZ; Biomedical Simulations Resource, Department of Biomedical Engineering, Viterbi School of Engineering, University of Southern California, Los Angeles, California, USA.
  • Beringer PM; Department of Clinical Pharmacy, School of Pharmacy, University of Southern California, Los Angeles, California, USA beringer@usc.edu.
Article em En | MEDLINE | ID: mdl-28784670
Acute pulmonary exacerbations (APE) involving Pseudomonas aeruginosa are associated with increased morbidity and mortality in cystic fibrosis (CF) patients. Drug resistance is a significant challenge to treatment. Ceftazidime-avibactam (CZA) demonstrates excellent in vitro activity against isolates recovered from CF patients, including drug-resistant strains. Altered pharmacokinetics (PK) of several beta-lactam antibiotics have been reported in CF patients. Therefore, this study sought to characterize the PK of CZA and perform target attainment analyses to determine the optimal treatment regimen. The PK of CZA in 12 adult CF patients administered 3 intravenous doses of 2.5 g every 8 h infused over 2 h were determined. Population modeling utilized the maximum likelihood expectation method. Monte Carlo simulations determined the probability of target attainment (PTA). An exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (fT>MIC) was evaluated for ceftazidime (CAZ), and an exposure target consisting of the cumulative percentage of a 24-h period that the free drug concentration exceeds a 1-mg/liter threshold concentration (fT>1 mg/liter) was evaluated for avibactam (AVI). Published CAZ and CZA MIC distributions were incorporated to evaluate cumulative response probabilities. CAZ and AVI were best described by one-compartment models. The values of total body clearance (CL; CAZ CL, 7.53 ± 1.28 liters/h; AVI CL, 12.30 ± 1.96 liters/h) and volume of distribution (V; CAZ V, 18.80 ± 6.54 liters; AVI V, 25.30 ± 4.43 liters) were broadly similar to published values for healthy adults. CZA achieved a PTA (fT>MIC, 50%) of >0.9 for MICs of ≤16 mg/liter. The overall likelihood of a treatment response was 0.82 for CZA, whereas it was 0.42 for CAZ. These data demonstrate improved pharmacodynamics of CZA in comparison with those of CAZ and provide guidance on the optimal dosing of CZA for future studies. (This study has been registered at ClinicalTrials.gov under registration no. NCT02504827.).
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Texto completo: 1 Base de dados: MEDLINE Métodos Terapêuticos e Terapias MTCI: Plantas_medicinales Assunto principal: Pseudomonas aeruginosa / Infecções por Pseudomonas / Infecções Respiratórias / Ceftazidima / Fibrose Cística / Compostos Azabicíclicos / Inibidores de beta-Lactamases / Antibacterianos Tipo de estudo: Guideline / Health_economic_evaluation / Observational_studies / Risk_factors_studies Idioma: En Revista: Antimicrob Agents Chemother Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos

Texto completo: 1 Base de dados: MEDLINE Métodos Terapêuticos e Terapias MTCI: Plantas_medicinales Assunto principal: Pseudomonas aeruginosa / Infecções por Pseudomonas / Infecções Respiratórias / Ceftazidima / Fibrose Cística / Compostos Azabicíclicos / Inibidores de beta-Lactamases / Antibacterianos Tipo de estudo: Guideline / Health_economic_evaluation / Observational_studies / Risk_factors_studies Idioma: En Revista: Antimicrob Agents Chemother Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Estados Unidos