Journal
JOURNAL OF CLINICAL PHARMACOLOGY
Volume 56, Issue 1, Pages 56-66Publisher
WILEY
DOI: 10.1002/jcph.566
Keywords
ceftolozane; tazobactam; epithelial lining fluid; nosocomial pneumonia; Pseudomonas aeruginosa; probability of target attainment; dose justification
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Funding
- Merck and Co., Inc., Kenilworth, New Jerse
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Ceftolozane/tazobactam is an antipseudomonal antibacterial approved for the treatment of complicated urinary tract infections (cUTIs) and complicated intra-abdominal infections (cIAIs) and in phase 3 clinical development for treatment of nosocomial pneumonia. A population pharmacokinetic (PK) model with the plasma-to-epithelial lining fluid (ELF) kinetics of ceftolozane/tazobactam was used to justify dosing regimens for patients with nosocomial pneumonia in phase 3 studies. Monte Carlo simulations were performed to determine ceftolozane/tazobactam dosing regimens with a >90% probability of target attainment (PTA) for a range of pharmacokinetic/pharmacodynamic targets at relevant minimum inhibitory concentrations (MICs) for key pathogens in nosocomial pneumonia. With a plasma-to-ELF penetration ratio of approximately 50%, as observed from an ELF PK study, a doubling of the current dose regimens for different renal functions that are approved for cUTIs and cIAIs is needed to achieve >90% PTA for nosocomial pneumonia. For example, a 3-g dose of ceftolozane/tazobactam for nosocomial pneumonia patients with normal renal function is needed to achieve a >90% PTA (actual 98%) for the 1-log kill target against pathogens with an MIC of 8mg/L in ELF, compared with the 1.5-g dose approved for cIAIs and cUTIs.
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