title: Ceftolozane/tazobactam pharmacokinetic/pharmacodynamic-derived dose justification for phase 3 studies in patients with nosocomial pneumonia.
abstract: 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 ≤ 8 mg/L in ELF, compared with the 1.5-g dose approved for cIAIs and cUTIs.
authors.affiliation: Merck and Co., Inc., Kenilworth, NJ, USA.
authors.forename: Alan J
authors.initials: AJ
authors.lastname: Xiao
authors.affiliation: Merck and Co., Inc., Kenilworth, NJ, USA.
authors.forename: Benjamin W
authors.initials: BW
authors.lastname: Miller
authors.affiliation: Merck and Co., Inc., Kenilworth, NJ, USA.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Huntington
authors.affiliation: Hartford Hospital, Hartford, CT, USA.
authors.forename: David P
authors.initials: DP
authors.lastname: Nicolau
mesh_terms: D000328:Adult; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002511:Cephalosporins / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003428:Cross Infection / Q000188:drug therapy / Q000378:metabolism; D004338:Drug Combinations; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D008954:Models, Biological; D009010:Monte Carlo Method; D010397:Penicillanic Acid / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology; D011014:Pneumonia / Q000188:drug therapy / Q000378:metabolism; D000078142:Tazobactam; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D002511:Cephalosporins; D004338:Drug Combinations; C519491:ceftolozane; D010397:Penicillanic Acid; D000078142:Tazobactam
keywords: Pseudomonas aeruginosa; ceftolozane/tazobactam; dose justification; epithelial lining fluid; nosocomial pneumonia; probability of target attainment