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.

What is the role of the new β-lactam/β-lactamase inhibitors ceftolozane/tazobactam and ceftazidime/avibactam?

“…Pending the outcomes of ongoing clinical trials, the results of off-label experiences with P. aeruginosa pneumonia are promising [40]. Nonetheless, in this setting, in the case of TOL/TAZ, the results of studies based on Monte Carlo simulations justify a doubling of the dose approved for cIAIs and cUTIs, also in the light of a plasma-to-epithelial lining fluid ratio of approximately 50% [41]. Other possible indications could be soft tissue and skin infections [42], bloodstream infections [43], and cystic fibrosis exacerbations [44].…”

Multidrug-resistant Gram-negative bacteria-resistant infections: epidemiology, clinical issues and therapeutic options

“…70 Spectrum of activity of ceftolozane/ tazobactam includes difficult-to-treat Gram-negative pathogens, including ESBL strains. 28,[71][72][73] Another new therapeutic option is represented by ceftazidime/avibactam, where the new b-lactam inhibitor agent avibactam improves the activity of ceftazidime against MDR P. aeruginosa. 74 Notably, ceftazidime/avibactam has demonstrated consistent activity against KPC-Kp.…”

Response to: ‘Letter to the Editor: “Management of multidrug-resistant Pseudomonas aeruginosa in the Intensive Care Unit: state of the art”’

“…In turn, the basis of the work was the 50% plasma-to-ELF penetration ratio of TOL/TAZ. The model clearly demonstrated that, in case of normal renal function, a 3-g dose (each 8 h) of TOL/TAZ is necessary to achieve a >90% probability of target attainment (namely 98%) against PA (as well as Enterobacteriaceae) strains with a minimum inhibitory concentrations (MIC) up to 8 mg/L in ELF [12].…”

“…The reason for this double dosage relies on an elegant study where a Monte Carlo simulation was used to assess the kinetics of TOL/TAZ between plasma and the epithelial lining fluid (ELF) [12]. In turn, the basis of the work was the 50% plasma-to-ELF penetration ratio of TOL/TAZ.…”