Optimizing antibiotic dosing regimens for nosocomial pneumonia: a window of opportunity for pharmacokinetic and pharmacodynamic modeling

IntroductionDetermining antibiotic exposure in the lung and the threshold(s) needed for effective antibacterial killing is paramount during development of new antibiotics for the treatment of nosocomial pneumonia, as these exposures directly affect clinical outcomes and resistance development. The use of pharmacokinetic and pharmacodynamic modeling is recommended by regulatory agencies to evaluate antibiotic pulmonary exposure and optimize dosage regimen selection. This process has been implemented in newer antibiotic development.Areas CoveredThis review will discuss the basis for conducting pharmacokinetic and pharmacodynamic studies to support dosage regimen selection and optimization for the treatment of nosocomial pneumonia. Pharmacokinetic/pharmacodynamic data that supported recent hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia indications for ceftolozane/tazobactam, ceftazidime/avibactam, imipenem/cilastatin/relebactam, and cefiderocol will be reviewed.Expert opinionOptimal drug development requires the integration of preclinical pharmacodynamic studies, healthy volunteers and ideally patient bronchoalveolar lavage pharmacokinetic studies, Monte-Carlo simulation, and clinical trials. Currently, plasma exposure has been successfully used as a surrogate for lung exposure threshold. Future studies are needed to identify the value of lung pharmacodynamic thresholds in nosocomial pneumonia antibiotic dosage optimization.

Automated summary

Determining the antibiotic exposure in the lung and the threshold(s) needed for effective antibacterial killing is crucial for the treatment of nosocomial pneumonia. Pharmacokinetic and pharmacodynamic modeling is recommended for evaluating antibiotic pulmonary exposure and optimizing dosage regimen selection. This review discusses the basis for conducting such studies and reviews the data supporting recent indications for different antibiotics.