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

ABSTRACT

Introduction

Determining 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 Covered

This 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 opinion

Optimal 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.

KEYWORDS:

• Antibiotics
• beta-lactam
• beta-lactamase inhibitor
• drug penetration
• pharmacokinetic
• pharmacodynamic
• PK/PD modeling
• nosocomial pneumonia

Article highlights

• Pharmacokinetic/pharmacodynamic analyses are powerful tools now recognized by both the Food and Drug Administration (FDA) and European Medicines Agency (EMA) for dosing optimization in hospital acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) antibiotic development.

• Pre-clinical in vivo infection and human intrapulmonary pharmacokinetic and pharmacodynamic studies facilitate antibiotic dose selection.

• High pulmonary penetration does not equivalent to adequate antibiotic exposure; instead, antibiotic exposure (i.e. concentration–time profiles) and pathogen minimal inhibitory concentrations (MICs) must be considered for dose selection.

• The approvals of recent beta-lactam and beta-lactam/beta-lactamase inhibitor combination antibiotics for HABP/VABP exemplify the utilization of pharmacokinetics and pharmacodynamics modeling to develop optimal dosing regimens.

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Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.