title: How severe is antibiotic pharmacokinetic variability in critically ill patients and what can be done about it?
abstract: The pharmacokinetics (PK) of antimicrobial agents administered to critically ill patients exhibit marked variability. This variability results from pathophysiological changes that occur in critically ill patients. Changes in volume of distribution, clearance, and tissue penetration all affect the drug concentrations at the site of infection. PK-pharmacodynamic indices (fCmax:MIC; AUC0-24:MIC; fT>MIC; fCmin:MIC) for both antimicrobial effect and suppression of emergence of resistance are described for many antimicrobial drugs. Changing the regimen by which antimicrobial drugs are delivered can help overcome the PK variability and optimise target attainment. This will deliver optimised antimicrobial chemotherapy to individual critically ill patients. Delivery of β-lactams antimicrobial agents by infusions, rather than bolus dosing, is effective at increasing the duration of the dosing interval that the drug concentration is above the MIC. Therapeutic drug monitoring, utilising population PK mathematical models with Bayesian estimation, can also be used to optimise regimens following measurement of plasma drug concentrations. Clinical trials are required to establish if patient outcomes can be improved by implementing these techniques.
authors.affiliation: The University of Manchester, Manchester Academic Health Science Centre, NIHR Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK. Electronic address: timothy.felton@manchester.ac.uk.
authors.forename: T W
authors.initials: TW
authors.lastname: Felton
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool L69 3GE, UK.
authors.forename: W W
authors.initials: WW
authors.lastname: Hope
authors.affiliation: Burns Trauma and Critical Care Research Centre, The University of Queensland, Brisbane and Royal Brisbane and Women's Hospital Brisbane, Queensland, Australia.
authors.forename: J A
authors.initials: JA
authors.lastname: Roberts
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D016638:Critical Illness / Q000628:therapy*; D016903:Drug Monitoring; D006801:Humans
chemical_list: D000900:Anti-Bacterial Agents
keywords: Critical care; Pharmacodynamics; Pharmacokinetics