Therapeutic drug monitoring of antimicrobials Jason A. Roberts, 1,4,5 Ross Norris, 2,7,8 David L. Paterson 3,6 & Jennifer H. Martin 9 1 Burns, Trauma and Critical Care Research Centre, 2 School of Pharmacy and 3 Centre for Clinical Research, The University of Queensland, Brisbane, Queensland, Australia, 4 Department of Intensive Care, 5 Pharmacy Department and 6 Department of Infectious Diseases, Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia, 7 Australian Centre for Paediatric Pharmacokinetics, Mater Pharmacy Services, Brisbane, Queensland, Australia, 8 School of Pharmacy, Griffith University, Gold Coast, Queensland, Australia and 9 The University of Queensland School of Medicine Southside, Princess Alexandra Hospital,Woolloongabba, Brisbane, Queensland, Australia Correspondence Dr Jason Roberts, Burns Trauma and Critical Care Research Centre, The University of Queensland, Level 3 Ned Hanlon Building, Royal Brisbane and Women’s Hospital, Butterfield Street, Brisbane, Queensland 4029, Australia. Tel.: +61 7 3636 4108 Fax: +61 7 3636 3542 E-mail: j.roberts2@uq.edu.au ---------------------------------------------------------------------- Keywords antibacterial, antibiotic, assay pharmacokinetics, pharmacodynamics, target concentration intervention, therapeutic drug management ---------------------------------------------------------------------- Received 14 June 2011 Accepted 1 August 2011 Accepted Article 10 August 2011 Optimizing the prescription of antimicrobials is required to improve clinical outcome from infections and to reduce the development of antimicrobial resistance. One such method to improve antimicrobial dosing in individual patients is through application of therapeutic drug monitoring (TDM). The aim of this manuscript is to review the place of TDM in the dosing of antimicrobial agents, specifically the importance of pharmacokinetics (PK) and pharmacodynamics (PD) to define the antimicrobial exposures necessary for maximizing killing or inhibition of bacterial growth. In this context, there are robust data for some antimicrobials, including the ratio of a PK parameter (e.g. peak concentration) to the minimal inhibitory concentration of the bacteria associated with maximal antimicrobial effect. Blood sampling of an individual patient can then further define the relevant PK parameter value in that patient and, if necessary, antimicrobial dosing can be adjusted to enable achievement of the target PK/PD ratio.To date, the clinical outcome benefits of a systematic TDM programme for antimicrobials have only been demonstrated for aminoglycosides, although the decreasing susceptibility of bacteria to available antimicrobials and the increasing costs of pharmaceuticals, as well as emerging data on pharmacokinetic variability, suggest that benefits are likely. Introduction Maximizing the effectiveness whilst minimizing the toxic- ity of antimicrobial agents is an essential step in the treat- ment of infections. Adequate control of the source of infection is also important. However, maximizing efficacy and minimizing toxicity requires an understanding of the pharmacokinetics (PK) of the prescribed antimicrobial and the susceptibility of the causative bacterial pathogen [1]. In the context of high morbidity and mortality associated with some patient populations [2–4], as well as escalating resistance to antimicrobials [5] and increased cost of phar- maceuticals, methods to optimize antimicrobial use should be considered. The aim of this manuscript is to review the place of therapeutic drug monitoring (TDM) in the use of antimicrobial agents and discuss the issues regarding analysis of these drug concentrations. We will focus on the role of TDM in optimizing antimicrobial dosing for patient populations with variable pharmacokinetics, such as the critically ill and obese. Discussion of the role of TDM of antifungals, antiparasitics and antiviral agents is beyond the scope of this paper, although other reviews for these agents are available [6, 7]. Therapeutic drug monitoring can be used to both maximize the efficacy and minimize the toxicity of antimi- crobial therapy for individual patients. In this context, TDM is used to personalize dosing to attain antimicrobial expo- sures associated with a high probability of therapeutic success, and suitably low probabilities of toxicity and gen- eration of antimicrobial resistance [8, 9]. Whilst most com- monly employed for drugs with a narrow therapeutic range, the desire to use TDM is increasing because of the increasing number of patients in groups for whom PK has not been clearly studied (e.g. critically ill, significant comor- bidities, elderly and extremes of body size), as well as the decreasing susceptibility of pathogens, which may require higher antimicrobial doses to maximize effect [9, 10]. Over the last 30 years, a significant body of research has emerged to inform researchers and clinicians about the concentration–effect relations for antimicrobials [11, 12]. British Journal of Clinical Pharmacology DOI:10.1111/j.1365-2125.2011.04080.x Br J Clin Pharmacol / 73:1 / 27–36 / 27 © 2011 The Authors British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society