Author's personal copy Pharmacology Comparison of 30-min and 3-h infusion regimens for imipenem/cilastatin and for meropenem evaluated by Monte Carlo simulation ☆ Lois S. Lee a , Martina Kinzig-Schippers b , Anne N. Nafziger c , Lei Ma d , Fritz Sörgel b,e , Ronald N. Jones f , George L. Drusano d , Joseph S. Bertino Jr. c, ⁎ a Bassett Healthcare, Cooperstown, NY 13326, USA b Institute for Biomedical and Pharmaceutical Research (IBMP), Nürnberg-Heroldsberg, Germany c Bertino Consulting, Schenectady, NY 12303, USA d Ordway Research Institute, Albany, NY 12203, USA e Department of Pharmacology, University of Duisburg-Essen, Essen, Germany f The Jones Group, JMI Laboratories, North Liberty, IA 52317, USA Received 23 July 2008; accepted 12 June 2010 Abstract Imipenem/cilastatin and meropenem are carbapenem antibiotics that are infused intravenously (IV) over 30 to 45 min. We evaluated probability of target attainment and cumulative probability of target attainment of 30-min and 3-h infusions for imipenem/cilastatin and meropenem. Eighteen healthy adults in a randomized, 4-phase, crossover study received 1000 mg of imipenem/cilastatin or meropenem as a single-dose IV over 30 min or 3 h. A population pharmacokinetics analysis using a 2-compartment IV infusion model was performed. Monte Carlo simulations using various dosage regimens at steady-state and 30-min and 3-h infusion rates were performed to evaluate the probabilities of attaining 20% (bacteriostatic), 30%, and 40% (maximum kill) time above the MIC. Three-hour infusions of imipenem/ cilastatin and meropenem improved the cumulative probability of target attainment for a variety of populations of microorganisms compared to 30-min infusions. Prolonged infusions have the potential to optimize efficacy of imipenem/cilastatin and meropenem. © 2010 Elsevier Inc. All rights reserved. Keywords: Antimicrobial pharmacokinetics; Pharmacodynamics; Antibiotics; Carbapenems 1. Introduction As with other β-lactams, imipenem/cilastatin (Primaxin (R) IV, 2007) and meropenem (Merrem(R) IV, 2007) demonstrate time-dependent killing. Efficacy of these agents is determined by the duration in percentage (%) of the dosing interval for which unbound drug concentrations are above the MIC of the pathogen. This pharmacodynamic index, also referred as time above MIC (T N MIC), has been used to predict activity against bacteria and clinical outcome. For carbapenems such as imipenem/cilastatin and meropenem, the T N MIC required for bacteriostatic effect (=inhibition of bacterial growth or stationary phase of bacterial growth) is approximately 20% of the dosing interval and for near- maximal bactericidal effect (=near the maximal bacterial kill) is approximately 40% of the dosing interval for organisms such as Pseudomonas aeruginosa and Escherichia coli (Drusano, 2003; Ong et al., 2007). In addition to attaining pharmacodynamic targets associated with efficacy, attaining the pharmacodynamic target associated with suppression of drug-resistant populations is important to minimize resis- tance (Tam et al., 2005). β-Lactams with long half-lives such as ceftriaxone or ertapenem (Invanz(R) Package Insert, 2009; Rocephin(R) Package Insert, 2009) have the advantage of achieving longer T N MIC with less frequent dosing. For drugs with short half-lives, frequent administration (e.g., every 6–8 h) is recommended to produce an optimal T N MIC. For drugs with short half-lives that are administered intravenously Available online at www.sciencedirect.com Diagnostic Microbiology and Infectious Disease 68 (2010) 251 – 258 www.elsevier.com/locate/diagmicrobio ☆ Presented in part at the 45th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy, December 16, 2005, Washing- ton, DC. ⁎ Corresponding author. Tel.: +1-518-280-1378. E-mail address: sbertino@ix.netcom.com (J.S. Bertino). 0732-8893/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.diagmicrobio.2010.06.012