Pharmacodynamics of Meropenem and Imipenem Against Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa

Joseph L. Kuti, Pharm.D.; Naomi R. Florea, Pharm.D.; Charles H. Nightingale, Ph.D.; David P. Nicolau, Pharm.D., FCCP

Disclosures

Pharmacotherapy. 2004;24(1) 

In This Article

Abstract and Introduction

Study Objective: To compare the pharmacodynamics of meropenem and imipenem, both administered as 500 mg every 6 hours, against populations of Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa.
Design: Ten thousand–subject Monte Carlo simulation.
Intervention: Variability in total body clearance (ClT), volume of distribution as calculated by the terminal elimination rate (Vdβ), and minimum inhibitory concentration (MIC) distributions (Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Serratia marcescens, A. baumannii, P. aeruginosa) were derived from the literature for both meropenem and imipenem. For the free drug concentrations, the percentage of the dosing interval that the drug concentrations remain above the MIC (%T>MIC) for each carbapenem-bacteria combination was calculated for 10,000 iterations, substituting a different ClT, Vdβ, fraction of unbound drug, and MIC into the equation each time based on the probability distribution for each parameter. Probabilities of attaining targets of 30%, 50%, and 100% T>MIC were calculated.
Measurements and Main Results: Meropenem free drug %T>MIC exposure was significantly greater than that of imipenem against Enterobacteriaceae and P. aeruginosa, whereas imipenem exposure was greater for A. baumannii. For both agents, free drug %T>MIC exposure was greatest against Enterobacteriaceae and less for A. baumannii and P. aeruginosa. Probabilities of target attainment for 30% and 50% T>MIC were similar between drugs for most bacteria. At 100% T>MIC, meropenem target attainments were greater than those of imipenem against Enterobacteriaceae and P. aeruginosa, and imipenem attainment was higher for A. baumannii.
Conclusion: The probability of attaining lower pharmacodynamic targets for most gram-negative bacteria is similar for these carbapenems; however, differences become apparent as the pharmacodynamic requirement increases. Further study of the benefits of achieving this pharmacodynamic breakpoint with a higher probability of attaining targets is necessary.

The principal goal of antimicrobial therapy for infection is complete eradication of the pathogen as quickly as possible with the fewest adverse effects to the patient. This is perhaps most important when treating severe, complicated infections, especially those caused by highly resistant bacteria. Because of their broad-spectrum microbiologic activity, the carbapenem antibiotics meropenem (Merrem; AstraZeneca Pharmaceuticals, Wilmington, DE) and imipenem-cilastatin (Primaxin; Merck & Co. West Point, PA) commonly are administered as empiric therapy in critically ill patients or as last-line treatment of multidrug-resistant bacteria against which they retain susceptibility. These agents differ, however, in their mechanisms of resistance and spectrum of activity, with meropenem being more potent against gram-negative bacteria and imipenem more potent against gram-positive bacteria.[1,2]

Use of these antimicrobials, together with the increasing concern for resistance over the last half-decade, has led to implementation of numerous surveillance programs, such as the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) study.[2] These programs are designed to monitor susceptibility patterns of various antimicrobials and identify key areas of concern.[3] Although they provide insight into susceptibility rates for meropenem and imipenem, they compare antimicrobial agents only by minimum inhibitory concentration (MIC), which is a poor predictor of clinical outcome as it disregards variability in pharmacokinetics among patients and subsequent differences in antibacterial exposure. Failure to identify these key differences may lead to therapy with drugs that are unlikely to attain appropriate pharmacodynamic targets. These considerations are vital to ensure optimum clinical outcomes and potentially prevent the emergence of resistance.[4–6]

Like other β-lactams (penicillins, cephalosporins), carbapenems have concentration-independent or time-dependent bactericidal activity; therefore, killing best correlates with the duration of time that drug concentrations remain above the MIC for the organism.[7] The pharmacodynamic variable used to measure this end point is percentage of the dosing interval that drug concentrations remain above the MIC (%T>MIC). Bacteriostatic and bactericidal responses in a murine model of infection were observed when concentrations of carbapenems remained above MICs for approximately 20% and 40% of the dosing interval, respectively.[8,9]

Monte Carlo simulation is a technique that uses a probability density function to generate thousands of single-point estimates and then plots probabilities to examine the entire range of possible drug exposures. It has been integrated with accepted pharmacodynamic models to compare antimicrobials and determine their abilities to achieve dynamic end points.[10–12] The purpose of this analysis was to determine and compare the probability of obtaining critical pharmacodynamic targets for meropenem and imipenem against Enterobacteriaceae, Acinetobacter baumannii, and Pseudomonas aeruginosa from the United States using Monte Carlo simulation to incorporate variability in microbiologic and pharmacokinetic data.

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