Pharmacodynamics of meropenem in critically ill patients with febrile neutropenia and bacteraemia

https://doi.org/10.1016/j.ijantimicag.2011.04.019Get rights and content

Abstract

The bactericidal activity of β-lactams is determined by the time that concentrations in tissue and serum are above the minimum inhibitory concentration (T > MIC) for the pathogen. The aim of this study was to compare the probability of target attainment (PTA) and the cumulative fraction of response (CFR) for meropenem between administration by bolus injection and a 3-h infusion. The study was a randomised, three-way, cross-over design in eight febrile neutropenic patients with bacteraemia. Each subject received meropenem in three regimens consecutively: (i) a bolus injection of 1 g every 8 h (q8h) for 24 h; (ii) a 3-h infusion of 1 g q8h for 24 h; and (iii) a 3-h infusion of 2 g q8h for 24 h. For pathogens with an MIC of 4 μg/mL, the PTA of achieving 40% T > MIC following administration of meropenem by a bolus injection of 1 g q8h, a 3-h infusion of 1 g q8h and a 3-h infusion of 2 g q8h was 75.7%, 99.24% and 99.96%, respectively. Only the 3-h infusion of 2 g q8h achieved a PTA >99% for 40% T > MIC for a MIC of 8 μg/mL. By referral to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) MIC distributions, the three regimens of meropenem were predicted to achieve a CFR  90% against Escherichia coli and Klebsiella spp. In conclusion, a 3-h infusion of 2 g of meropenem q8h resulted in the highest PTA rates. The three regimens of meropenem had high probabilities of achieving optimal impact against E. coli and Klebsiella spp.

Introduction

Pharmacodynamic (PD) studies suggest that the time course of antimicrobial activity can vary for different classes of antibiotics [1], [2], [3]. For β-lactam antibiotics, the antimicrobial activity of these agents exhibits primarily time-dependent killing. Therefore, the time that concentrations in tissue and serum are above the minimum inhibitory concentration (T > MIC) is the pharmacokinetic (PK)/PD index that best correlates with efficacy [2], [3], and the optimum method to maintain such serum drug concentrations would be to administer the agent by continuous infusion [4], [5], [6]. Meropenem, a carbapenem antibacterial agent with a broad spectrum of activity against several pathogens including Gram-negative bacilli, exhibits primarily time-dependent killing [7]. In common with other β-lactams, the main PK/PD index that correlates with its therapeutic efficacy is T > MIC, and meropenem can achieve fairly rapid killing for a β-lactam. Therefore, administration by continuous infusion is the preferred route to maximise this parameter. However, in tropical countries, the stability of meropenem is an important consideration when continuous infusion is to be used. A previous study showed that meropenem remained 90% stable for <3 h at 37 °C and was degraded by up to 60% within 24 h at that temperature [8].

Previous studies showed that a 3-h infusion regimen of meropenem provided PD benefits over a bolus injection [9], [10], [11]. Moreover, we conducted studies to compare the pharmacokinetics/pharmacodynamics of meropenem in normal volunteers and in patients with ventilator-associated pneumonia (VAP) when it was administered by a 3-h infusion or bolus injection regimen. The studies found that a 3-h infusion of meropenem gives greater values for T > MIC than a bolus injection [12], [13]. Other studies have found that a 2-h infusion of imipenem and a 4-h infusion of doripenem provide greater values for T > MIC than a bolus injection [14], [15], [16]. We have therefore suggested that administration by prolonging intermittent infusion may offer the opportunity to increase the T > MIC within the limitations of stability at room temperature. An earlier study has demonstrated that free drug is available for antimicrobial activity; however, meropenem has low (<10%) protein binding [17] and therefore the T > MIC both for free and total drug required for bactericidal effect is not much different.

In studies performed on febrile neutropenic patients, PK changes were found for several antimicrobial agents, including meropenem. The volume of distribution of meropenem was significantly greater in this patient population than in healthy subjects. Non-renal clearance in febrile neutropenic patients was similar to that found in young healthy subjects, but was significantly higher than in elderly healthy subjects. Total and renal clearances of patients were not significantly different compared with healthy subjects [18], [19]. Therefore, the aims of this study were to assess the pharmacokinetics and pharmacodynamics of meropenem in febrile neutropenic patients with bacteraemia and to compare the probability of target attainment (PTA) and cumulative fraction of response (CFR) for meropenem in three regimens: (i) a bolus injection of 1 g; (ii) a 3-h infusion of 1 g; and (iii) a 3-h infusion of 2 g.

Section snippets

Subjects

This study was conducted in febrile neutropenic patients with bacteraemia. Patients were eligible for the study if they met the following criteria: (i) age >18 years; (ii) body temperature ≥38.3 °C; (iii) neutrophil count <500 cells/μL; and (iv) bacteraemia, confirmed by at least one positive blood culture. Patients were excluded from the study if they were pregnant or in circulatory shock (defined as a systolic blood pressure of <90 mmHg and poor tissue perfusion) or had documented

Results

Eight patients were enrolled in the study (five males and three females), with a mean age of 43.37 ± 20.54 years (range 18–76 years) and a mean body weight of 50.62 ± 17.96 kg (range 25–82 kg). The characteristics of all patients and the MICs of meropenem for the isolated pathogens are shown in Table 2. PK parameters of meropenem for the three regimens are presented in Table 1. The PK parameters from this study were not significantly different from the PK parameters determined by Phoenix™ WinNonlin®

Discussion

For β-lactam antibiotics, the bactericidal activity is determined by the T > MIC for the pathogens. High peak concentrations do not enhance the bactericidal activity of these agents and once the concentration falls below the MIC, bacterial growth resumes immediately [2], [3]. In addition, T > MIC is the best predictor of bacterial eradication or clinical success [28]. Studies in animal infection models have shown that for most β-lactams concentrations do not need to exceed the MIC for 100% of the

Acknowledgments

Meropenem (Meronem®) was generously donated by AstraZeneca (Bangkok, Thailand). The authors thank Mr David Patterson for checking the English of the manuscript.

Funding: This work was supported by a faculty grant from the Faculty of Medicine, Prince of Songkla University (Hat Yai, Thailand).

Competing interests: None declared.

Ethical approval: This study was approved by the Ethics Committee of Songklanagarind Hospital (Prince of Songkla University, Hat Yai, Thailand). The study was conducted

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