Comparison of the pharmacodynamics of meropenem in healthy volunteers following administration by intermittent infusion or bolus injection

Sutep Jaruratanasirikul* and Somchai Sriwiriyajan

Department of Medicine, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkla 90110, Thailand

Received 22 January 2003; returned 8 April 2003; revised 12 June 2003; accepted 18 June 2003


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Objectives: The aim of this study was to compare the pharmacokinetics and pharmacodynamics of meropenem when administered by 3 h infusion or bolus injection regimens.

Patients and methods: The study was a randomized three-way crossover study with a 1 week wash-out period in 12 healthy volunteers. Each subject received a single dose of meropenem in three regimens: (i) bolus injection of 1 g meropenem; (ii) 3 h infusion of 1 g meropenem; and (iii) 3 h infusion of 0.5 g meropenem.

Results: Following bolus injection of 1 g meropenem, the mean ± S.D. percentages of the t > MIC of 4, 2 and 1 mg/L were 42.50 ± 6.20%, 54.38 ± 7.64% and 67.04 ± 8.47% of an 8 h dosing interval, respectively. For the 3 h infusion of 1 g meropenem, the percentages of the t > MIC of 4, 2 and 1 mg/L were 59.27 ± 7.34%, 71.97 ± 8.63% and 86.07 ± 9.41% of an 8 h dosing interval, respectively. For the 3 h infusion of 0.5 g meropenem, the percentages of the t > MIC of 4, 2 and 1 mg/L were 47.27 ± 5.34%, 59.36 ± 6.60% and 71.44 ± 8.45% of an 8 h dosing interval, respectively.

Conclusions: We conclude that a 3 h infusion of 0.5 g or 1 g of meropenem both give greater values for t > MIC than a 1 g bolus and that intermittent infusion may be a useful mode of administration in tropical countries where drug instability may prevent the use of continuous infusion.

Keywords: continuous infusion, intermittent injection, carbapenem


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Pharmacodynamic analyses have helped in the development of antibiotic administration regimens that maximize antibacterial effects. Aminoglycosides, for example, have been found to exhibit concentration-dependent bacterial killing, and increasing the peak serum drug concentration enhances the bactericidal activity of these agents.1 In contrast, the bactericidal activity of ß-lactam antibiotics is concentration-independent and is determined by the time that concentrations in tissue and serum are above the MIC (t > MIC) for the pathogens during the dosing interval.24 For ß-lactams, the optimal method to maintain serum drug concentrations above the MIC for a susceptible pathogen would be to administer the agent by continuous infusion.

Meropenem is a carbapenem antibacterial agent with a broad spectrum of activity against Gram-negative, Gram-positive and anaerobic bacteria.5 In common with other ß-lactams, the main pharmacokinetic/pharmacodynamic parameter that correlates with the therapeutic efficacy is the t > MIC and administration by continuous infusion is the preferred route of administration to maximize this parameter. However, in tropical countries the stability of meropenem is an important consideration when considering continuous infusion.

Although a previous study has shown that the use of a cold pouch is capable of extending the stability of meropenem by maintaining a refrigerated storage environment, concerns about the use of continuous infusion in tropical countries still exist.6 We have recently conducted a study that indicates that meropenem, reconstituted in normal saline solution, is unstable when stored at room temperature in a tropical country (32–37°C) for over 8 h. Drug concentrations decreased 4% and 12% when this agent was stored at room temperature for 3 and 8 h, respectively (S. Jaruratanasirikul & S. Sriwiriyajan, unpublished results). We have therefore suggested that intermittent infusion (3 h infusion every 8 h) may be a useful route of administration in tropical countries. In this study, we report a comparison of the pharmacodynamic parameter, t > MIC, of meropenem when administered by 3 h infusion and bolus injection regimens.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
Subjects

The study was conducted in 12 healthy, non-smoking, non-alcoholic, non-obese healthy normal volunteers. Ten were male and two were female. Their mean age was 32.58 ± 8.94 years (range 18–48) and their mean weight was 59.69 ± 7.83 kg (range 45–72). Subjects underwent a pre-study evaluation to ensure that they had no underlying illnesses and were not currently or had not recently taken any medication. All subjects had normal biochemical and haematological laboratory profiles. Subjects were excluded if they had a history of meropenem intolerance. The protocol for the study was approved by the Ethics Committee of Songklanagarind Hospital and written informed consent was obtained from each subject.

Drugs and chemicals

Meropenem was donated by AstraZeneca, Thailand and cefepime (internal standard) was donated by Bristol-Myers Squibb, Thailand. All of the solvents were high-performance liquid chromatography (HPLC) grade.

Study design and sample collection

The study was a randomized three-way crossover study with a 1 week wash-out period. Meropenem was reconstituted according to the manufacturer’s guidelines. It was then diluted into two preparations; 1 g in 50 mL of normal saline solution and 0.5 g in 25 mL of normal saline solution. Each subject received a single dose of meropenem in three regimens: (i) bolus injection of 1 g meropenem over 10 min; (ii) 3 h infusion of 1 g meropenem via an infusion pump at a constant flow rate; and (iii) 3 h infusion of 0.5 g meropenem via an infusion pump at a constant flow rate. Blood samples (approximately 5 mL each) were obtained by direct venepuncture at the following times: before drug administration (time 0) and 10 min, 30 min, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6 and 8 h after the meropenem dose. All blood samples were allowed to clot and then centrifuged at 2000g. The serum obtained was stored at –80°C until analysis.

Meropenem assay

The concentrations of meropenem were determined by reversed phase HPLC. Cefepime (100 mg/L) was used as the internal standard and the samples were extracted by the method of Ozkan et al.7 An aliquot of the extracted sample (50 µL) was injected, using an automated injection system (Waters 717 plus Autosampler, Waters Associates, Milford, MA, USA), onto a Nova-Pak C18 column (Waters Associates). The mobile phase was 15 mM KH2PO4/acetonitrile/methanol (84:12:4, v/v/v), pH 2.8, at a flow rate of 1 mL/min. The column eluate was monitored by UV detection (Waters 486, Waters Associates) at 308 nm. The peaks were recorded and integrated on a Waters 746 Data Module (Waters Associates). The limit of detection of meropenem was 70 µg/L.

The intra-assay reproducibility values characterized by coefficient of variation (CV) were 2.58%, 1.77% and 3.45% for samples containing 2, 32 and 128 mg/L, respectively. The inter-assay reproducibility precision values, calculated by CV, were 3.21%, 2.98% and 3.74% for samples containing 2, 32 and 128 mg/L, respectively.

Pharmacokinetic and statistical analysis

Meropenem data were analysed with a curve-fitting computer program, WinNonlin Version 1.1 (Scientific Consulting Inc., Apex, NC, USA).

For all patients, the best data fit was observed with a one-compartment model. The area under the concentration–time curve over 8 h (AUC0–8), serum half-life (t1/2), total clearance (CLtot), the volume of distribution (V) and elimination rate constant (kel) were calculated for each patient. The maximum plasma concentration (Cmax) and the minimum plasma concentration (Cmin) were determined by visual inspection of the individual plasma concentration–time profiles. From the individually fitted concentration–time curves, the t > MIC was calculated for MICs of 4, 2 and 1 mg/L. Results were expressed as mean values ± standard deviation and statistical comparisons were made using the Wilcoxon signed-rank test. P values of <0.05 were considered significant.


    Results and discussion
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
The mean serum meropenem concentrations for bolus injection and 3 h infusion are shown in Figure 1. The pharmacokinetic parameters for bolus injection and 3 h infusion of meropenem are presented in Table 1. Both bolus injection and 3 h infusion were well tolerated and there were no reported adverse events.



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Figure 1. Mean serum meropenem concentration–time data for 12 normal volunteers following administration of 1 g bolus injection (open triangles); 1 g 3 h infusion (open circles); and 0.5 g 3 h infusion (filled squares).

 

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Table 1. Pharmacokinetic parameters (mean ± S.D.) of meropenem administered by bolus injection and 3 h infusion
 
Over the last decade, investigators have attempted to establish the most appropriate administration techniques for optimization of bactericidal activity.2,3 For ß-lactams, although it is generally accepted that the bactericidal effect of these agents is determined by the t > MIC,24 following the manufacturers’ instructions, ß-lactams are usually administered by intermittent injections. However, with this mode of administration, the high peak concentrations do not enhance the bactericidal activity of these agents, and during the dosing interval, drug concentrations may fall below the MIC required to inhibit growth of the pathogen. A study by Thalhammer et al.8 compared 3 g continuous infusion of meropenem over 24 h with 2 g intravenous every 8 h, intermittent administration, in critically ill patients; the results showed that meropenem serum concentrations from both treatment groups remained above the MIC for most common bacterial pathogens. In addition, the authors found that a continuous infusion regimen can save costs, since bactericidal serum levels were achieved with only 50% of the amount of drug used for intermittent administration. However, meropenem is unstable when stored at room temperature in a tropical country for 8 h and we have proposed that a 3 h infusion every 8 h may be an alternative mode of administration.

In this study, the meropenem pharmacokinetic parameter estimates for bolus injection of 1 g meropenem in normal volunteers were similar to estimates in a previous study.9 Comparison of the mean pharmacokinetic parameters between this study and the previous study yielded: Cmax,118.62 versus 112 mg/L; AUC, 97.57 versus 83.20 mg/L per h; t1/2, 1.13 versus 1.02 h; and V, 16.79 versus 15.70 L. In contrast, infusion of meropenem (0.5 and 1 g) over a 3 h infusion resulted in lower Cmax and greater t > MIC values, than those seen after bolus injection (Table 1). Studies in animal infection models have shown that for most ß-lactams, concentrations do not need to exceed the MIC for 100% of the dosing interval to achieve a significant antibacterial effect.10,11 Bacteriostatic effects are observed when serum drug concentrations are above the MIC for 30–40% of the dosing interval, whereas maximum killing is approached when levels are above the MIC for 60–70% of the time. In this study the mean serum concentrations after a 3 h infusion of 1 g meropenem were above 4 and 1 mg/L for approximately 60% and 86% of an 8 h dosing interval, respectively, compared with values of 42% and 67% following an intravenous bolus. Even when a 3 h infusion of 0.5 g meropenem was used, the percentages of the t > MIC for 4 and 1 mg/L were still higher than those from a bolus injection of 1 g meropenem. In addition, meropenem, unlike other ß-lactam antibiotics, exhibits a post-antibiotic effect against Gram-positive and Gram-negative bacteria and has slightly different killing properties compared with penicillins and cephalosporins, suggesting that intermittent infusion may result in a greater effect than that predicted solely from t > MIC values.5,12

In conclusion, it was found that a 3 h infusion of 1 g meropenem can maintain serum drug concentrations above the MIC for most pathogens in patients for 60% of an 8 h dosing interval suggesting a possible route of administration in tropical areas where drug instability may prevent the use of continuous infusion. However, further prospective studies comparing 3 h infusion and bolus injection regimens with clinical outcomes in patients are still necessary to confirm these findings.


    Acknowledgements
 
Meropenem was generously donated by AstraZeneca, Thailand and cefepime was generously donated by Bristol-Myers Squibb, Thailand. We thank Mr David Patterson for checking our English. This work was supported by a faculty grant from the Faculty of Medicine, Prince of Songkla University.


    Footnotes
 
* Corresponding author. Tel/Fax: +66-74-429385; E-mail: jasutep{at}ratree.psu.ac.th Back


    References
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 Abstract
 Introduction
 Materials and methods
 Results and discussion
 References
 
1 . Nicolau, D., Quintiliani, R. & Nightingale, C. H. (1992). Once-daily aminoglycosides. Connecticut Medicine 56, 561–3.[Medline]

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7 . Ozkan, Y., Kucukguzel, L., Ozkan, S. A. et al. (2001). A rapid, sensitive high performance liquid chromatographic method for the determination of meropenem in pharmaceutical dosage form, human serum and urine. Biomedical Chromatography 15, 263–6.[CrossRef][ISI][Medline]

8 . Thalhammer, F., Traunmuller, F., El Menyawi, I. et al. (1999). Continuous infusion versus intermittent administration of meropenem in critically ill patients. Journal of Antimicrobial Chemotherapy 43, 523–7.[Abstract/Free Full Text]

9 . Kelly, H. C., Hutchison, M. & Haworth, S. J. (1995). A comparison of the pharmacokinetics of meropenem after administration by intravenous injection over 5 min and intravenous infusion over 30 min. Journal of Antimicrobial Chemotherapy 36, Suppl. A, 35–41.[ISI][Medline]

10 . Craig, W. A. (1995). Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins. Diagnostic Microbiology and Infectious Disease 22, 89–96.[CrossRef][ISI][Medline]

11 . Vogelman, B., Gudmundsson, S., Leggett, J. et al. (1988). Correlation of antimicrobial pharmacokinetic parameters with therapeutic efficacy in an animal model. Journal of Infectious Diseases 158, 831–47.[ISI][Medline]

12 . Keil, S. & Wiedemann, B. (1997). Antimicrobial effects of continuous versus intermittent administration of carbapenem antibiotics in an in vitro dynamic model. Antimicrobial Agents and Chemotherapy 41, 1215–9.[Abstract]