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
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Abstract |
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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
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Introduction |
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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 (3237°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.
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Materials and methods |
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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 1848) and their mean weight was 59.69 ± 7.83 kg (range 4572). 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 manufacturers 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 concentrationtime curve over 8 h (AUC08), 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 concentrationtime profiles. From the individually fitted concentrationtime 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.
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Results and discussion |
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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 3040% of the dosing interval, whereas maximum killing is approached when levels are above the MIC for 6070% 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.
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Acknowledgements |
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Footnotes |
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References |
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