a Laboratory of Pharmacokinetics, Hôpital de la Timone and Université de la Méditerranée, and b Department of Anesthesiology and Regional Burn Center, Hôpital de la Conception, Marseille, France
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Abstract |
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Introduction |
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The purpose of this study was therefore to characterize the pharmacokinetics of cefepime in burns patients after administration of 2 g bd iv doses.
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Materials and methods |
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Six burns patients (five males and one female) were studied. Their mean age was 39.8 ± 11.3 years (range 3062), height 169.5 ± 8.2 cm (range 155178), weight 72.1 ± 11 kg (range 5482), creatinine clearance 123 ± 26 mL/min (range 88152), abbreviated burn severity index (ABSI)5 score 8.5 ± 1.97 (range 610) and the body surface area deep burn was 31.5 ± 23.6 (range 860). Patients participated in the study after informed consent. This protocol was approved by the Committee for the Protection of the Rights of Human Subjects according to French law. Patient inclusion criteria included: absence of drug allergies or intolerance to ß-lactams, absence of pregnancy, a minimum of 18 years of age, burns at least 48 h old with ABSI score 610 and bacterial infection susceptible, or likely to be susceptible, to cefepime. All the patients were haemodynamically stable.
Drug administration and sample collection
Cefepime (2 g bd) was given as a constant rate iv infusion over 30 min. Eight heparinized blood samples were drawn from each subject after infusion at day 1 and day 3. Blood sampling times relative to the start of infusion were as follows: start of the infusion, 30 min and 1, 2, 4, 6, 8 and 12 h after the beginning of infusion. Four urine samples were collected: (02 h), (24 h), (48 h) and (812 h) after the beginning of the first infusion. Urine output was recorded for each period. At day 3, a burned skin biopsy was obtained 35 h after the start of infusion and stored at 80°C. For a given sampling time, the ratio between skin and plasma concentrations was determined.
Cefepime analysis
Cefepime was a gift from Bristol-Myers Squibb (Paris, La Defense, France), Plasma and urine samples were analysed for intact cefepime according to a validated HPLCUV method.6 Skin samples were pulverized following freezing with liquid nitrogen and incubated for 2 h in NaCl 0.9% at 4°C to allow diffusion. After centrifugation, the supernatant was recovered and processed as for plasma samples. The inter-day precision was 7.712.5% for cefepime concentrations ranging from 2 to 40 mg/L.
Pharmacokinetic analysis
The Siphar computer program was used to obtain pharmacokinetic parameter estimates.7 Weighted least squares regression was used to fit the data. Determination of the optimal compartment model was based on visual inspection of the concentrationtime curves. Two compartment models were used to fit the observed concentrationtime data for all patients. Vss, t1/2ß and the area under the serum concentrationtime curve (AUC) were estimated. Cefepime total clearance (ClT), renal clearance (ClR), non renal clearance (ClNR) and the percentage of cefepime excreted in urine were calculated using standard formulae.8
Statistical analysis
A paired Student's t test was used to compare the pharmacokinetic parameter estimates obtained after the initial cefepime dose and after multiple dosing. A P value of <0.05 was considered significant.
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Results |
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Discussion |
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In our study, the peak at day 1 (122 ± 23 mg/L) was consistent with that observed by Van der Auwera et al.9 in healthy volunteers (126 ± 21.7 mg/L). There was no statistical difference between day 1 and day 3. For AUC, t1/2ß, ClT and Vss, the individual data of the burns patients did not show wide inter-individual variability, although Kovaric et al.10 did observe a wide variability of this parameter in patients with respiratory tract infections.
The mean t1/2ß of 2.5 h was similar to the value of approximately 2.2 h reported in healthy volunteers. Generally, there is a tendency for a decrease in t1/2ß in burns patients (e.g. for aminoglycosides). Vss and ClT of cefepime as determined in our study were similar to those in normal subjects (19.3 ± 3.4 L and 138 ± 22 mL/min, respectively) with only a slight increase in the Vss. As in healthy volunteers, approximately 76% of the administered dose was recovered as unchanged cefepime in urine.
To our knowledge, there have been no studies on cefepime penetration of the skin. We demonstrated that cefepime has good penetration in burned skin and this phenomenon may be important in successful treatment of burn-associated infections. However, the interpretation of the skin/plasma ratio and skin concentration is difficult because of vascularization of the sample site, which exhibits wide variability between individuals.
The pharmacokinetic parameter estimates for cefepime (2 g bd) in six burns patients were similar to estimates in normal volunteers. These results demonstrate that it is not necessary to change the standard dosage of cefepime in burns patients.
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Acknowledgments |
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Notes |
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References |
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2
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7 . Gomeni, C. & Gomeni, R. (1987). Siphar: an integrated computer system for statistical and pharmacokinetic data analysis. In Proceedings of the Seventh International Congress of Medical Informatics Europe 87, Rome. Serio A, (O'Moore, R., Tardini, A. & Roger, F. H., Eds), pp. 50716. European Federation for Medical Informatics, Rome.
8 . Wagner, J. G. (1975). Fundamentals of Clinical Pharmacokinetics. Drug Intelligence Inc., Hamilton, IL.
9 . Van der Auwera, P. & Santella, P. J. (1993). Pharmacokinetics of cefepime: a review. Journal of Antimicrobial Chemotherapy 32, Suppl. B, 10315.[ISI][Medline]
10 . Kovarik, J. M., ter Maaten, J. C., Rademaker, C. M., Deenstra, M., Hoepelman, I. M., Hart, H. C. et al. (1990). Pharmacokinetics of cefepime in patients with respiratory tract infections. Antimicrobial Agents and Chemotherapy 38, 18858.
Received 25 November 1999; returned 13 February 2000; revised 23 March 2000; accepted 31 March 2000