Aminoglycoside Pharmacokinetics, Dosage Requirements, and Nephrotoxicity in Trauma Patients

Townsend, Paula L.; Fink, Mitchell P.; Stein, Keith L.; Murphy, Stephen

doi:10.1097/00003246-198704000-00183

Cited by 25 publications

(20 citation statements)

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“…This is in accordance with antibiotic pharmacokinetic studies of ICU patients, especially for ceftazidime (29). The increase in the total volume of distribution was reported to be correlated with body weight, the severity of illness, and the status of the trauma (16,38,39). The tissue edema induced by sepsis or by fluid resuscitation is also involved in the modification of the volume of distribution and could act as a reservoir from which ceftazidime slowly returns to the circulation (11,23,25).…”

Section: Discussionsupporting

confidence: 84%

Population Pharmacokinetics of Ceftazidime in Intensive Care Unit Patients: Influence of Glomerular Filtration Rate, Mechanical Ventilation, and Reason for Admission

Georges¹,

Conil²,

Seguin³

et al. 2009

Antimicrob Agents Chemother

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The aim of this study was to develop a population-pharmacokinetic model of ceftazidime in intensive care unit patients to include the influence of patients' characteristics on the pharmacokinetics. Forty-nine patients for model building and 23 patients for validation were included in a randomized study. They received ceftazidime at 2 g three times a day or as 6 g per day continuously. A NONMEM pharmacokinetic model was constructed, and the influences of covariates were studied. The model was validated by a comparison of the predicted and observed concentrations. A final model was elaborated from the whole population. Total clearance (CL) was significantly correlated with the glomerular filtration rate (GFR) calculated by modification of the diet in renal disease (MDRD), the central volume of distribution (V1) with intubation, and the peripheral volume of distribution (V2) with the reason for admission. The mean pharmacokinetic parameters were as follows: CL, 5.48 liters/h, 40%; V1, 10.48 liters, 34%; V2, 32.12 liters, 59%; total volume, 42.60 liters, 45%; and intercompartmental clearance, 16.19 liters/h, 42%. In the polytrauma population (mechanically ventilated), the time above the MIC at steady state never corresponds to 100% for discontinuous administration, and the target concentration of five times the MIC was reached with a 6-g/day dose only for patients with an MDRD of <150 ml/min. We showed that the GFR-MDRD, mechanical ventilation, and the reason for admission may influence the achieved concentrations of ceftazidime. Our model allows the a priori dosing to be adjusted to the individual patient.

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Section: Discussionsupporting

confidence: 84%

Population Pharmacokinetics of Ceftazidime in Intensive Care Unit Patients: Influence of Glomerular Filtration Rate, Mechanical Ventilation, and Reason for Admission

Georges¹,

Conil²,

Seguin³

et al. 2009

Antimicrob Agents Chemother

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“…V ss and Cl T of ceftazidime were higher in our patients compared with data from healthy volunteers. Previous studies have also described higher V ss and Cl T values for ceftazidime [4,32] and for other drugs [10,[33][34][35][36] in critically ill patients, probably due to an expanded extracellular compartment caused by increased quantities of intravenous fluid administration [32] .…”

Section: Discussionmentioning

confidence: 99%

In vitro AN69 and Polysulphone Membrane Permeability to Ceftazidime and in vivo Pharmacokinetics during Continuous Renal Replacement Therapies

et al. 2007

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Background: Ceftazidime is a third-generation cephalosporin almost entirely eliminated by glomerular filtration and dose reductions are essential in patients with renal impairment. The physicochemical and pharmacokinetic properties of ceftazidime make it susceptible to be eliminated by continuous renal replacement therapies (CRRT), but there is little clinical information to guide the correct administration in patients undergoing these techniques. Methods: In vitro procedures were carried out in three different fluids, using AN69 or polysulphone membranes. Four patients entered the in vivo study. Two patients received 1,000 mg every 6 h and the other two 2,000 mg every 6 h. Concentrations of ceftazidime were measured by high-performance liquid chromatography. Results: No differences were detected in thesieving coefficients (Sc) or saturation coefficients (Sa)between membranes during continuous venovenous hemofiltration (CVVH) or continuous venovenous hemodiafiltration (CVVHD). Sc-Sa values were close to 1 when Ringer’s lactate was used as ceftazidime vehicle, but were lower in plasma samples (p < 0.05). In patients, the Sc-Sa was 0.93 ± 0.06 and correlated well with the unbound fraction (0.86 ± 0.08). The contribution of CRRT to ceftazidime clearance was higher in anuric patients than in nonanuric patients. Conclusions: No differences were shown in vitro in the Sc obtained with both membranes during CVVH or the Sa obtained during CVVHD. The contribution of clearance by CRRT to total clearance is clearly dependent on the renal function. The administration of ceftazidime every 6 h could be associated with unnecessarily high trough levels which increase the risk of drug nephrotoxicity. Nonanuric patients undergoing CRRT need higher ceftazidime doses to reach adequate plasma concentrations against pathogens isolated in the critically ill.

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“…Previous studies have shown that both the therapeutic response and toxic effects depend on plasma amikacin concentrations. Achieving a therapeutic maximum concentration of amikacin in plasma is associated with a significant decrease in the rate of mortality due to infection in critically ill patients (2, 36, 37), and a relationship has also been found between the minimum plasma amikacin concentration and renal toxicity (20,49). Interindividual variability in the pharmacokinetics of amikacin may therefore make it difficult to achieve safe and effective treatment.…”

mentioning

confidence: 99%

Nonparametric Population Pharmacokinetic Analysis of Amikacin in Neonates, Infants, and Children

Tréluyer

Merlé

Tonnelier

et al. 2002

Antimicrob Agents Chemother

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The therapeutic and toxic effects of amikacin are known to depend on its concentration in plasma, but the pharmacokinetics of this drug in neonates, infants, and children and the influences of clinical and biological variables have been only partially assessed. Therapeutic drug monitoring data collected from 155 patients (49 neonates, 77 infants, and 29 children) receiving amikacin were analyzed by a nonparametric population-based approach, the nonparametric maximum-likelihood method. We assessed the effects of gestational and postnatal age, weight, Apgar score, and plasma creatinine and urea concentrations on pharmacokinetic parameters. There is no specific formulation of amikacin for neonates and infants. We therefore used an error model to account for errors due to dilution during preparation of the infusion. The covariates that reduced the variance of clearance from plasma and the volume of distribution by more than 10% were postnatal age (43 and 28%, respectively) and body weight (30.4 and 17.4%, respectively). The expected reduction of clearance was about 10% for the plasma creatinine concentration. The other covariates studied (Apgar scores, plasma urea concentration, gestational age, sex) were found to have little effect. Simulations showed that a smaller percentage of patients had a maximum concentration in plasma/MIC ratio greater than 8 with a regimen of 7.5 mg/kg of body weight twice daily than with a regimen of 15 mg/kg once a day for MICs of 1 to 8 mg/liter.Amikacin is widely used in neonates and infants, as well as in adults, for the treatment of severe infections caused by gramnegative bacteria. Previous studies have shown that both the therapeutic response and toxic effects depend on plasma amikacin concentrations. Achieving a therapeutic maximum concentration of amikacin in plasma is associated with a significant decrease in the rate of mortality due to infection in critically ill patients (2, 36, 37), and a relationship has also been found between the minimum plasma amikacin concentration and renal toxicity (20,49). Interindividual variability in the pharmacokinetics of amikacin may therefore make it difficult to achieve safe and effective treatment. The pharmacokinetics of aminoglycosides have been shown to be highly variable in neonates and children. Several factors account for the pharmacokinetic variabilities of other aminoglycosides in this population (50). The pharmacokinetics of netilmicin and gentamicin depend on gestational age, postnatal age, weight, renal clearance, and Apgar score (6,9,11,12,14,18,21,43,46,47,(51)(52)(53). Very few data are available concerning the effects of clinical and biological covariates on the pharmacokinetics of amikacin in neonates and the changes in the pharmacokinetic profile of amikacin that occur from birth into infancy. The lack of data on the pharmacokinetics of many drugs in neonates and children is related to blood sampling limitations for this population. One way around this problem is to collect a few samples from many individuals and analyze the...

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Aminoglycoside Pharmacokinetics, Dosage Requirements, and Nephrotoxicity in Trauma Patients

Cited by 25 publications

References 0 publications

Population Pharmacokinetics of Ceftazidime in Intensive Care Unit Patients: Influence of Glomerular Filtration Rate, Mechanical Ventilation, and Reason for Admission

Population Pharmacokinetics of Ceftazidime in Intensive Care Unit Patients: Influence of Glomerular Filtration Rate, Mechanical Ventilation, and Reason for Admission

In vitro AN69 and Polysulphone Membrane Permeability to Ceftazidime and in vivo Pharmacokinetics during Continuous Renal Replacement Therapies

Nonparametric Population Pharmacokinetic Analysis of Amikacin in Neonates, Infants, and Children

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