Aminoglycoside Pharmacokinetics: Volume of Distribution in Specific Adult           Patient Subgroups

Dager, William E.

doi:10.1177/106002809402800719

Cited by 43 publications

(21 citation statements)

References 25 publications

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“…16,30 Patients with infection in the ICU and especially those who are septic are receiving larger quantities early and large amounts of IV fluids. 15 ICU patients have also been shown to have a larger V, similar to the findings of this study, which in turn can lead to lower C max .…”

Section: Discussionmentioning

confidence: 99%

Suboptimal Aminoglycoside Dosing in Critically Ill Patients

Rea¹,

Capitano²,

Bies³

et al. 2008

Therapeutic Drug Monitoring

127

104

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Maximal aminoglycoside (AG) killing requires that the ratio of peak serum concentrations (Cmax) to the minimum inhibitory concentration (MIC) of the pathogen exceeds by > or =10. This has been shown to hasten resolution of infection in the general patient population. It was postulated that critically ill patients, likely to have larger intravascular volumes, are underdosed. The primary aim was to determine Cmax to MIC target attainment rate in medical intensive care unit (MICU) patients. A retrospective review of MICU patients who received at least 1 intravenous dose and serum concentration of either gentamicin or tobramycin was performed. A population pharmacokinetic model was developed, and MIC distributions for AG were used in determining the Cmax/MIC and in calculating the probability of attaining the pharmacodynamic (PD) target. One hundred two unique patients with 211 AG concentrations were analyzed to determine population pharmacokinetic parameters. Mean maximum clearance (CL) was 3.14L/h (95% confidence interval: 1.26-4.54 L/h), and mean volume of distribution (V) was 53 L (95% confidence interval: 38-66.8 L/h). Glomerular filtration rate and standardized body weight were identified as significant covariates for clearance in the final model. Standardized body weight also significantly affected V. There was only a 20% and 40% probability that patients receiving 7 mg/kg of gentamicin and tobramycin, respectively, will achieve PD target over the range of MIC distributions. Based on these data, the majority of critically ill patients would not be predicted to achieve the PD target under current dosing regimens. This may be a result of intensive care unit patients having a larger volume of distribution than reported in the literature. Future recommendations for treating gram-negative infections in the MICU population include using initial doses of 7 mg/kg of either gentamicin or tobramycin, measuring Cmax after the first dose, and determining MIC for the pathogen(s) with adjustment of subsequent doses to achieve the PD target.

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Section: Discussionmentioning

confidence: 99%

Suboptimal Aminoglycoside Dosing in Critically Ill Patients

Rea¹,

Capitano²,

Bies³

et al. 2008

Therapeutic Drug Monitoring

127

104

View full text Add to dashboard Cite

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“…this population (39,42). Similarly, model 5 (31) was developed using data from neonates, which may exhibit pharmacokinetics different from those exhibited by older pediatric patients (31,41).…”

Section: Figmentioning

confidence: 99%

Assessing Predictive Performance of Published Population Pharmacokinetic Models of Intravenous Tobramycin in Pediatric Patients

Bloomfield

Staatz

Unwin

et al. 2016

Antimicrob Agents Chemother

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bSeveral population pharmacokinetic models describe the dose-exposure relationship of tobramycin in pediatric patients. Before the implementation of these models in clinical practice for dosage adjustment, their predictive performance should be externally evaluated. This study tested the predictive performance of all published population pharmacokinetic models of tobramycin developed for pediatric patients with an independent patient cohort. A literature search was conducted to identify suitable models for testing. Demographic and pharmacokinetic data were collected retrospectively from the medical records of pediatric patients who had received intravenous tobramycin. Tobramycin exposure was predicted from each model. Predictive performance was assessed by visual comparison of predictions to observations, by calculation of bias and imprecision, and through the use of simulation-based diagnostics. Eight population pharmacokinetic models were identified. A total of 269 concentration-time points from 41 pediatric patients with cystic fibrosis were collected for external evaluation. Three models consistently performed best in all evaluations and had mean errors ranging from ؊0.4 to 1.8 mg/liter, relative mean errors ranging from 4.9 to 29.4%, and root mean square errors ranging from 47.8 to 66.9%. Simulation-based diagnostics supported these findings. Models that allowed a two-compartment disposition generally had better predictive performance than those that used a one-compartment disposition model. Several published models of the pharmacokinetics of tobramycin showed reasonable low levels of bias, although all models seemed to have some problems with imprecision. This suggests that knowledge of typical pharmacokinetic behavior and patient covariate values alone without feedback concentration measurements from individual patients is not sufficient to make precise predictions.

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“…In addition, because wide interpatient variations in pharmacokinetics are found in different adult subgroups, we investigated whether the pharmacokinetics of gentamicin in our group of patients could be described by one pharmacokinetic population model irrespective of the underlying disease and age (5).…”

mentioning

confidence: 99%

Once-Daily Versus Multiple-Daily Gentamicin in Infants and Children

Uijtendaal

Rademaker²,

Schobben³

et al. 2001

Therapeutic Drug Monitoring

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In this prospective randomized trial, the efficacy and safety of once-daily administration of gentamicin were compared with multiple-daily administration in infants and children. In addition, pharmacokinetic variables were calculated. Gentamicin therapy was started at a dose of 5 mg/kg per day under individual dose or dosage interval adjustments to achieve target levels. Fifty-two infants and children aged 1 month (postterm) to 16 years were enrolled. The duration of fever from the start of therapy, the percentage decline of C-reactive protein (CRP) on day 3 of treatment, and the clinical outcome were used as efficacy parameters. Nephrotoxicity was evaluated using creatinine serum levels. Basic characteristics in both groups were comparable. A good clinical response was observed in both groups. Fever may have resolved faster with multiple-daily administration, but this was not statistically significant. The percentage of decline of CRP was also comparable in both groups. Nephrotoxicity occurred in six patients, three per group. Many patients were too ill or too young to perform hearing tests, but no clinical signs of ototoxicity were observed. Mean doses of 6.8 mg/kg per day (multiple-daily administration) and 7.3 mg/kg per day (once-daily administration) were necessary to meet the target gentamicin levels. Triple-daily doses had to be reduced to a twice-daily regimen in 17 of 26 children. Dose and dosage interval adaptations can be performed by Bayesian forecasting using a one-compartment model with one set of K(e) and V(d) parameters. The authors consider both regimens equally effective, with a comparable incidence of nephrotoxicity. A starting dose of 6.5 mg/kg once daily is advised.

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Aminoglycoside Pharmacokinetics: Volume of Distribution in Specific Adult Patient Subgroups

Abstract: The expected aminoglycoside volume of distribution can vary, depending on a patient's clinical presentation. Data presented will allow a more refined initial estimation of volumes of distribution, which may facilitate the achievement of desired aminoglycoside serum concentrations.

Cited by 43 publications

References 25 publications

Suboptimal Aminoglycoside Dosing in Critically Ill Patients

Suboptimal Aminoglycoside Dosing in Critically Ill Patients

Assessing Predictive Performance of Published Population Pharmacokinetic Models of Intravenous Tobramycin in Pediatric Patients

Once-Daily Versus Multiple-Daily Gentamicin in Infants and Children

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