Abstract
Gentamicin shows large variations in half-life and volume of distribution (Vd) within and between individuals. Thus, monitoring and accurately predicting serum levels are required to optimize effectiveness and minimize toxicity. Currently, two population pharmacokinetic models are applied for predicting gentamicin doses in adults. For endocarditis patients the optimal model is unknown. We aimed at: 1) creating an optimal model for endocarditis patients; and 2) assessing whether the endocarditis and existing models can accurately predict serum levels. We performed a retrospective observational two-cohort study: one cohort to parameterize the endocarditis model by iterative two-stage Bayesian analysis, and a second cohort to validate and compare all three models. The Akaike Information Criterion and the weighted sum of squares of the residuals divided by the degrees of freedom were used to select the endocarditis model. Median Prediction Error (MDPE) and Median Absolute Prediction Error (MDAPE) were used to test all models with the validation dataset. We built the endocarditis model based on data from the modeling cohort (65 patients) with a fixed 0.277 L/h/70kg metabolic clearance, 0.698 (±0.358) renal clearance as fraction of creatinine clearance, and Vd 0.312 (±0.076) L/kg corrected lean body mass. External validation with data from 14 validation cohort patients showed a similar predictive power of the endocarditis model (MDPE -1.77%, MDAPE 4.68%) as compared to the intensive-care (MDPE -1.33%, MDAPE 4.37%) and standard (MDPE -0.90%, MDAPE 4.82%) models. All models acceptably predicted pharmacokinetic parameters for gentamicin in endocarditis patients. However, these patients appear to have an increased Vd, similar to intensive care patients. Vd mainly determines the height of peak serum levels, which in turn correlate with bactericidal activity. In order to maintain simplicity, we advise to use the existing intensive-care model in clinical practice to avoid potential underdosing of gentamicin in endocarditis patients.
Highlights
Infective endocarditis is an infection of the endothelial lining of the heart, most commonly involving the valvular leaflets [1,2,3,4,5]
It shows that the large variability in PK parameters results in a large variability in gentamicin serum levels between patients
The large inter individual variability seen in serum levels with a fixed starting dose of 3 mg/kg gentamicin, and the spectacularly smaller variability seen with dosing based on two measured serum concentrations, clarifies the need for therapeutic drug monitoring (TDM)
Summary
Infective endocarditis is an infection of the endothelial lining of the heart, most commonly involving the valvular leaflets [1,2,3,4,5]. Guidelines recommend the use of gentamicin combined with beta-lactams as antimicrobial treatment, mainly for Gram-positive pathogens [9,10]. Beta-lactams are thought to increase access of gentamicin to the bacterial cell membrane of Gram-positive micro-organisms, causing a synergistic effect [11]. Gentamicin needs to be administered intravenously, displaying a short half-life of 2–3 hours [11,12,13]. This hydrophilic molecule has a volume of distribution (Vd) similar to the extracellular fluid, and a clearance proportional to the glomerular filtration rate (90% renal clearance) [12,14]. A small proportion of gentamicin is cleared non-renally (CLm; 10%)
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