Gentamicin is known to have concentration-dependent bactericidal activity and its nephrotoxic effect is well described. We developed a population pharmacokinetic/pharmacodynamic model to optimize gentamicin dosing in pediatrics. Data were retrospectively collected for pediatric patients aged 1 month-12 years, admitted to general pediatric wards or ICUs and received gentamicin for suspected or proven gram-negative infections. at King Saud University Medical City, Riyadh, Saudi Arabia. A total of 306 gentamicin peak and trough concentrations sets from 107 patients were analyzed with mean (± SD) patient age and weight of 4.5 ± 3.5 years and 16.7 ± 10.8 kg, respectively. Gentamicin pharmacokinetics were adequately described with a one compartment system (R = 0.82, bias = 1.75% and precision = 88% for population predictions and R = 0.94, bias = 5 % and precision = 29 % for individual predictions). The gentamicin pharmacokinetic parameters were as follows: volume of distribution = 8.9 L, total body clearance = 2.8 L/hr for a 20 kg patient. Monte Carlo simulations showed that doses of 5-6 mg/kg/dose once daily are adequate only to treat infections with gram negative organisms having MIC less than 1 mcg/ml. While, at MIC of 1 mcg/ml, higher doses (7-8 mg/kg/dose once daily) are needed to maximize the efficacy of gentamicin. However, at MIC of 2 mcg/ml, even a 10 mg/kg dose showed poor target attainment (52 %). The finding of this study highlights the need to reevaluate the current breakpoints of gentamicin, and also to assess the safety of higher doses of gentamicin in pediatrics.
The simulation results indicated that amikacin 20 mg/kg once daily provided a higher probability of target attainment with lower toxicity than dosing three times daily. In addition, combination therapy is recommended for pathogens with an MIC of ≥ 8 mg/l.
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