Monitoramento terapêutico e modelagem farmacocinética de antimicrobianos em pacientes queimados da unidade de terapia intensiva / Therapeutic drug monitoring and pharmacokinetics of antimicrobial agents in burn patients from the Intensive care unit

A sepse após a injúria térmica é a maior causa de morbidade e mortalidade em pacientes queimados, uma vez que profundas alterações ocorrem na farmacocinética de agentes antimicrobianos. Investigaram-se trinta e um pacientes, portadores de sepse documentada e apresentando lesões ativas; utilizou-se o tratamento empírico conforme seguem os regimes de dose: 1 g, 12/12 h para a vancomicina, 1 g, 6/6 h para o imipenem e 2 g, 8/8 h para o cefepime. Sete coletas seriadas de sangue foram realizadas através de cateter venoso (2 mL/cada); o plasma foi obtido pela centrifugação e armazenado no congelador (-80o C) até o ensaio. A concentração plasmática dos antimicrobianos foi determinada simultaneamente pela aplicação do método bioanalítico desenvolvido no estudo. O método de cromatografia líquida de alta eficiência demonstrou boa linearidade, precisão e exatidão para a determinação simultânea da vancomicina, cefepime e imipenem plasmáticos; a plicação desse método bioanalítico permitiu o monitoramento plasmático terapêutico e o estudo farmacocinético. Com base nos resultados obtidos de concentração plasmática versus tempo, aplicou-se a modelagem para investigar a farmacocinética desses agentes antimicrobianos nos pacientes queimados. Os parâmetros cinéticos foram estimados com base no modelo aberto de um compartimento pela aplicação do programa PK Solutions v. 2.0; a estatística foi realizada pela utilização do programa GraphPad Prism v. 4.0. Com base na farmacocinética alterada, as concentrações obtidas para a vancomicina e imipenem se mostraram abaixo dos valores recomendados para atingir eficácia; por outro lado, as concentrações obtidas para o cefepime se mostraram dentro da faixa recomendada para atingir eficácia, uma vez que não se registrou alteração da farmacocinética deste antimicrobiano nos pacientes queimados. Desta forma, o monitoramento plasmático terapeutico se mostrou importante, permitindo o ajuste de dose para a vancomicina e para o imipenem, uma vez que...

Sepsis after thermal injury is the major cause of morbidity and mortality in burn patients, once deep changes on the pharmacokinetics of antimicrobials agents are expected. Thirty one burn patients were investigated, all of them had documented sepsis and presented active lesions; they were treated with empirical dose regimen as follows: 1 g, 12/12 h for vancomycin, 1 g, 6/6 h for imipenem and 2 g, 8/8 h for cefepime. A serial of seven blood samples were collected from the venous catheter (2 mL/each); plasma was obtained by centrifugation and storaged in an ultra-low freezer (-80o C) until assay. Drug plasma concentration was determined simultaneously by application of a bioanalytical method described previously. High performance liquid chromatographic method showed good linearity, precision and accuracy for vancomycin, cefepime and imipenem plasma measurements; its application permitted therapeutic drug monitoring and pharmacokinetic studies. Pharmacokinetic modeling was applied to data obtained based on drug plasma concentrations versus time, to investigate those antimicrobial agents in burn patients. Estimated kinetic parameters were based on the one compartment open model by application the software PK Solutions v. 2.0; statistics was performed by using the software GraphPad Prism v. 4.0. Based on altered pharmacokinetics, obtained plasma concentrations to reach drug efficacy were below the recommended values for vancomycin and imipenem; on the other hand, cefepime plasma concentrations to reach drug efficacy were in the recommended range, once its pharmacokinetics didnt change in burn patients. Then, therapeutic plasma monitoring was cost-effective permitting dose adjustment for vancomycin and imipenem, once the minimum effective concentration (MEC) wasnt reached for both antimicrobial agents by using the empirical dose regimen for burn patients. On the other hand, cefepime plasma monitoring was also cost-effective, since burn patients long term therapy can...

Farmacocinética y penetración en líquido tisular de cefepime administrado en conejos hipertérmicos / Pharmacokinetics and penetration into tissue fluid of cefepime administered to hyperthermic rabbits

La farmacocinética sérica y tisular de cefepime administrado por vía endovenosa (20 mg/kg de peso) fue determinada en conejos sanos, con hipertermia producida por lipopolisacáridos de E. coli e implantados en tejido subcutáneo con cajas para recolección de líquido tisular. Diez conejos adultos fueron utilizados en dos experiencias (E1 y E2). Las concentraciones de cefepime en suero (S) y líquido tisular (LT) fueron determinadas por método biológico. Para el análisis cinético se utilizó un modelo no compartimental. Los resultados farmacocinéticos (medias ± error estándar) fueron: tiempo medio de eliminación [t1/2 (E1 S)=1,5±0,2 y (E2 S)=2,0±0,2 h] (p<0,05), área bajo la curva [ABC (E1 S)=181,6±17,5 y (E2 S)=192,3±18,5 (µg/mL/h]; Volumen de distribución en estado estacionario [Vss (E1S)=0,31±0,05 y (E2 S)=0,69±0,28 L/kg] (p<0,05); aclaramiento sérico [CL(E1 S)=118,3±17,7 y (E2 S) =93,1±19,9 (mL/h)kg] (p<0,05); Concentración máxima [Cmax (E1 LT)= 23,5±3,4 y (E2 LT)= 27,6±3,6 (µg/mL]; tiempo en el que se logra la Cmax [t max (E1 LT)=2,3±0,4 y (E2 LT)=1,7±0,4 h)]; t1/2 (E1 LT)= 2,4±0,3 y (E2 LT)=3,4±0,3 h (p<0,05); ABC (E1 LT)=122,0±12,7 y (E2 LT)=156,9±13,6 (µg/mL/h). y penetración [P (E1 LT)=67,3±8,7 y (E2 LT)=88,5±8,7%].

The pharmacokinetic characteristics in serum and tissue of cefepime given intravenously (20 mg/kg body weight) were assessed in healthy rabbits and in rabbits with hyperthermia induced by lipopolysacharide of E. coli, with tissue fluid cages implanted subcutaneously. Ten adult rabbits were used in two trials (E1 and E2). Cefepime concentrations in serum (S) and tissue cage fluid (LT) were determined by biological methods. The kinetic analysis was performed by means of a noncompartmental model. Pharmacokinetic results (means ± standard error): half life of elimination [t1/2 (E1 S)=1.5±0.2 and (E2 S)=2.0±0.2 h] (p<0.05), area under the curve [ABC (E1 S)=181.6±17.5 and (E2 S)= 192.3±18.5 (µg/mL/h]; volume of distribution at steady-state [Vss (E1 S)=0.31±0.05 and (E2 S)=0.69±0.28 L/kg] (p<0.05); total serum clearance [CL (E1 S)=118.3±17.7 and (E2 S)=93.1±19.9 (mL/h)kg] (p<0.05); maximum concentration [Cmax (E1 LT)=23.5±3.4 and (E2 LT)=27.6±3.6 (µg/mL]; time to reach Cmax [t max (E1 LT) =2.3±0.4 and (E2 LT)=1.7±0.4 h)]; t1/2 (E1 LT)=2.4±0.3 and (E2 LT)=3.4±0.3 h (p<0.05); ABC (E1 LT)=122.0±12.7 and (E2 LT)=156.9±13.6 (µg/mL/h); penetration [P (E1 LT)=67.3±8.7 and (E2 LT)=88.5±8.7%]. In conclusion, the pharmacokinetic changes of cefepime observed in rabbits with hyperthermia induced by lipopolysacharide, could be clinically significant if not taken into account when designing the dosing regimens.