Farmacocinética y farmacodinamia de antimicrobianos: a propósito de pacientes con neutropenia y fiebre / Pharmacokinetics and pharmacodynamics of antibacterial agents: on account of febrile neutropenic patients

Febrile neutropenia is a serious complication of antineoplastic therapy and it is more commonly found in hematologic patients, associated with high mortality rates. Inadequate tissue concentration of antimicrobials has been described as a cause of therapeutic failure which also has been related to a low interstitial concentration for hydrophilic antibiotics. In critically ill patients it may occur an accumulation of compartmental fluids which can be related to an increase in the distribution volume or changes in clearance of antimicrobials. Pharmacokinetic and pharmacodynamic parameters of antimicrobials are reviewed, which can be used as a tool to optimize the efficacy of antimicrobial therapy in order to avoid failures and resistance selection.

La neutropenia febril es una complicación grave de la terapia antineoplásica que se presenta más frecuentemente en pacientes con neoplasias hematológicas, asociada a tasas elevadas de mortalidad. Uno de los factores descritos como causa de fracasos terapéuticos de la terapia antimicrobiana es la inadecuada concentración tisular de los antimicrobianos que a su vez se correlaciona con bajas concentraciones en el líquido intersticial en el caso de los fármacos hidrofílicos. En pacientes críticamente enfermos se puede presentar acumulación compartimental de líquidos que a su vez se puede asociar con aumento en el volumen de distribución de los medicamentos o alteraciones en la depuración de los mismos. Se revisan los parámetros farmacocinéticos y farmacodinámicos de los antimicrobianos que pueden ser usados como herramienta para optimizar la eficacia de la terapia antiinfecciosa en busca de disminuir la tasa de fracasos y la selección de cepas resistentes.

Increased levels of multiple forms of dihydrofolate reductase in peripheral blood leucocytes of cancer patients receiving haematopoietic colony-stimulating factors: interim analysis

The precise mechanism whereby granulocytes proliferate when haematopoietic colony stimulating factors (CSFs) are used in neutropenic cancer patients is poorly understood. The purpose of this study was to investigate whether these cytokines bring about leucocyte proliferation by increasing the levels of multiple forms of dihydrofolate reductase (DHFR). Blood samples were collected from 36 cancer patients (25 males and 11 females) with chemotherapy-induced neutropenia. One sample of blood from each patient was obtained before therapy either with CSF, such as granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) or with placebo, and another one at the time of resolution of neutropenia. Peripheral blood leucocytes in these blood samples were counted, separated and lysed. From lysates, cytoplasmic samples were prepared and analyzed for active DHFR by a methotrexate-binding assay and for total immunoreactive DHFR by an enzyme linked immunosorbent assay. The increase in total leucocyte count (TLC) was most prominent (P < 0.005) in the CSF group and less so (P < 0.05) in the placebo group. The mean +/- SD concentration values of active DHFR before and after stimulation with GM-CSF found were to be 0.34 +/- 0.4 ng/mg protein and 0.99 +/- 0.82 ng/mg protein, respectively, and in the group treated with G-CSF, 0.24 +/- 0.32 ng/mg protein and 1.18 +/- 2.4 ng/mg protein, respectively. This increase in active DHFR after stimulation with CSF was statistically significant (P <0.05). Similarly, concentration values of immunoreactive but nonfunctional form of DHFR (IRE) were 110 +/- 97 ng/mg protein and 605 +/- 475 ng/mg protein before and after stimulation with GM-CSF, and 115 +/- 165 ng/mg protein and 1,054 +/- 1,095 ng/ mg protein before and after stimulation with G-CSF. This increase in concentration of IRE after stimulation with GM-CSF or G-CSF was statistically significant (P < 0.005). In the control group, there was an increase in the concentration of both active DHFR and IRE after treatment with placebo. However, this was not statistically significant. Resolution of neutropenia was quicker in the groups treated with CSF compared to the control group. Results of this study indicate that colony stimulating factors (G-CSF and GM-CSF) induce white cell proliferation by increasing the levels of multiple forms of DHFR.