RESUMEN
Colistin remains one of the few available options for the treatment of infections caused by resistant bacteria. Pharmacokinetic (PK) studies have been successful in estimating the appropriate colistin methanesulfonate (CMS) dose to achieve a target colistin concentration. Currently, there is a consensus that the dose of CMS should vary according to the patient renal function since CMS is mainly eliminated by renal route. For this same reason, the loading dose should vary according to the patient's renal capacity; however, this is not the current clinical practice. In this study we develop a framework to determine two key parameters for the loading dose regimen: (1) the optimal dose according to the characteristics (renal function and weight) of the patient; (2) the waiting time before the maintenance dose. Based on a previous PK model, our framework allows a fast parameter sweep so as to select optimal loading dose and waiting time minimizing the deviation between the plasma concentration and a target value. The results showed that patients presenting low creatinine clearance (CrCL) should receive a lower CMS loading dose with longer interval to start maintenance treatment to avoid nephrotoxic colistin concentrations. In cases of high CrCL, the dose should be higher and the interval to the next dose shorter to avoid subtherapeutic concentrations. Optimization of the loading dose should considerably improve colistin therapy, as the target concentration is reached more quickly, without reaching toxic values.
Asunto(s)
Antibacterianos , Colistina , Humanos , Colistina/farmacocinética , Colistina/uso terapéutico , Antibacterianos/farmacocinética , Enfermedad CríticaRESUMEN
Polymyxins have been available since the 1960s, however, because of their adverse effects, their use has been reserved for the treatment of infections caused by multiresistant bacteria. The increase in the clinical experience acquired in recent years and the published medical literature have raised doubts about the information provided by the product, indicating the need to update dosage recommendations, pharmacokinetics and pharmacokinetic/pharmacodynamic information (PK/PD). In addition, differences in concentration and dose between the different products of colistin may lead to errors of indication/administration and pose a risk to patients. In 2013, the European Medicines Agency (EMA) commissioned the Committee for Medicinal Products for Human Use (CHPM) to review available data and to make updated recommendations on the use of colistin. This procedure yielded a first report in 2014. This review highlights critical safety and efficacy aspects, reviews the recent pharmacokinetic and stability advances, the available pharmaceutical forms in Chile, providing the schemes currently recommended by health care agencies and experts in the field.
Asunto(s)
Antibacterianos/administración & dosificación , Colistina/administración & dosificación , Antibacterianos/farmacocinética , Chile , Colistina/farmacocinética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , HumanosRESUMEN
Resumen Las polimixinas están disponibles desde la década de los 60; sin embargo, debido a sus efectos adversos su uso ha sido reservado para el tratamiento de infecciones provocadas por bacterias multi-resistentes. El aumento en la experiencia clínica adquirida en los últimos años y la literatura médica publicada han planteado dudas respecto de la información entregada del producto, poniendo en manifiesto la necesidad de actualizar las recomendaciones posológicas, su farmacocinética y la información farmacocinética/farmacodinámica. Además, las diferencias en cuanto a concentración y dosis entre los distintos productos del colistín pueden dar lugar a errores de indicación/administración y suponer un riesgo para los pacientes. El año 2013, la Agencia Europea de Medicamento (EMA) encargó al Comité de Productos Medicinales para uso Humano (CHPM) la revisión de los datos disponibles y que formulara recomendaciones actualizadas del uso de colistín. Dicho procedimiento arrojó un primer informe en 2014. Esta revisión destaca los aspectos críticos de seguridad y eficacia, revisa los recientes avances farmacocinéticos y de estabilidad, las formas farmacéuticas disponibles en Chile, proporcionando los esquemas actualmente recomendados por agencias sanitarias y expertos en el tema para distintos escenarios clínicos.
Polymyxins have been available since the 1960s, however, because of their adverse effects, their use has been reserved for the treatment of infections caused by multiresistant bacteria. The increase in the clinical experience acquired in recent years and the published medical literature have raised doubts about the information provided by the product, indicating the need to update dosage recommendations, pharmacokinetics and pharmacokinetic/pharmacodynamic information (PK/PD). In addition, differences in concentration and dose between the different products of colistin may lead to errors of indication/administration and pose a risk to patients. In 2013, the European Medicines Agency (EMA) commissioned the Committee for Medicinal Products for Human Use (CHPM) to review available data and to make updated recommendations on the use of colistin. This procedure yielded a first report in 2014. This review highlights critical safety and efficacy aspects, reviews the recent pharmacokinetic and stability advances, the available pharmaceutical forms in Chile, providing the schemes currently recommended by health care agencies and experts in the field.
Asunto(s)
Humanos , Colistina/administración & dosificación , Antibacterianos/administración & dosificación , Chile , Colistina/farmacocinética , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Antibacterianos/farmacocinéticaRESUMEN
Nephrotoxicity is a common adverse effect of the clinically used polymyxins, colistin and polymyxin B. This adverse effect is dose limiting for both polymyxins, as the plasma polymyxin concentrations associated with renal damage overlap those required for antibacterial effect. Since development of acute kidney injury (AKI) during therapy is highly undesirable, it is extremely important to know whether there is any difference between the nephrotoxic potential of colistin (administered as its inefficient prodrug, colistimethate) and polymyxin B (administered as the active form). Both polymyxins are cytotoxic to renal tubular cells and are prone to cause nephrotoxicity in vivo because of the renal handling mechanisms that facilitate accumulation of these compounds in these cells, processes that are reviewed in this article. Also reviewed are the emerging data that strongly suggest significantly higher rates of AKI in patients treated with colistimethate compared to patients treated with polymyxin B. This finding may be due to differences in pharmacokinetics and renal handling mechanisms of colistimethate and formed colistin versus polymyxin B, and consequently the relative amount of polymyxin material delivered to tubular cells. A lower risk of AKI with polymyxin B is one of several potential advantages over colistimethate. The relative safety and efficacy of the two agents require closer examination in well-designed clinical studies.
Asunto(s)
Lesión Renal Aguda/inducido químicamente , Antibacterianos/efectos adversos , Colistina/análogos & derivados , Riñón/efectos de los fármacos , Polimixina B/efectos adversos , Profármacos/efectos adversos , Lesión Renal Aguda/mortalidad , Lesión Renal Aguda/patología , Lesión Renal Aguda/prevención & control , Animales , Antibacterianos/farmacocinética , Infecciones Bacterianas/tratamiento farmacológico , Infecciones Bacterianas/microbiología , Infecciones Bacterianas/patología , Transporte Biológico , Ensayos Clínicos como Asunto , Colistina/efectos adversos , Colistina/farmacocinética , Humanos , Riñón/patología , Ratones , Polimixina B/farmacocinética , Profármacos/farmacocinética , Ratas , Análisis de SupervivenciaRESUMEN
The purpose of this study was to investigate the pharmacokinetic properties of colistin following intrapulmonary administration of colistin sulfate in rats. Colistin was infused or delivered in nebulized form at a dose of 0.35 mg/kg of body weight in rats, and plasma drug concentrations were measured for 4 h after administration. Bronchoalveolar lavages (BAL) were also conducted at 0.5, 2, and 4 h after intravenous (i.v.) administration and administration via nebulized drug to estimate epithelial lining fluid (ELF) drug concentrations. Unbound colistin plasma concentrations at distribution equilibrium (2 h postdosing) were almost identical after i.v. infusion and nebulized drug inhalation. ELF drug concentrations were undetectable in BAL samples after i.v. administration, but they were about 1,800 times higher than unbound plasma drug levels at 2 h and 4 h after administration of the nebulized drug. Simultaneous pharmacokinetic modeling of plasma and ELF drug concentrations was performed with a model characterized by a fixed physiological volume of ELF (VELF), a passive diffusion clearance (QELF) between plasma and ELF, and a nonlinear influx transfer from ELF to the central compartment, which was assessed by reducing the nebulized dose of colistin by 10-fold (0.035 mg kg(-1)). The km was estimated to be 133 µg ml(-1), and the Vmax, in-to-Km ratio was equal to 2.5 × 10(-3) liter h(-1) kg(-1), which was 37 times higher than the QELF (6.7 × 10(-5) liter h(-1) kg(-1)). This study showed that with the higher ELF drug concentrations after administration via nebulized aerosol than after intravenous administration, for antibiotics with low permeability such as colistin, nebulization offers a real potential over intravenous administration for the treatment of pulmonary infections.
Asunto(s)
Antibacterianos/administración & dosificación , Antibacterianos/farmacología , Colistina/administración & dosificación , Colistina/farmacología , Administración por Inhalación , Administración Intravenosa , Aerosoles , Algoritmos , Animales , Antibacterianos/farmacocinética , Área Bajo la Curva , Biofarmacia , Líquido del Lavado Bronquioalveolar/química , Colistina/farmacocinética , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The initial use of polymyxins, polymyxin B and colistin (administered as a pro-drug colistin methanesulfonate sodium [CMS]), mostly relied on old pharmacokinetic (PK) studies that lacked appropriate methodology. In recent years, many PK studies in both animals and humans have provided more consistent evidence supporting better use of these invaluable antibiotics. However, translating preclinical data to clinical practice is not always an easy task and some may experience difficulties on how recent knowledge on polymyxins can be applied into the patients' care. Although many questions are still unresolved, there are consistent data able to improve clinical practice when prescribing initial and maintenance doses of both polymyxin B and CMS. Considering the importance of optimal use of polymyxins, this editorial discusses recent PK findings and how to take advantage of them at the bedside to improve the treatment of patient with extensively-drug-resistant Gram-negative bacterial infections.