Abstract
Background: The mortality rate of patients with a drug-resistant bacterial infection is high, as are the associated treatment costs. To overcome these issues, optimization of the available therapeutic options is required. Beta-lactams are time-dependent antibiotics and their efficacy is determined by the amount of time the free concentration remains above the minimum inhibitory concentration. Therefore, the aim of this study was to assess the extent and variability of protein binding for meropenem, cefepime, and piperacillin. Methods: Plasma samples for the analysis of meropenem, cefepime, and piperacillin were collected from patients admitted to a tertiary care hospital as part of the standard care. The bound and unbound drug fractions in the samples were separated by ultrafiltration. Validated liquid chromatography-tandem mass spectrometry assays were used to quantify the total and free plasma concentrations, and the protein binding was determined. Results: Samples from 95 patients were analyzed. The median (range) age of patients was 56 years (17-87) and the median (range) body mass index was 25.7 kg/m(2) (14.7-74.2). Approximately 59% of the patients were men. The median (range) unbound fraction (f(u)) was 62.5% (41.6-99.1) for meropenem, 61.4% (51.6-99.2) for cefepime, and 48.3% (39.4-71.3) for piperacillin. In the bivariate analysis, as the total meropenem concentration increased, the f(u) increased (r = 0.37, P = 0.045). A decrease in piperacillin f(u) was observed as the albumin concentration increased (r = -0.56, P = 0.005). Conclusions: The average f(u) values were lower than those reported in the literature. There was also a large variability in f(u); hence, it should be considered when managing patients administered with these drugs through direct measurements of free drug concentrations.