This study describes the population pharmacokinetics of fosfomycin in critically ill patients. In this observational study, serial blood samples were taken over several dosing intervals of intravenous fosfomycin treatment. Blood samples were analyzed using a validated liquid chromatography-tandem mass spectrometry technique. A population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. Five hundred fifteen blood samples were collected over one to six dosing intervals from 12 patients. The mean (standard deviation) age was 62 (17) years, 67% of patients were male, and creatinine clearance (CL _CR ) ranged from 30 to 300 ml/min. A two-compartment model with between-subject variability on clearance and volume of distribution of the central compartment ( V _c ) described the data adequately. Calculated CL _CR was supported as a covariate on fosfomycin clearance. The mean parameter estimates for clearance on the first day were 2.06 liters/h, V _c of 27.2 liters, intercompartmental clearance of 19.8 liters/h, and volume of the peripheral compartment of 22.3 liters. We found significant pharmacokinetic variability for fosfomycin in this heterogeneous patient sample, which may be explained somewhat by the observed variations in renal function.

Background: Fosfomycin is an antibiotic of considerable interest for the treatment of infection by multidrug-resistant bacteria. Translating microsampling techniques into clinical PK studies may provide effective dosing information to improve patient outcomes and minimize the potential development of resistance. Results: Accuracy and precision results were within ±15%; the method was validated across the range of 5–2000 µg/ml of fosfomycin using volumetric absorptive microsampling (VAMS) devices. Conclusion: The VAMS techniques provide acceptable validation data as assessed for lower limit of quantification, linearity, intra- and interday precision and accuracy, selectivity and matrix effects. Results from the recovery and stability studies suggest challenges remain for the analysis of fosfomycin in whole blood using VAMS.

Recent studies suggest that contemporary antibiotic dosing is unlikely to achieve best outcomes for critically ill patients because of extensive pharmacokinetic variability and altered pharmacodynamics. Dose adaptation is considered quite challenging because of unpredictable dose–exposure relationships. Consequently, individualization of antibiotic dosing has been advocated. Herein, we describe recent developments in the optimization of antibiotic dosing in the critically ill. Conventional doses of many antibiotics frequently result in sub or supratherapeutic exposures in the critically ill. Clinical studies continue to illustrate that dose–exposure relationships are highly variable in severely ill patients. Dose optimization based on pharmacokinetic/pharmacodynamic principles can effectively improve antibiotic exposure. Therapeutic drug monitoring (TDM) with adaptive feedback is likely to be the most robust approach to optimize dosing for individual patients. This more accurate approach to dosing is made possible with the user-friendly dosing software that is emerging. The scope of TDM is broadening from the traditional focus on prevention of toxicity, to include optimization of antibiotic exposure thereby improving patient outcomes. However, the evidence relating TDM practice with improved clinical outcome remains limited. Well designed, multicentre, randomized controlled studies are warranted.

Conventional sampling techniques for clinical pharmacokinetic studies often require the removal of large blood volumes from patients. This can result in a physiological or emotional burden, particularly for neonates or pediatric patients. Antibiotic pharmacokinetic studies are typically performed on healthy adults or general ward patients. These may not account for alterations to a patient's pathophysiology and can lead to suboptimal treatment. Microsampling offers an important opportunity for clinical pharmacokinetic studies in vulnerable patient populations, where smaller sample volumes can be collected. This systematic review provides a description of currently available microsampling techniques and an overview of studies reporting the quantitation and validation of antibiotics using microsampling. A comparison of microsampling to conventional sampling in clinical studies is included.