The influence of sepsis on antimicrobials tissue penetration: The use of microdialysis technique to access free drug distribution

Abstract Sepsis is described as a life-threatening organ dysfunction caused by a host's response to infection, leading to an unbalance in body homeostasis. It is one of the leading causes of death in developed countries. Considering that in critically ill patients, such as those with sepsis, plasma concentrations do not necessarily reflect tissue concentrations, one way to assess tissue concentrations is through the microdialysis technique, which allows direct measurements of free drug at the site of action. This review was carried out after searching the Pubmed, Scielo and Web of Science databases, using the following descriptors: (microdialysis AND (sepsis OR septic shock OR severe sepsis OR septicemia)) OR (microdialysis AND (sepsis OR septic shock OR severe sepsis) OR septicemia) AND (antimicrobial OR antibiotic OR antifungal)). The physiological changes generated by sepsis may imply changes in pharmacokinetic parameters, such as in clearance, which may be reduced in these patients and in volume of distribution, which presents an expansion, mainly due to edema. Both events contribute to a high inter- individual variability in tissue penetration of antimicrobials which is generally observed in patients with sepsis.

Prediction of Pharmacokinetics and Penetration of Moxifloxacin in Human with Intra-Abdominal Infection Based on Extrapolated PBPK Model

The aim of this study is to develop a physiologically based pharmacokinetic (PBPK) model in intraabdominal infected rats, and extrapolate it to human to predict moxifloxacin pharmacokinetics profiles in various tissues in intra-abdominal infected human. 12 male rats with intra- abdominal infections, induced by Escherichia coli, received a single dose of 40 mg/kg body weight of moxifloxacin. Blood plasma was collected at 5, 10, 20, 30, 60, 120, 240, 480, 1440 min after drug injection. A PBPK model was developed in rats and extrapolated to human using GastroPlus software. The predictions were assessed by comparing predictions and observations. In the plasma concentration versus time profile of moxifloxcinin rats, Cmax was 11.151 microg/mL at 5 min after the intravenous injection and t1/2 was 2.936 h. Plasma concentration and kinetics in human were predicted and compared with observed datas. Moxifloxacin penetrated and accumulated with high concentrations in redmarrow, lung, skin, heart, liver, kidney, spleen, muscle tissues in human with intra-abdominal infection. The predicted tissue to plasma concentration ratios in abdominal viscera were between 1.1 and 2.2. When rat plasma concentrations were known, extrapolation of a PBPK model was a method to predict drug pharmacokinetics and penetration in human. Moxifloxacin has a good penetration into liver, kidney, spleen, as well as other tissues in intra-abdominal infected human. Close monitoring are necessary when using moxifloxacin due to its high concentration distribution. This pathological model extrapolation may provide reference to the PK/PD study of antibacterial agents.