Pharmacometrics to characterize innate immune response and antibacterial treatments
Sammanfattning: The immune system protects the host against pathogens by distinguishing self from non-self. However, it is most-often disregarded in pharmacokinetic-pharmacodynamic (PKPD) characterization of (new and old) antibiotics. Furthermore, the immune response may become dysregulated and result in life-threatening organ dysfunction, a clinical syndrome known as sepsis. In this work, assessment of immune-response time-courses and anti-bacterial treatments is made by use of non-linear mixed effects models. Analysis of in vitro and in vivo data characterized neutrophil-mediated phagocytosis of bacteria, and enabled prediction of neutrophil-bacteria dynamics in cancer patients. Further, in vitro bacterial release of lipopolysaccharide (LPS), a bacterial product that stimulates the innate mammalian immune response, was linked to natural bacterial growth and antibiotic-induced killing.In porcine studies, infused LPS and the resultant immune response, characterized by the two biomarkers tumor necrosis factor α and interleukin-6, was described with incorporation of tolerance dynamics. Further, developing organ dysfunction was characterized across cardiovascular, respiratory and blood-related variables, by utilizing physiologic relationships, providing significant insight into time-courses of sepsis.The translational potential of the preclinical models were assessed by scaling them to studies with LPS administration to healthy volunteers, identifying key differences in susceptibility to LPS and showing that humans respond stronger at much lower doses.The PK characteristics of piperacillin (a β-lactam antibiotic) was determined in four patient populations with the aim of optimizing treatment regimens. Whereas renal function determined antibiotic concentration-time course in critically ill patients, body weight was of higher importance in children. Aside from patients with augmented renal clearance or highly-insusceptible pathogens, probability to achieve fT>MIC-related PKPD targets increased with extended or continuous infusion regimens.The models developed in this thesis adds significantly to the quantitative understanding of time-courses in relation to host immune response, bacteria and antibacterial treatments.
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