Pharmacokinetics of antimicrobial agents : optimization and treatment individualization

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The central theme of this thesis was to study the pharmacokinetics of antimicrobial agents to optimize individual treatment of critically ill patients suffering from severe infectious diseases. The focus of the studies was on invasive fungal infections, tuberculosis and Buruli ulcer disease. Patients with tuberculosis and invasive fungal disease are at risk of severe morbidity and mortality, with import co-morbidities. While patients with invasive fungal disease are immuno-compromised, either due to underlying hemato-oncological conditions or the various treatments for these conditions, or have organ transplants for which they receive immunosuppressive agents, tuberculosis patients typically receive multiple drugs, especially if they have drug-resistant tuberculosis; and many suffer from morbid conditions including HIV/AIDS, or psychiatric co-morbidities including substance addiction with a myriad of potential drug interactions. Because these patient groups receive multiple drugs, they do not fit into a the definition of a general population of patients that can be assumed to be easily managed by standard fixed-dose treatment regimens, and we hypothesized therefore that these patient groups would benefit from individualised therapy to increase efficacy and limit toxicity. Buruli ulcer is a condition caused by a micro-organism sharing common phylogenetic ancestry with M. tuberculosis. We studied pharmacokinetics in patients receiving combination drug therapy, addressing questions derived from a randomized study in which these patients participated. We aimed to test whether we truly provided multiple drug therapy to prevent inadvertent monotherapy, and effective drug dosing, considering a complex array of possible drug-drug interactions resulting in potential inadvertent inappropriate drug dosing.
The main objectives are to gain insight in influence of disease severity, drug-drug interactions and ADME on pharmacokinetics of antimycobacterial and antifungal drugs and impact on PK/PD parameters.

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