Objective and methodsOur objective was to investigate the role of patient pharmacogenetic variability in determining site of action target attainment during tuberculous meningitis (TBM) treatment. ...Show moreObjective and methodsOur objective was to investigate the role of patient pharmacogenetic variability in determining site of action target attainment during tuberculous meningitis (TBM) treatment. Rifampin and isoniazid PBPK model that included SLCO1B1 and NAT2 effects on exposures respectively were obtained from literature, modified, and validated using available cerebrospinal-fluid (CSF) concentrations. Population simulations of isoniazid and rifampin concentrations in brain interstitial fluid and probability of target attainment according to genotypes and M. tuberculosis MIC levels, under standard and intensified dosing, were conducted.ResultsThe rifampin and isoniazid model predicted steady-state drug concentration within brain interstitial fluid matched with the observed CSF concentrations. At MIC level of 0.25 mg/L, 57% and 23% of the patients with wild type and heterozygous SLCO1B1 genotype respectively attained the target in CNS with rifampin standard dosing, improving to 98% and 91% respectively with 35 mg/kg dosing. At MIC level of 0.25 mg/L, 33% of fast acetylators attained the target in CNS with isoniazid standard dosing, improving to 90% with 7.5 mg/kg dosing.ConclusionIn this study, the combined effects of pharmacogenetic and M. tuberculosis MIC variability were potent determinants of target attainment in CNS. The potential for genotype-guided dosing during TBM treatment should be further explored in prospective clinical studies. Show less
The aim of this thesis was to stimulate rational and effective use of antimicrobials, by addressing the first two cornerstones: (1) refining stewardship of existing antimicrobials and (2) re... Show moreThe aim of this thesis was to stimulate rational and effective use of antimicrobials, by addressing the first two cornerstones: (1) refining stewardship of existing antimicrobials and (2) re-introducing old antibiotics within the framework of antimicrobial stewardship. The overall aim is to contribute to antimicrobial stewardship and to explore the value of the re-introduction of old antibiotics that are currently scarcely used. The basic step is the in vitro relationship expressed as minimal inhibitory concentration (MIC) for a given bacteria for a given antibiotic. The next step is the in vivo situation. This thesis concentrates on the in vivo situation. Show less
