Linezolid in multidrug-resistant tuberculosis

Tuberculosis is a major killer infectious disease caused by the bacterium Mycobacterium tuberculosis. A proportion of tuberculosis patients are infected with drug resistant M. tuberculosis strains. In multidrug-resistant tuberculosis (MDR-TB) the organism is resistant to the two most important anti-tuberculosis drugs rifampicin and isoniazid; some MDR-TB strains are resistant to even more drugs as well. To treat MDR-TB, the World Health Organisation recommends using at least four drugs that are probably effective, forcing physicians to prescribe drugs such as linezolid and clarithromycin as a last resort. Linezolid and clarithromycin are drugs with unclear efficacy and are therefore not recommended for routine use in treatment regimens for MDR-TB. However, more knowledge on the efficacy, toxicity, tolerability, i.e. the clinical pharmacology might unleash their untapped potential. The clinical pharmacology, with special attention for therapeutic drug monitoring, of linezolid is studied in this thesis to improve the treatment of MDR-TB.
In this thesis we performed a literature review on pharmacokinetic drug interactions of linezolid. Furthermore, we studied a potentially new drug interaction between two anti-MDR-TB drugs, linezolid and clarithromycin, and developed new methods to analyse linezolid in oral fluid and dried blood spots obtained from MDR-TB patients. We also retrospectively studied linezolid exposure in relation to safety and tolerability in MDR-TB patients in two hospitals in Italy and the Netherlands. Finally, we investigated synergy between linezolid and clarithromycin in MDR-TB isolates in a laboratory setting.