Therapeutic drug monitoring in Tuberculosis treatment: the use of alternative matrices and sampling strategies

Tuberculosis (TB) is the deadliest infectious disease worldwide. In 2018, approximately 1.45 million people died due to TB and an estimated 10 million individuals fell ill with TB. TB is transmitted by inhalation of small airborne droplets, containing the tubercle bacillus, produced by coughing or sneezing by individuals with contagious pulmonary TB. The treatment of TB starts with a combination of rifampicin, isoniazid, pyrazinamide, and ethambutol for 2 months followed by 4 months of rifampicin and isoniazid. Nowadays, a major problem is the increase in antibiotic resistance. When the tubercle bacillus is resistant to both rifampicin and isoniazid, this is defined as multidrug-resistant TB (MDR-TB). Treatment of MDR-TB is less successful and these drugs cause more side effects than drug-susceptible TB treatment. Antibiotic resistance can be developed by insufficient drug exposure; this means the blood concentration of a drug is too low to be effective. Even using standardized dosing, drug exposure shows large inter-individual variation. Therapeutic drug monitoring (TDM) is a method to determine the optimal dose for an individual by measuring the drug concentrations in collected blood samples with dose adjustment if needed. In this thesis we investigated methods to reduce the burden of TDM for patients and medical personnel by using saliva samples instead of blood samples, by reducing the number of required blood samples, and by centralising TDM in specialised laboratories. Using these methods, we want to increase feasibility of TDM in TB endemic areas to improve treatment success rates and decrease emergence of drug resistance.