Therapeutic drug monitoring:How to improve moxifloxacin exposure in tuberculosis patients

Tuberculosis is the world’s deadliest infectious disease, and, in particular the spread of multidrug-resistance is challenging the ending of the tuberculosis pandemic. With a treatment success rate of 54% and reported untreatable forms of tuberculosis, there is a dire need to improve drug-resistant tuberculosis treatment. Moxifloxacin is an antibiotic drug and is used in case of drug-resistance or in case of intolerability against first-line anti-tuberculosis drugs. The standard dosage (used for other infections) of moxifloxacin is currently recommended for tuberculosis. In this thesis, we aimed to contribute to the knowledge of the optimal drug-exposure of moxifloxacin in tuberculosis treatment in order to improve treatment success. Our second aim was to develop analytical diagnostics to measure moxifloxacin exposure for dose optimization in individual patients. We observed, in case of the same dose, a nine-fold variability in moxifloxacin exposure. Patients concomitantly treated with rifampicin, patients infected with a less susceptible form of tuberculosis or male patients are at risk for a too low moxifloxacin exposure. The severity of tuberculosis disease could also be a determining factor. Based on these results and literature searches, we concluded that treatment success of traditional and potentially shorter treatment regimens could be improved if there is more knowledge of the optimal moxifloxacin exposure. We finally developed analytical methods and sampling strategies for dose optimization based on individual drug exposure in blood and cerebrospinal fluid. We developed a simple low-tech tool to measure moxifloxacin in oral fluid in areas devoid of advanced technology