Pharmacokinetics of bedaquiline and emergence of drug resistance in a Haitian MDR/RR-TB cohort
Bedaquiline is a core drug of the currently-recommended WHO regimen to treat multidrug- resistant/rifampin-resistant tuberculosis (MDR/RR-TB). A major challenge in treating MDR/RR-TB is ensuring that drugs appropriately penetrate pulmonary cavities, where metabolically inactive colonies of M. tuberculosis (Mtb) persist. Phase I and II drug trials use plasma drug concentrations as a surrogate of penetrance into cavities. This does not always accurately reflect drug concentrations in pulmonary secretions. It is unknown whether plasma levels of bedaquiline reflect levels of bedaquiline in pulmonary secretions. Subtherapeutic drug concentrations contribute to acquired drug resistance. This is particularly concerning for bedaquiline. Given its long half-life, bedaquiline remains detectable in plasma for almost two years following the last administered dose, long past when other companion drugs have been fully excreted. This effective monotherapy could significantly contribute to emerging drug resistance. In this proposed research, Dr. Walsh will determine the ratio of bedaquiline in sputum to plasma in adult participants receiving treatment for MDR/RR-TB (Aim 1). She will also determine this ratio for the other drugs in this regimen: levofloxacin, linezolid, clofazimine and pyrazinamide. In Aim 2, she will perform whole genome sequencing on serial Mtb culture isolates from this same cohort of MDR/RR-TB participants to identify any emerging genotypic resistance to bedaquiline. She will also determine any mutations associated with resistance to levofloxacin, linezolid, clofazimine and pyrazinamide. This project will provide critical insight into emerging bedaquiline resistance and how bedaquiline pharmacokinetics may contribute to this resistance. It may also significantly impact how phase I and II drug trials are designed.