Serum Drug Concentrations Predictive of Pulmonary Tuberculosis Outcomes

Abstract

Low drug AUCs are predictive of clinical outcomes in tuberculosis patients.

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…191 This is because of the differential rapid elimination of some drugs in the regimen, leading to prolonged monotherapy with the drug that is not rapidly or extensively metabolised over tens to hundreds of rounds of bacterial replication. The in-silico study 181 predicted that 0·68% of patients would develop acquired drug resistance and MDR tuberculosis within 2 months despite 100% adherence, because of such differential pharmacokinetic variability of regimen components.…”

“…The in-silico study 181 predicted that 0·68% of patients would develop acquired drug resistance and MDR tuberculosis within 2 months despite 100% adherence, because of such differential pharmacokinetic variability of regimen components. A prospective clinical study 191 in the same population was performed, and identified suboptimal drug concentrations due to pharmacokinetic variability as the cause of failure of therapy in more than 90% of patients. Acquired drug resistance, including MDR tuberculosis, was encountered in 0·7% of patients during the first 2 months, despite adherence to standard doses of isoniazid, rifampicin, pyrazinamide, and ethambutol.…”

“…All cases of acquired drug resistance, including MDR tuberculosis, were preceded by suboptimal drug concentrations due to pharmacokinetic variability. 191 A meta-analysis of 13 randomised studies with 1631 rapid isoniazid acetylators and 1751 slow acetylators showed that rapid acetylators had 2·0 times higher occurrence of microbiological failure and acquired drug resistance compared with slow acetylators. 192 This increased microbial failure and acquired drug resistance was due to pharmacokinetic variability to only one of the three main drugs in the regimens.…”

“…Similarly, drug exposures predict the clearing of viable M tuberculosis from the sputum. 191,395 Capturing pharmacokinetic variability…”

“…[404][405][406][407][408][409][410][411][412][413][414][415][416] Predicting what concentration a patient will achieve is difficult, given the multiple determinants of pharmacokinetic variability. 191 Therefore, to identify the specific concentration-time profile, the drug concentrations should be measured in the patient directly.…”