Adverse Outcomes in Pulmonary Tuberculosis patients on Retreatment Regimen: Evaluation of Pharmacokinetic Estimates as Risk Indicators

Abstract Patients with pulmonary tuberculosis (PTB) who fail therapy or develop a relapse are initiated on re-treatment regimen. These patients are known to have adverse outcomes. This study aimed to determine the role of plasma levels of Anti-tubercular drugs in treatment outcome. Plasma levels of retreatment regimen drugs [Isoniazid(INH), Rifampicin(RIF), Pyrazinamide(PZA), Ethambutol(EMB), and Streptomycin(STM)] were compared between treatment responsive/cured and treatment failure/not-cured patients. Plasma drug levels were analysed by LC-MS/MS at different time points in 134 PTB patients on retreatment regimen. Of the 134 subjects, 108 were cured, 17 patients developed multi-drug resistant TB (MDR-TB), and 9 patients remained smear positive at treatment completion (8 months). The two-hour plasma levels (C 2hr ) (geometric mean) were lower in ‘Not Cured’ subjects compared to ‘Cured’ subjects Notably, in the 26 ‘Not Cured’ subjects, C 2hr plasma levels after first dose at Day0 were significantly low (INH: 0.86 vs 2.94 µg/ml p≤0.002, RIF: 0.56 vs 2.55 µg/ml p≤0.003, PZA: 1.85 vs 26.58 µg/ml p≤0.000 and EMB: 0.72 vs 1.53 µg/ml p≤0.010). In contrast, STM levels were higher (31.84 vs 18.08 µg/ml p ≤0.007). Based on ROC analysis of the data, therapeutic indicator values for successful treatment outcome were C 2hr plasma levels of 10.6 µg/ml for PZA, 1.14 µg/ml for RIF, 1.86 µg/ml for INH and 1.24 µg/ml for EMB. Therapeutic failure in PTB patients on retreatment regimen is associated with lower plasma drug levels. Therapeutic drug monitoring would prove useful to maintain drug levels above the minimum cut-off levels for obtaining favourable clinical outcome.