Clinical and animal model studies suggest that isoniazid contributes a significant level of early bactericidal activity (EBA) during the initial 2 days of treatment, but the bactericidal rates decline significantly beginning at day 3 in patients with uncomplicated, smear-positive pulmonary tuberculosis.
We conducted a 14-day randomized phase II early bactericidal activity (EBA0-14) trial to determine how isoniazid (INH) affects EBA in combination with rifampicin, pyrazinamide, and ethambutol (RZE). Four study arms included (1) isoniazid, rifampicin, pyrazinamide, and ethambutol (RHZE) for 14 days, (2) RHZE for 2 days and omitting INH for days 3-14, (3) RHZE for 2 days and replacing INH with moxifloxacin for days 3-14, and (4) RZE for 14 days. EBA0-14 was measured by: (1) rate of M. tuberculosis decline per day in sputum by colony forming unit (CFU) count [primary endpoint], and (2) increase in time to positivity in liquid culture [secondary endpoint].
Of the 69 randomized participants, 63 completed the study with 15-17 participants in each study arm. Most participants (83%) were male and HIV-negative (94%); median age was 31 and median BMI was 18.9. EBA0-14 was not different across all arms (figure 1). The mean baseline bacterial sputum load for all participants was 5.80 log10CFU (Standard Deviation [SD] 0.98) and the median daily decline in CFU count over 14 days was 0.12 log10CFU (Inter Quartile Range [IQR] 0.06 to 0.17). The mean baseline time to culture positivity in liquid medium was 109 hours (SD 29) and the median daily increase in time to positivity was 12 hours (IQR 9 to 16). EBA0-2 in the arms containing INH was not different compared to the arm without INH, and the median daily decline in CFU count over 2 days for all participants was 0.16 log10CFU (IQR -0.09 to 0.47). Exploratory sub-analysis revealed that participants with higher sputum baseline loads had higher initial EBA irrespective of treatment. Grade 3 or 4 adverse events were rare and not significantly different across arms.
The EBA over 14 days for all study arms was not different from each other. INH did not appear to significantly add to the 14-day EBA observed with RZE. Unlike earlier studies, significant EBA over 2 days due to INH was not observed. The absence of the expected bi-phasic INH response might be due to the relatively low baseline bacterial load in this study. Lower bacterial loads have been reported in recent EBA studies and it is likely due to early detection of TB.