Early Bactericidal Activity of High-Dose Isoniazid for Drug Resistant TB

Daily doses of 10 to 15 mg/kg isoniazid demonstrated similar activity against tuberculosis (TB) strains with inhA mutations as 5 mg/kg doses against drug-sensitive strains, according to data published in the American Journal of Respiratory and Critical Care Medicine.

High-dose isoniazid is recommended in short-course regimes for multidrug-resistant TB (MDR-TB). However, the optimal dose and its contributions to efficacy against TB strains with inhA mutations are not clear.

To define the optimal dose for patients with isoniazid-resistant TB mediated by inhA mutations, 59 patients from the AIDS Clinical Trials Group A5312 were enrolled from one site in South Africa. The AIDS Clinical Trials Group A5312 is a phase 2A, open-label trial in which individuals with smear-positive pulmonary TB with isoniazid resistance mediated by an inhA mutation were randomly assigned to receive isoniazid 5, 10 ,or 15 mg/kg daily for 7 days (inhA group). The control group with drug-sensitive TB received a standard dose of 5 mg/kg/day.

The 7-day early bactericidal activity of isoniazid was estimated as the average daily change in log10 colony-forming units (CFU) on solid media (EBACFU0-7) or as time to positivity in liquid media in hours (EBATTP0-7), using nonlinear mixed effects models. At doses of 5, 10, and 15 mg/kg in the inhA group, mean EBACFU0-7 was 0.07, 0.17, and 0.22 log10 CFU/mL/day, respectively. For control participants, it was 0.16 log10 CFU/mL/day. The patterns of EBATTP0-7 were similar and no drug-related grade >3 adverse events occurred.

The study had several reported limitations, the first being that minimal inhibitor concentration data were not available for all participants because of difficulties in regrowing strains after long storage periods. The current results also did not allow for individualization of dose selection for treatment with high-dose isoniazid. Further, it is possible that higher bacillary loads in terms of CFU in participants with isoniazid-resistant TB than in isoniazid-sensitive TB amplified the effect of isoniazid in the drug-resistant groups.

The investigators concluded that, “isoniazid at doses of 10-15 mg/kg daily had measurable early bactericidal activity against MDR-TB with inhA-mutation-mediated isoniazid resistance.” Also, the early bactericidal activity was similar to standard doses against drug-susceptible TB. They stated, however, that longer-term studies are needed to determine the safety and tolerability of higher isoniazid doses.

Reference

Dooley KE, Miyahara S, von Groote-Bidlingmaier F, et al. Early bactericidal activity of different isoniazid doses for drug Resistant TB (INHindsight): A randomized open-label clinical trial [published online January 16 2020]. Am J Respir Crit Care Med. doi:10.1164/rccm.201910-1960OC