A multicentre comparison of a novel surrogate marker for determining the specific potency of anti-tuberculosis drugs

Abstract

A model for evaluating the potency of a new anti-tuberculosis drug or a drug combination, based on a decline in the number of viable tubercle bacilli in patient’s sputum during 5 days mono-therapy has been reported. One popular measure is based on the analysis of the decline in bacterial counts during the first 48 h of therapy and has been called early bactericidal activity (EBA). Such analyses could detect EBA for only a few drugs and were subject to variations in results obtained in different sites. To address these problems we applied a reiterative exponential decay model to evaluate the data on bacterial counts during 5 days of mono-therapy. The validity of this approach was tested using data from three previously published studies. For patients treated with isoniazid 300 mg daily, the values for the time taken to reduce the viable count by 50% (vt₅₀) measured in days were, from a Kenyan study 0.58 days s.e.m. 0.18, from a Tanzanian study 0.41 days s.e.m. 0.04, and from a United States study 0.55 days s.e.m. 0.12. These differences were not statistically significant (P = 0.77 Kruskal–Wallis non-parametric ANOVA). Mean values of vt₅₀ for all of the major anti-tuberculosis agents showed that there was an overlapping spectrum of activity from isoniazid 300 mg (vt₅₀ 0.58 days) to para-amino-salicylic acid (vt₅₀ 2.9 days) The variation between column means was greater than could be expected by chance (P = 0.0002 Kruskal–Wallis non-parametric ANOVA). From this, we conclude that the reiterative exponential decay model permits comparison between the data obtained in different centres and would allow the activity of a new drug to be compared with that of the currently available agents.