Time Trends in Sputum Mycobacterial Load and Two-Day Bactericidal Activity of Isoniazid-Containing Antituberculosis...

Recent early bactericidal activity (EBA) studies of isoniazid-based antituberculosis therapies have shown a lower EBA over the first two treatment days than in earlier years. To quantify this trend and evaluate factors contributing to it, we extracted individual data from 18 studies with a total of 182 participants using isoniazid-containing therapies between 1992 and 2015 at a single site and laboratory in Cape Town, South Africa. We recalculated EBA as the daily fall in CFU per milliliter sputum up to day 2 of therapy (EBA_0-2) for individual patients and treatment groups and used mixed-effects linear models to investigate the correlation between pretreatment CFU, EBA_0-2, and year of study. We found that mean pretreatment CFU and year of study accounted for 46% and 47%, respectively, of the variation in mean EBA_0-2 Mean pretreatment CFU differed between the periods 1992 to 2001 and 2007 to 2015 by 0.92 log₁₀ CFU (95% confidence interval [CI], 0.57 to 1.28; P < 0.0001). On average, pretreatment CFU dropped by 0.053 log₁₀ CFU (95% CI, 0.029 to 0.076; P = 0.0004) and EBA_0-2 by 0.012 log₁₀ CFU (95% CI, 0.006 to 0.018; P = 0.001) per year. The EBA_0-2 of isoniazid-based antituberculosis therapy is strongly correlated with baseline mycobacterial load and shows a declining trend over the past 2 decades.