title: Time Trends in Sputum Mycobacterial Load and Two-Day Bactericidal Activity of Isoniazid-Containing Antituberculosis Therapies.
abstract: 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 (EBA0-2) for individual patients and treatment groups and used mixed-effects linear models to investigate the correlation between pretreatment CFU, EBA0-2, 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 EBA0-2Mean pretreatment CFU differed between the periods 1992 to 2001 and 2007 to 2015 by 0.92 log10CFU (95% confidence interval [CI], 0.57 to 1.28;P< 0.0001). On average, pretreatment CFU dropped by 0.053 log10CFU (95% CI, 0.029 to 0.076;P= 0.0004) and EBA0-2by 0.012 log10CFU (95% CI, 0.006 to 0.018;P= 0.001) per year. The EBA0-2of isoniazid-based antituberculosis therapy is strongly correlated with baseline mycobacterial load and shows a declining trend over the past 2 decades.
authors.affiliation: Task Applied Science, Tuberculosis Clinical Research Centre, Bellville, Cape Town, South Africa.
authors.forename: Veronique
authors.initials: V
authors.lastname: De Jager
authors.affiliation: Task Applied Science, Tuberculosis Clinical Research Centre, Bellville, Cape Town, South Africa.
authors.forename: Lize
authors.initials: L
authors.lastname: van der Merwe
authors.affiliation: Task Applied Science, Tuberculosis Clinical Research Centre, Bellville, Cape Town, South Africa.
authors.forename: Amour
authors.initials: A
authors.lastname: Venter
authors.affiliation: Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Donald
authors.affiliation: Task Applied Science, Tuberculosis Clinical Research Centre, Bellville, Cape Town, South Africa ahd@sun.ac.za.|Division of Medical Physiology, MRC Centre for Tuberculosis Research, DST/NRF Centre of Excellence for Biomedical Tuberculosis Research, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, South Africa.
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Diacon
mesh_terms: D000995:Antitubercular Agents / Q000627:therapeutic use*; D015169:Colony Count, Microbial / Q000639:trends; D004334:Drug Administration Schedule; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use*; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development; D013019:South Africa; D013183:Sputum / Q000382:microbiology; D013997:Time Factors; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D007538:Isoniazid
keywords: early bactericidal activity; isoniazid; tuberculosis