A Reiterative Method for Calculating the Early Bactericidal Activity of Antituberculosis Drugs

Abstract

Studies of early bactericidal activity (EBA) are important in the rapid evaluation of new antituberculosis drugs. Historically, these have concentrated on the log fall in the viable count in sputum during the first 48 hours of therapy. In this paper, we provide a mathematical model that suggests that the viable count in sputum follows an exponential decay curve with the equation V = S + Me(-kt) (where V is the viable count, M the population of bacteria susceptible to the test drug, S the population susceptible only to sterilizing agents, t the day of sputum collection as related to start of therapy, k the rate constant for the bacteria killed each day, and e the Napierian constant). We demonstrate that data from clinical trials fits the exponential decay model. We propose that future EBA studies should be performed by measuring daily quantitative counts for at least 5 days. We also propose that the comparison of the early bactericidal activity of antituberculosis drugs should be evaluated using the time taken to reduce the viable count by 50% (vt(50)). A further reiterative refinement following a rule set based on statistically the best fit to the exponential decay model is described that will allow investigators to identify anomalous results and thus enhance the accuracy in measuring early bactericidal activity.

The Molecular Bacterial Load Assay Replaces Solid Culture for Measuring Early Bactericidal Response to Antituberculosis Treatment

“…Extended early bactericidal activities (EBAs) from days 3 to 14 were also comparable, with Ϫ0.082 log 10 (Ϫ0.119, Ϫ0.045) and Ϫ0.124 log 10 (Ϫ0.170, Ϫ0.079) for CFU on solid medium and MBL, respectively. These data match other EBA studies measuring treatment response with solid culture (11)(12)(13)(14)(15)(16). The close comparability between MBL and culture contrasts with data for treatment monitoring using the GeneXpert MTB/RIF assay (Xpert; Cepheid, CA, USA).…”

Molecular Bacterial Load Assay, a Culture-Free Biomarker for Rapid and Accurate Quantification of Sputum Mycobacterium tuberculosis Bacillary Load during Treatment

“…Monoexponential and biexponential nonlinear models have been proposed to describe the decline in bacterial load over the first 2 months of treatment, with the biexponential model, reflecting two separate phases of decline, having been shown to best fit the data (4,8,25 the decline of the MBL assay-determined bacterial load in this study with the decline of bacterial load reported in other published studies, we used the same methods described in references 4 and 25 to fit and compare different nonlinear models. Nonlinear mixed-effects models were therefore used to analyze the decline in counts in the 111 patients.…”

“…At present, the only widely accepted biomarker of treatment response is culture negativity 56 days after the commencement of therapy (18). Some authors have suggested that measuring the decline in the bacterial load may permit the outcome of treatment to be predicted more accurately (4,8).…”

Early Bactericidal Activity of Moxifloxacin in Treatment of Pulmonary Tuberculosis: a Prospective, Randomized Study

“…The EBA was calculated for each patient by the formula (log CFU/ml day0 Ϫ log CFU/ml day5 )/5 and is given as the mean Ϯ standard deviation (SD). As recommended by several authors, we defined the EBA as the decrease in log 10 CFU per milliliter of sputum per day during the first 5 days of treatment (3,4).…”