TY - JOUR
T1 - A time-to-event pharmacodynamic model describing treatment response in patients with pulmonary tuberculosis using days to positivity in automated liquid mycobacterial culture
AU - Chigutsa, Emmanuel
AU - Patel, Kashyap
AU - Denti, Paolo
AU - Visser, Marianne
AU - Maartens, Gary
AU - Kirkpatrick, Carl Michael James
AU - McIlleron, Helen
AU - Karlsson, Mats O
PY - 2013
Y1 - 2013
N2 - Days to positivity in automated liquid mycobacterial culture have been shown to correlate with mycobacterial load and have been proposed as a useful biomarker for treatment responses in tuberculosis.However, there is currently no quantitative method or model to analyze the change in days to positivity with time on treatment.The objectives of this study were to describe the decline in numbers of mycobacteria in sputum collected once weekly for 8 weeks from patients on treatment for tuberculosis using days to positivity in liquid culture.One hundred forty-four patients with smear-positive pulmonary tuberculosis were recruited from a tuberculosis clinic in Cape Town, South Africa.A nonlinear mixed-effects repeated-time-to-event modeling approach was used to analyze the time-to-positivity data.A biexponential model described the decline in the estimated number of bacteria in patients sputum samples, while a logistic model with a lag time described the growth of the bacteria in liquid culture.At baseline, the estimated number of rapidly killed bacteria is typically 41 times higher than that of those that are killed slowly.The time to kill half of the rapidly killed bacteria was about 1.8 days, while it was 39 days for slowly killed bacteria.Patients with lung cavitation had higher bacterial loads than patients without lung cavitation.The model successfully described the increase in days to positivity as treatment progressed, differentiating between bacteria that are killed rapidly and those that are killed slowly.Our model can be used to analyze similar data from studies testing new drug regimens.
AB - Days to positivity in automated liquid mycobacterial culture have been shown to correlate with mycobacterial load and have been proposed as a useful biomarker for treatment responses in tuberculosis.However, there is currently no quantitative method or model to analyze the change in days to positivity with time on treatment.The objectives of this study were to describe the decline in numbers of mycobacteria in sputum collected once weekly for 8 weeks from patients on treatment for tuberculosis using days to positivity in liquid culture.One hundred forty-four patients with smear-positive pulmonary tuberculosis were recruited from a tuberculosis clinic in Cape Town, South Africa.A nonlinear mixed-effects repeated-time-to-event modeling approach was used to analyze the time-to-positivity data.A biexponential model described the decline in the estimated number of bacteria in patients sputum samples, while a logistic model with a lag time described the growth of the bacteria in liquid culture.At baseline, the estimated number of rapidly killed bacteria is typically 41 times higher than that of those that are killed slowly.The time to kill half of the rapidly killed bacteria was about 1.8 days, while it was 39 days for slowly killed bacteria.Patients with lung cavitation had higher bacterial loads than patients without lung cavitation.The model successfully described the increase in days to positivity as treatment progressed, differentiating between bacteria that are killed rapidly and those that are killed slowly.Our model can be used to analyze similar data from studies testing new drug regimens.
UR - http://aac.asm.org/content/57/2/789.full.pdf+html
U2 - 10.1128/AAC.01876-12
DO - 10.1128/AAC.01876-12
M3 - Article
SN - 0066-4804
VL - 57
SP - 789
EP - 795
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
IS - 2
ER -