spontaneous emergence of multiple drug resistance in tuberculosis before and during therapy自发出现多重耐药结核病疗法之前和期间.pdfVIP

Spontaneous Emergence of Multiple Drug Resistance in Tuberculosis before and during Therapy 1 2,3,* 4 2 Caroline Colijn , Ted Cohen , Ayalvadi Ganesh , Megan Murray 1 Department of Engineering Mathematics, University of Bristol, Bristol, United Kingdom, 2 Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, United States of America, 3 Division of Global Health Equity, Harvard Medical School, Boston, Massachusetts, United States of America, 4 School of Mathematics, University of Bristol, Bristol, United Kingdom Abstract The emergence of drug resistance in M. tuberculosis undermines the efficacy of tuberculosis (TB) treatment in individuals and of TB control programs in populations. Multiple drug resistance is often attributed to sequential functional monotherapy, and standard initial treatment regimens have therefore been designed to include simultaneous use of four different antibiotics. Despite the widespread use of combination therapy, highly resistant M. tb strains have emerged in many settings. Here we use a stochastic birth-death model to estimate the probability of the emergence of multidrug resistance during the growth of a population of initially drug sensitive TB bacilli within an infected host. We find that the probability of the emergence of resistance to the two principal anti-TB drugs before initiation of therapy ranges from 1025 to 1024; while rare, this is several orders of magnitude higher than previous estimates. This finding suggests that multidrug resistant M. tb may not be an entirely ‘‘man-made’’ phenomenon and may help explain how highly drug resistant forms of TB have independently emerged in many settings. Citati