01772nas a2200229   4500000000100000008004100001653001100042653001400053653001600067653001700083653003800100100001300138700001200151700001300163700001300176245009700189856007700286300001100363490000600374520114800380022001401528       2011                            d10aHumans10aIsoniazid10aProbability10aTime Factors10aTuberculosis, Multidrug-Resistant1 aColijn C1 aCohen T1 aGanesh A1 aMurray M00aSpontaneous emergence of multiple drug resistance in tuberculosis before and during therapy.  uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3068161/pdf/pone.0018327.pdf  ae183270 v63 a<p>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 10(-5) to 10(-4); 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.</p>
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