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 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.
Highlights
The World Health Organization estimates that there were approximately 440,000 incident multidrug resistant tuberculosis (MDR TB) cases in 2008
An infectious ‘‘dose’’ of M. tuberculosis may consist of only a few bacilli that lodge in distal alveoli of the lung, active pulmonary disease is not usually clinically evident until the population of bacilli has reached a size of 108–1010 organisms [6,7]
Using a stochastic birth-death model of the within-host emergence of drug resistant M. tb, we show that the probability of emergence of MDR TB is much higher than previously expected, even when combination chemotherapy is reliably delivered
Summary
The World Health Organization estimates that there were approximately 440,000 incident multidrug resistant tuberculosis (MDR TB) cases in 2008. The term extensively drug resistant tuberculosis (XDR TB) describes MDR strains with additional resistance to at least one agent in each of the two most effective classes of second line drugs: a fluoroquinolone and an injectable second-line drug (capreomycin, kanamycin, or amikacin). Drug resistance in TB is selected when individuals with active tuberculosis are treated with drugs. An infectious ‘‘dose’’ of M. tuberculosis may consist of only a few bacilli that lodge in distal alveoli of the lung, active pulmonary disease is not usually clinically evident until the population of bacilli has reached a size of 108–1010 organisms [6,7]. Fluctuation tests demonstrate that resistance to specific anti-tuberculosis drugs arises spontaneously at a rate of one in 106–109 cell divisions, depending on the drug [8,9]. Bacilli resistant to a single drug are highly likely to exist in any detectable TB lesion; combination therapy is a mainstay of current TB treatment regimens
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