Spontaneous emergence of multiple drug resistance in tuberculosis before and during therapy

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.

Figure 1. Distribution of INH-resistant mutants at the time of clinical detection of a TB patient.

A Expected number of INH monoresistant mutants at the time of detection, as a function of relative fitness and net growth rate. B The distribution of mutant numbers by relative fitness. Horizontal red lines show the mean values in simulation, and the blue boxes illustrate the inter-quartile range. Small blue squares are the 5^th and 95^th quantiles. The shaded blue region illustrates the 5^th–95^th quantile for the α-stable distribution.

Figure 2. Probability of dual resistance (p_dual).

Numbers are based on β = 2.25×10⁻⁸ (isoniazid resistance) and β₁₂ = 3.3×10⁻⁹ (rifampin resistance) , A Before treatment begins, showing that when mutants have higher relative fitness there is more mutant growth corresponding to a higher probability that dual resistance will arise; B After initiation of therapy; C After initiation of therapy, showing the dependence on the net rate of decline. During the decline of the bacterial population during therapy there may be some turnover, although the death rate will be greater than the division rate. In particular, if treatment increases the death rate but does not affect the division rate there may be substantial turnover, resulting in a larger probability that dual resistance may arise (green vs blue lines in panels B and C). A more rapid net decline results in fewer births and a lower risk of resistance. In each panel we allow the appearance of resistance to isoniazid or rifampin to occur first, but the rapid bactericidal effect of INH means that the net decline of INH-sensitive bacteria is much more rapid than that of INH-resistant ones, and isoniazid resistance is thus more likely to be observed before rifampin resistance in treated patients.