Article

Modeling epidemics of multidrug-resistant M. tuberculosis of heterogenous fitness

Harvard University, Cambridge, Massachusetts, United States
Nature Medicine (Impact Factor: 28.05). 11/2004; 10(10):1117-21. DOI: 10.1038/nm1110
Source: PubMed

ABSTRACT Mathematical models have recently been used to predict the future burden of multidrug-resistant tuberculosis (MDRTB). These models suggest the threat of multidrug resistance to TB control will depend on the relative 'fitness' of MDR strains and imply that if the average fitness of MDR strains is considerably less than that of drug-sensitive strains, the emergence of resistance will not jeopardize the success of tuberculosis control efforts. Multidrug resistance in M. tuberculosis is conferred by the sequential acquisition of a number of different single-locus mutations that have been shown to have heterogeneous phenotypic effects. Here we model the impact of initial fitness estimates on the emergence of MDRTB assuming that the relative fitness of MDR strains is heterogeneous. We find that even when the average relative fitness of MDR strains is low and a well-functioning control program is in place, a small subpopulation of a relatively fit MDR strain may eventually outcompete both the drug-sensitive strains and the less fit MDR strains. These results imply that current epidemiological measures and short-term trends in the burden of MDRTB do not provide evidence that MDRTB strains can be contained in the absence of specific efforts to limit transmission from those with MDR disease.

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    • "It is well-known that the condition R 0 < 1 is necessary for disease eradication [26]. Here, the relative reproductive fitness function will be approximated by the basic reproductive number of infection (R 0 ) in the absence of treatment or the effective reproductive number (R) in the presence of treatment [9], [13]. "
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    • "To take into consideration the externalities associated with the treatment of infectious diseases and assess how disease spreads and resistance emerges under various drug deployment policies, we extend the simplest general disease model (SIS) [3] [18] that allows for treatment with more than one different drug to include the emergence and evolution of resistance to a drug (for a similar models see [12] [24]). "
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    • "Initially, it was believed that resistance was always associated with a fitness reduction (fitness cost). More recent models have allowed for the variation in the relative fitness of Mycobacterium tuberculosis (Mtb) [4] [5], as supported by experimental studies both in vitro or epidemiological studies [6]. In [5], it was argued that the long term epidemiological landscape would be shaped not only by the impact of the relative fitness in transmission by assuming a distinct transmission rate for sensitive and resistant strains (β s and β r ) but also by reinfection through the distinct contribute of mixed infections to transmission depending on within-host competition. "
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