Impact of Bacterial Genetics on the Transmission of Isoniazid-Resistant Mycobacterium tuberculosis

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Abstract
Understanding the ecology of drug-resistant pathogens is essential for devising rational programs to preserve the effective lifespan of antimicrobial agents and to abrogate epidemics of drug-resistant organisms. Mathematical models predict that strain fitness is an important determinant of multidrug-resistant Mycobacterium tuberculosis transmission, but the effects of strain diversity have been largely overlooked. Here we compared the impact of resistance mutations on the transmission of isoniazid-resistant M. tuberculosis in San Francisco during a 9-y period. Strains with a KatG S315T or inhA promoter mutation were more likely to spread than strains with other mutations. The impact of these mutations on the transmission of isoniazid-resistant strains was comparable to the effect of other clinical determinants of transmission. Associations were apparent between specific drug resistance mutations and the main M. tuberculosis lineages. Our results show that in addition to host and environmental factors, strain genetic diversity can influence the transmission dynamics of drug-resistant bacteria. Resistance to antibiotics is an increasing global public health problem. Multidrug-resistant tuberculosis is threatening the control of this deadly infectious disease in many parts of the world. Studies to identify the factors that lead to the emergence and subsequent spread of drug-resistant organisms have clearly shown that patient adherence to a 6 mo course of treatment is very important to prevent the development of drug-resistant tuberculosis. However, little is known about how bacterial genetics might influence the spread of drug-resistant strains. This study showed that among the strains in San Francisco with resistance to isoniazid, one of the main anti-tuberculosis drugs, only certain strains were transmitted effectively. The transmission of specific isoniazid-resistant strains depended on the type of genetic mutation leading to resistance. Also, isoniazid-resistant strains coming from different parts of the world were associated with different resistance mutations. This study's results show that the spread of drug resistance is due to the strain of tuberculosis as well as the environment and characteristics of the patient, and may partially explain why some areas of the world have worse drug resistance problems than others.