The objective of this study is to determine the effect of isoniazid resistance-conferring mutations alone or in combination with resistance to other drugs (multidrug resistant [MDR] and extensively drug resistant [XDR]) on transmissibility and pathogenicity of Mycobacterium tuberculosis. Previous studies in San Francisco demonstrated that: 1) drug resistant strains of M. tuberculosis cause fewer secondary cases; 2) that the reduced pathogenicity is strongly associated with isoniazid resistance mutations other than the S315T mutation in KatG; and 3) that specific resistance mutations are associated with phylogeographic lineages of the organism. However, the applicability of these observations is limited because the study was conducted in a unique locale; characteristics of the contacts were not examined; new infections among contacts were not identified; and there was only a small number of MDR cases. The specific aims of the proposed study are based on the observations from San Francisco and are as follows: 1. to identify the isoniazid resistance-conferring mutations of M. tuberculosis from index cases; 2. to compare the rates of new tuberculosis infection and active tuberculosis in contacts of index cases with tuberculosis caused by: a. fully susceptible M. tuberculosis; b. isoniazid resistant organisms with the katG S315T mutation and inhA prom -15ct ; c. isoniazid resistant-organisms with katG mutations other than other than S315T; and d. MDR/XDR organisms; 3. to determine the phylogeographic lineage of M. tuberculosis isolated from index cases; 4. to determine if there are associations between resistance-conferring mutations and phylogeographic lineage of the organism. We propose to use data from a prospective study entitled "An analysis of Molecular Epidemiology of MDR in the United States" conducted by the Tuberculosis Epidemiologic Studies Consortium (M. tuberculosis ESC) sponsored by the CDC and with the participation of 14 M. tuberculosis ESC sites across the country. This project will provide sufficiently large numbers of MDR cases and fully susceptible cases for comparison. From one of the M. tuberculosis ESC sites, California, we will include, in addition, all patients with tuberculosis caused by isoniazid resistant organisms and a comparison group of patients with fully susceptible organisms. We will obtain epidemiological and clinical data, as well as the results of the contact investigations. We will determine isoniazid resistance mutations and phylogeographic lineage. The genotyping information will be integrated with the epidemiologic data to determine secondary infection rate ratios among the contacts named by the index cases and secondary case rate ratios defined by genotyping. The data generated will provide an indication of the transmissibility and pathogenicity of resistant M. tuberculosis compared with susceptible organisms in the context of modern tuberculosis control in a low-incidence area.

 To date, nearly all the global information on drug resistant tuberculosis, including multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis, is descriptive in nature. It has been established that Mycobacterium tuberculosis resistant strains are transmissible, but what remains completely unknown is the degree to which drug resistant strains are transmitted and cause disease as compared with fully susceptible organisms. Having information on the relative fitness of drug resistant M. tuberculosis would enable more accurate predictions about the impact of MDR and XDR on the tuberculosis epidemic globally, and would serve to identify the tuberculosis control interventions most likely to be effective.