PubMed · 8532010
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G Di Perri, S Vento, E Concia, A Cazzadori. 1996-01-25. Multidrug-resistant tuberculosis.. https://pubmed.ncbi.nlm.nih.gov/8532010/
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Antibiotic resistance is a growing impediment to the control of infectious diseases worldwide, tuberculosis (TB) being among them. TB kills two million people each year and foci of multidrug-resistant TB (MDR-TB) have been identified in Eastern Europe, Africa, Asia, and Latin America. A critical question for health policy is whether standardized short-course chemotherapy for TB, based on cheap first-line drugs, can prevent and reverse the spread of drug resistance. Here we use mathematical modeling, in conjunction with treatment results from six countries, to show that best-practice short-course chemotherapy is highly likely to bring strains resistant to either of the two key drugs isoniazid and rifampicin under control and to prevent the emergence of MDR-TB. However, it is not certain to contain MDR-TB once it has emerged, partly because cure rates are too low. We estimate that approximately 70% of prevalent, infectious MDR-TB cases should be detected and treated each year, and at least 80% of these cases should be cured, in order to prevent outbreaks of MDR-TB. Poor control programs should aim to increase case detection and cure rates together for three reasons: (i) these variables act synergistically; (ii) when either is low, the other cannot succeed alone; and (iii) the second-line drugs needed to raise MDR-TB cure rates are few and extremely costly. We discuss the implications of these results for World Health Organization policy on the management of antibiotic resistance.
Structural and genetic studies indicate that the antibacterial compound triclosan, an additive in many personal care products, is an inhibitor of EnvM, the enoyl reductase from Escherichia coli. Here we show that triclosan specifically inhibits InhA, the enoyl reductase from Mycobacterium tuberculosis and a target for the antitubercular drug isoniazid. Binding of triclosan to wild-type InhA is uncompetitive with respect to both NADH and trans-2-dodecenoyl-CoA, with K(i)' values of 0.22+/-0.02 and 0.21+/-0.01 microM, respectively. Replacement of Y158, the catalytic tyrosine residue, with Phe, reduces the affinity of triclosan for the enzyme and results in noncompetitive inhibition, with K(i) and K(i)' values of 36+/-5 and 47+/-5 microM, respectively. Consequently, the Y158 hydroxyl group is important for triclosan binding, suggesting that triclosan binds in similar ways to both InhA and EnvM. In addition, the M161V and A124V InhA mutants, which result in resistance of Mycobacterium smegmatis to triclosan, show significantly reduced affinity for triclosan. Inhibition of M161V is noncompetitive with K(i)' = 4.3+/-0.5 microM and K(i) = 4.4+/-0.9 microM, while inhibition of A124V is uncompetitive with K(i)' = 0. 81 +/- 0.11 microM. These data support the hypothesis that the mycobacterial enoyl reductases are targets for triclosan. The M161V and A124V enzymes are also much less sensitive to isoniazid compared to the wild-type enzyme, indicating that triclosan can stimulate the emergence of isoniazid-resistant enoyl reductases. In contrast, I47T and I21V, two InhA mutations that occur in isoniazid-resistant clinical isolates of M. tuberculosis, show unimpaired inhibition by triclosan, with uncompetitive inhibition constants (K(i)') of 0.18+/-0.01 and 0.12+/- 0.01 microM, respectively. The latter result indicates that InhA inhibitors targeted at the enoyl substrate binding site may be effective against existing isoniazid-resistant strains of M. tuberculosis.
Endobronchial tuberculosis is a form of pulmonary tuberculosis, thought to result from rupture of an infected node through the bronchial wall or from lymphatic spread to the mucosal surface of the bronchial tree. With the presence of multidrug resistant isolates of TB, and its incidence in an increasing number of foreign-born persons immigrating to the US, otolaryngologists must be aware of its often subtle presentation. The following case is an unusual presentation of endobronchial tuberculosis initially diagnosed as an airway foreign body.