tuberculosis

The rationale for using multiple drugs to treat TB are based on simple probability. The frequency of spontaneous mutations that confer resistance to an individual drug are well known: 1 in 107 for EMB, 1 in 108 for STM and INH, and 1 in 1010 for Rifampin (RMP).

A patient with extensive pulmonary TB has approximately 1012 bacteria in his body, and therefore will probably be harboring approximately 105 EMB-resistant bacteria, 104 STM-resistant bacteria, 104 INH-resistant bacteria and 10² RMP-resistant bacteria. Resistance mutations appear spontaneously and independently, so the chances of him harbouring a bacterium that is spontaneously resistant to both INH and RMP is 1 in 108 x 1 in 1010 = 1 in 1018, and the chances of him harbouring a bacterium that is spontaneously resistant to all four drugs is 1 in 1033. This is, of course, an oversimplification, but it is a useful way of explaining combination therapy.

There are other theoretical reasons for supporting combination therapy. The different drugs in the regimen have different modes of action. INH are bacteriocidal against replicating bacteria. EMB is bacteriostatic at low doses, but is used in TB treatment at higher, bactericidal doses. RMP is bacteriocidal and has a sterilizing effect. PZA is only weakly bactericidal, but is very effective against bacteria located in acidic environments, inside macrophages, or in areas of acute inflammation.