ABSTRACT
Drug resistance emerged as a central issue in tuberculosis (TB) control beginning with the earliest human trials of the first anti-TB drug, streptomycin (SM), in 1947 (1). SM-treated patients improved over three to sixmonths, but SM resistance developed in 85% of them, and long-term outcomes were little better than for untreated patients. Once para-aminosalicylic acid (PAS) became available in 1948, British researchers carried out the first-ever randomized controlled clinical trials comparing SMþPAS to each drug alone (1,2). Depending on the dose, the combination gave better results and SM resistance arose less frequently than either drug alone. A similar story unfolded when isoniazid (INH) was introduced in 1952 (3). INH was highly effective in the short term, but patients relapsed within months with INHresistant Mycobacterium tuberculosis. SMþINH together proved to be the most effective two-drug combination. By studying isolates from relapses
and treatment failures, microbiologists developed methods to identify drugresistant bacille (4,5). These methods were soon put to use because concerns over transmission of drug-resistant TB to the population led the British to conduct the first national drug resistance survey, 1955 to 1956. Resistance to SM, PAS, and INH was identified in 2.5%, 2.6%, and 1.3% of previously untreated patients. As a result, the British Medical Research Council (BMRC) introduced the concept of triple drug therapy to ensure that patients received at least two effective drugs. Numerous subsequent clinical trials demonstrated that three drugs, given for sufficient periods of time, cured over 90% of patients and almost eliminated the development of drug-resistant TB (1,6). The principle of multidrug treatment was firmly established, and it was thought at the time that the problem of acquired drug resistance had been overcome.
