The in Vitro Effect of Para-aminosalicylic Acid (pas) in Preventing Acquired Resistance to Streptomycin by Mycobacterium Tuberculosis.

Streptomycin was reported as being bacteriostatic and moderately bactericidal for Mycobacterium tuerculo8s by Schatz and Waksman (1944). These results were confirmed and extended by Youmans (1945), who reported that the drug was bacteriostatic at concentrations of 0.095 to 0.28 units per ml and bactericidal at concentrations in excess of 50 units per ml. Additional confirmatory observations have been reported (Smith and McClosky, 1945; Emmart, 1945; Wolinsky and Steenken, 1947). Youmans, Williston, Feldman, and Hinshaw (1946) and later Middlebrook and Yegian (1946) have shown that mycobacteria develop resistance to streptomycin in vitro. Youmans (1946) and Vennesland, Ebert, and Bloch (1948) have demonstrated that streptomycin-resistant strains are sensitive to para-aminosalicylic acid (PAS), the antitubercular activity of which was first-described by Lehmann (1946), and later confirmed by Youmans (1946) and Sievers (1946). Streptomycin-resistant strains from tuberculous patients treated with this antibiotic have been isolated (Youmans et al., 1946; Youmans and Karlson, 1947; Youmans and Feldman, 1946; Sadusk and Swift, 1947; Pyle, 1947) and when inoculated into susceptible animals produced infections refractory to streptomycin therapy (Youmans and Williston, 1946; Steenken and Wolinesky, 1948). The principle of combined therapy was recently revived by Ungar (1943), who demonstrated the synergistic action of para-aminobenzoic acid and sulfapyridine with penicillin upon bacteria. Carpenter, Bahn, Ackerman, and Stokinger (1945) observed that Neisseria gonorrhoeae exposed to a combination of four antibacterial agents failed to develop resistance, whereas resistance developed regularly on exposure to each drug alone. Other investigators (Middlebrook and Yegian, 1946; Alexander et al., 1946; Kolmer, 1947; Franks, 1946; Klein and Kimmelman, 1947) have reported on the advantages of combined therapy both in vitro and in vivo. The activity of PAS against M. tuberculo8i8 when combined with streptomycin in vitro has been reported to be additive (Vennesland, Ebert, and Bloch, 1948). An additive action was also obtained when the drugs were used in combination in animals infected with human tubercle bacilli (Youmans, Youmans, and Osborne, 1947; McCloskey, Smith, and Frias, 1948). To supplement these observations, it was considered advisable to study what effect PAS might have upon the rate of induced resistance of the tubercle bacillus to streptomycin in vitro.