112 



NATURE, FORMATION, AND ACTIVITIES 



Practical Aspects 



The recognition of potentialities of in- 

 creasing resistance of bacteria to a given 

 antibiotic, thus resulting in a decrease in the 

 thei-apeutic value of the antibiotic, led to 

 rather alarming generalizations. This was 

 brought out by JMolitor (1946), who said, 

 "Whether the high incidence of drug-fast- 

 ness is due to the liberal and indiscriminate 

 use of these new, practically non-toxic agents, 

 or whether these drugs are particularly likely 

 to produce resistant strains, is not known. 

 Regardless of the cause, however, there is the 

 prospect that in the relatively near future 

 penicillin and streptomycin maj^ to a con- 

 sideral)le degree lose their usefulness in the 

 therapy of some of the most prevalent infec- 

 tions unless some means can be devised to 

 restore the original susceptibility of either 

 host or pathogenic agent." 



In an effort to overcome the development 

 of drug resistance, it has been suggested that 

 the selected dose of the antibiotic be large 

 enough to eliminate the pathogenic organ- 

 isms from the body rapidly. Penicillin and 

 streptomycin, because of their low toxicity, 

 make possible the administration of doses 

 greater than those re(iuired to stop bacterial 

 growth. It is necessary to determine the 

 resistance of the pathogen prior to the treat- 

 ment. High initial concentrations of the 

 antibiotic insure the maintenance of high 

 blood concentrations. It has been empha- 

 sized that use of the antil)iotic in such prepa- 

 rations as salves, lozenges, chewing gum, and 

 sprays is likely to produce adequate concen- 

 trations only at the site of application and 

 would tend to create a hazard unless special 

 forms can be developed which will assure a 

 completely adequate drug concentration in 

 blood and body tissue. 



The possibility of developing new anti- 

 biotics offers further promise of overcoming 

 the resistance of an organism to a given 

 antibiotic. This makes possible the combined 

 use of two substances, which would tend to 



repress the few resistant cells. It has been 

 shown, for example, that use of penicilHn 

 and bacteriophages in combination produces 

 a synergistic effect. Malignant infections due 

 to staphylococci, colon bacilli, and certain 

 streptococci showed good response to such a 

 combination. 



Combinations of Antibiotics 



Among the procedures recommended for 

 overcoming the problem of bacterial resist- 

 ance, combined therapy of two or more drugs 

 has been given particular consideration. 

 Such combined activity may be synergistic, 

 additive, indifferent, or antagonistic, de- 

 pending upon the nature of the antibiotics 

 and upon the bacterial species or strain. 



Cavalli-Sforza and Lederberg (1953) ana- 

 lyzed in detail the phenomenon of combina- 

 tion of antibiotics. Thej^ considered true 

 synergism (the joint effect being greater 

 than expected on simple addition of effects), 

 simple addition, indifferent effect, and 

 antagonism. Physiological synergism was 

 believed to be negatively correlated with 

 genetic synergism (Klein and Schorr, 1953). 

 Additive interaction could be expected be- 

 tween chloramphenicol and tetracycline, 

 which show cross-resistance and therefore 

 genetic antagonism. Tetracycline and peni- 

 cillin show genetic synergism and physiologi- 

 cal antagonism. This was believed to be due 

 to the fact that penicillin has a bactericidal 

 effect only on growing cells, and a bacterio- 

 static agent would therefore greatly reduce 

 its action. The association of chlorampheni- 

 col and sulfa drugs and the association of 

 isoniazid and streptomycin in the therapy of 

 tuberculosis were considered as involving 

 both genetic and physiological synergism. 



Jawetz and Gunnison (1953) made a 

 detailed study of the synergistic or additive 

 properties of such combinations. Unfortu- 

 nately, there was freciuently a lack of correla- 

 tion between the activities of the combina- 



