DEVELOPMENT OF RESISTANCE 



113 



tions ill vitro and in vivo. Jtiwetz (1958) 

 emphasized that the basic mechanisms 

 underlying combined antibiotic action are 

 still unknown. He agreed, however, that 

 certain combinations may give good results 

 in clinical practice. This conclusion is based 

 upon laboratory data and clinical judgment. 

 He outlined the rational use of two anti- 

 microbial drugs, instead of one, as follows: 



1. In mixed infections it is possible that 

 two drugs, each acting on a separate portion 

 of the complex microbial flora, might be more 

 effective than one drug. This applies occa- 

 sionally to infections of skin, wounds, or 

 body cavities, particularly when nonabsorb- 

 able drugs of limited antibacterial spectrum 

 are used topically {e.g., polymyxin, baci- 

 tracin, or neonwcin). 



2. Toxic side effects may sometimes be 

 reduced by employing simultaneously two 

 drugs which have a similar antibacterial ac- 

 tion but distinct toxic effects. A combination 

 of such drugs could obtain a given antibac- 

 terial effect together with a lower toxicity 

 than would be feasi])le with either of the 

 components of the mixture used alone. 

 Streptomycin-dihydrostreptomycin mixtures 

 may serve as an example. 



3. In some clinical situations the rapid 

 emergence of bacteria resistant to one drug 

 may impair the chances for cure. The addi- 



tion of a second drug sometimes delays the 

 emergence of resistance. This effect has been 

 demonstrated uneciuivocally in tuberculosis. 

 In some other chronic infections the evidence 

 for its occurrence is questionable. In serious 

 systemic staphylococcal infections, strepto- 

 mycin, erythromjTin, novobiocin, or related 

 drugs should not be used singly, as a rule, 

 because resistance to each is likely to emerge 

 rapidly. 



4. In certain desperately ill patients with 

 suspected infection of unknown etiology it 

 may be desirable to administer several anti- 

 microbial drugs after all steps have been 

 taken to establish an etiologic diagnosis. 

 These drugs are aimed at the organisms 

 most likely to cause the clinical picture en- 

 countered and are usually continued o\\\y 

 until the discovery of an etiologic agent 

 permits specific therap.v. The initial treat- 

 ment of meningitis in a small child might 

 be an example in this category. 



"). In some infections the simultaneous 

 use of two drugs gives an effect not obtain- 

 able by either drug alone. Perhaps the best 

 estabhshed example is endocarditis due to 

 S. faecalis, for which the combined effect of 

 penicillin and sti'eptomycin is essential for 

 cure. The "synergistic" drug effects and the 

 known dynamics of combined drug action 

 are sunnnai-ized later (Chapter 11). 



