The Mode of Action of Antibiotic Synergism and Antagonism: the Effect in Vituo on Bacteria not Actively Multiplying

SUMMARY: The synergistic effect of certain pairs of antibiotics might be due to action on ‘persisters’; i.e. members of a bacterial population which survive exposure to single drugs, perhaps while in a state of reduced metabolic activity, although their offspring do not show enhanced resistance. Hence, antibiotics were tested in vitro under conditions minimizing bacterial multiplication and metabolism. At 37”, neomycin, polymyxin, and streptomycin were more effective in the absence of nutrients than in nutrient broth; oxytetracycline and bacitracin were equally effective in either environment; but penicillin had little effect in the absence of nutrients. At 4”, bactericidal action varied with the test organism so that differences could not be attributed solely to the ‘resting ’ state of the bacteria. Conditions not permitting bacterial multiplication prevented synergism and those antagonisms demonstrable in broth. Probably synergism depends upon rapid bactericidal action preventing the emergence of persisters rather than upon destruction of these relatively inactive forms. Most studies on the action of antimicrobial drugs in vitro have been made wit