Microbial kinetics of drug action against gram-positive and gram-negative organisms. II: Effect of clindamycin on Staphylococcus aureus and Escherichia coli.

Clindamycin-affected Staphylococcus aureus cultures show biphasic steady-state generation curves. An initial (phase I) generation of the clindamycin-affected Staph. aureus is followed by an ultimate (phase II) generation at the same dose level. The phase I apparent generation rate constant is greater than the phase II apparent generation rate constant and suggests the development of resistant Staph. aureus mutants to clindamycin action after a finite period of drug-bacteria contact at any subcompletely inhibitory concentration level. It is rationalized that the increased resistance to drug action in mutant strains is due to a comparatively reduced ribosomal binding affinity for clindamycin. In contrast, clindamycin-affected Escherichia coli cultures show monophasic steady-state generation curves at all concentration levels; E. coli cultures do not develop resistance to clindamycin action. The dependence of the apparent generation rate constant on drug concentration yields a sigmoidal curve, which is coincident by a potency factor for the phase I and phase II generations of clindamycin-affected Staph. aureus and suggests a common mechanism of action for both generation phases. That of clindamycin-affected E. coli yields an asymptote curve, which indicates a different mechanism of action. Clindamycin possesses both a bacteriostatic and a bactericidal action on initial and mutant resistant strains of Staph. aureus, whereas its action on E. coli is only bacteriostatic. Consequently, clindamycin has a minimum inhibitory concentration (MIC) against E. coli that is about 1000 times the MIC value against Staph. aureus at 37.5 degrees. The effect of pH changes in broth media on generation inhibition of both Staph. aureus and E. coli by clindamycin action indicates that the unprotonated fraction of drug concentration contributes to the activity, possibly because of its ready penetration through cell membranes.