Kinetics and Mechanisms of Action of Drugs on Microorganisms XV: Effect of Erythromycin on the Action of Lincomycin (Phase II) and the 7(S)-Chloro Analogs of Lincomycin against Escherichia coli

Abstract

Lincomycin-affected Escherichia coli cultures show two phases of steady-state generation. The initial (Phase I) steady-state generation, expressed as In N = kapp.It + constant, is followed after several generations by an ultimate (Phase II) steady-state generation, In N = kapp.IIt + constant, at the same dose level, where kapp.I >kapp.II. Cultures affected with erythromycin or the 7(S)-chloro analogs of lincomycin show only one steady-state generation. A fixed potency ratio of erythromycin lactobionate-lincomycin hydro-chloride (Phase I) as 1:5 (on weight basis) is operative over a wide drug concentration range. Combinations of erythromycin and lincomycin are quantifiable on the basis of this potency factor as kineti-cally equivalent in action to the equipotent lincomycin (in Phase I action) or erythromycin alone. However, the potency factor for erythromycin and lincomycin (Phase II) varies with the concentration level. Therefore, combinations of erythromycin and lincomycin, which a priori have the same potency as equivalent lincomycin alone (in Phase I action), are less potent in the Phase II action. This is attributed to an artifact of diluted lincomycin effect in Phase II action of the mixture and not to antagonism of effects. Combinations of erythromycin and the 7(S)-chloro analogs of lincomycin demonstrate a priori antagonism of effects because of possible allosteric interactions which decrease the effects of one drug in the presence of the other at their site of action. It is emphasized that the dose-response relationship over a wide concentration range, as well as the kinetics and mechanisms of the separate drug action, must be considered in the quantification and prediction of combined action of antibiotics.