Post-antibiotic effect induced by an antibiotic combination: influence of mode, sequence and interval of exposure

The effects of mode, sequence and interval of antibiotic exposure on the post-antibiotic effect (PAE) induced by rifampicin and tobramycin were studied using Escherichia coli ATCC 25922 as the test organism.

In triplicate, baseline PAEs were evaluated by exposing E. coli to rifampicin and tobramycin individually and simultaneously for 1 h. PAEs were further assessed in a second study, with the organism exposed first to rifampicin for 1 h, followed by a second 1 h tobramycin exposure, commencing at the beginning, middle and end of the PAE phase induced by rifampicin. The third study was similar to the above, but with the sequence of the two antibiotics reversed, i.e. tobramycin then rifampicin.

The PAE produced by simultaneous exposure of the combination showed an apparent additive interaction (PAE: 5.0+/-0.3 h) when compared with the PAE of individual antibiotics (rifampicin alone: 3.0+/-0.1 h; tobramycin alone: 1.5+/-0.1 h). However, an antagonistic interaction was observed in the second study, with a more pronounced degree of antagonism at the beginning, dissipating towards the end of the previous rifampicin PAE (PAE at the beginning: 2.6+/-0.3 h; the middle: 1.5+/-0.2 h; and at the end: 1.7+/-0.3 h). By subtracting the residual contribution from the first rifampicin exposure, the net average PAEs attributed to the second tobramycin exposure actually increased, from -0.4 to 1.7 h from the beginning to the end of the rifampicin PAE. For the third study, an additive interaction was again observed when the organism was exposed to tobramycin first (PAE at the beginning: 4.7+/-0.4 h; the middle: 3.7+/-0.7 h; and at the end: 3.1+/-0.4 h). The timing of the second rifampicin exposure had no impact to the interaction; after correction, the net mean PAEs attributed to the second rifampicin exposure were maintained at 3.2, 3.2 and 3.1 h.

The present data suggest that the expression of interaction type on PAE by an antibiotic combination was dependent on the mode, sequence and interval of exposure. The impact of these variables should not be overlooked when clinical dosing regimens are optimized.