Abstract

The principles for treatment with antibiotics were laid down over a century ago, well before, even, the discovery of antibiotics and before we knew much of the mechanisms of inheritance in evolution. Alexander Flemming knew about penicillin resistance and said that the problem with treatment was the ”...danger that the ignorant man may easily underdose himself and, by exposing his microbes to non-lethal quantities of the drug, make them resistant.”

This quote embodies the principle of “hit early, hit hard” already described as the “old therapeutic remedy” by Paul Erlich in 1913. So, as the use of drug combinations is a natural extension of the hit-hard logic, we take a closer look at synergistic drug combinations in the lab and ask, is it true that harsher therapies necessary reduce bacterial load?

The answer, at least for the two translational inhibitors we tested in vitro using E.coli is ‘no’. We’ll even show data indicating that synergistic drugs can lose out in the lab to treatments that rotate between the same drug pair, despite the presence of a fast-acting, cross-resistance operon.

The reason: selection for resistance is greater for harsher therapies and as tests for drug efficacy usually only last a day, much shorter than the length of exposure commonly found in clinical therapy, common pharmacological measures of drug efficacy miss features of drug-resistance adaptation that can occur within tens of bacterial generations.