It is generally assumed that the combination of two synergistic antibiotics is more effective for the treatment of bacterial infections than a single drug. A new study challenges this view by showing that synergism can actually select for higher bacterial loads owing to strong selection pressure for the rapid evolution of resistant bacteria. Mathematical modelling predicted that short-term aggressive treatment with two antibiotics could theoretically maximize bacterial numbers later in infection by eliminating drug-susceptible competitor bacteria. Consistent with this, in vitro evolution of Escherichia coli grown in the presence of erythromycin and doxycycline showed that the more aggressive the treatment, the higher the resulting bacterial loads; this was found to be due to rapid selection of resistant bacteria carrying an amplification of the genomic region containing the acrAB efflux operon (which confers multidrug resistance). These findings suggest that unless synergism clears the infection before efficient selection of resistant mutants, it might actually be the worst strategy for treatment.
Pena-Miller, R. et al. When the most potent combination of antibiotics selects for the greatest bacterial load: the smile-frown transition. PLoS Biol. 11, e1001540 (2013)
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Hofer, U. When synergism back-fires. Nat Rev Microbiol 11, 360 (2013). https://doi.org/10.1038/nrmicro3041