The sequential administration of two antibiotics at sublethal doses is a promising new approach to treating bacterial infection and reducing the risk of resistance, an international research team believes.
According to a study published in PLoS Biology
on 8 April 2015, sequential therapy with two synergistic antibiotics over a period of 96 hours cleared bacterial infection in an in vitro treatment model of Escherichia coli.
The same two antibiotics failed to clear the infection when administered concurrently, say the researchers, which would have resulted in drug resistance and sustained bacterial growth.
“Our study finds a complex relationship between dose, bacterial population densities and drug resistance,” says lead author Robert Beardmore from the University of Exeter. “As we demonstrate, it is possible to reduce bacterial load to zero at dosages that are usually said to be sublethal and, therefore, are assumed to select for increased drug resistance.”
The idea of sequential therapy is based on the observation of “collateral sensitivities” between antibiotics; when measures taken by a bacterium to counter the presence of one antibiotic sensitise it to the subsequent use of another.
“Our approach was to see if we could exploit these sensitivities by first deploying one drug, then removing it and instead deploying another, and then repeating this process,” Beardmore explains.
The team tested their hypothesis using an E. coli treatment model targeted with erythromycin (a macrolide) and doxycycline (a tetracycline), which are known to act synergistically. The E. coli strain used has a multidrug pump that effluxes both antibiotics.
A total of 136 sequential treatments were evaluated, each using erythromycin and doxycycline as monotherapy at low doses (IC50) or medium doses (IC70) but administered for different durations, although the total treatment duration was always 96 hours.
Some of the sequential treatments failed to clear the bacteria and others resulted in bacterial growth; however, five treatments were found to clear the bacterium in all replicant populations by 96 hours.
“These successes can be attributed to a collateral sensitivity whereby cross-resistance due to the duplicated pump proves insufficient to stop a reduction in E. coli growth rate following drug exchanges, a reduction that proves large enough for appropriately chosen drug switches to clear the bacterium,” the researchers write.
They say that while they have demonstrated the possibility of exploiting collateral sensitivities in a simple in vitro model, it will not necessarily translate to the treatment of bacterial infection in humans. To date, few sequential therapies have been evaluated in the clinic.
Paul Wade, consultant pharmacist in infectious diseases at Guy’s & St Thomas’ NHS Foundation Trust, says the research “challenged the conventional paradigm of ‘Start Smart, Then Focus’ with pharmacokinetic/pharmacodynamic dose optimisation, which is almost ubiquitous in UK practice”.
“There is obviously a long way to go before this ‘low-dose’ approach could be considered suitable for widespread clinical application, but the potential to be able to treat what are now considered resistant infections with existing agents deserves careful scrutiny and ongoing consideration as the data develops,” he says.