Using alternating doses of antibiotics – ‘sequential treatments’, might be an effective treatment against bacterial infection. Researchers from the University of Exeter have shown that the risk of bacteria becoming resistant to antibiotics can be reduced using this technique and thus, drugs will remain effective for a longer term.

Treatments with two antibiotics, at certain doses, normally cause rapid increase in drug resistance and sustained bacterial growth when administered alone or in combination. However, the research is indicative of the possibility that the same treatment can be designed to kill the bacteria. The key lies in the sequence.

A test-tube model of bacterial infection was used to show that the sequential treatments could combat even bacteria that already have drug resistance genes in them. Though much higher doses of single drugs or mixtures fail to do so, this form of treatment could be effective. The lead author, Professor Beardmore said, “As we demonstrate, it is possible to reduce bacterial load to zero at dosages that are usually said to be sub lethal and, therefore, are assumed to select for increased drug resistance.”

The study looks at the complex relationship between dose, bacterial population densities and drug resistance. Bacteria conquer an antibiotic challenge by adapting to it. This research suggests a way to break the hegemony by using a bacteria’s own adaptation against it. Well-designed sequential treatments create a fluctuating environment which can sensitize bacteria and leave them susceptible to concentrations of antibiotics that would otherwise induce drug resistance and continued thriving.

Though the rise of all drug resistance mutations in bacteria was not suppressed by sequential treatments, it would reduce the risk of resistance occurring because one drug would sensitize the bacteria to the second drug. The co-author of the study, Dr Ayari Fuentes-Hernandez said, “Research has concentrated for decades on synergistic drug cocktails. We believe ‘sequential synergies’ might be just as potent if we look for them. This research will therefore be of interest to the pharma and dwindling antibiotic discovery communities.”

In order for sequential treatments to find their way to clinics there must be further extensive research. An EPSRC-funded researcher, Dr Jessica Plucain, said, “One outcome of this highly surprising result will be to set in motion a series of studies to determine ways of using antibiotics not only in combination, but sequentially and with the potential for lower dosages than is currently thought possible.”

This collaborative international research is led by Professor Robert Beardmore from the University of Exeter and funded by EPSRC. It has been published in leading scientific journal PLOS Biology on Wednesday 8 April.

   Send article as PDF