Sequential treatment using similar antibiotics can kill bacteria and prevent drug resistance
Sequential treatment with similar but frequently exchanged antibiotics is an effective way to kill bacteria and prevent drug resistance, according to a study conducted in eLife reports.
The findings challenge a broad hypothesis that the use of similar antibiotics promotes cross-resistance to drugs and show that the available antibiotics could offer unexplored and very potent treatment options.
We are currently in an antibiotic crisis, where overuse of antibiotics leads to an increase in antibiotic resistance and some infections have become difficult or even impossible to treat. It is the ability of pathogens to evolve and adapt to drugs that underlies this resistance, but evolutionary theory predicts that adaptation is difficult when the environment changes rapidly. We wanted to test if we could use sequential antibiotic therapy to slow the progression of human pathogens and limit drug resistance.. “
Aditi Batra, first study author and graduate student, Max Planck Institute for Evolutionary Biology, University of Kiel
The team used bacteria called Pseudomonas aeruginosa (P. aeruginosa), which can cause pneumonia and other infections in humans. They tested three different sequences of antibiotics under laboratory conditions and measured their effectiveness in killing different subpopulations of advanced bacterial cells. Two sets of antibiotics belonged to a class of drugs called -lactams, which have a common structural component: a β-lactam ring. The other set of antibiotics all worked through different mechanisms.
To the team’s surprise, treatment with both sets of β-lactam antibiotics was more effective at killing bacterial populations than some of the unrelated antibiotics. Additionally, rapid switching between individual antibiotics produced much better extinction of bacterial populations than when switching between antibiotics was slower. This suggests that the rapid switching between antibiotics limited the ability of bacteria to adapt to drugs. Faced with this unexpected result, the team explored the mechanisms at the origin of this evolutionary constraint.
They studied changes in growth, resistance patterns and entire genome sequences of the P. aeruginosa populations treated with the most potent sequence of β-lactam antibiotics, which combined carbenicillin, doripenem and cefsulodin. They noted that when the sequences were switched rapidly, bacterial growth upon switching to doripenem was much lower than for the other two antibiotics, indicating that resistance to this drug might emerge more slowly.
They also investigated whether the physiological changes that occur as a result of drug treatment make the bacteria resistant or more sensitive to other drugs in the sequence. They found that the spontaneous development of resistance was much lower for doripenem than for the other two drugs.
There was also less cross resistance to this drug than the other two antibiotics. This absence of cross-resistance may indicate the presence of a so-called collateral sensitivity; this means that the mutant cells, which have become resistant to one drug, maintain at least ancestral levels of sensitivity against the second drug. Collateral sensitivity is known to be important for the effectiveness of sequential treatment.
“Although sequential treatments with such similar antibiotics should have accelerated the development of resistance, we have found that this is not the case if resistance to one of the antibiotics cannot emerge easily and the antibiotics exhibit collateral sensitivity to each other, ”explains lead author Hinrich Schulenburg. , member of the Max Planck Institute for Evolutionary Biology and professor at the University of Kiel. “It is ironic that the differential cross-resistance profile of the β-lactam drugs has been a key factor in the potency of the treatment, even though it is generally used to reject a treatment that exclusively uses these drugs. Our study shows that spontaneous resistance rates of antibiotic components could be used as a guiding principle for sequential treatments and could improve the potency of sequential protocols. “
Batra, A., et al. (2021) High potency of sequential therapy with only β-lactam antibiotics. eLife. doi.org/10.7554/eLife.68876.