Antibiotic resistance is a "ticking time bomb," according to top medical officials. Campaigns against resistant bacteria have focused mainly on the development of new antibiotics, using existing antibiotics properly, and preventing infections in the first place. A new study proposes something else entirely: treat bacterial infection using a sequence of drugs, optimized so that before germs develop resistance to one antibiotic, they get hammered with another.
Conventional approaches to antibiotic-resistant bacteria usually involve big doses of common antibiotic drugs like erythromycin or methicillin—the latter, incidentally, is the "M" in MRSA, a growing concern in hospitals. The idea is to kill off every last bacterium before it can evolve into something current drugs can't touch. But that's not really how antibiotics—or, more importantly, evolution—work. In actuality, mutations produce many different strains of bacteria, all fairly similar, but some more resistant to a given drug than others. Antibiotics kill what they can, leaving the strongest bugs to fight another day—that's just natural selection at work. And when only the strongest are left, how do we fight them?
One idea is to turn evolution against drug-resistant bacteria using a technique known as "sequential treatment," in which one treats an infection first with one antibiotic and then another. While bacteria that survive the first round will be more resistant to the first antibiotic, most of what's left won't survive a round with the second antibiotic. Repeat a few times, and you kill a lot more bacteria than you would with a single drug or a cocktail of two or more antibiotics. Even better, what's left over is less likely to be resistant to the antibiotics used during treatment.
Treat bacterial infection using a sequence of drugs, optimized so that before germs develop resistance to one antibiotic, they get hammered with another.
That's where things stood when a team led by Ayari Fuentes-Hernandez, a researcher at Universidad Nacional Autónoma de México, and Robert Beardmore, a professor of mathematical biosciences at the University of Exeter, had an idea: alternating back and forth between drugs—A, B, A, B, and so on—isn't the only possibility. Other, more complicated sequences are possible, and laboratory tests could help figure out which ones were most effective against a bacteria.
As a proof of concept, the team used four 12-hour rounds of erythromycin and doxycycline against Escherichia coli in the lab. For comparison, they also tested a 50-50 cocktail of the two drugs. While the cocktail worked best in the short term, it soon failed to stop E. coli from proliferating. Sequential treatments worked better, and one in particular, EDEDDDEE—where E stands for a round of erythromycin and D for a round of doxycycline—cut E. coli loads to a quarter of what the 50-50 cocktail did, despite relatively low doses of both drugs.
Though they haven't yet tested such treatments in people—just lab samples of E. coli at this point—the teams argues today in PLoS Biology that low- to mid-dose sequential treatments could be effective against a variety of infections, even when bacteria might become resistant to combinations of the drugs involved.
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