Antibiotic Cocktails Could Fight Resistant Bugs

May 21, 2019

The cocktail of antibiotics may be more than the sum of its parts in the fight against drug-resistant bacteria. New research finds that mixing three to five types of antibiotics can increase effectiveness…. Sometimes.

The more than 8,000 combinations of four and five drugs tested in the new study were more effective together than would have been expected based on their individual actions. Even so, “antagonistic interactions” – meaning that the combined drugs were more effective than expected – became more common when the number of drug combinations rose.

Studying how only two drugs combine to interact “is very complicated, so people haven’t really looked at these higher-order interactions,” says Pamela Yeh, a professor of ecology and evolutionary biology at the University of California, Los Angeles (UCLA), and a co-author of the study.

The new research suggests that interactions involving three, four or five drugs are more important than previously thought, Yeh said.

Defeating superbugs
However, it’s unclear whether the multi-drug cocktail will be a real solution to fighting infections treated with conventional antibiotics. The study only looked at antibiotics in a laboratory dish, and it didn’t ask important medical questions, such as how the side effects of a drug can change depending on the amount of antibiotic used.

Instead, the goal was to use bacteria and antibiotics as a tiny, controlled ecosystem to study how stressors interact, said study co-author Van Savage, who is also a professor of ecology and evolutionary biology at UCLA. In real-world ecosystems, stressors can be a combination of precipitation, temperature changes, invasive species, and so on. In a combination, any one of these factors can affect the others, and interactions are not always intuitive, Savage told Live Science.

“It’s easy to take things apart and study them,” Savage said.” That’s one thing that makes sense. But when you put them together, you have to make sure you’re putting them back together in the right way.”

The researchers tested eight antibiotics: ampicillin, cephalexin sodium salt, ciprofloxacin hydrochloride, oxytetracycline, erythromycin, fusidic acid sodium salt, streptomycin, and trimethoprim. These were chosen because they all attack bacteria in different ways. All of the two-, three-, four- and five-drug combinations were mixed with E. coli at several different doses in experimental dishes, and a total of 18,278 independent experiments were performed.

The researchers used bacterial growth rates to measure how effective the combinations were. If two or more antibiotics did not interact, the effect on bacterial growth rate would be the same as multiplying the effects of each antibiotic by each other; for example, two antibiotics were twice as effective as one, and three antibiotics were three times as effective as one. If the antibiotics work synergistically, the effect on growth rate will be greater than this baseline; if they antagonize each other, the effect will be smaller.

In 1,676 four-drug cases and 6,443 five-drug cases, the antibiotics were shown to work synergistically. These drugs were more effective in killing bacteria than would be expected if they were simply used side by side and not interacting.

Complex interactions
The researchers had expected that the more drugs that went into the mix, the less important the additional interactions would be, Savage said. Essentially, they expected that the first few drug interactions would be the most important. But that’s not what they saw.

“When you see three, four or five drugs, there’s something new going on [different from what you see in pairs],” Savage says.

But more antibiotics aren’t always better, even if they attack bacteria in different ways.Yeh says that as the number of drugs increases, so do the number of antagonistic interactions. As a result, some drug combinations perform worse than expected based on individual drugs alone.

Bacterial drug resistance is an important real-world problem, so Yeh said the researchers hope their work will have an impact on future medical research. Bacteria evolve defenses when exposed to antibiotics. The weakest strains are killed off, while drug-resistant strains flourish.

As a result of this phenomenon, the Centers for Disease Control and Prevention lists three drug-resistant strains of bacteria that pose an urgent threat to human health: clostridium difficile, which causes fatal inflammation of the colon; the carbapenem-resistant Enterobacteriaceae, which primarily infects hospital patients and nursing home residents; and Neisseria gonorrhoeae, a drug-resistant bacterium. Clostridium difficile, which can cause fatal inflammation of the colon; carbapenem-resistant Enterobacteriaceae, which primarily infect hospital patients and nursing home residents; and drug-resistant Neisseria gonorrhoeae, a sexually transmitted infection. Another dozen antibiotic-resistant bugs qualify as a serious threat, according to the CDC.

The new findings are important because they show that the effects of mixing antibiotics aren’t always intuitive, the researchers said. Combinations of drugs may be more effective than just one drug, or they may exceed expectations based on expectations of adding the effects of each drug together.

“We have to be very careful at all times where you’re dealing with multiple stressors because they’re interacting and they’re not interacting exactly the way we expected them to,” Yeh said.