To Beat Drug-Resistant Bacteria, Hit Them Hard and Early With Diverse Phage Cocktails

As multidrug antibiotic resistance grows into a major public health problem, researchers are taking a fresh look at bacteriophage therapy, which uses viruses called phages to infect and destroy specific bacteria. A new mathematical model, described in the journal PLOS Computational Biology, aims to explain why particular phage therapies succeed or fail and how to optimize the mix of phages used in a "cocktail" against infection.

"Phage are the most prevalent organisms on the planet," said Alan Perelson, a scientist at Los Alamos National Laboratory and a co-author of the research. "They exist everywhere bacteria exist. However, each phage has evolved to narrowly target specific bacteria, and bacteria have evolved various mechanisms of resistance." Because bacteria respond to phages quickly and in complex ways, it has not usually been clear why a given phage treatment worked or didn't.

The team, led by Rob J. de Boer, built on an existing model calibrated with data from phage therapy in a live mouse and extended it to humans, incorporating multiple phages infecting multiple bacterial strains with varying levels of resistance. The model showed that a bacterial infection's pretreatment resistance level, the diversity of the phage cocktail, and the timing of its delivery all shape whether the therapy succeeds. More infective phages kill off less-resistant bacteria faster, but that leaves the more resistant bacteria to expand and evolve stronger resistance through mutation. A diverse mix of phages overwhelms the bacteria's ability to evolve resistance quickly enough, and delivering the full cocktail immediately creates a high genetic barrier, forcing bacteria to accumulate several mutations at once to survive.

"The rapid evolution of resistance is the main challenge to therapy," Perelson said. "That capacity is why antibiotics may not work in the first place. For phage therapy to be effective, the cocktails should be diverse, sufficient and immediate." The approach, he said, amounts to hitting the bacteria hard and early.