Bacteriophage therapy: An idea whose time has come?

220px-PhageBacteriophages are viruses that attack bacteria–their name means “bacteria eater” in Latin. Here, you can see a bunch of bacteriophages on the surface of a bacterial cell. They look sort of like balloons tethered to the surface of the moon. They were discovered near the dawn of the twentieth century, and at first they enjoyed some spectacular therapeutic successes. Felix d’Herelle, one of the men who discovered bacteriophages, treated four dysentery patients with them in 1919. Soon after, he used bacteriophages to treat outbreaks of cholera in India and plague in Egypt. In the U.S., phage trials were performed at Baylor, and the researchers involved were impressed by phage therapy. It didn’t always work so well in practice, though. Phage therapy can be tricky. The organomercury used to preserve phage cocktails often destroyed them instead. Preparations could also be contaminated with exotoxins produced by the bacteria used to grow the phages. Finally, there have been problems in the past with inconsistency. The composition of a phage treatment may vary from batch to batch, with predictable effects on efficacy. Many physicians were less than happy with the results they got with phages. And when antibiotics were discovered, there was really no reason to continue to struggle with this form of therapy.

Things are different today, though. There are so many reasons why bacteriophage therapy makes sense. First, antibiotic resistance is increasingly becoming a problem. The utility of our antibiotics is dwindling, and the discovery of new antibiotics isn’t keeping pace. Antibiotics are static. But bacteriophages can evolve along with their bacterial prey. Instead of  struggling to identify new antibiotics, perhaps we could use phages and let natural selection do our work for us. If we’re lucky, maybe bacteriophages could replace some of the antibiotics we’re losing. In addition, we’re beginning to appreciate how important our microflora are. Wiping out our microbial ecosystem wholesale with antibiotics isn’t desirable, and it can increase susceptibility to pathogens like C. difficile. Bacteriophages, because they target only specific types of bacteria, might get around this problem–killing the problematic bacteria, but leaving everything else intact. Mixtures of phage could potentially be tailored to a person’s specific infection.

One of the reasons that phage therapy has been slow to catch on in the U.S. is that it has been primarily practiced in Eastern Europe and the Soviet Union. Today, phage therapy is routinely being used in Russia and the Republic of Georgia. But over the years, much of the work done was not published in English, so scientists in the West were unaware of it. In addition, many studies didn’t meet the standards that western scientists require. And, of course, getting approval to use a new therapy in the clinic is tough. As a result, companies have been wary of trying out phage therapy in humans and have been using it in different settings instead. Phages targeted to Listeria, a food-borne pathogen, have been approved by the FDA to help sterilize processed foods. Other phage mixtures have been approved to protect crops against pathogens. And more phage treatments are in the works.

Baby steps toward human treatments are being made, though. In the U.S., several safety studies in humans have shown promising results. And the first randomized controlled trial in the West was recently performed by Biocontrol Limited. It targeted adult patients with chronic ear infections caused by antibiotic resistant Pseudomonas aeruginosa; a bacteriophage solution was swabbed on infected ears. The researchers involved reported outcomes that were better than those achieved with a placebo, which is promising! As we have begun to appreciate the ecosystem in our guts, some researchers have proposed that bacteriophage therapy could help us perform more subtle manipulations than the ones to which we’re accustomed–by introducing certain phage, perhaps we could promote the biosynthesis of nutrients or the breakdown of parts of our diet.

Phage therapy faces some of the same major challenges that antibiotics do. Bacteria can develop resistance to bacteriophages. And a given phage can only target a relatively narrow range of bacteria. For these reasons, often a mixture of phage are administered to a patient. In terms of obtaining regulatory approval, this can be tricky, however. Although treating people with multiple phages does prolong the time until resistant bacteria arise, resistance may be inevitable. Therefore, researchers have been throwing around ideas like combining phage and antibiotic treatments (which seems to work especially well), cycling different phage mixtures, or engineering phage that can circumvent mechanisms of resistance.

Delivering the phage to where they need to go can also be tough. They have to spread from the site of application, and they also have to avoid being cleared from the bloodstream. For that reason, researchers have been focusing on infections that are localized (like ear infections and wounds). Over time, it may be possible to engineer delivery systems that will enable phage treatments to be used for more systemic infections. Some researchers have even shown that specially-engineered bacteriophages have the potential to break down biofilms, a gooey layer of protection that bacteria can hide behind.

Bacteriophage therapy may not be ready for primetime yet, but great strides have been made in the past few years. I’m really looking forward to seeing where this alternative type of treatment is going to go!