I have a New Year’s prediction for you. In 2020, you will see an article which claims that a forgotten remedy may be the answer to the antibiotic resistance crisis.

This prediction requires no special powers. Such articles appeared in the 1980s , 1990s , 2000 , 2001, 2002 , 2003, 2004, 2005, 2006, 2007 , 2008, 2009 , 2010, 2011, 2012, 2013, 2014, 2015, 2016, 2017, 2018, and of course 2019. It would be a miracle if none were written in 2020.

As you’ve guessed, I’m talking about phage therapy. Phage are viruses that infect and kill bacteria, including antibiotic resistant bacteria. They do indeed have the potential to treat infections, antibiotic resistant and otherwise. That potential has gone unrealized.

I’ll tell you why, and I’ll also tell you how phage therapy can progress from possibility to reality.

My perspective is a bit different from that of science journalists, or the professors and doctors they interview. I was the R&D Director at MicroPhage. While there, I led a team which developed the first (and only) phage product to win FDA approval (a rapid test for bloodstream infections).

I had to deal with all the messy realities of turning a technology into a product. That’s a much different proposition than pontificating on the potential of phage.

So here are a few takeaways I hope you’ll keep in mind when you read that next phage therapy article.

Antibiotics didn’t kill off phage therapy. It was already pretty much dead. Thousands of scientific reports on phage therapy were published in the 1920s. Infections were still the leading cause of death, and doctors could do little to treat them. Clinicians desperately wanted PT to succeed and did their best to make that happen. Inconsistent results and frequent adverse events dampened enthusiasm.

By the 1930s the medical community was skeptical of PT. It was more than ready to move on when penicillin became available in the 1940s.

Ad for phage therapies, probably from the 1930s. Credit: Wellcome Library, London. Wellcome Images images@wellcome.ac.uk http://wellcomeimages.org. CC BY 4.0.

Most of the evidence for the efficacy of phage therapy is crap. Although moribund in the West, PT thrived in the Soviet Union and Eastern Europe. But its practitioners never performed controlled trials. Most of the recent reports of PT efficacy in the West are also case studies: the patient failed other therapy, we gave her phage, she got better.

The problem with these types of studies is that humans tend to get better even without therapy. Scouring the historical literature, Brad Spellberg estimated cure rates for infections. Among complicated skin infections, cure rates for placebos are 66%-76%. Antibiotics improve these rates to 83–98%. Without a well-designed trial, it’s impossible to tell what the benefit of therapy actually is.

PT shows mixed results in well-designed studies. The first randomized placebo-controlled trial for PT took place in 2009. It showed good evidence for efficacy in treating ear infections. A trial of oral PT for E. coli diarrhea in children found no evidence of a therapeutic benefit. The Phagoburn trial of PT for burn wound patients also found no evidence of benefit. Other trials are at various stages of completion. Right now, the evidence for the efficacy of PT is very thin.

Phage are physically unlike other drugs. Most drugs are small molecules that persist for hours in the bloodstream and diffuse rapidly into tissues. Phage are very large molecules that are cleared from the bloodstream in minutes and diffuse into tissues very slowly. They also tend to provoke immune responses. These properties make phage unsuited for treating systemic infections.

Phage therapy should work best for localized infections. Systemic infections are not ideal, but there are plenty of other applications for PT. Infections of the skin, the vagina, and the lung (especially for cystic fibrosis patients), are all plausible targets for PT.

Persistence of bacteriophage in mouse lungs. This is the kind of work we need more of in order to make phage therapy reliable. From Pulmonary Bacteriophage Therapy on Pseudomonas aeruginosa Cystic Fibrosis Strains: First Steps Towards Treatment and Prevention. CC by SA.

Phage therapy is technically feasible. Despite the foregoing, I am optimistic about the future of phage therapy. The principle is sound. Although individual case studies are not convincing, in aggregate they show that PT has effected many cures. We just need to do better science.

Phage therapy is never going to replace antibiotics. Antibiotics are the most successful medicines ever developed. Doctors are not going to give them up, nor should they. Even in our age of resistance, nearly all bacteria are susceptible to at least one antibiotic. Antibiotics are never going away, and they will not become useless.

The principal barriers are economic, not technical. We need to work out pharmacokinetics, dosing, formulation, manufacturing, and quality control for phage. That’s a lot of work, but it’s just work. No breakthroughs are required.

The one thing required is the one thing that is missing: money. There isn’t any for antimicrobial development. Pharma has given up on antibiotics. Drug companies can’t charge much more than $1K for a round of antibiotic treatment. But they can get >$100K for a mediocre cancer drug. Both have roughly the same risks and development costs. Which path would you choose if you were running a drug company?

In all likelihood, phage therapy will have to be developed with non-profit money. The markets are small and pricing power is low. There isn’t any serious money to be made. But there is serious potential to save lives and reduce human suffering.

Bacteriophage. By GrahamColm at English Wikipedia [CC BY-SA 3.0 (https://creativecommons.org/licenses/by-sa/3.0)]

The real story with phage therapy isn’t the one about reviving forgotten cures or the one about good viruses. It’s the one about markets failing to value a treatment which has substantial value to society. My New Year’s wish for you is to see no more of the former stories and many of the latter. That in itself would be progress.