Saturday, August 31, 2013

Phage Therapy: A Brief Primer on the History and Current Outlook

As I discussed in a previous post, bacteriophages can play crucial roles in promoting bacterial pathogenesis by acting as reservoirs for antibiotic resistance genes, and by promoting the transfer of those genes across bacterial populations.  Interestingly, while phages can promote bacterial pathogenesis, they can also be used in "phage therapy", meaning they are used as therapeutic agents to treat bacterial infections.  While this idea may sound like a novel approach for treating bacterial infections, the use of phages to treat bacterial infections is quite old.

Felix d'Herelle (seated) at a bacteriophage research center.
Picture Source: Reference [6]
Bacteriophages were first described by Frederick Twort in 1915 [1], and again independently discovered by Felix d'Herelle in 1917 [2].  Early on, scientists (especially d'Herelle) recognized the potential of phages as therapeutic agents against bacterial infections, and while the interest continued in Eastern Europe (where even today, phage therapy centers treat patients), it was largely abandoned in the Americas and Western Europe.  This abandonment occurred in light of Alexander Fleming's discovery of Penicillin and the promise of the new antibiotic drug type.  With the recent rise in the threat of antibiotic resistant bacteria, and the increasingly apparent limitations of antibiotics in certain infectious scenarios (i.e. antibiotics are often unable to penetrate bacterial biofilms), phage therapeutics have gained a renewed interest as important antibiotic alternatives.

Because this renewed interest in phage therapy began recently, few clinical studies have been conducted and there are few phage therapeutics available for commercial use.  Only a handful of FDA or EMA approved clinical trials have been performed to study the safety or efficacy of phage therapies in humans [3].  The first FDA or EMA approved clinical trial to test the efficacy efficacy of a phage therapy was reported in 2009 [3-4].  The study used a phage cocktail to treat ears infected with antibiotic resistant Pseudomonas aeruginosa infections.  The team compared treatment of the phage therapy to a phosphate buffered saline (PBS) control and found the phage therapy to be safe and effective.  An interesting advantage of phage therapy noted by the authors was that, while antibiotics require gram amounts to be delivered, only a couple nano-grams of phage protein, delivered once, was required for therapy.  Other studies have also suggested phage therapies are safe, and future safety and efficacy studies are warranted.

E. coli attacked by T4 phages
While there are no FDA or EMA approved phage therapeutics for use in humans, there are phage cocktails approved for use on food to prevent bacterial growth, and therefore minimize the risk of food poisoning.  The US company Intralytix is currently the only company to provide an FDA approved phage preparation as a food-safety additive [3].  Intralytix has three separate food-additive phage cocktails that target Listeria monocytogenes, E. coli, and Salmonella.  Not only have these phage cocktails been shown to be safe on food, they are also certified as organic and kosher.  It is also worth noting that, while the first food-additive phage cocktail was approved by the FDA in 2006, the first phage-based product approved by a US regulatory agency was "Agriphage", which was product used to prevent bacteria from harming crops [3,5].

Looking forward, I think we are going to see many more advances in the field of phage therapy.  One of the major hurdles for phage therapy in the US and Europe will be dealing with the regulations of the FDA and EMA.  Because the interest in phage therapy is relatively new, the regulatory guidelines for phage therapeutics remain in development (including drug definitions, patent regulations, and clinical trial regulations) and will continue to limit translational research potential by, among other things, limiting clinical trials and discouraging investment [3].

Works Cited

1. An investigation on the nature of ultra-microscopic viruses by Twort FW, L.R.C.P. Lond., M.R.C.S. (From the Laboratories of the Brown Institution, London). Bacteriophage 2011; 1:127 - 129;
Download Free Article

2. On an invisible microbe antagonistic to dysentery bacilli. Note by M. F. d’Herelle, presented by M. Roux. Comptes Rendus Academie des Sciences 1917; 165:373–5. Bacteriophage 2011; 1:3 - 5;
Download Free Article

3. Parracho HM, Burrowes BH, Enright MC, McConville ML, Harper DR. The role of regulated clinical trials in the development of bacteriophage therapeutics. Journal of molecular and genetic medicine : an international journal of biomedical research. 2012;6:279-86. Epub 2012/08/09. PubMed PMID: 22872803; PubMed Central PMCID: PMC3410379.

4. Wright A, Hawkins CH, Anggard EE, Harper DR. A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery. 2009;34(4):349-57. Epub 2009/08/14. doi: 10.1111/j.1749-4486.2009.01973.x. PubMed PMID: 19673983.

5. United States Environmental Protection Agency Xanthomonas campestris pv. vesicatoria and Pseudomonas syringae pv. tomato specific bacteriophages: exemption from the requirement of a tolerance. Federal Register. 2005;70:76700–76704.
Download Free Article

6. Thacker PD. Set a microbe to kill a microbe: drug resistance renews interest in phage therapy. JAMA : the journal of the American Medical Association. 2003;290(24):3183-5. Epub 2003/12/25. doi: 10.1001/jama.290.24.3183. PubMed PMID: 14693857.

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