Posted on September 22, 2015
“The enemy of my enemy is my friend” is the approach of phage therapy.1 What is phage therapy? It is a fascinating human application of a natural phenomenon. Essentially, the naturally occurring, co-evolving enemies of bacteria, namely bacteriophages, which are viruses, destroy the infectious organism. The bacteriophages are specific to the type of cell they infect and therefore, pose little risk to the human host.2 Bacteriophages naturally occur in the mucus of the human gastrointestinal tract.3 The photo below illustrates bacteriophages attacking Escherichia coli (E. coli).3,4
An antimicrobial by definition is “any substance of natural, semisynthetic or synthetic origin that kills or inhibits the growth of microorganisms but causes little or no damage to the host.”5 Synthetic or semisynthetic drug molecules inappropriately dubbed as antibiotics fall into the broader antimicrobial category – as does phage therapy.5,6 It is important to note that bacteriophages are not antibiotics, therefore, they do not instigate antibiotic resistance when utilized.2
Colored scanning electron micrograph image of bacteriophages attacking E. coli3,4
Phage therapy has a long and complicated history throughout the world. The 1940s ushered in a golden era of antibiotics, at which time phage therapy waned throughout the world, however it never fell out of favor in Georgia (formerly the Georgian Soviet Socialist Republic8) and, as a result, phage therapy refinement continued.7 There are two preparations available for over-the-counter purchase in Georgia; one targets wounds infected with Staphylococcus, Streptococcus, Pseudomonas, Proteus and E. coli, while the other targets a multitude of gastrointestinal pathogens.7 The manufacturers of these preparations monitor the causative strains and adjust the product every six months to target the current pathogens much like we do for the influenza vaccine.7
In addition, the major medical school in the Georgian capital of Tbilisi has a training program for surgeons on how to manage severe surgical and wound infections using phages as key therapeutic elements.7 The long history of the safe utilization of phage therapy in this and other European countries makes a strong case for its use in the United States.
The FDA is practicing the due diligence our clinicians and public expects in regards to establishing the safety and efficacy of the phage approach by requiring clinical trials.7,9 There is currently a phase I/II topical phage therapy clinical trial recruiting patients in Belgium, France, and Switzerland targeting burn wounds infected with E.coli or Pseudomonas aeruginosa.9,10 Other biotech companies such as AmpliPhi Biosciences, TechnoPhage and Novolytics are on the verge of beginning trials as well.9,11 TechnoPhage expects to accomplish fast track approval for their topical phage treatment TP-102 targeting diabetic wounds infected with Pseudomonas or Staphylococcus, including methicillin-resistant Staphylococcus aureus.11
Bringing phage therapy products to market may still have some difficulties due to a lack of a regulatory pathway, similar to the problems biosimilars recently faced.12 Some scientists believe that phage therapy is the response we need in order to face the rapidly declining utility of current antibiotics. Hargreaves and Clokie have gone so far as to suggest phage therapy as a first line treatment option for Clostridium difficile infections, reserving traditional antibiotics as a last line of defense.13 There is concern that since we, as a nation, are ingrained to believe that traditional drug molecules are the only route to a cure for infectious disease, phage therapy will be dismissed out of hand.
The national push for reducing antimicrobial resistance through judicious use of antibiotics should provide the impetus to bring back into play previously dismissed therapy options such as phage therapy. If phage therapy does manage to gain well-deserved traction, does this mean that other alternative therapies previously dismissed in the 1940s due to the availability of antibiotics will also come back into favor, such as maggot debridement therapy (MDT)?
As a pharmacist, I have no way of providing a recommendation for therapeutic optimization of the larval ingestion of decaying flesh. However, even if I am working myself out of a job, if it improves patient outcomes and decreases antibiotic resistance, then bring it on! If it is proven these therapies are safe, efficacious, and cost effective, it will be incumbent upon the medication experts to help promote them and not allow them to fall by the wayside again.
Starpoli N. Swan song for antibiotics? Can phage therapy and gene editing fill the gap? Genetic Literacy Project. http://www.geneticliteracyproject.org/2015/07/26/swan-song-for-antibiotics-can-phage-therapy-and-gene-editing-fill-the-gap/
Loc-Carrillo C, Abedon ST. Pros and cons of phage therapy. Bacteriophage 2011;1:2, 111-114.
Yong E. Viruses in the gut protect from infection. Nature News. 2013. http://www.nature.com/news/viruses-in-the-gut-protect-from-infection-1.13023. Accessed September 18, 2015.
Wetware Ontologies. Image. http://wetwareontologies.tumblr.com/post/54671983753/juergen-bergerscience-photo-library-viruses
Michigan State University. Antimicrobials: an introduction. Antimicrobial Resistance Learning Site: Pharmacology. http://amrls.cvm.msu.edu/pharmacology/antimicrobials/antimicrobials-an-introduction
Amonov RI. A brief history of the antibiotic era: lessons learned and challenges for the future. Frontiers in Microbiology. 2010;1:1-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109405/pdf/fmicb-01-00134.pdf
Abedon ST, et al. Phage treatment of human infections. Bacteriophage March/April 2011: 1:2, 66-85. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3278644/pdf/bact0102_0066.pdf
One World – Nations Online. Georgia. http://www.nationsonline.org/oneworld/georgia.htm
Kingwell KK. Bacteriophage therapies re-enter clinical trials. Nature reviews. Drug discovery. 2015-07;14:515-516.
Phagoburn clinical trial info. https://clinicaltrials.gov/ct2/show/NCT02116010?term=phagoburn&rank=1
Technophage. Invest in our products. http://www.technophage.pt/index.php/business/investor-relations
De Vos, Daniel, et al. European regulatory conundrum of phage therapy. Future Microbiology Oct. 2007: 485+. Expanded Academic ASAP. Web. 18 Sept. 2015. http://go.galegroup.com.ezproxy.umassmed.edu/ps/i.do?id=GALE%7CA224840266&v=2.1&u=mlin_c_umassmed&it=r&p=EAIM&sw=w&asid=b960de8a2d0dfc3918be01a5f87c971f
Hargreaves KR and Clokie MR. Clostridium difficile phages: still difficult? Frontiers in microbiology:virology. 2014;5:1-14.