Editorial Commentary: Phage Therapy: Quo Vadis?

(See the Review Article by Knoll and Mylonakis on pages 528–34.) In this issue of Clinical Infectious Diseases, Knoll and Mylonakis provide a balanced review on the phage therapy literature. Their review covers both replication-competent phages and biotechnologically produced lytic phage enzymes as antimicrobial agents. The authors, and the editors of CID, are to be lauded for this timely review as phages and their enzymes represent at least theoretically an interesting alternative to antibiotics. Phage cocktails have been for decades a registered medicine in Russia and are there sold as over-the-counter products in pharmacies. The product information recommends these phage cocktails for the prevention and treatment of a long list of bacterial infections. In contrast, phages have not reached the attention of medical practitioners in the Western world. Even the research community did not embrace phage approaches when major grant agencies from the United States, Canada, and the United Kingdom called for research programs on alternatives to antibiotics. The phage therapy field seems to be split into phage-skeptics and phage-enthusiasts, where the former dismiss phage therapy as a “Stalinist cure” and the latter praise phages as a time-honored medicine. Skeptical scientists point to the lack of published scientific information on the efficacy of phage therapy. Indeed, Knoll and Mylonakis do not quote a single phage paper from Eastern Europe. This defect is not an overlook, but a reflection of a different publication policy in the former Soviet Union. Despite some recent efforts from the Eliava Institute in Tbilisi, the cradle of Soviet phage therapy, to collect data from the archives, Eastern phage therapy efforts are essentially not documented. From the viewpoint of evidence-based medicine, phage therapy is thus largely an unproven concept in human medicine backed so far by promising animal experiments. Detailed and convincing animal studies go back, in fact, to the 1940s and 1980s in US and UK laboratories using Shigella and Escherichia coli phages in mice and domesticated ruminants [1]. As stressed by Knoll and Mylonakis, with respect to human application only a few phase 1 safety data have so far been published, the only exception being a small phase 2 trial with a carefully targeted cocktail against Pseudomonas infection in chronic otitis externa. It is thus premature to consider phages currently as a credible alternative or adjunct to antibiotics. A number of reasons have been given as to why phage therapy research has not attracted more research groups. The lack of interest of the pharmaceutical industry for phage therapy could be explained by the fact that phage products would cannibalize antibiotic selling and thus be commercially counterproductive for this industry. The difficulty of patent protection for phage therapy approaches has been identified as another reason discouraging commercial groups going into phage research. The lack of clarity about regulatory requirements for medical phage application might be a further factor explaining industrial hesitation. Despite the fact that the production of phages is a straightforward biotechnology process, Harper (AmpliPhi BioSciences, oral presentation at First International Oxford bacteriophages conference, September 2011) has estimated that the development of “therapeutic” phages for a single registered medical application would need an investment in excess of 5 million dollars, which is beyond the reach of the relatively small biotech companies active in the field of phage therapy. Several of them have therefore turned to the use of phages in the field of food safety. Indeed, hurdles are lower in this area as demonstrated by US Food and Drug Administration approvals for phage cocktails in food processing as described by Knoll and Mylonakis. Importantly, Knoll and Mylonakis also stress that researchers should push regulatory agencies to play a more active role in providing guidelines for phage approaches. One might also argue that governmental agencies such as the Centers for Disease Control and Prevention or its European complement should take a lead in developing phage therapy, as such research is a public health priority in times of an antibiotic resistance crisis. An encouraging sign in that direction is the Phagoburn project (http://www.phagoburn.eu/), which is funded by the European Commission under the Seventh Framework Program for Research and Development. It coordinates activities conducted by the French Ministry of Defense, a Belgian military hospital, a Swiss university hospital, and several specialized French biotech companies. The targets are E. coli and Pseudomonas infections on the wounds of burn patients. The project was launched 5 months ago and has the budget to conduct a multicenter combined phase 1 and 2 trial. Escherichia coli and its phages sound familiar: Aren't they the basis and workhorses of molecular biology? To remain on the beaten path [2], we have also targeted E. coli diarrhea in children for treatment with T4 phages in a registered trial quoted by Knoll and Mylonakis. The familiarity of this biological system should, however, not give us a feeling of false security. As correctly pointed out by Knoll and Mylonakis, phage therapy is target specific. Sparing the patient the deleterious effect of antibiotics on the commensal microbiota is a clear advantage. However, this target specificity is at the same time a major hurdle for phage therapy when dealing with a genetically dynamic pathogen such as E. coli, which presents with many and still-developing pathotypes and even more serotypes. Indeed, in our E. coli diarrhea phage project, we had difficulties to achieve with a single phage cocktail a good coverage of E. coli pathogens isolated from different ecological settings. The situation might be more favorable in other infections where broad-host range phages have been reported (eg, with Staphylococcus aureus) or in diseases such as dysentery linked to a single, narrowly defined pathogen (Shigella is taxonomically just a small subgroup of the E. coli species). Not surprisingly, the best documented case of Soviet phage therapy reports on the prevention of dysentery by a Shigella phage. Knoll and Mylonakis rightly stress the importance of a threshold concentration needed for a pathogen to become an efficient target for phage replication. In vitro data demonstrated that coliphage amplification did not occur below 104E. coli cells/mL. Marine microbiologists calculated 105 cells/mL as minimal bacterial concentration for virus amplification [3]. Based on evolutionary reasoning, phage cannot be expected to wipe out low-abundance bacteria—otherwise they would lose their propagating hosts. This led ecologists to the concept of “phage killing the winning population” [4]. We hypothesized that intestinal E. coli is a winning population in acute diarrhea. This assumption might, however, not be correct: Brazilian children diagnosed with an acute enteropathogenic Escherichia coli (EPEC) infection only showed 3 × 105 EPEC/g stool, a mere 10-fold increase over the EPEC concentration in healthy control children [5]. Will this target size be sufficient for phage therapy? Further unorthodox observations emerged from mice inoculated with E. coli in experiments conducted in different laboratories, where only transient decreases in intestinal E. coli titers were observed after oral phage application. Apparently, fecal E. coli isolates that were in vitro fully susceptible to phage developed a type of physiological resistance to phage in the intestine [6, 7]. Unfortunately, knowledge on the interaction of phage with E. coli in the intestine, their natural niche, is largely nonexistent [8]. Clearly, we need more phage research with an ecological and physiological focus if we do not want to repeat the errors of the past, when phage therapy approaches in the 1930s failed because of lack of knowledge on the nature of phages. Potential conflicts of interest. The author works as an employee at the Nestlé Research Center in Lausanne, Switzerland, but beyond that has no financial interest in phage therapy (no shares in the Nestlé company nor consultant fees from other companies). The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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