Fish et. al. Biotherapy Journal Review Summer 2016

Reviewer: Ronald Sherman, MD

Journal Citation

Fish R, Kutter E, Wheat G, Blasdel B, Kutateladze M, Kuhl S. Bacteriophage treatment of intransigent diabetic toe ulcers: a case series. J Wound Care. 2016 Jul;25 Suppl 7:S27-33.

Published Abstract

Objective: Diabetic foot ulcer (DFU) infections are a growing public health problem, with increasing prevalence, poor response to antibiotics and bacterial resistance to traditional antimicrobials leading to increased morbidity and mortality. Bacteriophages (phages), the viruses that target specific bacteria, are one option for addressing bacterial infections, especially where antibiotics fail. Of particular value is a class of virulent staphylococcal phages that hit almost all

Staphylococcus aureus, including most methicillin-resistant Staphylococcus aureus (MRSA) strains. Here we report a continuous case series assessing the effectiveness of treating infected and poorly vascularised toe ulcers with exposed bone, after failure of recommended antibiotic therapy, using topically applied Staphylococcus aureus-specific phage.  Method: This was a compassionate-use case series of nine patients with diabetes and poorly perfused toe ulcers containing culture-proven Staphylococcus aureus infected bone and soft tissue, who had responded poorly to recommended antibiotic therapy. Six representative cases are presented here. The only generally accepted other option in each case was toe amputation. Exposed portions of the infected phalanges were removed in three cases and left in place in two cases. One case presented as a micro-clot induced gangrene following vascular stenting. In this case, phage were used to prevent infection. The phage used was a commercially available fully sequenced preparation of staphylococcal phage Sb-1. Phage solution was applied topically to the ulcerations once weekly, following standard good wound care. The amount of phage solution applied varied from 0.1 to 0.5 cc depending on volume and area of the ulceration.  Results: All infections responded to the phage applications and the ulcers healed in an average of seven weeks with infected bone debridement. One ulcer, where vascularity was extremely poor and bone was not removed to preserve hallux function, required 18 weeks of treatment. In the case of the toe with the micro-clot gangrene, the toe was salvaged and healed in seven weeks without complications.  Conclusion: Topical application of a staph mono-phage preparation can be used successfully to treat infected toe ulcerations with bone involvement, despite very poor vascularity and failure of antibiotic treatment. The success within this small series provides the groundwork for controlled clinical trials of staph phage for diabetic foot infections.

Context

This research – an exploration of the utility of bacteriophage to treat infected diabetic foot ulcers – was carried out to address several significant problems currently plaguing our society. Diabetes is on the rise, and so are the complications, not the least of which are foot ulcers that do not heal, and often result in amputations. While antibiotics are not a simple fix for infected diabetic foot ulcers, even under the best of circumstances, the fact that more and more bacteria are becoming resistant to our antibiotics have made the antibiotics less useful. Some organisms, such as methicillin-resistant Staphylococcus aureus (MRSA) are now susceptible only to the most toxic of antibiotics, if they are susceptible to any at all.

Bacteriophages are viruses that parasitize only specific bacteria. They do not infect other cells or other animals, and they die out when their host bacteria have been destroyed. The therapeutic use of bacteriophage died out, too, in most of the world, with the antibiotic era. Use and research continued only in a few centers, predominantly in Eastern Europe.

The past couple decades have seen a renewed interest in using bacteriophage to control pathogenic bacteria, but large-scale, controlled, prospective trials are stilS quite rare.

It is in this context that this project was undertaken: an analysis of the experience of treating diabetic foot ulcers at a hospital-based wound clinic with a 107 - 108 phage/ml solution of a commercial preparation of staphylococcal phage Sb-1 (Eliava Sb-1). Staphylococcal phage Sb-1 was first isolated in 1977 at the Eliava Institute (Tbilisi, Republic of Georgia) and is a relative of the phages already approved by the U.S. Food and Drug Administration (FDA) for eliminating Listeria monocytogenes in some prepared foods. In fact, a closely related phage can be found in another phage product (Staphage Lysate produced by Delmont Laboratories in Philadelphia) which is already legally marketed for use in animals in the U.S. as an immune stimulant against Staphylococcus infections.

Patients were considered eligible for the compassionate use of this investigational product if they failed to respond to conventional wound care and antibiotic therapy, with amputation being the only remaining routine option. The authors briefly described their treatment protocol as follows:

“Treatment involved standard wound care, including weekly soft tissue debridement if necessary. The softened, exposed and obviously infected bone was debrided in three cases and left in place in two cases where bone debridement would have led to a less favorable functional and cosmetic result. For experimental treatment, the phage preparation was dripped into the wound cavity; gauze packing was placed over the wound and soaked with the phage preparation (0.1 to 0.5cc, depending on ulcer volume), covered with petroleum gauze and wrapped with dry gauze. The patient was instructed to leave the treatment in place for 48 hours before removing it and replacing the treatment with moist dressings. This protocol was repeated weekly until the ulcer became too small to pack.”

Findings

A total of nine patients were treated over two years, all with vascular insufficiency, four with osteomyelitis and bone. MRSA was found in one of the wounds, methicillin-susceptible S aureus (MSSA) in all of the others. Eight of the wounds were clinically infected; one was gangrenous at considered to be “at high risk” of infection. All 9 infections responded to treatment; all nine wounds healed in an average of seven weeks (range: 4 - 18 weeks). There were no adverse events observed during treatment or follow-up.

Discussion

The authors concluded that ”Topical application of a staph mono-phage preparation can be used successfully to treat infected toe ulcerations with bone involvement, despite very poor vascularity and failure of antibiotic treatment. The success within this small series provides the groundwork for controlled clinical trials of staph phage for diabetic foot infections.” Both conclusions are valid.

It is worth noting that phage Sb-1 was not the only treatment administered. Subjects received the gamut of good wound care, including frequent debridement and antibiotics, where indicated. But standard of care treatments like these had been attempted all along, and these subjects failed to respond, as defined by the compassionate use protocol. We must assume that they would have gone on to receive an amputation, had they not been allowed to try phage therapy.

The authors have contributed not only to the literature of phage therapy, but also to our understanding of wound infections in general. This study has demonstrated that even though most wounds are colonized and often infected by multiple organisms, a treatment aimed at a single microbe was still associated with successful treatment of the infected wound. This gives us much food for thought, not only as we begin to design the much-needed and highly justified clinical trials of phage therapy, but also as we re-consider how we currently treat diabetic foot ulcers with broad-spectrum antibiotics in order to kill multiple organisms, despite the commonly seen risks of killing beneficial microbes in the gut (the gastrointestinal biome) and further selecting for microbes with even greater antimicrobial resistance. 

Some readers may ask: why did the subjects not receive maggot therapy? How can they be described as having no commercially available treatment options if they had not been considered for maggot therapy? At least in the biotherapy community, this is a valid question. The answer is quite simple: medicinal maggots are NOT currently approved for managing infection, even if they are approved for debridement in general. Could maggot therapy have been used successfully, either with or instead of phage therapy? While there is data to suggest that this is the case, and although many people may use maggot therapy in tough cases like this, there are no clinical trials to support it. And here we get to the crux of the matter: it is only through well-designed controlled studies – preferably randomized prospective studies, but at least controlled – that we can say with confidence that intervention A is significantly responsible for outcome B. The authors know that they have not proven that phage therapy was the deciding factor, but they hope (and I hope) that their experience and analysis contributes significantly to the body of evidence that we now have to support some good prospective clinical trials of phage therapy.

The authors have contributed not only by providing additional justification for clinical trials, but they have also identified some of the impediments that have blocked clinical trials from having already been done, and they have provided guidance to help overcome some of those impediments. Clinical trials are expensive, and are generally sponsored only by those organizations that believe they can adequately benefit from such a large investment. The authors propose that public money could kick-start some studies, or be combined with corporate money to sponsor such studies. Another obstacle to moving forwards with clinical trials is that there are many different phages and many different ways to combine them into a useful product; and many different infections that could likely benefit. Where do we start? By demonstrating the benefits of a pure strain of naturally occurring phage, they convincingly argue that perhaps we should start with clinical trials of pure, naturally occurring, inexpensive phage, and let the results of those trials generate private support to develop the more expensive – but more lucrative – modified and mixed phage products. This is another approach that may help move us forwards with conducting the clinical trials that are needed before phage therapy can become a reality for the rest of us.