References
Bacteriophage treatment of intransigent diabetic toe ulcers: a case series
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.
The escalating problem of antibiotic resistance and fear of returning to the pre-antibiotic era is driving the search for additional options. One possibility is the use of bacteriophages—viruses that only target specific bacteria, while leaving human cells and most other bacteria untouched. Bacteriophages (phages) have been used extensively in some countries as an alternative to antibiotics or together with antibiotics. This combination can shorten the duration of antibiotic treatment by creating two very different and complementary modes of attack, also potentially helping prevent the development of antibiotic resistant bacteria.1 Antibiotic resistance has no bearing on phage effectiveness. Phage treatment also offers a number of advantages in tackling recalcitrant peripheral ulcer infections, as not only can phage treat antibiotic-resistant infections, but they can also effectively treat cases where vascular compromise limits antibiotic effectiveness even when the bacteria are sensitive in vitro to the antibiotics prescribed.
More than 50% of diabetic foot ulcers (DFUs) become infected1 with ~18% resulting in minor amputation at best.2 The most common infective organism is meticillin-sensitive Staphylococcus aureus (MSSA), but meticillin-resistant Staphylococcus aureus (MRSA) makes the infection harder to treat.3 MRSA infections often lead to increased time to wound healing, longer hospitalisations, and increased amputations.4 Antibiotic treatment of the infection often fails, even when clinical treatment guidelines are closely followed,5 with failure common even when the bacteria are sensitive to the antibiotics prescribed, especially when the infection involves bone. Currently there is controversy regarding the recommended duration of antibiotic therapy.6 The failure of antibiotics to successfully treat ulcers with bone infection often leads to amputation, and this is associated with high costs, disability and significantly increased mortality, even after accounting for comorbidities such as peripheral vascular disease.7
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