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C OPYRIGHT 2013
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T HE J OURNAL

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S URGERY, I NCORPORATED

Commentary & Perspective

Exploring New Strategies for Infection Treatment
Commentary on an article by Cengiz Yilmaz, MD, et al.: Bacteriophage Therapy in Implant-Related Infections. An Experimental Study

Dirk Jan F. Moojen, MD, PhD Although many improvements have been made regarding the prevention of post-surgical infection during the last few decades, implant-related infections remain an important and challenging clinical problem. With the ever-increasing number of total joint arthroplasties implanted annually and the increasing emergence of antibiotic-resistant bacteria, this challenge will be even greater in the near future. Whereas most resistant bacteria can still be treated with last-resort antibiotics such as linezolid and carbapenems, more and more multiresistant species for which there is currently no available antibiotic treatment are being found. This forces us to look at antimicrobial options outside of the traditional eld of antibiotics. The efcacy of various potential new strategies has already been investigated in vitro and in vivo. These strategies included the use of antiseptics, antimicrobial peptides, silver, and autologous platelet-rich gel. Most studies have investigated the efcacy of these strategies in the prevention of implant-related infections rather than the treatment of such infections. Despite the promising results of some strategies, almost none have reached the clinical application phase. The authors of the current study investigated another novel strategy against implant-related infectionsthe use of bacteriophages as antimicrobial agents. Although the use of bacteriophages for this particular indication is novel, the use of bacteriophages to treat infection is actually a technique that is almost a century old. Although this technique never gained worldwide popularity because of the discovery of antibiotics, bacteriophages have been used to treat different kinds of infections in many countries of the former Soviet Union. This treatment is based on the nature of bacteriophages, which are viruses that invade bacterial cells and inject part of their genome, thereby taking over the bacteriums metabolic activity. This enables them to replicate themselves and to produce specic proteins, called endolysins, which ultimately kill the bacterium. In addition to lysing the bacterial cell wall, these endolysins would be able to destroy the polysaccharide matrix of biolms. The authors present a well-designed in vivo study that uses a previously developed implant-related animal infection model. The implant material used was a plastic catheter sheath, which was both precolonized and locally contaminated at the time of implantation. The authors studied the activity of two different bacteriophages, against biolm-forming methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, and compared the results of the bacteriophage treatment with no treatment, adequate antibiotic treatment, and combined bacteriophage and antibiotic treatment. The outcomes studied were infection markers in blood, microbiology, and histopathology using both light and electron microscopy. The results showed that, for MRSA, the antibiotic therapy and the bacteriophage therapy were each effective in decreasing the number of cases in which bacteria were still seen and in decreasing the quantitative number of bacteria (although the decreases in the bacteriophage group did not reach signicance). However, the combination of antibiotics and bacteriophages was the most effective, suggesting a synergistic effect. The combination therapy not only eradicated almost all bacteria but also completely destroyed the biolm. An interesting nding was the large increase in biolm thickness in the group treated with antibiotic therapy; this may illustrate the fact that many antibiotics are effective in killing the freeoating bacteria but do not inuence the adherent bacteria inside the polysaccharide matrix of the biolm. For Pseudomonas aeruginosa, the effect of the bacteriophage treatment was less pronounced. Although there was a signicant decrease in the number of bacteria found, most of the rats in each group remained infected, and there was no decrease in the biolm thickness. Even although the authors were able to demonstrate only partial success of the bacteriophage therapy, in my opinion the use of bacteriophages does sound like a promising option for future treatment of implant-related infections, most likely as a synergistic agent in combination with antibiotics. In this respect, the current study should be regarded as a rst step. A limitation of the study is the fact that a plastic catheter sheath rather than a metallic implant was used as the implant material. The authors setup does illustrate the idea of bacteriophage therapy nicely, but it is not fully representative of everyday orthopaedic practice. As the authors already mention in their discussion, there are still many areas that require further research. Although bacteriophage therapy has been used clinically for indications such as sepsis and local wound care, there are no guidelines regarding the optimal treatment dose, duration of treatment, and means of administration. The authors chose local injection in their study, but bacteriophages can be administered orally and systemically as well.

J Bone Joint Surg Am. 2013;95:e11(1-2)

http://dx.doi.org/10.2106/JBJS.L.01419

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Other potential problems regarding bacteriophage therapy can be found in the literature1. Most bacteriophages have quite a narrow host range and thus only act on specic bacteria, in contrast with the usual broad-spectrum activity of antibiotics. This could be a problem in polymicrobial infections or in infections in which no microorganism is cultured. In addition, bacteria can develop resistance against bacteriophages as well (for example, by modifying the expression of receptors necessary for bacteriophage absorption). Another problem involves the fact that bacteriophages incite an immune response, resulting in a risk that the human body will inactivate them after repeated exposure. Finally, there is little knowledge regarding bacteriophage safety and potential side effects. Even though there are many topics that require further investigation, I do support the prudent conclusions of the authors, who claim that there appears to be a role for bacteriophages in combination with antibiotics in the treatment of biolm-forming infections. The results of their study warrant further work in this eld.
Dirk Jan F. Moojen MD, PhD* University of Toronto, St. Michaels Hospital, Toronto, Ontario, Canada
*The author received no payments or services, either directly or indirectly (i.e., via his institution), from a third party in support of any aspect of this work. Neither the author nor his institution has had any nancial relationship, in the thirty-six months prior to submission of this work, with any entity in the biomedical arena that could be perceived to inuence or have the potential to inuence what is written in this work. Also, the author has not had any other relationships, or engaged in any other activities, that could be perceived to inuence or have the potential to inuence what is written in this work. The complete Disclosures of Potential Conicts of Interest submitted by authors are always provided with the online version of the article.

Reference
1. Donlan RM. Preventing biolms of clinically relevant organisms using bacteriophage. Trends Microbiol. 2009;17(2):66-72.