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The Effect of Proteolytic Enzyme Serratiopeptidase in the Treatment of Experimental Implant-Related Infection
Mete Mecikoglu, MD1; Baransel Saygi, MD1; Yakup Yildirim, MD2; Evrim Karadag-Saygi, MD3; Saime Sezgin Ramadan, MD3; Tanil Esemenli, MD3
1 Department of Orthopaedic Surgery, PTT Hospital, E-5 ûzeru Bostanci 34000, Istanbul, Turkey. E-mail address for B. Saygi: baranselsaygi@superonline.com
2 Department of Orthopaedic Surgery, Acibadem Hospital, Kadikóy 34010, Istanbul, Turkey
3 Departments of Physical Medicine and Rehabilitation (E.K.-S.), Pathology (S.S.R.), and Orthopaedics (T.E.), Marmara University Hospital, Tophanelioglu Cad 34100 Altunizade, Istanbul, Turkey
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The authors did not receive grants or outside funding in support of their research for or preparation of this manuscript. They did not receive payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.
Investigation performed at the Animal Research Laboratory, Marmara University School of Medicine, Istanbul, Turkey

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2006 Jun 01;88(6):1208-1214. doi: 10.2106/JBJS.E.00007
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Background: Infection around an implanted orthopaedic device is a devastating complication, and the treatment of infections involving slime-forming bacteria is especially difficult. The purpose of the present study was to evaluate the effectiveness of a proteolytic enzyme, serratiopeptidase, in the eradication of a periprosthetic infection in an in vivo animal model.

Methods: In sixty Sprague-Dawley rats, the medullary canal of the right femur was drilled through the intercondylar notch and was inoculated with a Staphylococcus epidermidis strain (ATCC 35984) with a high slime-producing capacity. The cavity was filled with polymethylmethacrylate cement, and a Kirschner wire that had contact with the knee joint was inserted. None of the animals received any treatment for two weeks. Twenty rats were killed at two weeks after the inoculation in order to determine if the infection had become established. The remaining forty rats were randomized into two groups. One group received serratiopeptidase enzyme injections into the knee joint in addition to antibiotic therapy for four weeks, and the other group received intra-articular saline solution injections together with the same antibiotic therapy. The animals from both groups were killed two weeks after the end of therapy (on Day 56). The knee specimens were evaluated bacteriologically and histologically to determine the prevalence of persistent infection and the effects of the enzyme on local tissue.

Results: At two weeks, inoculated bacteria grew on culture of specimens from twelve (63.2%) of nineteen animals in the no-treatment group. Microbiological testing suggested that infection persisted in only one (5.6%) of eighteen animals in the serratiopeptidase-and-antibiotic group, whereas it was present in six (37.5%) of sixteen animals in the antibiotic-only group (p = 0.001). Histological evaluation showed similar results (kappa = 0.92).

Conclusions: Serratiopeptidase was effective for eradicating infection caused by biofilm-forming bacteria in this experimental animal model. The antibiofilm property of the enzyme may enhance antibiotic efficacy in the treatment of staphylococcal infections.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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    Baransel Saygi, M.D.
    Posted on November 06, 2006
    Dr. Saygi et al. Respond to Professor Selan and Dr. Artini
    TCSB FSM Hospital, TURKEY

    We appreciate the interest of Professor Selan and Dr. Artini in our article entitled "The Effect of Proteolytic Enzyme Serratiopeptidase in the Treatment of Experimental Implant-Related Infection". The serratiopeptidase enzyme material was provided from Sigma Chemical Company, St Louis, MO, USA (not from Sigma-Aldrich) with the help of a Turkish Pharmaceutical firm.

    Their address is: Sigma Chemical Company, 3050 Spruce Street, Box 14508, St. Louis, MO 63178-5000 - USA, Phone: (314)771-5750, Fax: (314)-771-3814.

    We apologize for mistakenly publishing the product number as P27789; it should have been P2789.

    We hope this knowledge will be helpful to Drs. Selan and Artini, and to other interested investigators.

    Professor Laura Selan
    Posted on August 22, 2006
    Availability of Serratiopeptidase
    Dept. of Public Health Sciences, University of Rome, Rome, ITALY

    To The Editor:

    We read, with much interest, the paper entitled, "The Effect of Proteolytic Enzyme Serratiopeptidase in the Treatment of Experimental Implant-Related Infection"(1). We have studied serratiopeptidase and its possible use in prosthetic infections since 1993(2-11).

    We would ask the authors of this study where they obtained serratiopeptidase to perform their experiments? Serratiopeptidase, as quoted in their article(1), is not available from the manufacturer. We contacted Sigma-Aldrich to buy this substance (as described in the paper) and they answered that the code doesn't exist in the Sigma catalogue.

    The author(s) of this letter to the editor did not receive payment or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the author(s) are affiliated or associated.


    1. Mecikoglu M, Saygi B, Yildirim Y, Karadag-Saygi E, Ramadan SS, Esemenli T. The effect of proteolytic enzyme serratiopeptidase in the treatment of experimental implant-related infection. J Bone Joint Surg Am. 2006; 88: 1208-1214.

    2. Selan L. et al. Proteolytic enzymes: a new treatment strategy for prosthetic infections? Antimicrobial Agents and Chemotherapy, 37: 2618- 2621,1993.

    3. A novel therapeutical approach acting on extracellular biofilm matrix. ASM Conference on Biofilm 2003. Victoria (British Columbia). 1-6 Nov. 2003.

    4. Russo P., Ripavecchia V., Poggiali F., Passariello C., Schippa S., Artini M., Selan L. Reduction of in vitro resistence of bacterial biofilms to antibiotics by inhibition of biofilm formation process. 44th annual Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC, USA. 30 Oct, 2 Nov 2004.

    5. Artini M., Passariello C., Russo P., Schippa S., Poggiali F., Costerton W., Selan L. Modulation of AtlE gene product by serratiopeptidase reverts Staphylococcus epidermidis biofilm to antibiotic sensibility of the planktonic form. ASM Conferences Cell-Cell Communication in Bacteria. Banff, Alberta. 23-27 July 2004

    6. Artini M., Poggiali F., Scoarughi G., Selan L. Modulazione dell'espressione proteica in Staphyloccoccus spp. dopo trattamento con serratiopeptidase. 330 Congresso Nazionale Societa Italiana di microbiologia. Napoli 16-19 Ottobre 2005.

    7. Selan L., Russo P., Poggiali F., Passariello C., Costerton J.W., Artini M. Proteases modulators of quorum sensing as a new antibiofilm drugs. 105th ASM General Meeting Atlanta GA, USA. 5-9 June 2005.

    8. Artini M.Bacterial phenotype modulation as a therapeutic strategy against device-related infections: analysis on the molecular level. Big Bash Biofilm Symposium. University of Southern California (USC) Los Angeles CA, 24-28 October 2005.

    9. Scoarughi GL, Longhi C, Poggiali F, Cellini A, Carpentieri A, Seganti L, Pucci P, Amoresano A, Artini M, Selan L. Effect of a 50 kDa Metallo- Protease from Serratia marcescens on Listeria monocytogenes Entry in Enterocyte-Like Cells, 106th ASM General Meeting Orlando, Florida, 2125 May 2006

    10. Artini M, Poggiali F, Cellini A, Scoarughi GL, Pucci P, Amoresano A, Carpentieri A, Selan L. Modulation of Staphylococcus spp Surface Proteins Involved in Biofilm Phenotype by a MetalloProtease Obtained from Serratia marcescens 106th ASM General Meeting Orlando, Florida, 2125 May 2006

    11. Selan L., Cellini A , Poggiali F, Scoarughi GL , Artini M. Staphylococcus aureus Adhesion and Invasion Can be Blocked by Serratiopeptidase a Bacterial Metallo-Protease 106th ASM General Meeting Orlando, Florida, 21-25 May 2006

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