4Hospital-Acquired Infections United States Nearly 2 million nosocomial infections per year1,2~90,000 deaths>70% of the causal bacteria are resistantPatients with drug-resistant infections1Longer hospital staysTreatment with drugs that may be less effective, more toxic, and/or more expensiveNearly $11 billion annually2Campaign to prevent antimicrobial resistance in healthcare settings. Centers for Disease Control and Prevention web site. Available at Accessed September 12, 2005.Schierholz JM, Beuth J. Implant infections: a haven for opportunistic bacteria. Journal of Hospital Infection 2001;49:87-93.
5Surgical Site Infections United States ~700,000 surgical site infections per year1~$1.6 billion added hospital charges annually2One study2:OutcomeControl (n=193)MSSA (n=165)MRSA (n=121)Death (number)41125Hospital stay (days)51423Cost (median)$29,455$52,791$92,363The Engemann report was of a prospective, cohort study. The statistically significant differences between groups were:Mortality: Higher MRSA vs control (p<.001) and MRSA vs MSSA (p<.001)Hospitalization after surgery: Higher MSSA vs control, MRSA vs control, and MRSA vs MSSA (p<.001 for each)Hospitalization after infection: Higher MRSA (15 days) vs MSSA (10 days) (p=.001)Costs: Higher for MSSA vs control, MRSA vs control, and MRSA vs MSSA (p<.001 for each)MRSA = methicillin-resistant S. aureus; MSSA = methicillin-susceptible S. aureusNathens AB, Dellinger EP. Surgical site infections. Current Treatment Options in Infectious Diseases 2000;2:Engemann JJ, Carmeli Y, Cosgrove SE, et al. Adverse clinical and economic outcomes attributable to methicillin resistance among patients with Staphylococcus aureus surgical site infection. Clinical Infectious Diseases 2003;36:
6MRSA Prevalence1,2 Problems1,2 Precipitous rise 43% of hospital S. aureus infections28% of surgical site infectionsProblems1,2Generally multi-drug resistantMRSA only susceptible to vancomycin grew from 23% to 56% in 10 yearsResistance to vancomycin has emergedKuehnert MJ, Hill HA, Kupronis BA, Tokars JI, Solomon SL, Jernigan DB. Methicillin-resistant–Staphylococcus aureus hospitalizations, United States. Emerging Infectious Diseases [serial online] 2005;11(6). Available at: Accessed September 12, 2005.Fry DE. Complicated skin and skin structure infections caused by hospital- and community-acquired MRSA: What surgeons need to know [CME course on the Internet]. Available at: disclaimer_html.display?ip_mode =secure&ip_company_code=CMEZPHY&ip_test_id=8297&ip_cookie= Accessed August 19, 2005.
7Medical Device Infections 1-6% of implanted medical devices become infected1Account for ~45% of nosocomial infections2Ventral Hernia Repair3Open 7-18%Laparoscopic 0-2%TimeframeShort term – within first 10 daysLong term – up to several years post opThe 1-6% is an overall average for all implanted medical devices. There are higher and lower examples.Gristina AG, Naylor P, Myrvik Q. Infections form biomaterials and implants: a race for the surface. Medical Progress Through Technology 1998;4:Stamm WE. Infections related to medical devices. Annals of Internal Medicine 1978;89:Carbonell AM, Matthews BD, Dreau D, et al. The susceptibility of prosthetic biomaterials to infection. Surgical Endoscopy 2005;19:
8Consequences of Device Infections IncreasedPain and discomfortHospital stayHealing/recovery timeCostMorbidityMortalityMay require additional surgery to remove deviceInfected polypropylene mesh seven months post operatively.
9Pathogenesis of Infection A Race for the Surface1,2 Bacteria introduced primarily at time of implant or in the immediate post-op periodPatient’s own skin floraPre-existing infection at distant siteHospital environmentSurgical staffSupporting therapy (IV, etc.)Bacteria adhere to and colonize deviceBacteria can produce their own protective biofilmBacteria evade conventional antibiotic therapy and patient’s immune responseDespite one’s best efforts, some bacteria almost always find their way into wounds and onto implanted medical devices. According to Schierholz JM, Beuth J (Implant infections: a haven for opportunistic bacteria. Journal of Hospital Infection 2001;49:87-93.):It is impossible to create a predictably sterile wound, even under laminar flow.S. aureus can be recovered from ~90% of clean wounds at time of closure.Minor contamination of implant area may be regarded as a physiological phenomenon.An implant lowers the threshold of infection and generates local immunosuppressionGristina AG, Naylor P, Myrvik Q. Infections from biomaterials and implants: a race for the surface. Medical Progress Through Technology 1998;4:Deysine M. Pathophysiology, prevention, and management of prosthetic infections in hernia surgery. Surgical Clinics of North America 1998;78(6):
10Bacteria Want to Be in Biofilms “I just can’t go with the flow anymore. I’ve been thinking about joining a biofilm.”Biofilms are a safe haven for bacteria as they help them survive in a harsh environment.Center for Biofilm Engineering, Montana State University
12What Are Biofilms and Why Are They Important? Bacteria in a self-excreted slimy substance adhered to a surface1Bacteria in biofilms2No longer planktonicAct as a communityOften multiple speciesEstimated 65% of human infections involve biofilms3Provide protection from host’s immune responseCan require 1000x antibiotic concentration to kill versus planktonic2Costerton JW, Stewart PS, Greenberg EP. Bacterial biofilms: a common cause of persistent infections. Science 1999;284:What being in a biofilm means to bacteria. The Center for Biofilm Engineering at Montana State University Web Site. Available at: Accessed September 26, 2005.Cvitkovitch DG, Li Y-H, Ellen RP. Quorum sensing and biofilm formation in Streptococcal infections. Journal of Clinical Investigation 2003;112:
13Biofilms Can Be Difficult to Detect CultureShort culture times may lead to false negativesHistologyBacteria can be hidden in biofilmTypical culture times in a hospital lab are 24 hours. It may take up to a week of culturing to see growth by bacteria in a biofilm due to their sessile state.The two pictures are of an infected clinical sample. In a typical H&E or Gram stain (left) you may see necrotic cellular debris without being able to see cells because the biofilm doesn’t stain well (glycocalyx blocks the stain). But if you use TEM (right), you can clearly see the bacterial cells within the debris.It may require special training of histologists for them to correctly identify biofilms.Necrotic Cellular DebrisBacteria Within Debris
14Biofilm FormationWhen a medical device is implanted, it is “a race for the surface” between bacteria and host cells. If the host cells win the race, they are attached to or integrated into the surface of the device and help to protect it. If the bacteria win the race, they tend to form a biofilm and are very difficult to eradicate without removing the device.Center for Biofilm Engineering, Montana State University
15Biofilm FormationBiofilm resistance to antimicrobial agents (taken from1. Antimicrobial depletion in bulk fluid2. Transport limitation of antimicrobial penetration3. Physiological limitation of antimicrobial efficacy (at least some of the bacteria adopt a resistant state or phenotype)Center for Biofilm Engineering, Montana State University
17ePTFE Bacteria (cocci) Biofilm (slime) RBC Biofilm on ePTFEePTFEBacteria (cocci)Biofilm (slime)This is an SEM of an infected ePTFE clinical device. The colonizing bacteria is S. epidermidis.RBCBruce Wagner, W.L. Gore & Associates, Inc.
18Biofilm Formation 2 hours 8 hours 24 hours 4 hours These pictures are from an in-vitro study on a “plastic surface” using a strain of S. epidermidis from a patient with endocarditis. The important point is that within 24 hours a full biofilm can develop on a device surface.8 hours24 hoursOlson ME, Ruseka I, Costerton JW. Colonization of n-butyl-2-cyanoacrylate tissue adhesive by Staphylococcus epidermidis. Journal of Biomedical Materials Research 1988;22:
193-D Imaging of BiofilmUsing specialized techniques, biofilms can be imaged in three dimensions. In this video, there is an ePTFE film on top (not visible) and the biofilm has grown below it. The ePTFE film was exposed to a substantial amount of bacteria in an in-vitro model, somewhat analogous to an infected field clinically.Betsey Pitts, Center for Biofilm Engineering, Montana State University
20Clinical Impact of Biofilms Two main infection scenariosShort term – within 10 daysLong term – up to several years post opTreatment progressionBroad spectrum and/or specific antibioticsWound does not heal and is culture negativeDevice is removedBoth short-term and long-term infections can be attributed to biofilms. In the short term, the device becomes colonized and treatment is not effective due to the resilience of the biofilm. In the long term, the bacteria may form a biofilm at implant and remain dormant until some stimulus causes them to become active.
21Protect the device from colonization at time of implant. The ChallengeProtect the device from colonization at time of implant.
22Gore’s SolutionDevice coating as first line of defense against bacterial colonizationResist bacterial adherenceEffective against a broad spectrum of bacteriaLocal rather than systemic exposureSmall amounts of agentsProtect device, not treat surrounding tissueAgents not typically used to treat infectionsDoes not affect choice of local or systemic antibioticsMinimal tendency toward resistanceThe rationale for why Gore’s PLUS technology has a minimal tendency toward resistance is:Only a small population of bacteria, those introduced at implantation, are exposed to the agents for a short period of timePLUS agents are not mainstream therapeutic antibioticsThe mechanism of action is mechanical, not a target for a specific site of bacterial growthCombination of two antimicrobials with different mechanisms that are synergistic and complimentary
24Gore’s Antimicrobial Technology What is it?Synergistic combination of two antimicrobial agents, silver and chlorhexidineSilverBinds with and destroys bacterial cell proteins, causing loss of normal biological functionChlorhexidinePermeates bacterial cell wall causing disruption and leakage of the cell contents
25What Does Antimicrobial Technology Do? Inhibits bacterial colonization of, and resists initial biofilm formation on, the device for up to 14 days post implantation.
27Safety of Gore’s Antimicrobial Technology Clinical Experience Short-term study137 patients; controlled, randomizedPLUS products do “not appear to produce any adverse systemic or clinical effects after hernia repair”Almost 10 years and over 150,000 implantsTo date no confirmed reports of hypersensitivityIn this clinical study, blood samples were taken pre- and post-op at 1, 6, and ~12 weeks.DeBord JR, Bauer JJ, Grischkan DM, LeBlanc KA, Smoot Jr. RT, Voeller GR, Weiland LH. Short-term study on the safety of antimicrobial-agent-impregnated ePTFE patches for hernia repair. Hernia 1999;3:
28In-Vitro Efficacy of Gore’s Antimicrobial Technology Zone of inhibition bioassaysSubstantial antimicrobial activity against gram-positive and gram-negative organismsStaphylococcus aureusEscherichia coliPseudomonas aeruginosaKlebsiella pneumoniaeStaphylococcus epidermidisCandida albicansMethicillin-resistant Staphylococcus aureus (MRSA)Vancomycin-resitant enterococcus faecalisGroup A StreptococcusAcinetobacter baummaniiThe two example zone of inhibition plates are clinical isolates of S. aureus and E. coli from Flagstaff Medical Center.Also note that C. albicans is a yeast.
29In-Vivo Efficacy of Gore’s Antimicrobial Technology Rabbit model 10 days post-inoculation with S. aureusNon-antimicrobial TechnologyAntimicrobial TechnologyColonization of the implant surface and interstices.(H&E stain; 20x magnification)Protection of the implant surface and interstices from colonization.(H&E stain; 20x magnification)
30Susceptibility to MRSA Adherence AG Harrell, American Hernia Society Meeting, Feb. 2005Compared MRSA adherence to various types of meshes using an in-vitro modelMethodsInoculated with 108 MRSA in tryptic soy brothIncubated for 1 hour at 37 oCWashed and counted CFU in wash and brothSEM of meshesProducts testedGORE DUALMESH® PLUS BiomaterialGORE DUALMESH® BiomaterialBard® MeshBard® COMPOSIX® E/X MeshPROCEED™ Surgical MeshPARIETEX® COMPOSITE MeshTiMESH Mesh-ImplantULTRAPRO™ MeshVYPRO™ MeshHarrell AG. Prosthetic mesh biomaterial susceptibility to methicillin resistant Staphylococcus aureus adherence in an in-vitro model. Abstract presented at Hernia Repair American Hernia Society. San Diego, CA. Feb 9-12, Page 94. Abstract 36F.
31Results of MRSA Adherence GORE DUALMESH® PLUS BiomaterialHarrell AG. Prosthetic mesh biomaterial susceptibility to methicillin resistant Staphylococcus aureus adherence in an in-vitro model. Abstract presented at Hernia Repair American Hernia Society. San Diego, CA. Feb 9-12, Page 94. Abstract 36F.
32Susceptibility to MRSA Adherence GORE DUALMESH® PLUS BiomaterialNo detectable MRSA in the broth or the pooled wash samplesSEM confirmed bacterial adherence to all other mesh typesOnly mesh type in the nine tested that demonstrated a bactericidal propertyHarrell AG. Prosthetic mesh biomaterial susceptibility to methicillin resistant Staphylococcus aureus adherence in an in-vitro model. Abstract presented at Hernia Repair American Hernia Society. San Diego, CA. Feb 9-12, Page 94. Abstract 36F.
33Mesh Susceptibility to Infection AM Carbonell et al, Surg Endosc 2005Determine the susceptibility of mesh to S. aureus infection in a rat modelMethodsCreated 2 cm2 hernia defect and sutured mesh to itInoculated each mesh with 108 penicillin-sensitive S. aureus5 day incubationHarvested biomaterials sterilely, washed, cultured, counted CFUMeshes testedGORE DUALMESH® PLUS BiomaterialGORE DUALMESH® BiomaterialBard® MeshBard® COMPOSIX® MeshSEPRAMESH™ Biosurgical CompositeSURGISIS® Soft Tissue GraftALLODERM® Regenerative Tissue MatrixPLUS has been tested in numerous animal studies. This is a recent one not sponsored by Gore.Carbonell AM, Matthews BD, Dreau D, et al. The susceptibility of prosthetic biomaterials to infection. Surgical Endoscopy 2005;19:
34Mesh Susceptibility to Infection Log10 Values for Wash CountGORE DUALMESH® PLUS BiomaterialSignificant Values: 1) DM+ < DM, M, X, SM, S, A, P (p=0.05).2) SM < A (p=0.05).3) P < A (p=0.05)Carbonell AM, Matthews BD, Dreau D, et al. The susceptibility of prosthetic biomaterials to infection. Surgical Endoscopy 2005;19:
35Mesh Susceptibility to Infection Log10 Values for Broth CountSignificant Values: 1) DM+ < DM, M, X, SM, S, A, and P (p=0.05).2) P < DM, M, X, SM, S, and A (p=0.05).GORE DUALMESH® PLUS BiomaterialCarbonell AM, Matthews BD, Dreau D, et al. The susceptibility of prosthetic biomaterials to infection. Surgical Endoscopy 2005;19:
36Mesh Susceptibility to Infection GORE DUALMESH® PLUS BiomaterialWas the least susceptible to infectionAble to kill all the inoculated bacteria in a live-animal study of mesh infectionSilver/chlorhexidine meshesMay be the prosthetics of choice to minimize occurrence of mesh infectionCarbonell AM, Matthews BD, Dreau D, et al. The susceptibility of prosthetic biomaterials to infection. Surgical Endoscopy 2005;19:
37Clinical Experience with Gore’s Antimicrobial Technology Laparoscopic Ventral Hernia RepairKA LeBlanc, MD, MBA, FACS1The use of GORE DUALMESH® PLUS Biomaterial “appears to anecdotally decrease the rate of infections. We have not encountered a postoperative infection when this prosthesis was used.”AM Carbonell et al.2268 laparoscopic ventral hernia repairs using ePTFETwo mesh infections, neither of which occurred with GORE DUALMESH® PLUS BiomaterialLeBlanc KA. Laparoscopic incisional and ventral hernia repair: complications–how to avoid and handle. Hernia 2004;8(4):Carbonell AM, Matthews BD, Dreau D, et al. The susceptibility of prosthetic biomaterials to infection. Surgical Endoscopy 2005;19:
38Summary Medical Device Infections Gore’s Antimicrobial Technology Increase morbidity, mortality, cost, etc.Biofilm formation makes diagnosis and treatment difficultThe best treatment is preventionGore’s Antimicrobial TechnologyInhibits bacterial colonization for up to 14 days post implantationCurrently available in devices used for soft tissue repair