Vohme 13 Number 5 Mav 1991
4.
Special communication
Lorentzen JE, Nielsen OM, Are&up H, et al. Vascular graft infection: an analysis of sixty-two graft infections in 2411 consecutively implanted synthetic vascular grafts. Surgery 1985;98:81-6.
Mark AS, McCarthy SM, Moss AA, Price D. Detection of abdominal aortic graft infection: comparison of CT and in-labeled white blood cell scans. AJR 1985;144:315-8. 6. O’Hara PJ, Hertzer NR, Beven EG, Krajewski LP. Surgical management of infected abdominal aortic grafts: review of a 25-year experience. J VASC SURG 1986;3:725-31. 7. Olofsson PA, Auffermann W, Higgins CB, Rabahie GN, Tavares N, Stoney RJ. Diagnosis of prosthetic aortic graft infection by magnetic resonance imaging J VASC SURG 5.
1988;8:99-105. 8.
Riley LM, Altrnan H, Lusby RJ, et al. Late results following surgical management of vascular graft infection. J VASC SURG 1984;1:36-44.
Szilagyi DE, Smith RF, Elliot JP, Vrandecic Ml’. Infection in arterial reconstruction with synthetic grafts. Ann Surg 1972; 176:321-33. 10. Vogelzang RL, Limpert JD, Yao JS. Detection of prosthetic vascular complications: comparison of CT and angiography. AJR 1987;148:819-23.
753
different type of infection, often by bacteria that are not usually pathogenic, ensues. The biology of the host implant interface is just beginning to be unraveled. Recently our laboratory has shown that vascular prostheses induce the selective expression of the intercellular adhesion molecule (ICAM-I).’ The latter is the ligand for the LFA-I receptor on neutrophils. Activated neutrophils respond with a burst of oxidative metabolism, which produces highly reactive superoxide anion. Interleukins are also produced by activated effector cells. Rather than destruction of the implant, a milieu is established in which small numbers of bacteria survive, perhaps in fibrin, macrophages, or in the interstices of the implant, to become clinically obvious weeks or months after a seemingly successful vascular reconstruction.
9.
UTILIZING VASCULAR DRUG DELIVERY
PROSTHESES FOR
Infection is the most catastrophic complication associated with the use of prosthetic vascular conduits. The magnitude of this problem must be inferential, based on current estimates of the frequency of their use and retrospective reports of incidence. Eight years ago it was estimated that 350,000 prosthetic grafts were used. Assuming an increase of 5% per year, this number now approaches one-half million. The incidence of prosthetic graft infection varies according to the material and the location of the graft. Nevertheless, even at a rate of 2%, the conclusion is that as many as 10,000 such infections occur each year. Since morbidity and mortality rates are generally accepted to be at least one third each, including limb loss, the human toll is great. AU of this occurs in the face of the universal use of prophylactic systemic antibiotics. A prospective randomized trial clearly supports their use. Established vascular prosthetic infection is a notably intransigent clinical syndrome. Although there are advocates for less aggressive management, most surgeons agree that treatment of an established infection requires massive doses of parenteral antibiotics, removal of the infected graft and extraanatomic bypass.
Background Vascular prostheses are foreign bodies that provoke an inflammatory response that is undoubtedly a factor in their propensity to become infected. The classic paper of Elek and Cohen’ published 30 years ago set the stage for this concept by demonstrating the enhancement of infection by silk sutures. Tissue injury can usually be coped with by lost defenses even when challenged by large inocula of bacteria. The foreign body subverts these defenses and a new and
Surface modification During the 1960s the novel concept of noncovalently bonding heparin to implantable devices was described.3 In 1978 our group hypothesized that implant infections occurred because of contamination of the prosthesis by a small number of bacteria that were protected in the interstices of the implant or on its surface. Here they eventually multiplied, thrived, and became clinically obvious. It was our view that the implant itselfwas particularly susceptible because the matrix of the graft, lacking a blood supply, was unlikely to contain significant concentrations of the large doses of antibiotics given these patients parenterally. We, therefore, developed a system in which antibiotics were noncovalently bound to the vascular graft through electrostatic attraction to surfactants of opposite charge. We focused on quaternary ammonium compounds with long chain alkyl groups to generate positively-charged coatings. The surfactant must be water-insoluble so that the coating is not leached on exposure of the prosthesis to aqueous environments. Water insoluble quaternary compounds have the further advantage that they show low biologic toxicity. This contrasts with the well documented toxicity of water-soluble and moderately insoluble quaternary ammonium compounds widely used as emulsifiers and dispersing agents. The interaction of negatively charged drug with positively charged surfactant coating shows a simple hyperbolic binding isotherm. Surface-bound drugs are bound rather loosely with dissociation constants of about lo-?o 10m4 mol/l. Some high molecular weight ligands, such as tissue plasminogen activator, show a much higher binding affinity, but the stoichiometry of maximal binding is much less than one drug per surfactant. This suggests that only some surfactant molecules are involved in drug binding. The rate of dissociation of drug is relatively slow with half-times from hours to several days. The rate of release can be significantly decreased if the drug-surfactant complex is applied to the prosthesis in chloroform, or another solvent that causes the device to swell. The prosthesis is first allowed to swell in the presence of
754
Journal of VASCULAR SURGERY
Special cemmunicatim
drug/surfactant, then the device is removed from the solvent, and allowed to dry and to return to its original size. The drug with its large counter-ion is entrapped in the bulk polymer. After implantation, the pharmacologic agent very slowly diffises from the outer layers of the device. The limitations of this approach are the solubility of the drug in nonpolar organic solvents, and the ability of the solvent to nondestructively swell the polymer. Our initial experiments were facilitated by a family of positively charged surface active agents and an armada of negatively charged antibiotics, including all of the penicillins and all of the cephalosporins. Beginning in 1979 experiments were reported that showed that antibiotics bonded to vascular prostheses produced a surface that was infection resistant.4 In an in vitro bioassay and an in vivo model of implant infection, the bonded surfaces showed superior performance.5 Biochemical studies characterized the duration of binding and the efficacy of binding more than one drug.6 In a canine aortic graft model, bonded surfaces withstood challenge with a large inoculum of Staphylococcus aurem7 In 1981 we reported our initial experience with tridodecylmethylammonium chloride (TDMAC), a surfactant with three 12 carbon alkyl side chains. TDMAC bound far more antibiotic than other surfactants and appeared to produce an effective in situ reservoir for slow release from the surface. Subsequent studies showed that cephalosporins could be bound in concentrations similar to that of the penicillins and that both could bind to polytetrafluoroethylene (PTFE) and Dacron.8 Finally in 1985 we used an antibiotic bonded vascular graft to treat established vascular prosthetic infection in a canine modeL9 Data in this study shed some light on our basic hypotheses. First, by use of radiolabeled antibiotics, implanted grafts contained a huge reservoir of antibiotic, far in excess of that which can be achieved by parenteral administration. Second, residual antibiotics at the time of harvest did not correlate with an observed difference in infection rate indicating that it is the large initial dose that is the important factor. Finally, control grafts adsorbed very little of the parenterally administered antibiotics for 48 hours after implantation. These data indicate that grafts are at risk in the perioperative period and that a massive dose of antibiotic delivered at the site is the critical factor in eliminating infection. Subsequent studies reported in 1989 indicated that our in vivo experiments heretofore conducted with PTFE were equally effective with Dacron grafts.‘O
New strategies Recent evidence from our laboratory indicates that the custom synthesized surfactant trioctadecylmethylammonium chloride (TOMAC) is superior to TDMAC in binding to the graft surface. TOMAC differs from TDMAC in that it is much less water soluble and has 18 carbon side chains. Antibiotic binding is twice as effective with TOMAC at time zero, and the difference persists for up to a week in human plasma.
Recently, we have found that thrombolytic agents, like tissue plasminogen activator (@A), can also be bound to vascular grafts with surfactants and that the same graft can be bound as well to penicillins and cephalosporins. Our initial interest in binding tPA to grafts designed for infection resistance is derivative from work indicating that by entrapping bacteria fibrinogen may play a role in infections associated with clot. It is noteworthy that S. aweus binds fibrin and is the most common pathogen in vascular prosthetic infections. In the case of vascular grafts, this phenomenon may explain the latency period often observed in these infections and the reason the device must be removed for infection to be successfully treated. We have previously described an in vivo bioassay (ID-50) for evaluation of the relative infection resistance of implantable devices. By use of this method, control vascular grafts, control bonded to TPA alone and control bonded to penicillin alone, were compared to control grafts bonded to penicillin and tI?A. S. aureus in concentration of 1 x 10” to 1 x 10” was added to fibrinogen to which thrombin was added. Grafts were implanted in a rat subcutaneous pouch and harvested at 4 days. Bonding tPA and penicillin increased the ID-50 by 10 fold (p < 0.05)
Conclusions Established vascular prosthetic infections are a significant public health problem. Morbidity and mortality rates are excessive, and the costs of treating established infections are significant. The cause of vascular prosthetic infection remains obscure. The revolutionary technologies of the 1980s and 1990s have been applied, in the main, to graft healing and graft failure, most notably neointimal fibrous hyperplasia. The highly deranged microenvironment at the host implant interface undoubtedly plays a major role in the origin of these infections. The role of fibrin, macrophages, soluble mediators, and adhesion molecules, as well as those of the bacteria and the prosthetic surface itself, must be subjected to molecular scrutiny. This should be a major focus of research in the next decade. Vascular prosthetic materials have changed little in the last 3 decades. The necessity for such surfaces to be biocompatible, mechanically sound, antithrombogenic, and infection resistant is a daunting challenge. The development of a new surface with all these characteristics will require close collaboration among surgeons, molecular biologists, immunologists, and polymer chemists if it is to be successful. Another tack may be the modification of current surfaces with exemplary mechanical properties. Surfactant chemistry may have a valuable role here especially if the molecular biology is unraveled and methods for enhancing or blocking specific receptors, ligands, and mediators can be found. Drug delivery by means of surface modification and including, but not limited to antibiotics, antithrombogenic agents, thrombolytic agents, growth factors, calcium channel blockers and/or monoclonal anti-
Volume 13 Number 5 May 1991
bodies may thereby be more likely to develop a truly biocompatible vascular prosthesis. Ralph S. Greco, MD Untiersityof Medicine and Dentisty of New Jersey Robert Wood Johnson Medical School New Brunswick, NJ.
REFERENCES 1. Elek SD, Cohen PE. The virulenceof staphylococcus pyogenesfor man: a studyof the problemsof wound infection.Br J Exp Path01 1957;38:573. 2. Margiotta MS, Robertson FM, Greco RS. Selective induction of intercellular adhesion molecule (ICAM-I) expression by human endothelial cells following adherence to vascular grafts using an in vitro model. Surg Forum 1980;41:339-41. 3. Whiffen JD, Gott VL. In vivo adsorption of heparin by graphite-benzalkonium intravascular surfaces. Surg Gynecol Obstet 1965;121:287-90. 4. Harvey RA, Greco RS. The non-covalent bonding of antibiotics to a polytetrafluoroethylene graft. Ann Surg 1981;194: 642-7. 5. GrecoRS, Harvey BA, Henry R, et al. Preventionof graft infection by antibiotic bonding. Surg Forum 198O;XXXI:2930. 6. Greco RS, Harvey RA. The role of antibiotic bonding in the prevention of vascular prosthetic infections. Ann Surg 1982; 195:168-71. Greco RS, Harvey RA, Smilow PC, et al. Prevention of vascular prosthetic infection by a benzalkonium-oxacillin bonded polytetrafluoroethylene graft. Surg Gynecol Obstet 1982;155:28-32. Harvey RA, Greco RS. Antibiotic bonding to polytetralluoroethylene with tridodecylmethylammonium chloride. Surgery 1982;92:504-12. Greco RS, Donen. Al’, Harvey BA. The application of antibiotic bonding to the treatment of established vascular prosthetic infection. Arch Surg 1985;120:71-5. 10. Shue WB, Worosilo SC, Donetz Al’, Trooskin SZ, Harvey RA, Greco RS. Prevention of vascular prosthetic infection with an antibiotic bonded Dacron graft. J VASC SURG 1988;8:600-5.
PATHOGENESIS OF VASCULAR GIUFT INFECTIONS The increasingly routine use of prosthetic vascular grafts has revolutionized our ability to reperfuse and salvagepatients with severeperipheral vasculardisease.It is estimated that more than 60,000 vascular graft prostheses are implanted in the United States yearly.’ Despite improved prosthetic materials and surgical techniques, vascular graft infections remain a serious source of clinical morbidity and deaths. Approximately 2% of patients with vascular grafts will develop a prosthetic infection, the consequencesof which are often grave, that is, limb loss or death.’ To limit the incidence of these infections it is of paramount importance that we have a full understanding of the pathogenesis of graft infections. Only in this way can we hope to make significant inroads into the prevention and eradication of vascular prosthetic infections. Graft infections can be separated into those that occur acutely and those that occur late. Early postoperative graft
Special
cummunicatim
755
infections are often the result of wound infections and usually involve grafts anatomically superficial in location (femoral, axillary, popliteal sites). Late graft infections may occur months to yearsafter vascularreconstructive surgery. Indeed, there may be a long dormant period between the time of contamination and evidence of clinical infection.’ A wide spectrum of organisms has been reported to infect vascular prostheses.It has long been maintained that Staphylococcus aureus is the most common offending pathogen. However, multiple organisms, including gramnegative species, are frequently found.’ More recently, S. epidemtidis is being recognized as a common pathogen, and infections caused by this low virulence organism usually occur late after operation.’ It is well accepted that the introduction of bacteria commonly occurs at the time of implantation of a prosthetic device. Defective barriers, such as breaks in sterile technique, improper handling or sterilization of the graft material, or the development ofwound infections may play a role.’ Infections may also result from bacterial seeding. Of particular importance in the realm of peripheral vasculardiseaseis the presenceof lower extremity ischemic ulcers, which are often infected with polymicrobial flora.’ Any surgical incision involving the groin carries a higher incidence of wound infection and therefore graft infection. This is likely related to contaminated skin as a result of proximity to the perineum, redundant folds of moist skin, superficial location of the graft, and the transection of numerous lymphatics.2~3 The arterial wall itself might rarely be a source of contamination. Ilgenfiitz and Schwartz have respectively demonstrated a 10.4% and 19.6% incidence of positive bacterial cultures of the aortic wall taken at the time of aneurysmectomy. Cultures were more often positive in patients with ruptured or expanding aortic aneurysms.3 Interactions among the local host tissues and the prosthesis provide further insight into the pathogenesis of vasculargraft infections. Somehow local host defensesseem to fail in this environment, thus allowing bacterial propagation. Tissue reactivity in the presence of a foreign body has long been recognized as a potentiator of infection. Dougherty and Simmons* were able to demonstrate that infection could be produced with only 100 colony forming units of S. aureus in the presence of silk suture. The acute inflammatory processwill vary depending on the size and shape of the foreign material, its surface characteristics, and its chemical composition.*Most prosthetic materials commonly used in vascular surgery are fairly inert, but, nonetheless, they do endure some degree of inflammation when exposed to host tissues. The implantation site and mechanical interaction with host tissuesmay also influence the degree of inflammation.’ For example, the inflammation resulting from constant mechanical pulsatile interaction of an aortic graft against the bowel may lead to periprosthetic abscessformation and eventually enteroperivascular or enterovascular fistulas. At the cellular level there is evidence that host defenses are hampered. Many investigators believe that normal
4.
Special communication
Lorentzen JE, Nielsen OM, Are&up H, et al. Vascular graft infection: an analysis of sixty-two graft infections in 2411 consecutively implanted synthetic vascular grafts. Surgery 1985;98:81-6.
Mark AS, McCarthy SM, Moss AA, Price D. Detection of abdominal aortic graft infection: comparison of CT and in-labeled white blood cell scans. AJR 1985;144:315-8. 6. O’Hara PJ, Hertzer NR, Beven EG, Krajewski LP. Surgical management of infected abdominal aortic grafts: review of a 25-year experience. J VASC SURG 1986;3:725-31. 7. Olofsson PA, Auffermann W, Higgins CB, Rabahie GN, Tavares N, Stoney RJ. Diagnosis of prosthetic aortic graft infection by magnetic resonance imaging J VASC SURG 5.
1988;8:99-105. 8.
Riley LM, Altrnan H, Lusby RJ, et al. Late results following surgical management of vascular graft infection. J VASC SURG 1984;1:36-44.
Szilagyi DE, Smith RF, Elliot JP, Vrandecic Ml’. Infection in arterial reconstruction with synthetic grafts. Ann Surg 1972; 176:321-33. 10. Vogelzang RL, Limpert JD, Yao JS. Detection of prosthetic vascular complications: comparison of CT and angiography. AJR 1987;148:819-23.
753
different type of infection, often by bacteria that are not usually pathogenic, ensues. The biology of the host implant interface is just beginning to be unraveled. Recently our laboratory has shown that vascular prostheses induce the selective expression of the intercellular adhesion molecule (ICAM-I).’ The latter is the ligand for the LFA-I receptor on neutrophils. Activated neutrophils respond with a burst of oxidative metabolism, which produces highly reactive superoxide anion. Interleukins are also produced by activated effector cells. Rather than destruction of the implant, a milieu is established in which small numbers of bacteria survive, perhaps in fibrin, macrophages, or in the interstices of the implant, to become clinically obvious weeks or months after a seemingly successful vascular reconstruction.
9.
UTILIZING VASCULAR DRUG DELIVERY
PROSTHESES FOR
Infection is the most catastrophic complication associated with the use of prosthetic vascular conduits. The magnitude of this problem must be inferential, based on current estimates of the frequency of their use and retrospective reports of incidence. Eight years ago it was estimated that 350,000 prosthetic grafts were used. Assuming an increase of 5% per year, this number now approaches one-half million. The incidence of prosthetic graft infection varies according to the material and the location of the graft. Nevertheless, even at a rate of 2%, the conclusion is that as many as 10,000 such infections occur each year. Since morbidity and mortality rates are generally accepted to be at least one third each, including limb loss, the human toll is great. AU of this occurs in the face of the universal use of prophylactic systemic antibiotics. A prospective randomized trial clearly supports their use. Established vascular prosthetic infection is a notably intransigent clinical syndrome. Although there are advocates for less aggressive management, most surgeons agree that treatment of an established infection requires massive doses of parenteral antibiotics, removal of the infected graft and extraanatomic bypass.
Background Vascular prostheses are foreign bodies that provoke an inflammatory response that is undoubtedly a factor in their propensity to become infected. The classic paper of Elek and Cohen’ published 30 years ago set the stage for this concept by demonstrating the enhancement of infection by silk sutures. Tissue injury can usually be coped with by lost defenses even when challenged by large inocula of bacteria. The foreign body subverts these defenses and a new and
Surface modification During the 1960s the novel concept of noncovalently bonding heparin to implantable devices was described.3 In 1978 our group hypothesized that implant infections occurred because of contamination of the prosthesis by a small number of bacteria that were protected in the interstices of the implant or on its surface. Here they eventually multiplied, thrived, and became clinically obvious. It was our view that the implant itselfwas particularly susceptible because the matrix of the graft, lacking a blood supply, was unlikely to contain significant concentrations of the large doses of antibiotics given these patients parenterally. We, therefore, developed a system in which antibiotics were noncovalently bound to the vascular graft through electrostatic attraction to surfactants of opposite charge. We focused on quaternary ammonium compounds with long chain alkyl groups to generate positively-charged coatings. The surfactant must be water-insoluble so that the coating is not leached on exposure of the prosthesis to aqueous environments. Water insoluble quaternary compounds have the further advantage that they show low biologic toxicity. This contrasts with the well documented toxicity of water-soluble and moderately insoluble quaternary ammonium compounds widely used as emulsifiers and dispersing agents. The interaction of negatively charged drug with positively charged surfactant coating shows a simple hyperbolic binding isotherm. Surface-bound drugs are bound rather loosely with dissociation constants of about lo-?o 10m4 mol/l. Some high molecular weight ligands, such as tissue plasminogen activator, show a much higher binding affinity, but the stoichiometry of maximal binding is much less than one drug per surfactant. This suggests that only some surfactant molecules are involved in drug binding. The rate of dissociation of drug is relatively slow with half-times from hours to several days. The rate of release can be significantly decreased if the drug-surfactant complex is applied to the prosthesis in chloroform, or another solvent that causes the device to swell. The prosthesis is first allowed to swell in the presence of
754
Journal of VASCULAR SURGERY
Special cemmunicatim
drug/surfactant, then the device is removed from the solvent, and allowed to dry and to return to its original size. The drug with its large counter-ion is entrapped in the bulk polymer. After implantation, the pharmacologic agent very slowly diffises from the outer layers of the device. The limitations of this approach are the solubility of the drug in nonpolar organic solvents, and the ability of the solvent to nondestructively swell the polymer. Our initial experiments were facilitated by a family of positively charged surface active agents and an armada of negatively charged antibiotics, including all of the penicillins and all of the cephalosporins. Beginning in 1979 experiments were reported that showed that antibiotics bonded to vascular prostheses produced a surface that was infection resistant.4 In an in vitro bioassay and an in vivo model of implant infection, the bonded surfaces showed superior performance.5 Biochemical studies characterized the duration of binding and the efficacy of binding more than one drug.6 In a canine aortic graft model, bonded surfaces withstood challenge with a large inoculum of Staphylococcus aurem7 In 1981 we reported our initial experience with tridodecylmethylammonium chloride (TDMAC), a surfactant with three 12 carbon alkyl side chains. TDMAC bound far more antibiotic than other surfactants and appeared to produce an effective in situ reservoir for slow release from the surface. Subsequent studies showed that cephalosporins could be bound in concentrations similar to that of the penicillins and that both could bind to polytetrafluoroethylene (PTFE) and Dacron.8 Finally in 1985 we used an antibiotic bonded vascular graft to treat established vascular prosthetic infection in a canine modeL9 Data in this study shed some light on our basic hypotheses. First, by use of radiolabeled antibiotics, implanted grafts contained a huge reservoir of antibiotic, far in excess of that which can be achieved by parenteral administration. Second, residual antibiotics at the time of harvest did not correlate with an observed difference in infection rate indicating that it is the large initial dose that is the important factor. Finally, control grafts adsorbed very little of the parenterally administered antibiotics for 48 hours after implantation. These data indicate that grafts are at risk in the perioperative period and that a massive dose of antibiotic delivered at the site is the critical factor in eliminating infection. Subsequent studies reported in 1989 indicated that our in vivo experiments heretofore conducted with PTFE were equally effective with Dacron grafts.‘O
New strategies Recent evidence from our laboratory indicates that the custom synthesized surfactant trioctadecylmethylammonium chloride (TOMAC) is superior to TDMAC in binding to the graft surface. TOMAC differs from TDMAC in that it is much less water soluble and has 18 carbon side chains. Antibiotic binding is twice as effective with TOMAC at time zero, and the difference persists for up to a week in human plasma.
Recently, we have found that thrombolytic agents, like tissue plasminogen activator (@A), can also be bound to vascular grafts with surfactants and that the same graft can be bound as well to penicillins and cephalosporins. Our initial interest in binding tPA to grafts designed for infection resistance is derivative from work indicating that by entrapping bacteria fibrinogen may play a role in infections associated with clot. It is noteworthy that S. aweus binds fibrin and is the most common pathogen in vascular prosthetic infections. In the case of vascular grafts, this phenomenon may explain the latency period often observed in these infections and the reason the device must be removed for infection to be successfully treated. We have previously described an in vivo bioassay (ID-50) for evaluation of the relative infection resistance of implantable devices. By use of this method, control vascular grafts, control bonded to TPA alone and control bonded to penicillin alone, were compared to control grafts bonded to penicillin and tI?A. S. aureus in concentration of 1 x 10” to 1 x 10” was added to fibrinogen to which thrombin was added. Grafts were implanted in a rat subcutaneous pouch and harvested at 4 days. Bonding tPA and penicillin increased the ID-50 by 10 fold (p < 0.05)
Conclusions Established vascular prosthetic infections are a significant public health problem. Morbidity and mortality rates are excessive, and the costs of treating established infections are significant. The cause of vascular prosthetic infection remains obscure. The revolutionary technologies of the 1980s and 1990s have been applied, in the main, to graft healing and graft failure, most notably neointimal fibrous hyperplasia. The highly deranged microenvironment at the host implant interface undoubtedly plays a major role in the origin of these infections. The role of fibrin, macrophages, soluble mediators, and adhesion molecules, as well as those of the bacteria and the prosthetic surface itself, must be subjected to molecular scrutiny. This should be a major focus of research in the next decade. Vascular prosthetic materials have changed little in the last 3 decades. The necessity for such surfaces to be biocompatible, mechanically sound, antithrombogenic, and infection resistant is a daunting challenge. The development of a new surface with all these characteristics will require close collaboration among surgeons, molecular biologists, immunologists, and polymer chemists if it is to be successful. Another tack may be the modification of current surfaces with exemplary mechanical properties. Surfactant chemistry may have a valuable role here especially if the molecular biology is unraveled and methods for enhancing or blocking specific receptors, ligands, and mediators can be found. Drug delivery by means of surface modification and including, but not limited to antibiotics, antithrombogenic agents, thrombolytic agents, growth factors, calcium channel blockers and/or monoclonal anti-
Volume 13 Number 5 May 1991
bodies may thereby be more likely to develop a truly biocompatible vascular prosthesis. Ralph S. Greco, MD Untiersityof Medicine and Dentisty of New Jersey Robert Wood Johnson Medical School New Brunswick, NJ.
REFERENCES 1. Elek SD, Cohen PE. The virulenceof staphylococcus pyogenesfor man: a studyof the problemsof wound infection.Br J Exp Path01 1957;38:573. 2. Margiotta MS, Robertson FM, Greco RS. Selective induction of intercellular adhesion molecule (ICAM-I) expression by human endothelial cells following adherence to vascular grafts using an in vitro model. Surg Forum 1980;41:339-41. 3. Whiffen JD, Gott VL. In vivo adsorption of heparin by graphite-benzalkonium intravascular surfaces. Surg Gynecol Obstet 1965;121:287-90. 4. Harvey RA, Greco RS. The non-covalent bonding of antibiotics to a polytetrafluoroethylene graft. Ann Surg 1981;194: 642-7. 5. GrecoRS, Harvey BA, Henry R, et al. Preventionof graft infection by antibiotic bonding. Surg Forum 198O;XXXI:2930. 6. Greco RS, Harvey RA. The role of antibiotic bonding in the prevention of vascular prosthetic infections. Ann Surg 1982; 195:168-71. Greco RS, Harvey RA, Smilow PC, et al. Prevention of vascular prosthetic infection by a benzalkonium-oxacillin bonded polytetrafluoroethylene graft. Surg Gynecol Obstet 1982;155:28-32. Harvey RA, Greco RS. Antibiotic bonding to polytetralluoroethylene with tridodecylmethylammonium chloride. Surgery 1982;92:504-12. Greco RS, Donen. Al’, Harvey BA. The application of antibiotic bonding to the treatment of established vascular prosthetic infection. Arch Surg 1985;120:71-5. 10. Shue WB, Worosilo SC, Donetz Al’, Trooskin SZ, Harvey RA, Greco RS. Prevention of vascular prosthetic infection with an antibiotic bonded Dacron graft. J VASC SURG 1988;8:600-5.
PATHOGENESIS OF VASCULAR GIUFT INFECTIONS The increasingly routine use of prosthetic vascular grafts has revolutionized our ability to reperfuse and salvagepatients with severeperipheral vasculardisease.It is estimated that more than 60,000 vascular graft prostheses are implanted in the United States yearly.’ Despite improved prosthetic materials and surgical techniques, vascular graft infections remain a serious source of clinical morbidity and deaths. Approximately 2% of patients with vascular grafts will develop a prosthetic infection, the consequencesof which are often grave, that is, limb loss or death.’ To limit the incidence of these infections it is of paramount importance that we have a full understanding of the pathogenesis of graft infections. Only in this way can we hope to make significant inroads into the prevention and eradication of vascular prosthetic infections. Graft infections can be separated into those that occur acutely and those that occur late. Early postoperative graft
Special
cummunicatim
755
infections are often the result of wound infections and usually involve grafts anatomically superficial in location (femoral, axillary, popliteal sites). Late graft infections may occur months to yearsafter vascularreconstructive surgery. Indeed, there may be a long dormant period between the time of contamination and evidence of clinical infection.’ A wide spectrum of organisms has been reported to infect vascular prostheses.It has long been maintained that Staphylococcus aureus is the most common offending pathogen. However, multiple organisms, including gramnegative species, are frequently found.’ More recently, S. epidemtidis is being recognized as a common pathogen, and infections caused by this low virulence organism usually occur late after operation.’ It is well accepted that the introduction of bacteria commonly occurs at the time of implantation of a prosthetic device. Defective barriers, such as breaks in sterile technique, improper handling or sterilization of the graft material, or the development ofwound infections may play a role.’ Infections may also result from bacterial seeding. Of particular importance in the realm of peripheral vasculardiseaseis the presenceof lower extremity ischemic ulcers, which are often infected with polymicrobial flora.’ Any surgical incision involving the groin carries a higher incidence of wound infection and therefore graft infection. This is likely related to contaminated skin as a result of proximity to the perineum, redundant folds of moist skin, superficial location of the graft, and the transection of numerous lymphatics.2~3 The arterial wall itself might rarely be a source of contamination. Ilgenfiitz and Schwartz have respectively demonstrated a 10.4% and 19.6% incidence of positive bacterial cultures of the aortic wall taken at the time of aneurysmectomy. Cultures were more often positive in patients with ruptured or expanding aortic aneurysms.3 Interactions among the local host tissues and the prosthesis provide further insight into the pathogenesis of vasculargraft infections. Somehow local host defensesseem to fail in this environment, thus allowing bacterial propagation. Tissue reactivity in the presence of a foreign body has long been recognized as a potentiator of infection. Dougherty and Simmons* were able to demonstrate that infection could be produced with only 100 colony forming units of S. aureus in the presence of silk suture. The acute inflammatory processwill vary depending on the size and shape of the foreign material, its surface characteristics, and its chemical composition.*Most prosthetic materials commonly used in vascular surgery are fairly inert, but, nonetheless, they do endure some degree of inflammation when exposed to host tissues. The implantation site and mechanical interaction with host tissuesmay also influence the degree of inflammation.’ For example, the inflammation resulting from constant mechanical pulsatile interaction of an aortic graft against the bowel may lead to periprosthetic abscessformation and eventually enteroperivascular or enterovascular fistulas. At the cellular level there is evidence that host defenses are hampered. Many investigators believe that normal
