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Vol 8, No 5, September/October 2000 285 Infection occurring after internal fixation of a fracture is a devastat- ing complication and may be extra- ordinarily difficult to treat. The introduction of an implant allows bacterial invasion and alters both the local environment and the func- tion of immunocompetent cells. Additionally, the soft tissues sur- rounding the fracture site and the vascularity of the injured region are compromised, leading to delays in healing and deficits in the im- mune response. Although infection may occur after any form of surgical treat- ment, infections are more com- mon in patients with high-energy fractures (whether closed or open) and in patients who are immuno- compromised. Internal fixation has generally been considered to increase the risk of infection after fracture, 1 and it is recognized that many common species of bacteria are capable of colonizing the sur- face of metal implants. 2,3 Further- more, metal implants themselves Dr. Schmidt is Assistant Professor of Orthopaedic Surgery, University of Minnesota School of Medicine, Minneapolis. Dr. Swiontkowski is Professor and Chairman, Department of Orthopaedic Surgery, University of Minnesota School of Medicine, Minneapolis. Reprint requests: Dr. Schmidt, Hennepin County Medical Center, 701 Park Avenue, Minneapolis, MN 55415. Copyright 2000 by the American Academy of Orthopaedic Surgeons. Abstract Infection complicating internal fixation of fractures is a serious complication that is difficult to treat. Whenever metallic devices are implanted in vivo, successful biointegration requires that host cells colonize the highly reactive implant sur- face. Bacteria such as staphylococci can also become adherent to metallic or poly- meric implants and will compete with host cells for colonization of the implant surface. Once adherent, these bacteria form a biofilm and undergo phenotypic changes that make them resistant to the normal host immune response as well as to antibiotics. Furthermore, metallic implants themselves cause specific deficits in the function of the local immune system that may render the host response to infection inadequate. Any associated soft-tissue injury causes even greater impairment of local immune function. Despite the potentially detrimental impact of internal fixation, fracture stability is of paramount importance in achieving fracture union and in preventing infection. It has been demonstrated in animal models that contaminated fractures without internal fixation develop clinical infection more commonly than similar fractures treated with internal fix- ation at the time of colonization. Because of the potential for infection whenever internal fixation is utilized, appropriate prophylactic antibiotic coverage for staphylococci and Gram-negative organisms should be provided. Open wounds and severely damaged soft tissues require aggressive management so that a viable soft-tissue envelope is maintained around the implant. Host factors such as smoking and malnourishment should be corrected. Early diagnosis and aggressive treatment of implant-related infection with antibiotics, debridement, and maintenance of stable internal fixation are essential to successful treatment. J Am Acad Orthop Surg 2000;8:285-291 Pathophysiology of Infections After Internal Fixation of Fractures Andrew H. Schmidt, MD, and Marc F. Swiontkowski, MD appear to modulate local immune function. Therefore, eradication of implant-associated infection may appear to necessitate removal of the implant. 4 However, in the case of a fracture, the implant pro- vides stability to the injured limb, which in turn lessens the likeli- hood of infection and is necessary for optimal healing of the bone and soft tissues. 5 In a study of hamster osteotomies contaminated with Staphylococcus aureus, the infection rate decreased from 71% to 38% when internal fixation was added. 6 Thus, surgeons treating implant-associated infections after fracture surgery may be faced with competing priorities—treat- ing the infection (which may re- quire removal of the implant) and treating the fracture (which neces- sitates retention of the implant). Bacterial Colonization of Implants Bacterial colonization of ortho- paedic implants is a necessary, but not in itself sufficient, first step in the development of implant-related infection. To document rates of asymptomatic bacterial coloniza- tion, Moussa et al 3 cultured ortho- paedic fracture implants at the time of removal from 21 patients. The patients were scheduled to undergo elective implant removal because of hardware prominence, mal- union, or nonunion. Despite the absence of clinical infection in the patients, cultures from 50% of the implants grew organisms. There- fore, bacteria may colonize im- plants without causing sepsis, and other factors besides the mere pres- ence of bacteria must underlie the development of clinical infection. Important variables that may affect whether infection occurs in a given case include the specific organism, the type of material on the surface of the implant (i.e., dense versus porous), the configuration of the implant (i.e., solid versus hol- low), the timing of bacterial colo- nization, and the general health of the host. Melcher et al 7 studied infection after intramedullary nail- ing in a rabbit model and found that infection rates were higher for hollow slotted nails than for solid nails, higher for stainless steel nails than for pure titanium nails, and higher when reaming had been per- formed. Whether these factors are of clinical importance in humans is not known. Other factors that must be considered include the formation of a “biofilm” due to the adsorption of proteins, sugars, and other macromolecules onto the implant surface; possible changes in the material itself attributable to the host or the bacteria; the effects of the implant on the local environ- ment; and the systemic effects of the implant in the host. 4 Microbial Adherence Many types of bacteria, includ- ing most coagulase-negative Staph- ylococcus species, demonstrate an ability to adhere to surfaces, in- cluding metal. 2,4 Bacterial adher- ence is considered to be a major factor contributing to the develop- ment of implant-associated infec- tions. 2,8,9 Adherent Staphylococcus organisms are more resistant to antibiotics than the same strains grown in a nonadhered state. The mechanisms of bacterial adherence depend on a complex interplay between the infecting organism, the local milieu, and the properties of the biomaterial sur- face. 2,4 Bacterial adhesion proceeds through two stages. 10 First, nonspe- cific physicochemical forces result in an initial, reversible attachment of the bacterium to an available sur- face. Many factors, including the surface charge of the substrate and the relative hydrophobicity of both the bacterium and the substrate, modulate this process. Differences in these surface characteristics result in the variation in affinity for bacterial colonization among various metals. Once the bacterium is attached to the substrate, molecular reactions between bacterial surface macro- molecules and substrate surfaces result in permanent adherence to the surface. Fibronectin is a protein that modulates surface adhesion of eukaryotic cells and has been shown to promote S aureus adhesion as well. Metal Implants and Surface Reactions Gristina 2 has characterized the complex events that occur after im- plantation of a biomaterial as “the race for the surface.” This compli- cated series of interactions is poorly understood but is fundamental to the problem of biomaterial-related sepsis. In theory, a freshly implanted device presents a highly reactive surface destined for one of two fates: bacterial adhesion and colo- nization or tissue integration. If eukaryotic host cells integrate them- selves into the surface first, bacterial colonization will be actively inhibited, and the biomaterial will become tissue-integrated. If bacterial cells colonize the surface first, a so-called microzone may be established that is conducive to further bacterial growth and inhibits any immune response. A key feature of this pro- cess is the formation of “slime,” a mucopolysaccharide biofilm that enhances bacterial nutrition, inter- feres with phagocytosis, influences antibody function, and promotes further bacterial aggregation. 2 The production of one type of this so-called slime, bacterial glyco- calyx, is an important determinant of antibiotic resistance. Gristina and Costerton 8 reported that 76% of implants retrieved from patients with prosthesis-related infections had causative bacteria enclosed in a glycocalyx biofilm. The mature bio- film consists of both the accumulated bacterial mass and associated extra- cellular glycocalyx. When infec- tions about implants occur, bacterial adherence may limit the usefulness of cultures because infecting organ- isms may be protected within the biofilm. Knowledge of the mechanisms that promote bacterial adherence to the surfaces of implants provides a potential method to modulate this phenomenon. 10 For instance, the surface of titanium implants can be modified by the covalent attach- ment of an organic monolayer. This may provide a method to de- crease bacterial adherence, modify bacterial behavior by attachment of functional cell-surface receptors, or provide antibiotics or immuno- globulins to the surface of the im- plant. Surface modification of im- plants remains an area of active research. 2,10 In addition, Gristina’s theory highlights the importance of decreasing the likelihood of bacter- Infection After Internal Fixation of Fractures Journal of the American Academy of Orthopaedic Surgeons 286 ial colonization by the use of pro- phylactic antibiotics, atraumatic surgical technique, and materials that are designed to promote eukaryotic cellular integration and inhibit the formation of a biofilm. Implant Characteristics It is known that the rate of infec- tion about a foreign body is related to the material properties and shape of the implant. For example, infection rates are greater with multifilament sutures than with monofilament sutures of the same material. With respect to ortho- paedic implants, it has been shown that infections are more likely after intramedullary nailing with hollow nails than with solid-core nails. 11 With respect to material types, it has been shown that bacteria adhere differently to different sub- strates. The relative propensity of Staphylococcus epidermidis to adhere to a given material in vitro has been directly related to rates of bac- terial colonization and infection in vivo. 9 In a study by Chang and Merritt, 9 bacterial adherence to stainless steel was greater than that to polymethylmethacrylate and titanium, which is significant given that most fracture fixation devices are manufactured from stainless steel. Using a rabbit model, Arens et al 12 showed that the infection rate in a wound contaminated with S aureus was 75% with stainless steel plates, compared with 35% with titanium plates. The surface characteristics of the implant are important in determin- ing the degree of bacterial adher- ence; the resultant effect may be dif- ferent for acute infections and delayed infections. Dense materials promote fibrous encapsulation and generally provoke minimal tissue reaction. 13 Porous materials allow ingrowth of the surrounding tissue into their pores. In an animal model, Merritt et al 13 found that in- oculation of bacteria at the time of implantation favored infection in porous material, whereas late inocu- lation favored infection in dense material. Once fibrous ingrowth occurred about a porous implant, late infection was less likely than it was about a dense implant. The clin- ical implication is that porous im- plants may present a greater risk of infection in a contaminated wound. However, in a sterile wound, where there is little risk of immediate bac- terial contamination, use of porous devices may protect against delayed hematogenous infection. In another study, it was found that the dose of S aureus necessary to infect cobalt- chrome implants with polished sur- faces was 40 times greater than the dose needed to infect implants with porous surfaces. 14 Titanium im- plants were less susceptible to infec- tion but demonstrated the same effect. These differences in the propen- sity for infection can be explained by the fact that implant material, shape, and size are all factors that affect the nature of the reactive sur- face available for bacterial adher- ence. Both the material itself and its surface characteristics appear to be important determinants of the frequency of infectious complica- tions. Although titanium implants may be less susceptible to infection in animal studies, this has not been proved in humans. Immunomodulation by Metal Implants Up to 13% of the population is sen- sitive to nickel, cobalt, or chromi- um. 15 Other metals, including tita- nium, aluminum, and vanadium, may also cause hypersensitivity reactions in susceptible persons. The manifestations of metal sensi- tivity are subtle and may alter the host response to the implant and affect local immune function. In a hamster model, immunization with nickel chloride for 5 weeks protected against infection about stainless steel pellets, whereas immuniza- tion for 10 weeks increased the infection rate. 16 In patients with total joint implants or dynamic hip screws, metal is found in local and distant lymph nodes, bone mar- row, liver, and spleen. Morpho- logic changes occur within the lymph nodes, suggesting that im- mune function has been altered. Furthermore, changes in cytokine levels are found in patients with total joint replacements. Widespread alterations of im- munologic function are seen in re- sponse to metal implants. During the first few days after implantation, the specific cellular content of the inflammatory response varies de- pending on the material used. 16 Direct contact between the inflam- matory cells and the biofilm, as well as interactions promoted by metal ions, surface macromolecules, and free radicals present at the reactive metal surface, all influence the func- tion of these cells. Inhibition of T- cell activation, impairment of poly- morphonuclear leukocyte super- oxide production, and plasma-cell activation have all been reported. 17-19 In addition, biomaterials have been shown to influence chemotaxis and complement activation. 20 Although the precise meaning of these findings is unclear, alteration of the immune response is a defi- nite consequence of use of metallic implants. This may be of clinical importance, especially in patients with preexisting immunodeficiency or malnutrition. It is possible that these interactions could be harm- ful, promoting infection in some situations; in other circumstances, however, the very same effects might make the wound less suscep- tible to bacterial invasion. Much more research is necessary to fur- ther define these interactions and to delineate the ways that biomate- rials might enhance immune sys- Andrew H. Schmidt, MD, and Marc F. Swiontkowski, MD Vol 8, No 5, September/October 2000 287 tem function rather than limit its effectiveness. Clinical assessment of the general health of the patient, including im- mune function and nutritional sta- tus, is prudent if an implant-related infection is suspected. Specifically, patients should be asked whether they smoke, have received an allo- geneic blood transfusion, have a known immunodeficiency syn- drome, or have had possible expo- sure to the human immunodefi- ciency virus. Laboratory evidence of malnutrition includes a total lymphocyte count of fewer than 1,500 cells per cubic millimeter and a serum albumin concentration of less than 3.5 g/dL. The Role of Fracture Stability in Infection Although it is known that the pres- ence of a foreign body increases the risk of infection, clinical experience suggests that internal fixation of open fractures reduces the infec- tion rate. It is postulated that inter- nal fixation reduces the amount of soft-tissue damage caused by bone fragments, thereby making the wound a less hospitable environ- ment for bacterial growth. 6 In one study involving a hamster model, 6 71% of femoral osteotomies inoculated with S aureus organisms were culture-positive after 2 weeks. When the osteotomy was stabilized with 0.9-mm Kirschner wires, only 38% of the animals had positive cul- tures. However, when the osteotomy was contaminated with the Gram- negative organism Proteus mirabilis, the incidence of positive cultures was increased by internal fixation (57% vs 40%). Clinical infection was not evident in the adjacent soft tis- sues, which may reflect the greater propensity for P mirabilis to survive on the implant owing to its biofilm. In another study involving a rabbit model, tibial fractures were stabilized with either a dynamic compression plate (stable group) or a loose intramedullary rod (unsta- ble group) and inoculated with S aureus. 21 The infection rate was double in the unstable group (71% vs 35%). It is not known for certain why stable fractures are less susceptible to infection. Perhaps unstable frac- tures result in greater damage to surrounding tissues, thereby pro- moting inflammation and local immunosuppression. In contrast, stable soft tissues may promote more rapid vascularization. Prevention of Infections After Internal Fixation of Fractures Given the difficulty and increased expense of the treatment of infec- tion after internal fixation of frac- tures, 22 prevention is extremely im- portant. There are two essential steps in the prevention of infection: early administration of intravenous (IV) antibiotics and proper surgical management of fractures. Prophylactic Antibiotic Therapy Antimicrobial prophylaxis is a necessary adjunct to the manage- ment of fractures that require sur- gery. In cases of closed fracture, administration of a first-generation cephalosporin 30 minutes before surgery provides adequate cover- age. It is not necessary to continue prophylaxis for more than 24 hours. 23 Application of the bacteriostatic compound sulfanilamide to pre- vent infection in open fractures was first reported in 1939 and rep- resents one of the earliest success- ful examples of antibiotic prophy- laxis. Since then, the management of open fractures has advanced considerably. For open fractures that are contaminated by bacteria at the time of injury, early adminis- tration of parenteral antibiotics has been shown to reduce the infection rate. 24 The specific agent adminis- tered is chosen empirically on the basis of the severity of the injury and the type of contamination ex- pected (Table 1). For Gustilo grade I and grade II fractures, a first- generation cephalosporin is given. For grade III injuries, an aminogly- coside is added, or a third-genera- tion cephalosporin is used. Penicil- lin must be administered if the wound has been contaminated by soil. Tetanus prophylaxis should be given to any patient who has not had documented tetanus vaccina- tion. When combined with early and aggressive surgical debridement, it is not necessary to continue pro- phylactic antibiotics for more than 24 hours. The organisms that are typically cultured from infected fracture sites are Gram-positive (usually staphy- lococci) and nosocomial Gram- negative bacteria. Wound cultures are of little benefit except in unusu- al circumstances, such as a marine injury. Although cultures are of limited value in predicting infect- ing organisms, the final postde- bridement culture has the highest correlation with the development of infection. 25 Recently, the antibiotic bead- pouch technique has been recom- mended for use in more severe open fractures. 26 This involves placing polymethylmethacrylate beads impregnated with a heat- stable antibiotic into the wound and covering the wound with an occlusive bandage. The beads are made by hand or with a mold and are placed on 18-gauge surgical wire or a heavy nonabsorbable suture. Either tobramycin (2.4 to 4.8 g per batch of cement) or van- comycin (1 to 2 g per batch of ce- ment) is used. In a comparative study, this technique resulted in a decrease in infection rate from 16% to 4% in patients with severe open Infection After Internal Fixation of Fractures Journal of the American Academy of Orthopaedic Surgeons 288 tibial fractures treated with intra- medullary nailing. 27 Surgical Technique Given that rapid soft-tissue inte- gration with the implant and a healthy vascular supply are of key importance in limiting the ability of bacteria to win “the race for the surface,” the importance of atrau- matic surgical technique when operating on fractures becomes obvious. Minimizing the surface area of exposed bone and of im- plants will lessen the likelihood of infection, because the area avail- able for bacterial adherence will be smaller. Furthermore, one should ensure that healthy tissue is pres- ent adjacent to the implant and bone, so that viable host cells are available to cover the surface im- mediately. When operating on closed frac- tures, it is of paramount impor- tance to limit the degree of bone devascularization and to cover any implants with healthy soft tis- sue. Skin must be examined for areas of contusion or necrosis. Muscle viability is assessed on the basis of its color, capacity to bleed, and contractility. During exposure, skin edges should not be crushed or retracted under tension, and devitalized muscle should be re- moved. Sutures may be used to retract tissues, rather than forceps or hand-held retractors, which may further crush tissues. Periosteal stripping is generally not per- formed, and bone fragments are not further devascularized. Frac- ture reduction should be done when possible by using principles of ligamentotaxis, rather than direct reduction with unnecessary exposure of the bone. Open re- duction and fixation of articular injuries is best delayed until the soft-tissue envelope is healthy. Open fractures generally have more severe soft-tissue injury, as well as bacterial contamination. An open wound may be consid- ered infected if more than 8 hours elapsed after injury before treat- ment was initiated. Open fractures require immediate aggressive de- bridement, fracture stabilization, and early reconstruction of the soft tissues. The edges of the traumatic wound should be excised, along with any other devitalized skin and muscle. The entire zone of injury requires assessment for nonviable tissue and contamination. All ne- crotic and foreign material should be removed. Generally, some form of irriga- tion solution is used, but the role of antibiotic solution and the efficacy of high-pressure lavage are current- ly controversial. It has been shown that solutions containing antibiotic are no better at removing bacteria than plain saline. Detergents, such as castile soap and benzalkonium chloride, have shown promise in removing bacteria. There is evi- dence that the efficacy of these irri- gation solutions may vary with the type of bacterium, with soap more effective for Pseudomonas aeruginosa organisms and benzalkonium chlo- ride more effective for S aureus. 28 Current recommendations are to use sequential irrigation with sa- line, then soap, and finally benzal- konium chloride. High-pressure pulsatile lavage was developed to provide an effi- cient means of mechanical debride- ment. However, recent evidence suggests that high-pressure lavage contributes to further devascular- ization of the fracture edges. 29 One recent study showed that high- pressure lavage was of no benefit in removing bacteria from fresh frac- tures (those treated within 3 hours of injury). 29 For fractures first seen after 6 hours, bacterial adherence was more pronounced, and high- pressure lavage was needed to ster- ilize the implant. It seems prudent to use high-volume irrigation at a low pressure, except for fractures seen after a delay and those that are grossly contaminated. Regardless of whether one is treating open or closed injuries, fracture implants should never be left exposed. The use of a bead Andrew H. Schmidt, MD, and Marc F. Swiontkowski, MD Vol 8, No 5, September/October 2000 289 Table 1 Choice of Antibiotic Therapy for Closed and Open Fractures Fracture Type Recommended Antibiotic Closed First-generation cephalosporin (cefazolin, 2 g IV loading dose, 1 g IV every 8 hours for 3 doses) Grade I and II open First-generation cephalosporin (Ancef, 2 g IV loading dose, 1 g IV every 8 hours for 3 doses) Grade III open Third-generation cephalosporin (ticarcillin- clavulanate, 3.1 g IV every 8 hours) or first- generation cephalosporin plus aminoglycoside (gentamicin or tobramycin) All open fractures Add penicillin for injuries contaminated by soil. Add tetanus prophylaxis if history of tetanus immunization is not known. Discontinue antibiotics after 24 hours; start again for any major procedure (e.g., internal fixation, bone grafting, muscle flap). pouch is an effective way to manage dead space and to sterilize open wounds. This may be done by fash- ioning tobramycin-impregnated methylmethacrylate beads (con- taining 2.4 to 4.8 g of tobramycin per package of cement), placing them into the wound, and then sealing the wound with an occlu- sive, impermeable dressing. In general, wound debridement should be repeated every 48 hours. Definitive soft-tissue closure or reconstruction should be per- formed within the first week when possible. Summary Implant-associated infections pre- sent a formidable challenge to the orthopaedic surgeon. Tissue dam- age related to the initial injury is potentiated by the adverse biologic effects of internal fixation devices, which further decrease vascularity, suppress the function of local im- munocompetent cells, and provide a site for bacterial adherence. Knowledge of the pathophysiol- ogy of implant-related infections leads to a logical approach for man- agement. Skeletal stability must be maintained, for, as McNeur 30 has stated, “there is only one thing worse than a stable infected frac- ture and that is an unstable infected fracture.” As for other types of wound infection, antibiotic therapy and debridement are the corner- stones of treatment. In acute infec- tions with favorable soft tissues, the implant may be successfully re- tained as long as fracture union seems to be progressing favorably. In chronic infections, exchange or removal of the implant may be nec- essary, along with soft-tissue and skeletal reconstruction. 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Keating JF, Blachut PA, O’Brien PJ, Meek RN, Broekhuyse H: Reamed nailing of open tibial fractures: Does the antibiotic bead pouch reduce the deep infection rate? J Orthop Trauma 1996;10:298-303. 28. Conroy BP, Anglen JO, Simpson WA, et al: Comparison of castile soap, ben- zalkonium chloride, and bacitracin as irrigation solutions for complex conta- minated orthopaedic wounds. J Orthop Trauma 1999;13:332-337. 29. Bhandari M, Schemitsch EH, Adili A, Lachowski RJ, Shaughnessy SG: High and low pressure pulsatile lavage of contaminated tibial fractures: An in vitro study of bacterial adherence and bone damage. J Orthop Trauma 1999; 13:526-533. 30. McNeur JC: The management of open skeletal trauma with particular refer- ence to internal fixation. J Bone Joint Surg Br 1970;52:54-60. Andrew H. Schmidt, MD, and Marc F. Swiontkowski, MD Vol 8, No 5, September/October 2000 291