- Email: [email protected]
Antibacterial coating systems
Injury, Int. J. Care Injured (2006) 37, S81—S86
www.elsevier.com/locate/injury
Antibacterial coating systems Andrea Montali Synthes GmbH, Oberdorf, Switzerland
KEYWORDS: Antibacterial coatings; local application of antibacterials.
Summary1 The local application of antibiotics is a well-known procedure that has been in successful clinical use for more than 20 years. The most frequently used carrier substance for the antibiotic or other antibacterial substances is polymethylmethacrylate (PMMA). However, because PMMA is not resorbable, as much as 70% of the antibiotic dose is permanently sequestered in the PMMA cement and therefore not available to combat bacterial colonization. Antibacterial coatings of metal implants represent an attractive solution to simplify the local application of an antibacterial substance in fracture care. Several coating technologies have been investigated, involving different carrier materials as well as different antibacterial substances. A fully resorbable coating containing gentamicin sulphate has yielded promising results in animal studies and intramedullary tibial nails with this coating have already been implanted successfully in a few patients. In the future, the main developmental focus for antibacterial coatings for implants will lie in tailoring the release characteristics and the antibacterial substance to minimize the risk of breeding resistant bacterial strains while maximizing the efficacy of the coating.
Current solutions for local delivery of antibiotics The local application of antibiotics is a well-known and accepted tool in the treatment of osteomyelitis. In the early 1970s, Buchholz first used polymethylmethacrylate (PMMA) cements with antibiotics in joint replacement surgery [1]. In 1974, Klemm introduced PMMA beads for carrying gentamicin sulphate rather than massive cement forms [2]. Due to their higher surface-to-volume ratio, the smaller PMMA beads are a more favorable delivery vehicle for the contained antibiotic. After implantation, the water-soluble antibiotic is leached out of the surface of the implant by the surrounding body fluids. Both PMMA cements with antibiotics in joint replacement surgery and PMMA 1
Abstracts in German, French, Italian, Spanish, Japanese, and Russian are printed at the end of this supplement.
beads in osteomyelitis therapy are now common and extensively used procedures, the efficacy of which has been shown in several studies [3–5]. Other methods for the local application of antibiotics in conjunction with the treatment of fractures, joint replacements, or bone voids, include collagen fleeces impregnated with antibiotics, which have the combined effect of antibiotic delivery and hemostasis; PMMA pre-forms and temporary spacers; antibiotic-impregnated bone-substitute materials such as calcium sulphate or calcium phosphates; or a recently commercialized polyurethane sleeve impregnated with antibiotics to be applied over external fixation pins to prevent pin-track infections [6]. All the above-mentioned methods require a carrier material other than the orthopedic implant itself to deliver the antibacterial substance. From the point of view of the surgical technique in fracture treatment, this means that the antibiotic
0020–1383/$ — see front matter # 2006 Published by Elsevier Ltd. doi:10.1016/j.injury.2006.04.013
S82
delivery vehicle does not contribute actively to the primary goal of the surgery, which is restoration of the anatomical relationships. This implant needs to be placed in addition to the commonly used hardware for fracture fixation. Furthermore, as in the case of the nonresorbable PMMA implants, the antibiotic delivery vehicle may need to be removed at a later stage. These technical limitations have made the local application of antibiotics during fracture treatment an exceptional procedure, used nearly exclusively in cases where an infection is already present and needs to be treated. As opposed to fracture treatment, the use of locally delivered antibiotics in joint replacement surgery is now part of the standard procedure in approximately half of all implanted cemented joint replacements, its value lying in its prophylactic rather than therapeutic effect. The widespread use of antibiotic-containing cement in joint replacement surgeries has two primary reasons: the use of antibiotic-containing cements does not alter the surgical technique for implanting a cemented prosthesis and the safety and efficacy of the method have been demonstrated in several clinical studies. However, it must be pointed out that statistical relevance in showing a reduced infection rate when using antibiotic containing cements was only shown after several years of application, when large numbers of patients had been treated in a comparable clinical setting [3].
Local delivery in fracture treatment— requirements In fracture treatment surgery, the local delivery of antibiotics still requires substantial alteration of surgical technique since an antibiotic-containing implant must be used in addition to the hardware needed to treat the fracture. Furthermore, real clinical efficacy in prophylaxis remains to be proven with statistical relevance in large trials, although its efficacy has been shown in under-powered studies [7, 8]. Therefore, in osteosynthesis, the local application of antibiotics is mostly used to treat existing osteomyelitis and only exceptionally as a prophylactic measure. Three main issues remain to be resolved to make the local delivery of antibiotics, or of antibacterial substances in general, a more widely used procedure in osteosynthesis: • The surgical technique for implantation of an antibiotic-containing device and the standard device must be the same.
A Montali
• The safety and efficacy of an envisioned solution must be demonstrated. • Last but not least, resistance issues with respect to the use of antibiotics must be considered and addressed. Providing metal implants commonly used in fracture repair surgeries with a coating that contains and releases an antibacterial substance after implantation represents a logical and appealing solution to the above-mentioned requirements. However, before discussing in more detail the various solutions that are available or are being investigated currently for antibacterial coatings, the rationale for the local delivery of antibiotics in fracture treatment must be laid out. One question to be answered is: Is there a need for antibacterial coatings in trauma surgery?
The role of local delivery in trauma surgery Systemic antibiotic delivery is a very common procedure in hospitals all over the world. In operative fracture treatment, the systemic prophylactic administration of antibiotics is a standard procedure and its efficacy has been demonstrated in large trials and is no longer questioned [9]. In contrast to closed fractures, which have infection rates of 1% or 2%, a comparably high rate of infection is observed in the treatment of open fractures, ranging from a few percent to 30% or more, depending on the extent of soft tissue damage, the severity of the fracture, and its anatomical location [8, 10, 11]. Therefore, it appears evident that care of open fractures still has the potential for a wide margin of improvement in preventing infections. Despite its widespread use and efficacy, systemic antibiotic delivery carries certain drawbacks such as systemic toxicity, poor penetration into ischemic or necrotic tissues, and hospitalization during intravenous therapy to monitor drug levels and effects [12, 13]. It must be pointed out that the area most relevant when considering implant-related infections, i.e. the surface of the implant and its immediate surroundings, is either not or only insufficiently reached by systemic antibiotics. Thus, if bacteria colonize an implant, the possibility of developing an infection remains intact despite systemic antibiotic prophylaxis. Several authors and, in particular Gristina and co-workers, have extensively investigated the interaction between the body and the implant and the resulting complex environment at the interface [14].
Antibacterial coating systems
Bacteria, such as Staphylococcus aureus, can be found in contaminated fractures and compete with the cells of the bodyís immune system to colonize the surface of the implant. This situation, in which an inert foreign body is implanted into tissue that is already injured and weakened, has been described as a race for the surface of the implant. In this particular situation, the bacteria have a certain advantage in that they divide rapidly and are extremely flexible, which allows them to adapt to changing situations. As a result, bacteria gain an advantage competing against the bodyís immune system, which is locally weakened by the presence of a foreign body and a fractured bone; and in many cases the immune system is also systemically challenged due to other injuries. Studies indicate that the presence of an implant impairs the hostís local immune response and can reduce the number of bacteria required to cause an infection by a factor of 10,000 [15]. Thus, an antibacterial coating present from the very first moment of implantation and which starts releasing the active substance after implantation represents a valid possibility to avoid bacterial colonization of the implant surface. The main rationale for locally applying antibiotics in osteosynthesis is the possibility of achieving high local concentrations far above the minimal inhibitory concentration (MIC) of resident bacteria, while avoiding systemic concentrations high enough to have toxic effects [11, 14, 16]. The local concentrations that can be achieved through local application cannot be reached with systemic delivery, due to the toxic side effects that most antibiotics produce at such high systemic concentrations. The very high concentrations of antibiotics that can be reached after the local application of an antibiotic from a coated implant, for example in the medullary canal, have been shown to be effective even against organisms judged to be resistant to the employed antibiotic [17, 18]. This finding is due to the fact that resistance is determined with respect to the concentrations of antibiotics that can be reached by systemic application, where toxicity can be a serious issue. This very important point should be kept in mind when considering resistance issues connected with antibiotic-coated implants, because sub-lethal antibiotic concentrations provide an ideal environment for generating resistant strains. Given that resistance will remain an issue to be considered every time an antibiotic is used, any antibacterial coating must fulfill two important requirements: the optimal antibacterial substance must be chosen; and the release kinetics must be tailored to minimize the time of exposure to antibiotic concentrations below the MIC of the resident bacteria. Since the development of resistant strains is always a risk, the
S83
clinician must weigh this risk against the potential benefit when selecting the clinical indications for an antibiotic-coated implant in order to avoid using antibiotics in cases that do not present a recognizable risk for developing an implant-related infection. The optimal system for local antibacterial prophylaxis should satisfy multiple requirements. It should be: biocompatible to avoid rejection; the carrier should be biodegradable to avoid a subsequent operation for its removal; the release profile of the active substance should be tailored to the clinical needs; and its use should not influence the surgical technique.
Coatings current solutions Hydroxyapatite coatings Coatings have been in use for several years as a method for improving the fixation of prostheses. Coatings of hydroxyapatite (HA) are currently the method of choice in this application. The application of HA coatings in osteosynthesis is not as common as in joint replacement surgery. In the area of osteosynthesis, external fixation pins were the first implants to be coated with HA, since a need for improved fixation was recognized in this particular application. HA coated external fixation pins were thoroughly investigated in several animal studies. In particular, Moroni et al have shown that improved implant fixation also leads to a reduced rate of infection [19]. However, the need for improved implant fixation is not a priority in many osteosynthesis applications, since in most cases the implants are preferably removed after fracture healing and excessive fixation makes this removal difficult or even impossible [20].
Antiseptic coatings DeJong et al have gone one step further in the improvement of implant fixation and infection prophylaxis in external fixation in their goat studies, which demonstrated the efficacy of HA coatings containing antiseptic substances [21]. The substance used in these studies was chlorhexidine. In another study, a combination of chlorhexidine and chloroxylenol was successfully used as a coating for intramedullary implants in a rabbit model [22]. Chlorhexidine is already commonly used in local drug delivery as a coating for catheters and is accepted in this application. However, concerns remain concerning the toxicity of antiseptics on bone tissue; in particular
S84
A Montali
A silver coating is another method of providing implants with an antibacterial surface. This method has been well known for many years but has failed to find widespread use, mainly because its efficacy remains unproven and because of toxicity concerns. The use of nanoparticulate silver may represent a promising new possibility, where the active surface area is maximized while keeping the total amount of silver low. By embedding nanoparticles of silver in coatings for implants or directly into cements for joint replacement applications, it is possible to tailor the antibacterial activity of the silver ions while remaining below the toxicity threshold for other cell types [25]. From a resistance standpoint, silver is generally accepted as not inducing resistance in bacteria. However, the emergence of bacteria resistant to both antibiotics and silver has been observed lately in a clinical application in which the bacteria were exposed to silver [26]. The issue of selecting resistant bacterial strains through an excessive use of antibiotics is perhaps the main driving force behind research into new antibacterial substances. In a novel approach, the efficacy of an antibacterial peptide against MRSA was recently demonstrated in a rabbit model [27].
tions in an intramedullary infection model in rats [29]. Six weeks after implantation, the coating had effectively prevented infections in the test group while animals in the control group showed extensive symptoms of infection. These results were later reproduced in a rabbit model. The same group has successfully implanted intramedullary tibia nails with the same coating in patients with severe open tibia fractures, which may be the first ever clinical application of an antibiotic-coated implant in fracture care [30]. This PLA-based coating technology has been further investigated in our laboratories, where it was shown that the release kinetics could be tailored from a distinct burst release to a zeroorder release by the appropriate choice of the carrier polymer and the coating composition. By varying the active substance between a hydrophobic or a hydrophilic substance, a further degree of freedom can be achieved. Through an appropriate design of the coating, it is possible to envision the sequential release of different substances from one and the same coating. The release profile of an antibiotic coating containing gentamicin was completely reversed from a burst release, as observed with the PLA-gentamicin sulphate coatings described above, to a sustained long-time release. This process was achieved by substituting the sulphate group of gentamicin sulphate with a hydrophobic fatty acid, such as laurilic acid [31]. These selected examples show that the development of antibacterial coatings offers a wide range of possibilities and variability and that it is possible to adapt the coating properties to the multiple and diverse requirements found in different indications.
Resorbable polymeric coatings
Proving efficacy of antibacterial coatings
Fully resorbable polymeric coatings loaded with antibacterial substances come fairly close to the previously mentioned requirements. This technology allows a wide choice of substances to be used and it is possible to tailor the release kinetics by varying the formulation of the coating and its components. One of the first reports of a fully resorbable antibacterial implant coating for fracture repair with the goal of delivering an antibacterial substance was in 1997, when Price and co-workers applied a polylactide (PLA) coating loaded with gentamicin to osteosynthesis plates [28]. The coating was applied by a solvent-based dip coating process. Its suitability as an antibiotic carrier was shown. Lucke et al demonstrated the efficacy of a PLAbased coating with gentamicin in preventing infec-
The results shown in animal studies for various antibacterial coatings are encouraging. In many cases, the coatings can be optimized for antibiotic release kinetics and in vitro studies can reveal the extent to which the coatings prevent bacterial colonization on the implant. The systems can be shown to be biocompatible and efficacious in animal models. However, clinical efficacy remains to be confirmed by clinical data. Clinical trials have proven to be extremely difficult because low infection rates require large patient populations to show statistical relevance in the prevention of infections. Furthermore, the occurrence of infections is a multifactorial event, in which an antibacterial coating represents just one of many measures to be taken. This situation further increases the difficulty of unambiguously attributing
chlorhexidine is known to exhibit toxicity on articular cartilage [23]. The main rationale for the use of an antiseptic instead of an antibiotic is the lower potential for developing resistant bacterial strains. However, resistance is not an unknown phenomenon for antiseptics, as documented by Russell for chlorhexidine [24].
Silver coatings
Antibacterial coating systems
a clinical outcome to the effect of a coating. As a result, devices with antibacterial coatings will be introduced into the market with supporting data for biocompatibility and effectiveness in animal studies, but clinical evidence may only emerge after judicious use of the implants in large numbers of patients.
Summary In summary, the usefulness of locally delivering an antibacterial substance in the therapy or prophylaxis of an infection is recognized and several approaches have been investigated and shown to be feasible. Antibacterial coatings of implants allow the controlled release of the contained substance and the release characteristics can be tailored by varying the coating formulation. Furthermore, antibacterial coatings of implants do not influence the surgical technique for implantation. The efficacy of antibacterial coatings has been extensively documented in animal studies and the first coated implants are in clinical use. The properties of antibacterial, and in particular antibiotic, coatings can be tailored to minimize the risk of breeding or selecting resistant bacterial strains. However, this risk can never be excluded. The use of antibacterial-coated implants will always have to be considered carefully and evaluated on a case-by-case basis in accordance with the recognized risk of the patient developing an implantrelated infection.
Acknowledgements The author wishes to thank E Gruskin and S Gass-Rüede for support in the preparation of the manuscript, and G Schmidmaier, M Raschke, and B Wildemann for many interesting and inspiring discussions.
S85
Bibliography 1. Buchholz HW, Engelbrecht H (1970) [Depot effects of various antibiotics mixed with Palacos resins]. Chirurg; 41(11):511−515. 2. Klemm K (1979) [Gentamicin-PMMA beads in treating bone and soft tissue infections (author’s transl)]. Zentralbl Chir; 104(14):934−942. 3. Espehaug B, Engesaeter LB, Vollset SE, et al (1997) Antibiotic prophylaxis in total hip arthroplasty. Review of 10,905 primary cemented total hip replacements reported to the Norwegian arthroplasty register, 1987 to 1995. J Bone Joint Surg Br; 79(4):590−95. 4. Walenkamp GH, Kleijn LL, de Leeuw M (1998) Osteomyelitis treated with gentamicin-PMMA beads: 100 patients followed for 1-12 years. Acta Orthop Scand; 69(5): 518−522. 5. Wininger DA, Fass RJ (1996) Antibiotic-impregnated cement and beads for orthopedic infections. Antimicrob Agents Chemother; 40(12):2675−2679. 6. Forster H, Marotta JS, Heseltine K, et al (2004) Bactericidal activity of antimicrobial coated polyurethane sleeves for external fixation pins. J Orthop Res; 22(3):671−677. 7. Möhring H, Gravel C, Chapman M, et al (2000) Comparison of antibiotic beads and intravenous antibiotics in open fractures. Clin Orthop Relat Res; 372:254−261. 8. Ostermann PA, Seligson D, Henry SL (1997) Local antibiotic therapy for severe open fractures: A review of 1085 consecutive cases. J Bone Joint Surg Br; 77(1):93−97. 9. Boxma H, Broekhuizen T, Patka P, et al (1996) Randomised controlled trial of single-dose antibiotic prophylaxis in surgical treatment of closed fractures: the Dutch Trauma Trial. Lancet; 347(9009):1133−1137. 10. Maurer DJ, Merkow RL, Gustilo RB (1989) Infection after intramedullary nailing of severe open tibial fractures initially treated with external fixation. J Bone Joint Surg Am; 71(6):835−838. 11. Zalavras CG, Patzakis MJ, Holtom P (2004) Local antibiotic therapy in the treatment of open fractures and osteomyelitis. Clin Orthop Relat Res; 427:86−93. 12. Rosin H, Rosin A, Krämer JW (1974) Determination of antibiotic levels in the human bone: I. Gentamicin levels in bone. Infection; 2(1):3−6. 13. Scaglione F (1997) Pharmacotherapy—the facts and fantasies of prophylaxis and combined therapies, Eur J Surg Suppl; 578:11−15. 14. Gristina A (1987) Biomaterial centred infection: microbial adhesion versus tissue integration. Science; 237:1588−1595. 15. Flückiger U, Zimmerli W (2000) Factors influencing antimicrobial therapy of surface adhering microorganisms. Recent Res. Devel. Antimicrob Agents Chemother; 4:165−175. 16. Springer BD, Lee GC, Osmon D, et al (2004) Systemic safety of high-dose antibiotic-loaded cement spacers after resection of an infected total knee arthroplasty. Clin Orthop Relat Res; 427:47−51. 17. Scott CP, Higham PA, Dumbleton JH (1999) Effectiveness of bone cement containing tobramycin. An in vitro susceptibility study of 99 organisms found in infected joint arthroplasty. J Bone Joint Surg Br; 81(3):440−43.
S86
18. Stemberger A, Grimm H, Bader F, et al (1997) Local treatment of bone and soft tissue infections with the collagengentamicin sponge. Eur J Surg Suppl; 578:17−26. 19. Moroni A, Heikkila J, Magyar G, et al (2001) Fixation strength and pin tract infection of hydroxyapatite-coated tapered pins. Clin Orthop Relat Res; 338:209−217. 20. Sanden B, Larsson S, Olerud C, et al (1999) Hydroxyapatite coating of pedicle screws may give too good fixation. Acta Orthop Scand Suppl; 284:35. 21. DeJong E, DeBernardino T, Brooks D (2001) Antimicrobial efficacy of external fixator pins coated with a lipid stabilized hydroxyapatite/chlorhaxidine complex to prevent pin tract infection in a goat model. J Trauma; 50(6):1008−1014. 22. Darouiche RO, Farmer J, Chaput C (1998) Anti-infective efficacy of antiseptic-coated intramedullary nails. J Bone Joint Surg Am; 80(9):1336−1340. 23. Reading A, Rooney P, Taylor G (2000) Quantitative assessment on the effect of 0.05% chlorhexidine on rat articular cartilage metabolism in vitro and in vivo. J Orthop Res; 18:762−767. 24. Russell AD, Day MJ (1993) Antibacterial activity of chlorhexidine. J Hosp Infect; 25(4):229−238. 25. Alt V, Bechert T, Steinrucke P, et al (2004) An in vitro assessment of the antibacterial properties and cytotoxicity of nanoparticulate silver bone cement. Biomaterials, 25(18):4383−4391. 26. Davis IJ, Richards H, Mullany P (2005) Isolation of silver- and antibiotic-resistant Enterobacter cloacae from teeth. Oral Microbiol Immunol; 20(3):191− 194. 27. Faber C, Stallmann HP, Lyaruu DM, et al (2005) Comparable efficacies of the antimicrobial peptide human lactoferrin 1-11 and gentamicin in a chronic methicillin-resistant Staphylococcus aureus osteomyelitis model. Antimicrob Agents Chemother; 49(6):2438−2444. 28. Price JS, Tencer AF, Arm DM, et al (1996) Controlled release of antibiotics from coated orthopedic implants. J Biomed Mater Res; 30(3):281−286. 29. Lucke M, Schmidmaier G, Sadoni S, et al (2003) Gentamicin coating of metallic implants reduces implant-related osteomyelitis in rats. Bone; 32(5):52−531. 30. Raschke MJ, Schmidmaier G (2004) [Biological coating of implants in trauma and orthopedic surgery]. Unfallchirurg; 107(8):653−663. 31. Vogt S, Schnabelrauch M, Kühn K (2002) [Antibiotic coating of implants with sustained release of the active substance]. Biomaterialien; 3(2):103−107.
A Montali
Correspondence address: Andrea Montali Biomaterials Synthes GmbH Eimattstrasse 3 4436 Oberdorf, Switzerland Phone: +41 61 965 66 43 Fax: +41 61 965 66 04 E-mail: [email protected]
www.elsevier.com/locate/injury
Antibacterial coating systems Andrea Montali Synthes GmbH, Oberdorf, Switzerland
KEYWORDS: Antibacterial coatings; local application of antibacterials.
Summary1 The local application of antibiotics is a well-known procedure that has been in successful clinical use for more than 20 years. The most frequently used carrier substance for the antibiotic or other antibacterial substances is polymethylmethacrylate (PMMA). However, because PMMA is not resorbable, as much as 70% of the antibiotic dose is permanently sequestered in the PMMA cement and therefore not available to combat bacterial colonization. Antibacterial coatings of metal implants represent an attractive solution to simplify the local application of an antibacterial substance in fracture care. Several coating technologies have been investigated, involving different carrier materials as well as different antibacterial substances. A fully resorbable coating containing gentamicin sulphate has yielded promising results in animal studies and intramedullary tibial nails with this coating have already been implanted successfully in a few patients. In the future, the main developmental focus for antibacterial coatings for implants will lie in tailoring the release characteristics and the antibacterial substance to minimize the risk of breeding resistant bacterial strains while maximizing the efficacy of the coating.
Current solutions for local delivery of antibiotics The local application of antibiotics is a well-known and accepted tool in the treatment of osteomyelitis. In the early 1970s, Buchholz first used polymethylmethacrylate (PMMA) cements with antibiotics in joint replacement surgery [1]. In 1974, Klemm introduced PMMA beads for carrying gentamicin sulphate rather than massive cement forms [2]. Due to their higher surface-to-volume ratio, the smaller PMMA beads are a more favorable delivery vehicle for the contained antibiotic. After implantation, the water-soluble antibiotic is leached out of the surface of the implant by the surrounding body fluids. Both PMMA cements with antibiotics in joint replacement surgery and PMMA 1
Abstracts in German, French, Italian, Spanish, Japanese, and Russian are printed at the end of this supplement.
beads in osteomyelitis therapy are now common and extensively used procedures, the efficacy of which has been shown in several studies [3–5]. Other methods for the local application of antibiotics in conjunction with the treatment of fractures, joint replacements, or bone voids, include collagen fleeces impregnated with antibiotics, which have the combined effect of antibiotic delivery and hemostasis; PMMA pre-forms and temporary spacers; antibiotic-impregnated bone-substitute materials such as calcium sulphate or calcium phosphates; or a recently commercialized polyurethane sleeve impregnated with antibiotics to be applied over external fixation pins to prevent pin-track infections [6]. All the above-mentioned methods require a carrier material other than the orthopedic implant itself to deliver the antibacterial substance. From the point of view of the surgical technique in fracture treatment, this means that the antibiotic
0020–1383/$ — see front matter # 2006 Published by Elsevier Ltd. doi:10.1016/j.injury.2006.04.013
S82
delivery vehicle does not contribute actively to the primary goal of the surgery, which is restoration of the anatomical relationships. This implant needs to be placed in addition to the commonly used hardware for fracture fixation. Furthermore, as in the case of the nonresorbable PMMA implants, the antibiotic delivery vehicle may need to be removed at a later stage. These technical limitations have made the local application of antibiotics during fracture treatment an exceptional procedure, used nearly exclusively in cases where an infection is already present and needs to be treated. As opposed to fracture treatment, the use of locally delivered antibiotics in joint replacement surgery is now part of the standard procedure in approximately half of all implanted cemented joint replacements, its value lying in its prophylactic rather than therapeutic effect. The widespread use of antibiotic-containing cement in joint replacement surgeries has two primary reasons: the use of antibiotic-containing cements does not alter the surgical technique for implanting a cemented prosthesis and the safety and efficacy of the method have been demonstrated in several clinical studies. However, it must be pointed out that statistical relevance in showing a reduced infection rate when using antibiotic containing cements was only shown after several years of application, when large numbers of patients had been treated in a comparable clinical setting [3].
Local delivery in fracture treatment— requirements In fracture treatment surgery, the local delivery of antibiotics still requires substantial alteration of surgical technique since an antibiotic-containing implant must be used in addition to the hardware needed to treat the fracture. Furthermore, real clinical efficacy in prophylaxis remains to be proven with statistical relevance in large trials, although its efficacy has been shown in under-powered studies [7, 8]. Therefore, in osteosynthesis, the local application of antibiotics is mostly used to treat existing osteomyelitis and only exceptionally as a prophylactic measure. Three main issues remain to be resolved to make the local delivery of antibiotics, or of antibacterial substances in general, a more widely used procedure in osteosynthesis: • The surgical technique for implantation of an antibiotic-containing device and the standard device must be the same.
A Montali
• The safety and efficacy of an envisioned solution must be demonstrated. • Last but not least, resistance issues with respect to the use of antibiotics must be considered and addressed. Providing metal implants commonly used in fracture repair surgeries with a coating that contains and releases an antibacterial substance after implantation represents a logical and appealing solution to the above-mentioned requirements. However, before discussing in more detail the various solutions that are available or are being investigated currently for antibacterial coatings, the rationale for the local delivery of antibiotics in fracture treatment must be laid out. One question to be answered is: Is there a need for antibacterial coatings in trauma surgery?
The role of local delivery in trauma surgery Systemic antibiotic delivery is a very common procedure in hospitals all over the world. In operative fracture treatment, the systemic prophylactic administration of antibiotics is a standard procedure and its efficacy has been demonstrated in large trials and is no longer questioned [9]. In contrast to closed fractures, which have infection rates of 1% or 2%, a comparably high rate of infection is observed in the treatment of open fractures, ranging from a few percent to 30% or more, depending on the extent of soft tissue damage, the severity of the fracture, and its anatomical location [8, 10, 11]. Therefore, it appears evident that care of open fractures still has the potential for a wide margin of improvement in preventing infections. Despite its widespread use and efficacy, systemic antibiotic delivery carries certain drawbacks such as systemic toxicity, poor penetration into ischemic or necrotic tissues, and hospitalization during intravenous therapy to monitor drug levels and effects [12, 13]. It must be pointed out that the area most relevant when considering implant-related infections, i.e. the surface of the implant and its immediate surroundings, is either not or only insufficiently reached by systemic antibiotics. Thus, if bacteria colonize an implant, the possibility of developing an infection remains intact despite systemic antibiotic prophylaxis. Several authors and, in particular Gristina and co-workers, have extensively investigated the interaction between the body and the implant and the resulting complex environment at the interface [14].
Antibacterial coating systems
Bacteria, such as Staphylococcus aureus, can be found in contaminated fractures and compete with the cells of the bodyís immune system to colonize the surface of the implant. This situation, in which an inert foreign body is implanted into tissue that is already injured and weakened, has been described as a race for the surface of the implant. In this particular situation, the bacteria have a certain advantage in that they divide rapidly and are extremely flexible, which allows them to adapt to changing situations. As a result, bacteria gain an advantage competing against the bodyís immune system, which is locally weakened by the presence of a foreign body and a fractured bone; and in many cases the immune system is also systemically challenged due to other injuries. Studies indicate that the presence of an implant impairs the hostís local immune response and can reduce the number of bacteria required to cause an infection by a factor of 10,000 [15]. Thus, an antibacterial coating present from the very first moment of implantation and which starts releasing the active substance after implantation represents a valid possibility to avoid bacterial colonization of the implant surface. The main rationale for locally applying antibiotics in osteosynthesis is the possibility of achieving high local concentrations far above the minimal inhibitory concentration (MIC) of resident bacteria, while avoiding systemic concentrations high enough to have toxic effects [11, 14, 16]. The local concentrations that can be achieved through local application cannot be reached with systemic delivery, due to the toxic side effects that most antibiotics produce at such high systemic concentrations. The very high concentrations of antibiotics that can be reached after the local application of an antibiotic from a coated implant, for example in the medullary canal, have been shown to be effective even against organisms judged to be resistant to the employed antibiotic [17, 18]. This finding is due to the fact that resistance is determined with respect to the concentrations of antibiotics that can be reached by systemic application, where toxicity can be a serious issue. This very important point should be kept in mind when considering resistance issues connected with antibiotic-coated implants, because sub-lethal antibiotic concentrations provide an ideal environment for generating resistant strains. Given that resistance will remain an issue to be considered every time an antibiotic is used, any antibacterial coating must fulfill two important requirements: the optimal antibacterial substance must be chosen; and the release kinetics must be tailored to minimize the time of exposure to antibiotic concentrations below the MIC of the resident bacteria. Since the development of resistant strains is always a risk, the
S83
clinician must weigh this risk against the potential benefit when selecting the clinical indications for an antibiotic-coated implant in order to avoid using antibiotics in cases that do not present a recognizable risk for developing an implant-related infection. The optimal system for local antibacterial prophylaxis should satisfy multiple requirements. It should be: biocompatible to avoid rejection; the carrier should be biodegradable to avoid a subsequent operation for its removal; the release profile of the active substance should be tailored to the clinical needs; and its use should not influence the surgical technique.
Coatings current solutions Hydroxyapatite coatings Coatings have been in use for several years as a method for improving the fixation of prostheses. Coatings of hydroxyapatite (HA) are currently the method of choice in this application. The application of HA coatings in osteosynthesis is not as common as in joint replacement surgery. In the area of osteosynthesis, external fixation pins were the first implants to be coated with HA, since a need for improved fixation was recognized in this particular application. HA coated external fixation pins were thoroughly investigated in several animal studies. In particular, Moroni et al have shown that improved implant fixation also leads to a reduced rate of infection [19]. However, the need for improved implant fixation is not a priority in many osteosynthesis applications, since in most cases the implants are preferably removed after fracture healing and excessive fixation makes this removal difficult or even impossible [20].
Antiseptic coatings DeJong et al have gone one step further in the improvement of implant fixation and infection prophylaxis in external fixation in their goat studies, which demonstrated the efficacy of HA coatings containing antiseptic substances [21]. The substance used in these studies was chlorhexidine. In another study, a combination of chlorhexidine and chloroxylenol was successfully used as a coating for intramedullary implants in a rabbit model [22]. Chlorhexidine is already commonly used in local drug delivery as a coating for catheters and is accepted in this application. However, concerns remain concerning the toxicity of antiseptics on bone tissue; in particular
S84
A Montali
A silver coating is another method of providing implants with an antibacterial surface. This method has been well known for many years but has failed to find widespread use, mainly because its efficacy remains unproven and because of toxicity concerns. The use of nanoparticulate silver may represent a promising new possibility, where the active surface area is maximized while keeping the total amount of silver low. By embedding nanoparticles of silver in coatings for implants or directly into cements for joint replacement applications, it is possible to tailor the antibacterial activity of the silver ions while remaining below the toxicity threshold for other cell types [25]. From a resistance standpoint, silver is generally accepted as not inducing resistance in bacteria. However, the emergence of bacteria resistant to both antibiotics and silver has been observed lately in a clinical application in which the bacteria were exposed to silver [26]. The issue of selecting resistant bacterial strains through an excessive use of antibiotics is perhaps the main driving force behind research into new antibacterial substances. In a novel approach, the efficacy of an antibacterial peptide against MRSA was recently demonstrated in a rabbit model [27].
tions in an intramedullary infection model in rats [29]. Six weeks after implantation, the coating had effectively prevented infections in the test group while animals in the control group showed extensive symptoms of infection. These results were later reproduced in a rabbit model. The same group has successfully implanted intramedullary tibia nails with the same coating in patients with severe open tibia fractures, which may be the first ever clinical application of an antibiotic-coated implant in fracture care [30]. This PLA-based coating technology has been further investigated in our laboratories, where it was shown that the release kinetics could be tailored from a distinct burst release to a zeroorder release by the appropriate choice of the carrier polymer and the coating composition. By varying the active substance between a hydrophobic or a hydrophilic substance, a further degree of freedom can be achieved. Through an appropriate design of the coating, it is possible to envision the sequential release of different substances from one and the same coating. The release profile of an antibiotic coating containing gentamicin was completely reversed from a burst release, as observed with the PLA-gentamicin sulphate coatings described above, to a sustained long-time release. This process was achieved by substituting the sulphate group of gentamicin sulphate with a hydrophobic fatty acid, such as laurilic acid [31]. These selected examples show that the development of antibacterial coatings offers a wide range of possibilities and variability and that it is possible to adapt the coating properties to the multiple and diverse requirements found in different indications.
Resorbable polymeric coatings
Proving efficacy of antibacterial coatings
Fully resorbable polymeric coatings loaded with antibacterial substances come fairly close to the previously mentioned requirements. This technology allows a wide choice of substances to be used and it is possible to tailor the release kinetics by varying the formulation of the coating and its components. One of the first reports of a fully resorbable antibacterial implant coating for fracture repair with the goal of delivering an antibacterial substance was in 1997, when Price and co-workers applied a polylactide (PLA) coating loaded with gentamicin to osteosynthesis plates [28]. The coating was applied by a solvent-based dip coating process. Its suitability as an antibiotic carrier was shown. Lucke et al demonstrated the efficacy of a PLAbased coating with gentamicin in preventing infec-
The results shown in animal studies for various antibacterial coatings are encouraging. In many cases, the coatings can be optimized for antibiotic release kinetics and in vitro studies can reveal the extent to which the coatings prevent bacterial colonization on the implant. The systems can be shown to be biocompatible and efficacious in animal models. However, clinical efficacy remains to be confirmed by clinical data. Clinical trials have proven to be extremely difficult because low infection rates require large patient populations to show statistical relevance in the prevention of infections. Furthermore, the occurrence of infections is a multifactorial event, in which an antibacterial coating represents just one of many measures to be taken. This situation further increases the difficulty of unambiguously attributing
chlorhexidine is known to exhibit toxicity on articular cartilage [23]. The main rationale for the use of an antiseptic instead of an antibiotic is the lower potential for developing resistant bacterial strains. However, resistance is not an unknown phenomenon for antiseptics, as documented by Russell for chlorhexidine [24].
Silver coatings
Antibacterial coating systems
a clinical outcome to the effect of a coating. As a result, devices with antibacterial coatings will be introduced into the market with supporting data for biocompatibility and effectiveness in animal studies, but clinical evidence may only emerge after judicious use of the implants in large numbers of patients.
Summary In summary, the usefulness of locally delivering an antibacterial substance in the therapy or prophylaxis of an infection is recognized and several approaches have been investigated and shown to be feasible. Antibacterial coatings of implants allow the controlled release of the contained substance and the release characteristics can be tailored by varying the coating formulation. Furthermore, antibacterial coatings of implants do not influence the surgical technique for implantation. The efficacy of antibacterial coatings has been extensively documented in animal studies and the first coated implants are in clinical use. The properties of antibacterial, and in particular antibiotic, coatings can be tailored to minimize the risk of breeding or selecting resistant bacterial strains. However, this risk can never be excluded. The use of antibacterial-coated implants will always have to be considered carefully and evaluated on a case-by-case basis in accordance with the recognized risk of the patient developing an implantrelated infection.
Acknowledgements The author wishes to thank E Gruskin and S Gass-Rüede for support in the preparation of the manuscript, and G Schmidmaier, M Raschke, and B Wildemann for many interesting and inspiring discussions.
S85
Bibliography 1. Buchholz HW, Engelbrecht H (1970) [Depot effects of various antibiotics mixed with Palacos resins]. Chirurg; 41(11):511−515. 2. Klemm K (1979) [Gentamicin-PMMA beads in treating bone and soft tissue infections (author’s transl)]. Zentralbl Chir; 104(14):934−942. 3. Espehaug B, Engesaeter LB, Vollset SE, et al (1997) Antibiotic prophylaxis in total hip arthroplasty. Review of 10,905 primary cemented total hip replacements reported to the Norwegian arthroplasty register, 1987 to 1995. J Bone Joint Surg Br; 79(4):590−95. 4. Walenkamp GH, Kleijn LL, de Leeuw M (1998) Osteomyelitis treated with gentamicin-PMMA beads: 100 patients followed for 1-12 years. Acta Orthop Scand; 69(5): 518−522. 5. Wininger DA, Fass RJ (1996) Antibiotic-impregnated cement and beads for orthopedic infections. Antimicrob Agents Chemother; 40(12):2675−2679. 6. Forster H, Marotta JS, Heseltine K, et al (2004) Bactericidal activity of antimicrobial coated polyurethane sleeves for external fixation pins. J Orthop Res; 22(3):671−677. 7. Möhring H, Gravel C, Chapman M, et al (2000) Comparison of antibiotic beads and intravenous antibiotics in open fractures. Clin Orthop Relat Res; 372:254−261. 8. Ostermann PA, Seligson D, Henry SL (1997) Local antibiotic therapy for severe open fractures: A review of 1085 consecutive cases. J Bone Joint Surg Br; 77(1):93−97. 9. Boxma H, Broekhuizen T, Patka P, et al (1996) Randomised controlled trial of single-dose antibiotic prophylaxis in surgical treatment of closed fractures: the Dutch Trauma Trial. Lancet; 347(9009):1133−1137. 10. Maurer DJ, Merkow RL, Gustilo RB (1989) Infection after intramedullary nailing of severe open tibial fractures initially treated with external fixation. J Bone Joint Surg Am; 71(6):835−838. 11. Zalavras CG, Patzakis MJ, Holtom P (2004) Local antibiotic therapy in the treatment of open fractures and osteomyelitis. Clin Orthop Relat Res; 427:86−93. 12. Rosin H, Rosin A, Krämer JW (1974) Determination of antibiotic levels in the human bone: I. Gentamicin levels in bone. Infection; 2(1):3−6. 13. Scaglione F (1997) Pharmacotherapy—the facts and fantasies of prophylaxis and combined therapies, Eur J Surg Suppl; 578:11−15. 14. Gristina A (1987) Biomaterial centred infection: microbial adhesion versus tissue integration. Science; 237:1588−1595. 15. Flückiger U, Zimmerli W (2000) Factors influencing antimicrobial therapy of surface adhering microorganisms. Recent Res. Devel. Antimicrob Agents Chemother; 4:165−175. 16. Springer BD, Lee GC, Osmon D, et al (2004) Systemic safety of high-dose antibiotic-loaded cement spacers after resection of an infected total knee arthroplasty. Clin Orthop Relat Res; 427:47−51. 17. Scott CP, Higham PA, Dumbleton JH (1999) Effectiveness of bone cement containing tobramycin. An in vitro susceptibility study of 99 organisms found in infected joint arthroplasty. J Bone Joint Surg Br; 81(3):440−43.
S86
18. Stemberger A, Grimm H, Bader F, et al (1997) Local treatment of bone and soft tissue infections with the collagengentamicin sponge. Eur J Surg Suppl; 578:17−26. 19. Moroni A, Heikkila J, Magyar G, et al (2001) Fixation strength and pin tract infection of hydroxyapatite-coated tapered pins. Clin Orthop Relat Res; 338:209−217. 20. Sanden B, Larsson S, Olerud C, et al (1999) Hydroxyapatite coating of pedicle screws may give too good fixation. Acta Orthop Scand Suppl; 284:35. 21. DeJong E, DeBernardino T, Brooks D (2001) Antimicrobial efficacy of external fixator pins coated with a lipid stabilized hydroxyapatite/chlorhaxidine complex to prevent pin tract infection in a goat model. J Trauma; 50(6):1008−1014. 22. Darouiche RO, Farmer J, Chaput C (1998) Anti-infective efficacy of antiseptic-coated intramedullary nails. J Bone Joint Surg Am; 80(9):1336−1340. 23. Reading A, Rooney P, Taylor G (2000) Quantitative assessment on the effect of 0.05% chlorhexidine on rat articular cartilage metabolism in vitro and in vivo. J Orthop Res; 18:762−767. 24. Russell AD, Day MJ (1993) Antibacterial activity of chlorhexidine. J Hosp Infect; 25(4):229−238. 25. Alt V, Bechert T, Steinrucke P, et al (2004) An in vitro assessment of the antibacterial properties and cytotoxicity of nanoparticulate silver bone cement. Biomaterials, 25(18):4383−4391. 26. Davis IJ, Richards H, Mullany P (2005) Isolation of silver- and antibiotic-resistant Enterobacter cloacae from teeth. Oral Microbiol Immunol; 20(3):191− 194. 27. Faber C, Stallmann HP, Lyaruu DM, et al (2005) Comparable efficacies of the antimicrobial peptide human lactoferrin 1-11 and gentamicin in a chronic methicillin-resistant Staphylococcus aureus osteomyelitis model. Antimicrob Agents Chemother; 49(6):2438−2444. 28. Price JS, Tencer AF, Arm DM, et al (1996) Controlled release of antibiotics from coated orthopedic implants. J Biomed Mater Res; 30(3):281−286. 29. Lucke M, Schmidmaier G, Sadoni S, et al (2003) Gentamicin coating of metallic implants reduces implant-related osteomyelitis in rats. Bone; 32(5):52−531. 30. Raschke MJ, Schmidmaier G (2004) [Biological coating of implants in trauma and orthopedic surgery]. Unfallchirurg; 107(8):653−663. 31. Vogt S, Schnabelrauch M, Kühn K (2002) [Antibiotic coating of implants with sustained release of the active substance]. Biomaterialien; 3(2):103−107.
A Montali
Correspondence address: Andrea Montali Biomaterials Synthes GmbH Eimattstrasse 3 4436 Oberdorf, Switzerland Phone: +41 61 965 66 43 Fax: +41 61 965 66 04 E-mail: [email protected]