566937
research-article2014
IJLXXX10.1177/1534734614566937The International Journal of Lower Extremity WoundsPanagopoulos et al
Review
Local Antibiotic Delivery Systems in Diabetic Foot Osteomyelitis: Time for One Step Beyond?
The International Journal of Lower Extremity Wounds 2015, Vol. 14(1) 87–91 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1534734614566937 ijl.sagepub.com
Periklis Panagopoulos, MD1, Georgios Drosos, MD2, Efstratios Maltezos, MD1,3, and Nikolaos Papanas, MD3
Abstract In patients with diabetes mellitus, osteomyelitis is a severe, difficult-to-treat form of foot infection. In the management of diabetic foot osteomyelitis, carriers for local delivery of antimicrobial agents have begun to be tried, in an attempt to provide high local antibiotic concentrations. Randomized clinical trials are now expected to clarify when this new approach should be used and how it can be integrated into the overall therapeutic strategy for diabetic foot osteomyelitis. Keywords antibiotics, delivery systems, diabetes mellitus, diabetic foot, infections, osteomyelitis, treatment. Osteomyelitis is a common infection that is difficult to treat because of both multidrug resistance of common pathogens and poor penetration of antibiotic agents into bone. Longterm antimicrobial treatment is hampered by tissue penetration issues and the development of adverse events.1 Additionally, surgical intervention may be required.2,3 Especially in patients with diabetes mellitus (DM), osteomyelitis represents a very common complication of foot infections.2-4 The latter arise from ulceration, especially that of long standing.5,6 Factors associated with increased risk for foot ulcers in such patients are foot deformity, peripheral neuropathy, peripheral arterial disease, and cardiovascular disease.5,7 There has been considerable progress in the management of infection and ischemia in the diabetic foot.5,8,9 However, diabetic foot osteomyelitis (DFO) remains a major therapeutic challenge.2-5 Therefore, new modalities are being explored. In this context, the aim of the present brief review is to examine the evidence for the use of local antibiotic delivery systems in patients with DFO.
consensus was reached according to majority. We included reports describing local antibiotic systems in DFO. Exclusion criteria were skin and soft tissue infections, as well as other forms and locations of osteomyelitis. All types of articles written in English were included, while works written in other languages were studied only in abstract form. Reports referring to in vivo and in vitro models were included as well.
Results DFO: Current Therapeutic Principles DFO must be promptly and accurately diagnosed, on the basis of clinical presentation and imaging studies (mainly plain radiography, magnetic resonance imaging, and scintigraphy).10-12 Treatment involves the use of antibiotic agents with adequate penetration to bone, choice of which is best guided by bone culture.11,13,14 At present, no specific antibiotic regimen has shown superiority for the treatment 1
Methods Search Strategy Our electronic search was based on the PubMed, Embase, and Google Scholar databases up to July 2014 using the following keywords and their combinations: antibiotics, delivery systems, diabetes, diabetic, diabetic foot, infection, local delivery, osteomyelitis, and treatment. Overall, 3770 reports were searched electronically by 3 reviewers, and
Unit of Infectious Diseases, 2nd Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece 2 Orthopaedic Department, Democritus University of Thrace, Alexandroupolis, Greece 3 Outpatient Clinic of the Diabetic Foot, 2nd Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece Corresponding Author: Nikolaos Papanas, Outpatient Clinic of the Diabetic Foot, 2nd Department of Internal Medicine, Democritus University of Thrace, G. Kondyli 22c, Alexandroupolis 68100, Greece. Email: [email protected]
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of DFO.11,13 Two further issues still under dispute are treatment duration and choice of surgical versus medical treatment.11,15-17 In general, long antibiotic duration is necessary (several weeks to months), depending on bacterial isolates, use or not of concomitant surgery, and other factors. During this conservative or medical treatment, the erythrocyte sedimentation rate (and, less so, other inflammation markers) is useful in patient follow-up and treatment monitoring.18 Surgery is required primarily when there are exposed or necrotic bones, large sequestra, and severe gangrenous soft tissue necrosis.11,13,16 Of note, choice of therapy is additionally influenced by available options, the medical team’s experience, and the patient’s willingness or not to undergo surgery, as well as comorbidities.11,13,16
Use of Local Antibiotic Delivery Systems Generally, treatment of osteomyelitis with local delivery systems has become common practice, while several biodegradable and nonbiodegradable substances have been used as vehicles for delivery, attempting to provide locally high concentrations of antibiotics.19 The first use of implantable drug delivery systems (IDDSs) was described in 1970 by Bucholz and Engelbrecht20 (cement). Since then, IDDSs have been used in a variety of cases, such as fractures, soft tissue infections, and chronic osteomyelitis. The first antimicrobial to be used for elution was gentamicin, while tobramycin, kanamycin, ceftriaxone, and, more recently, vancomycin have also been used successfully.21 Polymethylmethacrylate (PMMA) beads are the major representative of nonbiodegradable carrier systems, but they require surgical removal upon completion of drug release.22 Conversely, biodegradable carriers do not necessitate surgical removal. The semihydrate form of calcium sulfate (CaSO4), commonly known as plaster of Paris, may be applied as a system for local drug delivery. It has been used for decades to fill bone cavities resulting from disease, trauma, or surgery, although evolution took place in the 1990s, when it began to be used as an IDDS.23 Staphylococci are the main pathogens as causative agents in bone and joint infections. The emergence of methicillin-resistant Staphylococcus aureus has created a need for new antibiotics to treat osteomyelitis.24,25 Calcium sulfate cement (Stimulan; Biocomposites) has already been used in vitro and has shown excellent results of elution for either moxifloxacin and fusidic acid or daptomycin.26,27 It was used in a powder and mixing solution form, and its major advantages were 100% purity and ability of biodegradation.28 In DM, in addition to aerobic Gram-positive cocci (particularly staphylococci), foot infections are frequently caused by mixed flora, including aerobic Gram-negative bacilli or obligate anaerobes.5-7,29 Nowadays, novel antibiotics and alternative delivery systems (eg, antibiotic beads,
impregnated sponges) may improve outcomes. Nonetheless, the literature is sparse, and randomized controlled trials (RCTs) are urgently needed to improve our understanding and guide treatment decisions.30,31 As reflected in the specific guidelines on DFO issued by the International Working Group on the Diabetic Foot and the Infectious Disease Society of America, available data are insufficient to assess the efficacy of locally administered antibiotics in DFO.32 So far, only case reports or case series with this novel approach have been published.33,34 In a 41-year-old patient with type 1 DM and osteomyelitis of the right fourth metatarsal head and adjacent phalanx, tobramycin-impregnated pellets in addition to systemic antibiotics achieved clinical and radiologic improvement with bone reconstruction.33 Similarly, application of antibiotic-impregnated calcium sulfate pellets has occasionally improved the outcome of forefoot DFO.34 On the basis of the aforementioned preliminary findings, the benefits of antibiotic-impregnated pellets in addition to oral antibiotics will be shorter hospital admission, costeffectiveness, and reduction of amputations. Furthermore, the goal of therapy will be to prevent amputation and to preserve as much of the weight-bearing surface as possible.35,36 Karr37 recently presented a case of diabetic forefoot osteomyelitis successfully managed with surgical bone resection and off-label use of vancomycin Cerament Bone Void Filler (calcium sulfate and hydroxyapatite; Biomet Biologics) antibiotic beads. The patient required no additional surgery to complete treatment and or remove antibiotic beads. We have used IDDSs delivering gentamicin in 8 patients with chronic metatarsal or calcaneal DFO: these were antibiotic-loaded (gentamicin) PMMA cement beads (PALACOS R+G; Heraeus Medical GmbH) or antibioticloaded (gentamicin) bone graft substitutes (Herafill beads G; Heraeus Medical GmbH) (unpublished data; Figures 1 and 2). Concomitant antibiotics (initially intravenously and subsequently orally) and minor surgery (eg, metatarsal head resection) were used as well, guided by surgical or swab cultures. Cultures revealed Staphylococcus spp and Gramnegative bacteria. In all patients, DFO was successfully treated. Gentamycin beads were absorbed in ≤2 months without surgical removal. Wound healing was seen in 6 patients. Finally, 1 patient developed new ulcerations in the ipsilateral and contralateral feet within a period of 24 months, despite the use of customized orthotic footwear.
Discussion The emergent serious problem of resistant Gram-positive pathogens and the lack of new antimicrobial agents have created the need to use new antibiotic agents and IDDSs in the management of DFO. In theory, the main advantages of
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Figure 1. (a) Diabetic foot with chronic infection. (b) Magnetic resonance image showing soft tissue infection. (c) Bone infection (diabetic foot osteomyelitis). (d) Surgical debridement and application of antibiotic-loaded (gentamicin) Polymethylmethacrylate (PMMA) cement beads (PALACOS R+G; Heraeus Medical GmbH), removed after 7 days. (e) Postoperative photograph and (f) radiograph of the foot. The foot at (g) 2 weeks, (h) 6 weeks, and (i) 3 months after the operation.
Figure 2. (a-c) Diabetic foot with soft tissue infection and (d) bone infection (diabetic foot osteomyelitis) of the great toe, fifth toe, and fifth metatarsal. (e) Surgical debridement, amputation of the fifth ray, and application of antibiotic-loaded (gentamicin) bone graft substitutes (Herafill beads G; Heraeus Medical GmbH). (f) Postoperative radiograph of the foot, (g,h) photographs and (i) radiograph at 6 weeks after the operation showing complete wound healing and complete resorption of the beads.
IDDS are higher levels of antibiotic concentration in the affected area, pharmacokinetic advantages, the ability to overcome the possibility of resistant pathogens, and, in cases of biodegradable material, avoidance of further surgical procedures. Thus far, however, experience in DFO has been limited to case reports and case series. Because of the paucity of data, no summary on different IDDS treatments can be offered at present. IDDS have not been compared with standard best medical therapy either. For these reasons, there can be no concrete recommendation as to when and how they should be used. Instead of practical recommendations, we are left with several questions that remain unanswered. The most vital of these pertains to antibiotic agent, delivery system, and patient selection; treatment duration and/or repetition; combination with orally administered antibiotic agents and surgery; and the effects on healing and amputation rates. Clinicians will need suggestions on when and how to choose IDDSs, and carefully designed RCTs are required to clarify the aforementioned and other queries. Therapeutic choices will be facilitated once we know in more detail what to expect from IDDS use, along with resistance to treatment and any adverse events. Certainly, IDDSs represent an important innovation with promising results for DFO.37 If more widely and efficaciously used, they might be anticipated to increase infection control and contribute to the reduction of amputations, which is still a major goal.38,39 It may then be more precisely determined which patients should be chosen for IDDS and how this new treatment approach can be used in urgent expert management. The latter is progressively
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indispensable, given the increasing patient numbers with the diabetic foot, which renders prompt multiple-expert treatment crucial.40,41 In conclusion, local antibiotic delivery systems appear promising for the management of DFO. However, results are so far preliminary, and more experience is eagerly awaited. Because of the paucity of data and the plethora of questions, the next step should be well-designed RCTs to provide answers as to when this new approach should be used and how it can be integrated into the multidisciplinary diabetic foot care. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Panagopoulos has been an advisory board member for GS and Merck Sharp & Dohme; has received honoraria from AbbVie and GS; and attended conferences sponsored by Actelion, Janssen, Bristol-Myers Squibb, and Merck Sharp & Dohme. Professor Maltezos has participated in studies sponsored by Novo Nordisk and Novartis and has attended conferences sponsored by Wyeth, Pfizer, and Bayer. Dr Papanas has been an advisory board member for TrigoCare International; has participated in studies sponsored by Novo Nordisk and Novartis; has received honoraria as a speaker for AstraZeneca, Eli Lilly, Novo Nordisk, and Pfizer; and has attended conferences sponsored by TrigoCare International, Novo Nordisk, Sanofi-Aventis, and Pfizer.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. Caric PJ, Dickerson LM, Sack JL. Diagnosis and management of osteomyelitis. Am Fam Phys. 2001;63:2413-2420. 2. Aragón-Sánchez J. Treatment of diabetic foot osteomyelitis: a surgical critique. Int J Low Extrem Wounds. 2010;9:37-59. 3. Aragón-Sánchez J. Seminar review: a review of the basis of surgical treatment of diabetic foot infections. Int J Low Extrem Wounds. 2011;10:33-65. 4. Aragón-Sánchez J, Lipsky BA, Lázaro-Martínez JL. Gramnegative diabetic foot osteomyelitis: risk factors and clinical presentation. Int J Low Extrem Wounds. 2013;12:63-68. 5. Edmonds M. Modern treatment of infection and ischaemia to reduce major amputation in the diabetic foot. Curr Pharm Des. 2013;19:5008-5015. 6. Demetriou M, Papanas N, Panopoulou M, Papatheodorou K, Bounovas A, Maltezos E. Tissue and swab culture in diabetic foot infections: neuropathic versus neuroischemic ulcers. Int J Low Extrem Wounds. 2013;12:87-93. 7. Papanas N, Maltezos E. The diabetic foot: established and emerging treatments. Acta Clin Belg. 2007;62:230-238. 8. Papanas N, Mani R. Advances in infections and wound healing for the diabetic foot: the die is cast. Int J Low Extrem Wounds. 2013;12:83-86. 9. Georgakarakos E, Charalampidis D, Kakagia D, Georgiadis GS, Lazarides MK, Papanas N. Current achievements with topical negative pressure to improve wound healing in
dehiscent ischemic stumps of diabetic patients: a case series. Int J Low Extrem Wounds. 2013;12:138-145. 10. Shone A, Burnside J, Chipchase S, Game F, Jeffcoate W. Probing the validity of the probe-to-bone test in the diagnosis of osteomyelitis of the foot in diabetes. Diabetes Care. 2006;29:945. 11. Game FL. Osteomyelitis in the diabetic foot: diagnosis and management. Med Clin North Am. 2013;97:947-956. 12. Papanas N, Zissimopoulos A, Maltezos E. The role of nuclear medicine in the diagnosis of common and specific diabetic infections. Hell J Nucl Med. 2010;13:150-157. 13. Byren I, Peters EJ, Hoey C, Berendt A, Lipsky BA. Pharmacotherapy of diabetic foot osteomyelitis. Expert Opin Pharmacother. 2009;10:3033-3047. 14. Kessler L, Piemont Y, Ortega F, et al. Comparison of microbiological results of needle puncture vs. superficial swab in infected diabetic foot ulcer with osteomyelitis. Diabet Med. 2006;23:99-102. 15. Game FL, Jeffcoate WJ. Primarily non-surgical manage ment of osteomyelitis of the foot in diabetes. Diabetologia. 2008;51:962-967. 16. Game F. The advantages and disadvantages of non-surgical management of the diabetic foot. Diabetes Metab Res Rev. 2008;24(Suppl 1):S72-S75. 17. Lázaro-Martínez JL, Aragón-Sánchez J, García-Morales E. Antibiotics versus conservative surgery for treating diabetic foot osteomyelitis: a randomized comparative trial. Diabetes Care. 2014;37:789-795. 18. Michail M, Jude E, Liaskos C, et al. The performance of serum inflammatory markers for the diagnosis and followup of patients with osteomyelitis. Int J Low Extrem Wounds. 2013;12:94-99. 19. Yamashita Y, Uchida A, Yamakawa T, et al. Treatment of osteomyelitis using calcium hydroxyapatite ceramic implants impregnated with antibiotic. Int Orthop. 1998;22:247-251. 20. Bucholz HW, Engelbrecht H. Depot effect of various antibiotics mixed with Palacos resins. Chirurg. 1970;40:511-515. 21. Seligson D, Klemm K. Antibiotic bone cement combinations. Orthop Infect. 1989;385-417. 22. Klem K. The use of antibiotic-containing bed-chains in the treatment of chronic bone infections. Clin Microbiol Infect. 2001;7:28-31. 23. Nelson CL, McLaren SG, Skinner RA, et al. The treatment of experimental osteomyelitis by surgical debridement and the implantation of calcium sulphate tobramycin pellets. J Orthop Res. 2002;20:643-647. 24. Tentolouris N, Petrikkos G, Vallianou N, et al. Prevalence of methicillin-resistant Staphylococcus aureus in infected and uninfected diabetic foot ulcers. Clin Microbiol Infect. 2006;12:186-189. 25. Eleftheriadou I, Tentolouris N, Argiana V, Jude E, Boulton AJ. Methicillin-resistant Staphylococcus aureus in diabetic foot infections. Drugs. 2010;70:1785-1797. 26. Panagopoulos P, Tsaganos T, Plachouras D, et al. In vitro elusion of moxifloxacin and fusidic acid by a synthetic crystallic semihydrate form of calcium sulphate (Stimulan™). Int J Antimicrob Agents. 2008;32:485-487. 27. Kanellakopoulou K, Giamarellos-Bourboulis EJ. Carrier systems for the local delivery of antibiotics in bone infection. Drugs. 2000;59:1223-1232.
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Panagopoulos et al 28. Kanellakopoulou K, Panagopoulos P, Giannitsioti E, et al. In vitro elution of daptomycin by a synthetic crystallic semihydrate form of calcium sulphate. Stimulan Ant Agents Chemother. 2009;3106-3107. 29. Foster A. Changes in the care of the diabetic foot: part two. Pract Diabetes Intern. 2001;18:165-169. 30. Armstrong DG, Lipsk BA. Advances in the treatment of diabetic foot infections Diabetes Technol Ther. 2004;6: 167-177. 31. Lipsky BA, Peters EJ, Berendt AR, et al; International Working Group on Diabetic Foot. Specific guidelines for the treatment of diabetic foot infections 2011. Diabetes Metab Res Rev. 2012;28(Suppl 1):234-235. 32. Lipsky BA, Peters EJ, Senneville E, et al. Expert opinion on the management of infections in the diabetic foot. Diabetes Metab Res Rev. 2012;28(Suppl 1):163-178. 33. Salgami EV, Bowling FL, Whitehouse RW, et al. Use of tobramycin-impregnated calcium sulphate pellets in addition to oral antibiotics. Diabetes Care. 2007;30:181-182. 34. Armstrong DG, Findlow AH, Oyibo SO, et al. The use of absordable antibiotic-impregnated calcium sulphate pellets in the management of diabetic foot infections. Diabetic Med. 2001;18:942-943.
35. Sagray BA, Malthotra S, Steinberg JS. Current therapies for diabetic foot infections and osteomyelitis. Clin Podiatr Med Surg. 2014;31:58-70. 36. Roeder B, Van Gils CC, Mailing S. Antibiotic beads in the treatment of diabetic pedal osteomyelitis. J Foot Ankle Surg. 2000;39:124-130. 37. Karr JC. Management in the wound-care center outpatient setting of a diabetic patient with forefoot osteomyelitis using Cerament Bone Void Filler impregnated with vancomycin: off label use. J Am Podiatr Med Assoc. 2011;101:259-264. 38. Papanas N, Lazarides MK. Diabetic foot amputations in Greece: where do we go from here? Int J Low Extrem Wounds. 2011;10:4-5. 39. Papanas N, Maltezos E, Edmonds M. Salvation of the diabetic foot: still a quest for the Holy Grail? Vasa. 2011;40:267269. 40. Manu CA, Mustafa OG, Bates M, et al. Transformation of the multidisciplinary diabetic foot clinic into a multidisciplinary diabetic foot day unit: results from a service evaluation. Int J Low Extrem Wounds. 2014;13:173-179. 41. Papanas N, Mani R. How to cope with the increasing burden of the diabetic foot: better three hours too soon than a minute too late. Int J Low Extrem Wounds. 2014;13:171-172.
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research-article2014
IJLXXX10.1177/1534734614566937The International Journal of Lower Extremity WoundsPanagopoulos et al
Review
Local Antibiotic Delivery Systems in Diabetic Foot Osteomyelitis: Time for One Step Beyond?
The International Journal of Lower Extremity Wounds 2015, Vol. 14(1) 87–91 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1534734614566937 ijl.sagepub.com
Periklis Panagopoulos, MD1, Georgios Drosos, MD2, Efstratios Maltezos, MD1,3, and Nikolaos Papanas, MD3
Abstract In patients with diabetes mellitus, osteomyelitis is a severe, difficult-to-treat form of foot infection. In the management of diabetic foot osteomyelitis, carriers for local delivery of antimicrobial agents have begun to be tried, in an attempt to provide high local antibiotic concentrations. Randomized clinical trials are now expected to clarify when this new approach should be used and how it can be integrated into the overall therapeutic strategy for diabetic foot osteomyelitis. Keywords antibiotics, delivery systems, diabetes mellitus, diabetic foot, infections, osteomyelitis, treatment. Osteomyelitis is a common infection that is difficult to treat because of both multidrug resistance of common pathogens and poor penetration of antibiotic agents into bone. Longterm antimicrobial treatment is hampered by tissue penetration issues and the development of adverse events.1 Additionally, surgical intervention may be required.2,3 Especially in patients with diabetes mellitus (DM), osteomyelitis represents a very common complication of foot infections.2-4 The latter arise from ulceration, especially that of long standing.5,6 Factors associated with increased risk for foot ulcers in such patients are foot deformity, peripheral neuropathy, peripheral arterial disease, and cardiovascular disease.5,7 There has been considerable progress in the management of infection and ischemia in the diabetic foot.5,8,9 However, diabetic foot osteomyelitis (DFO) remains a major therapeutic challenge.2-5 Therefore, new modalities are being explored. In this context, the aim of the present brief review is to examine the evidence for the use of local antibiotic delivery systems in patients with DFO.
consensus was reached according to majority. We included reports describing local antibiotic systems in DFO. Exclusion criteria were skin and soft tissue infections, as well as other forms and locations of osteomyelitis. All types of articles written in English were included, while works written in other languages were studied only in abstract form. Reports referring to in vivo and in vitro models were included as well.
Results DFO: Current Therapeutic Principles DFO must be promptly and accurately diagnosed, on the basis of clinical presentation and imaging studies (mainly plain radiography, magnetic resonance imaging, and scintigraphy).10-12 Treatment involves the use of antibiotic agents with adequate penetration to bone, choice of which is best guided by bone culture.11,13,14 At present, no specific antibiotic regimen has shown superiority for the treatment 1
Methods Search Strategy Our electronic search was based on the PubMed, Embase, and Google Scholar databases up to July 2014 using the following keywords and their combinations: antibiotics, delivery systems, diabetes, diabetic, diabetic foot, infection, local delivery, osteomyelitis, and treatment. Overall, 3770 reports were searched electronically by 3 reviewers, and
Unit of Infectious Diseases, 2nd Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece 2 Orthopaedic Department, Democritus University of Thrace, Alexandroupolis, Greece 3 Outpatient Clinic of the Diabetic Foot, 2nd Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece Corresponding Author: Nikolaos Papanas, Outpatient Clinic of the Diabetic Foot, 2nd Department of Internal Medicine, Democritus University of Thrace, G. Kondyli 22c, Alexandroupolis 68100, Greece. Email: [email protected]
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of DFO.11,13 Two further issues still under dispute are treatment duration and choice of surgical versus medical treatment.11,15-17 In general, long antibiotic duration is necessary (several weeks to months), depending on bacterial isolates, use or not of concomitant surgery, and other factors. During this conservative or medical treatment, the erythrocyte sedimentation rate (and, less so, other inflammation markers) is useful in patient follow-up and treatment monitoring.18 Surgery is required primarily when there are exposed or necrotic bones, large sequestra, and severe gangrenous soft tissue necrosis.11,13,16 Of note, choice of therapy is additionally influenced by available options, the medical team’s experience, and the patient’s willingness or not to undergo surgery, as well as comorbidities.11,13,16
Use of Local Antibiotic Delivery Systems Generally, treatment of osteomyelitis with local delivery systems has become common practice, while several biodegradable and nonbiodegradable substances have been used as vehicles for delivery, attempting to provide locally high concentrations of antibiotics.19 The first use of implantable drug delivery systems (IDDSs) was described in 1970 by Bucholz and Engelbrecht20 (cement). Since then, IDDSs have been used in a variety of cases, such as fractures, soft tissue infections, and chronic osteomyelitis. The first antimicrobial to be used for elution was gentamicin, while tobramycin, kanamycin, ceftriaxone, and, more recently, vancomycin have also been used successfully.21 Polymethylmethacrylate (PMMA) beads are the major representative of nonbiodegradable carrier systems, but they require surgical removal upon completion of drug release.22 Conversely, biodegradable carriers do not necessitate surgical removal. The semihydrate form of calcium sulfate (CaSO4), commonly known as plaster of Paris, may be applied as a system for local drug delivery. It has been used for decades to fill bone cavities resulting from disease, trauma, or surgery, although evolution took place in the 1990s, when it began to be used as an IDDS.23 Staphylococci are the main pathogens as causative agents in bone and joint infections. The emergence of methicillin-resistant Staphylococcus aureus has created a need for new antibiotics to treat osteomyelitis.24,25 Calcium sulfate cement (Stimulan; Biocomposites) has already been used in vitro and has shown excellent results of elution for either moxifloxacin and fusidic acid or daptomycin.26,27 It was used in a powder and mixing solution form, and its major advantages were 100% purity and ability of biodegradation.28 In DM, in addition to aerobic Gram-positive cocci (particularly staphylococci), foot infections are frequently caused by mixed flora, including aerobic Gram-negative bacilli or obligate anaerobes.5-7,29 Nowadays, novel antibiotics and alternative delivery systems (eg, antibiotic beads,
impregnated sponges) may improve outcomes. Nonetheless, the literature is sparse, and randomized controlled trials (RCTs) are urgently needed to improve our understanding and guide treatment decisions.30,31 As reflected in the specific guidelines on DFO issued by the International Working Group on the Diabetic Foot and the Infectious Disease Society of America, available data are insufficient to assess the efficacy of locally administered antibiotics in DFO.32 So far, only case reports or case series with this novel approach have been published.33,34 In a 41-year-old patient with type 1 DM and osteomyelitis of the right fourth metatarsal head and adjacent phalanx, tobramycin-impregnated pellets in addition to systemic antibiotics achieved clinical and radiologic improvement with bone reconstruction.33 Similarly, application of antibiotic-impregnated calcium sulfate pellets has occasionally improved the outcome of forefoot DFO.34 On the basis of the aforementioned preliminary findings, the benefits of antibiotic-impregnated pellets in addition to oral antibiotics will be shorter hospital admission, costeffectiveness, and reduction of amputations. Furthermore, the goal of therapy will be to prevent amputation and to preserve as much of the weight-bearing surface as possible.35,36 Karr37 recently presented a case of diabetic forefoot osteomyelitis successfully managed with surgical bone resection and off-label use of vancomycin Cerament Bone Void Filler (calcium sulfate and hydroxyapatite; Biomet Biologics) antibiotic beads. The patient required no additional surgery to complete treatment and or remove antibiotic beads. We have used IDDSs delivering gentamicin in 8 patients with chronic metatarsal or calcaneal DFO: these were antibiotic-loaded (gentamicin) PMMA cement beads (PALACOS R+G; Heraeus Medical GmbH) or antibioticloaded (gentamicin) bone graft substitutes (Herafill beads G; Heraeus Medical GmbH) (unpublished data; Figures 1 and 2). Concomitant antibiotics (initially intravenously and subsequently orally) and minor surgery (eg, metatarsal head resection) were used as well, guided by surgical or swab cultures. Cultures revealed Staphylococcus spp and Gramnegative bacteria. In all patients, DFO was successfully treated. Gentamycin beads were absorbed in ≤2 months without surgical removal. Wound healing was seen in 6 patients. Finally, 1 patient developed new ulcerations in the ipsilateral and contralateral feet within a period of 24 months, despite the use of customized orthotic footwear.
Discussion The emergent serious problem of resistant Gram-positive pathogens and the lack of new antimicrobial agents have created the need to use new antibiotic agents and IDDSs in the management of DFO. In theory, the main advantages of
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Figure 1. (a) Diabetic foot with chronic infection. (b) Magnetic resonance image showing soft tissue infection. (c) Bone infection (diabetic foot osteomyelitis). (d) Surgical debridement and application of antibiotic-loaded (gentamicin) Polymethylmethacrylate (PMMA) cement beads (PALACOS R+G; Heraeus Medical GmbH), removed after 7 days. (e) Postoperative photograph and (f) radiograph of the foot. The foot at (g) 2 weeks, (h) 6 weeks, and (i) 3 months after the operation.
Figure 2. (a-c) Diabetic foot with soft tissue infection and (d) bone infection (diabetic foot osteomyelitis) of the great toe, fifth toe, and fifth metatarsal. (e) Surgical debridement, amputation of the fifth ray, and application of antibiotic-loaded (gentamicin) bone graft substitutes (Herafill beads G; Heraeus Medical GmbH). (f) Postoperative radiograph of the foot, (g,h) photographs and (i) radiograph at 6 weeks after the operation showing complete wound healing and complete resorption of the beads.
IDDS are higher levels of antibiotic concentration in the affected area, pharmacokinetic advantages, the ability to overcome the possibility of resistant pathogens, and, in cases of biodegradable material, avoidance of further surgical procedures. Thus far, however, experience in DFO has been limited to case reports and case series. Because of the paucity of data, no summary on different IDDS treatments can be offered at present. IDDS have not been compared with standard best medical therapy either. For these reasons, there can be no concrete recommendation as to when and how they should be used. Instead of practical recommendations, we are left with several questions that remain unanswered. The most vital of these pertains to antibiotic agent, delivery system, and patient selection; treatment duration and/or repetition; combination with orally administered antibiotic agents and surgery; and the effects on healing and amputation rates. Clinicians will need suggestions on when and how to choose IDDSs, and carefully designed RCTs are required to clarify the aforementioned and other queries. Therapeutic choices will be facilitated once we know in more detail what to expect from IDDS use, along with resistance to treatment and any adverse events. Certainly, IDDSs represent an important innovation with promising results for DFO.37 If more widely and efficaciously used, they might be anticipated to increase infection control and contribute to the reduction of amputations, which is still a major goal.38,39 It may then be more precisely determined which patients should be chosen for IDDS and how this new treatment approach can be used in urgent expert management. The latter is progressively
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indispensable, given the increasing patient numbers with the diabetic foot, which renders prompt multiple-expert treatment crucial.40,41 In conclusion, local antibiotic delivery systems appear promising for the management of DFO. However, results are so far preliminary, and more experience is eagerly awaited. Because of the paucity of data and the plethora of questions, the next step should be well-designed RCTs to provide answers as to when this new approach should be used and how it can be integrated into the multidisciplinary diabetic foot care. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr Panagopoulos has been an advisory board member for GS and Merck Sharp & Dohme; has received honoraria from AbbVie and GS; and attended conferences sponsored by Actelion, Janssen, Bristol-Myers Squibb, and Merck Sharp & Dohme. Professor Maltezos has participated in studies sponsored by Novo Nordisk and Novartis and has attended conferences sponsored by Wyeth, Pfizer, and Bayer. Dr Papanas has been an advisory board member for TrigoCare International; has participated in studies sponsored by Novo Nordisk and Novartis; has received honoraria as a speaker for AstraZeneca, Eli Lilly, Novo Nordisk, and Pfizer; and has attended conferences sponsored by TrigoCare International, Novo Nordisk, Sanofi-Aventis, and Pfizer.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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