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Current Insights On Antibiotic-Loaded Cement And The Use of Bioceramics In Diabetic Limb Salvage
Soft tissue and bone infections affecting the foot and ankle can be complex problems to treat. The cornerstone for ensuring adequate debridement is aggressive removal of infected, non-viable tissue to optimize the surgical outcome. This can often result in the creation of “dead space,” an area prone to hematoma collection and subsequent infection. In such surgical scenarios, the utility of antibiotics may be insufficient and dosing is limited by the potential for adverse effects associated with their use.
Antibiotic carriers that address dead space while locally delivering antibiosis are a useful tool to combat infection. We will examine the current role of cement for this indication as well as the potential use of bioceramic calcium sulfate cement to assist with wound healing.
Polymethylmethacrylate cement (PMMA) is a safe and popular option for addressing dead space. One common application is the insertion of an antibiotic-impregnated spacer following resection of osteomyelitic bone at the first metatarsophalangeal joint. One must utilize heat-stable antibiotics due to the exothermic reaction emitted during the curing process of PMMA. Vancomycin, tobramycin, gentamicin and amphotericin B have been well studied for this purpose and researchers have been shown that these antibiotics reach high local levels without causing systemic toxicity.1,2
Polymethylmethacrylate cement is not absorbable and clinical judgment should guide decision-making for planned exchange or removal although studies have suggested that surgeons can leave spacers permanently in place. A previous study revealed a 50 percent retention rate in 21 patients treated for pedal osteomyelitis with debridement and a spacer at a mean follow-up of 21.2 months.3 The authors noted plantar callosities to the sites where the spacer remained in place, suggesting functional utility of the spacer. Another retrospective series of 38 feet with osteomyelitis that received a PMMA spacer showed a retention or successful exchange rate of 20/38 patients at an average follow-up of 52 months.4 In this study, the longest retained spacer was 76 months while the longest time to spacer exchange was 111 months.
However, removal may become necessary if the spacer becomes an infected foreign body. Antibiotic elution from PMMA is variable and is dependent on several factors, including speed of mixing, timing of antibiotic addition and dose of antibiotic(s).5 Antibiotic release is high during the first 48 to 72 hours of implantation but falls to subtherapeutic levels in up to 14 days, eventually reaching a steady state with the surrounding tissue.6 Antibiotic may continue to elute from PMMA for up to five years following initial elution.7 This can be problematic as a prolonged low-level release of antibiotic below the minimum inhibitory concentration may create selection pressure for antibiotic-resistant organisms, leaving the spacer at risk for bacterial colonization.8
Examining The Indications For Bioceramics
Bioceramic cement, such as calcium sulfate or calcium phosphate, is an absorbable option that mitigates the need for removal. This can be an important consideration in several clinical scenarios, such as patients with tenuous blood supply or when there is poor soft tissue covering the implant.
Early evidence of calcium sulfate’s use as an antibiotic delivery agent was presented in an in vitro study from Japan that suggested calcium suflate avoids thermal damage.9 Studies have examined the use of various antibiotics, such as gentamicin, tobramycin, vancomycin and rifampicin in bioceramic cement applications.10,11 As it degrades, calcium sulfate provides high concentrations of antibiotics locally until the carrier is absorbed without resulting in high systemic levels.12,13
Another benefit of bioceramic cement is its osteoconductive potential, which allows it to act as a scaffold and facilitate osseous growth, allowing it to function as a bone filler.14 In a prospective series of 100 cases, McNally and colleagues showed that surgical debridement of chronic osteomyelitis, IV antibiotics, void filling with antibiotic-loaded calcium sulfate and primary closure provided effective treatment in 96 patients with a single procedure.15
Another prospective randomized control trial compared the use of antibiotic-loaded PMMA and calcium sulfate in 30 patients requiring surgical debridement of chronic long bone osteomyelitis or infected nonunions. Although the PMMA group required more reoperations (15 versus seven), the study showed that both modalities are equivalent in their ability to eradicate bone infection.
Calcium sulfate certainly does have limited ability to provide structural support in comparison to PMMA. Notably, calcium phosphate has better compressive strength than calcium sulfate and its relative macroporosity allows for better bony ingrowth.16 Large defects in anatomic areas that provide weightbearing functionality are more likely to need the insertion of a PMMA spacer. Combining different forms of cement results in a carrier with polyphasic resorption and may alter structural properties.17
What The Literature Reveals About Calcium Sulfate Cement
In 2001, Armstrong and colleagues authored a letter to Diabetes Medicine suggesting the use of antibiotic-loaded calcium sulfate pellets for treating infections in diabetic foot wounds with or without osteomyelitis.18 Multiple authors have since detailed their experience using this strategy to heal wound infections complicated by forefoot osteomyelitis and calcaneal osteomyelitis.19–21
However, many practitioners are hesitant to use bioceramic cement for pedal infections due to the propensity for drainage or a sterile inflammatory reaction as it degrades. Previous studies have revealed local reaction and drainage from the carrier are self-limiting, and researchers have not found them to be risk factors for wound dehiscence. However, these studies did not include patients with diabetic foot osteomyelitis.15,22
A retrospective cohort study further examined this, comparing the outcome of applying tobramycin-impregnated calcium sulfate beads into the soft tissues of transmetatarsal amputation (TMA) stumps upon primary closure versus a control group of closure without beads.23 In this study, there was no significant difference between time to healing, conversion to major amputation or length of hospital stay in both groups at an average follow-up of 28.8 months while the need for revisional surgery was significantly higher in the control group. Drainage typically decreases over four to six weeks and one should not perform surgical site exploration unless other clinical or diagnostic studies indicate an infectious process is present.24
Additionally, researchers have shown the high local concentration of antibiotic provided by this technique to be beneficial in this patient population. In a retrospective study involving 323 patients with lower extremity osteomyelitis refractory to the standard of care treatment, Gauland assessed the combination of surgical debridement and subsequent placement of calcium sulfate impregnated with vancomycin and gentamicin.25 In the study, Gauland opted not to close the wounds to allow for drainage. According to the study, 279 patients (86.4 percent) achieved epithelialization without the use of IV antibiotics postoperatively although the study did not report the average time to healing. Twenty-four (7.4 percent) patients healed while receiving IV antibiotics while 20 (6.2 percent) patients required minor or major amputation. Gauland noted that this specific combination of antibiotics was effective even when operative cultures were resistant to vancomycin and gentamicin, and suggested that the high local concentration of antibiotic may provide in vivo efficacy that susceptibility results do not indicate.
Surgeons can also use antibiotic-loaded calcium sulfate to minimize the extent of surgical excision of tissue required. In a series of 20 patients with open ulceration due to diabetic foot osteomyelitis, Jogia and colleagues combined surgical wound debridement, fenestration of affected bone and local delivery of vancomycin and gentamicin using calcium sulfate as a carrier.26 The wounds were previously recalcitrant to standard of care therapies for an average of 11.5 weeks. All patient wounds healed in a median time span of five weeks and there was no recurrence within 12 months following surgical intervention.
The literature largely depicts calcium sulfate’s utility in the arena of infection by its antibiotic delivery characteristics. Interestingly, the process of wound healing originates at the cellular level with a rise in extracellular calcium and calcium-dependent channels that stimulate a cascade of signals to begin cell repair and hemostasis.27,28 With in vitro experiments, authors have proposed development of a membrane “patch” at the site of cell damage via calcium-mediated fusion of intracellular compartments to prevent loss of cytoplasm while the influx of calcium mediates fibroblast proliferation and keratinocyte differentiation.29,30 Examinations of calcium alginate dressings have suggested the beneficial role of calcium ions as a hemostatic agent due to calcium’s ability to recruit platelet aggregating factors.31 However, the contribution of calcium carrying scaffolds to the extracellular calcium level in the wound environment has not been quantitatively demonstrated and calcium sulfate’s ability to directly stimulate wound healing has yet to be proven.
Practical Insights On The Use Of Calcium Sulfate Cement
We have found antibiotic-loaded calcium sulfate cement to be useful in the setting of deep cavitary soft tissue recesses, especially in areas that are suspect for bacterial colonization. The surgeon applies the cement during the final stage of serial debridement or during the initial stage if he or she is planning osseous reconstruction with hardware placement.
There are a variety of products available to use as synthetic calcium sulfate, all of which have varying setting times. One prepares the cement at the beginning of the surgical procedure. Surgeons typically use vancomycin and gentamicin to provide broad spectrum coverage, and can adjust this based on culture and sensitivity analysis. Other antibiotics we have used include amikacin. Depending on anatomic location and the size of the defect, 5 to 20 mL of calcium sulfate cement may be required. Before the cement hardens, one can use a syringe to inject the cement into the bone defect or cavity. We may also apply calcium sulfate cement topically with a sterile instrument.
This technique is useful following removal of infected hardware if the cement is not required to provide stability. We have effectively treated postoperative draining wounds with intact underlying hardware with topical application of antibiotic-loaded calcium cement. Doing so avoids exposure of hardware or removal of fixation that leads to osseous instability. We have found antibiotic loaded calcium sulfate cement to be a useful tool in the setting of infection to attempt tissue preservation and as a valuable tool when systemic antibiotic treatment is contraindicated.
Systemic Toxicity Of Antibiotic-Coated Cement: What You Should Know
Throughout the orthopedic literature, there is the underlying concern of acute renal insufficiency and other systemic effects of antibiotic-coated cement. In an ideal situation, the antibiotic should remain in the tissues for which it was intended and much of the risk has been postulated to arise from elution kinetics of various substances.
To our knowledge, there is no literature specifically addressing systemic toxicity with foot and ankle surgical application. Biodegradeable substances appear to have a reduced risk of systemic toxicity. In a 2017 study, Wahl and colleagues analyzed 680 postoperative blood samples and 233 fluid samples after employing vancomycin-impregnated calcium sulfate cement to treat bone and soft tissue infection with the exposure remaining in the “safe region” according to the study authors.32 Additionally, the concentration of antibiotic remained well above the minimum inhibitory concentration for treating Staphylococcus species for up to three months postoperatively.
Conversely, some authors recognize the potential for systemic side effects and have evaluated a commercially available tobramycin-laden calcium sulfate formulation.33 These authors do not recommend the use of this formulation in patients with creatinine clearance of less than 30 mL/min as potentially cytotoxic concentrations have occurred with amounts of 10 g or more.
In Conclusion
Several reports have suggested that calcium sulfate can serve as an effective local antibiotic carrier in diabetic limb salvage. However, the available evidence is limited and use of this technique is not widespread. Future studies may look into the use of polyphasic cement spacers that utilize a combination of bioceramics or addition of PMMA based on the patient’s needs. With this approach, the surgeon can use a faster resorbing cement to allow for early release and high concentration of antibiotic, leaving a scaffold which allows for bony ingrowth and possible functionality. Currently, the standard of care for treating infections in the diabetic foot requires swift removal of all affected tissue in order to preserve the limb. Continued refinement of implanting antibiotic-loaded cement may serve as a means to mitigate the need for bone and tissue resection in this setting when concerns for stability or functionality arise.
Dr. Ragothaman is a second-year resident with the MedStar Washington Hospital Center and Georgetown University Hospital.
Dr. Wynes is an Assistant Professor in the Department of Orthopaedics at the University of Maryland School of Medicine. He is the Co-Director of the University of Maryland Limb Preservation Clinic. Dr. Wynes is a Fellow of the American College of Foot and Ankle Surgeons.
References
1. Salvati EA, Callaghan JJ, Brause BD, Klain RF, Small RD. Reimplantation in infection: elution of gentamicin from cement and beads. Clin Ortho Relat Res. 1986;207:83-93.
2. Mounasamy V, Fulco P, Desai P, Adelaar R, Bearman G. The successful use of vancomycin-impregnated cement beads in a patient with vancomycin systemic toxicity: a case report with review of literature. Eur J Orthop Surg Traumatol. 2013;23 Suppl 2:S299-302.
3. Melamed EA, Peled E. Antibiotic impregnated cement spacer for salvage of diabetic osteomyelitis. Foot Ankle Int. 2012;33(3):213-219.
4. Elmarsafi T, Oliver NG, Steinberg JS, Evans KK, Attinger CE, Kim PJ. Long-term outcomes of permanent cement spacers in the infected foot. J Foot Ankle Surg. 2017;56(2):287-290.
5. Pithankuakul K, Samranvedhya W, Visutipol B, Rojviroj S. The effects of different mixing speeds on the elution and strength of high-dose antibiotic-loaded bone cement created with the hand-mixed technique. J Arthroplasty. 2015;30(5):858-63.
6. Minelli EB, Caveiari C, Benini A. Release of antibiotics from polymethylmethacrylate cement. J Chemother. 2002;14(5):492–500.
7. Neut D, van de Belt H, van Horn JR, van der Mei HC, Busscher HJ. Residual gentamicin-release from antibiotic-loaded polymethylmethacrylate beads after 5 years of implantation. Biomaterials. 2003;24(10):1829-31.
8. Anagnostakos K, Hitzler P, Pape D, Kohn D, Kelm J. Persistence of bacterial growth on antibiotic-loaded beads: Is it actually a problem? Acta Orthopaedica. 2008;79(2):302-307.
9. Shinto Y, Uchida A, Korkusuz F, Araki N, Ono K. Calcium hydroxyapatite ceramic used as a delivery system for antibiotics. J Bone Joint Surg Br. 1992;74(4):600-4.
10. Aiken SS, Cooper JJ, Florance H, Robinson MT, Michell S. Local release of antibiotics for surgical site infection management using high-purity calcium sulfate: An in vitro elution study. Surgical Infect (Larchmt). 2015;16(1):54-61.
11. Karr JC, Lauretta J, Keriazes G. In vitro antimicrobial activity of calcium sulfate and hydroxyapatite (Cerament Bone Void Filler) discs using heat-sensitive and non-heat-sensitive antibiotics against methicillin-resistant Staphylococcus aureus and. Pseudomonas aeruginosa. J Am Podiatr Med Assoc. 2011;101(2):146-152.
12. Wahl P, Guidi M, Benninger E, et al. The levels of vancomycin in the blood and the wound after the local treatment of bone and soft tissue infection with antibiotic-loaded calcium sulphate as carrier material. Bone Joint J. 2017;99-B(11):1537-1544.
13. Wichelhaus TA, Dingeldeln E, Rauschmann M, et al. Elution characteristics of vancomycin, teicoplanin, gentamicin, and clindamycin from calcium sulphate beads. J Antimicrob Chemother. 2001;48(1):117-119.
14. Aquino-Martinez R, Angelo APm Pujol FV. Calcium-containing scaffolds induce bone regeneration by regulating mesenchymal stem cell differentiation and migration. Stem Cell Res Ther. 2017;8(1):265.
15. McNally MA, Ferguson JY, Lau ACK, Diefenbeck M, Ramsden AJ, Atkins BL. Single-stage treatment of chronic osteomyelitis with a new absorbable, gentamicin-loaded, calcium sulphate/hydroxyapatite biocomposite: A prospective series of 100 cases. Bone Joint J. 2016;98-B(9):1289-96.
16. Zhang J, Liu W, Schnitzler V, Tancret F, Bouler JM. Calcium phosphate cements for bone substitution chemistry, handling and mechanical properties. Acta Biomater. 2014;10(3):1035-49.
17. Luo S, Jiang T, Yang Y, Yang X, Zhao J. Combination therapy with vancomycin-loaded calcium sulfate and vancomycin-loaded PMMA in the treatment of chronic osteomyelitis. BMC Musculoskelet Disord. 2016; 17(1):502.
18. Armstrong DG, Findlow AH, Oyibo SO, Boulton AJ. The use of absorbable antibiotic-impregnated calcium sulphate pellets in the management of diabetic foot infections. Diabet Med. 2001;18(11):942-3.
19. Karr JC. Management in the wound-care outpatient setting of a diabetic patient with forefoot osteomyelitis using Cerament bone void filler impregnated with vancomycin. J Am Podiatr Med Assoc. 2011;101(3):259-264.
20. Morely R, Lopez F, Webb F. Calcium sulphate as a drug delivery system in a deep diabetic foot infection. Foot (Edinb). 2016;27:36-40.
21. Papagelopoulos PJ, Mavrogenis AF, Tsiodras S, Vlastou C, Giamarellou H, Soucacos PN. Calcium sulphate delivery system with tobramycin for the treatment of chronic calcaneal osteomyelitis. J Int Med Res. 2006;34(6):704-712.
22. Lee GH, Khoury JG, Bell J, Buckwalter JA. Adverse reactions to Osteoset bone graft substitute: the incidence in a consecutive series. Iowa Orthop J. 2002;22:25-38.
23. Krause FG. Devries G. Meakin C. Kalia TP. Younger AS. Outcome of transmetatarsal amputations in diabetics using antibiotic beads. Foot Ankle Int. 2009;30(6):486-93.
24. Menon A, Soman R, Rodrigues C, Phadke S, Agashe VM. Careful interpretation of the wound status is needed with use of antibiotic impregnated biodegrable synthetic pure calcium sulfate beads: Series of 39 cases. J Bone Jt Infect. 2018;3(2):87-93.
25. Gauland C. Managing lower extremity osteomyelitis locally with surgical debridement and synthetic calcium sulfate antibiotic tablets. Adv Skin Wound Care. 2011;24(11):515-23.
26. Jogia RM, Modha DE, Nisal K, Berrington R, Kong M. Use of highly purified synthetic calcium sulfate impregnated with antibiotics for the management of diabetic foot ulcers complicated by osteomyelitis. Diabetes Care. 2015;38:e79-e80.
27. Wood W. Wound healing: Calcium flashes illuminate early events. Current Biol. 2012;22(1);R14-16.
28. Lansdown AB. Calcium: a potential central regulator in wound healing in the skin. Wound Repair Regen. 2002;10(5):271-85.
29. Davenport NR, Sonnemann KJ, Eliceiri KW, Bement WM. Membrane dynamics during cellular wound repair. Mol Biol Cell. 2016;27(14):2272-85.
30. Bikle DD, Ng D, Tu CL, Oda Y, Xie Z (2001) Calcium- and vitamin D-regulated keratinocyte differentiation. Mol Cell Endocrinol. 2001;177(1-2):161–171.
31. Motta GJ. Calcium alginate topical wound dressings: a new dimension in the cost-effective treatment for exudating dermal wounds and pressure sores. Ostomy Wound Manage. 1989;25:52–56.
32. Wahl P, Guidi M, Benninger E, et al. The levels of vancomycin in the blood and the wound after the local treatment of bone and soft-tissue infection with antibiotic-loaded calcium sulphate as carrier material. Bone Joint J. 2017;99-B(11):1537-1544.
33. Livio F, Wahl P, Csajka C, Gautier E, Buclin T. Tobramycin exposure from active calcium sulfate bone graft substitute. BMC Pharmacol Toxicol. 2014;15:12.
