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A Guide To Using Antibiotic-Loaded PMMA Beads And Spacers In The Diabetic Foot

Polymethyl methacrylate (PMMA) beads may provide an effective adjunctive option for treating a variety of infected wounds in high-risk patients with diabetes mellitus. Accordingly, in a thorough review of the literature, these authors discuss the evolution of this modality, keys to appropriate antibiotic selection and pertinent surgical considerations.

Diabetic foot infections (DFIs) comprise a wide range of clinical presentations, such as those involving soft tissue and/or bone, acute versus chronic infections, local infections versus widespread and systemic infections, and those with or without vascular impairment. Diabetic foot infections remain the leading cause for hospitalization in patients with diabetes mellitus and timely treatment in any case is imperative to prevent major lower extremity amputations.1

In diabetic foot osteomyelitis and depending on the severity of infection and anatomic location, treatment options often include a combination of both medical and surgical methods. Hospital admission for intravenous antibiotic therapy and surgical debridement may be optimal for the management of acutely moderate to severe DFIs with clinical and radiographic evidence of osteomyelitis. Noninvasive vascular testing may also identify any abnormalities that one might need to address through consultation with a vascular interventionist. Further advanced medical imaging such as computed tomography, magnetic resonance imaging and nuclear imaging may be warranted for surgical planning.

Surgical debridement should be selective but in severe cases of osteomyelitis, partial foot amputations such as an isolated partial ray (toe and metatarsal) amputation, multiple ray amputations or transmetatarsal amputation may be necessary to eradicate the infection effectively. Major soft tissue and/or osseous defects can result from these surgical procedures, leading to challenges for definitive wound closure and functional reconstruction. Physicians often address moderate to severe DFIs in a staged fashion with adjunctive modalities such as negative pressure wound therapy (NPWT) and/or allogenic skin grafting.

Physicians have used non-biodegradable antibiotic cement beads and/or spacers for supplemental surgical management of diabetic foot and/or ankle infections, and Charcot neuroarthropathy. The vehicle of delivery is most commonly polymethyl methacrylate (PMMA). One would combine PMMA with a heat-stable antibiotic and form this mixture into either beads or spacers for local application within the surgical wound after adequate surgical debridement. The antibiotic-loaded PMMA beads or spacers remain intact and within the surgical wound while the patient is also receiving culture-specific systemic or oral antibiotic therapy, and one would remove the beads or spacers surgically depending on the clinical, medical imaging and systemic presentation. In certain complex cases, one can leave the antibiotic-loaded PMMA beads or spacers within the surgical wound permanently. While delivering antibiotic locally, the antibiotic-loaded PMMA beads or spacers also provide a void filler to stabilize the soft tissues and bone structures surrounding them.

A Closer Look At The Evolution Of PMMA

Local antibiotic delivery with antibiotic-loaded acrylic bone cement such as PMMA has been in extensive use in orthopedic surgery for chronic osteomyelitis and implant-related infections.

Buchholz and colleagues initially described the concept of local antibiotic delivery by the incorporation of gentamicin into acrylic bone cement in the 1970s.2,3 A laboratory study by Marks and coworkers showed the elution of oxacillin, cefazolin, and gentamicin in a microbiologically active form from Palacos (Heraeus Medical) and Simplex bone cements (Heraeus Medical).4

Elson and colleagues showed that when surgeons placed antibiotic-loaded acrylic bone cement next to cortical bone, the eluted antibiotic penetrated bone and its concentration in the bone was much higher than that achieved safely by systemic administration.5 In vivo animal studies later confirmed the elution of pharmacologically active gentamicin from acrylic bone cement.6,7

Wahlig and coworkers specifically described their work with gentamicin-loaded bone cement in patients with infection of either bone or soft tissue, mainly of the lower extremity.7 They reported that high concentrations of gentamicin were measurable in the exudate from the wound and that patients tolerated this form of treatment well without complications. In 1981, Buchholz and colleagues published their landmark article on the treatment of infected total joint replacement using antibiotic-loaded PMMA.8  

Once gentamicin-loaded bone cement became readily available in Germany in the 1970s, many efforts to treat osteomyelitis by filling the debrided cavity with solid plugs of antibiotic-loaded bone cement were not successful.9 Klemm then started to make handmade beads in Frankfurt to treat chronic osteomyelitis and in recent reports, this method has been effective in increasing surface area-volume ratio.10-12 Klemm also utilized this technique to treat infected osteosynthesis and infected nonunions.13

Ostermann and colleagues in 1989 described the antibiotic bead pouch technique for the management of severe open fractures.14 Building on the concept, Paley and Herzenberg first described the use of antibiotic-impregnated cement rods to treat post-traumatic intramedullary infections in 2002 since placement and removal of beads were difficult at these anatomical locations.15   

For DFIs, antibiotic-loaded PMMA beads and spacers have been in use not only for local delivery of antibiotics but also to fill dead space and provide stabilization of surrounding structures in preparation for further soft tissue and/or osseous reconstruction.

Case series by Stabile and Jacobs in 1990 and Calhoun and coworkers in 1994 provided positive outcomes for the use of antibiotic-loaded PMMA in foot infections for patients without diabetes.16,17 In 2000, Roeder and colleagues described their experience with tobramycin- and vancomycin-impregnated PMMA beads in the treatment of diabetic foot osteomyelitis with partial ray amputations and partial calcanectomy.18 Since then, antibiotic-loaded PMMA has become a useful adjunct for several types of DFIs with the ability to deliver antibiotic locally while limiting systemic toxicity.  

Current Insights On The Mechanism Of Action And Antibiotic Selection

While the mechanism by which the antibiotics are released from the cement is still under debate, research has shown that elution of antibiotics follows a biphasic pattern—with an initial rapid phase and a secondary slow phase—and that only a small amount of the antibiotic incorporated in bone cement is released.19 The most commonly accepted theory is that the initial elution of antibiotics occurs from the surface of the bone cement and also from the pores and cracks in the cement’s matrix while sustained release over several days was a bulk diffusion phenomenon.20

Elution improves with increasing surface area and porosity of the cement.21 The size of the antibiotic beads can affect elution properties. Therefore, having equal surface areas for each bead (as well as the shape in a slightly oval or elongated spherical appearance) is optimal, and one determines the size of the spacer depending upon the osseous or joint resection.

The choice of the antibiotic usually depends upon intraoperative soft tissue and/or bone cultures, previous surgeries and antibiotic therapy, and planned staged reconstruction. The antibiotic(s) one selects must be safe, thermostable, water-soluble, hypoallergenic, bactericidal with a broad spectrum of activity, and in powder form. While gentamicin has historically been the most commonly used antibiotic, concern for increasing bacterial resistance has led to a demand for alternative drugs. Some of the most common antibiotics clinicians use in diabetic foot and ankle cases are gentamicin, tobramycin and vancomycin. One can choose two antibiotics in the presence of polymicrobial infections and researchers have demonstrated the advantage of this approach for increasing the elution of the antibiotics.22  

What Are The Indications And Contraindications Of PMMA?

The most common indications for the use of antibiotic-loaded beads or spacers include but are not limited to: acute or chronic osteomyelitis; DFIs involving soft tissue or bone; infected Charcot neuroarthropathy; open fractures; infected arthroplasties; and infected non-unions. Physicians can use antibiotic-loaded PMMA beads and spacers in the management of dead space in the setting of infection or trauma along with temporary or definitive skeletal stabilization by external fixation.

One can utilize PMMA beads to achieve a high concentration of local antibiotic delivery where intravenous antibiotics may not be able to penetrate the tissue due to suboptimal blood flow or the presence of biofilm.23 Due to limited systemic absorption of antibiotics eluted from antibiotic beads and/or spacers, one can also use the beads for patients who cannot tolerate systemic antibiotics due to liver or kidney impairment.   

Contraindications for the use of antibiotic beads and/or spacers include but are not limited to: patient-specific allergy or intolerance to a specific type of antibiotic; small non-infected wounds that can be closed primarily; limb-threatening infections (i.e., necrotizing fasciitis); large soft tissue loss in unsalvageable limbs due to trauma; and resistance to antibiotics used in the antibiotic beads or spacers.  

Essential Surgical Considerations

One of the most important factors before the application of the antibiotic-loaded PMMA beads or spacers is adequate surgical resection of any infected soft tissue and/or osseous structures in the diabetic foot. Surgeons also perform intraoperative soft tissue cultures, bone cultures and/or biopsies in order to choose an appropriate antibiotic, which is heat stable, hydrophilic and hypoallergenic. Multiple staged surgical debridements might be necessary prior to the local antibiotic delivery based on the severity of the infection and overall medical optimization of the patient with diabetes mellitus.

After deciding to apply antibiotic-loaded PMMA beads or spacers, the patient returns to the operating room for the surgical implantation and any other simultaneous adjunctive procedures such as surgical offloading or stabilization with an external fixation system.

Hand mold the antibiotic beads and add them onto twisted wires (see photo 1). Hand mold the spacer to fit the appropriate dimensions of the void or deficit that it is expected to fill. Ensure sufficient operative time for the mixture of the antibiotic-loaded PMMA beads/spacers to become firm. This is an exothermic process and one should allow the final structured product to cool prior to implantation in the diabetic foot and/or ankle.

After implanting the antibiotic beads/spacers, perform layered closure for complete coverage of the implanted antibotic-loaded PMMA beads/spacers (see photos 2-4). One can apply NPWT, if necessary, to achieve complete closure (see photo at left). It is important to create a close compartment in order to maintain a high concentration of local antibiotic delivery in the area, and avoid exposure and movement of the antibiotic-loaded PMMA beads/spacers.

Pertinent Post-Op Principles

Patients should remain non-weightbearing on the affected extremity throughout the postoperative period with the use of splinting, casting or external fixation.  

In most cases, one would seek an infectious disease consultation based on the clinical and systemic signs of infection, and overall medical status of the patient with diabetes mellitus. Ensure close monitoring of the patient by all medical and surgical disciplines postoperatively, and that the patient is adhering with offloading of the affected extremity. Monitor the surgical site with local wound care dressings and order the proper laboratory and medical imaging studies.

Explantation of the antibiotic-loaded PMMA beads and/or spacers depends on the overall clinical, medical imaging and systemic improvement of the patient. Another factor is whether there is a planned staged reconstruction versus local antibiotic delivery removal as a definitive procedure. Upon removal of the antibiotic-loaded PMMA beads/spacers, it is advisable to obtain additional soft tissue and/or bone cultures/biopsies to further guide the duration and/or route of antibiotics if necessary.  

In Conclusion

Antibiotic-loaded PMMA has many applications in the diabetic foot and ankle. The formation of PMMA into beads versus spacers depends on the clinical defect itself and its relation to other necessary reconstructive considerations based on the specific patient. In cases of smaller wound defects affected by osteomyelitis such as those with partial ray or transmetatarsal amputations, antibiotic beads are ideal.24-26 Antibiotic spacers are better suited for use in larger defects such as those left from joint resections leading to increased instability as one would see with diabetic Charcot reconstruction in the presence of osteomyelitis.27,28

The ability of these local antibiotic delivery systems to facilitate sterilization at the site with decreased bacterial count can also be optimal in preparation for further soft tissue reconstructive procedures such as local flaps, muscle flaps and pedicle flaps.29 Currently, the best results occur with the combined use of local antibiotic-loaded cement and systemic antibiotic administration based on deep intraoperative cultures.

While the technical application of antibiotic-loaded PMMA cement beads and spacers continues to evolve, there is growing evidence for their role as an adjunctive treatment in DFIs. Further studies are necessary to determine firm recommendations on exact antibiotic dosing and the duration of placement. Likewise, studies are needed to address remaining questions such as the formation of antibiotic resistance and biofilms with the use of these antibiotic delivery systems.

Dr. Patel is a Specialist and Fellow in Reconstructive Foot and Ankle Surgery within the Division of Podiatric Medicine and Surgery in the Department of Orthopaedics at the University of Texas Health San Antonio.

Dr. Ramanujam is an Assistant Clinical Professor and Chief of the Division of Podiatric Medicine and Surgery in the Department of Orthopaedics at the University of Texas Health San Antonio.

Dr. Zgonis is a Professor and the Externship and Fellowship Director in Reconstructive Foot and Ankle Surgery within the Division of Podiatric Medicine and Surgery in the Department of Orthopaedics at the University of Texas Health San Antonio. He is the Founder and Scientific Chairman of the Annual International External Fixation Symposium (IEFS) in San Antonio.

References

1.    Uçkay I, Aragón-Sánchez J, Lew D, Lipsky BA. Diabetic foot infections: what have we learned in the last 30 years? Int J Infect Dis. 2015;40:81-91.
2.    Buchholz HW, Engelbrecht H. [Depot effects of various antibiotics mixed with Palacos resins]. Chirurg. 1970;41(11):511-515.
3.    Buchholz HW, Engelbrecht E, Röttger J, Siegel A, Lodenkämper H, Elson RA. Management of deep infection involving joint implants. J Bone Joint Surg Br. 1979;61-B(1):118.
4.    Marks KE, Nelson CL, Lautenschlager EP. Antibiotic-impregnated acrylic bone cement. J Bone Joint Surg Am. 1976;58(3):358-364.
5.    Elson RA, Jephcott AE, McGechie DB, Verettas D. Antibiotic-loaded acrylic cement. J Bone Joint Surg Br. 1977;59(2):200-205.
6.    Schurman DJ, Trindade C, Hirshman HP, Moser K, Kajiyama G, Stevens P. Antibiotic-acrylic bone cement composites. Studies of gentamicin and Palacos. J Bone Joint Surg Am. 1978;60(7):978-984.
7.    Wahlig H, Dingeldein E, Bergmann R, Reuss K. The release of gentamicin from polymethylmethacrylate beads. An experimental and pharmacokinetic study. J Bone Joint Surg Br. 1978;60-B(2):270-275.
8.    Buchholz HW, Elson RA, Engelbrecht E, Lodenkämper H, Röttger J, Siegel A.  Management of deep infection of total hip replacement. J Bone Joint Surg Br. 1981;63-B(3):342-353.
9.    Walenkamp GH. Self-mixed antibiotic bone cement: western countries learn from developing countries. Acta Orthop. 2009;80(5):505-507.
10.    Klemm K. [Gentamicin-PMMA-beads in treating bone and soft tissue infections (author’s transl)]. Zentralbl Chir. 1979;104(14):934-942.
11.    Klemm KW. Gentamicin-PMMA chains (Septopal chains) for the local antibiotic treatment of chronic osteomyelitis. Reconstr Surg Traumatol. 1988;20:11-35.
12.    Klemm K. The use of antibiotic-containing bead chains in the treatment of chronic bone infections. Clin Microbiol Infect. 2001;7(1):28-31.
13.    Klemm KW. Antibiotic bead chains. Clin Orthop Relat Res. 1993;(295):63-76.
14.    Ostermann PA, Henry SL, Seligson D. [Treatment of 2d and 3d degree complicated tibial shaft fractures with the PMMA bead pouch technic]. Unfallchirurg. 1989;92(11):523-530.
15.    Paley D, Herzenberg JE. Intramedullary infections treated with antibiotic cement rods: preliminary results in nine cases. J Orthop Trauma. 2002;16(10):723-729.
16.    Stabile DE, Jacobs AM. Local antibiotic treatment of soft tissue and bone infections of the foot. J Am Podiatr Med Assoc. 1990;80(7):345-353.
17.    Calhoun JH, Klemm K, Anger DM, Mader JT. Use of antibiotic-PMMA beads in the ischemic foot. Orthopaedics. 1994;17(5):453-458.
18.    Roeder B, Van Gils CC, Maling S. Antibiotic beads in the treatment of diabetic pedal osteomyelitis. J Foot Ankle Surg. 2000;39(2):124-130.
19.    Bistolfi A, Massazza G, Verné E, Massè A, Deledda D, Ferraris S, Miola M, Galetto F, Crova M. Antibiotic-loaded cement in orthopedic surgery: a review. ISRN Orthop. 2011 Aug 7;2011:290851.
20.    Van de Belt H, Neut D, Schenk W, van Horn JR, van der Mei HC, Busscher HJ. Infection of orthopedic implants and the use of antibiotic-loaded bone cements. A review. Acta Orthop Scand. 2001;72(6):557-571.
21.    Van de Belt H, Neut D, Uges DR, Schenk W, van Horn JR, van der Mei HC, Busscher HJ. Surface roughness, porosity and wettability of gentamicin-loaded bone cements and their antibiotic release. Biomaterials. 2000;21(19):1981-1987.
22.    Baleani M, Persson C, Zolezzi C, Andollina A, Borrelli AM, Tigani D. Biological and biomechanical effects of vancomycin and meropenem in acrylic bone cement. J Arthroplasty. 2008;23(8):1232-1238.
23.    Markakis K, Faris AR, Sharaf H, Faris B, Rees S, Bowling FL. Local antibiotic delivery systems: current and future applications for diabetic foot infections. Int J Low Extrem Wounds. 2018;17(1):14-21.
24.    Schade VL, Roukis TS. The role of polymethylmethacrylate antibiotic-loaded cement in addition to debridement for the treatment of soft tissue and osseous infections of the foot and ankle. J Foot Ankle Surg. 2010;49(1):55-62.
25.    Ramanujam CL, Zgonis T. Salvage of Charcot foot neuropathy superimposed with osteomyelitis: a case report. J Wound Care. 2010;19(11):485-487.
26.    Ramanujam CL, Zgonis T. Antibiotic-loaded cement beads for Charcot ankle osteomyelitis. Foot Ankle Spec. 2010;3(5):274-277.
27.    Hong CC, Jin Tan K, Lahiri A, Nather A. Use of a definitive cement spacer for simultaneous bony and soft tissue reconstruction of mid- and hindfoot diabetic neuroarthropathy:a case report. J Foot Ankle Surg. 2015;54(1):120-125.
28.    Melamed EA, Peled E.  Antibiotic impregnated cement spacer for salvage of diabetic osteomyelitis. Foot Ankle Int. 2012;33(3):213-219.
29.    Ramanujam CL, Facaros Z, Zgonis T. Abductor hallucis muscle flap with circular external fixation for Charcot foot osteomyelitis: a case report. Diabet Foot Ankle. 2011;2.

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By Shrunjay R. Patel, DPM, Crystal L. Ramanujam, DPM, MSc, FACFAS and Thomas Zgonis, DPM, FACFAS
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