Antimicrobial Beads: Are They Worthwhile For Postoperative Treatment Of Osteomyelitis?
Point
By Christopher Kennedy, DPM, AACFAS
Osteomyelitis of the foot and ankle presents unique treatment challenges. The peripheral anatomy, limited soft tissue envelope and highly articular, weight bearing surfaces all contribute to complications in treatment. These vulnerabilities increase the incidence of extension osteomyelitis and advanced disease processes in a highly comorbid population commonly compound these challenges. With a four-fold increased risk for major lower extremity amputation compared to patients with soft tissue disease only, osteomyelitis of the foot and ankle carries massive morbidity.1 In a population concurrently battling major systemic diseases and multiple comorbidities, this translates into high mortality rates. Aggressive, adjuvant techniques are not only warranted, they are a necessity for patients in this high stakes, at-risk cohort.
For decades, surgeons have used polymethyl methacrylate (PMMA), a non-reactive acrylic polymer, extensively for orthopedic structural repair and anchoring implants.2 Colloquially known as “bone cement,” discoveries revealed it as an ideal carrier for antibiotic therapy and highly beneficial following failed or infected arthroplasty.3 Its utility in the foot and ankle, especially in deep diabetic foot infections, has undergone and is still undergoing investigation. Numerous researchers and authors report its benefits and widely promote its use.4-8
Considering The Benefits Of Antibiotic Eluting Beads
PMMA - Antibiotic Eluting Beads (PMMA-AEB) provide the following confirmed benefits:
• Local delivery of extended antibiotic therapy with adjacent tissue concentrations ranging from 20 to 200 μg/dl for up to six weeks; 5
• High dose concentrations of antibiotic therapy that easily exceed the minimum inhibitory concentration (MIC) of four μg/dl used to define bacterial resistance; 6
• Dead space-occupying mass effect, which can maintain length and prevent soft tissue contracture; 7
• Fully customizable implant size and shape;
• Tolerance to numerous antibiotic additives;
• Accommodation of aggressive bone debridement and resection of osseous bioburden;
• Limited systemic absorption, reported maximally to be between 0.4 to 2 μg/ml, which is well under the threshold generally associated with adverse events such as nephro- and oto-toxicity;4 and
• In certain cases, permits the bioproduction of a vascularized internal membrane which assists in subsequent structural graft incorporation; the Masqulete technique.8
The utility of PMMA-AEB in complex cases of foot and ankle osteomyelitis may be substantial given varied clinical scenarios that support its use. Roukis and colleagues described their technique for protocol-based irrigation, debridement and antibiotic-laden cement in 2010.9 It involved the insertion of numerous, approximately eight mm beads made from a mixture of 40 g PMMA, 500 mg gentamycin and 2.4 g tobramycin. Surgeons implanted these beads on the index procedure and allowed them to elute over the following 72 hours, at which time they performed repeat irrigation, debridement and obtained new cultures. They repeated this process to halt additional necrosis for an average of 1.3 cycles. The authors noted greater than 90 percent culture clearance following the final explant.9
Elmarsafi and team examined the process of extended implantation of antibiotic eluting cement spacers to replace defect voids.10 They noted challenges associated with altered kinematics and plantar pressure distribution with a single spacer, but fully recognized the utility in extended distribution of local antibiotic therapy.10
Answering Key Questions About Antibiotic Beads
Surprisingly, the exact mechanism of elution is unknown. Some feel antibiotic releases from the various cracks and fissures formed during back-table bead construction.11 Others feel a controlled diffusion occurs either from the surface of the spacer or through the acrylic matrix itself.12 More agreed upon in the community is the timing of elution, which follows a bimodal curve with the highest antibiotic release occurring in the first 96 hours and tapering over the following two weeks. After this, there is trickle elution for a period of up to five years.13
Discussions routinely revolve around the specifics of implant technique. A 2004 review assessed elution kinetics in a variety of implant shapes and sizes.14 They found the only variable to increase local concentrations was the total mass of antibiotic implanted and not specific shape, surface area or bead construct.14 Similarly, back-table sterile formation of beads had no impact on elution characteristics compared to pre-formed or templated implants.4 To increase immediate concentrations, a study by Dunne and colleagues recommends one maintain a coarse consistency of antibiotic additive. This appears to create a porous structure with pockets that immediately elute and distribute based upon location.15
Given the high local elution concentrations seen with antibiotic laden bone cement, some have concerns regarding systemic effects. Early work by Salvatorie and team examined both urine and serum concentrations of gentamycin following implant. They noted low concentrations of the drug, and out of 56 individuals there were no reports of toxicity. Springer and colleagues placed relatively high vancomycin concentrations in PMMA (3 g Vancomycin + 3.6 g gentamicin to 40 g PMMA) in spacer blocks inserted following knee arthroplasty explant.16 Out of 34 patients, the authors concluded that even in these concentrations, the cement spacer implant was safe.16
As with all intervention, the benefit of PMMA-AEB in foot and ankle surgery is not without risk and burden. Implant is often accompanied by a need for subsequent interventions and usually explant, although the timing and details remain case-specific. It may be difficult to justify return to OR for simple bead removal, but this rarely is the case. The staged approach follows well with the described technique for managing osteomyelitis, and allows further debridement, additional resection of the margins, biopsy, closure and occasional reconstruction. One should consider the financial impact of PMMA-AEB use in foot and ankle surgery, but this is nominal in comparison to average financial burdens associated with required amputation, etc. In 2017, the national cost of PMMA-AEB implant in patients with chronic osteomyelitis was $484.54.17 The average grand total for major lower extremity amputation per patient in the 2010 fiscal year alone was $60,647.18
Final Thoughts
Even with an extensive body of research, questions as to PMMA-AEB use in podiatric osteomyelitis treatment regimens remain. There is no consensus as to the precise ratio of pharmaceuticals to acrylic cement or the exact timing of implantation during set. The location, duration, and discrete procedure itself all have certain unknowns. However, the established and proven benefits, as well as extensive literature to date, seem to encourage its serious consideration in treating high risk patient populations with deep infections of the foot and ankle.
Dr. Kennedy is a fellowship-trained foot and ankle surgeon and an Associate of the American College of Foot and Ankle Surgeons. He is in practice in Petoskey, Mich.
Counterpoint
By Windy Cole, DPM, CWSP
Acute bacterial skin and deep structure infections can lead to substantial morbidity and mortality, increased health care costs and societal burden.1 Hospital admissions for these infections among U.S. adults increased by an estimated 17 percent between 2005 and 2011.1 Americans aged 45 to 64 years admitted for skin and deep structure infections will incur medical costs of over $7,235 per episode.2 Median length of stay for these admissions is between four and five days.2 Major factors contributing to this figure are room fees, OR charges and pharmacy costs.3 Diabetic foot ulcers are the most common precursor to such infections with a global prevalence of 6.3 percent.4 It is not uncommon for DFU complications to lead to hospitalization.5 According to the International Working Group on the Diabetic Foot, hospitalization and surgical evaluation should be considered for all persons with diabetes and severe foot infections.6 Evidence-based clinical pathways are imperative to provide the best care to this population while also being cognizant to health care expenditures.
Historically, debridement of infected wounds is the most critical step in successfully treating diabetic foot infections.7 Thorough debridement consists of excision of all necrotic and non-vascularized tissue, including all indurated and inflamed soft tissue at all borders to ensure removal of all deeply buried biofilms known to recolonize the wound base.7 Irrigation can further decease bacterial loads, preferably using normal saline at low pressure to avoid bacterial seeding.8 One should continue irrigation until the wound appears macroscopically clean. Tissue samples are also necessary for culture and diagnostic purposes. Systemic antibiotics along with proper postop dressings is the current standard of care for diabetic foot infections, both with and without osteomyelitis.9
What About Antibiotic Beads As An Adjunctive Therapy?
With little clinical evidence available, adjunctive therapies such as antibiotic-impregnated beads to treat diabetic foot infections have yet to be fully defined, though there is continued interest among clinicians. Research on pharmaceutical-grade calcium sulfate beads shows they have the potential for targeted local release of tobramycin, gentamicin, vancomycin and rifampicin into surrounding tissues.10 To date, there are few published studies investigating the outcomes of antibiotic-impregnated beads in the treatment of diabetic neuropathic foot infections. Published literature on this cohort primarily consists of case reports and comparative case series with seemingly favorable results, but none included a control group.11
A 2019 retrospective cohort study compared surgical debridement plus bioabsorbable antibiotic-impregnated beads versus surgical debridement alone in diabetic foot infections.11 Fifty patients took part in this two-arm study and all subjects presented with similar demographic features.11 All patients also received appropriate systemic antibiotics. The study concluded that antibiotic-impregnated beads in conjunction with surgical debridement in diabetic neuropathic infected foot ulcers did not result in significantly faster healing, reduce length of stay or decrease the need for further surgical debridement. Also, added cost of antibiotic bead materials in this study was $340 per patient.11
Another retrospective comparative study evaluated 46 patients with osteomyelitis from 2015 through 2017.12 When comparing infected bone resection combined with adjunctive antibiotic-impregnated calcium sulfate versus infected bone resection alone, there was no improvement in healing rates, reduction of postop amputations or shorter time to healing.13 Accordingly, further prospective randomized controlled trials are necessary to provide a higher level of evidence for routine use of antibiotic-impregnated beads for diabetic foot infections.
Evidence continues to question our current standard of care for the treatment of diabetic foot infections. Conservative versus surgical management, as well as the route and duration or antibiotic therapy, is an area of ongoing global research. The recent OVIVA trial provided evidence that challenges the belief that treatment of infections with evidence of osteomyelitis requires intravenous antibiotics.13 Researchers concluded that appropriately selected oral regimens can be as effective, more convenient and less costly.13 In this study, conservative nonsurgical treatment per-patient savings was estimated at £2,740 GBP.13 In addition, they noted that oral antibiotics eliminates IV catheter-related adverse events. Oral antibiotics alone are not preferred for all cases of foot infection with osteomyelitis; but conversely, not all cases of foot infections with osteomyelitis mandate surgical intervention and IV antibiotics.
In Conclusion
Management of DFUs with osteomyelitis results in increased costs to the health care system in the U.S. and globally. It is imperative we employ only evidence-based therapies in managing this difficult-to-treat population. The most recent literature appears to support a more conservative approach to treating skin and deep structure infections. Choosing the right clinical pathway for each individual should weigh evidence-based treatment guidelines. Based on so little evidence for antimicrobial beads for pedal osteomyelitis paired with increased cost and OR time, their use is not considered standard of care. For adjunctive therapies to gain wide acceptance, non-biased, large randomized controlled clinical trials are necessary. Employing evidence-based therapy is the best way to improve outcomes and control costs.
Dr. Cole is an Adjunct Professor and Director of Wound Care Research at the Kent State University School of Podiatric Medicine.
Point References
1. Mutluoglu M, Sivrioglu AK, Eroglu M, et al. The implications of the presence of osteomyelitis on outcomes of infected diabetic foot wounds. Scand J Infect Dis. 2013;45(7):497-503.
2. Haboush EJ. A new operation for arthroplasty of the hip based on biomechanics, photoelasticity, fast-setting dental acrylic, and other considerations. Bull Hosp Joint Dis. 1953;14(2):242- 277.
3. Buchholz HW, Engelbrecht H. Uber die Depotwirkung einiger Antibiotica bei Vermischung mit dem Kunstharz Palacos [Depot effects of various antibiotics mixed with Palacos resins]. Chirurg. 1970;41(11):511-515.
4. Seligson D, Popham GJ, Voos K, Henry SL, Faghri M. Antibiotic-leaching from polymethylmethacrylate beads. J Bone Joint Surg Am. 1993;75(5):714-720.
5. Henry SL, Hood GA, Seligson D. Long-term implantation of gentamicin-polymethylmethacrylate antibiotic beads. Clin Orthop Relat Res. 1993;(295):47-53.
6. Henry SL, Seligson D, Mangino P, Popham GJ. Antibiotic-impregnated beads. Part I: Bead implantation versus systemic therapy. Orthop Rev. 1991;20(3):242-247.
7. Hanssen AD. Local antibiotic delivery vehicles in the treatment of musculoskeletal infection. Clin Orthop Relat Res. 2005;(437):91-96.
8. Masquelet A, Kanakaris NK, Obert L, Stafford P, Giannoudis PV. Bone repair using the Masquelet technique. J Bone Joint Surg Am. 2019;101(11):1024-1036.
9. 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.
10. 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.
11. Baker AS, Greenham LW. Release of gentamicin from acrylic bone cement. Elution and diffusion studies. J Bone Joint Surg Am. 1988;70(10):1551-1557.
12. Bayston R, Milner RD. The sustained release of antimicrobial drugs from bone cement. An appraisal of laboratory investigations and their significance. J Bone Joint Surg Br. 1982;64(4):460- 464.
13. Anagnostakos K, Wilmes P, Schmitt E, Kelm J. Elution of gentamicin and vancomycin from polymethylmethacrylate beads and hip spacers in vivo. Acta Orthop. 2009;80(2):193-197.
14. Seeley SK, Seeley JV, Telehowski P, Martin S, Tavakoli M, Colton SL, Larson B, Forrester P, Atkinson PJ. Volume and surface area study of tobramycin-polymethylmethacrylate beads. Clin Orthop Relat Res. 2004;(420):298-303.
15. Dunne NJ, Hill J, McAfee P, Kirkpatrick R, Patrick S, Tunney M. Incorporation of large amounts of gentamicin sulphate into acrylic bone cement: effect on handling and mechanical properties, antibiotic release, and biofilm formation. Proc Inst Mech Eng H. 2008;222(3):355-365.
16. Springer BD, Lee GC, Osmon D, Haidukewych GJ, Hanssen AD, Jacofsky DJ. Systemic safety of high-dose antibiotic-loaded cement spacers after resection of an infected total knee arthroplasty. Clin Orthop Relat Res. 2004;427:47–51.
17. Wright BA, Roberts CS, Seligson D, Malkani AL, McCabe SJ. Cost of antibiotic beads is justified: a study of open fracture wounds and chronic osteomyelitis. J Long Term Eff Med Implants. 2007;17(3):181-5.
18. Franklin H, Rajan M, Tseng CL, Pogach L, Sinha A, Mph M. Cost of lower-limb amputation in U.S. veterans with diabetes using health services data in fiscal years 2004 and 2010. J Rehabil Res Dev. 2014;51(8):1325-30.
Counterpoint References
1. Kaye KS, Patel DA, Stephens JM, et al. Rising United States hospital admissions for acute bacterial skin and skin structure infections: recent trends and economic impact. PLoS One. 2015;10(11):e0143276.
2. Lee BY, Singh A, David MZ, et al. The economic burden of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA). Clin Microbiol Infect. 2013;19(6):528-536.
3. LaPensee K, Lodise T. Potential cost-savings with once-daily aminomethylcycline antibiotic versus vancomycin in hospitalized patients with acute bacterial skin and skin structure infections. Am Health Drug Benefits. 2018;11(9):449-459.
4. Zhang P, Lu J, Jing Y, et al. Global epidemiology of diabetic foot ulceration: a systematic review and meta-analysis. Ann Med. 2017;49(2):106–116.
5. Gemechu FW, Seemant F, Curley CA. Diabetic foot infections. Am Fam Physician. 2013;88(3):177-184.
6. Lipsky BA, Senneville É, Abbas ZG, et al. Guidelines on the diagnosis and treatment of foot infection in persons with diabetes (IWGDF 2019 update). Diabetes Metab Res Rev. 2020;36 Suppl 1:e3280.
7. Boulton AJM, Armstrong DG, Hardman MJ, et al. Diagnosis and management of diabetic foot infections. Arlington, VA: American Diabetes Association; 2020.
8. Draeger RW, Dahners LE. Traumatic wound debridement: a comparison of irrigation methods. J Orthop Trauma. 2006 Feb;20(2):83-88.
9. Cortés-Penfield NW, Kulkarni PA. The history of antibiotic treatment of osteomyelitis. Open Forum Infect Dis. 2019;6(5).
9. 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. Surg Infect. 2015;16(1):54–61.
10. Dekker A, Uzoho C, Scammell B. Do antibiotic-impregnated calcium sulfate beads improve the healing of neuropathic foot ulcers with osteomyelitis undergoing surgical debridement? Wounds. 2019;31(6):145–150.
11. Qin C-H, Zhou C-H, Song H-J, et al. Infected bone resection plus adjuvant antibiotic-impregnated calcium sulfate versus infected bone resection alone in treatment of diabetic forefoot osteomyelitis. BMC Musculoskel Disord. 2019;20:246.
12. Li HK, et al. Oral versus intravenous antibiotics for bone and joint infection. New Eng J Med. 2019;380(5):425-436.
