Antibiotic beads are both a complementary and alternative treatment option to intravenous antibiotic therapy for the treatment of osteomyelitis.
Polymethylmethacrylate (PMMA) antibiotic beads were introduced clinically 30 years ago and have been the main local antibiotic delivery system in osteomyelitis therapy until recently.1,2 New local antibiotic delivery systems currently in development and testing offer several advantages over PMMA beads.
Polymethylmethacrylate Antibiotic Beads
Polymethylmethacrylate antibiotic beads serve two functions in the treatment of osteomyelitis. Following surgical debridement of osteomyelitis, antibiotic-impregnated PMMA beads are surgically placed in the infected bone cavity to both sterilize and maintain dead space in the bone.3,4 A seroma, which is a collection of serum, inflammatory mediators, and antibiotics, soon forms in the bone cavity following surgical closure. Effective sterilization and treatment requires the beads to maintain a therapeutic antibiotic drug concentration in the seroma for three to four weeks.
Clearly, the use of antibiotic PMMA beads alone in osteomyelitis therapy offers several advantages. Studies reported these beads produce negligible to no systemic antibiotic serum concentrations, thereby leading to decreased systemic toxicity and adverse effects.3,5,6 Antibiotic-impregnated PMMA beads also decrease hospitalization duration and overall treatment cost.5-7 By eliminating the need for intravenous (IV) access, they also may increase both patient comfort and early ambulation.6,8
The use of PMMA as a delivery vehicle for antibiotic beads has several limitations. Antibiotic PMMA beads are non-biodegradable and therefore must be removed.4,6,9 This requires a second surgery to remove large quantities of beads. An alternative for small quantities of beads is to leave the last bead on a string protruding out of the skin for removal on completion of treatment by withdrawing the string slowly over several days.
The pharmacokinetic profile of antibiotic release from PMMA beads is not ideal. In vitro pharmacokinetic and in vivo animal studies demonstrated a peak local antibiotic concentration on the first day followed by a drop-off that for many drugs is not sufficient to maintain a therapeutic concentration for the desired three to four weeks.3,4 A canine model examined seroma, tissue, and bone concentrations of cefazolin, ciprofloxacin, ticarcillin, tobramycin, and vancomycin with the use of antibiotic-impregnated PMMA beads.3 Clindamycin and tobramycin alone maintained seroma drug concentrations above the minimum inhibitory concentration at 21 days. Additionally, only clindamycin and vancomycin achieved bone concentrations above the minimum inhibitory concentration at 28 days. Antibiotic release from the PMMA beads is as low as 25% to 50%.10,11 Additionally, in vitro tobramycin release is greater than gentamicin release, illustrating that drug release also may vary within drug classes.8 The possibility of these subtherapeutic drug concentrations leading to antibiotic resistance is a concern.6
While commercial formulations of PMMA beads are available outside the United States, they currently are not available within the United States, leaving the hospital pharmacy or orthopedic surgeon to produce their own formulation (Table).12 Commercially-available PMMA cement and antibiotic powder may be combined to form a liquid-like substance and then placed into molds or hand-rolled by the surgeon in the operating room to form beads.12
Precise mixing directions or instructions on duration of mixing do not exist.8 As a result, many extemporaneously prepared batches lack thorough mixing. Hand-rolled beads often vary in size, producing differences in drug elution due to un-identical surface areas.8 Additionally, different brands of commercially-available PMMA cement vary in their drug release profiles.13 Debate exists in the literature about the quality of extemporaneously prepared beads compared to the commercially-available formulation. One in vitro study found no significant difference in commercial, mold-made, or hand-rolled antibiotic release profiles, while another found a more favorable profile for commercial beads compared to extemporaneously prepared beads.8,12
While the high local concentration of antibiotics produced by antibiotic PMMA beads is advantageous as it minimizes systemic toxicity, there may be unfavorable effects on bone healing and regeneration. An animal fracture model has shown adverse effects on healing with systemic use of ciprofloxacin, making the use of quinolones in local antibiotic delivery systems producing high local concentrations concerning.14 In vitro studies examining the effect of high concentrations of gentamicin, tobramycin, cefazolin, and vancomycin on osteoblasts showed decreased replication and even cell death for extremely high concentrations.15-17 Vancomycin appears to be less toxic than aminoglycosides or cefazolin.18
Polymethylmethacrylate Antibiotic Beads: Clinical Data
Clinical trials with large numbers of patients and strong study design are lacking, despite the introduction of antibiotic beads >30 years ago. The study with the strongest design randomized patients with osteomyelitis to six weeks of IV antibiotic treatment (conventional treatment) or gentamicin PMMA bead treatment plus five days of IV antibiotics for surgical prophylaxis (bead treatment).5 Unfortunately, many patients violated protocol and received extended duration IV antibiotics in addition to the bead treatment. At the conclusion of the trial, 186 patients had received conventional treatment, 145 patients combined treatment, and 49 patients bead treatment. After 52 weeks, osteomyelitis recurred in 44, 62, and 14 patients in the conventional, combined, and bead treatment groups, respectively. The only conclusion that could be reached is that neither conventional or gentamicin PMMA bead treatment was superior. Adverse experiences were not defined and occurred in the conventional, combined, and bead group at a rate of 54%, 46%, and 30%, respectively.
Additional clinical investigations are deficient in sample size or study design. A small trial randomized patients with chronic osteomyelitis to IV antibiotics for four weeks (n=24) or gentamicin PMMA beads and perioperative IV antibiotics for two to five days (n=28) following debridement.19 Infection arrest and nonunions healed were similar between the IV antibiotic group and gentamicin PMMA bead group with 83.3% versus 89.3% and 83.3% versus 85%, respectively. The study did not evaluate adverse events.
A case series of 405 patients with chronic osteomyelitis treated with debridement, gentamicin PMMA bead placement, and one to two days of perioperative IV antibiotics reported a similar cure rate of 90.4%.9 This case series did not report duration of bead therapy or side effects. Another study reported no recurrence of infection or complications in a small subset of patients (n=12) with chronic osteomyelitis treated with gentamicin PMMA beads for an unreported duration.6 Lastly, a small study randomly assigned patients with subacute osteomyelitis to appropriate parenteral antibiotic therapy for two weeks followed by oral antibiotics for four weeks (n=10), or to commercial gentamicin PMMA bead implantation for two months with up to three days of parenteral perioperative antibiotics (n=13).7 Infection was controlled in 100% of patients in both groups. No patients receiving gentamicin PMMA beads experienced complications.
Strong clinical data supporting the use of antibiotic PMMA beads for the treatment of osteomyelitis are lacking. The aforementioned trials all used the commercially-available preparation of the gentamicin PMMA bead, Septopal (Biomet Europe B.V., Dordrecht, Netherlands), which is not available in the United States. This limits the ability to generalize the data as noncommercial antibiotic beads must be used in the United States and debate exists in the literature regarding their equivalence to Septopal. Additionally, safety is a concern due to the lack of adverse effects examined and reported in the studies.5-7,9,19
Biodegradable Local Drug Delivery Systems
New biodegradable drug delivery systems in development and testing offer hope in improving treatment for osteomyelitis. These new systems do not necessitate removal and should therefore eliminate the need for a second surgery.4 They will still serve to maintain the dead space in the bone and some may help facilitate new bone formation.20,21
Polylactic acid (PLA) has been used for structural support following orthopedic procedures for years and has recently been studied as a delivery system for antibiotics.1 Previous use in humans for this purpose has produced rare adverse effects including non-infected draining sinuses and non-infected local inflammatory responses. The clinical significance of these adverse effects currently is unclear.
In vitro studies of PLA and poly(DL-lactide)-coglycolide (PLA/PGA) in combinations of 90:10, 80:20, and 70:30 showed a sustained antibiotic release superior when compared to PMMA beads.4 The PLA/PGA 90:10 combination showed the best release for clindamycin and tobramycin with concentrations that remained above the minimum inhibitory concentration for 48 days and 65 days, respectively. Vancomycin concentrations from PMMA beads dropped below the minimum inhibitory concentration at 12 days compared to vancomycin PLA beads, which maintained a therapeutic concentration for 68 days. The beads dissolved in 37 to 180 days depending on the antibiotic and PLA/PGA combination used.
Studies of various combinations of this vehicle in animal models have produced some promising results. A rabbit model of Staphylococcus aureus osteomyelitis compared vancomycin beads (95% 70:30 PLA/PGA and 5% 2000 d PLA) alone, vancomycin beads and parenteral vancomycin, and systemic vancomycin alone.22 After 28 days of treatment, colony forming units of S aureus were significantly lower in rabbits receiving vancomycin beads with systemic vancomycin (102.93) and vancomycin beads without systemic vancomycin (102.84), compared to systemic vancomycin alone (104.57). This study did not examine radiographic grading, serum vancomycin levels, or histologic scores.
Another trial using the rabbit S aureus osteomyelitis model randomized animals to five treatment groups following surgical debridement: control, tobramycin microspheres (50:50 PLA/PGA), tobramycin microspheres and parenteral cefazolin, tobramycin PMMA beads plus parenteral cefazolin, and parenteral cefazolin alone.23 After four weeks of treatment, only the tobramycin microspheres plus parenteral cefazolin group had significantly fewer rabbits positive for S aureus compared to control (25% versus 75%, P<.01). additionally,="" after="" four="" weeks="" of="" treatment,="" all="" but="" two="" tobramycin="" microspheres="" were="" maintaining="" a="" concentration="" above="" the="" minimum="" inhibitory="" concentration="" compared="" to="" none="" of="" the="" tobramycin="" pmma="" beads="">P=.03). Radiographic grading also was significantly worse for the PMMA beads compared to the control group, illustrating how the PMMA beads form a barrier to new bone formation, whereas the PLA/PGA microspheres allow new bone formation as they degrade. Serum and urine tobramycin levels remained undetectable and histologic scores indicated no difference in inflammation among the five groups. Large comparative clinical trials in humans are now required.
Calcium sulfate is a promising vehicle that is biodegradable, obliterates dead space, and may aid in new bone formation.20,21,24 Animal model studies have assessed efficacy and safety, and early preliminary studies have been conducted in humans.
An early study using a rabbit model of osteomyelitis evaluated clinical efficacy. Following debridement, rabbits (n=52) were randomized to one of four groups: 10% tobramycin calcium sulfate pellets, placebo calcium sulfate pellets and parenteral tobramycin, placebo calcium sulfate pellets, and control.24 Infection eradication with tobramycin calcium sulfate pellets (86%) was significantly higher than control (41.7%, P=.04), placebo calcium sulfate pellets plus parenteral tobramycin (35.7%, P=.028), and placebo calcium sulfate pellets (23.1%, P=.006). Animals receiving calcium sulfate pellets showed no increase in serum calcium levels and experienced a greater increase in bone formation in the defect over the control group. Local and systemic tobramycin concentrations were not assessed.
A recent study examined the safety of 10% tobramycin calcium sulfate pellets in a canine model at doses equivalent to the maximum prescribed human dose (20 mg/kg) and greater than the maximum human dose (36 mg/kg).25 Local antibiotic concentrations remained therapeutic for 14 days but were subtherapeutic at the next measured time point of 28 days. Systemic tobramycin concentrations peaked one hour after implantation at concentrations of 30.3 mcg/mL and 46.7 mcg/mL and were undetectable at 24 hours. There was no increase in serum calcium, and examination of the lungs, kidneys, liver, and bone marrow revealed no adverse effects secondary to the tobramycin or the calcium sulfate.
Currently, the literature contains two small studies examining the use of antibiotic-impregnated calcium sulfate pellets for the treatment of osteomyelitis in humans. Commercially-available calcium sulfate pellets containing tobramycin (OsteoSet T; Wright Medical Technology Inc, Arlington, Tenn) were used to treat 25 patients with chronic osteomyelitis following surgical debridement.20 Perioperative IV antibiotics were allowed for 3 to 7 days.20 The infection was eradicated in 92% of patients and the average pellet reabsorption time was 2.7 months with a range of 1 to 6 months. One patient experienced a superficial wound necrosis and eight developed a sterile draining sinus. Another study reported the use of tobramycin and/or vancomycin impregnated calcium sulfate pellets in patients (n=6) with chronic osteomyelitis following surgical debridement, in addition to parenteral antibiotics.21 After a mean follow-up of 28 months, there were no infection relapses and the bone showed progressive bone repair (91%). No patients experienced adverse events.
The Bottom Line
- Antibiotic-impregnated PMMA beads have been available for >30 years; however, there is limited clinical data supporting their use, and they require a second operation for removal.
- Antibiotic PLA microspheres and calcium sulfate pellets are new biodegradable drug delivery systems currently being researched.
- Antibiotic PLA microspheres have yet to be studied in humans, but in vitro and in vivo animal data suggest they have superior drug release profiles compared to PMMA beads. Antibiotic calcium sulfate pellets have preliminarily been studied in humans and may aid in repairing bone.
- Strong clinical data and antibiotic containing commercial forms of these local drug delivery systems need to become available in the United States to propel them into common use.
- Garvin K, Feschuk C. Polylactide-polyglycolide antibiotic implants. Clin Orthop. 2005; 437:105-110.
- Kanellakopoulou K, Giamarellos-Bourboulis EJ. Carrier systems for the local delivery of antibiotics in bone infections. Drugs. 2000; 59:1223-1232.
- Adams K, Couch L, Cierny G, Calhoun J, Mader JT. In vitro and in vivo evaluation of antibiotic diffusion from antibiotic-impregnated polymethylmethacrylate beads. Clin Orthop. 1992; 278:244-252.
- Mader JT, Calhoun J, Cobos J. In vitro evaluation of antibiotic diffusion from antibiotic-impregnated biodegradable beads and polymethylmethacrylate beads. Antimicrob Agents Chemother. 1997; 41:415-418.
- Blaha JD, Calhoun JH, Nelson CL, et al. Comparison of the clinical efficacy and tolerance of gentamicin PMMA beads on surgical wire versus combined and systemic therapy for osteomyelitis. Clin Orthop. 1993; 295:8-12.
- Patzakis MJ, Mazur K, Wilkins J, Sherman R, Holtom P. Septopal beads and autogenous bone grafting for bone defects in patients with chronic osteomyelitis. Clin Orthop. 1993; 295:112-118.
- Shih HN, Shih LY, Wong YC. Diagnosis and treatment of subacute osteomyelitis. J Trauma. 2005; 58:83-87.
- Nelson CL, Griffin FM, Harrison BH, Cooper RE. In vitro elution characteristics of commercially and noncommercially prepared antibiotic PMMA beads. Clin Orthop. 1992; 284:303-309.
- Klemm K. The use of antibiotic-containing bead chains in the treatment of chronic bone infections. Clin Microbiol Infect. 2001; 7:28-31.
- Rushton N. Applications of local antibiotic therapy. Eur J Surg Suppl. 1997; 578:27-30.
- Wilson KJ, Cierny G, Adams KR, Mader JT. Comparative evaluation of the diffusion of tobramycin and cefotaxime out of antibiotic-impregnated polymethylmethacrylate beads. J Orthop Res. 1988; 6:279-286.
- Seligson D, Popham GJ, Voos K, Henry SL, Faghri M. Antibiotic-leaching from polymethylmethacrylate beads. J Bone Joint Surg Am. 1993; 75:714-720.
- Kuechle DK, Landon GC, Musher DM, Noble PC. Elution of vancomycin, daptomycin, and amikacin from acrylic bone cement. Clin Orthop. 1991; 264:302-308.
- Huddleston PM, Steckelberg JM, Hanssen AD, Rouse MS, Bolander ME, Patel R. Ciprofloxacin inhibition of experimental fracture healing. J Bone Joint Surg Am. 2000; 82:161-173.
- Edin ML, Miclau T, Lester GE, Lindsey RW, Dahners LE. Effect of cefazolin and vancomycin on osteoblasts in vitro. Clin Orthop. 1996; 333:245-251.
- Isefuku S, Joyner CJ, Simpson AH. Gentamicin may have an adverse effect on osteogenesis. J Orthop Trauma. 2003; 17:212-216.
- Miclau T, Edin ML, Lester GE, Lindsey RW, Dahners LE. Bone toxicity of locally applied aminoglycosides. J Orthop Trauma. 1995; 9:401-406.
- Hanssen AD. Local antibiotic delivery vehicles in the treatment of musculoskeletal infection. Clin Orthop. 2005; 437:91-96.
- Calhoun JH, Henry SL, Anger DM, Cobos JA, Mader JT. The treatment of infected nonunions with gentamicin-polymethylmethacrylate antibiotic beads. Clin Orthop. 1993; 295:23-27.
- McKee MD, Wild LM, Schemitsch EH, Waddell JP. The use of an antibiotic-impregnated, osteoconductive, bioabsorbable bone substitute in the treatment of infected long bone defects: early results of a prospective trial. J Orthop Trauma. 2002; 16:622-627.
- Gitelis S, Brebach GT. The treatment of chronic osteomyelitis with a biodegradable antibiotic-impregnated implant. J Orthop Surg (Hong Kong). 2002; 10:53-60.
- Calhoun JH, Mader JT. Treatment of osteomyelitis with a biodegradable antibiotic implant. Clin Orthop. 1997; 341:206-214.
- Ambrose CG, Clyburn TA, Louden K, et al. Effective treatment of osteomyelitis with biodegradable microspheres in a rabbit model. Clin Orthop. 2004; 421:293-299.
- Nelson CL, McLaren SG, Skinner RA, Smeltzer MS, Thomas JR, Olsen KM. The treatment of experimental osteomyelitis by surgical debridement and the implantation of calcium sulfate tobramycin pellets. J Orthop Res. 2002; 20:643-647.
- Turner TM, Urban RM, Hall DJ, Chye PC, Segreti J, Gitelis S. Local and systemic levels of tobramycin delivered from calcium sulfate bone graft substitute pellets. Clin Orthop. 2005; 437:97-104.
Dr Kent is from Chandler Medical Center, and Drs Rapp and Smith are from the College of Pharmacy, University of Kentucky, Lexington, Ky.
Reprint requests: Kelly M. Smith, PharmD, 800 Rose St, Rm C-117, Lexington, KY 40536-0293.