*This article also appears in volume 16, issue 10 of podiatrytoday.com
Dr. Yung reviews the use of absorbable antibiotics in the treatment of bone infections.
Can Antibiotic Beads have an impact on osteomyelitis
Surgical debridement of infected bone is an unfortunate reality for those of us who frequently treat patients with diabetes. While adequate debridement is the most important step in treating osteomyelitis, many authors have commented on the adjunctive role of antibiotics in this clinical dilemma.1-3 Systemic antibiotics are routinely used preoperatively and have been advocated for six weeks or more. However, infected bone may become devascularized, making the delivery of systemic antibiotics less than desirable. Delivering systemic antibiotics may also be compromised when there is associated peripheral arterial disease in that extremity. The local insertion of antibiotic-impregnated materials has been commonly used to supplement surgical debridement of infected tissue and systemic antibiotics. Locally implanted antibiotics may provide reliably high concentrations of antibiotic to areas of infection while minimizing the potential systemic side effect from the use of high dose IV, IM or PO antibiotics.4Systemic levels of locally implanted antibiotics are rarely detectable (less than 1 percent) and there have been no reports of associated nephrotoxicity. The traditional vehicle of choice for locally introduced antibiotics has been polymethylmethacrylate (PMMA). One would combine PMMA with a heat stable antibiotic such as vancomycin or gentamycin and form it into beads. Then you would place the beads within the wound or bony cavity, forming a closed compartment either through primary closure or by using an occlusive film dressing to create a “bead pouch” for maintaining high levels of eluted antibiotic. Unfortunately, PMMA has several disadvantages including in vitro reports of local immune compromise and poor elution properties (less than 50 percent elution of antibiotic at four weeks).5-7 In addition, PMMA is not bioabsorbable so it must be surgically removed or left within the wound permanently. If one leaves the beads in, they may harbor bacteria in the future. However, if you remove them, overgrowth of granulation tissue and adherence to bone may make removal difficult and require a second surgical procedure. A Closer Look At Calcium Sulfate Beads For these reasons, biodegradable delivery systems for local antibiotic treatment are an attractive alternative to PMMA beads. At the University of Texas, we have begun using calcium sulfate beads impregnated with antibiotics to follow debridement and amputation procedures with primary closure in the diabetic foot wounds. We use the absorbable beads as an adjunct to surgical debridement and systemic antibiotics when we are treating patients who are recovering from osteomyelitis and extensive soft tissue infections. Calcium sulfate has been used as a bone graft substitute since the late 1800s. In 1997, medical grade calcium sulfate impregnated with tobramycin was introduced overseas. There have been positive reports of its use in combination treatment for osteomyelitis/surgical defects. Its favorable osteoconductive and elution properties have led to its use as an antibiotic delivery method for treating osteomyelitis and local soft tissue infection. Calcium sulfate is biodegradable and radiopaque with a predictable linear in vivo absorption and antibiotic elution rate.8-12 At one month, 33 percent of the calcium sulfate is absorbed and 91 percent and 100 percent are reabsorbed at three and six months respectively. Local elution of antibiotic is predictably linear over time with resulting high local concentrations.11 Systemic levels of tobramycin were undetectable following the first 24 hours. How To Create The Antibiotic Mixture Calcium sulfate is a commercially available product (OsteoSet, Wright Medical) but it is not FDA-approved to be sold with an impregnated antibiotic. Therefore, it is necessary to add the antibiotic of your choice to the calcium sulfate. One would mix the calcium sulfate, curing solution and antibiotic (vancomycin 500 mg or tobramycin/gentamicin 1 g) together and pour them into the pellet template that comes with the kit. Allow the pellets of 3 or 4 mm to harden in an exothermic reaction. After two minutes, they are ready to be implanted into the wound. Proceed to perform primary closure of the wound. Doing so facilitates a higher concentration of eluted antibiotic. You can see the antibiotic pellets on X-ray for up to three months
We have found sterile serous drainage from the wound in a number of our wounds postoperatively. This represents the breakdown product of the calcium sulfate beads. Be advised that placing too many calcium sulfate beads may result in significant exudate production, which may delay primary wound closure. Kelly, et. al., in a large study of the use of calcium sulfate as a bone graft substitute, reported that 4 percent of cases may have postoperative drainage with complete resolution after four to six weeks.8 One should be careful to differentiate this drainage from continued infection or fibrous tissue. It’s important to achieve a balance between the need for a large number of beads for the desired antibiotic effect versus having too many and the resulting complication of serous drainage. We normally use five of the 4 mm pellets in a single ray resection and 15 to 20 in a mid-foot amputation without a delay in wound healing from serous drainage. What The Literature Reveals As with most treatment options regarding osteomyelitis, there are few reports regarding the efficacy of calcium sulfate antibiotic beads in a clinical setting. Similar to PMMA, its use is considered off-label and without FDA approval. Using calcium sulfate beads as an antibiotic delivery system packed within bony defects has been reported in the literature with good success. No studies to date have reported on using the modality in the soft tissues as adjunctive therapy to amputation surgery or for soft tissue infections. Its proximity to bony stumps may be of concern for increased incidence of bony regrowth. However, we have not experienced any bony regrowth when we have used these beads adjacent to amputation sites including digit, ray and midfoot amputations. Other reports have emerged fairly recently in the literature. Reporting on an animal model study, Nelson, et. al., noted an 84.6 percent cure with calcium sulfate antibiotic beads alone compared with 41.7 percent with debridement alone and 35 percent with systemic antibiotics.13 McKee, et. al., reported on 25 patients with culture-confirmed long bone osteomyelitis. All patients were treated with local debridement, systemic oral antibiotics and absorbable calcium sulfate beads impregnated with tobramycin. In 92 percent of cases, the researchers found no clinical and radiographic signs of infection at a mean 28-month follow-up. In eight cases, they noted sterile draining sinus postoperatively.14 Turner, et. al., reported on a single patient they treated for intramedullary osteomyelitis with calcium sulfate tobramycin beads. They achieved resolution of infection with filling of dead space cavity at 31 months.12 Final Notes Calcium sulfate is biodegradable, an important consideration in that it eliminates the need for removal and associated costs. We have found this surgical adjunct to be of value when performing a delayed closure of a problem wound site. Complete resorption of the beads occurs at six months or sooner and you can follow this clinically with serial radiographs. It also has the advantage of a more reliable elution profile of antibiotic than traditional PMMA as more antibiotic is delivered in the postoperative period. The antibiotic is completely released over a two- to three-month period with high concentrations detectable for at least four weeks. Calcium sulfate beads seem to be a viable bioabsorbable alternative to PMMA antibiotic beads in the adjunctive treatment of musculoskeletal infections, and warrant further study. Dr. Yung is a Chief Resident and Dr. Steinberg (shown at right) is an Assistant Professor within the Department of Orthopaedics, Podiatry Division at the University of Texas Health Science Center in San Antonio, Texas. Editor’s Note: For a related article, see “Can The Osteoset Lead To Better, Cost-Effective Healing?,” on page 70 of the December 2002 issue or check out the archives at www.podiatrytoday.com.