The basics of antibiotic bead therapy

December 2006

Locally applied antimicrobial agents have been attractive for prevention and treatment of orthopedic infections since antibacterials were first introduced in the 1930s. The ability to provide high drug concentrations at the site of infection offers several theoretical advantages compared with traditional, systemic treatment options. The ability to avoid prolonged courses of parenteral therapy and the associated risks for drug resistance and toxicity lead the list of proposed benefits.

The practice of incorporating antibiotic powders into bone cement was initiated in the 1970s as a prophylactic technique and has become standard of care at many institutions. This practice has spread to treatment of bone and joint infections either with or without concomitant systemic antibacterials in cases where bone cement is required for fusion procedures.

By the late 1970s, reports were emerging that indicated the use of antibiotic impregnated cement beads as a therapeutic modality. In these cases, bone cement was not required for the therapeutic procedure, but rather was used simply as a release vehicle for the antimicrobial agent. During the subsequent 30 years, the list of agents used in this manner has grown considerably. Data regarding the efficacy of these treatments are largely limited to case reports and animal data, however.

When discussing the use of antibiotic beads in managing orthopedic infections, one fact often surprises clinicians who practice outside of the operating room: there are no commercially available antibiotic beads in the United States. In addition, there are few bone cement preparations manufactured that contain antibiotic powders. Therefore, the overwhelming majority of antibiotic impregnated beads are compounded locally, in the operating room at the time of the surgical procedure.

Not surprisingly, the process for manufacturing beads, including the antibiotic concentrations used, is not standardized between institutions and may differ among clinicians in a given medical center. As the popularity of this practice increases, it is important for providers who assist in managing orthopedic infections to have a better understanding of issues involved in antibiotic bead placement including available vehicles, antibiotic considerations and future products currently under investigation, all of which may change how this therapy is delivered.

Materials for bead construction

Bone cement, the traditional material used to prepare antibiotic beads, is composed of a polymerized polymethacrylate (PMMA). This powder is mixed with liquid methylmethacrylate at the time of use. Within minutes, the mixture forms the cement that is used as an adhesive material. If antibiotic beads are needed, antibiotic powder is added to the PMMA powder prior to mixing with the liquid methylmethacrylate. Small beads in varying diameters are then hand-formed from the adhesive material as it begins to set.

There are currently three available PMMA bone cement products pre-mixed with antibiotic powder, all of which incorporate aminoglycoside antibiotics. They are marketed under the trade names Palacos G with gentamicin, Simplex P with tobramycin, and Depuy 1 Gentamicin. The kinetic profile of tobramycin delivered by these products when used for fixation has been described. Localized concentrations exceed the MIC for most common pathogens within hours of application. Serum concentrations can be detected but are low (< 1 mcg/mL), and the drug is eliminated from systemic circulation within three to four days of administration.

PMMA beads are not biodegradable and therefore, need to be removed after treatment is finished. There are two methods that may be used for bead removal. The first is to perform a second surgery to extract the majority of beads that were placed. In some instances, methylene blue is added to the cement mixture before hardening to facilitate bead recovery at the time of the second operation. An alternate approach is to form the beads along a surgical wire. This results in a string of beads similar in appearance to a pearl necklace. The end of the wire remains exposed at the completion of the surgical procedure, and the strand is slowly extracted from the wound over a period of weeks to months.

The other material currently used for bead construction is calcium sulfate. This product is available in the United States, and is sold under the trade name Osteoset in either pellet form or as a kit that includes mold forms to construct beads. The primary clinical application of these products is to serve as dead space fillers during a period of bone regeneration. The beads or pellets slowly resorb over six to 12 weeks at a rate that mimics bone growth. The primary advantage to using such a compound for antibiotic bead delivery is that no second procedure is required for product removal after implantation.

Antibiotic powder can be added to the materials in the mixing kit. The kit includes molds in two different sizes that are used to form beads. It takes approximately 20 to 30 minutes for the material to harden after mixing and filling the mold. Therefore, mixing these preparations prior to the surgical procedure would be desirable. Initial investigations into the stability of these products suggest that advanced preparation is possible; however, further investigation is needed before this practice should be routinely undertaken.

The company that produces Osteoset also has a tobramycin-impregnated product that is available in Canada and Europe and is pending approval by the FDA. The elution characteristics of tobramycin for this device have been well described. Local concentrations exceed MICs for common pathogens through 28 days following preparation. Detectable serum concentrations were observed through two weeks following device implantation.

Important considerations

Given the limited commercial availability of products to use for formulating antibiotic beads, it is likely that localized compounding will persist. It should only be performed, however, after careful consideration of several key factors affecting antibiotic activity, drug elution and integrity of the vehicle.

First, the process relies on the availability of pharmaceutical grade antibiotic powders. Many agents are only prepared as pre-mixed solutions and therefore cannot be used. Reagent grade powders, available from many chemical supply companies are not of the guaranteed quality needed for implantation.

Antibiotic stability is also a key factor. For antibiotics added to PMMA bone cement, the polymerization process that occurs after adding liquid methylmethacrylate is an exothermic reaction. Therefore, any antibiotic selected must be stable to the temperatures generated during this process.

Drug release can also vary between products. When compounded locally, it is difficult to ensure uniform distribution of the antibiotic powder throughout the adhesive agent. Surface area also can significantly affect elution characteristics. Together, these factors can result in a set of beads that vary greatly in terms of the rate and quantity of available drug. Previous investigators have studied the differences in drug release between commercially available and locally compounded antibiotic beads. Results are conflicting and it appears that in cases where bead size is carefully controlled, drug release can mimic that from commercially available antibiotic-impregnated beads available outside of the United States.

Finally, it is unknown what effect these antimicrobial agents may have on the integrity of the bone cement. When being used simply as a vehicle for drug delivery, there are concerns of potential infection risk. This is particularly true in cases where surgical wire is used to link the beads as a portion of the wire remains outside of the wound closure.

Toxicities

Antibiotic beads are an attractive therapy as they may minimize toxicities associated with systemic drug administration. However, the toxic antibiotics are still being administered with this technique and therefore, safety remains an important concern. Many reports suggest that systemic adverse effects from the various bead preparations are minimal if not nonexistent. In limited clinical trial data that are available, the incidence of adverse effects has certainly been lower than that observed with systemic antibacterial therapy. Case reports have emerged, however, of nephrotoxicity and ototoxicity occurring after implantation of aminoglycoside-containing antibiotic beads.

This is not surprising given the high concentration of drug that is often used in bead preparation. For example, up to 1 g of tobramycin is incorporated into a single unit of bone cement mixture. Drug elution occurs over prolonged periods following bead implantation. For many drugs, serum exposure appears negligible, however, it has not been studied for many agents and variability among patients does occur. Therefore, while the antibiotic beads remain in place, it is imperative that patients are observed for toxic drug effects. This is particularly true for agents that have not been commonly used as antibiotic bead preparations.

Future directions

Antibiotic impregnated beads are available in Europe for aminoglycosides as well as glycopeptide antibiotics. Investigations are underway to bring similar products to the United States. Hopefully, this will provide consistency in drug administration for the most commonly implanted products in the near future.

Other advances have focused on improving the drug delivery vehicles and have stemmed from advances in synthetic bone material technology. As experience with each of these products increases, it is likely that they will also be evaluated as antibiotic delivery devices. One example is the biodegradable product, polylactic acid (PLA) that is used for structural support following orthopedic surgeries. This may also be an attractive delivery device for antibiotics. Initial in vitro studies suggest that drug release from these polymers may be superior to that seen with PMMA. Similar to calcium acetate, these products do not require a second removal procedure, another advantage over the PMMA products.

Localized antibiotic therapy remains an attractive option for treating severe orthopedic infections. Whether used in lieu of or adjuvant to systemic therapy, it is important to have an understanding of what therapy a patient may have received as part of surgical interventions. Peri-operative antimicrobial administration in these cases is not limited to the brief period surrounding the procedure, but may now involve implantation of a drug delivery device that provides drug for weeks to months. Therefore, it is essential for clinicians managing these patients post-operatively to have some understanding of the process by which beads are prepared and used. This will facilitate appropriate discussions at the time of patient care transfer and allow adequate treatment for these serious infections.