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Local Antibiotic Therapy in the Treatment of Open Fractures and Osteomyelitis

Zalavras, Charalampos, G; Patzakis, Michael, J; Holtom, Paul

Clinical Orthopaedics and Related Research: October 2004 - Volume 427 - Issue - p 86-93
doi: 10.1097/01.blo.0000143571.18892.8d
SECTION 1: SYMPOSIUM: Papers Presented at the 2003 Meeting of the Musculoskeletal Infection Society: Depot Antibiotics
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Local antibiotic therapy is part of the treatment protocol of open fractures and osteomyelitis. However, there are limitations in the literature evaluating the efficacy of the technique and controversies remain. Polymethylmethacrylate cement commonly is used as a delivery vehicle, but bioabsorbable vehicles are being investigated. The vehicle is impregnated with antibiotic(s) active against the suspected pathogens, usually an aminoglycoside and/or vancomycin. Elution depends on the surface area, the characteristics and permeability of the delivery vehicle, type and concentration of the antibiotic(s) used, presence of fluid, rate of fluid turnover, and time postimplantation. Local antibiotic therapy is a safe technique resulting in high local concentration of antibiotics with minimal systemic levels. Local antibiotics effectively have controlled infection in animal models and, despite limitations of the existing literature, seem to be useful in the clinical setting. The length of implantation and the need for removal of the delivery vehicle remain controversial. Nonabsorbable vehicles may eliminate the need for reoperation and removal.

From the Department of Orthopaedic Surgery, University of Southern California Keck School of Medicine, LAC + USC Medical Center, Los Angeles, CA.

DOI: 10.1097/01.blo.0000143571.18892.8d

Each author certifies that he or she has no commercial associations (eg consultancies, stock ownership, equity interest, patent/licensing arrangements, etc) that might pose a conflict of interest in connection with the submitted article.

Correspondence to: Michael J. Patzakis, MD, Professor and Chairman, Department of Orthopaedic Surgery, University of Southern California Keck School of Medicine, 2025 Zonal Avenue, GNH 3900, Los Angeles, CA 90089-9312. Phone: 323 226 7201; Fax: 323 226 2221; E-mail: edkwong@hsc.usc.edu.

Prevention of infection in open fractures and eradication of infection in nonunions and chronic osteomyelitis is a critical part of the treatment protocol, which consists of infection control, soft tissue coverage, and bony union. Infection control is based on surgical debridement and microbial-specific antibiotic administration.

Local antibiotic delivery as a means of increasing the local concentration of antibiotics while simultaneously minimizing their systemic toxicity was based on the pioneering work of Buchholz and Engelbrecht.6 These investigators reported that antibiotics can be incorporated into polymethylmethacrylate (PMMA) cement, elute into the surrounding tissues, achieve high local concentrations, and reduce early postoperative infections in arthroplasty surgery. In addition, local antibiotic therapy in the form of antibiotic-impregnated PMMA beads was introduced in the treatment of osteomyelitis20 and open fractures.15

Subsequent studies evaluated the elution properties of locally deposited antibiotics, their pharmacokinetic properties, and their role in infection. Local antibiotic delivery seems to be a safe and useful method in the setting of open fractures and osteomyelitis with a favorable experience reported in the literature. However, limited level I evidence (randomized control trial of good quality) is currently available to support their use.

The purpose of the current review is to discuss and summarize the existing knowledge on the methods, safety, and efficacy of local antibiotic therapy, present the authors’ preferred techniques, and highlight the existing controversies regarding their use.

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COMPOSITION AND PROPERTIES OF LOCAL ANTIBIOTIC DELIVERY SYSTEMS

Composition

The two key elements of a local antibiotic delivery system are the delivery vehicle and the antimicrobial agents.

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Delivery Vehicle

The most commonly used delivery vehicle is PMMA cement. Polymethylmethacrylate cement is produced by mixing two components: (1) a packet of powder containing PMMA particles, radiopaque barium sulfate, and a polymerization initiator; and (2) a vial of liquid containing methylmethacrylate monomer and an activator. The polymerization reaction is exothermic. The PMMA cement can be molded to bead-resembling spheres (diameter usually ranging from 5–10 mm) or to spacer blocks of larger size.

Bioabsorbable delivery vehicles also have been used, including plaster of Paris, calcium sulfate, synthetic polymers (lactic acid oligomer, polyglycolic acid, polylactide–polyglycolide copolymers), and fibrin clots.18,22,23,41

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Antimicrobial Agents

Many antimicrobial agents have been successfully incorporated into PMMA cement for local delivery, including aminoglycosides, vancomycin, and cephalosporins. The following factors determine whether an antibiotic is appropriate for local delivery. First, the antibiotic must be available in powder form because antibiotics in aqueous solution show limited incorporation into the cement; second, the agent must be heat stable enough to withstand the temperatures generated during the exothermic polymerization reaction; finally, the antibiotic should be active against the targeted microbial pathogens.

If preoperative cultures and sensitivity tests are present, they will determine the selection of appropriate antibiotics. Otherwise, the locally delivered antibiotic should target the most common pathogens, which in chronic osteomyelitis are Staphylococcus aureus in 65 to 70% of patients, and Pseudomonas aeruginosa in 20 to 37% of patients.32,33 Aminoglycosides and vancomycin are common choices because of their broad spectrum of activity, heat stability, and low allergenicity. Although gentamicin has been widely used in Europe, it was not available until recently in powder form in the United States and can be substituted by tobramycin.

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Elution, Pharmacokinetic Properties, and Tissue Penetration

Elution is the process of release of antibiotic from the delivery vehicle to the surrounding tissues. The antibiotic may be released from the cement surface, through pores, and through a network of voids (containing the antibiotic and radiopaque marker) and interconnecting cracks in the matrix of the cement.2 Passive diffusion through the cement matrix may also take place.3 Elution is governed by the difference in the concentration of antibiotics between the antibiotic delivery system and its environment and depends on several factors associated with the delivery vehicle, the antibiotic, the environment, and the time postimplantation (Table 1).

Table 1

Table 1

The surface area and composition of the antibiotic delivery vehicle affect elution. An increased surface–area-to-volume ratio facilitates elution of antibiotics from both beads and spacers.17,39 Plaster of Paris pellets have shown increased elution compared with PMMA pellets.5 Moreover, elution differences may exist even among different brands of PMMA cement12,25 A high concentration of antibiotic in the beads or spacer promotes elution.2,5 The type of antibiotic also is important, with tobramycin having superior elution to vancomycin.12 The presence of a fluid medium is necessary for elution of antibiotics, and the rate of fluid turnover influences the elution and the local antibiotic concentration.16

Elution of antibiotics from PMMA beads follows a biphasic pattern, with an initial rapid phase and a secondary slow phase.36 Elution is at its maximum during the first day, greatly declines on the second day, and then gradually decreases over time and seems to stabilize between Days 5 and 10.25 Beads implanted in patients for fewer than 10 weeks elute considerably higher antibiotic levels than do beads implanted for more than 14 weeks.26 Interestingly, elution has been reported even 5 years after bead implantation.37

Animal1,27,38 and clinical studies9,34,38,40 consistently have shown high local concentrations and nondetectable or very low serum levels of the locally delivered antibiotics, with no systemic antibiotic toxicity. Elution and pharmacokinetic data are summarized in Table 2.

Table 2

Table 2

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Preparation of Delivery Systems

Gentamicin-impregnated PMMA cement in the form of beads is commercially available in Europe (Septopal, Biomet-Merck, Bridgend, UK). However, no similar antibiotic-impregnated product is available in the United States. Therefore, the delivery system has to be physician made and prepared in the operating room immediately before use. Antimicrobial agents that can be used for antibiotic bead preparation (with the suggested dose in grams of powder per 40 g of PMMA cement) are as follows: tobramycin (3.6 g), vancomycin (4 g), cefepime (4 g), cefazolin (6 g), nafcillin (6 g), and imipenem (4 g).

The antibiotic powder is added to the cement powder and mixed together to ensure uniform distribution of the antibiotic within the cement. Then the powder preparation is mixed with the liquid monomer and the mixture is used to make beads either by hand or by using a mold. The physician should avoid creating beads of inconsistent shape and large diameter and should aim to replicate the uniformly spherical shape and standardized size (7 mm) of the Septopal beads, which increases the surface area and promotes elution. The beads subsequently are strung onto a 22-gauge to 24-gauge wire before the cement hardens.

A comparison of commercially manufactured and physician-made beads showed superior elution of antibiotic with the commercial beads, which was attributed to the different composition and heat treatment of the cement in commercially manufactured beads.25 However, a subsequent study found no difference among manufactured, hand-made, and mold-made beads.35

Open wound treatment is incompatible with the implantation of antibiotic-impregnated beads.21 If wound closure is not possible, the wound containing antibiotic beads is sealed with OpSite (Smith and Nephew, Largo, FL), Tegaderm (3M, Saint Paul, MN), or their equivalent so that the eluted antibiotic(s) remains at the involved area to achieve a high local concentration. For the same reason, drains should not be used to ensure the presence of fluid and minimize the rate of fluid turnover.

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Authors’ Preferences

Our experience with use of local antibiotic therapy in the setting of open fractures, infected nonunions, and osteomyelitis has been positive. We use antibiotic-impregnated beads whenever dead space is present and reoperation is needed (second-look debridement, soft tissue coverage, bone grafting). Specifically, if a bone and soft tissue defect is present after debridement, as in severe open fractures and osteomyelitis, we place the beads in the gap area (Fig 1). We do not insert beads in the medullary canal of long bones unless a reoperation is planned within a week because their removal becomes increasingly difficult and may be incomplete. If no bone defect exists in open fractures but wound closure can not be accomplished without leaving bone exposed, we place beads on top of the exposed bone (Fig 2).

Fig 1.

Fig 1.

Fig 2.

Fig 2.

We use Palacos (Biomet, Inc, Warsaw, IN) PMMA cement and select the antibiotic(s) depending on the clinical setting. In chronic osteomyelitis, depending on culture results, we may use both tobramycin (3.6 g per 40 g of PMMA) and vancomycin (4 g per 40 g of PMMA). In open fractures, we use tobramycin only; we do not add vancomycin in order to minimize problems with vancomycin-resistant organisms. No systemic aminoglycoside is administered when tobramycin beads are used. Our preference is to use beads instead of spacers. The spherical shape of the beads increases the surface area, which promotes the release of antibiotics, and the available space between individual beads facilitates drainage of secretions.

The duration of implantation depends on the timing of the subsequent planned procedure. In our experience, antibiotic beads are implanted for a period of up to 1 week when a soft tissue procedure is planned. If soft tissue coverage is not needed but a bone defect is present, then we keep the beads until the subsequent bone grafting, usually at 6 weeks. We do not monitor our patients with implanted antibiotic beads, because of the well-documented extremely low serum levels and systemic toxicity.

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Local Antibiotic Therapy for Prevention of Infection

Animal Experiments

Animal studies have supported the beneficial role of local antibiotic delivery in prevention of infection after bone contamination with pathogens.8,11 Fitzgerald,11 in a canine model of subacute osteomyelitis, showed that gentamicin-impregnated cement prevented development of osteomyelitis in nine of 10 tibias (90%) contaminated with Staphylococcus aureus, whereas sepsis developed in all contralateral tibias that were implanted with plain cement.

Chen et al8 evaluated in a rabbit model the effect of local antibiotic delivery in well-perfused wounds containing contaminated bone in the presence of concomitant systemic antibiotic therapy. Tobramycin-impregnated beads considerably reduced the bacterial count of Staphylococcus aureus (2 × 102 compared with 1.3 × 106 in the absence of beads), showing an independent additive effect.

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Clinical Studies

Several retrospective studies14,15,19,28,29 evaluating local antibiotic therapy in the treatment of open fractures have reported favorable results regarding prevention of infectious complications when the antibiotic bead pouch technique was used in addition to systemic antibiotics. In a large series of 1085 open fractures, Ostermann et al29 compared the bead pouch technique (combined with systemic antibiotics) with systemic antibiotics alone. In the antibiotic bead pouch group, the infection rate was 3.7% (31 of 845 fractures), which was considerably lower compared with the 12% (29 of 240 fractures) infection rate in fractures treated with systemic antibiotics alone.

Moehring et al,24 in a randomized controlled trial, compared antibiotic beads as the only method of antibiotic therapy (after a single systemic dose in the emergency room) with systemic antibiotics in open fractures and observed an infection rate of 8.3% (2 of 24 fractures) versus 5.3% (2 of 38 fractures), respectively.

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Local Antibiotic Therapy in the Treatment of Osteomyelitis

Animal Experiments

In a canine osteomyelitis model,38 implantation of gentamicin-impregnated beads resulted in clinical and bacteriologic cure of osteomyelitis, compared with persistence of the disease in the control group.

Evans and Nelson10 used a rabbit osteomyelitis model to compare the efficacy of treatment with intravenous ceftriaxone, gentamicin-impregnated PMMA beads, and a combination of systemic antibiotics plus beads. All three groups had debridement. Two control groups had debridement without antibiotic therapy and in one of these groups PMMA beads not impregnated with antibiotic were implanted. The infection control rate for gentamicin-impregnated beads, intravenous ceftriaxone, and the combined antibiotic treatment was 79% (22 of 28 rabbits), 92% (11 of 12 rabbits), and 100% (9 of 9 rabbits), respectively.10 In contrast, debridement alone had a success rate of only 43% (six of 14 rabbits), which dropped to 27% (three of 11 rabbits) when nonantibiotic-containing PMMA was implanted.

Nelson et al.27 reported that after debridement, osteomyelitis in the rabbit radius was eradicated in 93% of animals treated with bioabsorbable beads impregnated with 20% gentamicin, in 67% of those treated with 10% gentamicin beads, in 25% of those treated with placebo beads and systemic gentamicin, in 7% of those treated with placebo beads alone, and in 12.5% of those treated with debridement only.

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Clinical Studies

A multicenter randomized controlled study4 attempted to compare systemic antibiotic therapy to local therapy with Septopal beads (supplemented with as much as 5 days of systemic antibiotics) in the treatment of osteomyelitis. The authors reported reduced cost and fewer adverse experiences in the Septopal group, with no difference in the recurrence rate compared with the systemic antibiotic group.

A randomized controlled trial by Calhoun et al7 compared 4 weeks of intravenous antibiotics with Septopal beads in 52 patients with infected nonunions having debridement and reconstructive surgery. Patients in the antibiotic bead group also received perioperative (2 to 5 days) systemic antibiotic therapy. The success rate for treating the infection was 83% (20 of 24 patients) in the systemic antibiotic group and 89% (25 of 28 patients) in the antibiotic bead group, suggesting that long-term systemic antibiotic therapy can be substituted by local antibiotic therapy in infected nonunions.

Patzakis et al31 compared Septopal beads (supplemented with as much as 5 days of systemic antibiotics) to systemic antibiotic therapy in 33 patients with chronic osteomyelitis and bone defects. The infection control rate was 100% (12 of 12 patients) in the Septopal group and 95% (20 of 21 patients) in the systemic antibiotic group. Bony union was accomplished in all patients.

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DISCUSSION

Local antibiotic delivery seems to be a useful and safe component in the armamentarium of the physician dealing with the complex problems of open fractures and osteomyelitis, by maximizing the local concentration of antibiotics while minimizing their systemic toxicity.

The safety of local antibiotic therapy has been well documented in clinical studies.9,34,38,40 The systemic absorption of the locally delivered antimicrobial agent is limited and results in extremely low serum levels, which have ranged from 0.3 to 0.5 μg/mL. In a study by Wahlig et al38 serum levels did not exceed 0.5 μg/mL even in the subgroup of patients with implantation of 80 to 180 beads. Salvati et al,34 in a prospective study, found that mean serum gentamicin levels at 1 hour after implantation were approximately 0.3 μg/mL in patients with gentamicin-impregnated beads or cement. No nephrotoxicity was reported in the above studies.9,34,38,40 Walenkamp et al40 precisely measured renal function in 5 patients with implantation of 48 to 360 gentamicin-impregnated beads, but no adverse effect on renal function could be shown.

Therefore, local antibiotic delivery offers the main advantage of high local antibiotic concentration that could not be safely achieved with systemic administration. Moreover, the antibiotic bead pouch technique, by sealing the open wound with a fluid impervious material, seems to help control infection by minimizing secondary contamination with nosocomial organisms. In addition, antibiotic-impregnated beads or spacers fill the dead space that results after debridement and facilitate subsequent reconstruction.

The efficacy of local antibiotic therapy has been reported in several clinical studies on open fractures and osteomyelitis. However, despite the favorable experience of several authors, limitations exist in the available literature when evaluating the clinical role of local antibiotic therapy.

In the largest series of open fractures treated with the bead pouch technique, Ostermann et al,29 reported a lower infection rate in patients treated with systemic antibiotics supplemented with antibiotic beads compared with systemic antibiotics alone. However, when subgroups of fractures were compared based on the Gustilo classification, a considerable difference in the infection rate was observed only in Type III open fractures. A limitation of this retrospective study29 is that wound treatment was different between the two groups. In the systemic antibiotic group only 37% of wounds were closed primarily and the remaining wounds were left open initially, predisposing the wounds to secondary contamination. In the antibiotic bead pouch group, 95% of wounds were either closed primarily or sealed with OpSite. Therefore, the relative contribution of the local antibiotic versus the sealing of the wound can not be determined.

Moehring et al,24 in their randomized controlled trial, reported a nonsignificant difference of the infection rate in patients with open fractures treated with antibiotic beads only compared with systemic antibiotics. However, this study has limitations; the sample size was small, 1-year followup was available only in 67 (59%) of 113 enrolled patients, and an unanticipated nonrandomized third group emerged (12 of 67 patients, 18%), consisting of patients treated with beads who also received antibiotics secondary to limb-threatening injuries or nonorthopaedic reasons.24

Septopal beads in combination with short-term systemic antibiotics resulted in success rates comparable to long-term systemic antibiotics in the management of infected nonunions and chronic osteomyelitis,4,7,31 suggesting that long-term systemic antibiotic therapy can be substituted by local antibiotic therapy. However, in the multicenter study by Blaha et al,4 a serious limitation existed; 145 of 194 patients (75%) randomized to receive Septopal did not follow the protocol and received additional systemic antibiotic therapy exceeding the 5-day limit.

Nevertheless, despite the limitations of existing studies, local delivery of antibiotics seems to be a useful adjunct in the treatment of open fractures and osteomyelitis with no reported systemic toxicity. It should be emphasized that local antibiotic therapy is part of the infection control protocol but is not sufficient by itself and definitely cannot substitute for adequate debridement. Fitzgerald11 showed that locally delivered gentamicin in the absence of debridement was not effective in the presence of established osteomyelitis of the canine tibia. In contrast, Evans and Nelson10 by combining debridement with gentamicin-PMMA beads and systemic antibiotics achieved a 100% (9/9) infection control rate for rabbit osteomyelitis.

Controversies regarding local antibiotic therapy include the length of implantation, the need for removal, and the choice of nonabsorbable versus bioabsorbable delivery vehicles. The optimal length of implantation of antibiotic beads and spacers remains controversial. Prolonged implantation of nonabsorbable antibiotic delivery vehicles is accompanied by two concerns; behavior of the vehicle as a foreign body after elution of antibiotic has been completed, predisposing to secondary infection, and potential development of resistant organisms by prolonged subtherapeutic antibiotic levels.

Although these concerns have not been shown to translate into clinical problems, bead removal within 4 to 6 weeks from implantation has been recommended34 because the beads progressively get enclosed in fibrous tissue or even incorporated into callus, resulting in reduced elution, and complicated or incomplete removal. On the other hand, a study on patients with chronic osteomyelitis reported a higher remission rate with increased duration of implantation of Septopal beads and suggested leaving them in situ in select patients with large dead space cavities, poor soft tissue coverage, and increased surgical risk.13 Elution of antibiotics from retrieved beads has been shown even after prolonged implantation.26,34 However, this may not correlate with the situation in vivo because the development of fibrous tissue around the beads and the lack of surrounding fluid reduce anticipated elution.

Use of nonabsorbable delivery vehicles in open fractures and chronic osteomyelitis usually is followed by subsequent procedures for wound treatment and bone grafting, allowing for bead removal at that time. Despite the use of antibiotic beads in the treatment of chronic osteomyelitis, bacteria may still present in the surrounding tissues, as shown by positive cultures after bead removal.7,30 Although this had no effect on the ultimate control of infection, it underscores the importance of a repeat debridement and antibiotic therapy after bead removal at the time of wound coverage or bone grafting.

Bioabsorbable delivery vehicles seem to be a promising alternative and are currently being investigated. They would eliminate the need for reoperation and removal and allow a wider variety of antimicrobials, including thermolabile agents, to be incorporated in the vehicle depending on the manufacturing process, overcoming some of the current limitations. However, sustaining antibiotic concentrations above the minimum inhibitory concentration for prolonged periods and consistent biodegrading are current concerns. Moreover, bioabsorbable vehicles do not maintain the potential space needed for future reconstruction. In a recent study, McKee et al23 used tobramycin-impregnated calcium sulfate pellets in the treatment of 25 patients with infected long-bone defects and nonunions. Infection was eradicated in 23 of 25 patients (92%) and union was achieved in five of seven nonunions treated only with calcium sulfate without autogenous bone grafting. However, eight patients developed sterile draining sinuses that healed after pellet resorption.

Local antibiotic therapy, by achieving high local antibiotic concentrations without systemic toxicity, seems to be a safe and useful adjunct in the management of open fractures and osteomyelitis. Randomized control trials are needed to provide high-quality evidence on the exact role of local antibiotic therapy in controlling infection. Improvement of bioabsorbable delivery vehicles may enhance the potential for antibiotic delivery and eliminate the need for removal and the concerns regarding prolonged implantation of the vehicle.

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