Heterotopic ossification prophylaxis with indomethacin increases the risk of long-bone nonunion.

Indomethacin is commonly administered for the prophylaxis of heterotopic ossification (HO) after the surgical treatment of acetabular fractures. Non-steroidal anti-inflammatory drugs such as indomethacin, have been associated with delayed healing of fractures and mechanically weaker callus. Our aim was to determine if patients with an acetabular fracture, who received indomethacin for prophylaxis against HO, were at risk of delayed healing or nonunion of any associated fractures of long bones. We reviewed 282 patients who had had open reduction and internal fixation of an acetabular fracture. Patients at risk of HO were randomised to receive either radiation therapy (XRT) or indomethacin. Of these patients, 112 had sustained at least one concomitant fracture of a long bone; 36 needed no prophylaxis, 38 received focal radiation and 38 received indomethacin. Fifteen patients developed 16 nonunions. When comparing patients who received indomethacin with those who did not, a significant difference was noted in the rate of nonunion (26% v 7%; p = 0.004). Patients with concurrent fractures of the acetabulum and long bones who receive indomethacin have a significantly greater risk of nonunion of the fractures of the long bones when compared with those who receive XRT or no prophylaxis.

Indomethacin compared with localized irradiation for the prevention of heterotopic ossification following surgical treatment of acetabular fractures.

BACKGROUND: There is controversy surrounding the relative effectiveness of local irradiation and oral indomethacin for prophylaxis against heterotopic ossification following surgical treatment of acetabular fractures. The purpose of this study was to compare the efficacy of these two commonly used methods in a prospective, randomized trial. METHODS: From July 1992 to June 1999, 166 patients in whom a fracture of the acetabulum was treated surgically through a posterior, extensile, or combination approach were randomized to receive either indomethacin or radiation therapy postoperatively. Seventy-eight patients received 800 cGy of local radiation therapy within seventy-two hours after surgery, and seventy-two patients received a six-week course of indomethacin (25 mg three times a day) beginning within twenty-four hours after surgery. Sixteen additional patients were randomized but did not receive treatment with either prophylactic regimen. At an average of fourteen months, the extent of heterotopic ossification was assessed on plain radiographs with use of the classification of Brooker et al. The grade of ossification was correlated with hip motion. RESULTS: There was no significant difference between treatment groups with regard to patient age, gender, Glasgow Coma Scale, operative time, estimated operative blood loss, duration of follow-up, or presence of closed head injury. The Injury Severity Score appeared to be the only covariate that was significantly different between the groups (p = 0.019). Grade-III or IV ossification developed in eight (11%) of the patients in the indomethacin group and three (4%) in the radiation therapy group. The difference was not significant (p = 0.22; 95% confidence interval, -1.1%, +15.7%). No complications related to the prophylaxis were noted in either group. Heterotopic ossification developed in all sixteen patients who did not receive prophylaxis, with six demonstrating grade-III or IV changes. The overall prevalence of grade-III or IV heterotopic ossification was 7% (eleven of 150) in the treated groups and 38% (six of sixteen) in the untreated group. We did not find any association between the prevalence of heterotopic ossification and fracture type (p = 0.296) or posterior hip dislocation (p = 0.306). Grade-I, II, and III heterotopic ossification did not decrease the range of motion of the hip except in flexion. CONCLUSIONS: Both local radiation therapy and indomethacin were found to provide effective prophylaxis against heterotopic ossification following surgical treatment of acetabular fractures through a posterior or extensile approach. We detected no significant difference in efficacy between the two prophylactic regimens.

Elution characteristics of tobramycin from polycaprolactone in a rabbit model.

This study investigated the elution characteristics of tobramycin from polycaprolactone, a bioabsorbable polymer, in a rabbit model. Sixty rabbits were divided into two groups. Group 1 had polycaprolactone rods impregnated with 6% tobramycin surgically implanted into the proximal femoral intramedullary canal. Group 2 received polymethylmethacrylate rods of like size, shape, and antibiotic concentration. Serum and urine samples were obtained, and tobramycin levels were determined via fluorescent immunosorbent assay. Rabbits were sacrificed as long as 56 days after surgery. Local bone tobramycin concentration was determined using the agar diffusion method. Polycaprolactone delivered a significantly higher peak bone concentration of tobramycin (22.4 microg/mL) than did polymethylmethacrylate (13.59 microg/mL). Polycaprolactone also had a more gradual decrease in local tobramycin concentration than did polymethylmethacrylate. Neither polycaprolactone nor polymethylmethacrylate yielded consistently detectable (> 0.1 microg/mL) serum tobramycin levels. Urine concentrations mirrored those seen in bone, with polycaprolactone achieving significantly higher tobramycin concentrations than did polymethylmethacrylate. Polycaprolactone had superior elution characteristics compared with polymethylmethacrylate in this lapine model, suggesting that polycaprolactone might be a promising local antibiotic delivery vehicle for the treatment of osteomyelitis.

In vitro elution of tobramycin from bioabsorbable polycaprolactone beads.

OBJECTIVES: To compare the in vitro elution characteristics of tobramycin impregnated beads made of polycaprolactone (PCL) and polymethylmethacrylate (PMMA). DESIGN: Six-millimeter PCL and PMMA beads with 6% tobramycin were formed and placed in phosphate-buffered saline or newborn calf serum and incubated at room temperature or 37 degrees C. Aliquots were taken at intervals for eight weeks. Tobramycin levels were determined by fluorescent assay and antibacterial efficacy was assessed by measuring the zones of inhibition against Staphylococcus aureus and Pseudomonas aeruginosa on agar diffusion plates. RESULTS: Tobramycin elution rates at room temperature were similar up to three weeks. At three weeks, elution rates from PCL beads were twice those from PMMA beads, and at eight weeks, elution from PCL was quadruple that from PMMA. At 37 degrees C, tobramycin elution rates from PCL were eight times greater than those from PMMA by eight weeks. Total tobramycin eluted from PCL beads was 38.9% and 20% in PMMA beads. All samples showed bacteriostatic activity against S. aureus and P. aeruginosa at eight weeks. CONCLUSIONS: These in vitro results show that PCL has superior antibiotic elution characteristics compared with PMMA, and this may translate into a more effective antibiotic delivery vehicle. In addition, PCL is a bioabsorbable polymer, which may decrease the need for a second surgical procedure to remove retained beads.

Synergy between Staphylococcus aureus and Pseudomonas aeruginosa in a rat model of complex orthopaedic wounds.

BACKGROUND: We observed an interaction in animals inoculated concomitantly with Staphylococcus aureus and Pseudomonas aeruginosa during a study of the efficacy of surfactants for disinfection of orthopaedic wounds. This led us to investigate whether synergy could be demonstrated between Staphylococcus aureus and Pseudomonas aeruginosa in a rat model of complex orthopaedic wounds. METHODS: A wire was implanted into the spinous process of a lumbar vertebra of Sprague-Dawley rats through a dorsal incision. Animals were divided into two groups: group one was inoculated with either Staphylococcus aureus or Pseudomonas aeruginosa, and group two received a polymicrobial inoculation with both test organisms in varying concentrations. After inoculation, the wounds were irrigated and closed. On postoperative day 14, all animals were killed and specimens from the wounds were cultured. The number of colony-forming units (CFU) of Staphylococcus aureus or Pseudomonas aeruginosa needed to cause infection in 50% of the animals (ID50) was determined with use of the Reed-Muench method. The infection rate associated with each inoculum combination was calculated, and the two groups were compared. RESULTS: The ID50 was 2.8 x 10(4) CFU for Staphylococcus aureus and 4.8 x 10(5) CFU for Pseudomonas aeruginosa. The combination of 10(3) CFU of Staphylococcus aureus with low concentrations (10(2), 10(3), or 10(4) CFU) of Pseudomonas aeruginosa yielded infection rates that were higher than those found with either organism alone at the same concentrations. The combination of 10(3) CFU of Staphylococcus aureus and 10(3) CFU of Pseudomonas aeruginosa yielded a 75% infection rate, which was significantly higher (p = 0.004) than that associated with 10(3) CFU of either organism alone. As the Pseudomonas aeruginosa concentration was increased (to 10(5), 10(6), and 10(7) CFU), this trend reversed, and the infection rate decreased to 33% (p = 0.004). Low concentrations of Pseudomonas aeruginosa (0 to 10(5) CFU) combined with 10(6) CFU of Staphylococcus aureus yielded infection rates ranging from 83% to 100%. At the higher concentrations of Pseudomonas aeruginosa (10(6) and 10(7) CFU), however, the infection rate again decreased, to 33% (p = 0.005). Only Staphylococcus aureus was isolated from the cultures of the specimens from the animals that had received a polymicrobial inoculum. CONCLUSIONS: Synergy between Staphylococcus aureus and Pseudomonas aeruginosa was demonstrated when low levels of each organism were present in the wound. As the Pseudomonas aeruginosa concentration was increased, the infection rates fell well below what would be anticipated, suggesting that low concentrations of Pseudomonas aeruginosa enhance the ability of Staphylococcus aureus to cause infection in this orthopaedic wound model. At the same time, the presence of Staphylococcus aureus in the ratios tested decreased the rate of infection by Pseudomonas aeruginosa. CLINICAL RELEVANCE: Staphylococcus aureus is a pathogen commonly seen in orthopaedic patients. The pathogenicity of Staphylococcus aureus was shown to be increased in the presence of anaerobic bacteria. This study is the first one that we are aware of that demonstrated synergy between Staphylococcus aureus and Pseudomonas aeruginosa, at low concentrations, in a wound model while at the same time showing that Staphylococcus aureus lowers the rate of Pseudomonas aeruginosa infection.