Efficacy of ciprofloxacin-releasing bioabsorbable osteoconductive bone defect filler for treatment of experimental osteomyelitis due to Staphylococcus aureus

Abstract

The concept of local antibiotic delivery via biodegradable bone defect fillers with multifunctional properties for the treatment of bone infections is highly appealing. Fillers can be used to obliterate surgical dead space and to provide targeted local bactericidal concentrations in tissue for extended periods. Eventually, the osteoconductive component of the filler could guide the healing of the bone defect. The present experimental study was carried out to test this concept in a localized Staphylococcus aureus osteomyelitis model in the rabbit (n = 31). A metaphyseal defect of the tibia was filled with a block of bone cement, followed by insertion of a bacterial inoculum. After removal of the bone cement and surgical debridement at 2 weeks, the defect was filled with a ciprofloxacin-containing (7.6% +/- 0.1%, by weight) composite (treated-infection group) or with a composite without antibiotic (sham-treated group). Both a positive control group (untreated-infection group) and a negative control group were also produced. The treatment response, monitored by positron emission tomography (PET) with fluorine-18-labeled fluorodeoxyglucose ([18F]FDG) at 3 and 6 weeks, showed rapidly decreasing amounts of [18F]FDG uptake in the treated-infection group (P = 0.001 compared with the results for the untreated-infection group at 6 weeks). The bacteriological analysis confirmed the eradication of the bone pathogen in the treated-infection group. However, three animals had culture-positive soft tissue infections. All animals in the sham-treated and untreated-infection groups had culture-positive bone infections with typical radiographic changes of osteomyelitis. Histomorphometry, peripheral quantitative computed tomography, and backscattered electron imaging of scanning electron microscopy images verified the osteoconductive properties of the bioactive glass microspheres within the composite. The median bone ciprofloxacin concentrations were 1.2 and 2.1 microg/g at two anatomic locations of the tibia. This is the first report to show the value of [18F]FDG PET for quantitative monitoring of the treatment response in bone infections. The collaborative results of bacteriologic and [18F-FDG] PET studies showed that use of the multifunctional composite was successful for eradication of the S. aureus pathogen from bone.

Figures

FIG. 1.

[18F-FDG] PET imaging at 3 and 6 weeks. The bars represent the mean SUV ratios ± SD (n = 5 to 9). Treatment with AB-PDLLA-BaG significantly decreased the level of [18F]FDG uptake compared with those for the untreated-infection group and the sham-treated infection group at 6 weeks.

FIG. 2.

Cortical defect healing evaluated at 6 weeks. The bars represent the defect closure expressed as the mean ± SD (n = 5 to 9) percentage of the original defect length based on pQCT measurements. Healing of the cortical defect was significantly delayed in the untreated-infection and sham-treated groups compared with that in the negative control group (**, P = 0.007; ***, P < 0.001).

FIG. 3.

pQCT density of the medullary cavity at the defect area at 3 and 6 weeks. The bars represent the mean pQCT density values ± SD (n = 5 to 9), expressed as milligrams per cubic centimeter. The densities for the untreated-infection group, the treated-infection group and the sham-treated group differed significantly (*, P < 0.05; **, P < 0.01; ***, P < 0.001) from those for the negative control group.

FIG. 4.

BEI-SEM micrograph demonstrating new bone formation in intimate contact with a BaG microsphere (white arrow) in the treated-infection group. Magnification, ×100.

FIG. 5.

Histological sections demonstrating the healing of cortical bone. (A) Healed cortical window (black arrow) in negative control group; (B) extensive reactive new bone formation in cortical defect of untreated-infection group; (C) healed cortical window (white arrow) and associated intramedullary new bone formation (black arrow) in treated-infection group; (D) unhealed cortical defect with extruding biomaterial fillers in sham-treated group. Modified van Gieson stain. Magnification, ×25.

FIG. 6.

The amount of intramedullary new bone measured by histomorphometry. The bars represent the mean areas of new bone ± SD (n = 5 to 9) expressed as the percentage of the cross-sectional area of the medullary canal. Treatment with AB-PDLLA-BaG resulted in significantly (*, P < 0.05) increased new intramedullary bone formation compared with that in the negative control group.