Delivery of antifungal agents using bioactive and nonbioactive bone cements

BACKGROUND: Management of fungal osteomyelitis is prolonged and frequently unsuccessful. Antifungal-impregnated cement is sometimes used as adjunctive therapy. OBJECTIVE: To examine the release of antifungals from biodegradable and nonbiodegradable cement carriers. METHODS: In vitro methods were used to assess antifungal drug release and antifungal activity of impregnated cements commonly used as adjunctive treatment of osteomyelitis. Cements included thermoplastic, nonbioactive polymers (polymethylmethacrylate [PMMA]) or bioactive agents (hydroxyapatite [HAP], beta-tricalcium phosphate [beta-TCP]) and were formed into spheres (beads). RESULTS: Amphotericin B provided consistent supernatant concentrations (release), between 1.75 and 2.0 microg/mL, over 110 days from all bone cements. Flucytosine and fluconazole were observed for 33-42 days before becoming undetectable from a nonbioactive sphere and 18-22 days from a bioactive sphere. Serum concentrations for micafungin, terbinafine, and anidulafungin impregnated into PMMA rapidly became undetectable, regardless of the matrix used. Investigational beta-TCP spheres prolonged release for fluconazole and micafungin, but had no effect on amphotericin B. Serum calcium concentrations decreased 60-80% in all HAP-impregnated drug sphere supernatants. Only amphotericin B-impregnated PMMA impacted supernatant calcium, decreasing concentrations by 50-60%. The antifungal-impregnated beads did not appear to be toxic to osteoblasts during 72 hours of exposure in tissue culture medium. CONCLUSIONS: Elution characteristics of most antifungals from bone cement spheres are probably not optimal for treatment of deep-seated fungal infections if a similar phenomenon of antifungal release manifests in vivo. Ceramic nonabsorbable impregnated devices must be removed after their lifespan expires and may necessitate another surgical procedure that can increase surgical risk and cost. Bioactive osteoconductive materials may provide a surgical alternative to nonabsorbable matrices. However, there have been no controlled trials demonstrating improved therapeutic outcomes with local therapy and assessing whether biodegradable materials act as a new focus for infection.

Delivery of antifungal agents using bioactive and nonbioactive bone cements.

BACKGROUND: Management of fungal osteomyelitis is prolonged and frequently unsuccessful. Antifungal-impregnated cement is sometimes used as adjunctive therapy. OBJECTIVE: To examine the release of antifungals from biodegradable and nonbiodegradable cement carriers. METHODS: In vitro methods were used to assess antifungal drug release and antifungal activity of impregnated cements commonly used as adjunctive treatment of osteomyelitis. Cements included thermoplastic, nonbioactive polymers (polymethylmethacrylate [PMMA]) or bioactive agents (hydroxyapatite [HAP], beta-tricalcium phosphate [beta-TCP]) and were formed into spheres (beads). RESULTS: Amphotericin B provided consistent supernatant concentrations (release), between 1.75 and 2.0 microg/mL, over 110 days from all bone cements. Flucytosine and fluconazole were observed for 33-42 days before becoming undetectable from a nonbioactive sphere and 18-22 days from a bioactive sphere. Serum concentrations for micafungin, terbinafine, and anidulafungin impregnated into PMMA rapidly became undetectable, regardless of the matrix used. Investigational beta-TCP spheres prolonged release for fluconazole and micafungin, but had no effect on amphotericin B. Serum calcium concentrations decreased 60-80% in all HAP-impregnated drug sphere supernatants. Only amphotericin B-impregnated PMMA impacted supernatant calcium, decreasing concentrations by 50-60%. The antifungal-impregnated beads did not appear to be toxic to osteoblasts during 72 hours of exposure in tissue culture medium. CONCLUSIONS: Elution characteristics of most antifungals from bone cement spheres are probably not optimal for treatment of deep-seated fungal infections if a similar phenomenon of antifungal release manifests in vivo. Ceramic nonabsorbable impregnated devices must be removed after their lifespan expires and may necessitate another surgical procedure that can increase surgical risk and cost. Bioactive osteoconductive materials may provide a surgical alternative to nonabsorbable matrices. However, there have been no controlled trials demonstrating improved therapeutic outcomes with local therapy and assessing whether biodegradable materials act as a new focus for infection.

The interaction of mannose binding lectin (MBL) with mannose containing glycopeptides and the resultant potential impact on invasive fungal infection.

Mannnose-binding lectin (MBL) binds oligosaccharides on the surface of microorganisms to form complexes that activate the complement cascade and facilitate phagocytosis. Teicoplanin and dalbavancin glycopeptide antibiotics possess N-acetyl glucosamine and mannose oligosaccharides that may bind MBL. Pharmaceuticals capable of binding to MBL may decrease clearance of significant pathogens such as yeast. An invasive candidemia murine model was utilized to evaluate differences in survival between mannose- and teicoplanin-treated groups compared to a control group administered normal saline. Three groups of BALB/c mice were injected with Candida albicans ATCC 44858 (1.4 x 10(6) CFU). Pharmaceutical agents were administered 2 h pre-infection and 8 h post-infection. In vivo cumulative survival at 52 h revealed 10%, 30% and 90% survival rates for mice administered mannose, teicoplanin, and saline, respectively. There was 0% survival for mice given mannose or teicoplanin at 56 h, compared with 70% for the normal saline treated mice at the same time point (P < 0.05). This in vivo study shows 'accelerated progression of infection' for Candida-inoculated mice exposed to mannose or teicoplanin compared to those given normal saline. Further, protein polyacrylamide gel electrophoresis studies suggested a potential MBL-drug interaction which may attenuate complement activation, opsonization and phagocytosis.