Delivery of antifungal agents using bioactive and nonbioactive bone cements
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Patricia I Sealy1, Cam Nguyen, Michelle Tucci
1School of Pharmacy, Faculty of Medical Sciences, The University of The West Indies, St. Augustine Campus, Trinidad and Tobago, West Indies.
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.
Insights
Antifungal bone cement beads show varied drug release, with amphotericin B being most consistent. Most antifungals elute suboptimally from cement carriers for deep fungal infections.
Area of Science:
- Biomaterials Science
- Pharmacology
- Infectious Diseases
Background:
- Fungal osteomyelitis management is challenging and often unsuccessful.
- Antifungal-impregnated cement is a potential adjunctive therapy.
Purpose of the Study:
- To evaluate antifungal release from biodegradable and nonbiodegradable cement carriers.
- To assess the efficacy of antifungal-impregnated cements for osteomyelitis treatment.
Main Methods:
- In vitro assessment of antifungal drug release and activity from polymethylmethacrylate (PMMA), hydroxyapatite (HAP), and beta-tricalcium phosphate (beta-TCP) cement spheres.
- Evaluation of drug concentrations in supernatants and impact on serum calcium levels.
- Assessment of osteoblast toxicity.
Main Results:
- Amphotericin B showed consistent release (>110 days) from all cements.
- Flucytosine and fluconazole release varied by cement type (nonbioactive vs. bioactive spheres).
- Micafungin, terbinafine, and anidulafungin showed rapid undetectable concentrations; beta-TCP prolonged release for fluconazole and micafungin. HAP and PMMA affected calcium levels.
Conclusions:
- Most antifungals exhibit suboptimal elution from bone cement spheres for deep fungal infections.
- Nonabsorbable ceramic devices require removal, increasing surgical risk.
- Bioactive materials offer alternatives, but clinical trials are needed to confirm therapeutic benefits and safety.
