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.
Sealy
Patricia I
PI
School of Pharmacy, Faculty of Medical Sciences, The University of The West Indies, St. Augustine Campus, Trinidad and Tobago, West Indies.
Nguyen
Cam
C
Tucci
Michelle
M
Benghuzzi
Ham
H
Cleary
John D
JD
D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D001672:Biocompatible Materials / Q000737:chemistry*; D001843:Bone Cements / Q000737:chemistry*; D002118:Calcium / Q000097:blood / Q000378:metabolism; D002130:Calcium Phosphates / Q000737:chemistry; D002417:Cattle; D002478:Cells, Cultured; D003692:Delayed-Action Preparations; D004337:Drug Carriers / Q000737:chemistry*; D006801:Humans; D006882:Hydroxyapatites / Q000737:chemistry; D066298:In Vitro Techniques; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism; D010019:Osteomyelitis / Q000188:drug therapy / Q000382:microbiology; D019904:Polymethyl Methacrylate / Q000737:chemistry
D000935:Antifungal Agents; D001672:Biocompatible Materials; D001843:Bone Cements; D002130:Calcium Phosphates; D003692:Delayed-Action Preparations; D004337:Drug Carriers; D006882:Hydroxyapatites; C485817:beta-tricalcium phosphate; C475044:hydroxyapatite cement; D019904:Polymethyl Methacrylate; D002118:Calcium