Liposomal Formulation Increases Local Delivery of Amphotericin from Bone Cement: A Pilot Study

Abstract

Background Amphotericin is a highly toxic hydrophobic antifungal. Delivery of amphotericin from antifungalloaded bone cement (ALBC) is much lower than would be expected for an equivalent load of water-soluble antibacterials. Lipid formulations have been developed to decrease amphotericin toxicity. It is unknown how lipid formulations affect amphotericin release and compressive strength of amphotericin ALBC. Questions/purposes We asked if amphotericin release from liposomal amphotericin ALBC (1) changed with amphotericin load; (2) differed from release from amphotericin deoxycholate ALBC; (3) was an active drug; and (4) if liposomal amphotericin affected the bone cement strength.Methods Forty-five standardized test cylinders were fabricated from three formulations of ALBC: Simplex TM P bone cement with 200 mg liposomal amphotericin, 800 mg liposomal amphotericin, or 800 mg amphotericin deoxycholate per batch. For each ALBC formulation, cumulative released amphotericin was determined from five cylinders, and compressive strength was measured for 10 cylinders, five before elution and five after. Activity of released amphotericin was determined by growth inhibition assay. Results Amphotericin release was greater for increased load of liposomal amphotericin: 770 lg for 800 mg versus 118 lg for 200 mg. Amphotericin release was greater from liposomal ALBC than from deoxycholate ALBC: 770 lg versus 23 lg over 7 days for 800 mg amphotericin. Released amphotericin was active. Compressive strength of liposomal ALBC is decreased, 67 MPa and 34 MPa by Day 7 in elution for the 200-mg and 800-mg formulations, respectively. Conclusions Liposomal amphotericin has greater amphotericin release from ALBC than amphotericin deoxycholate. Compressive strength of liposomal amphotericin ALBC decreases to less than recommended for implant fixation. Local toxicity data are needed before liposomal amphotericin ALBC can be used clinically.

Voriconazole Is Delivered From Antifungal-Loaded Bone Cement

“…This report confirms the activity of delivered voriconazole at all collection time points, verifying that active voriconazole is delivered from the cement. Recent work in our laboratory has confirmed the activity of both liposomal and deoxycholate formulations of amphotericin B eluted from bone cement [2].…”

“…Various studies describe surgeon-directed antifungal formulations of antimicrobial-loaded bone cement (ALBC) [2,6,9,10,15,16]. Published data from amphotericin B studies establish limited release occurs, increased release using the liposome formulation, higher than expected compressive strength, possibly related to crosslinking with PMMA, and cytotoxicity at low concentrations [2,5,8,9]. However, clinical experience in a case report by Marra et al [10] suggests that sufficient amphotericin B is released in vivo to be measurable and clinically efficacious.…”

Liposomal Formulation Decreases Toxicity of Amphotericin B In Vitro and In Vivo

“…Toxicity from amphotericin B from the deoxycholate formulation occurred at lower concentrations than from the liposomal formulation. The phospholipid in the liposomal formulation of amphotericin B leads to higher release from ALBC but likely also reduces toxicity through the formation of liposomes, limiting exposure to free drug [4]. After removal of amphotericin B from the growth media, cells that were exposed to these sublethal concentrations increased their numbers over 3 days [6].…”

“…We have previously studied ALBC with amphotericin B deoxycholate [8], finding limited release and significant toxicity to fibroblasts and osteoblasts at relatively low concentrations [6]. We subsequently showed that both liposomal amphotericin B [4] and voriconazole [12] are delivered from ALBC in much greater amounts than amphotericin B deoxycholate. Liposomal amphotericin B is known to be less toxic than amphotericin B deoxycholate when delivered intravenously [2]; however, there are no reported data on the local toxicity from locally delivered liposomal amphotericin B.…”

Antimicrobial Distribution From Local Delivery Depends on Dose

“…In an effort to determine the important parameters for effective local delivery, many authors have studied antimicrobial elution in vitro [8,18,19]. Elution studies evaluate the delivery vehicle's maximum capability to release antimicrobial, often inappropriately comparing eluant concentrations to the minimum inhibitory concentration (MIC) of target organisms.…”