Author(s): Mark S. Smeltzer, Brian Weiss, Warren O, Haggard, and *Richard Evans; University of Arkansas for Medical Sciences,Little Rock, Arkansas
Title: Optimization of Polymethylmethacrylate Formulations for Elution of Daptomycin in the Treatmentof Staphylococcal Infection
Purpose: To develop a formulation of daptomycin PMMA with an elution profile of 100X the minimum inhibitory concentration (MIC) for Staph. aureus and a sustained concentration of at least 5X the MIC that that did not alter the structural integrity of PMMA.
Methods: Introduction : We previously demonstrated that xylitol can be used as a filler to increase the elution of daptomycin from polymethylmethacrylate (PMMA) beads (McLaren et al., 2006, Clin. Ortho. Rel. Res., 451:25-28). This was true both in terms of peak and sustained levels of antibiotic. However, this earlier study was limited to single concentrations of both daptomycin and xylitol, and it did not include studies examining the elution profiles of other commonly used antibiotics. In this report, we describe in vitro elution studies aimed at optimizing the formulation of PMMA beads containing xylitol for the elution of daptomycin as well as studies demonstrated that this same formulation can be used for the effective elution of both vancomycin and gentamicin.
Methods: Assays of different bead formulations were done at 24 hr intervals over the course of 10 days using bioassays for antibacterial activity, HPLC analysis to determine absolute levels, and mechanical load testing. Results A formulation consisting of 2 gm daptomycin and 22 gm xylitol per 40 gm package of PMMA (Palacose"¥) met all of our experimental objectives. Specifically, this formulation resulted in a peak concentration on day 1 of 640 ug/ml and a sustained concentration on day 10 of 5 ug/ml as determined by bioassay. As determined in concomitant control assays using freshly-prepared daptomycin, these values correspond to over 1000X and 8X the MIC of the test strain respectively. HPLC analysis yielded comparable values of 640.2 ug/ml on day 1 and 9.56 ug/ml on day 10. These results not only confirm our bioassay data but also indicate that daptomycin eluted from PMMA beads containing xylitol remains active even after 10 days of incubation at 37oC. Structural studies confirmed that addition of xylitol resulted in a decrease in both peak load and stiffness, but this reduction did not exceed acceptable limits. We also demonstrated that this same formulation was effective for the delivery of vancomycin or gentamicin and, at least in the case of gentamicin, that the stated objectives could be achieved with considerably less antibiotic by comparison to PMMA beads without xylitol.
Discussion: Our results demonstrate that xylitol can be used as an inexpensive filler to enhance the elution profile of daptomycin and other commonly-used antibiotics from PMMA beads. This was true both in terms of achieving a transient, high level of antibiotic and in terms of achieving a level that significantly exceeds the minimum inhibitory concentration for a sustained period. This suggests that our approach could be used to enhance therapy with drugs that exhibit both concentration and time-dependent killing.