A Daptomycin-Xylitol-loaded Polymethylmethacrylate Bone Cement: How Much Xylitol Should Be Used?

Abstract

Background The rate of release of an antibiotic from an antibiotic-loaded polymethylmethacrylate (PMMA) bone cement is low. This may be increased by adding a particulate poragen (eg, xylitol) to the cement powder. However, the appropriate poragen amount is unclear.Questions/purposes We explored the appropriate amount of xylitol to use in a PMMA bone cement loaded with daptomycin and xylitol. Methods We prepared four groups of cement, each comprising the same amount of daptomycin in the powder (1.36 g/40 g dry powder) but different amounts of xylitol (0, 0.7, 1.4, and 2.7 g); the xylitol mass ratio (X) (mass divided by mass of the final dry cement-daptomycin-xylitol mixture) ranged from 0 to 6.13 wt/wt%. Eight mechanical, antibiotic release, and bacterial inhibitory properties were determined using three to 22 specimens or replicates per test. We then used an optimization method to determine an appropriate value of X by (1) identifying the best-fit relationship between the value of each property and X, (2) defining a master objective function incorporating all of the best fits; and (3) determining the value of X at the maximum master objective function.

Modeling of Daptomycin Release from Medium-Dose Daptomycin-Xylitol-Loaded PMMA Bone Cements

“…The study design comprised four parts: 1) fabrication of four groups of specimens, one not loaded with the xylitol (XYL-00 group) and three having different amounts of xylitol per 40 g of dry cement powder; namely, 0.7 g (XYL-07 group), 1.4 g (XYL-14 group), and 2.7 g (XYL-27 group), corresponding to xylitol loadings of 1.66, 3.27, and 6.13 wt/wt%, respectively. The range of xylitol loading used was the same as that in our previous study in which we computed what we designated an "appropriate xylitol loading" being the loading that yields a cement that has an optimal combination of the seven properties we determined, namely, daptomycin release rate; an index of inhibition of the daptomycin eluate against S. aureus; coefficient of diffusion of egress of daptomycin; coefficient of diffusion of ingress of 1X phosphate buffered saline (PBS) solution, at 37˚C; polymerization rate, at 37˚C; fracture toughness; and fatigue limit [25]; 2) for each group, determination of the daptomycin release profile (amount of released daptomycin-versus-length of time of specimen in 1X PBS solution, at 37˚C); 3) for each group, determination of the morphology of the specimens at the end of the daptomycin release studies; and 4) for each group, determination of the applicable daptomycin release mechanism by fitting four antibiotic elution kinetics models to the release profile.…”

“…The protocols used in the preparing the cement specimens were the same as presented in our previous work [25]. In essence, 1) the cement powder, daptomycin, and xylitol were mixed using a commercially-available cement powder mixer (OmoMix ® ; Tecres SpA, Verona, Italy) and then the mixture was vacuum-mixed with the liquid monomer of the cement (18.37 mL); 2) the resulting cement dough was injected into a silicone mold that has four cells, with each cell having internal configuration and dimensions of a solid cylindrical dog-bone, whose dimensions conformed to those stipulated in ASTM F2118 [36]; and 3) after curing in the mold, in ambient laboratory air, for 20 minutes, the specimens (Figure 1) were removed, lightly sanded, and then inspected for flaws.…”

“…As such, a new generation of antibiotics is emerging, among which are ceftobiprole, dalbavancin, daptomycin, telavancin, and tigecycline [12]- [19]. Of these, only daptomycin has been incorporated in a PMMA bone cement and reported in some in vitro studies [20]- [25] and only daptomycin and telavancin have been used in PJI treatment [18] [19].…”

“…Results of the few studies on the release of daptomycin from cylindrical specimens of medium-dose daptomycin-loaded PMMA bone cement show that 1) it is characterized by an initial burst of the antibiotic within 24 h, followed by low amount of sustained elution; and 2) the released daptomycin is effective against S. aureus [21] [25]. There are a plethora of methods to increase the rate of an antibiotic from ALPBC specimens, such as incorporation of a poragen (for example, particulate xylitol and glycine) in the cement powder, low-level ultrsonication, and mechanical mixing [26]- [32].…”

“…The literature on enhancement of release of daptomycin from daptomycin-loaded PMMA bone cement specimens is limited, with the only method used being incorporation of particulate xylitol in the cement powder [24] [25] [33]. It has also been shown that daptomycin released from cylindrical daptomycin-particulate xylitol-PMMA bone cement specimens is effective against S. aureus [25]. Thus, the daptomycin-particulate xylitol-PMMA bone cement system is clinically relevant.…”