An Approach for determining antibiotic loading for a physician-directed antibiotic-loaded PMMA bone cement formulation

Abstract

Background: When a physician-directed antibiotic-loaded polymethylmethacrylate (PMMA) bone cement (ALBC) formulation is used in total hip arthroplasties (THAs) and total knee arthroplasties (TKAs), current practice in the United States involves arbitrary choice of the antibiotic loading (herein defined as the ratio of the mass of the antibiotic added to the mass of the cement powder). We suggest there is a need to develop a rational method for determining this loading.

Questions/purposes: We propose a new method for determining the antibiotic loading to use when preparing a physician-directed ALBC formulation and illustrate this method using three in vitro properties of an ALBC in which the antibiotic was daptomycin.

Materials and methods: Daptomycin was blended with the powder of the cement using a mechanical mixer. We performed fatigue, elution, and activity tests on three sets of specimens having daptomycin loadings of 2.25, 4.50, and 11.00 wt/wt%. Correlational analyses of the results of these tests were used in conjunction with stated constraints and a nonlinear optimization method to determine the daptomycin loading to use.

Results: With an increase in daptomycin loading, the estimated mean fatigue limit of the cement decreased, the estimated elution rate of the antibiotic increased, and the percentage inhibition of staphylococcal growth by the eluate remained unchanged at 100%. For a daptomycin-loaded PMMA bone cement we computed the optimum amount of daptomycin to mechanically blend with 40 g of cement powder is 1.36 g.

Conclusions: We suggest an approach that may be used to determine the amount of antibiotic to blend with the powder of a PMMA bone cement when preparing a physician-directed ALBC formulation, and highlighted the attractions and limitations of this approach.

Clinical relevance: When a physician-directed ALBC formulation is selected for use in a TKA or THA, the approach we detail may be employed to determine the antibiotic loading to use rather than the empirical approach that is taken in current clinical practice.

Fig. 1

A flowchart shows the study design. The key features of the three cement property characterization tests conducted are shown. Study sets included: A, 2.25 wt/wt% daptomycin; B, 4.50 wt/wt% daptomycin; C, 11.00 wt/wt% daptomycin; and D, no daptomycin (control set).

Fig. 2

A fully dimensioned drawing shows the specimen used in the fatigue tests. All dimensions are in millimeters. Specimen configuration and dimensions conform to those stipulated in ASTM F2118-03 [1], which was the standard used for the determination of the estimated mean fatigue limits of the cements.

Fig. 3A–D

Graphs show the results of the fatigue tests at (A) ± 20.0 MPa, (B) ± 15.0 MPa, (C) ± 12.5 MPa, and (D) ± 10.0 MPa. The patterns in the variation of the fatigue test results with daptomycin loading at ± 20.0 MPa, ± 15.0 MPa, and ± 12.5 MPa are the same but different from the one at ± 10.0 MPa.

Fig. 4

The graph shows the fatigue results (solid diamonds) and the fit of the Olgive equation (Equation 1) to these results in Set B. The continuous curve is the mean fit, and the dotted curves are the 95% confidence limits of the fit. The estimated mean fatigue limit is the stress corresponding to the asymptote to the lower horizontal section of the continuous curve (in this case, 6.1 MPa).

Fig. 5A–B

Graphs show profiles of release of the daptomycin from the bone cement specimens: (A) current amount and (B) cumulative amount. For each of these profiles, the pattern is the same for all the daptomycin loadings; namely, initial rapid release of the antibiotic followed by a much slower release.