Polymethylmethacrylate loaded with antimicrobial agents (most commonly vancomycin and/or aminoglycosides) is used for treatment and prevention of orthopaedic infections. Emergence of organisms resistant to vancomycin or aminoglycosides or both has been reported. Therefore, we studied in vitro release from polymethylmethacrylate beads of antimicrobials with suitable spectra for orthopaedic infections, including cefazolin, ciprofloxacin, gatifloxacin, levofloxacin, linezolid, and rifampin (2.5%, 7.5%, and 15%). Beads were placed in a continuous flow chamber, and antimicrobial concentrations in chamber outflow were determined by bioassay at timed intervals thereafter. Release profiles were bimodal with initial rapid release of high concentrations followed by sustained, slow release. Antimicrobial agents studied showed varied release profiles, indicating that elution from polymethylmethacrylate is unique to individual antimicrobial agents. Increasing antimicrobial concentration in polymethylmethacrylate increased peak concentrations and area under the curve. Cefazolin, ciprofloxacin, gatifloxacin, levofloxacin, linezolid, and rifampin may be suitable for incorporation into polymethylmethacrylate for management of orthopaedic infections.

Gentamicin and tobramycin are two aminoglycosides commonly impregnated into polymethylmethacrylate for treatment and prevention of prosthetic joint infection. Susceptibilities of staphylococci to aminoglycosides are not reported routinely in the United States. The gentamicin and tobramycin minimum inhibitory value of 93 staphylococci from patients with PJI were determined. Forty-one and 66% of the isolates were resistant to gentamicin and tobramycin, respectively. Methicillin-resistant Staphylococcus aureus isolates were more likely to be resistant to gentamicin or tobramycin than were their methicillin susceptible counterparts. The findings suggest that consideration should be given to the further study of agents other than aminoglycosides for incorporation into polymethylmethacrylate for the treatment and prevention of prosthetic joint infection.

Staphylococci, common orthopedic pathogens, form antibiotic-resistant biofilms. Polymethylmethacrylate (PMMA) beads loaded with the quorum-sensing inhibitor RNAIII-inhibiting peptide (RIP) were implanted in rats and shown to prevent methicillin-resistant Staphylococcus aureus infection. RIP release was bimodal, typical of previously-tested antibiotics. These results suggest that RIP-PMMA warrants further evaluation for management of orthopedic infections caused by staphylococci.Bacterial biofilms are important in the pathogenesis of many diseases, including osteomyelitis and prosthetic joint infections (8). Staphylococci are common pathogens in orthopedic infections (2, 10). The quorum-sensing inhibitor RNAIII-inhibiting peptide (RIP) inhibits staphylococcal-biofilm formation by inhibiting the phosphorylation of its target protein, TRAP, leading to suppression of virulence factors produced by staphylococci (4-7).Polymethylmethacrylate (PMMA) is used in orthopedic surgery as a drug delivery system wherein antimicrobial agents are loaded into PMMA to deliver drugs to tissues with limited blood flow and to deliver high local antimicrobial concentrations (9).The aims of this study were to determine the in vitro compatibility of RIP with PMMA, to measure the release of RIP from PMMA beads in a continuous-flow chamber, and to determine whether RIP-coated PMMA beads prevent Staphylococcus aureus biofilm formation in an experimental animal model.In vitro experiments. Vancomycin hydrochloride was purchased from USP, Novaplus, Harrisburg, PA. The amide form of RIP (YSPWTNF-NH2) was synthesized by Neosystem (Strasbourg, France). Beads were prepared by adding RIP or vancomycin powder to Surgical Simplex P radioopaque bone cement (Stryker Orthopedics, Mahwah, NJ) containing powder (3 g PMMA, 15 g methyl methacrylate-styrene-copolymer, 2 g barium sulfate, USP) and liquid (9.75 ml methyl methacrylate, 0.25 ml N, N-dimethyl-para-toluidine, 75 Ϯ 15 ppm hydroquinone).Beads containing 7.5%, 15%, and 22.5% (weight/weight) of drug were prepared by mixing 150, 200, or 340 mg RIP powder with 1,850, 1,132, or 1,170 mg of cement powder, respectively. We then added 0.925, 0.626, or 0.585 ml of methyl methacrylate liquid monomer, respectively, and spread the mixture into a mold to form beads, as previously described (3). We used a previously described continuous flow chamber (13) to test release of RIP from PMMA beads. Samples were collected for 48 h. Soluble material released from the PMMA beads at different time points (1 to 48 h) from three different 7.5% RIP-loaded beads (run A, B, and C) and from pulverized PMMA beads was applied to a reverse-phase C 18 column (Hypersil GOLD; Thermo Electron Corp.) at a flow rate of 1 ml/min in mobile phase containing 0.1% trifluoroacetic acid in water. RIP was eluted using a gradient of acetonitrile from 0 to 70% for 15 min; RIP was eluted with 54% acetonitrile. The concentration of RIP released from the PMMA beads at different time points was compared to the elution profile (peak height) of 5 g RIP...

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