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82.BJRBJR Follow us @BoneJointRes Freely available online OPEN ACCESS BJR BIOMATERIALS Radical scavenging of poly(methyl methacrylate) bone cement by rifampin and clinically relevant properties of the rifampin-loaded cement G. A. Funk, Objectives E. M. Menuey, The objective of this study was to characterize the effect of rifampin incorporation into K. A. Cole, poly(methyl methacrylate) (PMMA) bone cement. While incompatibilities between the T. P. Schuman, two materials have been previously noted, we sought to identify and quantify the cause K. V. Kilway, of rifampin’s effects, including alterations in curing properties, mechanical strength, and T. E. McIff residual monomer content. Methods The University of Four cement groups were prepared using commercial PMMA bone cement: a control; one Kansas Medical with 1 g of rifampin; and one each with equimolar amounts of ascorbic acid or hydroquinone Center, Kansas City, relative to the amount of rifampin added. The handling properties, setting time, exothermic Kansas, United States output, and monomer loss were measured throughout curing. The mechanical strength of each group was tested over 14 days. A radical scavenging assay was used to assess the scav- enging abilities of rifampin and its individual moieties. Results Compared with control, the rifampin-incorporated cement had a prolonged setting time and a reduction in exothermic output during polymerization. The rifampin cement showed significantly reduced strength and was below the orthopaedic weight-bearing threshold of 70 MPa. Based on the radical scavenging assay and strength tests, the hydroquinone struc- ture within rifampin was identified as the polymerization inhibitor. Conclusion G. A. Funk, BS, BS, Research The incorporation of rifampin into PMMA bone cement interferes with the cement’s radical Associate, polymerization. This interference is due to the hydroquinone moiety within rifampin. This K. A. Cole, BS, MS, Graduate combination alters the cement’s handling and curing properties, and lowers the strength Student, T. E. McIff, PhD, MBA, Associate below the threshold for weight-bearing applications. Additionally, the incomplete polym- Professor, Department of erization leads to increased toxic monomer output, which discourages its use even in non- Orthopedic Surgery, University weight-bearing applications. of Kansas Medical Center, Kansas City, Kansas, USA. Cite this article: Bone Joint Res 2019;8:81–89. E. M. Menuey, BS, Graduate Student, Keywords: Poly(methyl methacrylate) (PMMA), Rifampin, Strength, Radical K. V. Kilway, PhD, Associate Professor and Chair, Department of Chemistry, University of Article focus Key messages Missouri-Kansas City, Kansas City, Missouri, USA. The purpose of this study was to charac- The addition of rifampin to PMMA bone terize rifampin-loaded poly(methyl meth- cement interferes with the radical polym- T. P. Schuman, PhD, Associate Professor, Department of acrylate) (PMMA) bone cement. erization mechanism, resulting in delayed Chemistry, Missouri University of The cause of chemical incompatibility cement curing and reduced compressive Science and Technology, Rolla, Missouri, USA. between rifampin and the cement was strength. investigated, and various clinically rele- The hydroquinone structure within Correspondence should be sent to G. A. Funk; email: gfunk@ vant properties of the rifampin-loaded rifampin acts as a radical scavenger. kumc.edu cement were determined. The resulting incomplete polymerization doi: 10.1302/2046-3758.82.BJR- Surgical contraindications of rifampin- of the cement causes unreacted toxic 2018-0170.R2 loaded PMMA bone cement were monomer to leach from the cement over Bone Joint Res 2019;8:81–89. identified. time. VOL. 8, NO. 2, FEBRUARY 2019 81 82 G. A. FUNK, E. M. MENUEY, K. A. COLE, T. P. SCHUMAN, K. V. KILWAY, T. E. MCIFF Strengths and limitations polymerization and strength, and, as a result, has long A multitude of tests were performed to give a full been discounted as a possible additive to bone cement. characterization of rifampin-loaded PMMA bone Although clearly recognized, the cause of rifampin’s cement. incompatibility has never been experimentally deter- Compressive properties of, and unreacted monomer mined, nor has the effect been quantified. loss from, the cement may vary in vivo. An understanding of possible mechanisms for the effect of rifampin on PMMA bone cement may be Introduction obtained by analyzing the chemical structure and prop- Infection associated with orthopaedic surgery, and more erties of the antibiotic. Rifampin contains both a hydro- specifically total joint arthroplasty (TJA), is a severe com- quinone and piperazine moiety within its structure plication to patients and burdens the healthcare system.1 (Fig. 1). Both are known radical scavengers. The ability of While prosthetic joint infection (PJI) occurs in only 1% to rifampin to act as a radical scavenger was noted previ- 3% of TJA cases, the associated costs to the United States ously by Tomiyama et al20 in a 1996 study, where they healthcare system are projected to be US$1.62 billion by used rifampin to inhibit β protein aggregation in an the year 2020.2-4 Poly(methyl methacrylate) (PMMA) is Alzheimer’s model. Pozdeeva and Denisov21 investigated the major component of commercially available ortho- the mechanism of hydroquinone-mediated oxidation of paedic bone cement. It is used to anchor the implant in methyl methacrylate (MMA), and determined its impact the bone during primary cases, and in fabricating weight- on slowing the rate of the reaction. Aware of the scaveng- bearing spacers during revision surgery. Bone cement is ing potential of rifampin, McPherson and Portugal19 pro- routinely loaded with antibiotic(s), both prophylactically posed that rifampin reacted with the cement’s initiators and as part of infected revision as a means of delivering to quench the polymerization process. They reported high local doses of antibiotics, while avoiding the sys- increases in cement curing time, but this work was a case temic toxicity associated with intravenous administra- study and mechanical properties were not determined. tion.5,6 Staphylococcus aureus (S. aureus) and Little experimental work has been performed to under- coagulase-negative Staphylococcus spp. are the most stand and overcome rifampin’s effect on PMMA. One prevalent infectious organisms following orthopaedic paper by Rose et al18 evaluated rifampin release from surgery.7 Therefore, glycopeptide antibiotics such as van- poly(styrene-co-MMA monomer) (PS-PMMA) films rather comycin, and aminoglycosides such as gentamicin, are than from PMMA bone cement itself. In two separate stud- the most commonly incorporated drugs to treat PJI.8-10 ies by Sanchez et al16 and Shiels et al,17 the elution and Often, PJI will result in the formation of a biofilm on or effectiveness of rifampin-loaded PMMA bone cement near the implant. A biofilm is a collection of bacteria that beads using in vitro bioassays16 and in a rat infection forms a protective barrier with innate resistance to antibi- model17 were investigated. While the investigators found otics, and has a high propensity to develop on inert sur- reasonable antibacterial effectiveness, they also remarked faces such as implants and post-surgical bone.11,12 The on the slow and incomplete curing of the cement. Low presence of these biofilms can make standard antibiotic strength and stiffness of rifampin-loaded cement remain treatments ineffective, as both vancomycin and gen- major shortcomings for weight-bearing applications. In tamicin are ineffective at clearing biofilms.13 Unlike van- the referenced studies, the mechanism of rifampin’s chem- comycin and gentamicin, rifampin is highly effective ical interaction with the cement was not investigated. against staphylococcal biofilms.13,14 Rifampin is used sys- The purpose of the present study was to elucidate the temically in nearly all orthopaedic infection treatment interaction between rifampin and a commercially availa- regimens, especially when the presence of methicillin- ble PMMA bone cement, and to determine a number of resistant S. aureus (MRSA) is suspected.15 Even at easily clinically relevant properties of the composite material. achievable infection site concentrations of 1 μg/ml to These characteristics include its biomechanical strength 8 μg/ml, rifampin can lead to a 5 log10 to 9 log10 reduc- and modulus over time, surface morphology, curing tion in bacterial biofilms and suppress bacterial recovery time, and the amount of unreacted monomer still pre- by up to 24 hours post-treatment, which indicates almost sent within the cement. Additionally, we sought to utilize complete eradication of the biofilm.16 a radical scavenging assay to verify experimentally the Recently, there has been increased interest in charac- mechanism of interaction between rifampin and the terizing the ability of PMMA bone cement to act as a car- cement. We hypothesized that the hydroquinone unit rier for local delivery of rifampin to fight infection in the contained within rifampin acts as a radical scavenger, presence of biofilms.16-18 In this regard, a number of and is responsible for the interaction of rifampin with the adverse effects associated with rifampin-loaded PMMA cement’s polymerization process. Two known radical bone cement have been reported.17,19 Rifampin, which scavenging molecules, ascorbic acid and hydroquinone, was approved in the United States in 1971, was recog- were also added to PMMA bone cement to further

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