Efficacy of colistin-impregnated beads to prevent multidrug-resistant A. baumannii implant-associated osteomyelitis†‡
Daniel P. Crane
The Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York 14642
Disclaimer: The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of the Army, Department of Defense, or the US government. This work was prepared as part of their official duties.
Search for more papers by this authorKirill Gromov
The Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York 14642
The Department of Orthopedics, Aarhus University Hospital, Aarhus, Denmark
These authors contributed equally to this work.
Search for more papers by this authorDan Li
The Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York 14642
Search for more papers by this authorKjeld Søballe
The Department of Orthopedics, Aarhus University Hospital, Aarhus, Denmark
Search for more papers by this authorChristian Wahnes
Research & Development, Heraeus Medical GmbH, Wehrheim, Germany
Search for more papers by this authorHubert Büchner
Research & Development, Heraeus Medical GmbH, Wehrheim, Germany
Search for more papers by this authorMatthew J. Hilton
The Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York 14642
Search for more papers by this authorRegis J. O'Keefe
The Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York 14642
Search for more papers by this authorClinton K. Murray
Infectious Disease Service, Department of Medicine, Brooke Army Medical Center, Fort Sam Houston, San Antonio, Texas
Search for more papers by this authorCorresponding Author
Edward M. Schwarz
The Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York 14642
The Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York 14642. T: 585-275-3063; F: 585-756-4727.Search for more papers by this authorDaniel P. Crane
The Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York 14642
Disclaimer: The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of the Army, Department of Defense, or the US government. This work was prepared as part of their official duties.
Search for more papers by this authorKirill Gromov
The Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York 14642
The Department of Orthopedics, Aarhus University Hospital, Aarhus, Denmark
These authors contributed equally to this work.
Search for more papers by this authorDan Li
The Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York 14642
Search for more papers by this authorKjeld Søballe
The Department of Orthopedics, Aarhus University Hospital, Aarhus, Denmark
Search for more papers by this authorChristian Wahnes
Research & Development, Heraeus Medical GmbH, Wehrheim, Germany
Search for more papers by this authorHubert Büchner
Research & Development, Heraeus Medical GmbH, Wehrheim, Germany
Search for more papers by this authorMatthew J. Hilton
The Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York 14642
Search for more papers by this authorRegis J. O'Keefe
The Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York 14642
Search for more papers by this authorClinton K. Murray
Infectious Disease Service, Department of Medicine, Brooke Army Medical Center, Fort Sam Houston, San Antonio, Texas
Search for more papers by this authorCorresponding Author
Edward M. Schwarz
The Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York 14642
The Center for Musculoskeletal Research, University of Rochester Medical Center, 601 Elmwood Avenue, Box 665, Rochester, New York 14642. T: 585-275-3063; F: 585-756-4727.Search for more papers by this authorThis article is a US Government work and, as such, is in the public domain in the United States of America.
Abstract
Osteomyelitis (OM) from multidrug-resistant (MDR) Acinetobacter has emerged in >30% of combat-related injuries in Iraq and Afghanistan. While most of these strains are sensitive to colistin, the drug is not availible in bone void fillers for local high-dose delivery. To address this, we developed a mouse model with MDR strains isolated from wounded military personnel. In contrast to S. aureus OM, which is osteolytic and characterized by biofilm in necrotic bone, A. baumannii OM results in blastic lesions that do not contain apparent biofilm. We also found that mice mount a specific IgG response against three proteins (40, 47, and 56 kDa) regardless of the strain used, suggesting that these may be immuno-dominant antigens. PCR for the A. baumannii-specific parC gene confirmed a 100% infection rate with 75% of the MDR strains, and in vitro testing confirmed that all strains were sensitive to colistin. We also developed a real-time quantitative PCR (RTQ-PCR) assay that could detect as few as 10 copies of parC in a sample. To demonstrate the efficacy of colistin prophylaxis in this model, mice were treated with either parenteral colistin (0.2 mg colistinmethate i.m. for 7 days), local colistin (PMMA bead impregnated with 1.0 mg colistin sulfate), or an unloaded PMMA bead control. While the parenteral colistin failed to demonstrate any significant effects versus the placebo, the colistin PMMA bead significantly reduced the infection rate such that only 29.2% of the mice had detectable levels of parC at 19 days (p < 0.05 vs. i.m. colistin and placebo). © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 1008–1015, 2009
REFERENCES
- 1 Covey DC. 2006. Iraq war injuries. Orthopedics 29: 884–886.
- 2 Owens BD, Kragh JF Jr, Macaitis J, et al. 2007. Characterization of extremity wounds in Operation Iraqi Freedom and Operation Enduring Freedom. J Orthop Trauma 21: 254–257.
- 3 Owens BD, Kragh JF Jr, Wenke JC, et al. 2008. Combat wounds in operation Iraqi Freedom and operation Enduring Freedom. J Trauma 64: 295–299.
- 4 Covey DC. 2006. Combat orthopaedics: a view from the trenches. J Am Acad Orthop Surg 14 (Suppl): S10–S17.
- 5 Covey DC, Aaron RK, Born CT, et al. 2008. Orthopaedic war injuries: from combat casualty care to definitive treatment: a current review of clinical advances, basic science, and research opportunities. Instr Course Lect 57: 65–86.
- 6 Murray CK, Hsu JR, Solomkin JS, et al. 2008. Prevention and management of infections associated with combat-related extremity injuries. J Trauma 64 (Suppl): S239–S251.
- 7 Yun HC, Branstetter JG, Murray CK. 2008. Osteomyelitis in military personnel wounded in Iraq and Afghanistan. J Trauma 64 (Suppl): S163–S168.
- 8 Anonymous. 2004. Acinetobacter baumannii infections among patients at military medical facilities treating injured U.S. service members, 2002–2004. MMWR 53(45): 1063–1066.
- 9 Murray CK, Hospenthal DR. 2005. Treatment of multidrug resistant Acinetobacter. Curr Opin Infect Dis 18: 502–506.
- 10 Davis KA, Moran KA, McAllister CK, et al. 2005. Multidrug-resistant Acinetobacter extremity infections in soldiers. Emerg Infect Dis 11: 1218–1224.
- 11 Abbo A, Navon-Venezia S, Hammer-Muntz O, et al. 2005. Multidrug-resistant Acinetobacter baumannii. Emerg Infect Dis 11: 22–29.
- 12 Darouiche RO. 2004. Treatment of infections associated with surgical implants. N Engl J Med 350: 1422–1429.
- 13 Scott P, Deye G, Srinivasan A, et al. 2007. An outbreak of multidrug-resistant Acinetobacter baumannii-calcoaceticus complex infection in the US military health care system associated with military operations in Iraq. Clin Infect Dis 44: 1577–1584.
- 14 Hawley JS, Murray CK, Jorgensen JH. 2008. Colistin heteroresistance in Acinetobacter and its association with previous colistin therapy. Antimicrob Agents Chemother 52: 351–352.
- 15 Li D, Gromov K, Soballe K, et al. 2008. Quantitative mouse model of implant-associated osteomyelitis and the kinetics of microbial growth, osteolysis, and humoral immunity. J Orthop Res 26: 96–105.
- 16 Marks KE, Nelson CL Jr, Schwartz J. 1974. Antibiotic-impregnated acrylic bone cement. Surg Forum 25: 493–494.
- 17 Wininger DA, Fass RJ. 1996. Antibiotic-impregnated cement and beads for orthopedic infections. Antimicrob Agents Chemother 40: 2675–2679.
- 18 Parvizi J, Saleh KJ, Ragland PS, et al. 2008. Efficacy of antibiotic-impregnated cement in total hip replacement. Acta Orthop 79: 335–341.
- 19 Falagas ME, Kasiakou SK. 2005. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis 40: 1333–1341.
- 20 Hamouda A, Amyes SG. 2006. Development of highly ciprofloxacin-resistant laboratory mutants of Acinetobacter baumannii lacking topoisomerase IV gene mutations. J Antimicrob Chemother 57: 155–156.
- 21 Montero A, Ariza J, Corbella X, et al. 2004. Antibiotic combinations for serious infections caused by carbapenem-resistant Acinetobacter baumannii in a mouse pneumonia model. J Antimicrob Chemother 54: 1085–1091.
- 22 Zhang X, Schwarz EM, Young DA, et al. 2002. Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair. J Clin Invest 109: 1405–1415.
- 23 Koefoed M, Ito H, Gromov K, et al. 2005. Biological effects of rAAV-caAlk2 coating on structural allograft healing. Mol Ther 12: 212–218.
- 24 Ito H, Koefoed M, Tiyapatanaputi P, et al. 2005. Remodeling of cortical bone allografts mediated by adherent rAAV-RANKL and VEGF gene therapy. Nat Med 11: 291–297.
- 25 Brady RA, Leid JG, Calhoun JH, et al. 2008. Osteomyelitis and the role of biofilms in chronic infection. FEMS Immunol Med Microbiol 52: 13–22.
- 26 Kurtz SM, Lau E, Schmier J, et al. 2008. Infection burden for hip and knee arthroplasty in the United States. J Arthroplasty 23: 984–991.
- 27 Pulido L, Ghanem E, Joshi A, et al. 2008. Periprosthetic joint infection: the incidence, timing, and predisposing factors. Clin Orthop Relat Res 466: 1710–1715.
- 28 Klevens RM, Morrison MA, Nadle J, et al. 2007. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 298: 1763–1771.
- 29 Johnson EN, Burns TC, Hayda RA, et al. 2007. Infectious complications of open type III tibial fractures among combat casualties. Clin Infect Dis 45: 409–415.
- 30 Virk MS, Lieberman JR. 2007. Tumor metastasis to bone. Arthritis Res Ther 9 (Suppl 1): S5.
- 31 Akira S, Takeda K, Kaisho T. 2001. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol 2: 675–680.
- 32 Bi Y, Collier TO, Goldberg VM, et al. 2002. Adherent endotoxin mediates biological responses of titanium particles without stimulating their phagocytosis. J Orthop Res 20: 696–703.
- 33 Bi Y, Seabold JM, Kaar SG, et al. 2001. Adherent endotoxin on orthopedic wear particles stimulates cytokine production and osteoclast differentiation. J Bone Miner Res 16: 2082–2091.
- 34 Bi Y, Van De Motter RR, Ragab AA, et al. 2001. Titanium particles stimulate bone resorption by inducing differentiation of murine osteoclasts. J Bone Joint Surg [Am] 83-A: 501–508.
- 35 Nalepka JL, Lee MJ, Kraay MJ, et al. 2006. Lipopolysaccharide found in aseptic loosening of patients with inflammatory arthritis. Clin Orthop Relat Res 451: 229–235.
- 36 Antoci V Jr, King SB, Jose B, et al. 2007. Vancomycin covalently bonded to titanium alloy prevents bacterial colonization. J Orthop Res 25: 858–866.
- 37 Parvizi J, Antoci V Jr, Hickok NJ, et al. 2007. Selfprotective smart orthopedic implants. Expert Rev Med Devices 4: 55–64.
