Calcium Phosphate Spacers for the Local Delivery of Sitafloxacin and Rifampin to Treat Orthopedic Infections: Efficacy and Proof of Concept in a Mouse Model of Single-Stage Revision of Device-Associated Osteomyelitis

Overview

Journal Pharmaceutics

Publisher MDPI

Date 2019 Mar 1

PMID 30813284

Citations 15

Authors

Ryan P Trombetta

Mark J Ninomiya

Ihab M El-Atawneh

Emma K Knapp

Karen L de Mesy Bentley

Paul M Dunman

Edward M Schwarz

Stephen L Kates

Hani A Awad

Affiliations

Soon will be listed here.

Abstract

Osteomyelitis is a chronic bone infection that is often treated with adjuvant antibiotic-impregnated poly(methyl methacrylate) (PMMA) cement spacers in multi-staged revisions. However, failure rates remain substantial due to recurrence of infection, which is attributed to the poor performance of the PMMA cement as a drug release device. Hence, the objective of this study was to design and evaluate a bioresorbable calcium phosphate scaffold (CaPS) for sustained antimicrobial drug release and investigate its efficacy in a murine model of femoral implant-associated osteomyelitis. Incorporating rifampin and sitafloxacin, which are effective against bacterial phenotypes responsible for bacterial persistence, into 3D-printed CaPS coated with poly(lactic co-glycolic) acid, achieved controlled release for up to two weeks. Implantation into the murine infection model resulted in decreased bacterial colonization rates at 3- and 10-weeks post-revision for the 3D printed CaPS in comparison to gentamicin-laden PMMA. Furthermore, a significant increase in bone formation was observed for 3D printed CaPS incorporated with rifampin at 3 and 10 weeks. The results of this study demonstrate that osteoconductive 3D printed CaPS incorporated with antimicrobials demonstrate more efficacious bacterial colonization outcomes and bone growth in a single-stage revision in comparison to gentamicin-laden PMMA requiring a two-stage revision.

Citing Articles

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References

Wehrli W . Rifampin: mechanisms of action and resistance. Rev Infect Dis. 1983; 5 Suppl 3:S407-11. DOI: 10.1093/clinids/5.supplement_3.s407. View

Metsemakers W, Kuehl R, Moriarty T, Richards R, Verhofstad M, Borens O . Infection after fracture fixation: Current surgical and microbiological concepts. Injury. 2016; 49(3):511-522. DOI: 10.1016/j.injury.2016.09.019. View

Sanchez Jr C, Shiels S, Tennent D, Hardy S, Murray C, Wenke J . Rifamycin Derivatives Are Effective Against Staphylococcal Biofilms In Vitro and Elutable From PMMA. Clin Orthop Relat Res. 2015; 473(9):2874-84. PMC: 4523531. DOI: 10.1007/s11999-015-4300-3. View

Cosgrove S, Sakoulas G, Perencevich E, Schwaber M, Karchmer A, Carmeli Y . Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis. 2002; 36(1):53-9. DOI: 10.1086/345476. View

Minier K, Toure A, Fusellier M, Fellah B, Bouvy B, Weiss P . BMP-2 delivered from a self-crosslinkable CaP/hydrogel construct promotes bone regeneration in a critical-size segmental defect model of non-union in dogs. Vet Comp Orthop Traumatol. 2014; 27(6):411-21. DOI: 10.3415/VCOT-14-03-0036. View

Vella J, Trombetta R, Hoffman M, Inzana J, Awad H, Benoit D . Three dimensional printed calcium phosphate and poly(caprolactone) composites with improved mechanical properties and preserved microstructure. J Biomed Mater Res A. 2017; 106(3):663-672. PMC: 5785440. DOI: 10.1002/jbm.a.36270. View

Street J, Bao M, deGuzman L, Bunting S, Peale Jr F, Ferrara N . Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proc Natl Acad Sci U S A. 2002; 99(15):9656-61. PMC: 124965. DOI: 10.1073/pnas.152324099. View

Inzana J, Trombetta R, Schwarz E, Kates S, Awad H . 3D printed bioceramics for dual antibiotic delivery to treat implant-associated bone infection. Eur Cell Mater. 2015; 30:232-47. PMC: 4663047. DOI: 10.22203/ecm.v030a16. View

Castilho M, Rodrigues J, Pires I, Gouveia B, Pereira M, Moseke C . Fabrication of individual alginate-TCP scaffolds for bone tissue engineering by means of powder printing. Biofabrication. 2015; 7(1):015004. DOI: 10.1088/1758-5090/7/1/015004. View

10.

Colman M, Wright A, Gruen G, Siska P, Pape H, Tarkin I . Prolonged operative time increases infection rate in tibial plateau fractures. Injury. 2012; 44(2):249-52. PMC: 4034524. DOI: 10.1016/j.injury.2012.10.032. View

11.

He F, Chen Y, Li J, Lin B, Ouyang Y, Xia Y . Improving bone repair of femoral and radial defects in rabbit by incorporating PRP into PLGA/CPC composite scaffold with unidirectional pore structure. J Biomed Mater Res A. 2014; 103(4):1312-24. DOI: 10.1002/jbm.a.35248. View

12.

Kaigler D, Wang Z, Horger K, Mooney D, Krebsbach P . VEGF scaffolds enhance angiogenesis and bone regeneration in irradiated osseous defects. J Bone Miner Res. 2006; 21(5):735-44. DOI: 10.1359/jbmr.060120. View

13.

Sanchez-Sotelo J, Berry D, Hanssen A, Cabanela M . Midterm to long-term followup of staged reimplantation for infected hip arthroplasty. Clin Orthop Relat Res. 2008; 467(1):219-24. PMC: 2600996. DOI: 10.1007/s11999-008-0480-4. View

14.

Parvizi J, Pawasarat I, Azzam K, Joshi A, Hansen E, Bozic K . Periprosthetic joint infection: the economic impact of methicillin-resistant infections. J Arthroplasty. 2010; 25(6 Suppl):103-7. DOI: 10.1016/j.arth.2010.04.011. View

15.

McLaren A, Nugent M, Economopoulos K, Kaul H, Vernon B, McLemore R . Hand-mixed and premixed antibiotic-loaded bone cement have similar homogeneity. Clin Orthop Relat Res. 2009; 467(7):1693-8. PMC: 2690765. DOI: 10.1007/s11999-009-0847-1. View

16.

Reynolds D, Hock C, Shaikh S, Jacobson J, Zhang X, Rubery P . Micro-computed tomography prediction of biomechanical strength in murine structural bone grafts. J Biomech. 2007; 40(14):3178-86. DOI: 10.1016/j.jbiomech.2007.04.004. View

17.

Herrmann M, Vaudaux P, Pittet D, Auckenthaler R, Lew P, Peters G . Fibronectin, fibrinogen, and laminin act as mediators of adherence of clinical staphylococcal isolates to foreign material. J Infect Dis. 1988; 158(4):693-701. DOI: 10.1093/infdis/158.4.693. View

18.

Vergidis P, Rouse M, Euba G, Karau M, Schmidt S, Mandrekar J . Treatment with linezolid or vancomycin in combination with rifampin is effective in an animal model of methicillin-resistant Staphylococcus aureus foreign body osteomyelitis. Antimicrob Agents Chemother. 2010; 55(3):1182-6. PMC: 3067063. DOI: 10.1128/AAC.00740-10. View

19.

Garcia L, Lemaire S, Kahl B, Becker K, Proctor R, Denis O . Antibiotic activity against small-colony variants of Staphylococcus aureus: review of in vitro, animal and clinical data. J Antimicrob Chemother. 2013; 68(7):1455-64. DOI: 10.1093/jac/dkt072. View

20.

Grammatico-Guillon L, Baron S, Gettner S, Lecuyer A, Gaborit C, Rosset P . Bone and joint infections in hospitalized patients in France, 2008: clinical and economic outcomes. J Hosp Infect. 2012; 82(1):40-8. DOI: 10.1016/j.jhin.2012.04.025. View