Review Article | Published:

Implant infections: adhesion, biofilm formation and immune evasion

Nature Reviews Microbiologyvolume 16pages397409 (2018) | Download Citation


Medical device-associated infections account for a large proportion of hospital-acquired infections. A variety of opportunistic pathogens can cause implant infections, depending on the type of the implant and on the anatomical site of implantation. The success of these versatile pathogens depends on rapid adhesion to virtually all biomaterial surfaces and survival in the hostile host environment. Biofilm formation on implant surfaces shelters the bacteria and encourages persistence of infection. Furthermore, implant-infecting bacteria can elude innate and adaptive host defences as well as biocides and antibiotic chemotherapies. In this Review, we explore the fundamental pathogenic mechanisms underlying implant infections, highlighting orthopaedic implants and Staphylococcus aureus as a prime example, and discuss innovative targets for preventive and therapeutic strategies.

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  1. 1.

    Arciola, C. R., Campoccia, D., Ehrlich, G. D. & Montanaro, L. Biofilm-based implant infections in orthopaedics. Adv. Exp. Med. Biol. 830, 29–46 (2015).

  2. 2.

    Montanaro, L. et al. Scenery of Staphylococcus implant infections in orthopedics. Future Microbiol. 6, 1329–1349 (2011).

  3. 3.

    Magill, S. S. et al. Emerging infections program healthcare-associated infections and antimicrobial use prevalence survey team. Multistate point-prevalence survey of health care-associated infections. N. Engl. J. Med. 370, 1198–1208 (2014).

  4. 4.

    Arciola, C. R., An, Y. H., Campoccia, D., Donati, M. E. & Montanaro, L. Etiology of implant orthopedic infections: a survey on 1027 clinical isolates. Int. J. Artif. Organs. 28, 1091–1100 (2005).

  5. 5.

    Anderson, J. M. Future challenges in the in vitro and in vivo evaluation of biomaterial biocompatibility. Regen. Biomater. 3, 73–77 (2016).

  6. 6.

    Menkin, V. Studies on inflammation: VII. Fixation of bacteria and of particulate matter at the site of inflammation. J. Exp. Med. 53, 647–660 (1931).

  7. 7.

    Gristina, A. G. Implant failure and the immuno-incompetent fibroinflammatory zone. Clin. Orthop. Relat. Res. 298, 106–118 (1994).

  8. 8.

    Schierholz, J. M. & Beuth, J. Implant infections: a haven for opportunistic bacteria. J. Hosp. Infect. 49, 87–93 (2001).

  9. 9.

    Arciola, C. R., Campoccia, D., Speziale, P., Montanaro, L. & Costerton, J. W. Biofilm formation in Staphylococcus implant infections. A review of molecular mechanisms and implications for biofilm-resistant materials. Biomaterials 33, 5967–5982 (2012). This article reviews the formation and composition of biofilms on biomaterials and anti-biofilm biomaterials.

  10. 10.

    Southwood, R. T. et al. Infection in experimental hip arthroplasties. J. Bone Joint Surg. Br. 67, 229–231 (1985).

  11. 11.

    von Eiff, C., Arciola, C. R., Montanaro, L., Becker, K. & Campoccia, D. Emerging Staphylococcus species as new pathogens in implant infections. Int. J. Artif. Organs. 29, 360–367 (2003).

  12. 12.

    Zimmerli, W. Clinical presentation and treatment of orthopaedic implant-associated infection. J. Intern. Med. 276, 111–119 (2014). This article discusses old and new criteria for the classification of periprosthetic joint infections.

  13. 13.

    Osmon, D. R. et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the infectious diseases society of America. Clin. Infect. Dis. 56, e1–e25 (2013).

  14. 14.

    Tande, A. J. & Patel, R. Prosthetic joint infection. Clin. Microbiol. Rev. 27, 302–345 (2014).

  15. 15.

    Cobo, J. & Del Pozo, J. L. Prosthetic joint infection: diagnosis and management. Expert. Rev. Anti Infect. Ther. 9, 787–802 (2011).

  16. 16.

    Campoccia, D., Montanaro, L. & Arciola, C. R. A review of the clinical implications of anti-infective biomaterials and infection-resistant surfaces. Biomaterials 34, 8018–8029 (2013).

  17. 17.

    Trampuz, A. & Widmer, A. F. Infections associated with orthopedic implants. Curr. Opin. Infect. Dis. 19, 349–356 (2006).

  18. 18.

    Aggarwal, V. K. et al. Organism profile in periprosthetic joint infection: pathogens differ at two arthroplasty infection referral centers in Europe and in the United States. J. Knee Surg. 27, 399–406 (2014).

  19. 19.

    Campoccia, D., Montanaro, L. & Arciola, C. R. The significance of infection related to orthopedic devices and issues of antibiotic resistance. Biomaterials 27, 2331–2339 (2006).

  20. 20.

    Li, B. & Webster, T. J. Bacteria antibiotic resistance: new challenges and opportunities for implant-associated orthopedic infections. J. Orthop. Res. 36, 22–32 (2018).

  21. 21.

    Guo, G., Wang, J., You, Y., Tan, J. & Shen, H. Distribution characteristics of Staphylococcus spp. in different phases of periprosthetic joint infection: a review. Exp. Ther. Med. 13, 2599–2608 (2017).

  22. 22.

    Campoccia, D. et al. Cluster analysis of ribotyping profiles of Staphylococcus epidermidis isolates recovered from foreign body-associated orthopedic infections. J. Biomed. Mater. Res. A. 88, 664–672 (2009).

  23. 23.

    Campoccia, D. et al. Molecular epidemiology of Staphylococcus aureus from implant orthopaedic infections: ribotypes, agr polymorphism, leukocidal toxins and antibiotic resistance. Biomaterials 29, 4108–4116 (2008).

  24. 24.

    An, Y. H. Dickinson, R. B. & Doyle, R. J. in Handbook of bacterial adhesion: principles, methods, and applications (eds An, Y. H. & Friedman, R. J.) 1–27 (Humana Press, 2000).

  25. 25.

    Dunne, W. M. Jr. Bacterial adhesion: seen any good biofilms lately? Clin. Microbiol. Rev. 15, 155–166 (2002).

  26. 26.

    Franz, S., Rammelt, S., Scharnweber, D. & Simon, J. C. Immune responses to implants - a review of the implications for the design of immunomodulatory biomaterials. Biomaterials 32, 6692–6709 (2011).

  27. 27.

    Speziale, P. et al. Structural and functional role of Staphylococcus aureus surface components recognizing adhesive matrix molecules of the host. Future Microbiol. 4, 1337–1352 (2009).

  28. 28.

    Wilson, C. J., Clegg, R. E., Leavesley, D. I. & Pearcy, M. J. Mediation of biomaterial-cell interactions by adsorbed proteins: a review. Tissue Eng. 11, 1–18 (2005).

  29. 29.

    Otto, M. Staphylococcus epidermidis — the ‘accidental’ pathogen. Nat. Rev. Microbiol. 7, 555–567 (2009).

  30. 30.

    Paharik, A. E. & Horswill, A. R. The Staphylococcal biofilm: adhesins, regulation, and host response. Microbiol. Spectr. 4, 2 (2016).

  31. 31.

    Bos, R., van der Mei, H. C. & Busscher, H. J. Physico-chemistry of initial microbial adhesive interactions — its mechanisms and methods for study. FEMS Microbiol. Rev. 23, 179–230 (1999).

  32. 32.

    Ribeiro, M., Monteiro, F. J. & Ferraz, M. P. Infection of orthopedic implants with emphasis on bacterial adhesion process and techniques used in studying bacterial-material interactions. Biomatter 2, 176–194 (2012).

  33. 33.

    Nguyen, V. T., Chia, T. W., Turner, M. S., Fegan, N. & Dykes, G. A. Quantification of acid-base interactions based on contact angle measurement allows XDLVO predictions to attachment of Campylobacter jejuni but not Salmonella. J. Microbiol. Methods. 86, 89–96 (2011).

  34. 34.

    Perni, S., Preedy, E. C. & Prokopovich, P. Success and failure of colloidal approaches in adhesion of microorganisms to surfaces. Adv. Colloid Interface Sci. 206, 265–274 (2014).

  35. 35.

    Kline, K. A., Fälker, S., Dahlberg, S., Normark, S. & Henriques-Normark, B. Bacterial adhesins in host-microbe interactions. Cell Host Microbe. 5, 580–592 (2009).

  36. 36.

    Mandlik, A., Swierczynski, A., Das, A. & Ton-That, H. Pili in grampositive bacteria: assembly, involvement in colonization and biofilm development. Trends Microbiol. 16, 33–40 (2008).

  37. 37.

    Katsutoshi, H. & Shinya, M. Bacterial adhesion: from mechanism to control. Biochem. Eng. J. 48, 424–434 (2010).

  38. 38.

    Heilmann, C., Hussain, M., Peters, G. & Götz, F. Evidence for autolysin-mediated primary attachment of Staphylococcus epidermidis to a polystyrene surface. Mol. Microbiol. 24, 1013–1024 (1997).

  39. 39.

    Foster, S. J. Molecular characterization and functional analysis of the major autolysin of Staphylococcus aureus 8325/4. J. Bacteriol. 177, 5723–5725 (1995).

  40. 40.

    Bose, J. L., Lehman, M. K., Fey, P. D. & Bayles, K. W. Contribution of the Staphylococcus aureus Atl AM and GL murein hydrolase activities in cell division, autolysis, and biofilm formation. PLoS ONE. 7, e42244 (2012).

  41. 41.

    Hirschhausen, N. et al. A novel staphylococcal internalization mechanism involves the major autolysin Atl and heat shock cognate protein Hsc70 as host cell receptor. Cell. Microbiol. 12, 1746–1764 (2010).

  42. 42.

    Mohamed, J. A., Huang, W., Nallapareddy, S. R., Teng, F. & Murray, B. E. Influence of origin of isolates, especially endocarditis isolates, and various genes on biofilm formation by Enterococcus faecalis. Infect. Immun. 72, 3658–3663 (2004).

  43. 43.

    Boland, T., Latour, R. A. & Stutzenberger, F. J. in Handbook of bacterial adhesion: principles, methods, and applications (eds An, Y. H. & Friedman, R. J.) 1–27 (Humana Press, 2000).

  44. 44.

    Patti, J. M., Allen, B. L., McGavin, M. J. & Höök, M. MSCRAMM-mediated adherence of microorganisms to host tissues. Annu. Rev. Microbiol. 48, 585–617 (1994).

  45. 45.

    Chavakis, T., Wiechmann, K., Preissner, K. T. & Herrmann, M. Staphylococcus aureus interactions with the endothelium: the role of bacterial “secretable expanded repertoire adhesive molecules” (SERAM) in disturbing host defense systems. Thromb. Haemost. 94, 278–285 (2005).

  46. 46.

    Foster, T. J., Geoghegan, J. A., Ganesh, V. K. & Höök, M. Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus. Nat. Rev. Microbiol. 12, 49–62 (2014). This review presents the structural and functional properties of MSCRAMMs.

  47. 47.

    Campoccia, D. et al. The presence of both bone sialoprotein-binding protein gene and collagen adhesin gene as a typical virulence trait of the major epidemic cluster in isolates from orthopedic implant infections. Biomaterials. 30, 6621–6628 (2009).

  48. 48.

    Mao, Y. & Schwarzbauer, J. E. Fibronectin fibrillogenesis, a cell-mediated matrix assembly process. Matrix Biol. 24, 389–399 (2005).

  49. 49.

    Arciola, C. R. et al. Staphylococcus epidermidis-fibronectin binding and its inhibition by heparin. Biomaterials 24, 3013–3019 (2003).

  50. 50.

    Arciola, C. R., Campoccia, D., Gamberini, S., Donati, M. E. & Montanaro, L. Presence of fibrinogen-binding adhesin gene in Staphylococcus epidermidis isolates from central venous catheters-associated and orthopaedic implant-associated infections. Biomaterials 25, 4825–4829 (2004).

  51. 51.

    Gristina, A. G., Naylor, P. & Myrvik, Q. Infections from biomaterials and implants: a race for the surface. Med. Prog. Technol. 14, 205–224 (1988–1989).

  52. 52.

    Subbiahdoss, G., Kuijer, R., Grijpma, D. W., van der Mei, H. C. & Busscher, H. J. Microbial biofilm growth versus tissue integration: “the race for the surface” experimentally studied. Acta Biomater 5, 1399–1404 (2009). The fate of biomaterial implants depends on the balance between integration by host cells and tissues and bacterial colonization, and this paper studies this competition with an interesting experimental approach.

  53. 53.

    Gristina, A. G. Biomaterial-centered infection: microbial adhesion versus tissue integration. Science 237, 1588–1595 (1987).

  54. 54.

    Stones, D. H. & Krachler, A. M. Against the tide: the role of bacterial adhesion in host colonization. Biochem. Soc. Trans. 44, 1571–1580 (2016).

  55. 55.

    Roberts, A. E., Kragh, K. N., Bjarnsholt, T. & Diggle, S. P. The limitations of in vitro experimentation in understanding biofilms and chronic infection. J. Mol. Biol. 427, 3646–3661 (2015).

  56. 56.

    Gristina, A. G. & Costerton, J. W. Bacterial adherence to biomaterials and tissue. The significance of its role in clinical sepsis. J. Bone Joint Surg. Am. 67A, 264–273 (1985).

  57. 57.

    Costerton, J. W., Stewart, P. S. & Greenberg, E. P. Bacterial biofilms: a common cause of persistent infections. Science 284, 1318–1322 (1999).

  58. 58.

    Coenye, T. Response of sessile cells to stress: from changes in gene expression to phenotypic adaptation. FEMS Immunol. Med. Microbiol. 59, 239–225 (2010).

  59. 59.

    Sørensen, S. J., Bailey, M., Hansen, L. H., Kroer, N. & Wuertz, S. Studying plasmid horizontal transfer in situ: a critical review. Nat. Rev. Microbiol. 3, 700–710 (2005).

  60. 60.

    Monds, R. D. & O’Toole, G. A. The developmental model of microbial biofilms: ten years of a paradigm up for review. Trends Microbiol. 17, 73–87 (2009).

  61. 61.

    Moormeier, D. E. & Bayles, K. W. Staphylococcus aureus biofilm: a complex developmental organism. Mol. Microbiol. 104, 365–376 (2017).

  62. 62.

    Flemming, H. C. et al. Biofilms: an emergent form of bacterial life. Nat. Rev. Microbiol. 14, 563–575 (2016).

  63. 63.

    Arciola, C. R., Campoccia, D., Ravaioli, S. & Montanaro, L. Polysaccharide intercellular adhesin in biofilm: structural and regulatory aspects. Front. Cell. Infect. Microbiol. 5, 7 (2015).

  64. 64.

    Arciola, C. R. et al. Antibiotic resistance in exopolysaccharide-forming Staphylococcus epidermidis clinical isolates from orthopaedic implant infections. Biomaterials. 26, 6530–6535 (2005).

  65. 65.

    Vuong, C. et al. Staphylococcus epidermidis polysaccharide intercellular adhesin production significantly increases during tricarboxylic acid cycle stress. J. Bacteriol. 187, 2967–2973 (2005).

  66. 66.

    Knobloch, J. K. et al. Biofilm formation by Staphylococcus epidermidis depends on functional RsbU, an activator of the sigB operon: differential activation mechanisms due to ethanol and salt stress. J. Bacteriol. 183, 2624–2633 (2001).

  67. 67.

    Ferreira, A., Gray, M., Wiedmann, M. & Boor, K. J. Comparative genomic analysis of the sigB operon in Listeria monocytogenes and in other gram-positive bacteria. Curr. Microbiol. 48, 39–46 (2004).

  68. 68.

    Savage, V. J., Chopra, I. & O’Neill, A. J. Staphylococcus aureus biofilms promote horizontal transfer of antibiotic resistance. Antimicrob. Agents Chemother. 57, 1968–1970 (2013).

  69. 69.

    Obolski, U. & Hadany, L. Implications of stress-induced genetic variation for minimizing multidrug resistance in bacteria. BMC Med. 10, 89 (2012).

  70. 70.

    Schaeffer, C. R. et al. Versatility of biofilm matrix molecules in Staphylococcus epidermidis: clinical isolates and importance of polysaccharide intercellular adhesin expression during high shear stress. mSphere 1, e00165–16 (2016).

  71. 71.

    Ziebuhr, W. et al. A novel mechanism of phase variation of virulence in Staphylococcus epidermidis: evidence for control of the polysaccharide intercellular adhesin synthesis by alternating insertion and excision of the insertion sequence element IS256. Mol. Microbiol. 32, 345–356 (1999).

  72. 72.

    Kozitskaya, S. et al. The bacterial insertion sequence element IS256 occurs preferentially in nosocomial Staphylococcus epidermidis isolates: association with biofilm formation and resistance to aminoglycosides. Infect. Immun. 72, 1210–1215 (2004).

  73. 73.

    Montanaro, L. et al. Extracellular DNA in biofilms. Int. J. Artif. Organs 34, 824–831 (2011).

  74. 74.

    Roberts, A. P. & Kreth, J. The impact of horizontal gene transfer on the adaptive ability of the human oral microbiome. Front. Cell. Infect. Microbiol. 4, 124 (2014).

  75. 75.

    Thurlow, L. R. et al. Staphylococcus aureus biofilms prevent macrophage phagocytosis and attenuate inflammation in vivo. J. Immunol. 186, 6585–6596 (2011).

  76. 76.

    Vorkapic, D., Pressler, K. & Schild, S. Multifaceted roles of extracellular DNA in bacterial physiology. Curr. Genet. 62, 71–79 (2016).

  77. 77.

    Turnbull, L. et al. Explosive cell lysis as a mechanism for the biogenesis of bacterial membrane vesicles and biofilms. Nat. Commun. 7, 11220 (2016).

  78. 78.

    Zatorska, B. et al. Does extracellular DNA production vary in Staphylococcal biofilms isolated from infected implants versus controls? Clin. Orthop. Relat. Res. 475, 2105–2113 (2017).

  79. 79.

    Thomas, V. C., Thurlow, L. R., Boyle, D. & Hancock, L. E. Regulation of autolysis-dependent extracellular DNA release by Enterococcus faecalis extracellular proteases influences biofilm development. J. Bacteriol. 90, 5690–5698 (2008).

  80. 80.

    Thomas, V. C. & Hancock, L. E. Suicide and fratricide in bacterial biofilms. Int. J. Artif. Organs. 32, 537–544 (2009).

  81. 81.

    Xia, G., Kohler, T. & Peschel, A. The wall teichoic acid and lipoteichoic acid polymers of Staphylococcus aureus. Int. J. Med. Microbiol. 300, 148–154 (2010).

  82. 82.

    Fedtke, I. et al. A Staphylococcus aureus ypfP mutant with strongly reduced lipoteichoic acid (LTA) content: LTA governs bacterial surface properties and autolysin activity. Mol. Microbiol. 65, 1078–1091 (2007).

  83. 83.

    Fabretti, F. et al. Alanine esters of enterococcal lipoteichoic acid play a role in biofilm formation and resistance to antimicrobial peptides. Infect. Immun. 74, 4164–4171 (2006).

  84. 84.

    Sabaté Brescó, M. et al. Pathogenic mechanisms and host interactions in Staphylococcus epidermidis device-related infection. Front. Microbiol. 8, 1401 (2017).

  85. 85.

    Patel, J. D., Colton, E., Ebert, M. & Anderson, J. M. Gene expression during S. epidermidis biofilm formation on biomaterials. J. Biomed. Mater. Res. A. 100, 2863–2869 (2012). This paper describes how the enhanced expression of the atlE, aap, agr and ica genes has an important role in initial foreign body colonization and, potentially, in the establishment of a device-associated infections.

  86. 86.

    Vandecasteele, S. J., Peetermans, W. E., Merckx, R. & Van Eldere, J. Expression of biofilm-associated genes in Staphylococcus epidermidis during in vitro and in vivo foreign body infections. J. Infect. Dis. 188, 730–737 (2003).

  87. 87.

    Le, K. Y. & Otto, M. Quorum-sensing regulation in staphylococci-an overview. Front. Microbiol. 6, 1174 (2015).

  88. 88.

    Boles, B. R. & Horswill, A. R. Agr-mediated dispersal of Staphylococcus aureus biofilms. PLoS Pathog. 4, e1000052 (2008).

  89. 89.

    Yu, D., Zhao, L., Xue, T. & Sun, B. Staphylococcus aureus autoinducer-2 quorum sensing decreases biofilm formation in an icaR-dependent manner. BMC Microbiol. 12, 288 (2012).

  90. 90.

    Xue, T., Ni, J., Shang, F., Chen, X. & Zhang, M. Autoinducer-2 increases biofilm formation via an ica- and bhp-dependent manner in Staphylococcus epidermidis RP62A. Microbes Infect. 17, 345–352 (2015).

  91. 91.

    McDougald, D., Rice, S. A., Barraud, N., Steinberg, P. D. & Kjelleberg, S. Should we stay or should we go: mechanisms and ecological consequences for biofilm dispersal. Nat. Rev. Microbiol. 10, 39–50 (2011).

  92. 92.

    Solano, C., Echeverz, M. & Lasa, I. Biofilm dispersion and quorum sensing. Curr. Opin. Microbiol. 18, 96–104 (2014).

  93. 93.

    Peschel, A. & Otto, M. Phenol-soluble modulins and staphylococcal infection. Nat. Rev. Microbiol. 11, 667–673 (2013). This paper describes how PSMs cause lysis of red and white blood cells, stimulate inflammatory responses and contribute to biofilm development and the dissemination of biofilm-associated infections. Moreover, they kill human neutrophils after phagocytosis.

  94. 94.

    Lister, J. L. & Horswill, A. R. Staphylococcus aureus biofilms: recent developments in biofilm dispersal. Front. Cell. Infect. Microbiol. 4, 178 (2014).

  95. 95.

    Le, K. Y., Dastgheyb, S., Ho, T. V. & Otto, M. Molecular determinants of staphylococcal biofilm dispersal and structuring. Front. Cell. Infect. Microbiol. 4, 167 (2014).

  96. 96.

    Wang, R. et al. Staphylococcus epidermidis surfactant peptides promote biofilm maturation and dissemination of biofilm-associated infection in mice. J. Clin. Invest. 121, 238–248 (2011).

  97. 97.

    Karatan, E. & Watnick, P. Signals, regulatory networks, and materials that buildand break bacterial biofilms. Microbiol. Mol. Biol. Rev. 73, 310–347 (2009).

  98. 98.

    Patel, J. D., Krupka, T. & Anderson, J. M. iNOS-mediated generation of reactive oxygen and nitrogen species by biomaterial-adherent neutrophils. J. Biomed. Mater. Res. A. 80, 381–390 (2007).

  99. 99.

    Kaplan, S. S., Basford, R. E., Mora, E., Jeong, M. H. & Simmons, R. L. Biomaterial-induced alterations of neutrophil superoxide production. J. Biomed. Mater. Res. 26, 1039–1051 (1992).

  100. 100.

    Zimmerli, W., Waldvogel, F. A., Vaudaux, P. & Nydeggerm, U. E. Pathogenesis of foreign body infection: description and characteristics of an animal model. J. Infect. Dis. 146, 487–497 (1982).

  101. 101.

    Campoccia, D. et al. Orthopedic implant infections: incompetence of Staphylococcus epidermidis. Staphylococcus lugdunensis, and Enterococcus faecalis to invade osteoblasts. J. Biomed. Mater. Res. A 104, 788–801 (2016).

  102. 102.

    Josse, J., Velard, F. & Gangloff, S. C. Staphylococcus aureus versus osteoblast: relationship and consequences in osteomyelitis. Front. Cell. Infect. Microbiol. (2015).

  103. 103.

    Fowler, T. et al. Cellular invasion by Staphylococcus aureus involves a fibronectin bridge between the bacterial fibronectin-binding MSCRAMMs and host cell beta1 integrins. Eur. J. Cell Biol. 279, 672–679 (2000).

  104. 104.

    Alexander, E. H. et al. Staphylococcus aureus-induced tumor necrosis factor – related apoptosis–inducing ligand expression mediates apoptosis and caspase-8 activation in infected osteoblasts. BMC Microbiol. 3, 5–16 (2003).

  105. 105.

    Reilly, S. S., Hudson, M. C., Kellam, J. F. & Ramp, W. K. In vivo internalization of Staphylococcus aureus by embryonic chick osteoblasts. Bone 26, 63–70 (2000).

  106. 106.

    Maali, Y. et al. Pathophysiological mechanisms of Staphylococcus non-aureus bone and joint infection: interspecies homogeneity and specific behavior of S. pseudintermedius. Front. Microbiol. 7, 1063 (2016).

  107. 107.

    Bui, L. M., Conlon, B. P. & Kidd, S. P. Antibiotic tolerance and the alternative lifestyles of Staphylococcus aureus. Essays Biochem. 61, 71–79 (2017).

  108. 108.

    Proctor, R. A. et al. Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections. Nat. Rev. Microbiol. 4, 295–305 (2006).

  109. 109.

    Tuchscherr, L. et al. Staphylococcus aureus small-colony variants are adapted phenotypes for intracellular persistence. J. Infect. Dis. 202, 1031–1040 (2010).

  110. 110.

    Garzoni, C. & Kelley, W. L. Staphylococcus aureus: new evidence for intracellular persistence. Trends Microbiol. 17, 59–65 (2009).

  111. 111.

    Sendi, P. et al. Staphylococcus aureus small colony variants in prosthetic joint infection. Clin. Infect. Dis. 43, 961–967 (2006).

  112. 112.

    Hamza, T. et al. Intra-cellular Staphylococcus aureus alone causes infection in vivo. Eur. Cell. Mater. 25, 341–350 (2013).

  113. 113.

    de Mesy Bentley, K. L. et al. Evidence of Staphylococcus aureus deformation, proliferation, and migration in canaliculi of live cortical bone in murine models of osteomyelitis. J. Bone Miner. Res. 32, 985–990 (2017).

  114. 114.

    Crémet, L. et al. Innate immune evasion of Escherichia coli clinical strains from orthopedic implant infections. Eur. J. Clin. Microbiol. Infect. Dis. 35, 993–999 (2016).

  115. 115.

    McGuinness, W. A., Kobayashi, S. D. & DeLeo, F. R. Evasion of neutrophil Killing by Staphylococcus aureus. Pathogens 5, E32 (2016).

  116. 116.

    Thammavongsa, V., Kim, H. K., Missiakas, D. & Schneewind, O. Staphylococcal manipulation of host immune responses. Nat. Rev. Microbiol. 13, 529–543 (2015). This is a very comprehensive review illustrating the many mechanisms that S. aureus uses to elude the host immune response.

  117. 117.

    Scherr, T. D. et al. Staphylococcus aureus biofilms induce macrophage dysfunction through leukocidin AB and alpha-toxin. mBio. 6, e01021–15 (2015).

  118. 118.

    Foster, T. J. Immune evasion by staphylococci. Nat. Rev. Microbiol. 3, 948–958 (2005).

  119. 119.

    Cheung, G. Y. et al. Staphylococcus epidermidis strategies to avoid killing by human neutrophils. PLoS Pathog. 6, e1001133 (2010).

  120. 120.

    Donaldson, K., Murphy, F. A., Duffin, R. & Poland Asbestos, C. A. carbon nanotubes and the pleural mesothelium: a review of the hypothesis regarding the role of long fibre retention in the parietal pleura, inflammation and mesothelioma. Part. Fibre Toxicol. 7, 5 (2010).

  121. 121.

    Leid, J. G., Shirtliff, M. E., Costerton, J. W. & Stoodley, P. Human leukocytes adhere to, penetrate, and respond to Staphylococcus aureus biofilms. Infect. Immun. 70, 6339–6345 (2002).

  122. 122.

    Hanke, M. L., Angle, A. & Kielian, T. MyD88-dependent signaling influences fibrosis and alternative macrophage activation during Staphylococcus aureus biofilm infection. PLoS One. 7, e42476 (2012).

  123. 123.

    Hanke, M. L. & Kielian, T. Deciphering mechanisms of staphylococcal biofilm evasion of host immunity. Front. Cell. Infect. Microbiol. 2, 62 (2012).

  124. 124.

    Gries, C. M. & Kielian, T. Staphylococcal biofilms and immune polarization during prosthetic joint infection. J. Am. Acad. Orthop. Surg. 25, S20–S24 (2017).

  125. 125.

    Benoit, M., Desnues, B. & Mege, J. L. Macrophage polarization in bacterial infections. J. Immunol. 181, 3733–3739 (2008).

  126. 126.

    Mbalaviele, G., Novack, D. V., Schett, G. & Teitelbaum, S. L. Inflammatory osteolysis: a conspiracy against bone. J. Clin. Invest. 127, 2030–2039 (2017).

  127. 127.

    Heim, C. E. et al. IL-12 promotes myeloid-derived suppressor cell recruitment and bacterial persistence during Staphylococcus aureus orthopedic implant infection. J. Immunol. 194, 3861–3872 (2015).

  128. 128.

    Fernández-Sampedro, M. et al. Accuracy of different diagnostic tests for early, delayed and late prosthetic joint infection. BMC Infect. Dis. 17, 592 (2017).

  129. 129.

    Costerton, J. W. et al. New methods for the detection of orthopedic and other biofilm infections. FEMS Immunol. Med. Microbiol. 61, 133–140 (2011).

  130. 130.

    Arciola, C. R., Montanaro, L. & Costerton, J. W. New trends in diagnosis and control strategies for implant infections. Int. J. Artif. Organs. 34, 727–736 (2011).

  131. 131.

    Harris, L. G. et al. Rapid identification of staphylococci from prosthetic joint infections using MALDI-TOF mass-spectrometry. Int. J. Artif. Organs. 33, 568–574 (2010).

  132. 132.

    Deurenberg, R. H. et al. Application of next generation sequencing in clinical microbiology and infection prevention. J. Biotechnol. 243, 16–24 (2017).

  133. 133.

    Mühlhofer, H. M. et al. Prosthetic joint infection development of an evidence-based diagnostic algorithm. Eur. J. Med. Res. 22, 8 (2017).

  134. 134.

    Tagini, F. & Greub, G. Bacterial genome sequencing in clinical microbiology: a pathogen-oriented review. Eur. J. Clin. Microbiol. Infect. Dis. 36, 2007–2020 (2017).

  135. 135.

    van Belkum, A., Welker, M., Pincus, D., Charrier, J. P. & Girard, V. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry in clinical microbiology: what are the current issues? Ann. Lab Med. 7, 475–483 (2017).

  136. 136.

    Deirmengian, C. et al. The alpha-defensin test for periprosthetic joint infection responds to a wide spectrum of organisms. Clin. Orthop. Relat. Res. 473, 2229–2235 (2015).

  137. 137.

    Aggarwal, V. K. et al. Mitigation and education. J. Orthop. Res. 32, S16–25 (2014).

  138. 138.

    Greenky, M., Gandhi, K., Pulido, L., Restrepo, C. & Parvizi, J. Preoperative anemia in total joint arthroplasty: is it associated with periprosthetic joint infection? Clin. Orthop. Relat. Res. 470, 2695–2701 (2012).

  139. 139.

    Ma, N. et al. Systematic review of a patient care bundle in reducing staphylococcal infections in cardiac and orthopaedic surgery. ANZ J. Surg. 87, 239–246 (2017).

  140. 140.

    Bode, L. G. et al. Preventing surgical-site infections in nasal carriers of Staphylococcus aureus. N. Engl. J. Med. 362, 9–17 (2010).

  141. 141.

    Gurusamy, K. S., Koti, R., Wilson, P. & Davidson, B. R. Antibiotic prophylaxis for the prevention of methicillin-resistant Staphylococcus aureus (MRSA) related complications in surgical patients. Cochrane Database Syst. Rev. 8, CD010268 (2013).

  142. 142.

    Voigt, J., Mosier, M. & Darouiche, R. Antibiotics and antiseptics for preventing infection in people receiving revision total hip and knee prostheses: a systematic review of randomized controlled trials. BMC Infect. Dis. 16, 749 (2016).

  143. 143.

    Campoccia, D., Montanaro, L. & Arciola, C. R. A review of the biomaterials technologies for infection-resistant surfaces. Biomaterials 34, 8533–8554 (2013). This paper describes innovative technologies that are used to develop new biomaterials and surfaces endowed with anti-infective properties, based on antifouling, bactericidal and anti-biofilm activities.

  144. 144.

    Alt, V. Antimicrobial coated implants in trauma and orthopaedics-a clinical review and risk-benefit analysis. Injury 48, 599–607 (2017).

  145. 145.

    Maddikeri, R. R. et al. Reduced medical infection related bacterial strains adhesion on bioactive RGD modified titanium surfaces: a first step toward cell selective surfaces. J. Biomed. Mater. Res. A. 84, 425–435 (2008).

  146. 146.

    Raphel, J., Holodniy, M., Goodman, S. B. & Heilshorn, S. C. Multifunctional coatings to simultaneously promote osseointegration and prevent infection of orthopaedic implants. Biomaterials 84, 301–314 (2016).

  147. 147.

    Chung, K. K. et al. Impact of engineered surface microtopography on biofilm formation of Staphylococcus aureus. Biointerphases 2, 89–94 (2007).

  148. 148.

    Jaggessar, A., Shahali, H., Mathew, A. & Yarlagadda, P. K. D. V. Bio-mimicking nano and micro-structured surface fabrication for antibacterial properties in medical implants. J. Nanobiotechnology 15, 64 (2017).

  149. 149.

    Leite, P. S., Figueiredo, S. & Sousa, R. Prosthetic joint infection: report on the one versus two-stage exchange EBJIS survey. J. Bone Joint Infect. 1, 1–6 (2016).

  150. 150.

    Coiffier, G., Albert, J. D., Arvieux, C. & Guggenbuhl, P. Optimizing combination rifampin therapy for staphylococcal osteoarticular infections. Joint Bone Spine. 80, 11–17 (2013).

  151. 151.

    Achermann, Y. et al. Factors associated with rifampin resistance in staphylococcal periprosthetic joint infections (PJI): a matched case-control study. Infection 41, 431–437 (2013).

  152. 152.

    König, D. P., Schierholz, J. M., Münnich, U. & Rütt, J. Treatment of staphylococcal implant infection with rifampicin-ciprofloxacin in stable implants. Arch. Orthop. Trauma Surg. 121, 297–299 (2001).

  153. 153.

    Hancock, R. E., Haney, E. F. & Gill, E. E. The immunology of host defence peptides: beyond antimicrobial activity. Nat. Rev. Immunol. 16, 321–234 (2016).

  154. 154.

    Pendleton, J. N., Gorman, S. P. & Gilmore, B. F. Clinical relevance of the ESKAPE pathogens. Expert. Rev. Anti Infect. Ther. 11, 297–308 (2013).

  155. 155.

    Bionda, N. et al. Identification of novel cyclic lipopeptides from a positional scanning combinatorial library with enhanced antibacterial and antibiofilm activities. Eur. J. Med. Chem. 108, 354–363 (2016).

  156. 156.

    Malcher, J., Wesoły, J. & Bluyssen, H. A. Molecular properties and medical applications of peptide nucleic acids. Mini Rev. Med. Chem. 14, 401–410 (2014).

  157. 157.

    Hansen, A. M. et al. Antibacterial peptide nucleic acid-antimicrobial peptide (PNA-AMP) conjugates: antisense targeting of fatty acid biosynthesis. Bioconjug. Chem. 27, 863–867 (2016).

  158. 158.

    Bai, H. et al. Antisense inhibition of gene expression and growth in gram-negative bacteria by cell-penetrating peptide conjugates of peptide nucleic acids targeted to rpoD gene. Biomaterials 33, 659–667 (2012).

  159. 159.

    Küçükdurmaz, F. & Parvizi, J. The prevention of periprosthetic joint infections. Open Orthop. J. 10, 589–599 (2016).

  160. 160.

    Brauner, A., Fridman, O., Gefen, O. & Balaban, N. Q. Distinguishing between resistance, tolerance and persistence to antibiotic treatment. Nat. Rev. Microbiol. 14, 320–330 (2016). This is an opinion article that clarifies and defines the different concepts of resistance, tolerance and persistence to antibiotics.

  161. 161.

    Wang, X. et al. Increased intracellular activity of MP1102 and NZ2114 against Staphylococcus aureus in vitro and in vivo. Sci. Rep. 8, 4204 (2018).

  162. 162.

    Feldman, M. D., Petersen, A. J., Karliner, L. S. & Tice, J. A. Who is responsible for evaluating the safety and effectiveness of medical devices? The role of independent technology assessment. J. Gen. Intern. Med. 23, 57–63 (2008).

  163. 163.

    McIntyre, W. F. & Healey, J. S. Cardiac implantable electronic device infections: from recognizing risk to prevention. Heart Rhythm. 14, 846–847 (2017).

  164. 164.

    Andersen, O. Z. et al. Accelerated bone ingrowth by local delivery of strontium from surface functionalized titanium implants. Biomaterials 34, 5883–5890 (2013).

  165. 165.

    Eaves, F. 3rd & Nahai, F. Anaplastic large cell lymphoma and breast implants: FDA report. Aesthet. Surg. J. 31, 467–468 (2011).

  166. 166.

    Rello, J. et al. VAP outcomes scientific advisory group. Epidemiology and outcomes of ventilator-associated pneumonia in a large US database. Chest 122, 2115–2121 (2002).

  167. 167.

    del Pozo, J. L. & Patel, R. The challenge of treating biofilm-associated bacterial infections. Clin. Pharmacol. Ther. 82, 204–209 (2007).

  168. 168.

    Michiels, J. E., Van den Bergh, B., Verstraeten, N. & Michiels, J. Molecular mechanisms and clinical implications of bacterial persistence. Drug Resist. Updat. 29, 76–89 (2016).

  169. 169.

    Lewis, K. Persister cells. Annu. Rev. Microbiol. 64, 357–372 (2010). This paper describes persister cells, which are dormant variants that form in microbial populations and are highly tolerant to antibiotics. Stress responses may act as general activators of persister formation.

  170. 170.

    Fisher, R. A., Gollan, B. & Helaine, S. Persistent bacterial infections and persister cells. Nat. Rev. Microbiol. 15, 453–464 (2017). This paper describes how bacterial persister cells avoid antibiotic-induced death by entering a physiologically dormant state, which makes them a major cause of antibiotic treatment failure and relapsing infections.

  171. 171.

    Allison, K. R., Brynildsen, M. P. & Collins, J. J. Metabolite-enabled eradication of bacterial persisters by aminoglycosides. Nature 473, 216–220 (2011).

  172. 172.

    Mina, E. G. & Marques, C. N. Interaction of Staphylococcus aureus persister cells with the host when in a persister state and following awakening. Sci. Rep. 6, 31342 (2016). This paper describes that, upon awakening, persister cells regain their ability to infect hosts.

  173. 173.

    Daghighi, S. et al. Persistence of a bioluminescent Staphylococcus aureus strain on and around degradable and non-degradable surgical meshes in amurine model. Acta Biomater. 8, 3991–3996 (2012).

  174. 174.

    Ravindran, S. & George, A. Multifunctional ECM proteins in bone and teeth. Exp. Cell. Res. 325, 148–154 (2014).

  175. 175.

    Ekdahl, K. N. et al. Dangerous liaisons: complement, coagulation, and kallikrein/kinin cross-talk act as a linchpin in the events leading to thromboinflammation. Immunol. Rev. 274, 245–269 (2016).

  176. 176.

    Janatova, J. Activation and control of complement, inflammation, and infection associated with the use of biomedical polymers. ASAIO J. 46, S53–62 (2000).

  177. 177.

    Vroman, L., Adams, A. L., Fischer, G. C. & Munoz, P. C. Interaction of high molecular weight kininogen, factor XII, and fibrinogen in plasma at interfaces. Blood 55, 156–159 (1980).

  178. 178.

    Selders, G. S. et al. An overview of the role of neutrophils in innate immunity, inflammation and host-biomaterial integration. Regen. Biomater. 4, 55–68 (2017).

  179. 179.

    Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).

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The authors gratefully acknowledge M. P. Landini for the inspiring atmosphere at the Rizzoli Orthopaedic Institute. This work was supported by the POR-FESR 2014–2020 grant (Project No. 725827) and by the “5 per mille” grants to the Rizzoli Orthopaedic Institute.

Author information


  1. Research Unit on Implant Infections, Rizzoli Orthopaedic Institute, Bologna, Italy

    • Carla Renata Arciola
    • , Davide Campoccia
    •  & Lucio Montanaro
  2. Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, Bologna, Italy

    • Carla Renata Arciola
    •  & Lucio Montanaro


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All authors researched data for the article, contributed substantially to discussion of the content and wrote, reviewed and edited the manuscript before submission.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Carla Renata Arciola.


Health-care-associated infections

An infection contracted by a patient while receiving medical care in a hospital or in another health-care facility (synonymous with nosocomial and hospital infection).

Opportunistic pathogens

Microorganisms that generally live harmlessly as commensals but can cause infection in hosts with lowered resistance to disease.

Granulation tissue

New connective tissue and capillaries that replace the fibrin matrix during wound healing.

Coagulase-negative staphylococci

(CNS). A broad group of staphylococci devoid of coagulase activity that includes some of the staphylococcal species that often cause hospital-acquired infections.

Total arthroplasty

A reconstructive surgical procedure consisting of replacement of a joint with an artificial prosthesis.


Ability of a solid surface to reduce the surface tension of a liquid in contact with it so that the liquid spreads over the surface and wets it.

Extended Derjaguin–Landau–Verwey–Overbeek theory

(XDLVO theory). A theory that describes the interactions between material surfaces immersed in a liquid, taking into account the different attractive and repulsive forces (Lifshitz–van der Waals, electrical double layer and Lewis acid–base forces). It can be used to predict the interactions of bacteria and biomaterial surfaces.


A mechanism by which genetic material can transfer between bacterial cells. It involves direct cell-to-cell contact or a bridge-like connection between cells.

Quorum sensing system

A bacterial regulatory system based on signalling molecules (autoinducers) that reflect bacterial cell-population density and regulate gene expression in response to it.

Surfactant molecules

Compounds that lower the surface tension between two liquids or between a liquid and a solid.

Non-professional phagocytes

A variety of non-immune cells that are capable of phagocytosis, including fibroblasts, osteoblasts, keratinocytes and endothelial cells.

Professional phagocytes

A group of cells that includes phagocytes of the innate immune system, such as neutrophils, monocytes, macrophages, mast cells and dendritic cells.

Small colony variant

Slow-growing variant of bacteria that arises spontaneously and forms small colonies when grown in the laboratory. These variants are implicated in persistent infections.


Thin, hair-like channels in the bone that link the lacunae with one another and with the Haversian canal.


Small cavities within the bone matrix in which single osteocytes are lodged.

ESKAPE pathogens

Acronym for a group of pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species) that are some of the main species that cause antimicrobial-resistant infections.

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