Tissue Colonization in Biomaterial-Associated Infection

  • Sebastian A. J. ZaatEmail author


Biomedical devices made of biomaterials predispose to infection as they provide surfaces for biofilm formation by microorganisms. Moreover, their presence in host tissue also compromises the local host immune response, allowing bacteria to persist in the vicinity of medical devices to cause infection. Biofilm formation, particularly by staphylococci, has been described in depth in  Chaps. 2 and  Chaps. 6. This chapter therefore focuses on the colonization of peri-biomaterial tissue and host cells by bacteria, particularly staphylococci, on the characteristics of staphylococci residing intracellularly, the efficacy of antibiotics against intracellular staphylococci, and the pathogenic process leading to peri-implant tissue ­colonization and how immune modulation can contribute to prevent this.


Colony Form Unit Intracellular Activity Intracellular Survival Foreign Body Response Small Colony Variant 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The research on biomaterial-associated infection at our Department builds on the work of Professor Jacob Dankert, who passed away much too early. Much of our own research described in this chapter has been performed by Corine Broekhuizen and Jaap Jan Boelens during their PhD periods, with excellent support of Leonie de Boer, Kim Schipper, Jean Luc Murk, and Jan Meeldijk.


  1. 1.
    Al Laham N, Rohde H, Sander G, et al. Augmented expression of polysaccharide intercellular adhesin in a defined Staphylococcus epidermidis mutant with the small-colony-variant phenotype. J Bacteriol. 2007;189:4494–501.CrossRefGoogle Scholar
  2. 2.
    Arciola CR, Baldassarri L, Montanaro L. Presence of icaA and icaD genes and slime production in a collection of staphylococcal strains from catheter-associated infections. J Clin Microbiol. 2001;39:2152–6.CrossRefGoogle Scholar
  3. 3.
    Arciola CR, Campoccia D, Gamberini S, et al. Search for the insertion element IS256 within the ica locus of Staphylococcus epidermidis clinical isolates collected from biomaterial-associated infections. Biomaterials. 2004;25:4117–25.CrossRefGoogle Scholar
  4. 4.
    Arciola CR, Visai L, Testoni F, et al. Concise survey of Staphylococcus aureus virulence factors that promote adhesion and damage to peri-implant tissues. Int J Artif Organs. 2011;34:771–80.CrossRefGoogle Scholar
  5. 5.
    Auwerx J. The human leukemia cell line, THP-1—a multifaceted model for the study of monocyte-macrophage differentiation. Experientia. 1991;47:22–31.CrossRefGoogle Scholar
  6. 6.
    Bach A, Eberhardt H, Frick A, Schmidt H, Bottiger BW, Martin E. Efficacy of silver-coating central venous catheters in reducing bacterial colonization. Crit Care Med. 1999;27:515–21.CrossRefGoogle Scholar
  7. 7.
    Baddour LM, Christensen GD. Prosthetic valve endocarditis due to small-colony staphylococcal variants. Rev Infect Dis. 1987;9:1168–74.CrossRefGoogle Scholar
  8. 8.
    Baddour LM, Barker LP, Christensen GD, Parisi JT, Simpson W. Phenotypic variation of Staphylococcus epidermidis in infection of transvenous endocardial pacemaker electrodes. J Clin Microbiol. 1990;28:676–9.Google Scholar
  9. 9.
    Balwit JM, van Langevelde P, Vann JM, Proctor RA. Gentamicin-resistant menadione and hemin auxotrophic Staphylococcus aureus persist within cultured endothelial cells. J Infect Dis. 1994;170:1033–7.CrossRefGoogle Scholar
  10. 10.
    Bantel H, Sinha B, Domschke W, Peters G, Schulze-Osthoff K, Jänicke RU. Alpha-toxin is a mediator of Staphylococcus aureus-induced cell death and activates caspases via the intrinsic death pathway independently of death receptor signaling. J Cell Biol. 2001;155:637–48.CrossRefGoogle Scholar
  11. 11.
    Baquir B, Lemaire S, Van Bambeke F, Tulkens PM, Lin L, Spellberg B. Macrophage killing of bacterial and fungal pathogens is not inhibited by intense intracellular accumulation of the lipoglycopeptide antibiotic oritavancin. Clin Infect Dis. 2012;54:S229–32.CrossRefGoogle Scholar
  12. 12.
    Barcia-Macay M, Seral C, Mingeot-Leclerq M, Tulkens P, Van Bambeke F. Pharmacodynamic evaluation of the intracellular activities of antibiotics against Staphylococcus aureus in a model of THP-1 macrophages. Antimicrob Agents Chemother. 2006;50:841–51.CrossRefGoogle Scholar
  13. 13.
    Barcia-Macay M, Lemaire S, Mingeot-Leclercq M-P, Tulkens PM, Van Bambeke F. Evaluation of the extracellular and intracellular activities (human THP-1 macrophages) of telavancin versus vancomycin against methicillin-susceptible, methicillin-resistant, vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus. J Antimicrob Chemother. 2006;58:1177–84.CrossRefGoogle Scholar
  14. 14.
    Baudoux P, Lemaire S, Denis O, Tulkens PM, Van Bambeke F, Glupczynski Y. Activity of quinupristin/dalfopristin against extracellular and intracellular Staphylococcus aureus with various resistance phenotypes. J Antimicrob Chemother. 2010;65:1228–36.CrossRefGoogle Scholar
  15. 15.
    Bayles KW, Wesson CA, Liou LE, et al. Intracellular Staphylococcus aureus escapes the endosome and induces apoptosis in epithelial cells intracellular. Infect Immun. 1998;66:336–42.Google Scholar
  16. 16.
    Beam TR. Sequestration of staphylococci at an inaccessible focus. Lancet. 1979;2(8136):227–8.CrossRefGoogle Scholar
  17. 17.
    Boelens JJ, Dankert J, Murk JL, et al. Biomaterial-associated persistence of Staphylococcus epidermidis in pericatheter macrophages. J Infect Dis. 2000;181:1337–49.CrossRefGoogle Scholar
  18. 18.
    Boelens JJ, Zaat SAJ, Meeldijk J, Dankert J. Subcutaneous abscess formation around catheters induced by viable and nonviable Staphylococcus epidermidis as well as by small amounts of bacterial cell wall components. J Biomed Mater Res. 2000;50:546–56.CrossRefGoogle Scholar
  19. 19.
    Boelens JJ, van der Poll T, Dankert J, Zaat SAJ. Interferon-gamma protects against biomaterial-associated Staphylococcus epidermidis infection in mice. J Infect Dis. 2000;181:1167–71.CrossRefGoogle Scholar
  20. 20.
    Boelens JJ, van der Poll T, Zaat SAJ, Murk JL, Weening JJ, Dankert J. Interleukin-1 receptor type I gene-deficient mice are less susceptible to Staphylococcus epidermidis biomaterial-associated infection than are wild-type mice. Infect Immun. 2000;68:6924–31.CrossRefGoogle Scholar
  21. 21.
    Boelens JJ, Zaat SAJ, Murk JL, Weening JJ, Van der Poll T, Dankert J. Enhanced susceptibility to subcutaneous abscess formation and persistent infection around catheters is associated with sustained interleukin-1 beta levels. Infect Immun. 2000;68:1692–5.CrossRefGoogle Scholar
  22. 22.
    Bonfield TL, Colton E, Anderson JM. Plasma protein adsorbed biomedical polymers: activation of human monocytes and induction of interleukin-1. J Biomed Mater Res. 1989;23:535–48.CrossRefGoogle Scholar
  23. 23.
    Bonfield TL, Colton E, Marchant RE, Anderson JM. Cytokine and growth factor production by monocytes/macrophages on protein preadsorbed polymers. J Biomed Mater Res. 1992;26: 837–50.CrossRefGoogle Scholar
  24. 24.
    Bosse MJ, Gruber HE, Ramp W. Internalization of bacteria by osteoblasts in a patient with recurrent, long-term osteomyelitis. J Bone Joint Surg Am. 2005;87A:1343–7.CrossRefGoogle Scholar
  25. 25.
    Brinch KS, Tulkens PM, Van BF, Frimodt-Moller N, Hoiby N, Kristensen HH. Intracellular activity of the peptide antibiotic NZ2114: studies with Staphylococcus aureus and human THP-1 monocytes, and comparison with daptomycin and vancomycin. J Antimicrob Chemother. 2010;65:1720–4.CrossRefGoogle Scholar
  26. 26.
    Brinch KS, Sandberg A, Baudoux P, et al. Plectasin shows intracellular activity against Staphylococcus aureus in human THP-1 monocytes and in a mouse peritonitis model. Antimicrob Agents Chemother. 2009;53:4801–8.CrossRefGoogle Scholar
  27. 27.
    Broekhuizen CAN, De Boer L, Schipper K, et al. Peri-implant tissue is an important niche for Staphylococcus epidermidis in experimental biomaterial-associated infection in mice. Infect Immun. 2007;75:1129–36.CrossRefGoogle Scholar
  28. 28.
    Broekhuizen CAN, De Boer L, Schipper K, et al. The influence of antibodies on Staphylococcus epidermidis adherence to polyvinylpyrrolidone-coated silicone elastomer in experimental biomaterial-associated infection in mice. Biomaterials. 2009;30:6444–50.CrossRefGoogle Scholar
  29. 29.
    Broekhuizen CAN, Sta M, Vandenbroucke-Grauls CM, Zaat SAJ. Microscopic detection of viable Staphylococcus epidermidis in peri-implant tissue in experimental biomaterial-associated infection, identified by bromodeoxyuridine incorporation. Infect Immun. 2010;78:954–62.CrossRefGoogle Scholar
  30. 30.
    Broekhuizen CA, De Boer L, Schipper K, et al. Staphylococcus epidermidis is cleared from biomaterial implants but persists in peri-implant tissue in mice despite rifampicin/vancomycin treatment. J Biomed Mater Res A. 2008;85:498–505.Google Scholar
  31. 31.
    Broekhuizen CA, Schultz MJ, van der Wal AC, et al. Tissue around catheters is a niche for bacteria associated with medical device infection. Crit Care Med. 2008;36:2395–402.CrossRefGoogle Scholar
  32. 32.
    Busscher HJ, van der Mei HC. How do bacteria know they are on a surface and regulate their response to an adhering state? PLoS Pathog. 2012;8:e1002440.CrossRefGoogle Scholar
  33. 33.
    Cafiso V, Bertuccio T, Santagati M, et al. Presence of the ica operon in clinical isolates of Staphylococcus epidermidis and its role in biofilm production. Clin Microbiol Infect. 2004;10:1081–8.CrossRefGoogle Scholar
  34. 34.
    Cardona MA, Simmons RL, Kaplan SS. TNF and IL-1 generation by human monocytes in response to biomaterials. J Biomed Mater Res. 1992;26:851–9.CrossRefGoogle Scholar
  35. 35.
    Christensen GD, Baddour LM, Madison BM, et al. Colonial morphology of staphylococci on Memphis agar: phase variation of slime production, resistance to beta-lactam antibiotics, and virulence. J Infect Dis. 1990;161:1153–69.CrossRefGoogle Scholar
  36. 36.
    Christensen GD, Simpson WA, Bisno AL, Beachey EH. Experimental foreign body infections in mice challenged with slime-producing Staphylococcus epidermidis. Infect Immun. 1983; 40:407–10.Google Scholar
  37. 37.
    Christensen L, Breiting V, Janssen M, Vuust J, Hogdall E. Adverse reactions to injectable soft tissue permanent fillers. Aesthetic Plast Surg. 2005;29:34–48.CrossRefGoogle Scholar
  38. 38.
    Ciampolini J, Harding KG. Pathophysiology of chronic bacterial osteomyelitis. Why do antibiotics fail so often? Postgrad Med J. 2000;76:479–83.CrossRefGoogle Scholar
  39. 39.
    Costerton JW, Stewart PS, Greenberg EP. Bacterial biofilms: a common cause of persistent infections. Science. 1999;284:1318–22.CrossRefGoogle Scholar
  40. 40.
    Darouiche R, Hamill RJ. Antibiotic penetration of and bactericidal activity within endothelial cells. Antimicrob Agents Chemother. 1994;38:1059–64.CrossRefGoogle Scholar
  41. 41.
    De Silva GDI, Kantzanou M, Justice A, et al. The ica operon and biofilm production in coagulase-negative staphylococci associated with carriage and disease in a neonatal intensive care unit. J Clin Microbiol. 2002;40:382–8.CrossRefGoogle Scholar
  42. 42.
    Deighton MA, Borland R, Capstick JA. Virulence of Staphylococcus epidermidis in a mouse model: significance of extracellular slime. Epidemiol Infect. 1996;117:267–80.CrossRefGoogle Scholar
  43. 43.
    Dobbins BM, Kite P, Kindon A, McMahon MJ, Wilcox MH. DNA fingerprinting analysis of coagulase negative staphylococci implicated in catheter related bloodstream infections. J Clin Pathol. 2002;55:824–8.CrossRefGoogle Scholar
  44. 44.
    Elek SD, Conen PE. The virulence of Staphylococcus pyogenes for man: a study of the problems of wound infection. Br J Exp Pathol. 1957;38(6):573.Google Scholar
  45. 45.
    Ellington JK, Harris M, Webb L, et al. A mechanism for the indolence of osteomyelitis. J Bone Joint Surg Br. 2003;85-B:918–21.Google Scholar
  46. 46.
    Engelsman AF, Saldarriaga-Fernandez IC, Nejadnik MR, et al. The risk of biomaterial-associated infection after revision surgery due to an experimental primary implant infection. Biofouling. 2010;26:761–7.CrossRefGoogle Scholar
  47. 47.
    Fernandez J, Hilliard JJ, Morrow BJ, et al. Efficacy of a new fluoroquinolone, JNJ-Q2, in murine models of Staphylococcus aureus and Streptococcus pneumoniae skin, respiratory, and systemic infections. Antimicrob Agents Chemother. 2011;55:5522–8.CrossRefGoogle Scholar
  48. 48.
    Frank KL, Hanssen AD, Patel R. icaA is not a useful diagnostic marker for prosthetic joint infection. J Clin Microbiol. 2004;42:4846–9.CrossRefGoogle Scholar
  49. 49.
    Franz S, Rammelt S, Scharnweber D, Simon JC. Immune responses to implants—a review of the implications for the design of immunomodulatory biomaterials. Biomaterials. 2011;32:6692–709.CrossRefGoogle Scholar
  50. 50.
    Gao G, Lange D, Hilpert K, et al. The biocompatibility and biofilm resistance of implant coatings based on hydrophilic polymer brushes conjugated with antimicrobial peptides. Biomaterials. 2011;32:3899–909.CrossRefGoogle Scholar
  51. 51.
    Garzoni C, Kelley WL. Staphylococcus aureus: new evidence for intracellular persistence. Trends Microbiol. 2009;17:59–65.CrossRefGoogle Scholar
  52. 52.
    Gotz F, Heilmann C, Cramton SE. Molecular basis of catheter associated infections by staphylococci. Adv Exp Med Biol. 2000;485:103–11.CrossRefGoogle Scholar
  53. 53.
    Gresham HD, Lowrance JH, Caver TE, et al. Survival of Staphylococcus aureus inside neutrophils contributes to infection. J Immunol. 2000;164:3713–22.Google Scholar
  54. 54.
    Gristina A, Costerton J. Bacterial adherence to biomaterials and tissue; the significance of its role in clinical sepsis. J Bone Joint Surg Am. 1985;67:264–73.Google Scholar
  55. 55.
    Grundmeier M, Tuchscherr L, Brück M, et al. Staphylococcal strains vary greatly in their ability to induce an inflammatory response in endothelial cells. J Infect Dis. 2010;201:871–80.CrossRefGoogle Scholar
  56. 56.
    Guaní-Guerra E, Santos-Mendoza T, Lugo-Reyes SO, Terán LM. Antimicrobial peptides: general overview and clinical implications in human health and disease. Clin Immunol. 2010;135:1–11.CrossRefGoogle Scholar
  57. 57.
    Hamill RJ, Vann JM, Proctor RA. Phagocytosis of Staphylococcus aureus by cultured bovine aortic endothelial cells: model for postadherence events in endovascular infections. Infect Immun. 1986;54:833–6.Google Scholar
  58. 58.
    Hanses F, Kopp A, Bala M, et al. Intracellular survival of Staphylococcus aureus in adipocyte-like differentiated 3T3-L1 cells is glucose dependent and alters cytokine, chemokine, and adipokine secretion. Endocrinology. 2011;152:4148–57.CrossRefGoogle Scholar
  59. 59.
    Haslinger B, Strangfeld K, Peters G, Schulze-Osthoff K, Sinha B. Staphylococcus aureus alpha-toxin induces apoptosis in peripheral blood mononuclear cells: role of endogenous tumour necrosis factor-alpha and the mitochondrial death pathway. Cell Microbiol. 2003;5:729–41.CrossRefGoogle Scholar
  60. 60.
    Holmberg A, Lood R, Mörgelin M, et al. Biofilm formation by Propionibacterium acnes is a characteristic of invasive isolates. Clin Microbiol Infect. 2009;15:787–95.CrossRefGoogle Scholar
  61. 61.
    Hudson MC, Ramp WK, Nicholson NC, Williams AS, Nousiainen MT. Internalization of Staphylococcus aureus by cultured osteoblasts. Microb Pathog. 1995;19:409–19.CrossRefGoogle Scholar
  62. 62.
    Hughes SP, Anderson FM. Infection in the operating room. J Bone Joint Surg Br. 1999;81:754–5.CrossRefGoogle Scholar
  63. 63.
    Høiby N, Bjarnsholt T, Givskov M, Molin S, Ciofu O. Antibiotic resistance of bacterial biofilms. Int J Antimicrob Agents. 2010;35:322–32.CrossRefGoogle Scholar
  64. 64.
    James RC, MacLeod CM. Induction of staphylococcal infections in mice with small inocula introduced on sutures. Br J Exp Pathol. 1961;42:266–77.Google Scholar
  65. 65.
    Jevon M, Guo C, Ma B, et al. Mechanisms of internalization of Staphylococcus aureus by cultured human osteoblasts. Infect Immun. 1999;67:2677–81.Google Scholar
  66. 66.
    Johnson G, Lee D, Regelmann W, Gray E, Peters G, Quie PG. Interference with granulocyte function by Staphylococcus epidermidis slime. Infect Immun. 1986;54:13–20.Google Scholar
  67. 67.
    Kahl BC, Belling G, Becker P, et al. Thymidine-dependent Staphylococcus aureus small-colony variants are associated with extensive alterations in regulator and virulence gene expression profiles. Infect Immun. 2005;73:4119–26.CrossRefGoogle Scholar
  68. 68.
    Kazemzadeh-Narbat M, Kindrachuk J, Duan K, Jenssen H, Hancock REW, Wang R. Antimicrobial peptides on calcium phosphate-coated titanium for the prevention of implant-associated infections. Biomaterials. 2010;31:9519–26.CrossRefGoogle Scholar
  69. 69.
    Kim KW, Im J, Jeon JH, Lee H-G, Yun C-H, Han SH. Staphylococcus aureus induces IL-1β expression through the activation of MAP kinases and AP-1, CRE and NF-κB transcription factors in the bovine mammary gland epithelial cells. Comp Immunol Microbiol Infect Dis. 2011;34:347–54.CrossRefGoogle Scholar
  70. 70.
    Klug D, Wallet F, Kacet S, Courcol RJ. Involvement of adherence and adhesion Staphylococcus epidermidis genes in pacemaker lead-associated infections. J Clin Microbiol. 2003;41:3348–50.CrossRefGoogle Scholar
  71. 71.
    Kohler C, Eiff CV, Peters G, Proctor RA, Hecker M, Engelmann S. Physiological characterization of a heme-deficient mutant of Staphylococcus aureus by a proteomic approach. J Bacteriol. 2003;185:6928–37.CrossRefGoogle Scholar
  72. 72.
    Koskela A, Nilsdotter-Augustinsson A, Persson L, Söderquist B. Prevalence of the ica operon and insertion sequence IS256 among Staphylococcus epidermidis prosthetic joint infection isolates. Eur J Clin Microbiol Infect Dis. 2009;28:655–60.CrossRefGoogle Scholar
  73. 73.
    Kretschmer D, Gleske A-K, Rautenberg M, et al. Human formyl peptide receptor 2 senses highly pathogenic Staphylococcus aureus. Cell Host Microbe. 2010;7:463–73.CrossRefGoogle Scholar
  74. 74.
    Kretschmer D, Nikola N, Dürr M, Otto M, Peschel A. The virulence regulator agr controls the staphylococcal capacity to activate human neutrophils via the formyl peptide receptor 2. J Innate Immun. 2012;4:201–12.CrossRefGoogle Scholar
  75. 75.
    Krimmer V, Merkert H, Eiff CV, et al. Detection of Staphylococcus aureus and Staphylococcus epidermidis in clinical samples by 16S rRNA-directed in situ hybridization. J Clin Microbiol. 1999;37:2667–73.Google Scholar
  76. 76.
    Kubica M, Guzik K, Koziel J, et al. A potential new pathway for Staphylococcus aureus dissemination: the silent survival of S aureus phagocytosed by human monocyte-derived macrophages. PLoS One. 2008;3(1):e1409.CrossRefGoogle Scholar
  77. 77.
    Kwakman PHS, te Velde AA, Vandenbroucke-Grauls CMJE, van Deventer SJH, Zaat SAJ. Treatment and prevention of Staphylococcus epidermidis experimental biomaterial-associated infection by bactericidal peptide 2. Antimicrob Agents Chemother. 2006;50:3977–83.CrossRefGoogle Scholar
  78. 78.
    Lambe Jr DW, Ferguson KP, Keplinger JL, Gemmell CG, Kalbfleisch J. Pathogenicity of Staphylococcus lugdunensis, Staphylococcus schleiferi, and 3 other coagulase-negative staphylococci in a mouse model and possible virulence factors. Can J Microbiol. 1990;36:455–63.CrossRefGoogle Scholar
  79. 79.
    Lannergard J, von Eiff C, Sander G, et al. Identification of the genetic basis for clinical menadione-auxotrophic small-colony variant isolates of Staphylococcus aureus. Antimicrob Agents Chemother. 2008;52:4017–22.CrossRefGoogle Scholar
  80. 80.
    Lemaire S, Kosowska-Shick K, Julian K, Tulkens PM, Van Bambeke F, Appelbaum PC. Activities of antistaphylococcal antibiotics towards the extracellular and intraphagocytic forms of Staphylococcus aureus isolates from a patient with persistent bacteraemia and endocarditis. Clin Microbiol Infect. 2008;14:766–77.CrossRefGoogle Scholar
  81. 81.
    Lemaire S, Van Bambeke F, Appelbaum PC, Tulkens PM. Cellular pharmacokinetics and intracellular activity of torezolid (TR-700): studies with human macrophage (THP-1) and endothelial (HUVEC) cell lines. J Antimicrob Chemother. 2009;64:1035–43.CrossRefGoogle Scholar
  82. 82.
    Lemaire S, Van Bambeke F, Mingeot-Leclercq MP, Tulkens PM. Modulation of the cellular accumulation and intracellular activity of daptomycin towards phagocytized Staphylococcus aureus by the P-glycoprotein (MDR1) efflux transporter in human THP-1 macrophages and madin-darby canine kidney cells. Antimicrob Agents Chemother. 2007;51:2748–57.CrossRefGoogle Scholar
  83. 83.
    Lemaire S, Glupczynski Y, Duval V, Joris B, Tulkens PM, Van Bambeke F. Activities of ceftobiprole and other cephalosporins against extracellular and intracellular (THP-1 macrophages and keratinocytes) forms of methicillin-susceptible and methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2009;53:2289–97.CrossRefGoogle Scholar
  84. 84.
    Lemaire S, Kosowska-Shick K, Appelbaum PC, Glupczynski Y, Van Bambeke F, Tulkens PM. Activity of moxifloxacin against intracellular community-acquired methicillin-resistant Staphylococcus aureus: comparison with clindamycin, linezolid and co-trimoxazole and attempt at defining an intracellular susceptibility breakpoint. J Antimicrob Chemother. 2011;66:596–607.CrossRefGoogle Scholar
  85. 85.
    Lemaire S, Kosowska-Shick K, Appelbaum PC, Verween G, Tulkens PM, Van Bambeke F. Cellular pharmacodynamics of the novel biaryloxazolidinone radezolid: studies with infected phagocytic and nonphagocytic cells, using Staphylococcus aureus, Staphylococcus epidermidis, Listeria monocytogenes, and Legionella pneumophila. Antimicrob Agents Chemother. 2010;54:2549–59.CrossRefGoogle Scholar
  86. 86.
    Lemaire S, Tulkens PM, Van Bambeke F. Contrasting effects of acidic pH on the extracellular and intracellular activities of the anti-gram-positive fluoroquinolones moxifloxacin and delafloxacin against Staphylococcus aureus. Antimicrob Agents Chemother. 2011;55:649–58.CrossRefGoogle Scholar
  87. 87.
    Lemaire S, Van Bambeke F, Pierard D, Appelbaum PC, Tulkens PM. Activity of fusidic acid against extracellular and intracellular Staphylococcus aureus: influence of pH and comparison with linezolid and clindamycin. Clin Infect Dis. 2011;52:S493–503.CrossRefGoogle Scholar
  88. 88.
    Lemaire S, Van Bambeke F, Mingeot-Leclercq M-P, Tulkens PM. Activity of three beta-lactams (ertapenem, meropenem and ampicillin) against intraphagocytic Listeria monocytogenes and Staphylococcus aureus. J Antimicrob Chemother. 2005;55:897–904.CrossRefGoogle Scholar
  89. 89.
    Lemaire S, Van Bambeke F, Tulkens PM. Activity of finafloxacin, a novel fluoroquinolone with increased activity at acid pH, towards extracellular and intracellular Staphylococcus aureus, Listeria monocytogenes and Legionella pneumophila. Int J Antimicrob Agents. 2011;38:52–9.CrossRefGoogle Scholar
  90. 90.
    Lemaire S, Van Bambeke F, Tulkens PM. Cellular accumulation and pharmacodynamic evaluation of the intracellular activity of CEM-101, a novel fluoroketolide, against Staphylococcus aureus, Listeria monocytogenes, and Legionella pneumophila in human THP-1 macrophages. Antimicrob Agents Chemother. 2009;53:3734–43.CrossRefGoogle Scholar
  91. 91.
    Lewis K. Persister cells, dormancy and infectious disease. Nat Rev Microbiol. 2007;5:48–56.CrossRefGoogle Scholar
  92. 92.
    Li B, Jiang B, Boyce BM, Lindsey BA. Multilayer polypeptide nanoscale coatings incorporating IL-12 for the prevention of biomedical device-associated infections. Biomaterials. 2009;30:2552–8.CrossRefGoogle Scholar
  93. 93.
    Li B, Jiang B, Dietz MJ, Smith ES, Clovis NB, Rao KMK. Evaluation of local MCP-1 and IL-12 nanocoatings for infection prevention in open fractures. J Orthop Res. 2010;28:48–54.CrossRefGoogle Scholar
  94. 94.
    Liu L, Xu K, Wang H, et al. Self-assembled cationic peptide nanoparticles as an efficient antimicrobial agent. Nat Nanotechnol. 2009;4:457–63.CrossRefGoogle Scholar
  95. 95.
    Loftus RW, Koff MD, Burchman CC, et al. Transmission of pathogenic bacterial organisms in the anesthesia work area. Anesthesiology. 2008;109:399–407.CrossRefGoogle Scholar
  96. 96.
    Lâm T-T, Giese B, Chikkaballi D, et al. Phagolysosomal integrity is generally maintained after Staphylococcus aureus invasion of nonprofessional phagocytes but is modulated by strain 6850. Infect Immun. 2010;78:3392–403.CrossRefGoogle Scholar
  97. 97.
    Löffler B, Hussain M, Grundmeier M, et al. Staphylococcus aureus panton-valentine leukocidin is a very potent cytotoxic factor for human neutrophils. PLoS Pathog. 2010;6:e1000715.CrossRefGoogle Scholar
  98. 98.
    Ma M, Kazemzadeh-Narbat M, Hui Y, et al. Local delivery of antimicrobial peptides using self-organized TiO(2) nanotube arrays for peri-implant infections. J Biomed Mater Res A. 2011;100A:278–85.Google Scholar
  99. 99.
    Marrie TJ, Costerton JW. Morphology of bacterial attachment to cardiac pacemaker leads and power packs. J Clin Microbiol. 1984;19:911–4.Google Scholar
  100. 100.
    Marrie TJ, Costerton JW. Scanning and transmission electron microscopy of in situ bacterial colonization of intravenous and intra-arterial catheters. J Clin Microbiol. 1984;19:687–93.Google Scholar
  101. 101.
    Marrie TJ, Nelligan J, Costerton JW. A scanning and transmission electron microscopic study of an infected endocardial pacemaker lead. Circulation. 1982;66:1339–41.CrossRefGoogle Scholar
  102. 102.
    Marrie TJ, Noble MA, Costerton JW. Examination of the morphology of bacteria adhering to peritoneal dialysis catheters by scanning and transmission electron microscopy. J Clin Microbiol. 1983;18:1388–98.Google Scholar
  103. 103.
    Matussek A, Strindhall J, Stark L, et al. Infection of human endothelial cells with Staphylococcus aureus induces transcription of genes encoding an innate immunity response. Scand J Immunol. 2005;61:536–44.CrossRefGoogle Scholar
  104. 104.
    Morrow BJ, He W, Amsler KM, et al. In vitro antibacterial activities of JNJ-Q2, a new broad-spectrum fluoroquinolone. Antimicrob Agents Chemother. 2010;54:1955–64.CrossRefGoogle Scholar
  105. 105.
    Murillo O, Pachón ME, Euba G, et al. Intracellular antimicrobial activity appearing as a relevant factor in antibiotic efficacy against an experimental foreign-body infection caused by Staphylococcus aureus. J Antimicrob Chemother. 2009;64:1062–6.CrossRefGoogle Scholar
  106. 106.
    Neut D, Van Horn J, Van Kooten T, Van der Mei H, Busscher H. Detection of biomaterial-associated infections in orthopaedic joint implants. Clin Orthop Relat Res. 2003;413:261–8.CrossRefGoogle Scholar
  107. 107.
    Nguyen HA, Denis O, Vergison A, et al. Intracellular activity of antibiotics in a model of human THP-1 macrophages infected by a Staphylococcus aureus small-colony variant strain isolated from a cystic fibrosis patient: pharmacodynamic evaluation and comparison with isogenic normal-phenotype. Antimicrob Agents Chemother. 2009;53:1434–42.CrossRefGoogle Scholar
  108. 108.
    Nguyen HA, Denis O, Vergison A, Tulkens PM, Struelens MJ, Van Bambeke F. Intracellular activity of antibiotics in a model of human THP-1 macrophages infected by a Staphylococcus aureus small-colony variant strain isolated from a cystic fibrosis patient: study of antibiotic combinations. Antimicrob Agents Chemother. 2009;53:1443–9.CrossRefGoogle Scholar
  109. 109.
    Nguyen HA, Grellet J, Paillard D, Dubois V, Quentin C, Saux M-C. Factors influencing the intracellular activity of fluoroquinolones: a study using levofloxacin in a Staphylococcus aureus THP-1 monocyte model. J Antimicrob Chemother. 2006;57:883–90.CrossRefGoogle Scholar
  110. 110.
    Noble WC. Production of subcutaneous staphylococcal skin lesions in mice. Br J Exp Pathol. 1965;46:254–62.Google Scholar
  111. 111.
    Otto M. Staphylococcus epidermidis—the “accidental” pathogen. Nat Rev Microbiol. 2009; 7:555–67.CrossRefGoogle Scholar
  112. 112.
    Oviedo-Boyso J, Bravo-Patiño A, Cajero-Juárez M, Valdez-Alarcón JJ, Baizabal-Aguirre VM. TNF-alpha reduces the level of Staphylococcus epidermidis internalization by bovine endothelial cells. FEMS Microbiol Lett. 2009;292:92–9.CrossRefGoogle Scholar
  113. 113.
    Oviedo-Boyso J, Cardoso-Correa BI, Cajero-Juárez M, Bravo-Patiño A, Valdez-Alarcón JJ, Baizabal-Aguirre VM. The capacity of bovine endothelial cells to eliminate intracellular Staphylococcus aureus and Staphylococcus epidermidis is increased by the proinflammatory cytokines TNF-alpha and IL-1beta. FEMS Immunol Med Microbiol. 2008;54:53–9.CrossRefGoogle Scholar
  114. 114.
    Paillard D, Grellet J, Dubois V, Saux M-C, Quentin C. Discrepancy between uptake and intracellular activity of moxifloxacin in a Staphylococcus aureus—human THP-1 monocytic cell model. Antimicrob Agents Chemother. 2002;46:288–93.CrossRefGoogle Scholar
  115. 115.
    Passerini L, Lam K, Costerton JW, King EG. Biofilms on indwelling vascular catheters. Crit Care Med. 1992;20:665–73.CrossRefGoogle Scholar
  116. 116.
    Passerini L, Phang PT, Jackson FL, Lam K, Costerton JW, King EG. Biofilms on right heart flow-directed catheters. Chest. 1987;92:440–6.CrossRefGoogle Scholar
  117. 117.
    Patrick CC, Hetherington SV, Roberson PK, Henwick S, Sloas MM. Comparative virulence of Staphylococcus epidermidis isolates in a murine catheter model. Pediatr Res. 1995;37:70–4.CrossRefGoogle Scholar
  118. 118.
    Patrick S, Mcdowell A, Glenn JV, Tunney MM. Improved detection and treatment of prosthetic joint infection. Eur Cell Mater. 2008;16:30.Google Scholar
  119. 119.
    Peters G, Locci R, Pulverer G. Microbial colonization of prosthetic devices. II. Scanning electron microscopy of naturally infected intravenous catheters. Zentralbl Bakteriol Mikrobiol Hyg B. 1981;173:293–9.Google Scholar
  120. 120.
    Proctor RA, von Eiff C, Kahl BC, et al. Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections. Nat Rev Microbiol. 2006;4:295–305.CrossRefGoogle Scholar
  121. 121.
    Raad I, Costerton W, Sabharwal U, Sacilowski M, Anaissie E, Bodey GP. Ultrastructural analysis of indwelling vascular catheters: a quantitative relationship between luminal colonization and duration of placement. J Infect Dis. 1993;168:400–7.CrossRefGoogle Scholar
  122. 122.
    Sadowska B, Bonar A, von Eiff C, et al. Characteristics of Staphylococcus aureus, isolated from airways of cystic fibrosis patients, and their small colony variants. FEMS Immunol Med Microbiol. 2002;32:191–7.CrossRefGoogle Scholar
  123. 123.
    Sandberg A, Hessler JHR, Skov RL, Blom J, Frimodt-Møller N. Intracellular activity of antibiotics against Staphylococcus aureus in a mouse peritonitis model. Antimicrob Agents Chemother. 2009;53:1874–83.CrossRefGoogle Scholar
  124. 124.
    Sandberg A, Jensen KS, Baudoux P, Van Bambeke F, Tulkens PM, Frimodt-Møller N. Intra- and extracellular activities of dicloxacillin against Staphylococcus aureus in vivo and in vitro. Antimicrob Agents Chemother. 2010;54:2391–400.CrossRefGoogle Scholar
  125. 125.
    Sandberg A, Jensen KS, Baudoux P, Van Bambeke F, Tulkens PM, Frimodt-Møller N. Intra- and extracellular activity of linezolid against Staphylococcus aureus in vivo and in vitro. J Antimicrob Chemother. 2010;65:962–73.CrossRefGoogle Scholar
  126. 126.
    Sandberg A, Lemaire S, Van Bambeke F, et al. Intra- and extracellular activities of dicloxacillin and linezolid against a clinical Staphylococcus aureus strain with a small-colony-variant phenotype in an in vitro model of THP-1 macrophages and an in vivo mouse peritonitis model. Antimicrob Agents Chemother. 2011;55:1443–52.CrossRefGoogle Scholar
  127. 127.
    Schröder A, Kland R, Peschel A, von Eiff C, Aepfelbacher M. Live cell imaging of phagosome maturation in Staphylococcus aureus infected human endothelial cells: small colony variants are able to survive in lysosomes. Med Microbiol Immunol. 2006;195: 185–94.CrossRefGoogle Scholar
  128. 128.
    Seifert H, Wisplinghof H, Schnabel P, Von Eiff C. Small colony variants of Staphylococcus aureus and pacemaker-related infection. Emerg Infect Dis. 2003;9:1316–8.CrossRefGoogle Scholar
  129. 129.
    Seral C, Barcia-Macay M, Mingeot-Leclercq MP, Tulkens PM, Van Bambeke F. Comparative activity of quinolones (ciprofloxacin, levofloxacin, moxifloxacin and garenoxacin) against extracellular and intracellular infection by Listeria monocytogenes and Staphylococcus aureus in J774 macrophages. J Antimicrob Chemother. 2005;55:511–7.CrossRefGoogle Scholar
  130. 130.
    Seral C, Bambeke FV, Tulkens PM, Bambeke V. Quantitative analysis of gentamicin, azithromycin, telithromycin, ciprofloxacin, moxifloxacin, and oritavancin (LY333328) activities against intracellular Staphylococcus aureus in mouse J774 macrophages. Antimicrob Agents Chemother. 2003;47:2283–92.CrossRefGoogle Scholar
  131. 131.
    Shiau AL, Wu CL. The inhibitory effect of Staphylococcus epidermidis slime on the phagocytosis of murine peritoneal macrophages is interferon-independent. Microbiol Immunol. 1998;42:33–40.Google Scholar
  132. 132.
    Sjollema J, Sharma PK, Dijkstra RJB, et al. The potential for bio-optical imaging of biomaterial-associated infection in vivo. Biomaterials. 2010;31:1984–95.CrossRefGoogle Scholar
  133. 133.
    Southwood RT, Rice JL, McDonald PJ, Hakendorf PH, Rozenbilds M. Infection in experimental hip arthroplasties. J Bone Joint Surg Br. 1985;67:229–31.Google Scholar
  134. 134.
    Stoodley P, Nistico L, Johnson S, et al. Direct demonstration of viable Staphylococcus aureus biofilms in an infected total joint arthroplasty. A case report. J Bone Joint Surg Am. 2008;90:1751–8.CrossRefGoogle Scholar
  135. 135.
    Swartbol P, Truedsson L, Pärsson H, Norgren L. Tumor necrosis factor-alpha and interleukin-6 release from white blood cells induced by different graft materials in vitro are affected by pentoxifylline and iloprost. J Biomed Mater Res. 1997;36:400–6.CrossRefGoogle Scholar
  136. 136.
    Taubler JH, Kapral FA. Staphylococcal population changes in experimentally infected mice: infection with suture-adsorbed and unadsorbed organisms grown in vitro and in vivo. J Infect Dis. 1966;116:257.CrossRefGoogle Scholar
  137. 137.
    Testoni F, Montanaro L, Poggi A, Visai L, Campoccia D, Arciola CR. Internalization by osteoblasts of two Staphylococcus aureus clinical isolates differing in their adhesin gene pattern. Int J Artif Organs. 2011;34:789–98.CrossRefGoogle Scholar
  138. 138.
    Trampuz A, Piper KE, Hanssen AD, et al. Sonication of explanted prosthetic components in bags for diagnosis of prosthetic joint infection is associated with risk of contamination. J Clin Microbiol. 2006;44:628–31.CrossRefGoogle Scholar
  139. 139.
    Tuchscherr L, Heitmann V, Hussain M, et al. Staphylococcus aureus small-colony variants are adapted phenotypes for intracellular persistence. J Infect Dis. 2010;202:1031–40.CrossRefGoogle Scholar
  140. 140.
    Tulkens PM. Intracellular distribution and activity of antibiotics. Eur J Clin Microbiol Infect Dis. 1991;10:100–6.CrossRefGoogle Scholar
  141. 141.
    Tunney MM, Patrick S, Curran MD, et al. Detection of prosthetic hip infection at revision arthroplasty by immunofluorescence microscopy and PCR amplification of the bacterial 16S rRNA gene. J Clin Microbiol. 1999;37:3281–90.Google Scholar
  142. 142.
    Vallet CM, Marquez B, Ngabirano E, et al. Cellular accumulation of fluoroquinolones is not predictive of their intracellular activity: studies with gemifloxacin, moxifloxacin and ciprofloxacin in a pharmacokinetic/pharmacodynamic model of uninfected and infected macrophages. Int J Antimicrob Agents. 2011;38:249–56.Google Scholar
  143. 143.
    Van Bambeke F, Carryn S, Seral C, et al. Cellular pharmacokinetics and pharmacodynamics of the glycopeptide antibiotic oritavancin (LY333328) in a model of J774 mouse macrophages. Antimicrob Agents Chemother. 2004;48:2853–60.CrossRefGoogle Scholar
  144. 144.
    Van Bambeke F, Saffran J, Mingeot-Leclercq M-P, Tulkens PM. Mixed-lipid storage disorder induced in macrophages and fibroblasts by oritavancin (LY333328), a new glycopeptide antibiotic with exceptional cellular accumulation. Antimicrob Agents Chemother. 2005;49:1695–700.CrossRefGoogle Scholar
  145. 145.
    Vann J, Proctor R. Cytotoxic effects of ingested Staphylococcus aureus on bovine endothelial cells: role of S. aureus alpha-hemolysin. Microb Pathog. 1988;4:443–53.CrossRefGoogle Scholar
  146. 146.
    Vesga O, Groeschel MC, Otten MF, Brar DW, Vann JM, Proctor RA. Staphylococcus aureus small colony variants are induced by the endothelial cell intracellular milieu. J Infect Dis. 1996;173:739–42.CrossRefGoogle Scholar
  147. 147.
    Virden CP, Dobke MK, Stein P, Parsons CL, Frank D. Subclinical infection of the silicone breast implant surface as a possible cause of capsular contracture. Aesthetic Plast Surg. 1992;16:173–9.CrossRefGoogle Scholar
  148. 148.
    Von Eiff C, Vaudaux P, Kahl BC, et al. Bloodstream infections caused by small-colony variants of coagulase-negative staphylococci following pacemaker implantation. Clin Infect Dis. 1999;29:932–4.CrossRefGoogle Scholar
  149. 149.
    Von Eiff C, Becker K, Metze D, Lubritz G. Intracellular persistence of Staphylococcus aureus small-colony variants within keratinocytes: a cause for antibiotic treatment failure in a patient with Darier’ s disease. Clin Infect Dis. 2001;32:1643–7.CrossRefGoogle Scholar
  150. 150.
    Vuong C, Kocianova S, Yao Y, Carmody AB, Otto M. Increased colonization of indwelling medical devices by quorum-sensing mutants of Staphylococcus epidermidis in vivo. J Infect Dis. 2004;190:1498–505.CrossRefGoogle Scholar
  151. 151.
    Waldvogel F, Bisno A, editors. Infections associated with indwelling medical devices. Washington, DC: ASM Press; 2000.Google Scholar
  152. 152.
    Wang R, Braughton KR, Kretschmer D, et al. Identification of novel cytolytic peptides as key virulence determinants for community-associated MRSA. Nat Med. 2007;13:1510–4.CrossRefGoogle Scholar
  153. 153.
    Zaat S, Broekhuizen C, De Boer L, et al. Biomaterial-associated infection: breaking out of the biofilm. Eur Cell Mater. 2008;16:10.Google Scholar
  154. 154.
    Zaat S, Broekhuizen C, Riool M. Host tissue as a niche for biomaterial-associated infection. Future Microbiol. 2010;5:1149–51.CrossRefGoogle Scholar
  155. 155.
    Zautner AE, Krause M, Stropahl G, et al. Intracellular persisting Staphylococcus aureus is the major pathogen in recurrent tonsillitis. PLoS One. 2010;5:e9452.CrossRefGoogle Scholar
  156. 156.
    Zimmerli W, Lew PD, Waldvogel FA. Pathogenesis of foreign body infection Evidence for a local granulocyte defect. J Clin Invest. 1984;73:1191–200.CrossRefGoogle Scholar
  157. 157.
    Zimmerli W, Waldvogel FA, Vaudaux P, Nydegger HE. Pathogenesis of foreign body infection: description and characteristics of an animal model. J Infect Dis. 1982;146:487.CrossRefGoogle Scholar
  158. 158.
    Zimmerli W, Moser C. Pathogenesis and treatment concepts of orthopaedic biofilm infections. FEMS Immunol Med Microbiol. 2012;1:1–11.Google Scholar
  159. 159.
    Zimmerli W, Sendi P. Pathogenesis of implant-associated infection: the role of the host. Semin Immunopathol. 2011;33:295–306.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA)University of AmsterdamAmsterdamThe Netherlands

Personalised recommendations