Skip to main content
SpringerLink
Log in

Chronisch rezidivierende Infektionen der Haut und Weichgewebe durch Staphylococcus aureus

Klinische Bedeutung des Small-colony-variant (SCV)-Phänotyps und von Panton-Valentine-Leukozidin (PVL)-positiven S.-aureus-Isolaten

Persistent and recurrent skin and soft tissue infections by Staphylococcus aureus

Impact of the small colony-variant (SCV) phenotype and of Panton-Valentine leukocidin (PVL)-positive S. aureus isolates

  • Leitthema
  • Published:
Der Hautarzt Aims and scope Submit manuscript

Zusammenfassung

Staphylococcus (S.) aureus zählt zu den häufigsten Erregern chronischer Infektionen der Haut und Weichgewebe. Durch Isolate, die das Panton-Valentine Leukozidin (PVL) aufweisen, werden aggressivere und verstärkt chronisch verlaufende Hautinfektionen verursacht. Dieses Toxin kann sowohl bei „community-associated“ Methicillin-resistenten S. aureus (CA-MRSA) als auch bei Methicillin-sensitiven Isolaten nachgewiesen werden. Ein weiterer Grund für chronisch rezidivierende Infektionsverläufe ist die Fähigkeit von S. aureus, den Small-colony-variant (SCV)-Phänotyp auszubilden. SCVs sind in der Lage, intrazellulär zu persistieren und somit der Wirtsabwehr als auch der Antibiotikatherapie, wenn sie nicht intrazellulär aktive Substanzen einbezieht, auszuweichen. Diese phänotypische Resistenz kann eine Ursache für Therapieversagen trotz Einsatz von in vitro als empfindlich eingestuften Antibiotika darstellen. Das reduzierte Wachstumsverhalten, die abweichende Koloniemorphologie und Veränderungen im bakteriellen Stoffwechsel der SCV erschweren den Nachweis, die Identifizierung und die Resistenztestung. Der Verdacht auf PVL-positive bzw. SCV-Isolate erfordert eine enge Abstimmung mit dem mikrobiologischen Laboratorium.

Abstract

Staphylococcus aureus is one of the major pathogens causing chronic skin and soft tissue infections. Particularly isolates producing Panton-Valentine leukocidin (PVL) comprising methicillin-susceptible and community-associated methicillin-resistant S. aureus (CA-MRSA) have been associated with more aggressive and persistent or relapsing courses. Beyond classical resistance mechanisms, functional resistance as shown by the small colony-variant (SCV) phenotype could be also responsible for treatment failures, despite the administration of antibiotics tested in vitro as susceptible. Also this phenotype has been associated with chronic courses of infections often with multiple exacerbations. Due to their ability to persist intracellularly, SCVs are protected from host defense and antibiotic treatment if only extracellularly active agents are administered. Reduced growth, abnormal colony morphology and changes in the metabolism of the SCVs aggravate drastically their identification, differentiation and susceptibility testing. The diagnostic and therapeutic challenges of PVL-positive and SCV isolates necessitate close collaboration with microbiological and infectious disease specialists.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1
Abb. 2
Abb. 3
Abb. 4

Literatur

  1. Abele-Horn M, Schupfner B, Emmerling P et al (2000) Persistent wound infection after herniotomy associated with small-colony variants of Staphylococcus aureus. Infection 28:53–54

    Article  CAS  PubMed  Google Scholar 

  2. Abu-Qatouseh LF, Chinni SV, Seggewiß J et al (2010) Identification of differentially expressed small non-protein-coding RNAs in Staphylococcus aureus displaying both the normal and the small-colony variant phenotype. J Mol Med 88:565–575

    Article  CAS  PubMed  Google Scholar 

  3. Baggett HC, Hennessy TW, Leman R et al (2003) An outbreak of community-onset methicillin-resistant Staphylococcus aureus skin infections in southwestern Alaska. Infect Control Hosp Epidemiol 24:397–402

    Article  PubMed  Google Scholar 

  4. Baumert N, Eiff C von, Schaaff F et al (2002) Physiology and antibiotic susceptibility of Staphylococcus aureus small colony variants. Microb Drug Resist 8:253–260

    Article  CAS  PubMed  Google Scholar 

  5. Becker K (2008) Virulenzfaktoren und molekulare Epidemiologie von Staphylococcus aureus – Renaissance eines alten Erregers? Kind Jugendmed 8:73–82

    Google Scholar 

  6. Becker K (2013) Staphylokokken. In: Rascher W (Hrsg) Therapie-Handbuch Infektionskrankheiten, 1. (Sonderedition) Aufl. Elsevier, Urban & Fischer, München, S 444–451

  7. Becker K, Harmsen D, Mellmann A et al (2004) Development and evaluation of a quality-controlled ribosomal sequence database for 16S ribosomal DNA-based identification of Staphylococcus species. J Clin Microbiol 42:4988–4995

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Becker K, Laham NA, Fegeler W et al (2006) Fourier-transform infrared spectroscopic analysis is a powerful tool for studying the dynamic changes in Staphylococcus aureus small-colony variants. J Clin Microbiol 44:3274–3278

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Becker K, Peters G (2009) „Staphylococcaceae“, Micrococcaceae und Dermacoccaceae. In: Neumeister B, Geiss HK, Braun RW, Kimmig P (Hrsg) Mikrobiologische Diagnostik. Bakteriologie – Mykologie – Virologie – Parasitologie, 2. Aufl. Thieme, Stuttgart, S 333–351

  10. Becker K, Podbielski A, Sunderkötter et al (2013) MiQ 6a/b: Infektionen der Haut und der subkutanen Weichgewebe – Teil I und II. Urban & Fischer (Elsevier), München

  11. Becker K, Eiff C von (2011) Staphylococcus, Micrococcus, and other catalase-positive cocci. In: Versalovic J, Carroll KC, Funke G, Jorgensen JH et al (Hrsg) Manual of clinical microbiology, 10. Aufl. ASM press, Washington, DC

  12. Bodmann KF, Grabein B, Expertenkommission der Paul-Ehrlich-Gesellschaft für Chemotherapie e.V. (2010) Empfehlungen zur kalkulierten parenteralen Initialtherapie bakterieller Erkrankungen bei Erwachsenen – Update 2010. Chemother J 19:179–255

    Google Scholar 

  13. Bubeck Wardenburg J, Bae T, Otto M et al (2007) Poring over pores: α-hemolysin and Panton-Valentine leukocidin in Staphylococcus aureus pneumonia. Nat Med 13:1405–1406

    Article  Google Scholar 

  14. Cribier B, Prévost G, Couppie P et al (1992) Staphylococcus aureus leukocidin: a new virulence factor in cutaneous infections? An epidemiological and experimental study. Dermatology 185:175–180

    Article  CAS  PubMed  Google Scholar 

  15. Diep BA, Chan L, Tattevin P et al (2010) Polymorphonuclear leukocytes mediate Staphylococcus aureus Panton-Valentine leukocidin-induced lung inflammation and injury. Proc Natl Acad Sci U S A 107:5587–5592

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  16. Dryden MS (2010) Complicated skin and soft tissue infection. J Antimicrob Chemother 65(Suppl 3):iii35–iii44

    Article  CAS  PubMed  Google Scholar 

  17. Garcia LG, Lemaire S, Kahl BC et al (2012) Pharmacodynamic evaluation of the activity of antibiotics against hemin- and menadione-dependent small-colony variants of Staphylococcus aureus in models of extracellular (broth) and intracellular (THP-1 monocytes) infections. Antimicrob Agents Chemother 56:3700–3711

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  18. Gillet Y, Issartel B, Vanhems P et al (2002) Association between Staphylococcus aureus strains carrying gene for Panton-Valentine leukocidin and highly lethal necrotising pneumonia in young immunocompetent patients. Lancet 359:753–759

    Article  CAS  PubMed  Google Scholar 

  19. Holzinger D, Gieldon L, Mysore V et al (2012) Staphylococcus aureus Panton-Valentine leukocidin induces an inflammatory response in human phagocytes via the NLRP3 inflammasome. J Leukoc Biol 92:1069–1081

    Article  CAS  PubMed  Google Scholar 

  20. Hörnig-Franz I, Kahl BC, Tebbe W et al (2007) Nekrotisierende Pneumonie mit Staphylococcus aureus (pvl-Gen positiv). Letal verlaufende Pneumonie bei einem 12-jährigen immunkompetenten Mädchen. Monatsschr Kinderheilkd 155:S10–S15

    Article  Google Scholar 

  21. Horst SA, Hoerr V, Beineke A et al (2012) A novel mouse model of Staphylococcus aureus chronic osteomyelitis that closely mimics the human infection: an integrated view of disease pathogenesis. Am J Pathol 181:1206–1214

    Article  PubMed  Google Scholar 

  22. Jappe U, Heuck D, Strommenger B et al (2008) Staphylococcus aureus in dermatology outpatients with special emphasis on community-associated methicillin-resistant strains. J Invest Dermatol 128:2655–2664

    Article  CAS  PubMed  Google Scholar 

  23. Kahl B, Herrmann M, Everding AS et al (1998) Persistent infection with small colony variant strains of Staphylococcus aureus in patients with cystic fibrosis. J Infect Dis 177:1023–1029

    Article  CAS  PubMed  Google Scholar 

  24. Kahl BC, Duebbers A, Lubritz G et al (2003) Population dynamics of persistent Staphylococcus aureus isolated from the airways of cystic fibrosis patients during a 6-year prospective study. J Clin Microbiol 41:4424–4427

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Kaneko J, Kamio Y (2004) Bacterial two-component and hetero-heptameric pore-forming cytolytic toxins: structures, pore-forming mechanism, and organization of the genes. Biosci Biotechnol Biochem 68:981–1003

    Article  CAS  PubMed  Google Scholar 

  26. King MD, Humphrey BJ, Wang YF et al (2006) Emergence of community-acquired methicillin-resistant Staphylococcus aureus USA 300 clone as the predominant cause of skin and soft-tissue infections. Ann Intern Med 144:309–317

    Article  PubMed  Google Scholar 

  27. Kipp F, Becker K, Peters G, Eiff C von (2004) Evaluation of different methods to detect methicillin resistance in small-colony variants of Staphylococcus aureus. J Clin Microbiol 42:1277–1279

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Kipp F, Kahl BC, Becker K et al (2005) Evaluation of two chromogenic agar media for recovery and identification of Staphylococcus aureus small-colony variants. J Clin Microbiol 43:1956–1959

    Article  PubMed Central  PubMed  Google Scholar 

  29. Kobayashi SD, Malachowa N, Whitney AR et al (2011) Comparative analysis of USA300 virulence determinants in a rabbit model of skin and soft tissue infection. J Infect Dis 204:937–941

    Article  CAS  PubMed  Google Scholar 

  30. Kriegeskorte A, König S, Sander G et al (2011) Small colony variants of Staphylococcus aureus reveal distinct protein profiles. Proteomics 11:2476–2490

    Article  CAS  PubMed  Google Scholar 

  31. Lannergård J, Eiff C von, Sander G et al (2008) Identification of the genetic basis for clinical menadione-auxotrophic small-colony variant isolates of Staphylococcus aureus. Antimicrob Agents Chemother 52:4017–4022

    Article  PubMed Central  PubMed  Google Scholar 

  32. Lemaire S, Olivier A, Van Bambeke F et al (2008) Restoration of susceptibility of intracellular methicillin-resistant Staphylococcus aureus to beta-lactams: comparison of strains, cells, and antibiotics. Antimicrob Agents Chemother 52:2797–2805

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Lina G, Piémont Y, Godail-Gamot F et al (1999) Involvement of Panton-Valentine leukocidin-producing Staphylococcus aureus in primary skin infections and pneumonia. Clin Infect Dis 29:1128–1132

    Article  CAS  PubMed  Google Scholar 

  34. Lipinska U, Hermans K, Meulemans L et al (2011) Panton-Valentine leukocidin does play a role in the early stage of Staphylococcus aureus skin infections: a rabbit model. PLoS One 6:e22864

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Löffler B, Hussain M, Grundmeier M et al (2010) Staphylococcus aureus panton-valentine leukocidin is a very potent cytotoxic factor for human neutrophils. PLoS Pathog 6:e1000715

    Article  PubMed Central  PubMed  Google Scholar 

  36. Ma X, Chang W, Zhang C et al (2012) Staphylococcal Panton-Valentine leukocidin induces pro-inflammatory cytokine production and nuclear factor-kappa B activation in neutrophils. PLoS One 7:e34970

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Menestrina G, Serra MD, Prévost G (2001) Mode of action of β-barrel pore-forming toxins of the staphylococcal α-hemolysin family. Toxicon 39:1661–1672

    Article  CAS  PubMed  Google Scholar 

  38. Miller LS, Cho JS (2011) Immunity against Staphylococcus aureus cutaneous infections. Nat Rev Immunol 11:505–518

    Article  CAS  PubMed  Google Scholar 

  39. Musher DM, Baughn RE, Templeton GB, Minuth JN (1977) Emergence of variant forms of Staphylococcus aureus after exposure to gentamicin and infectivity of the variants in experimental animals. J Infect Dis 136:360–369

    Article  CAS  PubMed  Google Scholar 

  40. Niemann S, Ehrhardt C, Medina E et al (2012) Combined action of influenza virus and Staphylococcus aureus Panton-Valentine leukocidin provokes severe lung epithelium damage. J Infect Dis 206:1138–1148

    Article  PubMed  Google Scholar 

  41. Nippe N, Varga G, Holzinger D et al (2011) Subcutaneous infection with S. aureus in mice reveals association of resistance with influx of neutrophils and Th2 response. J Invest Dermatol 131:125–132

    Article  CAS  PubMed  Google Scholar 

  42. Proctor RA (2008) Role of folate antagonists in the treatment of methicillin-resistant Staphylococcus aureus infection. Clin Infect Dis 46:584–593

    Article  CAS  PubMed  Google Scholar 

  43. Proctor RA, Balwit JM, Vesga O (1994) Variant subpopulations of Staphylococcus aureus as cause of persistent and recurrent infections. Infect Agents Dis 3:302–312

    CAS  PubMed  Google Scholar 

  44. Proctor RA, Langevelde P van, Kristjansson M et al (1995) Persistent and relapsing infections associated with small-colony variants of Staphylococcus aureus. Clin Infect Dis 20:95–102

    Article  CAS  PubMed  Google Scholar 

  45. Proctor RA, Eiff C von, Kahl BC et al (2006) Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections. Nat Rev Microbiol 4:295–305

    Article  CAS  PubMed  Google Scholar 

  46. Rutar T, Zwick OM, Cockerham KP, Horton JC (2005) Bilateral blindness from orbital cellulitis caused by community-acquired methicillin-resistant Staphylococcus aureus. Am J Ophthalmol 140:740–742

    Article  PubMed  Google Scholar 

  47. Sachse F, Becker K, Eiff C von et al (2010) Staphylococcus aureus invades the epithelium in nasal polyposis and induces IL-6 in nasal epithelial cells in vitro. Allergy 65:1430–1437

    Article  CAS  PubMed  Google Scholar 

  48. Sass V, Schneider T, Wilmes M et al (2010) Human β-defensin 3 inhibits cell wall biosynthesis in staphylococci. Infect Immun 78:2793–2800

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. Schaaff F, Bierbaum G, Baumert N et al (2003) Mutations are involved in emergence of aminoglycoside-induced small colony variants of Staphylococcus aureus. Int J Med Microbiol 293:427–435

    Article  CAS  PubMed  Google Scholar 

  50. Schaumburg F, Köck R, Friedrich AW et al (2011) Population structure of Staphylococcus aureus from remote African Babongo Pygmies. PLoS Negl Trop Dis 5:e1150

    Article  PubMed Central  PubMed  Google Scholar 

  51. Schaumburg F, Köck R, Mellmann A et al (2012) Population dynamics among methicillin resistant Staphylococcus aureus in Germany during a 6-year period. J Clin Microbiol 50:3186–3192

    Article  PubMed Central  PubMed  Google Scholar 

  52. Schefold JC, Esposito F, Storm C et al (2007) Therapy-refractory Panton Valentine leukocidin-positive community-acquired methicillin-sensitive Staphylococcus aureus sepsis with progressive metastatic soft tissue infection: a case report. J Med Case Reports 1:165

    Article  PubMed Central  Google Scholar 

  53. Seggewiß J, Becker K, Kotte O et al (2006) Reporter metabolite analysis of transcriptional profiles of a Staphylococcus aureus strain with normal phenotype and its isogenic hemB mutant displaying the small-colony-variant phenotype. J Bacteriol 188:7765–7777

    Article  PubMed Central  PubMed  Google Scholar 

  54. Seifert H, Eiff C von, Fätkenheuer G (1999) Fatal case due to methicillin-resistant Staphylococcus aureus small colony variants in an AIDS patient. Emerg Infect Dis 5:450–453

    Article  CAS  PubMed  Google Scholar 

  55. Soehnlein O, Lindbom L (2010) Phagocyte partnership during the onset and resolution of inflammation. Nat Rev Immunol 10:427–439

    Article  CAS  PubMed  Google Scholar 

  56. Spaan AN, Henry T, Rooijen WJ van et al (2013) The staphylococcal toxin Panton-Valentine leukocidin targets human C5a receptors. Cell Host Microbe 13:584–594

    Article  CAS  PubMed  Google Scholar 

  57. Szmigielski S, Prevost G, Monteil H et al (1999) Leukocidal toxins of staphylococci. Zentralbl Bakteriol 289:185–201

    Article  CAS  PubMed  Google Scholar 

  58. Tseng CW, Kyme P, Low J et al (2009) Staphylococcus aureus Panton-Valentine leukocidin contributes to inflammation and muscle tissue injury. PLoS One 4:e6387

    Article  PubMed Central  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  60. Tuchscherr L, Medina E, Hussain M et al (2011) Staphylococcus aureus phenotype switching: an effective bacterial strategy to escape host immune response and establish a chronic infection. EMBO Mol Med 3:129–141

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Vaudaux P, Francois P, Bisognano C et al (2002) Increased expression of clumping factor and fibronectin-binding proteins by hemB mutants of Staphylococcus aureus expressing small colony variant phenotypes. Infect Immun 70:5428–5437

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  62. Vesga O, Groeschel MC, Otten MF et al (1996) Staphylococcus aureus small colony variants are induced by the endothelial cell intracellular milieu. J Infect Dis 173:739–742

    Article  CAS  PubMed  Google Scholar 

  63. Eiff C von, Becker K (2007) Small-colony variants (SCVs) of staphylococci: a role in foreign body-associated infections. Int J Artif Organs 30:778–785

    Google Scholar 

  64. Eiff C von, Becker K, Metze D et al (2001) 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 32:1643–1647

    Article  Google Scholar 

  65. Eiff C von, Bettin D, Proctor RA et al (1997) Recovery of small colony variants of Staphylococcus aureus following gentamicin bead placement for osteomyelitis. Clin Infect Dis 25:1250–1251

    Article  Google Scholar 

  66. Eiff C von, Heilmann C, Proctor RA et al (1997) A site-directed Staphylococcus aureus hemB mutant is a small-colony variant which persists intracellularly. J Bacteriol 179:4706–4712

    Google Scholar 

  67. Eiff C von, McNamara P, Becker K et al (2006) Phenotype microarray profiling of Staphylococcus aureus menD and hemB mutants with the small-colony-variant phenotype. J Bacteriol 188:687–693

    Article  Google Scholar 

  68. Eiff C von, Peters G, Becker K (2006) The small colony variant (SCV) concept – the role of staphylococcal SCVs in persistent infections. Injury 37(Suppl 2):S26–S33

    Article  Google Scholar 

  69. Wagenlehner FM, Naber KG, Bambl E et al (2007) Management of a large healthcare-associated outbreak of Panton-Valentine leucocidin-positive meticillin-resistant Staphylococcus aureus in Germany. J Hosp Infect 67:114–120

    Article  CAS  PubMed  Google Scholar 

  70. Wolter DJ, Emerson JC, McNamara S et al (2013) Staphylococcus aureus small-colony variants are independently associated with worse lung disease in children with cystic fibrosis. Clin Infect Dis 57:384–391

    Article  CAS  PubMed  Google Scholar 

  71. Wright J (1936) Staphylococcal leucocidin (Neisser-Wechsberg type) and antileucocidin. Lancet 227:1002–1005

    Article  Google Scholar 

  72. Ziv G, Sompolinsky D (1976) Biological and ecological investigations on thiamineless dwarf-colony variants of Staphylococcus aureus of bovine udder origin. Res Vet Sci 20:281–287

    CAS  PubMed  Google Scholar 

Download references

Danksagung

Der Artikel wurde zum Teil mit Mitteln des BMBF („SkIn Staph“ im Verbundprojekt „Suszeptibilität von Infektionen“; K.B., 01KI1009A und C.S., 01Kl07100) und der DFG (K.B., BE 2546/1-1 und B.L., SFB1009/B1) gefördert.

Einhaltung ethischer Richtlinien

Interessenkonflikt. C. von Eiff ist Angestellter bei Pfizer GmbH Deutschland. K. Becker erhielt Reisekostenunterstützungen, Vortragshonorare bzw. Studien-Grants von MSD Sharp & Dohme, Novartis und Pfizer. C. Sunderkötter erhielt zur Thematik Hautinfektionen Unterstützung von Astra Zeneca, Bayer, GlaxoSmithKline, Infectopharm, Novartis und Schering Plough. A. Kriegeskorte und B. Löffler geben an, dass keine Interessenkonflikte bestehen. Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

Author information

Authors and Affiliations

  1. Institut für Medizinische Mikrobiologie, Universitätsklinikum Münster, Domagkstr. 10, 48149, Münster, Deutschland

    K. Becker, A. Kriegeskorte, B. Löffler & C. von Eiff

  2. Klinik für Hautkrankheiten des Universitätsklinikums Münster, Münster, Deutschland

    C. Sunderkötter

  3. Pfizer Pharma GmbH, Berlin, Deutschland

    C. von Eiff

Authors
  1. K. Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Kriegeskorte
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. C. Sunderkötter
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. B. Löffler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. C. von Eiff
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to K. Becker.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Becker, K., Kriegeskorte, A., Sunderkötter, C. et al. Chronisch rezidivierende Infektionen der Haut und Weichgewebe durch Staphylococcus aureus . Hautarzt 65, 15–25 (2014). https://doi.org/10.1007/s00105-013-2636-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00105-013-2636-8

Schlüsselwörter

Keywords

Search

Navigation