title: Staphylococcus aureus develops increased resistance to antibiotics by forming dynamic small colony variants during chronic osteomyelitis.
abstract: OBJECTIVE
  Staphylococcus aureus osteomyelitis often develops to chronicity despite antimicrobial treatments that have been found to be susceptible in in vitro tests. The complex infection strategies of S. aureus, including host cell invasion and intracellular persistence via the formation of dynamic small colony variant (SCV) phenotypes, could be responsible for therapy-refractory infection courses.
  
  
  METHODS
  To analyse the efficacy of antibiotics in the acute and chronic stage of bone infections, we established long-term in vitro and in vivo osteomyelitis models. Antibiotics that were tested include β-lactams, fluoroquinolones, vancomycin, linezolid, daptomycin, fosfomycin, gentamicin, rifampicin and clindamycin.
  
  
  RESULTS
  Cell culture infection experiments revealed that all tested antibiotics reduced bacterial numbers within infected osteoblasts when treatment was started immediately, whereas some antibiotics lost their activity against intracellular persisting bacteria. Only rifampicin almost cleared infected osteoblasts in the acute and chronic stages. Furthermore, we detected that low concentrations of gentamicin, moxifloxacin and clindamycin enhanced the formation of SCVs, and these could promote chronic infections. Next, we treated a murine osteomyelitis model in the acute and chronic stages. Only rifampicin significantly reduced the bacterial load of bones in the acute phase, whereas cefuroxime and gentamicin were less effective and gentamicin strongly induced SCV formation. During chronicity none of the antimicrobial compounds tested showed a beneficial effect on bone deformation or reduced the numbers of persisting bacteria.
  
  
  CONCLUSIONS
  In all infection models rifampicin was most effective at reducing bacterial loads. In the chronic stage, particularly in the in vivo model, many tested compounds lost activity against persisting bacteria and some antibiotics even induced SCV formation.
authors.affiliation: Institute of Medical Microbiology, Jena University Hospital, Jena, Germany Lorena.TuchscherrdeHauschopp@med.uni-jena.de.
authors.forename: L
authors.initials: L
authors.lastname: Tuchscherr
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, University Hospital of Münster, Münster, Germany.
authors.forename: C A
authors.initials: CA
authors.lastname: Kreis
authors.affiliation: Institute of Medical Microbiology, Jena University Hospital, Jena, Germany Department for Clinical Radiology, University Hospital of Münster, Münster, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Hoerr
authors.affiliation: Institute of Medical Microbiology, University Hospital of Münster, Münster, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Flint
authors.affiliation: Institute of Medical Microbiology, University Hospital of Münster, Münster, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Hachmeister
authors.affiliation: Institute of Medical Microbiology, Jena University Hospital, Jena, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Geraci
authors.affiliation: Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Bremer-Streck
authors.affiliation: Department of Clinical Chemistry and Laboratory Medicine, Jena University Hospital, Jena, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Kiehntopf
authors.affiliation: Helmholtz Center for Infection Research, Braunschweig, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Medina
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, Jena University Hospital, Jena, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Kribus
authors.affiliation: Department of Trauma, Hand and Reconstructive Surgery, University Hospital of Münster, Münster, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Raschke
authors.affiliation: Center for Infectious Diseases and Infection Control, Jena University Hospital, Jena, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Pletz
authors.affiliation: Institute of Medical Microbiology, University Hospital of Münster, Münster, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Peters
authors.affiliation: Institute of Medical Microbiology, Jena University Hospital, Jena, Germany Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Löffler
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D002908:Chronic Disease; D004195:Disease Models, Animal; D024881:Drug Resistance, Bacterial; D005260:Female; D006801:Humans; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010006:Osteoblasts / Q000382:microbiology; D010019:Osteomyelitis / Q000382:microbiology*; D013203:Staphylococcal Infections / Q000382:microbiology*; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000254:growth & development* / Q000302:isolation & purification
chemical_list: D000900:Anti-Bacterial Agents