title: Regional Intraosseous Administration of Prophylactic Antibiotics is More Effective Than Systemic Administration in a Mouse Model of TKA.
abstract: BACKGROUND
  In human TKA studies, intraosseous regional administration (IORA) of prophylactic antibiotics achieves local tissue antibiotic concentrations 10 times greater than systemic administration. However, it is unclear if such high concentrations provide more effective prophylaxis.
  
  
  OBJECTIVE
  We asked: (1) What prophylaxis dosage and route (intravenous [IV] versus IORA of prophylactic antibiotics) produce less in vivo bacterial burden compared with no-antibiotic controls? (2) Compared with controls, what prophylaxis dosage and route yield fewer colony-forming units (CFUs) in euthanized animals in a model of TKA? (3) Is prophylactic IORA of antibiotics more effective than same-dose IV antibiotic administration in reducing CFUs?
  
  
  METHODS
  Mice (six to nine per group) were block randomized to one of six prophylaxis regimens: control, systemic cefazolin (C100IV), IORA of cefazolin (C100IORA), systemic vancomycin (V110IV), low-dose systemic vancomycin (V25IV), and low-dose IORA of vancomycin (V25IORA). Surgery involved placement of an intraarticular knee prosthesis, followed by an inoculum of bioluminescent Staphylococcus aureus strain Xen36. Biophotonic imaging assessed in vivo bacterial loads, and after 4 days bacterial load was quantified using culture-based techniques. Comparisons were made for each prophylactic regimen to controls and between same-dose IV and IORA of prophylactic antibiotic regimens.
  
  
  RESULTS
  Mice treated with systemic high-dose vancomycin, IORA of vancomycin, or IORA of cefazolin had lower in vivo Staphylococcus aureus burdens (median area under curve, Control: 5.0 × 10(6); V110IV: 1.5 × 10(6), difference of medians 3.5 × 10(6), p = 0.003; V25IV: 1.94 × 10(6), difference 3.07 × 10(6), p = 0.49; V25IORA: 1.51 × 10(6), difference 3.5 × 10(6), p = 0.0011; C100IORA: 1.55 × 10(6), difference 3.46 × 10(6), p = 0.0016; C100IV: 2.35 × 10(6), difference 2.66 × 10(6), p = 0.23.) Similar findings were seen with culture-based techniques on recovered implants. IORA of prophylactic antibiotics was more effective than same-dose IV administration in reducing bacterial load on recovered implants (median CFUs < 7.0 × 10(0) vs 2.83 × 10(2), p = 0.0183).
  
  
  CONCLUSIONS
  IORA of prophylactic cefazolin and vancomycin was more effective than the same dose of antibiotic given systemically. The effectiveness of vancomycin in particular was enhanced by IORA of prophylactic antibiotics despite using a lower dose.
  
  
  CONCLUSIONS
  Our study supports previous studies of IORA of prophylactic antibiotics in humans and suggests this novel form of administration has the potential to enhance the effectiveness of prophylaxis in TKA. Because of concerns regarding antibiotic stewardship, IORA of prophylactic vancomycin may be more appropriately restricted to patients having TKA who are at greater risk of infection, and clinical trials are in progress.
authors.affiliation: Department of Surgery, University of Auckland, Auckland, New Zealand. simonwyoung@gmail.com.|Department of Orthopaedic Surgery, North Shore Hospital, 124 Shakespeare Road, Takapuna, Private Bag 93-503, Auckland, 0740, New Zealand. simonwyoung@gmail.com.
authors.forename: Simon W
authors.initials: SW
authors.lastname: Young
authors.affiliation: Department of Orthopaedic Surgery, North Shore Hospital, 124 Shakespeare Road, Takapuna, Private Bag 93-503, Auckland, 0740, New Zealand.
authors.forename: Tim
authors.initials: T
authors.lastname: Roberts
authors.affiliation: Bioluminescent Superbugs Laboratory, Faculty of Medical & Health Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Sarah
authors.initials: S
authors.lastname: Johnson
authors.affiliation: Bioluminescent Superbugs Laboratory, Faculty of Medical & Health Sciences, University of Auckland, Auckland, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand.
authors.forename: James P
authors.initials: JP
authors.lastname: Dalton
authors.affiliation: Department of Orthopaedic Surgery, North Shore Hospital, 124 Shakespeare Road, Takapuna, Private Bag 93-503, Auckland, 0740, New Zealand.
authors.forename: Brendan
authors.initials: B
authors.lastname: Coleman
authors.affiliation: Bioluminescent Superbugs Laboratory, Faculty of Medical & Health Sciences, University of Auckland, Auckland, New Zealand.|Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand.
authors.forename: Siouxsie
authors.initials: S
authors.lastname: Wiles
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D019072:Antibiotic Prophylaxis / Q000379:methods*; D019645:Arthroplasty, Replacement, Knee / Q000009:adverse effects* / Q000295:instrumentation; D058491:Bacterial Load; D002437:Cefazolin / Q000008:administration & dosage*; D015169:Colony Count, Microbial; D005260:Female; D007275:Injections, Intravenous; D007720:Knee Prosthesis / Q000009:adverse effects*; D051379:Mice; D023421:Models, Animal; D016459:Prosthesis-Related Infections / Q000175:diagnosis / Q000382:microbiology / Q000517:prevention & control*; D013203:Staphylococcal Infections / Q000175:diagnosis / Q000382:microbiology / Q000517:prevention & control*; D013997:Time Factors; D014640:Vancomycin / Q000008:administration & dosage*
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin; D002437:Cefazolin