title: Cathodic Electrical Stimulation Combined With Vancomycin Enhances Treatment of Methicillin-resistant Staphylococcus aureus Implant-associated Infections.
abstract: BACKGROUND
  Effective treatments for implant-associated infections are often lacking. Cathodic voltage-controlled electrical stimulation has shown potential as a treatment of implant-associated infections of methicillin-resistant Staphylococcus aureus (MRSA).
  
  
  OBJECTIVE
  The primary purpose of this study was to (1) determine if cathodic voltage-controlled electrical stimulation combined with vancomycin therapy is more effective at reducing the MRSA bacterial burden on the implant, bone, and synovial fluid in comparison to either treatment alone or no treatment controls. We also sought to (2) evaluate the histologic effects of the various treatments on the surrounding bone; and to (3) determine if the cathodic voltage-controlled electrical stimulation treatment had an effect on the mechanical properties of the titanium implant as a result of possible hydrogen embrittlement.
  
  
  METHODS
  Thirty-two adult male Long-Evans rats (Harlan Laboratories, Indianapolis, IN, USA) with surgically placed shoulder titanium implants were infected with a clinical strain of MRSA (NRS70). One week after infection, eight animals received a treatment of cathodic voltage-controlled electrical stimulation at -1.8 V versus Ag/AgCl for 1 hour (STIM), eight received vancomycin twice daily for 1 week (VANCO), eight received the cathodic voltage-controlled electrical stimulation and vancomycin therapy combined (STIM + VANCO), and eight served as controls with no treatment (CONT). Two weeks after initial infection, the implant, bone, and synovial fluid were collected for colony-forming unit (CFU) enumeration, qualitative histological analysis by a pathologist blinded to the treatments each animal received, and implant three-point bend testing.
  
  
  RESULTS
  The implant-associated CFU enumerated from the STIM + VANCO (mean, 3.7 × 10(3); SD, 6.3 × 10(3)) group were less than those from the CONT (mean, 1.3 × 10(6); SD, 2.8 × 10(6); 95% confidence interval [CI] of difference, -4.3 × 10(5) to -9.9 × 10(3); p < 0.001), STIM (mean, 1.4 × 10(6); SD, 2.0 × 10(6); 95% CI of difference, -2.1 × 10(6) to -1.8 × 10(3); p = 0.002), and VANCO (mean, 5.8 x 10(4); SD, 5.7 × 10(4); 95% CI of difference, -6.4 × 10(4) to -1.7 × 10(4); p < 0.001) group. The bone-associated CFU enumerated from the STIM + VANCO group (6.3 × 10(1); SD, 1.1 × 10(2)) were less than those from the CONT (mean, 2.8 × 10(5); SD, 4.8 × 10(5); 95% CI of difference, -9.4 × 10(4) to -5.0 × 10(3); p < 0.001) and STIM (mean, 2.6 × 10(4); SD, 2.5 × 10(4); 95% CI of difference, -4.1 × 10(4) to -1.6 × 10(3); p < 0.001) groups. The VANCO group (4.3 × 10(5); SD, 6.3 × 10(2)) also had lower bone-associated CFU as compared with the CONT (mean 95% CI of difference, -9.3 × 10(4) to -4.5 × 10(3); p < 0.001) and STIM (95% CI of difference, -4.0 × 10(4) to -1.5 × 10(3); p < 0.001) groups. In comparison to the synovial fluid CFU enumerated from the CONT group (mean, 3.3 × 10(4); SD, 6.0 × 10(4)), lower synovial CFU were reported for both the STIM + VANCO group (mean, 4.6 × 10(1); SD, 1.2 × 10(2); 95% CI of difference, -4.9 × 10(3) to -3.0 × 10(2); p < 0.001) and the VANCO group (mean, 6.8 × 10(1); SD, 9.2 × 10(1); 95% CI of difference, -4.9 × 10(3) to -2.8 × 10(2); p = 0.007). The histological analysis showed no discernable deleterious effects on the surrounding tissue as a result of the treatments. No brittle fracture occurred during mechanical testing and with the numbers available, no differences in implant flexural yield strength were detected between the groups.
  
  
  CONCLUSIONS
  In this rodent model, cathodic voltage-controlled electrical stimulation combined with vancomycin is an effective treatment for titanium implant-associated infections showing greater than 99.8% reduction in bacterial burden on the implant, surrounding bone, and synovial fluid as compared with the controls and the stimulation alone groups.
  
  
  CONCLUSIONS
  Cathodic voltage-controlled electrical stimulation combined with vancomycin may enable successful treatment of titanium orthopaedic implant-associated infections with implant retention. Future studies will focus on optimization of the stimulation parameters for complete eradication of infection and the ability to promote beneficial host tissue responses.
authors.affiliation: Department of Orthopedics, State University of New York at Buffalo, Buffalo, NY, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Nodzo
authors.forename: Menachem
authors.initials: M
authors.lastname: Tobias
authors.forename: Lisa
authors.initials: L
authors.lastname: Hansen
authors.forename: Nicole R
authors.initials: NR
authors.lastname: Luke-Marshall
authors.forename: Ross
authors.initials: R
authors.lastname: Cole
authors.forename: Linda
authors.initials: L
authors.lastname: Wild
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Campagnari
authors.forename: Mark T
authors.initials: MT
authors.lastname: Ehrensberger
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D019643:Arthroplasty, Replacement / Q000009:adverse effects* / Q000295:instrumentation*; D058491:Bacterial Load; D015169:Colony Count, Microbial; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004599:Electric Stimulation Therapy / Q000295:instrumentation*; D004566:Electrodes; D004867:Equipment Design; D058430:Humeral Head / Q000187:drug effects* / Q000382:microbiology / Q000473:pathology / Q000601:surgery; D007595:Joint Prosthesis; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000472:pathogenicity; D011474:Prosthesis Design; D016459:Prosthesis-Related Infections / Q000382:microbiology / Q000473:pathology / Q000628:therapy*; D020318:Rats, Long-Evans; D013203:Staphylococcal Infections / Q000382:microbiology / Q000473:pathology / Q000628:therapy*; D013582:Synovial Fluid / Q000382:microbiology; D013997:Time Factors; D014025:Titanium; D014640:Vancomycin / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D014640:Vancomycin; D014025:Titanium
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