title: Local gentamicin delivery from resorbable viscous hydrogels is therapeutically effective.
abstract: BACKGROUND
  Local delivery can achieve the high antimicrobial concentrations necessary to kill biofilm-related microbes. Degradation times for resorbable carriers are too long. Hydrogels (gels of hydrophilic polymer in water) can degrade faster but release antimicrobials too quickly. We previously developed hydrogels based on the copolymer poly(N-isopropylacrylamide-co-dimethyl-γ-butyrolactone acrylate-co-Jeffamine® M-1000 acrylamide) (PNDJ) with delivery times of several days with complete degradation in less than 6 weeks.
  
  
  OBJECTIVE
  We asked: (1) What is the elution profile of gentamicin from PNDJ hydrogels? (2) Is gentamicin released from gentamicin-loaded PNDJ (G-PNDJ) hydrogel effective for treatment of orthopaedic infection? (3) Does local gentamicin delivery from G-PNDJ hydrogel cause renal dysfunction?
  
  
  METHODS
  (1) Two formulations of G-PNDJ, lower dose (1.61 wt%) and higher dose (3.14 wt%), five samples each, were eluted in buffered saline under infinite sink conditions. (2) Infections were induced in 16 New Zealand White rabbits by inserting a Kirschner wire in a devascularized radius segment and inoculating with 7.5×10(6) colony-forming units Staphylococcus aureus. At 3 weeks, débridement was performed and a new Kirschner wire was placed in the dead space. Treatment was randomized to higher-dose G-PNDJ or no hydrogel. No systemic antimicrobials were used. Positive culture and acute inflammation on histology were used to determine the presence of infection 4 weeks postdébridement. (3) 3.14 wt% G-PNDJ, 0.75, 1.5, or 3.0 mL, was injected subcutaneously in nine Sprague-Dawley rats, three of each dose. Serum gentamicin, blood urea nitrogen, and creatinine were measured on Days 1, 3, 7, 14, and 28.
  
  
  RESULTS
  (1) Gentamicin release was sustained over 7 days with the higher-dose formulation release profile similar to release from high-dose antimicrobial-loaded bone cement. (2) Four weeks postdébridement, infection was present in eight of eight no-hydrogel rabbits but zero of eight rabbits treated with G-PNDJ hydrogel (p<0.001). (3) Blood urea nitrogen and creatinine were transiently elevated (p<0.05) only for the two of three rats receiving the 3.0-mL dose on Days 3 and 7.
  
  
  CONCLUSIONS
  Gentamicin is delivered from PNDJ hydrogel with low systemic exposure and decreased treatment failure for orthopaedic infection. Transient renal dysfunction occurs at high doses. Biodistribution and toxicity testing are needed for G-PNDJ to be clinically usable.
  
  
  CONCLUSIONS
  Resorbable viscous hydrogels for local antimicrobial delivery may improve outcomes for one-stage management of implant infections when uncemented reconstructions are performed.
authors.affiliation: Sonoran Biosciences, Chandler, AZ, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: Overstreet
authors.forename: Alex
authors.initials: A
authors.lastname: McLaren
authors.forename: Francis
authors.initials: F
authors.lastname: Calara
authors.forename: Brent
authors.initials: B
authors.lastname: Vernon
authors.forename: Ryan
authors.initials: R
authors.lastname: McLemore
mesh_terms: D020341:Absorbable Implants; D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D000891:Anti-Infective Agents, Local / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D001806:Blood Urea Nitrogen; D001864:Bone Wires / Q000009:adverse effects*; D002626:Chemistry, Pharmaceutical; D003404:Creatinine / Q000097:blood; D003646:Debridement; D004195:Disease Models, Animal; D004337:Drug Carriers; D004343:Drug Implants; D005260:Female; D005839:Gentamicins / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D020100:Hydrogels; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000097:blood / Q000139:chemically induced; D020714:Maximum Tolerated Dose; D011108:Polymers / Q000737:chemistry*; D016459:Prosthesis-Related Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D011817:Rabbits; D011884:Radius / Q000187:drug effects* / Q000382:microbiology / Q000601:surgery; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013203:Staphylococcal Infections / Q000175:diagnosis / Q000188:drug therapy* / Q000382:microbiology; D013997:Time Factors; D014783:Viscosity
chemical_list: D000900:Anti-Bacterial Agents; D000891:Anti-Infective Agents, Local; D004337:Drug Carriers; D004343:Drug Implants; D005839:Gentamicins; D020100:Hydrogels; D011108:Polymers; D003404:Creatinine