A doxycycline-loaded polymer-lipid encapsulation matrix coating for the prevention of implant-related osteomyelitis due to doxycycline-resistant methicillin-resistant Staphylococcus aureus

J Control Release. 2015 Jul 10;209:47-56. doi: 10.1016/j.jconrel.2015.04.022. Epub 2015 Apr 21.

Abstract

Implant-associated bone infections caused by antibiotic-resistant pathogens pose significant clinical challenges to treating physicians. Prophylactic strategies that act against resistant organisms, such as methicillin-resistant Staphylococcus aureus (MRSA), are urgently required. In the present study, we investigated the efficacy of a biodegradable Polymer-Lipid Encapsulation MatriX (PLEX) loaded with the antibiotic doxycycline as a local prophylactic strategy against implant-associated osteomyelitis. Activity was tested against both a doxycycline-susceptible (doxy(S)) methicillin-susceptible S. aureus (MSSA) as well as a doxycycline-resistant (doxy(R)) methicillin-resistant S. aureus (MRSA). In vitro elution studies revealed that 25% of the doxycycline was released from the PLEX-coated implants within the first day, followed by a 3% release per day up to day 28. The released doxycycline was highly effective against doxy(S) MSSA for at least 14days in vitro. A bolus injection of doxycycline mimicking a one day release from the PLEX-coating reduced, but did not eliminate, mouse subcutaneous implant-associated infection (doxy(S) MSSA). In a rabbit intramedullary nail-related infection model, all rabbits receiving a PLEX-doxycycline-coated nail were culture negative in the doxy(S) MSSA-group and the surrounding bone displayed a normal physiological appearance in both histological sections and radiographs. In the doxy(R) MRSA inoculated rabbits, a statistically significant reduction in the number of culture-positive samples was observed for the PLEX-doxycycline-coated group when compared to the animals that had received an uncoated nail, although the reduction in bacterial burden did not reach statistical significance. In conclusion, the PLEX-doxycycline coating on titanium alloy implants provided complete protection against implant-associated MSSA osteomyelitis, and resulted in a significant reduction in the number of culture positive samples when challenged with a doxycycline-resistant MRSA.

Keywords: Antibiotic resistance; Doxycycline; MRSA; Orthopedic implant; Osteomyelitis; PLEX technology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / administration & dosage*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / therapeutic use
  • Doxycycline / administration & dosage*
  • Doxycycline / chemistry
  • Doxycycline / therapeutic use
  • Drug Liberation
  • Drug Resistance, Bacterial
  • Female
  • Lipids / chemistry
  • Methicillin-Resistant Staphylococcus aureus*
  • Mice, Inbred C57BL
  • Osteomyelitis / prevention & control*
  • Polymers / chemistry
  • Prostheses and Implants
  • Rabbits
  • Staphylococcal Infections / prevention & control*
  • Titanium

Substances

  • Anti-Bacterial Agents
  • Lipids
  • Polymers
  • Ti-6Al-7Nb alloy
  • Titanium
  • Doxycycline