title: A doxycycline-loaded polymer-lipid encapsulation matrix coating for the prevention of implant-related osteomyelitis due to doxycycline-resistant methicillin-resistant Staphylococcus aureus.
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.
authors.affiliation: AO Research Institute Davos, AO Foundation, Clavadelerstrasse 8, Davos Platz CH7270, Switzerland.
authors.forename: Willem-Jan
authors.initials: WJ
authors.lastname: Metsemakers
authors.affiliation: PolyPid Ltd., 18 Hasivim St., Petach-Tikva 4959376, Israel.
authors.forename: Noam
authors.initials: N
authors.lastname: Emanuel
authors.affiliation: PolyPid Ltd., 18 Hasivim St., Petach-Tikva 4959376, Israel.
authors.forename: Or
authors.initials: O
authors.lastname: Cohen
authors.affiliation: PolyPid Ltd., 18 Hasivim St., Petach-Tikva 4959376, Israel.
authors.forename: Malka
authors.initials: M
authors.lastname: Reichart
authors.affiliation: AO Research Institute Davos, AO Foundation, Clavadelerstrasse 8, Davos Platz CH7270, Switzerland.
authors.forename: Inga
authors.initials: I
authors.lastname: Potapova
authors.affiliation: AO Research Institute Davos, AO Foundation, Clavadelerstrasse 8, Davos Platz CH7270, Switzerland.
authors.forename: Tanja
authors.initials: T
authors.lastname: Schmid
authors.affiliation: PolyPid Ltd., 18 Hasivim St., Petach-Tikva 4959376, Israel.
authors.forename: David
authors.initials: D
authors.lastname: Segal
authors.affiliation: Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Martijn
authors.initials: M
authors.lastname: Riool
authors.affiliation: Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Paulus H S
authors.initials: PH
authors.lastname: Kwakman
authors.affiliation: Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Leonie
authors.initials: L
authors.lastname: de Boer
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: Anna
authors.initials: A
authors.lastname: de Breij
authors.affiliation: Department of Infectious Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.
authors.forename: Peter H
authors.initials: PH
authors.lastname: Nibbering
authors.affiliation: AO Research Institute Davos, AO Foundation, Clavadelerstrasse 8, Davos Platz CH7270, Switzerland.
authors.forename: R Geoff
authors.initials: RG
authors.lastname: Richards
authors.affiliation: Department of Medical Microbiology, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Sebastian A J
authors.initials: SA
authors.lastname: Zaat
authors.affiliation: AO Research Institute Davos, AO Foundation, Clavadelerstrasse 8, Davos Platz CH7270, Switzerland. Electronic address: fintan.moriarty@aofoundation.org.
authors.forename: T Fintan
authors.initials: TF
authors.lastname: Moriarty
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D004318:Doxycycline / Q000008:administration & dosage* / Q000737:chemistry / Q000627:therapeutic use; D065546:Drug Liberation; D024881:Drug Resistance, Bacterial; D005260:Female; D008055:Lipids / Q000737:chemistry; D055624:Methicillin-Resistant Staphylococcus aureus; D008810:Mice, Inbred C57BL; D010019:Osteomyelitis / Q000517:prevention & control*; D011108:Polymers / Q000737:chemistry; D019736:Prostheses and Implants; D011817:Rabbits; D013203:Staphylococcal Infections / Q000517:prevention & control*; D014025:Titanium
chemical_list: D000900:Anti-Bacterial Agents; D008055:Lipids; D011108:Polymers; C070282:Ti-6Al-7Nb alloy; D014025:Titanium; D004318:Doxycycline
keywords: Antibiotic resistance; Doxycycline; MRSA; Orthopedic implant; Osteomyelitis; PLEX technology