In Vivo Assessment of Phage and Linezolid Based Implant Coatings for Treatment of Methicillin Resistant S. aureus (MRSA) Mediated Orthopaedic Device Related Infections

Abstract

Staphylococcus comprises up to two-thirds of all pathogens in orthopaedic implant infections with two species respectively Staphylococcus aureus and Staphylococcus epidermidis, being the predominate etiological agents isolated. Further, with the emergence of methicillin-resistant S. aureus (MRSA), treatment of S. aureus implant infections has become more difficult, thus representing a devastating complication. Use of local delivery system consisting of S.aureus specific phage along with linezolid (incorporated in biopolymer) allowing gradual release of the two agents at the implant site represents a new, still unexplored treatment option (against orthopaedic implant infections) that has been studied in an animal model of prosthetic joint infection. Naked wire, hydroxypropyl methylcellulose (HPMC) coated wire and phage and /or linezolid coated K-wire were surgically implanted into the intra-medullary canal of mouse femur bone of respective groups followed by inoculation of S.aureus ATCC 43300(MRSA). Mice implanted with K-wire coated with both the agents i.e phage as well as linezolid (dual coated wires) showed maximum reduction in bacterial adherence, associated inflammation of the joint as well as faster resumption of locomotion and motor function of the limb. Also, all the coating treatments showed no emergence of resistant mutants. Use of dual coated implants incorporating lytic phage (capable of self-multiplication) as well as linezolid presents an attractive and aggressive early approach in preventing as well as treating implant associated infections caused by methicillin resistant S. aureus strains as assessed in a murine model of experimental joint infection.

Colonization of medical devices by staphylococci

“…For example, phage K attacks a variety of staphylococci (O'Flaherty et al, 2004), including some drug-resistant S. aureus (O'Flaherty et al, 2005). Orthopedic wires coated with phage K were colonized less by S. aureus in a murine model of PJI, and the inhibition effect could be increased by simultaneous linezolid treatment (Kaur et al, 2016), exemplifying the potential of bacteriophage/antibiotic combination therapy.…”

Virulence Factor Targeting of the Bacterial Pathogen Staphylococcus aureus for Vaccine and Therapeutics

“…When used specifically against the USA300 LAC strain, the phage highly effective in reducing the infection against this S. aureus strain, and this protection was extended to several routes of infection [209]. Phage treatment has also been proposed to prevent infections during implanted medical devices [210]. S. aureus has also been a major concern in causing hospital associated infections especially during surgeries where devices are implanted [211–213].…”

“…S. aureus has also been a major concern in causing hospital associated infections especially during surgeries where devices are implanted [211–213]. Wires impregnated with a biodegradable polymer containing a specific bacteriophage in combination with an antibiotic compound were implanted into mice, followed by infection with the S. aureus MRSA strain 43300 [210]. Mice that were implanted with the wire containing both the phage and antibiotic treatments exhibited significantly lower CFU counts [210].…”

“…Wires impregnated with a biodegradable polymer containing a specific bacteriophage in combination with an antibiotic compound were implanted into mice, followed by infection with the S. aureus MRSA strain 43300 [210]. Mice that were implanted with the wire containing both the phage and antibiotic treatments exhibited significantly lower CFU counts [210]. Using a functional measure of how well the mice healed post-surgery, mice who received both bacteriophage and antibiotic treatment exhibited faster recovery than mice who received untreated wires or mono phage or antibiotic treatment [210].…”

“…Mice that were implanted with the wire containing both the phage and antibiotic treatments exhibited significantly lower CFU counts [210]. Using a functional measure of how well the mice healed post-surgery, mice who received both bacteriophage and antibiotic treatment exhibited faster recovery than mice who received untreated wires or mono phage or antibiotic treatment [210]. …”