Use of Bacteriophage Therapy in Implant Related Orthopedic Infections

Biofilm producers pose a major challenge in treating implant-related orthopedic infections (IROIs). The incidence of IROIs for the closed fracture amounts to 1% to 2% whereas for open fracture it is up to 30%. Due to inappropriate and irrational use of antibiotics in the management of infections, there is an emergence of a global "antimicrobial resistance crisis". To combat these antimicrobial resistance crises, a few innovative and targeted therapies like nanomedicine, phage therapy, antimicrobial peptides, and sonic therapies have been introduced.

In a review article published in Indian Journal of Orthopaedics, Madhan Jeyaraman et al detailed the basic mechanisms involved in the employment of bacteriophage therapy for IROIs, along with the preclinical and clinical data on its utility. The authors also presented the guidelines on its regulation, processing, and limitations of bacteriophage therapy to combat the upcoming era of antibiotic resistance.

Bacteriophages are bacteria-specific viruses that are used against treating specific bacteria. Phages possess the properties of host-specificity, self-amplification, narrow spectrum of activity, degradation of biofilm, high safety and tolerability, and pose a least or no toxic effect to humans. The proteolytic enzymes of bacteriophages destroy the polysaccharides present in the biofilms.

Phages replicate by lytic (virulent phages) and lysogenic (temperate phages) cycle by integrating its genome with host's genome and releases the newly formed phage particles and hence they become a potent antimicrobial agent against multi-drug resistant infections. Along with phages, the combination of phage bacterial lysine enzymes and appropriate antibiotics may help in treating implant-related orthopaedic infections.

Due to low mobility of phages, the local delivery (intramuscular, intravenous, or intraperitoneal) is plausible at the site of infection. The ideal phage delivery systems must possess biomaterials (natural or synthetic biopolymers, ceramics), biomaterial constructs (hydrogel, particles, macro-sized constructs, and lipid carriers), and mode of phage incorporation (embedding, encapsulation, and surface adsorption).

The various modalities employed in the administration of the phage therapy against IROIs include using phage cocktails, phage enzymes, phage antibiotic synergy, phage CRISPR therapy, and phage engineering.

Barros et al. reported lytic phages against MDR S. aureus, E. faecalis, and E. coli from implant-associated osteoarticular infections. These phages demonstrate higher efficacy towards MRSA and VRE. In the osteoarticular system, phages are used to treat diabetic toe ulcers with exposure of bone, osteomyelitis, periprosthetic joint infections, postoperative infection, and the infection of complex fractures.

The authors commented that - "The future relies on bacteriophage therapy for eradicating MDR organisms, especially in IROIs. The development of various phage cocktails to eradicate MDR organisms is the prime area for further research in orthopedics."

The authors concluded that – "We note the re-emergence of phage therapy as a promising strategy to combat IROIs with antibiotic resistance. Being a high-precision targeted therapy without the side effects of the traditional wide spectrum antibiotics such as collateral damage on non-pathogenic bacterial flora, phage therapy has attracted a lot of attention with encouraging preclinical and clinical evidence. This supporting evidence is of great value in re-opening the therapeutic field to combat antibiotic resistance that poses an imminent threat to humanity. Given the relevance to large-scale production, consideration to the implementation of GMP guidelines is a necessity with a need for evolution of the regulatory framework to better handle the potential of the phages leading to the availability of the phage therapeutic medicinal product for clinical use in the near future with assured potency and quality."

Further reading:

The 2021 Association Research Circulation Osseous Classification for Early-Stage Osteonecrosis of the Femoral Head to Computed Tomography Based Study

Madhan Jeyaraman, Naveen Jeyaraman et al

Indian Journal of Orthopaedics (2022) 56:1685–1693

https://doi.org/10.1007/s43465-022-00728-y