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Infection after fracture fixation (IAFF) in orthopaedic surgery is a significant complication that can lead to disability due to chronic infection and/or relapsing disease, non-union necessitating revision surgery. Management of IAFF is a major challenge facing orthopaedic surgeons across the world due to two key pathogenic mechanisms of Biofilm formation and antimicrobial resistance (AMR) against traditional antibiotics. Advanced prophylactic and treatment strategies to help eradicate established infections and prevent the development of such infections are necessary. Bacteriophage therapy represents an innovative modality to treat IAFF due to multi-drug resistant organisms. We assess the current role and potential therapeutic applications of the novel bacteriophage therapy in the management of these recalcitrant infections to achieve a successful outcome.
Infection after fracture fixation (IAFF) in orthopedics is a well-known complication after trauma surgery with a quoted incidence of 1%–2% after closed fractures and reaching up to 30% in open fractures.
The real incidence of IAFF is probably misjudged due to a lack of precise definition and universally accepted classification. Metsemakers et al. classified IAFF into early (less than 2 weeks), delayed (between 2 and 10 weeks), and late (more than 10 weeks) infections based on the formation and maturation of biofilm and the severity of invasion of pathogens into bone and soft tissues.
Implant-associated infection is predominantly due to surface-adhering bacteria that form biofilms and the emergence of antimicrobial resistance (AMR) against conventional antibiotics.
Though the reasons for antibiotic resistance are complex such as inappropriate use of antibiotics in the management of infections, failure to eradicate IAFF can lead to non-union, osteomyelitis, loss of function, and increased socio-economic burden.
Biofilm formation makes eradication of infection difficult owing to inherent endurance to host defense mechanisms and AMR resulting from biofilm embedded bacterial organisms which also propagate resistance due to altered cell signaling systems such as ‘Quorum sensing’.
Gram-positive organisms such as Staphylococcus aureus (20%–30%), coagulase-negative staphylococci (CoNS) (18%–40%), Streptococci (1%–10%), and Enterococci (3%–7%) are commonly encountered organisms after fracture fixation. However, increasingly Gram-negative bacilli, including Pseudomonas aeruginosa, Enterobacteriaceae, Acinetobacter, Klebsiella, and Propionibacterium acnes species have been associated with IAFF and orthopaedic device-related infection (ODRI) with issues of significant AMR.
Consequently, to combat this AMR crisis, a few innovative and targeted therapies like nanomedicine, bacteriophage (phage) therapy, antimicrobial peptides (AMP), silver iontophoresis, and sonic therapies have been introduced. Increasing clinical data supports the use of bacteriophage therapy for infections of prosthetic joints due to bacteriophages' capacity to dissolve biofilms, multiply themselves, and induce bacteriolysis.
2. Bacteriophage therapy
Bacteriophages (phages) are ubiquitous viruses that infect bacteria and can be used against specific bacterial species. Phage replication within the infected bacterium can occur as a lytic cycle (virulent phages) or a part of the lysogenic (temperate phages) cycle.
Lytic phages lead to the destruction of the host bacteria and release newly formed phage particles to continue as potent antimicrobial agents, especially against multi-drug resistant infections.
The main bacteriophage attachment receptor for S. aureus is teichoic acid. Temperate phages act by integrating their genome with the host's genome and are not used in the anti-microbial activity, lying dormant till the host's stress response leads to them entering a lytic phage cycle. The portals of the approach of Bacteriophage therapy are through phage cocktails [‘prêt-à-porter’ approach (the production of fixed/phage cocktails to have at least one that will be effective on the bacteria)
and “Sur-mesure” approach (patients are administered a few specific phages that are active on the strain or species responsible for their AMR infection)]
and synergistic approach (phage cocktails are used synergistically with complementary antibiotics to combat AMR infection).
The pharmacokinetics of phages differ greatly from antibiotics in terms of tissue uptake and diffusion. Phages are composed of agglomerated proteins whereas antibiotics are small molecules.
Due to this low mobility of phages, local delivery (intramuscular, intradermal, subcutaneous, intravenous, intraperitoneal, or topical) is plausible at the site of infection.
No serious side effects have been reported in the literature.
3. Applications of bacteriophage therapy in orthopaedic implant and prosthesis-related infections
The understanding of phage-antibiotic synergy (PAS) is crucial in the usage of bacteriophage therapy in eradicating osteoarticular infections. Various studies have shown PAS reduces the development of multi-drug resistant organisms by bactericidal mechanisms. The proteolytic enzymes of bacteriophages destroy the polysaccharides present in the biofilms. Phages possess anti-biofilm properties and hence it is used in IAFFs. The forms of phage therapy are a combination of antimicrobial agents and phages, phage cocktails (combination of different phages), and genetically engineered phages as shown in Fig. 1.
Fig. 1Forms of Phage therapy techniques studied for the management of osteo-articular infection shown on a Total Hip Replacement associated infection.
A few animal studies [1 rabbit, 1 rat, and 4 mouse studies] have been published on the usage of bacteriophages in treating osteoarticular infections. In-vitro studies on the orthopaedic implant with a preformed biofilm model support the prophylactic and therapeutic usage of bacteriophages alone or in combination with antimicrobials in eradicating multidrug-resistant infections.
Preclinical studies have established the role of bacteriophage therapy in patients undergoing immunosuppressant therapy to prevent microbial colonization.
Wroe et al. demonstrated hydrogel scaffold-based phage (ΦPaer4, ΦPaer14, ΦPaer22, ΦW2005A) delivery to treat local osteoarticular infections caused by P.aeruginosa in a mouse model.
Phages loaded scaffolds produce a bactericidal effect in planktonic and biofilm forms in vitro without disturbing the metabolic activity of human mesenchymal stromal cells. Bacteriophages-loaded hydrogel significantly decreases the bacterial counts in mouse model osseous defect at 1-week post-implantation.
The prospect of scaffold-based phage delivery is used as a prophylactic modality in established osteoarticular infections as they need a continuous supply of antibiofilm agents to curb the infections.
Barros et al. reported lytic phages against MDR S. aureus, E. faecalis, and E. coli from implant-associated osteoarticular infections.
Patey et al. reported the disappearance of organisms with negative cultures in 7 cases of osteoarticular infections and concluded that a combination of phages and appropriate antibiotics helps in eradicating antibiotic-resistance or difficult-to-treat infections.
Few clinical studies demonstrated that bacteriophage therapy has successfully eradicated extremely drug-resistant P.aeruginosa and multi-drug resistant A.baumannii in sacroiliac joint osteomyelitis and postoperative infection followed by traumatic brain injury and craniotomy respectively.
Innovations for the treatment of a complex bone and joint infection due to XDR Pseudomonas aeruginosa including local application of a selected cocktail of bacteriophages.
The results of bacteriophage therapy are safe without any complications with rapid clinical improvement. The combination of ɸAbKT21phi3 and ɸKpKT21phi1 phages were used to treat A.baumannii and K.pneumoniae infections in left tibial bicondylar fracture. By the end of the 8th-month follow-up, the patient was reported with a negative culture of the organisms and with good tissue healing.
A recent study evaluated the in vitro activity of a group of bacteriophages against clinical S. aureus prosthetic joint infection (PJI) isolates; more than 95% of these isolates demonstrated adequate growth inhibition of the predominate planktonic colonies by at least one bacteriophage strain, suggesting the therapeutic utility of bacteriophage therapy.
Clinical reports have shown the successful role of adjuvant personalized intravenous bacteriophage therapy in recalcitrant MRSA prosthetic infection with failed conventional surgical and medical treatment.
Innovations for the treatment of a complex bone and joint infection due to XDR Pseudomonas aeruginosa including local application of a selected cocktail of bacteriophages.
Salvage debridement, antibiotics and implant retention (“DAIR”) with local injection of a selected cocktail of bacteriophages: is it an option for an elderly patient with relapsing Staphylococcus aureus prosthetic-joint infection?.
The potential innovative use of bacteriophages within the DAC® hydrogel to treat patients with knee megaprosthesis infection requiring “debridement antibiotics and implant retention” and soft tissue coverage as salvage therapy.
Lessons learned from the first 10 consecutive cases of intravenous bacteriophage therapy to treat multidrug-resistant bacterial infections at a single center in the United States.
Nadareishvili L, Hoyle N, Nakaidze N, et al. Bacteriophage therapy as a potential management option for surgical wound infections. PHAGE. Published online September 16, 2020. doi:10.1089/phage.2020.0010.
Phage therapy for limb-threatening prosthetic knee Klebsiella pneumoniae infection: case report and in vitro characterization of anti-biofilm activity.
Case report: arthroscopic “debridement antibiotics and implant retention” with local injection of personalized phage therapy to salvage a relapsing Pseudomonas aeruginosa prosthetic knee infection.
The potential limitation of bacteriophage therapies are a) absence of specific activity for a particular bacterial strain, b) plausible emergence of bacterial resistance against bacteriophages, c) decreased activity due to immunological response against bacteriophages, and d) technical difficulties in pharmaceutical preparation of bacteriophages. To overcome the emergence of phage resistance, phage engineering is being developed to make genetically engineered bacteriophages that are less immunogenic to eradicate the infection. To validate these ATMPs, technologies such as next-generation sequencing have emerged as a powerful tool to analyze the phage and bacteria utilized, however, it could not be implemented as a GMP-compliant assay due to the lack of a strong validation framework that needs to be developed.
US-FDA approved phage therapy via the “Emergency Investigational New Drug Scheme” through the Centre for Innovative Phage Applications and Therapeutics (IPATH).
In the case of genetically modified phages (GMPs), some additional requirements such as environmental risk assessment need to be analyzed before clinical use. These products are considered advanced therapeutic medicinal product (ATMP) by the European Medical Agency and needs a centralized authorization procedure.
The future relies on bacteriophage therapy for eradicating MDR organisms, especially in IAFFs. The development of various phage cocktails to eradicate MDR organisms is the prime area for further research in orthopedics. Due to the lack of preclinical and clinical evidence, further research on bacteriophage therapy is warranted. Studies on the development and evaluation of the delivery of multiple microbe-specific bacteriophages to combat chronic IAFF are advocated. To overcome the emergence of phage resistance, phage engineering is being developed to make genetically engineered bacteriophages that are less immunogenic, and target-specific with CRISPR repeats to eradicate the infection. The ideal phage release kinetics with phage-specific and patient-specific phages must be developed for the future.
Funding sources
Nil.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Innovations for the treatment of a complex bone and joint infection due to XDR Pseudomonas aeruginosa including local application of a selected cocktail of bacteriophages.
Salvage debridement, antibiotics and implant retention (“DAIR”) with local injection of a selected cocktail of bacteriophages: is it an option for an elderly patient with relapsing Staphylococcus aureus prosthetic-joint infection?.
The potential innovative use of bacteriophages within the DAC® hydrogel to treat patients with knee megaprosthesis infection requiring “debridement antibiotics and implant retention” and soft tissue coverage as salvage therapy.
Lessons learned from the first 10 consecutive cases of intravenous bacteriophage therapy to treat multidrug-resistant bacterial infections at a single center in the United States.
Nadareishvili L, Hoyle N, Nakaidze N, et al. Bacteriophage therapy as a potential management option for surgical wound infections. PHAGE. Published online September 16, 2020. doi:10.1089/phage.2020.0010.
Phage therapy for limb-threatening prosthetic knee Klebsiella pneumoniae infection: case report and in vitro characterization of anti-biofilm activity.
Case report: arthroscopic “debridement antibiotics and implant retention” with local injection of personalized phage therapy to salvage a relapsing Pseudomonas aeruginosa prosthetic knee infection.
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