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Bacteriophage therapy in infection after fracture fixation (IAFF) in orthopaedic surgery

Published:November 11, 2022DOI:https://doi.org/10.1016/j.jcot.2022.102067

      Abstract

      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.

      Keywords

      1. Introduction

      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.
      • Steinmetz S.
      • Wernly D.
      • Moerenhout K.
      • Trampuz A.
      • Borens O.
      Infection after fracture fixation.
      ,
      • Metsemakers W.J.
      • Kuehl R.
      • Moriarty T.F.
      • et al.
      Infection after fracture fixation: current surgical and microbiological concepts.
      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.
      • Metsemakers W.J.
      • Kuehl R.
      • Moriarty T.F.
      • et al.
      Infection after fracture fixation: current surgical and microbiological concepts.
      Implant-associated infection is predominantly due to surface-adhering bacteria that form biofilms and the emergence of antimicrobial resistance (AMR) against conventional antibiotics.
      • Costerton J.W.
      • Montanaro L.
      • Arciola C.R.
      Biofilm in implant infections: its production and regulation.
      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.
      • Steinmetz S.
      • Wernly D.
      • Moerenhout K.
      • Trampuz A.
      • Borens O.
      Infection after fracture fixation.
      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’.
      • Høiby N.
      • Bjarnsholt T.
      • Givskov M.
      • Molin S.
      • Ciofu O.
      Antibiotic resistance of bacterial biofilms.
      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.
      • Ruppé É.
      • Woerther P.L.
      • Barbier F.
      Mechanisms of antimicrobial resistance in Gram-negative bacilli.
      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.
      • Kasman L.M.
      • Porter L.D.
      Bacteriophages.
      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)
      • Abedon S.T.
      • Danis-Wlodarczyk K.M.
      • Wozniak D.J.
      Phage cocktail development for bacteriophage therapy: toward improving spectrum of activity breadth and depth.
      and “Sur-mesure” approach (patients are administered a few specific phages that are active on the strain or species responsible for their AMR infection)]
      • Brives C.
      • Pourraz J.
      Phage therapy as a potential solution in the fight against AMR: obstacles and possible futures.
      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.
      • Roach D.R.
      • Donovan D.M.
      Antimicrobial bacteriophage-derived proteins and therapeutic applications.
      Due to this low mobility of phages, local delivery (intramuscular, intradermal, subcutaneous, intravenous, intraperitoneal, or topical) is plausible at the site of infection.
      • Rosner D.
      • Clark J.
      Formulations for bacteriophage therapy and the potential uses of immobilization.
      The ideal phage delivery systems must possess biomaterials, biomaterial constructs, and a mode of phage incorporation.
      • Rotman S.G.
      • Sumrall E.
      • Ziadlou R.
      • et al.
      Local bacteriophage delivery for treatment and prevention of bacterial infections.
      The therapeutic phages should be lytic and hence those phages must be screened for lysogeny and antibiotic resistance genes.
      • Lin D.M.
      • Koskella B.
      • Lin H.C.
      Phage therapy: an alternative to antibiotics in the age of multi-drug resistance.
      ,
      • Sulakvelidze A.
      • Alavidze Z.
      • Morris J.G.
      Bacteriophage therapy.
      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. 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.
      • Gibb B.P.
      • Hadjiargyrou M.
      Bacteriophage therapy for bone and joint infections.
      Preclinical studies have established the role of bacteriophage therapy in patients undergoing immunosuppressant therapy to prevent microbial colonization.
      • Zimecki M.
      • Artym J.
      • Kocięba M.
      • Weber-Dąbrowska B.
      • Borysowski J.
      • Górski A.
      Effects of prophylactic administration of bacteriophages to immunosuppressed mice infected with Staphylococcus aureus.
      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.
      • Wroe J.A.
      • Johnson C.T.
      • García A.J.
      Bacteriophage delivering hydrogels reduce biofilm formation in vitro and infection in vivo.
      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.
      • Wroe J.A.
      • Johnson C.T.
      • García A.J.
      Bacteriophage delivering hydrogels reduce biofilm formation in vitro and infection in vivo.
      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.
      • Barros J.
      • Melo L.D.R.
      • Poeta P.
      • et al.
      Lytic bacteriophages against multidrug-resistant Staphylococcus aureus, Enterococcus faecalis and Escherichia coli isolates from orthopaedic implant-associated infections.
      These phages demonstrate higher efficacy towards MRSA and VRE.
      • Barros J.
      • Melo L.D.R.
      • Poeta P.
      • et al.
      Lytic bacteriophages against multidrug-resistant Staphylococcus aureus, Enterococcus faecalis and Escherichia coli isolates from orthopaedic implant-associated 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.
      • Patey O.
      • McCallin S.
      • Mazure H.
      • Liddle M.
      • Smithyman A.
      • Dublanchet A.
      Clinical indications and compassionate use of phage therapy: personal experience and literature review with a focus on osteoarticular 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.
      • Ferry T.
      • Boucher F.
      • Fevre C.
      • et al.
      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.
      ,
      • LaVergne S.
      • Hamilton T.
      • Biswas B.
      • Kumaraswamy M.
      • Schooley R.T.
      • Wooten D.
      Phage therapy for a multidrug-resistant acinetobacter baumannii craniectomy site infection.
      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.
      • Nir-Paz R.
      • Gelman D.
      • Khouri A.
      • et al.
      Successful treatment of antibiotic-resistant, poly-microbial bone infection with bacteriophages and antibiotics combination.
      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.
      • DePalma B.J.
      • Nandi S.
      • Chaudhry W.
      • Lee M.
      • Johnson A.J.
      • Doub J.B.
      Assessment of staphylococcal clinical isolates from periprosthetic joint infections for potential 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.
      • Doub J.B.
      • Ng V.Y.
      • Lee M.
      • et al.
      Salphage: salvage bacteriophage therapy for recalcitrant MRSA prosthetic joint infection.
      ,
      • Schoeffel J.
      • Wang E.W.
      • Gill D.
      • et al.
      Successful use of salvage bacteriophage therapy for a recalcitrant MRSA knee and Hip prosthetic joint infection.
      The evidence of clinical studies of phage therapy in osteoarticular infections from 2016 till date is tabulated in Table 1.
      Table 1Evidence of clinical studies of phage therapy in osteoarticular infections.
      Author (Year)ModelBacteriaPhage usedResults
      Fish et al.
      • Fish R.
      • Kutter E.
      • Wheat G.
      • Blasdel B.
      • Kutateladze M.
      • Kuhl S.
      Bacteriophage treatment of intransigent diabetic toe ulcers: a case series.
      (2016)
      Diabetic toe ulcers (n = 6)S.aureusStaphylococcal phage Sb-1Despite the antibiotic failure, topical Sb-1 phage curbs off diabetic toe ulcers
      Fish et al.
      • Fish R.
      • Kutter E.
      • Bryan D.
      • Wheat G.
      • Kuhl S.
      Resolving digital staphylococcal osteomyelitis using bacteriophage—a case report.
      (2018)
      Staphylococcal osteomyelitis (n = 1)MRSAStaphylococcal phage Sb-1Phage therapy treatment offers the potential for improved outcomes in this era of escalating antibiotic resistance.
      Ferry et al.
      • Ferry T.
      • Boucher F.
      • Fevre C.
      • et al.
      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.
      (2018)
      Right sacro-iliac joint osteomyelitis (n = 1)Extremely drug resistant (XDR) P.aeruginosaPhage cocktail (1450, 1777, 1792 and 1797)Eradication of XDR-P.aeruginosa within 14 days
      Ferry et al.
      • Ferry T.
      • Leboucher G.
      • Fevre C.
      • et al.
      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?.
      (2018)
      Periprosthetic joint infection of right hip (n = 1)Methicillin-sensitive S.aureusPhage cocktail (1493, 1815, and 1957)Phage act as antibiofilm producer in relapsing S.aureus periprosthetic joint infection
      Onsea et al.
      • Onsea J.
      • Soentjens P.
      • Djebara S.
      • et al.
      Bacteriophage application for difficult-to-treat musculoskeletal infections: development of a standardized multidisciplinary treatment protocol.
      (2019)
      Osteomyelitis of pelvis and femur (n = 4)S.aureusStaph species and P.aeruginosa - BFC1; E.faecalis - PyoA single course of phage therapy prevents recurrence of infection ranging from 8 to 16 months
      S.epidermidis
      S.agalactiae
      E.faecalis
      P.aeruginosa
      LaVergne et al.
      • LaVergne S.
      • Hamilton T.
      • Biswas B.
      • Kumaraswamy M.
      • Schooley R.T.
      • Wooten D.
      Phage therapy for a multidrug-resistant acinetobacter baumannii craniectomy site infection.
      (2019)
      Postoperative infection followed by traumatic brain injury and craniotomy (n = 1)MDR A.baumannii104 A.baumanii bacteriophages from the NMRC's phage-Biolog systemAbsence of infection in the craniotomy site
      Patey et al.
      • Patey O.
      • McCallin S.
      • Mazure H.
      • Liddle M.
      • Smithyman A.
      • Dublanchet A.
      Clinical indications and compassionate use of phage therapy: personal experience and literature review with a focus on osteoarticular infections.
      (2019)
      Pelvic bone infection (n = 1)S. aureus;Anti S.aureus and anti-P.aeruginosa suspensionComplete resolution of infection in 24 months
      P. aeruginosa
      Complex fracture of right foot (n = 1)S.aureusAnti S.aureus suspensionClearance of infection within 6 months
      Mandibular fracture, osteosynthesis, and fistulised infection (n = 1)MRSATbilisi phage therapy and anti S.aureus suspensionClearance of infection within 6 months
      Femoral fracture under hip prosthesis (n = 1)MRSAAnti S.aureus suspensionClearance of MRSA infection within 12 months
      Left knee prosthesis infection (n = 1)P.aeruginosaPhage cocktailClearance of P.aeruginosa infection within 2 years
      Osteomyelitis of the left tibia (n = 1)MRSAAnti S.aureus suspensionClearance of infection within 6 months
      Left tibia fracture, followed by reopened bone infection (n = 1)S.aureusAnti S.aureus suspensionClearance of S.aureus infection within 12 months
      Nir-Paz et al.
      • Nir-Paz R.
      • Gelman D.
      • Khouri A.
      • et al.
      Successful treatment of antibiotic-resistant, poly-microbial bone infection with bacteriophages and antibiotics combination.
      (2019)
      Left bicondylar tibial plateau fracture (n = 1)A.baumannii;Combination of ɸAbKT21phi3 and ɸKpKT21phi1Tissue healing along with negative bacterial culture observed at the end of the 8th-month follow-up
      K.pneumoniae
      Tkhilaishvili et al.
      • Tkhilaishvili T.
      • Winkler T.
      • Müller M.
      • Perka C.
      • Trampuz A.
      Bacteriophages as adjuvant to antibiotics for the treatment of periprosthetic joint infection caused by multidrug-resistant Pseudomonas aeruginosa.
      (2019)
      Right knee periprosthetic infection and chronic osteomyelitis of the femur (n = 1)MDR P.aeruginosaP.aeruginosa specific phage cocktailPhage act as an adjuvant to antimicrobial in curbing MDR P.aeruginosa infection
      Ferry et al. (2020)
      • Ferry T.
      • Batailler C.
      • Petitjean C.
      • et al.
      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.
      Megaprosthesis joint infection (n = 1)S.aureusPhage cocktail [PP1493 and PP1815] loaded onto DAC hydrogelPhage therapy exhibit potential antimicrobial effect in megaprosthetic joint infections.
      Ferry et al.
      • Ferry T.
      • Kolenda C.
      • Batailler C.
      • et al.
      Phage therapy as adjuvant to conservative surgery and antibiotics to salvage patients with relapsing S. aureus prosthetic knee infection.
      (2020)
      Left knee relapsing PJI (n = 1)S. aureusPhage cocktail [PP1493, PP1815, and PP1957]Clearance of S.aureus infections were achieved in all 3 cases ranging from 3 months to 3 years
      Right knee relapsing PJI (n = 2)
      Aslam et al.
      • Aslam S.
      • Lampley E.
      • Wooten D.
      • et al.
      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.
      (2020)
      Cranial osteomyelitis with subdural and epidural empyema (n = 1)MDR A.baumanniiSingle phagePatient expired due to ventilator-associated pneumonia
      Sternal osteomyelitis due to ventricular assist device infection (n = 1)MDR P.aeruginosaGD-1 phageDeveloped bacteremia 1 week after starting phage therapy which resolved with change in antibiotics indicated failure of phage therapy
      Sternal osteomyelitis due to ventricular assist device infection (n = 1)S.aureusAB-SA 01 phageInfection resolved with phage therapy and antibiotics
      PJI (n = 1)S.aureusAB-SA01 phage and SaGR51øK phageRe-treated almost 6 months later with surgical revision, systemic antibiotics, and phage therapy with resolution of S. aureus infection
      Nadareishvili et al.

      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.

      (2020)
      Recurrent sternal osteomyelitis (n = 1)S.aureusPer os infiltration of staphylococcal bacteriophage, and SES bacteriophage;Wound covered with fresh granulation tissue in first 20 days of the treatment
      Local infiltration of Pyo bacteriophage
      Right tibial chronic osteomyelitis (n = 1)S.aureusPer os infiltration of staphylococcus bacteriophage and Intesti bacteriophageComplete closure of wound attained at 18 weeks of phage therapy
      Diabetic ulcer left foot (n = 1)Burkholderia cepacia, S. aureus, and Enterococcus faecalisPer os infiltration of staphylococcus bacteriophage and Intesti bacteriophage;Resolution of osteomyelitis in CT after 6 weeks of phage therapy
      Topical infiltration of Intesti bacteriophage
      Post surgical infection of skin graft over left thigh (n = 1)Pseudomonas aeruginosaPer os infiltration of Pyo bacteriophage and Intesti bacteriophageComplete wound resolution attained after 3 months of phage therapy
      Ramirez-Sanchez et al.
      • Ramirez-Sanchez C.
      • Gonzales F.
      • Buckley M.
      • et al.
      Successful treatment of Staphylococcus aureus prosthetic joint infection with bacteriophage therapy.
      (2021)
      Right knee PJI (n = 1)Methicillin sensitive S.aureus1st treatment - AB-SA01 cocktail [J-Sa36, Sa83, Sa87]Bacteriophage therapy is an adjunct modality along with routine surgery and antibiotics in curbing MSSA.
      2nd treatment – Single lytic phage SaGR51ø1
      Cano et al.
      • Cano E.J.
      • Caflisch K.M.
      • Bollyky P.L.
      • et al.
      Phage therapy for limb-threatening prosthetic knee Klebsiella pneumoniae infection: case report and in vitro characterization of anti-biofilm activity.
      (2021)
      Right knee relapsing PJI (n = 1)K.pneumoniaeKpJH46Φ2Recommended further clinical studies on evaluating safety and efficacy of phage therapy in PJI
      Ferry et al.
      • Ferry T.
      • Kolenda C.
      • Batailler C.
      • et al.
      Case report: arthroscopic “debridement antibiotics and implant retention” with local injection of personalized phage therapy to salvage a relapsing Pseudomonas aeruginosa prosthetic knee infection.
      (2021)
      Left knee relapsing PJI (n = 1)P.aeruginosaPhage cocktail [PP1450, PP1777, and PP1792]Phage therapy act as a salvage therapy for patients with P. aeruginosa relapsing PJI along with antibiotics
      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).
      • Kwiatek M.
      • Parasion S.
      • Nakonieczna A.
      Therapeutic bacteriophages as a rescue treatment for drug-resistant infections – an in vivo studies overview.
      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.
      • EMA
      Advanced therapy medicinal products: overview. European medicines agency.

      4. Conclusion

      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.

      Acknowledgments

      Nil.

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