The promising role of bacteriophage therapy in managing total hip and knee arthroplasty related periprosthetic joint infection, a systematic review.

doi:10.21203/rs.3.rs-2095418/v1

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Research Article

The promising role of bacteriophage therapy in managing total hip and knee arthroplasty related periprosthetic joint infection, a systematic review.

https://doi.org/10.21203/rs.3.rs-2095418/v1

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Background

Total hip and knee arthroplasty periprosthetic joint infection (PJI) poses a management dilemma owing to the emergence of resistant organisms. Bacteriophage therapy (BT) was introduced as a promising management option for PJI. The current review aimed to demonstrate the role and safety of using BT as an adjuvant to treat PJIs.

Methods

A systematic search was performed through four databases (Embase, PubMed, Web of Science, and Scopus) up to March 2022, according to the predetermined inclusion and exclusion criteria.

Results

our systematic review included 12 case reports of 17 patients in which 18 joints (15 TKAs and three THAs) were treated. The patients' average age was 76.3 years, underwent an average of 4 previous surgeries. The most common organism was the Staphylococcus aureus species. All patients underwent surgical debridement; 13 were treated with bacteriophages (eight received cocktail and five received monophage therapy), while in one report (four patients), all received bacteriophage-derived lysin. All patients received postoperative suppressive antibiotic therapy. After an average follow-up of 13.5 months, all patients had satisfactory outcomes. No recurrence of infection in any patient. Transaminitis complicating BT was developed in three patients, needed stoppage in only one, and the condition was reversible and non-life-threatening.

Conclusion

BT is an effective and safe option for treating resistant and relapsing PJIs; Further investigations are needed to clarify some issues related to BT's best route and duration; furthermore, new ethical regulations should be implemented to facilitate its widespread use.

Bacteriophage therapy

periprosthetic infection

total hip arthroplasty

total knee arthroplasty

Although total hip and knee arthroplasties proved their effectiveness in improving patients' function and life quality on long-term follow-ups, failures attributed to various modes are still occurring where periprosthetic joint infection (PJI) is considered the leading cause of total knee arthroplasty (TKA) revision, and the third common cause for revision after total hip arthroplasty (THA) [1–3].

PJI is considered one of the devastating complications after total joint arthroplasty; besides the drawbacks to the patients, it poses a significant economic burden on the healthcare systems, with an even more expected increase in PJI rates owing to the expected rise of the number of primary arthroplasties which was estimated to reach 1.26 million by 2030 [4–6].

Managing PJIs could be performed as a single-stage procedure or, as some surgeons prefer to be performed as a two-stage procedure, where the first stage consists of implant removal, debridement, and insertion of a cement spacer, and the second stage consists of placement of the final implant after infection eradication, with a success rate reaching up to 85% [7, 8]. Unfortunately, in case of failed two-stage revision and the patient undergoes another debridement session, the success rates drop to around 50–75% [9, 10].

In patients with relapsing PJI, mainly the elderly, where repeated surgeries could not be feasible, especially in the knee joint, as extensive bone loss in combination with infection might complicate the revision surgery with alternative options such as girdle stone procedures or amputation, which is usually not accepted by the patients, alternatively, a debridement, antibiotics and implant retention (DAIR procedure) followed by suppressive antibiotic therapy (SAT) could be offered in an attempt to get rid of the infection without implants removal [11, 12]; however, DAIR procedure had a variable success rate ranging from 21–93% [13].

The incomplete success of these surgical procedures could be attributed to the presence of a dense biofilm which hinders the conventional antimicrobial therapy from totally eradicating the bacteria or the emergence of antimicrobial resistance [14, 15]. A search for alternative management options led to the reconsideration of bacteriophage therapy (BT) as an adjuvant to classic antimicrobial therapy [16].

Many reports showed the effectiveness of BT in managing bone and joint infections [17, 18]; hence the current review aimed to document and demonstrate the role and safety of using BT as an adjuvant to treat total hip and knee arthroplasty periprosthetic infections.

Search strategy and selection criteria

A systematic search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [19] was performed on March 2022 for articles handling the role of BT in managing PJI.

We created a search strategy based on a predefined population, intervention, comparison, and outcome (PICO) model. The population of interest was patients who had PJI (either in the hip or knee joints), the intervention was BT (or agents derived from bacteriophages such as lysin) via different administration routes, and the comparison (if present) was to standard-of-care treatments. The main outcome parameters were bacteriophage therapy's safety and infection clearance.

A comprehensive English literature search was performed by both authors through four databases (Embase, PubMed, Web of Science, and Scopus), using various combinations of the terms "bacteriophages," "therapy," "periprosthetic," and "infection."

The inclusion criteria were English language studies (cohort studies, case series, and case reports) reporting on the use of bacteriophages in treating PJI in humans. Studies not published in English performed on animal models and other publication types (reviews and editorials) were excluded. After downloading the results to Endnote 20, duplicates were excluded, followed by screening the title and abstracts for eligibility. The full text of the final eligible studies was evaluated for inclusion; this resulted in 12 studies eligible for inclusion and formulation of this review (Fig. 1) [20–31].

Data Extraction and Critical Appraisal

The following information was extracted from each eligible study: author(s); date of publication; country of origin; study type; the number of included patients; joint affected, comorbidities, previous surgeries; and type of organism causing the infection. For the management details, the following information was collected: type of therapy used (for expanding the eligible studies in the current review, we included one study where the authors reported using bacteriophage-derived lysins as the management agent [27]), monophage or cocktail therapy, route of administration, period of follow up, complications, and the outcomes.

Studies and patient characteristics (Table 1):

The 12 articles included in the current review were all case reports of 17 patients in which 18 joints (15 TKAs and three THAs) were affected (in one study, the patient had an infection in an ipsilateral THA and TKA [31]). The average age of the included patients was 76.3 (49:89) years, and the average number of previous surgeries was 4 (2:12).

Five reports originated from France, five from the USA, one from Germany, and one from the Netherlands. In two reports, the authors mentioned that the BT was prepared or administered in another country; Neuts et al. reported that their patient had his BT in Georgia [29], while Doub et al. stated that their patient had her BT prepared in Austria [26]. For the infecting organisms, various bacterial species were defined and treated; the most common infecting organism was Staphylococcus aureus. Further details are shown in Table 1.

Management details (Table 2):

In all reports, the authors mentioned that patients underwent various types of surgical procedures, including mainly debridement; however, the exact definition of these procedures differs among the included reports, especially the definition of "DAIR procedure," which originally entails debridement with retention of the implants, and changing the modular parts (tibial insert in case of TKA or acetabular liner and femoral head in case of THA) which were performed in the report by Doub et al. [26]; however, some authors used the term "PhagoDAIR," but they reported performing only debridement without changing the modular parts [20, 23, 27, 28]. Furthermore, the debridement procedure was performed arthroscopically in two reports [27, 28]. In reports where the authors performed two-stage revision, the use of BT during which stage varied among reports, where it was reported to be used during the first stage only [24] and during both stages [21, 30, 31].

Regarding the details of the BT, 13 patients were treated with bacteriophages (eight received cocktail and five received monophage therapy), while in one report by Ferry et al. [27], including four patients, all received Exebacase, which is a bacteriophage-derived lysin. The exact type of bacteriophages used for management was mentioned in ten reports (Table 2).

The route of bacteriophage therapy administration differed among reports into only intraarticular (IA) [20-24, 27, 28], only oral [29], only intravenous (IV) [25], and combined IA with IV [26, 30, 31]; furthermore, the IA administration was given by different techniques, first by direct injection in the joint cavity, second by infusion to the joint postoperatively through drainage tubes [24], and third by application with Defensive Antibacterial Coating (DAC) hydrogel on the surface of the implant [22]. All patients received postoperative suppressive antibiotic therapy (SAT) as part of their management plan for at least six weeks.

Complications and outcomes (Table 2):

After an average follow up of 13.5 (5:36) months, the outcomes were satisfactory in all reports; in five reports, it was mentioned that patients refused amputation option (for TKA PJI) or girdle stone (for THA PJI) and preferred to undergo BT as a salvage procedure [21, 22, 25, 29, 30]. In all reports, no recurrence of infection was reported. However, in three reports [22, 24, 30], the authors mentioned that their patients suffered from recurrent discharge, which necessitates further debridement; in two of these reports [22, 24], the authors mentioned that the samples taken during these sessions of debridement did not reveal organisms targeted initially by the BT, in the third report, the authors did not mention details regarding the organism diagnosed during the infection recurrence [30].

Regarding bacteriophage therapy-related complications, Transaminitis was developed in three reports [21, 26, 31]; only in one report by Doub et al. the BT was stopped [21], and the condition was reversible and non-life-threatening; in the other two reports, the condition was mild and did not lead to treatment stoppage.

Several strategies to manage infected hip and knee total joint arthroplasties are present, mainly the DAIR procedure for early infection, single-stage revision, and two-stage revision, which is considered the gold standard by most surgeons; these procedures had various success rates [13, 32, 33]. For these procedures to be successful, the host factors, infection extent, duration, and the causative organism virulence should all be taken into account side by side with the surgical procedure [34]. As bacteria are capable of developing various resistance mechanisms such as biofilm formation, which made them resistant to antimicrobial therapy [35], BT was reintroduced to overcome the resistance developed against commonly used antimicrobial therapy.

Although the current review was formulated only of case reports, however an increasing trend in reconsidering BT for managing resistant and recurrent total hip and knee PJI cases. Furthermore, BT showed efficiency in curing the infection, especially in patients with resistant or recurrent infection and in situations where revision surgery is deemed problematic, or the patients refused the other option, such as amputations. Moreover, BT showed a considerable safety profile.

Bacteriophages are viruses that target specific bacteria and were first described in 1917; they had a good repetition in treating bone-related infections throughout the 20th century, especially in western Europe [18, 36, 37]. They have a narrow activity spectrum which could be either lytic or lysogenic; the former is the most promising for incorporation in the clinical medicine applications for infection management, as they can cause bacterial lysis and present in a dynamic relationship with bacteria [21]. Bacteriophages are different from antibiotics as they target a specific bacterium; furthermore, they continue to multiply as long as their hosting bacteria are present at a specific concentration, then the concentration will decrease gradually with bacteria elimination; this makes BT amenable to be administered as a single or few multiple doses [36, 38].

As bacteriophages have a peculiar mode of action different from antibiotics, resistance against bacteriophages rarely develops, unlike what happens with various antibiotics; thus, it can treat multiple antibiotic-resistant infections [39].

The treatment challenge of PJI is related partially to biofilm-associated infections, which are usually resistant to antibiotics [40], as the biofilm forms structured communities for bacteria enabling them to survive against the host immune defense and antimicrobial therapy [15]. In order to attack bacteria in biofilms, conventional antibiotics should be given in a concentration of 1000 times the doses needed to attack the same bacteria in a planktonic state [41]. This created the need for a new strategy and therapies focusing on biofilm disruption, where bacteriophages fit in this role [21].

Bacteriophages developed innate biofilm penetration ability followed by biofilm bacterial lysis, even if the bacteria are metabolically inactive [14, 42, 43]. They also can disrupt the extracellular matrix of the biofilm using the depolymerase enzymes, making BT efficient in treating bone and joint-related reluctant infections, including biofilm formation-related infection, and becoming an attractive option for managing resistant PJIs [14, 23, 42–45].

Additionally, a novel approach using lysins derived from bacteriophages which can penetrate the biofilm and attack antimicrobial-resistant bacteria [46]. Lysins act by rapidly activating peptidoglycan hydrolysis, osmotic lysis, and subsequent cell death upon contact with bacteria, unlike antibiotic-mediated bactericidal effects, which might require hours to be fully active [47]. These lysins showed broad-spectrum hydrolytic activity against planktonic and biofilm bacteria, unlike usual antibiotics [48, 49]. In the current review, one report by Ferry et al. [27] used Exebacase, a bacteriophage-derived lysin, instead of using the BT in treating four patients, which showed acceptable outcomes. Sosa et al. conducted a Study on a murine PJI model treated by DAIR to test the effectiveness of PlySs2, a bacteriophage-derived lysin, in targeting S. aureus biofilm in a periprosthetic environment compared to vancomycin. They found that PlySs2 treatment reduced 99% more colony-forming units (CFUs) and 75% more biofilm compared with vancomycin in vitro; furthermore, A combination of both used in vivo worked synergistically and reduced the number of CFUs on the surface of implants by 92% and in the periprosthetic tissue by 88% [50].

Most of the patients included in the current review underwent some surgical debridement, either open or arthroscopic; this step is helpful and synergistic for BT in many ways; first, it will help to dilute and minimize the bacterial count within the field; second, it allows for manual removal of the biofilm, third it ensures proper application of the bacteriophages near the biofilm when BT is used locally [21, 44, 45].

It is believed that the bacteria and their antagonist bacteriophages are present in nature in a balanced manner, where an increase in bacterial concentration is followed by an increase in bacteriophage concentration and vice versa [51]. Furthermore, one characteristic of bacteriophages' action against bacteria is that it finds difficulties dealing with a low concentration of bacteria when it drops below 104 ml or g, known as the "phage proliferation threshold" [52, 53]; at this level, bacteriophages will not eradicate bacteria unless the immune system is fully functional or additive management is used; and here comes the role of suppressive antibiotic therapy (SAT) [54]. In the current review, all patients treated with BT received SAT in combination; data showed that SAT has a synergistic effect when used with BT; some believe that using BT will lower the doses and concentration of antibiotics needed, owing to a decrease in the bacterial load [37, 43]. Noteworthy that SAT should be used judiciously as if the antibiotics were given in less than optimum doses; this could lead to the emergence of bacterial variants resistant to antibiotics which subsequently make phage therapy useless [55].

Regarding the safety and efficacy of adopting BT for managing PJIs, besides obtaining clearance of BT targeted infection in all patients included in the current review, no complications related to BT necessitating stoppage of the treatment developed in any of the patients, except for one patient who developed non-fatal transaminitis which improved after holding the BT. In a systematic review by Clarke et al. evaluating the efficacy of BT in managing bone and joint infections, the authors reported that about 93% of the included 277 patients achieved clinical clearance of infection, with no safety concerns expressed among the included studies [56]. Furthermore, the efficacy of BT in treating infection, especially if combined with antibiotic therapy and its high safety profile, was reported in the literature outcomes [37].

Although BT is an appealing option for managing resistant and relapsing PJIs, in the reports included in the current review, we found some unclear issues which need further investigation. First is the use of mono or cocktail BT; of the 13 patients who received frank BT, eight received cocktail and five mono BT; some authors preferred the cocktail therapy because multiple bacteriophages could expand the activity spectrum and decrease the chances of resistant development during the management course [57]. Second is the preparation of the BT; in two reports, the authors mentioned that the BT was prepared in other countries, namely Georgia and Austria, and one of the patients had his BT in the institution where the BT was prepared (Georgia). The third is the route of administration and duration of BT, which varies among the included reports; Cano et al. reported that the ideal duration for IV phage therapy is unclear, as they reported normalization of CRP by the last day of therapy (which lasted for about eight weeks), suggesting the potential need for a long management course [25]. On the contrary, Onsea et al. reported a small series of four patients who suffered from chronic osteomyelitis and were successfully treated by local cocktail phage therapy for only 7 to 10 days [44].

Furthermore, Doub et al. reported giving IV phage therapy for three days, which was explained by the fact that bacteriophages are capable of self-replicate, so a few days of management is only required as an adjunct to surgical debridement [21]. Fourth is the ethical approval for its use; as in all the included reports, the authors mentioned that they had to go through a different pathway to get ethical approval and clearance for BT use on their patients; this could be explained by the inadequate literature, documentation, and a regulatory framework [58, 59]. However, in countries with no authorization for phage use as a medicine, phage therapy could be carried out under Article 37 of the Helsinki Declaration or under national regulatory frameworks for treating individual patients with unauthorized treatments [60].

The current review had some inherent limitations, first is the exclusive inclusion of English literature while BT is a common practice in Western Europe; this might have led to depriving the review of studies published in languages other than English. Second is the inclusion of only case reports; however, this was related to the search results based on the search terms and search engines we used. Third, we could not report on BT's exact availability and cost as these data were lacking in the included reports.

Bacteriophage therapy is an effective and safe option for treating resistant and relapsing total hip and knee arthroplasty-related PJIs; it is considered a beneficial adjuvant for surgical debridement, even in cases where the implants cannot be removed. Administration of concomitant suppressive antibiotic therapy seems to be mandatory. Further investigations are needed to clarify some issues related to BT's best route and duration; furthermore, new ethical regulations should be implemented to facilitate its widespread use.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Conflict of Interest: The authors declare that they have no conflict of interest.
Availability of data and material: All the data related to the study are mentioned within the manuscript, however, the raw data are available with the corresponding author and will be provided upon a written request.
Code availability: not applicable
Authors’ contribution: A.A.K. carried out the review idea and conception, A.A.K. and S.M.H. carried out data acquisition, literature search. Both authors drafted the manuscript, and designed the figures and table, A.A.K. did the critical revision. Both authors discussed the results and commented on the manuscript. Both authors read and approved the final manuscript and are responsible for the content and similarity index of the manuscript.
Ethical approval: Not applicable, this article does not contain any experimental studies with human participants or animals performed by any of the authors. Ethical approval was not needed.
Consent to participate not applicable

Boelch SP, Jakuscheit A, Doerries S, Fraissler L, Hoberg M, Arnholdt J, Rudert M (2018) Periprosthetic infection is the major indication for TKA revision - experiences from a university referral arthroplasty center. BMC Musculoskelet Disord 19:395. DOI 10.1186/s12891-018-2314-1
Karachalios T, Komnos G, Koutalos A (2018) Total hip arthroplasty: Survival and modes of failure. EFORT Open Rev 3:232–239. DOI 10.1302/2058-5241.3.170068
Nugent M, Young SW, Frampton CM, Hooper GJ (2021) The lifetime risk of revision following total hip arthroplasty. The Bone & Joint Journal 103–B:479–485. DOI 10.1302/0301-620x.103b3.Bjj-2020-0562.R2
Sloan M, Premkumar A, Sheth NP (2018) Projected Volume of Primary Total Joint Arthroplasty in the U.S., 2014 to 2030. J Bone Joint Surg Am 100:1455–1460. DOI 10.2106/jbjs.17.01617
Beringer DC (2017) CORR Insights(®): What is the Long-term Economic Societal Effect of Periprosthetic Infections After THA? A Markov Analysis. Clin Orthop Relat Res 475:1901–1903. DOI 10.1007/s11999-017-5365-y
Serrier H, Julien C, Batailler C, Mabrut E, Brochier C, Thevenon S, Maynard-Muet M, Henry A, Lustig S, Huot L, Ferry T (2021) Economic Study of 2-Stage Exchange in Patients With Knee or Hip Prosthetic Joint Infection Managed in a Referral Center in France: Time to Use Innovative(s) Intervention(s) at the Time of Reimplantation to Reduce the Risk of Superinfection. Front Med (Lausanne) 8:552669. DOI 10.3389/fmed.2021.552669
Natsuhara KM, Shelton TJ, Meehan JP, Lum ZC (2019) Mortality During Total Hip Periprosthetic Joint Infection. J Arthroplasty 34:S337–s342. DOI 10.1016/j.arth.2018.12.024
Xu C, Goswami K, Li WT, Tan TL, Yayac M, Wang SH, Parvizi J (2020) Is Treatment of Periprosthetic Joint Infection Improving Over Time? J Arthroplasty 35:1696–1702e1691. DOI 10.1016/j.arth.2020.01.080
Vadiee I, Backstein DJ (2019) The Effectiveness of Repeat Two-Stage Revision for the Treatment of Recalcitrant Total Knee Arthroplasty Infection. J Arthroplasty 34:369–374. DOI 10.1016/j.arth.2018.10.021
Fehring KA, Abdel MP, Ollivier M, Mabry TM, Hanssen AD (2017) Repeat Two-Stage Exchange Arthroplasty for Periprosthetic Knee Infection Is Dependent on Host Grade. J Bone Joint Surg Am 99:19–24. DOI 10.2106/jbjs.16.00075
Osmon DR, Berbari EF, Berendt AR, Lew D, Zimmerli W, Steckelberg JM, Rao N, Hanssen A, Wilson WR (2013) Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 56:e1–e25. DOI 10.1093/cid/cis803
Ariza J, Cobo J, Baraia-Etxaburu J, Benito N, Bori G, Cabo J, Corona P, Esteban J, Horcajada JP, Lora-Tamayo J, Murillo O, Palomino J, Parra J, Pigrau C, Del Pozo JL, Riera M, Rodríguez D, Sánchez-Somolinos M, Soriano A, Del Toro MD, de la Torre B (2017) Executive summary of management of prosthetic joint infections. Clinical practice guidelines by the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC). Enferm Infecc Microbiol Clin 35:189–195. DOI 10.1016/j.eimc.2016.08.012
Anagnostakos K, Schmitt C (2014) Can periprosthetic hip joint infections be successfully managed by debridement and prosthesis retention? World J Orthop 5:218–224. DOI 10.5312/wjo.v5.i3.218
Fong SA, Drilling A, Morales S, Cornet ME, Woodworth BA, Fokkens WJ, Psaltis AJ, Vreugde S, Wormald PJ (2017) Activity of Bacteriophages in Removing Biofilms of Pseudomonas aeruginosa Isolates from Chronic Rhinosinusitis Patients. Front Cell Infect Microbiol 7:418. DOI 10.3389/fcimb.2017.00418
del Pozo JL, Patel R (2007) The challenge of treating biofilm-associated bacterial infections. Clin Pharmacol Ther 82:204–209. DOI 10.1038/sj.clpt.6100247
Hall CW, Mah TF (2017) Molecular mechanisms of biofilm-based antibiotic resistance and tolerance in pathogenic bacteria. FEMS Microbiol Rev 41:276–301. DOI 10.1093/femsre/fux010
Ferry T, Kolenda C, Briot T, Souche A, Lustig S, Josse J, Batailler C, Pirot F, Medina M, Leboucher G, Laurent F, On Behalf Of The Lyon Bji Study G, On Behalf Of The PSG (2021) Past and Future of Phage Therapy and Phage-Derived Proteins in Patients with Bone and Joint Infection. Viruses 13. DOI 10.3390/v13122414
Gibb BP, Hadjiargyrou M (2021) Bacteriophage therapy for bone and joint infections. Bone Joint J 103-b 234–244. DOI 10.1302/0301-620x.103b2.Bjj-2020-0452.R2
Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ 339:b2535. DOI 10.1136/bmj.b2535
Ferry T, Leboucher G, Fevre C, Herry Y, Conrad A, Josse J, Batailler C, Chidiac C, Medina M, Lustig S, Laurent F (2018) 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? Open Forum Infect Dis 5:ofy269. DOI 10.1093/ofid/ofy269
Doub JB, Ng VY, Johnson AJ, Slomka M, Fackler J, Horne B, Brownstein MJ, Henry M, Malagon F, Biswas B (2020) Salvage Bacteriophage Therapy for a Chronic MRSA Prosthetic Joint Infection. Antibiot (Basel) 9. DOI 10.3390/antibiotics9050241
Ferry T, Batailler C, Petitjean C, Chateau J, Fevre C, Forestier E, Brosset S, Leboucher G, Kolenda C, Laurent F, Lustig S (2020) The Potential Innovative Use of Bacteriophages Within the DAC((R)) Hydrogel to Treat Patients With Knee Megaprosthesis Infection Requiring "Debridement Antibiotics and Implant Retention" and Soft Tissue Coverage as Salvage Therapy. Front Med (Lausanne) 7:342. DOI 10.3389/fmed.2020.00342
Ferry T, Kolenda C, Batailler C, Gustave CA, Lustig S, Malatray M, Fevre C, Josse J, Petitjean C, Chidiac C, Leboucher G, Laurent F (2020) Phage Therapy as Adjuvant to Conservative Surgery and Antibiotics to Salvage Patients With Relapsing S. aureus Prosthetic Knee Infection. Front Med (Lausanne) 7:570572. DOI 10.3389/fmed.2020.570572
Tkhilaishvili T, Winkler T, Muller M, Perka C, Trampuz A (2020) Bacteriophages as Adjuvant to Antibiotics for the Treatment of Periprosthetic Joint Infection Caused by Multidrug-Resistant Pseudomonas aeruginosa.Antimicrobial Agents and Chemotherapy64(1) (no pagination)
Cano EJ, Caflisch KM, Bollyky PL, Van Belleghem JD, Patel R, Fackler J, Brownstein MJ, Horne B, Biswas B, Henry M, Malagon F, Lewallen DG, Suh GA (2021) Phage Therapy for Limb-threatening Prosthetic Knee Klebsiella pneumoniae Infection: Case Report and In Vitro Characterization of Anti-biofilm Activity. Clin Infect Dis 73:e144–e151. DOI 10.1093/cid/ciaa705
Doub JB, Ng VY, Wilson E, Corsini L, Chan BK (2021) Successful Treatment of a Recalcitrant Staphylococcus epidermidis Prosthetic Knee Infection with Intraoperative Bacteriophage Therapy. Pharmaceuticals (Basel) 14. DOI 10.3390/ph14030231
Ferry T, Batailler C, Souche A, Cassino C, Chidiac C, Perpoint T, le Corvaisier C, Josse J, Gaillard R, Roger J, Kolenda C, Lustig S, Laurent F (2021) Arthroscopic "Debridement and Implant Retention" With Local Administration of Exebacase (Lysin CF-301) Followed by Suppressive Tedizolid as Salvage Therapy in Elderly Patients for Relapsing Multidrug-Resistant S. epidermidis Prosthetic Knee Infection. Frontiers in Medicine 8 (no pagination)
Ferry T, Kolenda C, Batailler C, Gaillard R, Gustave CA, Lustig S, Fevre C, Petitjean C, Leboucher G, Laurent F, Lyon BJISg (2021) Case Report: Arthroscopic "Debridement Antibiotics and Implant Retention" With Local Injection of Personalized Phage Therapy to Salvage a Relapsing Pseudomonas Aeruginosa Prosthetic Knee Infection. Front Med (Lausanne) 8:569159. DOI 10.3389/fmed.2021.569159
Neuts AS, Berkhout HJ, Hartog A, Goosen JHM (2021) Bacteriophage therapy cures a recurrent Enterococcus faecalis infected total hip arthroplasty? A case report. Acta Orthop 92:678–680. DOI 10.1080/17453674.2021.1968714
Ramirez-Sanchez C, Gonzales F, Buckley M, Biswas B, Henry M, Deschenes MV, Horne B, Fackler J, Brownstein MJ, Schooley RT, Aslam S (2021) Successful Treatment of Staphylococcus aureus Prosthetic Joint Infection with Bacteriophage Therapy. Viruses 13. DOI 10.3390/v13061182
Schoeffel J, Wang EW, Gill D, Frackler J, Horne B, Manson T, Doub JB (2022) Successful Use of Salvage Bacteriophage Therapy for a Recalcitrant MRSA Knee and Hip Prosthetic Joint Infection.Pharmaceuticals15(2) (no pagination)
Kini SG, Gabr A, Das R, Sukeik M, Haddad FS (2016) Two-stage Revision for Periprosthetic Hip and Knee Joint Infections. Open Orthop J 10:579–588. DOI 10.2174/1874325001610010579
Zahar A, Gehrke TA (2016) One-Stage Revision for Infected Total Hip Arthroplasty. Orthop Clin North Am 47:11–18. DOI 10.1016/j.ocl.2015.08.004
Alamanda VK, Springer BD (2018) Perioperative and Modifiable Risk Factors for Periprosthetic Joint Infections (PJI) and Recommended Guidelines. Curr Rev Musculoskelet Med 11:325–331. DOI 10.1007/s12178-018-9494-z
Kim MK, Zhao A, Wang A, Brown ZZ, Muir TW, Stone HA, Bassler BL (2017) Surface-attached molecules control Staphylococcus aureus quorum sensing and biofilm development. Nat Microbiol 2:17080. DOI 10.1038/nmicrobiol.2017.80
Kutateladze M, Adamia R (2010) Bacteriophages as potential new therapeutics to replace or supplement antibiotics. Trends Biotechnol 28:591–595. DOI 10.1016/j.tibtech.2010.08.001
Akanda ZZ, Taha M, Abdelbary H (2018) Current review-The rise of bacteriophage as a unique therapeutic platform in treating peri-prosthetic joint infections. J Orthop Res 36:1051–1060. DOI 10.1002/jor.23755
Clokie MR, Millard AD, Letarov AV, Heaphy S (2011) Phages in nature. Bacteriophage 1:31–45. DOI 10.4161/bact.1.1.14942
Loc-Carrillo C, Abedon ST (2011) Pros and cons of phage therapy. Bacteriophage 1:111–114. DOI 10.4161/bact.1.2.14590
Tzeng A, Tzeng TH, Vasdev S, Korth K, Healey T, Parvizi J, Saleh KJ (2015) Treating periprosthetic joint infections as biofilms: key diagnosis and management strategies. Diagn Microbiol Infect Dis 81:192–200. DOI 10.1016/j.diagmicrobio.2014.08.018
Mah TF, O'Toole GA (2001) Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol 9:34–39. DOI 10.1016/s0966-842x(00)01913-2
Khalifa L, Brosh Y, Gelman D, Coppenhagen-Glazer S, Beyth S, Poradosu-Cohen R, Que YA, Beyth N, Hazan R (2015) Targeting Enterococcus faecalis biofilms with phage therapy. Appl Environ Microbiol 81:2696–2705. DOI 10.1128/aem.00096 – 15
Yilmaz C, Colak M, Yilmaz BC, Ersoz G, Kutateladze M, Gozlugol M (2013) Bacteriophage therapy in implant-related infections: an experimental study. J Bone Joint Surg Am 95:117–125. DOI 10.2106/jbjs.K.01135
Onsea J, Soentjens P, Djebara S, Merabishvili M, Depypere M, Spriet I, De Munter P, Debaveye Y, Nijs S, Vanderschot P, Wagemans J, Pirnay JP, Lavigne R, Metsemakers WJ (2019) Bacteriophage Application for Difficult-to-treat Musculoskeletal Infections: Development of a Standardized Multidisciplinary Treatment Protocol. Viruses 11. DOI 10.3390/v11100891
Tkhilaishvili T, Winkler T, Müller M, Perka C, Trampuz A (2019) Bacteriophages as Adjuvant to Antibiotics for the Treatment of Periprosthetic Joint Infection Caused by Multidrug-Resistant Pseudomonas aeruginosa. Antimicrob Agents Chemother 64. DOI 10.1128/aac.00924 – 19
Schuch R, Lee HM, Schneider BC, Sauve KL, Law C, Khan BK, Rotolo JA, Horiuchi Y, Couto DE, Raz A, Fischetti VA, Huang DB, Nowinski RC, Wittekind M (2014) Combination therapy with lysin CF-301 and antibiotic is superior to antibiotic alone for treating methicillin-resistant Staphylococcus aureus-induced murine bacteremia. J Infect Dis 209:1469–1478. DOI 10.1093/infdis/jit637
Watson A, Sauve K, Cassino C, Schuch R (2020) Exebacase Demonstrates In Vitro Synergy with a Broad Range of Antibiotics against both Methicillin-Resistant and Methicillin-Susceptible Staphylococcus aureus. Antimicrob Agents Chemother 64. DOI 10.1128/aac.01885-19
Schuch R, Khan BK, Raz A, Rotolo JA, Wittekind M (2017) Bacteriophage Lysin CF-301, a Potent Antistaphylococcal Biofilm Agent. Antimicrob Agents Chemother 61. DOI 10.1128/aac.02666-16
Linden SB, Zhang H, Heselpoth RD, Shen Y, Schmelcher M, Eichenseher F, Nelson DC (2015) Biochemical and biophysical characterization of PlyGRCS, a bacteriophage endolysin active against methicillin-resistant Staphylococcus aureus. Appl Microbiol Biotechnol 99:741–752. DOI 10.1007/s00253-014-5930-1
Sosa BR, Niu Y, Turajane K, Staats K, Suhardi V, Carli A, Fischetti V, Bostrom M, Yang X (2020) 2020 John Charnley Award: The antimicrobial potential of bacteriophage-derived lysin in a murine debridement, antibiotics, and implant retention model of prosthetic joint infection. Bone Joint J 102–b:3–10. DOI 10.1302/0301-620x.102b7.Bjj-2019-1590.R1
Faruque SM, Naser IB, Islam MJ, Faruque AS, Ghosh AN, Nair GB, Sack DA, Mekalanos JJ (2005) Seasonal epidemics of cholera inversely correlate with the prevalence of environmental cholera phages. Proc Natl Acad Sci U S A 102:1702–1707. DOI 10.1073/pnas.0408992102
Payne RJ, Jansen VA (2002) Evidence for a phage proliferation threshold? J Virol 76:13123; author reply 13123–13124. DOI 10.1128/jvi.76.24.13123-13124.2002
Payne RJ, Jansen VA (2001) Understanding bacteriophage therapy as a density-dependent kinetic process. J Theor Biol 208:37–48. DOI 10.1006/jtbi.2000.2198
Roach DR, Leung CY, Henry M, Morello E, Singh D, Di Santo JP, Weitz JS, Debarbieux L (2017) Synergy between the Host Immune System and Bacteriophage Is Essential for Successful Phage Therapy against an Acute Respiratory Pathogen. Cell Host Microbe 22:38–47e34. DOI 10.1016/j.chom.2017.06.018
Saha D, Mukherjee R (2019) Ameliorating the antimicrobial resistance crisis: phage therapy. IUBMB Life 71:781–790. DOI 10.1002/iub.2010
Clarke AL, De Soir S, Jones JD (2020) The Safety and Efficacy of Phage Therapy for Bone and Joint Infections: A Systematic Review. Antibiot (Basel) 9. DOI 10.3390/antibiotics9110795
Yang Y, Shen W, Zhong Q, Chen Q, He X, Baker JL, Xiong K, Jin X, Wang J, Hu F, Le S (2020) Development of a Bacteriophage Cocktail to Constrain the Emergence of Phage-Resistant Pseudomonas aeruginosa. Front Microbiol 11:327. DOI 10.3389/fmicb.2020.00327
Pirnay JP, Ferry T, Resch G (2022) Recent progress toward the implementation of phage therapy in Western medicine. FEMS Microbiol Rev 46. DOI 10.1093/femsre/fuab040
Verbeken G, Pirnay JP (2022) European regulatory aspects of phage therapy: magistral phage preparations. Curr Opin Virol 52:24–29. DOI 10.1016/j.coviro.2021.11.005
McCallin S, Sacher JC, Zheng J, Chan BK (2019) Current State of Compassionate Phage Therapy. Viruses 11. DOI 10.3390/v11040343

Table 1: Basic characteristics of the included reports.
NO.	Author	YOP	Country	Patient		CO-Morbidity	Prosthetic joint	Index surgery	No. Of previous surgeries	Organism
NO.	Author	YOP	Country	Sex	Age	CO-Morbidity	Prosthetic joint	Index surgery	No. Of previous surgeries	Organism
1	Ferry et al.	2018	France	Female	80	obese-DM-mild chronic kidney injury	hip	NR	6	Initially phage therapy was prepared against Multidrug-resistant Pseudomonas aeruginosa and methicillin-susceptible Staphylococcus aureus. However, operative samples confirmed MSSA but not Pseudomonas aeruginosa, Furthermore Enterococcus faecalis and Staphylococcus lugdunensis were also detected as numerous colonies (the authors reported treating these bacteria by antibiotics).
2	Doub et al.	2020	USA	Male	72	morbid obesity-hyperlipidemia	knee	2012	6	methicillin-resistant Staphylococcus aureus
3	Ferry et al.	2020	France	Male	49	NR	knee	2013	2	Staphylococcus aureus
4	Ferry et al. (Series of 3 cases)	2020	France	1- Male	80	Parkinson disease-cardiac arrhythmia-hypertension	knee	2004	2	methicillin-susceptible Staphylococcus aureus
				2- Male	84	dyslipidemia	knee	2006	4	methicillin-susceptible Staphylococcus aureus
				3- Female	83	hypertension and lymphoedema	knee	2000	3	methicillin-susceptible Staphylococcus aureus
5	Tkhilaishivili et al.	2020	Germany	Female	80	DM, obesity, hypertension, and chronic kidney failure	knee	NR	4	Multi-drug resistant Pseudomonas aeruginosa
6	Cano et al.	2021	USA	Male	62	DM-obesity	knee	2008	12	Klebsiella pneumoniae complex
7	Doub et al.	2021	USA	female	79	aplastic anemia	knee	2012	4	Multi-drug resistant Staphylococcus epidermidis
8	Ferry et al. (Series of 4 cases)	2021	France	1- Female	89	Recurrent lymphoma-splenectomy	knee	NR	2	Multi-drug resistant Staphylococcus epidermidis
				2- Male	79	severe ankylosing spondylitis under corticosteroids therapy	knee	NR	2	Multi-drug resistant Staphylococcus epidermidis
				3- Female	88	active chronic myeloid leukemia (under imatinib therapy requiring blood perfusions). chronic kidney disease (indicated for dialysis but the patient refused)	knee	NR	2	Multi-drug resistant Staphylococcus epidermidis
				4- Male	83	Severe cardiomyopathy requiring anticoagulation-dyslipidemia-DM	knee	NR	3	Multi-drug resistant Staphylococcus epidermidis
9	Ferry et al.	2021	France	Male	88	congestive heart failure-bed ridden	knee	NR	2	relapsing Pseudomonas aeruginosa
10	Neuts et al.	2021	Netherlands	Male	76	NR	hip	2015	6	Enterococcus faecalis
11	Ramirez-Sanchez et al.	2021	USA	Female	61	NR	knee	1999	Not exactly reported (at least more than 6)	Methicillin-susceptible Staphylococcus aureus
12	Schoeffel et al.	2022	USA	Female	64	NR	knee	2018	4	Methicillin-resistant Staphylococcus aureus
12	Schoeffel et al.	2022	USA	Female	64	NR	hip	2018	4	Methicillin-resistant Staphylococcus aureus
YOP: year of publication, DM: diabetes mellitus, NR: not reported,

Table 2: Management details, results, and outcomes.
NO.	Author		mono or cocktail BT	BT used	Route of BT administration	Follow up	BT related complications	Results and outcomes
1	Ferry et al		cocktail	PhagoDAIR: A mixture of P aeruginosa and the S aureus phages was used. three Phages (1493, 1815, and 1957) +SAT	IA	18 months	None	The authors reported that the patient developed acute hematogenous Citrobacter koseri hip infection, managed by a new DAIR procedure (intraoperative samples did not grow S aureus ). By the last follow up, the outcome was favorable without any clinical signs of persistent infection
2	Doub et al.		monophage	phage SaGR51Φ1 +SAT	IA (with each debridement and with final prosthesis implantation) + IV for 3 days	NR	Transaminitis related to IV phage therapy administration which was reversible and non-life-threatening. No complications of repeated IA administration.	Satisfactory outcomes, limb salvage instead of amputation, reimplantation of a Megaprostheses.
3	Ferry et al.		cocktail	phages PP1493 and PP1815	IA (Phage within DAC hydrogel)	12 months	None	Although phage therapy was used as a salvage procedure as the patient refused transfemoral amputation, The authors reported that the surgery failed due to bleeding and hematoma formation after receiving antiplatelet therapy (to treat myocardial infarction) with subsequent exposure of the free flap and re-infection; however, a bacterial culture of the hematoma revealed superinfection with Pseudomonas aeruginosa, Achromobacter spp., and Proteus mirabilis in culture. No S. aureus grew in culture (which was the target of the phage therapy)
4	Ferry et al. (series of 3 cases)	1	cocktail	PhagoDAIR (PP1493, PP1815, and PP1957) + SAT	IA	30 months	None	The patient had a serous discharge at 3 months which required a new DAIR procedure that showed non-specific synovitis and no infection recurrence. By the last follow up, the patient had a satisfactory outcome, limb and implant salvage, no recurrence or superinfection
		2	cocktail	PhagoDAIR	IA	7 months	None	Satisfactory outcomes, limb and implant salvage, no signs of infection, and pain-free walking.
		3	cocktail	PhagoDAIR	IA	11 months	None	Persistent discharge at 4 months required new DAIR procedures; cultures obtained during the procedure revealed no infection. By the last follow up, the patient had pain-free walking and no recurrence of infection.
5	Tkhilaishivili et al		monophage	bacteriophage therapy against MDR P. aeruginosa (no specific therapy was mentioned) + SAT	During the 1^st stage of surgery(debridement and cement spacer), phage therapy was administered IA, followed postoperatively by IA infusion through drain tubes	10 months	None	After 2 weeks of the 1^st stage of surgery, the patient experienced purulent discharge, upon which the authors decided to perform another session of debridement and change the spacer; the sample obtained during this surgery showed methicillin-resistant Staphylococcus epidermidis growth (treated with antibiotics) but no P. aeruginosa (which was the target of phage therapy). By the last follow up, the patient had satisfactory outcomes, no knee pain, functional range of motion, no loosening, and no infection recurrence.
6	Cano et al.		monophage	phage KpJH46Φ2 +SAT	IV (40 doses, each dose was taken on a weekday)	8.5 months	None	Satisfactory outcomes, limb salvage instead of amputation option, no recurrence of infection, implants were retained.
7	Doub et al		monophage	DAIR+ phage PM448 +SAT	IA + IV	5 months	A transient increase in aspartate aminotransferase (AST) and alanine aminotransferase (ALT), upon which the IV therapy was stopped owing to patient concerns and requests.	The patient was sent home after five days of the procedure. Satisfactory outcomes, limb salvage, implants were retained, and full knee function. (The authors reported that the patient was suffering from aplastic anemia, which was improved after phage therapy)
8	Ferry et al. (series of 4 cases)	1	Exebacase (the first bacteriophage-derived lysin)	LysinDAIR (arthroscopic DAIR, and local application of Exebacase) + SAT.	IA	6 months	None	satisfactory outcomes, and limb salvage
		2	Exebacase	LysinDAIR + SAT	IA	16 months	None (The patient experienced eosinophilic pneumonia attributed to daptomycin and diarrhea attributed to linezolid.)	The clinical outcome was favorable under SAT, and the patient was able to resume sports activities. Complete disappearance of clinical signs of infection
		3	Exebacase	LysinDAIR + SAT.	IA	6 months	None (severe thrombopenia attributed to linezolid which was switched to tedizolid.)	Even though the patient was under SAT, a new discharge occurred through the sinus tract; however, no further intervention was needed till the last follow up.
		4	Exebacase	LysinDAIR + SAT	IA	14 months	None (The patient developed eosinophilic pneumonia attributed to daptomycin before being switched to tedizolid.)	the clinical outcome was favorable under SAT-complete disappearance of clinical signs of infection
9	Ferry et al		cocktail	Arthroscopic debridement and the local application of phages, Three phages: PP1450, PP1777, and PP1792. + SAT	IA	12 months	None	By the last follow up, the knee joint was normal with painless motion and walking. No infection recurrence.
10	Neuts et al		cocktail	phages: Pyophage and IntestiPhage +SAT	oral suspension (for 19 days as a start, then a 2-week pause, followed by another 19 days of therapy).	36 months	None	Limb salvage after the patient refused the Girdlestone option, a favorable outcome, no hip complaints, no infection recurrence.
11	Ramirez-Sanchez et al		Cocktail	Three phages were used for the first treatment cycle: J-Sa36, Sa83, and Sa87. + SAT For the second treatment cycle, a single phage was used: SaGR51ø1. + SAT	For both treatment cycles, phage therapy was administered IA+IV (1^st cycle was IA injection followed by IV therapy for 2 weeks) (2^nd cycle was IA during the first stage of 2 stages revision)	14 months (Calculated from the 2^nd treatment cycle)	None	The patient developed a recurrent infection after the 1^st cycle of management, upon which she underwent two stages revision, during which she received the 2^nd cycle of management. Satisfactory outcomes, limb salvage after the patient refused the above knee amputation option, no recurrence of infection, and samples from the synovial fluid showed no bacterial growth till the last follow up.
12	Schoeffel et al knee and hip joints		monophage	Phage SaWIQ0488ø1 + SAT	IA+IV (Phage therapy was administered twice, the first was during debridement sessions for both hip and knee joints and after inserting a temporary spacer, where the patient received both IA and IV, and the second was during the implantation of the final prosthesis, during which the authors mentioned that the patient received only IA phages therapy)	11 months	A slight transaminitis did not lead to phage therapy holding and returned to normal levels after treatment stoppage.	Satisfactory outcomes, samples obtained during the final implantation of the prosthesis for both hip and knee joints revealed no bacterial growth; the patient is ambulating without a cane, able to climb stairs, and driving. No recurrence of infection.
BT: bacteriophage therapy, SAT: suppressive antibiotic therapy, IV: intravenous, IA: intraarticular, NR: not reported, DAIR: debridement, antibiotics, and implant retention, DAC: Defensive Antibacterial Coating,

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The promising role of bacteriophage therapy in managing total hip and knee arthroplasty related periprosthetic joint infection, a systematic review.

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