Case report: Continuous infusions of ceftazidime-avibactam and aztreonam in combination through elastomeric infusors for 12 weeks for the treatment of bone and joint infections due to metallo-ß-lactamase producing Enterobacterales.

Among carbapenem-resistant Enterobacterales, metallo-beta-lactamase producing strains represent a growing therapeutic challenge. While the association of aztreonam and ceftazidime-avibactam has been investigated in recent years for the treatment of infections involving these strains, little to no clinical data support the use of this association for the treatment of bone and joint infections. We report two cases of complex bone and joint infections involving metallo-beta-lactamase-producing Enterobacterales, successfully treated at our referral center with aztreonam and ceftazidime-avibactam for 12 weeks in continuous infusions through elastomeric infusors.

Sensitivity of the PBP2a SA Culture Colony Test on shortly incubated subcultures of methicillin-resistant staphylococci from positive blood cultures.

The sensitivity of an immunochromatographic assay for detecting methicillin resistance (PBP2a SA Culture Colony Test, Alere-Abbott) on shortly incubated subcultures of staphylococci in blood cultures was evaluated. The assay is highly sensitive for the detection of methicillin-resistant Staphylococcus aureus after 4 hour-subculture but requires 6 hour-incubation for methicillin-resistant coagulase-negative staphylococci.

Linezolid resistance: detection of the cfr(B) gene in French clinical MRSA strains.

OBJECTIVES: To describe two linezolid-resistant MRSA strains carrying the cfr(B) gene detected in the French National Reference Centre for staphylococci. METHODS: Two linezolid-resistant MRSA strains isolated from cystic fibrosis patients in two different French hospitals in 2017 and 2019 were examined to explore the mechanisms of linezolid resistance. Antimicrobial susceptibility was tested using broth microdilution and gradient strips. The genetic determinants of linezolid resistance were assessed by a multiplex PCR targeting cfr/cfr(B), optrA and poxtA genes, by amplification and sequencing of individual 23S rRNA genes and by WGS using both Illumina and Nanopore technologies. RESULTS: The two MRSA strains were resistant to linezolid but susceptible to tedizolid, and PCR-positive for cfr/cfr(B). The WGS analysis indicated that they belonged to two different STs (ST8-MRSA-IV and ST5382-MRSA-IV) and that they both harboured the cfr(B) gene on the same 9.7 kb Tn6218-like chromosomal transposon, a finding only previously reported in Enterococcus sp. and Clostridioides difficile. CONCLUSIONS: To the best of our knowledge, this is the first description of the presence of cfr(B) in staphylococci, more specifically in linezolid-resistant MRSA strains. This finding illustrates the risk of horizontal intergenus transfer of oxazolidinone resistance genes in Staphylococcus aureus and highlights the need to monitor such emergence in this species.

Bacteriophage-based decontamination to control environmental colonization by Staphylococcus capitis in neonatal intensive care units: An in vitro proof-of-concept.

Introduction: In neonatal intensive care units (NICUs), the standard chemical-based disinfection procedures do not allow a complete eradication of pathogens from environmental surfaces. In particular, the clone Staphylococcus capitis NRCS-A, a significant pathogen in neonates, was shown to colonize neonatal incubators. The aim of this study was to evaluate the in vitro effect of a bacteriophage cocktail on NRCS-A eradication. Methods: Three bacteriophages were isolated, genetically characterized and assessed for their host range using a collection of representative clinical strains (n=31) belonging to the clone NRCS-A. The efficacy of a cocktail including these three bacteriophages to eradicate the reference strain S. capitis NRCS-A CR01 was determined in comparison or in combination with the chemical disinfectant Surfanios Premium on either dry inoculum or biofilm-embedded bacteria. The emergence of bacterial resistance against the bacteriophages alone or in cocktail was evaluated by growth kinetics. Results: The three bacteriophages belonged to two families and genera, namely Herelleviridae/Kayvirus for V1SC01 and V1SC04 and Rountreeviridae/Andhravirus for V1SC05. They were active against 17, 25 and 16 of the 31 tested strains respectively. Bacteriophage cocktails decreased the bacterial inoculum of both dry spots and biofilms, with a dose dependent effect. The sequential treatment with bacteriophages then Surfanios Premium did not show enhanced efficacy. No bacterial resistance was observed when using the bacteriophage cocktail. Discussion: This study established a proof-of-concept for the use of bacteriophages to fight against S. capitis NRCS-A. Further investigations are needed using a larger bacterial collection and in real-life conditions before being able to use such technology in NICUs.

Phage Therapy against Staphylococcus aureus: Selection and Optimization of Production Protocols of Novel Broad-Spectrum Silviavirus Phages.

Background: Phage therapy a promising antimicrobial strategy to address antimicrobial resistance for infections caused by the major human pathogen Staphylococcus aureus. Development of therapeutic phages for human use should follow pharmaceutical standards, including selection of strictly lytic bacteriophages with high therapeutic potential and optimization of their production process. Results: Here, we describe three novel Silviavirus phages active against 82% of a large collection of strains (n = 150) representative of various methicillin-susceptible and -resistant S. aureus clones circulating worldwide. We also investigated the optimization of the efficiency and safety of phage amplification protocols. To do so, we selected a well-characterized bacterial strain in order to (i) maximize phage production yields, reaching phage titres of 1011 PFU/mL in only 4 h; and (ii) facilitate phage purity while minimizing the risk of the presence of contaminants originating from the bacterial host; i.e., secreted virulence factors or induced temperate phages. Conclusions: In sum, we propose a quality-by-design approach for the amplification of broad-spectrum anti-S. aureus phages, facilitating the subsequent steps of the manufacturing process; namely, purification and quality control.

Activity of Exebacase (CF-301) against Biofilms Formed by Staphylococcus epidermidis Strains Isolated from Prosthetic Joint Infections.

Staphylococcus epidermidis is one of the main pathogens responsible for bone and joint infections, especially those involving prosthetic materials, due to its ability to form biofilms. In these cases, biofilm formation, combined with increased antimicrobial resistance, often results in therapeutic failures. In this context, the development of innovative therapies active against S. epidermidis is a priority. The aim of this study was to evaluate the in vitro activity of the lysin exebacase (CF-301) against biofilms formed by 19 S. epidermidis clinical strains isolated from prosthetic joint infections (PJI). We determined the biomass and the remaining viable bacteria inside biofilms after 24 h of exposure to exebacase. Exebacase activity was compared to that of rifampicin, vancomycin, and daptomycin. The use of exebacase in addition to antibiotics was also assessed. Exebacase displayed (i) a significant anti-biomass activity on S. epidermidis biofilms at concentrations ≥5 mg/L (mean decrease up to 66% at 150 mg/L), (ii) significant bactericidal activity on biofilms at concentrations ≥50 mg/L (mean decrease up to 1.7 log CFU at 150 mg/L), (iii) synergistic effects when used in addition to rifampicin, vancomycin, or daptomycin. The extent of these activities varied by isolate. Exebacase can be considered a promising therapy in addition to rifampicin, vancomycin, or daptomycin in the context of PJI. Further in vitro studies are needed to understand its mechanism of action on S. epidermidis biofilms and in vivo investigations are required to confirm these data.

Paving the way for phage therapy using novel drug delivery approaches.

Bacterial resistance against antibiotics is an emergent medical issue. The development of novel therapeutic approaches is urgently needed and, in this context, bacteriophages represent a promising strategy to fight multi resistant bacteria. However, for some applications, bacteriophages cannot be used without an appropriate drug delivery system which increases their stability or provides an adequate targeting to the site of infection. This review summarizes the main application routes for bacteriophages and presents the new delivery approaches designed to increase phage's activity. Clinical successes of these formulations are also highlighted. Globally, this work paves the way for the design and optimization of nano and micro delivery systems for phage therapy.

Clinical Metagenomic Sequencing for Species Identification and Antimicrobial Resistance Prediction in Orthopedic Device Infection.

Diagnosis of orthopedic device-related infection is challenging, and causative pathogens may be difficult to culture. Metagenomic sequencing can diagnose infections without culture, but attempts to detect antimicrobial resistance (AMR) determinants using metagenomic data have been less successful. Human DNA depletion may maximize the amount of microbial DNA sequence data available for analysis. Human DNA depletion by saponin was tested in 115 sonication fluid samples generated following revision arthroplasty surgery, comprising 67 where pathogens were detected by culture and 48 culture-negative samples. Metagenomic sequencing was performed on the Oxford Nanopore Technologies GridION platform. Filtering thresholds for detection of true species versus contamination or taxonomic misclassification were determined. Mobile and chromosomal genetic AMR determinants were identified in Staphylococcus aureus-positive samples. Of 114 samples generating sequence data, species-level positive percent agreement between metagenomic sequencing and culture was 50/65 (77%; 95% confidence interval [CI], 65 to 86%) and negative percent agreement was 103/114 (90%; 95% CI, 83 to 95%). Saponin treatment reduced the proportion of human bases sequenced in comparison to 5-µm filtration from a median (interquartile range [IQR]) of 98.1% (87.0% to 99.9%) to 11.9% (0.4% to 67.0%), improving reference genome coverage at a 10-fold depth from 18.7% (0.30% to 85.7%) to 84.3% (12.9% to 93.8%). Metagenomic sequencing predicted 13/15 (87%) resistant and 74/74 (100%) susceptible phenotypes where sufficient data were available for analysis. Metagenomic nanopore sequencing coupled with human DNA depletion has the potential to detect AMR in addition to species detection in orthopedic device-related infection. Further work is required to develop pathogen-agnostic human DNA depletion methods, improving AMR determinant detection and allowing its application to other infection types.

Bacteriophages Combined With Subtherapeutic Doses of Flucloxacillin Act Synergistically Against Staphylococcus aureus Experimental Infective Endocarditis.

Background The potential of phage therapy for the treatment of endovascular Staphylococcus aureus infections remains to be evaluated. Methods and Results The efficacy of a phage cocktail combining Herelleviridae phage vB_SauH_2002 and Podoviriae phage 66 was evaluated against a methicillin-sensitive S. aureus strain in vitro and in vivo in a rodent model of experimental endocarditis. Six hours after bacterial challenge, animals were treated with (1) the phage cocktail. (2) subtherapeutic flucloxacillin dosage, (3) combination of the phage cocktail and flucloxacillin, or (4) saline. Bacterial loads in cardiac vegetations at 30 hours were the primary outcome. Secondary outcomes were phage loads at 30 hours in cardiac vegetations, blood, spleen, liver, and kidneys. We evaluated phage resistance 30 hours post infection in vegetations of rats under combination treatment. In vitro, phages synergized against S. aureus planktonic cells and the cocktail synergized with flucloxacillin to eradicated biofilms. In infected animals, the phage cocktail achieved bacteriostatic effect. The addition of low-dose flucloxacillin elevated bacterial suppression (∆ of -5.25 log10 colony forming unit/g [CFU/g] versus treatment onset, P<0.0001) and synergism was confirmed (∆ of -2.15 log10 CFU/g versus low-dose flucloxacillin alone, P<0.01). Importantly, 9/12 rats given the combination treatment had sterile vegetations at 30 hours. In vivo phage replication was partially suppressed by the antibiotic and selection of resistance to the Podoviridae component of the phage cocktail occurred. Plasma-mediated inhibition of phage killing activity was observed in vitro. Conclusions Combining phages with a low-dose standard of care antibiotic represents a promising strategy for the treatment of S. aureus infective endocarditis.

[Viruses for health: Bacteriophages]. / Les virus au service de la santé : les bactériophages.

Bacteriophages are naturally occurring viruses that specifically target bacteria. They are widely distributed in the environment. The concept of phage therapy is to isolate phages, characterize them, cultivate them and then purify them to treat bacterial infections. There is currently a revival of phage therapy, and its implementation presupposes the availability of active phages of pharmaceutical quality. From a regulatory point of view, the status of phages is not yet clearly defined by the authorities. The availability of phages produced by the pharmaceutical industry and through academic development programs such as the PHAGEinLYON program represents a breakthrough in the development of phage therapy. Prosthetic joint infections and digestive diseases seem to be relevant indications, but preclinical studies and randomized clinical trials are now needed to be done.

Title: Les virus au service de la santé : les bactériophages. Abstract: Les bactériophages sont des virus naturels très répandus dans l'environnement qui ciblent spécifiquement les bactéries. Leur utilisation en médecine, connue sous le terme phagothérapie, consiste à les isoler, les caractériser, les cultiver, puis les purifier pour traiter des infections bactériennes. Il existe actuellement un renouveau pour la thérapie phagique, et sa mise en œuvre présuppose de disposer de phages actifs de qualité pharmaceutique. D'un point de vue réglementaire, le statut des phages n'est pas encore clairement défini par les autorités, mais la mise à disposition de phages produits par l'industrie pharmaceutique et les programmes de développement académiques, comme le programme PHAGEinLYON, constituent un tournant dans le déploiement de la phagothérapie.

Past and Future of Phage Therapy and Phage-Derived Proteins in Patients with Bone and Joint Infection.

Phage-derived therapies comprise phage therapy and the use of phage-derived proteins as anti-bacterial therapy. Bacteriophages are natural viruses that target specific bacteria. They were proposed to be used to treat bacterial infections in the 1920s, before the discovery and widespread over-commercialized use of antibiotics. Phage therapy was totally abandoned in Western countries, whereas it is still used in Poland, Georgia and Russia. We review here the history of phage therapy by focusing on bone and joint infection, and on the development of phage therapy in France in this indication. We discuss the rationale of its use in bacterial infection and show the feasibility of phage therapy in the 2020s, based on several patients with complex bone and joint infection who recently received phages as compassionate therapy. Although the status of phage therapy remains to be clarified by health care authorities, obtaining pharmaceutical-grade therapeutic phages (i.e., following good manufacturing practice guidelines or being "GMP-like") targeting bacterial species of concern is essential. Moreover, multidisciplinary clinical expertise has to determine what could be the relevant indications to perform clinical trials. Finally "phage therapy 2.0" has to integrate the following steps: (i) follow the status of phage therapy, that is not settled and defined; (ii) develop in each country a close relationship with the national health care authority; (iii) develop industrial-academic partnerships; (iv) create academic reference centers; (v) identify relevant clinical indications; (vi) use GMP/GMP-like phages with guaranteed quality bioproduction; (vii) start as salvage therapy; (vii) combine with antibiotics and adequate surgery; and (viii) perform clinical trials, to finally (ix) demonstrate in which clinical settings phage therapy provides benefit. Phage-derived proteins such as peptidoglycan hydrolases, polysaccharide depolymerases or lysins are enzymes that also have anti-biofilm activity. In contrast to phages, their development has to follow the classical process of medicinal products. Phage therapy and phage-derived products also have a huge potential to treat biofilm-associated bacterial diseases, and this is of crucial importance in the worldwide spread of antimicrobial resistance.

Case Report: Arthroscopic "Debridement Antibiotics and Implant Retention" With Local Injection of Personalized Phage Therapy to Salvage a Relapsing Pseudomonas Aeruginosa Prosthetic Knee Infection.

Bacteriophages are viruses that specifically target bacteria. They are considered to have a high potential in patients with prosthetic joint infection (PJI), as they have a synergistic anti-biofilm activity with antibiotics. We report here the case of an 88-year-old man (63 kg) with relapsing Pseudomonas aeruginosa prosthetic knee infection. The patient had severe alteration of the general status and was bedridden with congestive heart failure. As prosthesis explantation and/or exchange was not feasible, we proposed to this patient the use of phage therapy to try to control the disease in accordance with the local ethics committee and the French National Agency for Medicines and Health Products Safety (ANSM). Three phages, targeting P. aeruginosa, were selected based on their lytic activity on the patient's strain (phagogram). Hospital pharmacist mixed extemporaneously the active phages (initial concentration 1 ml of 1 × 1010 PFU/ml for each phage) to obtain a cocktail of phages in a suspension form (final dilution 1 × 109 PFU/ml for both phages). Conventional arthroscopy was performed and 30 cc of the magistral preparation was injected through the arthroscope (PhagoDAIR procedure). The patient received intravenous ceftazidime and then oral ciprofloxacin as suppressive antimicrobial therapy. Under this treatment, the patient rapidly improved with disappearance of signs of heart failure and pain of the left knee. During the follow-up of 1 year, the local status of the left knee was normal, and its motion and walking were unpainful. The present case suggests that the PhagoDAIR procedure by arthroscopy has the potential to be used as salvage therapy for patients with P. aeruginosa relapsing PJI, in combination with suppressive antimicrobial therapy. A Phase II clinical study deserves to be performed to confirm this hypothesis.

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.

Exebacase, a recombinantly produced lysin has recently (i) reported proof-of-concept data from a phase II study in S. aureus bacteremia and (ii) demonstrated antibiofilm activity in vitro against S. epidermidis. In patients with relapsing multidrug-resistant (MDR) S. epidermidis prosthetic knee infection (PKI), the only surgical option is prosthesis exchange. In elderly patients who have undergone several revisions, prosthesis explantation could be associated with definitive loss of function and mortality. In our BJI reference regional center, arthroscopic debridement and implant retention with local administration of exebacase (LysinDAIR) followed by suppressive tedizolid as salvage therapy is proposed for elderly patients with recurrent MDR S. epidermidis PKI with no therapeutic option or therapeutic dead end (for whom revision or transfemoral amputation is not feasible and no other oral option is available). Each use was decided in agreement with the French health authority and in accordance with the local ethics committee. A written consent was obtained for each patient. Exebacase (75 mg/mL; 30 mL) was administered directly into the joint during arthroscopy. Four patients (79-89 years old) were treated with the LysinDAIR procedure. All had several previous prosthetic knee revisions without prosthesis loosening. Three had relapsing PKI despite suppressive antibiotics following open DAIR. Two had clinical signs of septic arthritis; the two others had sinus tract. After the LysinDAIR procedure, no adverse events occurred during arthroscopy; all patients received daptomycin 8 mg/kg and linezolid 600 mg bid (4-6 weeks) as primary therapy, followed by tedizolid 200 mg/day as suppressive therapy. At 6 months, recurrence of the sinus tract occurred in the two patients with sinus tract at baseline. After >1 year follow up, the clinical outcome was favorable in the last two patients with total disappearance of clinical signs of septic arthritis even if microbiological persistence was detected in one of them. Exebacase has the potential to be used in patients with staphylococci PKI during arthroscopic DAIR as salvage therapy to improve the efficacy of suppressive antibiotics and to prevent major loss of function.

Experience With the Use of the MicroDTTect Device for the Diagnosis of Low-Grade Chronic Prosthetic Joint Infections in a Routine Setting.

Background: In prosthetic joint infections (PJIs), identification of the causative microorganisms is critical to successfully adapt and optimize treatment. However, microbiological diagnosis of PJIs remains a challenge notably because bacteria are embedded in biofilm adhered to the prosthetic material. Recently, dithiothreitol (DTT) treatment of prosthesis has been proposed as a new strategy to release bacteria from biofilm and to improve the yield of microbiological diagnosis. In this study, we evaluated the interest of a commercial device using DTT, the MicroDTTect system (Heraeus, Hanau, Germany), for the diagnosis of low-grade chronic PJIs, compared to the conventional culture of periprosthetic tissue (PPT) samples. Methods: Twenty patients undergoing a surgery procedure for removal of prosthetic material because of a suspicion of low-grade PJI without pre-operative microbiological documentation were included (NCT04371068). Bacteriological results using the fluid obtained after prosthesis treatment with the MicroDTTect system were compared to results obtained with conventional culture of PPT samples. Results: All the bacteria considered as responsible for PJIs recovered from culture of PPT samples were also detected using the MicroDTTect device. For one patient, an additional bacterial isolate (Staphylococcus haemolyticus) suspected to be involved in a polymicrobial PJI was identified using DTT treatment. Time to positivity of the cultures was also reduced using the MicroDTTect system, notably in case of Cutibacterium acnes infection. However, probable bacterial contaminants were found (MicroDTTect system, n = 5; PPT samples, n = 1). Conclusion: This study showed that DTT treatment of the prosthetic component using the MicroDTTect device could improve the microbiological diagnosis of low-grade PJIs.

Phage Therapy as Adjuvant to Conservative Surgery and Antibiotics to Salvage Patients With Relapsing S. aureus Prosthetic Knee Infection.

Objectives: To report the management of three consecutive patients with relapsing Staphylococcus aureus prosthetic knee infection (PKI) for whom explantation was not feasible who received a phage therapy during a "Debridement Antibiotics and Implant Retention" (DAIR) procedure followed by suppressive antimicrobial therapy. Methods: Each case was discussed individually in our reference center and with the French National Agency (ANSM). The lytic activity of three phages targeting S. aureus, which was produced with a controlled and reproducible process, was assessed before surgery (phagogram). A hospital pharmacist extemporaneously assembled the phage cocktail (1 ml of 1 × 1010 PFU/ml for each phage) as "magistral" preparation (final dilution 1 × 109 PFU/ml), which was administered by the surgeon directly into the joint, after the DAIR procedure and joint closure (PhagoDAIR procedure). Results: Three elderly patients were treated with the PhagoDAIR procedure. Phagograms revealed a high susceptibility to at least two of the three phages. During surgery, all patients had poor local conditions including pus in contact to the implant. After a prolonged follow-up, mild discharge of synovial fluid persisted in two patients, for whom a subsequent DAIR was performed showing only mild synovial inflammation without bacterial persistence or super-infection. The outcome was finally favorable with a significant and impressive clinical improvement of the function. Conclusions: The PhagoDAIR procedure has the potential to be used as salvage for patients with relapsing S. aureus PKI, in combination with suppressive antibiotics to avoid considerable loss of function. This report provides preliminary data supporting the setup of a prospective multicentric clinical trial.

Assessment of Respiratory Bacterial Coinfections Among Severe Acute Respiratory Syndrome Coronavirus 2-Positive Patients Hospitalized in Intensive Care Units Using Conventional Culture and BioFire, FilmArray Pneumonia Panel Plus Assay.

BACKGROUND: Approximately 15% of patients infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) present with severe forms of the disease and require hospitalization in intensive care units, which has been associated with high mortality rates. The prevalence of bacterial infections in these patients is not well established, and more data are needed to guide empiric antibiotic therapy and improve patient outcomes. METHODS: In this prospective multicenter study, we assessed bacterial coinfections identified in culture from 99 French patients infected by SARS-Cov-2 and hospitalized in intensive care units. We concomitantly evaluated an innovative molecular diagnostic technology technique, the BioFire, FilmArray Pneumonia Panel plus (FA-pneumo) assay, to identify these coinfections at an early stage, and its concordance with conventional culture. RESULTS: We showed that a bacterial coinfection was detected in 15% of patients based on conventional culture. Staphylococcus aureus and Haemophilus influenzae were the most prevalent pathogens. The sensitivity of FA-pneumo compared with culture was 100%. In contrast, the specificity varied between 88.4% and 100% according to the pathogen, and our results highlighted that 60.5% of bacterial targets reported using this assay were not recovered by culture; 76.9% of discordant results corresponded to bacteria belonging to commensal oral flora and/or reported with ≤105 copies/mL bacterial nucleic acids. CONCLUSIONS: Based on its excellent sensitivity, the FA-pneumo assay is useful to rule out bacterial coinfections in the context of severe SARS-CoV-2 infection and avoid the inappropriate prescription of antibiotics. However, positive tests should be interpreted carefully, taking into consideration deoxyribonucleic acid bacterial load and all clinical and biological signs.

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.

Infection is the most dramatic complication in patients with knee megaprosthesis. Its management is more complex in comparison with patients with primary arthroplasty, with a high risk of relapse. Lytic bacteriophages are considered to have a high potential in patients with prosthetic joint infection as it has been demonstrated that they have a synergistic anti-biofilm activity with antibiotics. The Defensive Antibacterial Coating (DAC®) hydrogel is a hydrogel available in the market that has been designed to prevent the adherence of bacteria on a prosthetic joint and to have the ability to transport and release anti-bacterial substances such as antibiotics. We report here the case of a patient with a catastrophic relapsing Staphylococcus aureus knee megaprosthesis infection without prosthesis loosening. We firstly perform phage susceptibility testing of the patient's strain to select an active cocktail, under the supervision of the French health authority. Then, we performed, as salvage therapy, a debridement and implant retention procedure with application of a selected cocktail of bacteriophages that was prepared extemporaneously within the DAC® hydrogel. A free flap for soft tissue coverage was required and empirical antibiotic treatment was started immediately after the surgery. Unfortunately, at 5 days after the surgery, while the local aspect of the surgical site was favorable, the patient developed myocardial infarction which required emergency stenting and dual antiplatelet therapy that were rapidly associated with bleeding at the surgical site, leading to a new prosthesis exposition. As a consequence, a transfemoral amputation was finally performed several months later. We also evaluated in vitro the impact of DAC® hydrogel on bacteriophage activity and showed that the selected phages were released very rapidly from the DAC® hydrogel, and then their titers were stable for at least 6 h. This case demonstrated the feasibility of the use of bacteriophages within a hydrogel to treat patients for knee megaprosthesis infection during a debridement procedure. The implementation requires identification of the pathogen before the debridement in order to perform phage susceptibility testing of the patient's strain and to identify a hospital pharmacist who will accept to do the preparation and to take the responsibility of the magistral preparation.

Medical innovations to maintain the function in patients with chronic PJI for whom explantation is not desirable: a pathophysiology-, multidisciplinary-, and experience-based approach.

INTRODUCTION: PJI is the most dramatic complication after joint arthroplasty. In patients with chronic infection, prosthesis exchange is in theory the rule. However, this surgical approach is sometimes not desirable especially in elderly patients with multiple comorbidities, as it could be associated with a dramatic loss of function, reduction of the bone stock, fracture, or peroperative death. We propose here to report different approaches that can help to maintain the function in such patients based on a pathophysiology-, multidisciplinary-, and an experience-based approach. METHODS: We describe the different points that are needed to treat such patients: (i) the multidisciplinary care management; (ii) understanding the mechanism of bacterial persistence; (iii) optimization of the conservative surgical approach; (iv) use of suppressive antimicrobial therapy (SAT); (v) implementation of innovative agents that could be used locally to target the biofilm. RESULTS: In France, a nation-wide network called CRIOAc has been created and funded by the French Health ministry to manage complex bone and joint infection. Based on the understanding of the complex pathophysiology of PJI, it seems to be feasible to propose conservative surgical treatment such as "debridement antibiotics and implant retention" (with or without soft-tissue coverage) followed by SAT to control the disease progression. Finally, there is a rational for the use of particular agents that have the ability to target the bacteria embedded in biofilm such as bacteriophages and phage lysins. DISCUSSION: This multistep approach is probably a key determinant to propose innovative management in patients with complex PJI, to improve the outcome. CONCLUSION: Conservative treatment has a high potential in patients with chronic PJI for whom explantation is not desirable. The next step will be to evaluate such practices in nation-wide clinical trials.