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 × 10
10
PFU/ml for each phage) as “magistral” preparation (final dilution 1 × 10
9
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.
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 × 10
10
PFU/ml for each phage) to obtain a cocktail of phages in a suspension form (final dilution 1 × 10
9
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.
Background The potential of phage therapy for the treatment of endovascular
infections remains to be evaluated. Methods and Results The efficacy of a phage cocktail combining
phage vB_SauH_2002 and
...phage 66 was evaluated against a methicillin-sensitive
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
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 log
colony forming unit/g CFU/g versus treatment onset,
<0.0001) and synergism was confirmed (∆ of -2.15 log
CFU/g versus low-dose flucloxacillin alone,
<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
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
infective endocarditis.
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.
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-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.
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.
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.
mecC-MRSA in French Dairy Farms All mecC-positive strains belonged to the clonal complex CC130 and harbored the same spa-type t1736. Conclusion: This study found that mecC-positive MRSA isolates are ...able to persist within the same farms for several years after being introduced in this setting and are able to widely disseminate but only among dairy cows suggesting that milking machines might be a key player.
A 71-year-old man (85 kg) has a past history of vitiligo, ischemic myocardiopathy, and bilateral knee arthroplasties. A 1-stage exchange of the right prosthetic-joint infection (PJI) was done in 2016 ...for a mechanical prosthetic loosening. A massive constrained prosthetic joint was used to compensate for the bone loss (Supplementary Figure S1A). Iterative postoperative dislocations were followed by occurrence of a fistula in January 2017 and prosthetic loosening (Supplementary Figure S1B) without any pain. Because it was impossible to imagine a 2-stage exchange, a debridement and implant retention (DAIR) procedure followed by suppressive antimicrobial therapy was proposed. Daptomycin (700 mg/day) and ceftaroline (1200 mg/day) were prescribed after the surgery. A multidrug-resistant Staphylococcus epidermidis, which is only susceptible to daptomycin, vancomycin, fosfomycin, and linezolid, was found in culture from all operative samples. After 6 weeks of intravenous antimicrobial therapy, 600 mg of linezolid bid was prescribed in August 2017. Concomitant medications were ramipril, bisoprolol, furosemide, and aspirin. Under therapy, the patient experienced a progressive decrease of hemoglobin and hematocrit (without decrease of white blood cells or platelets). Five months after linezolid introduction, the patient developed asthenia related to anemia, with a decrease of hemoglobin to 65 mg/dL, and without leucopenia or thrombocytopenia (Figure 1). The patient did not take any treatment with potential bone marrow toxicity, except linezolid. The patient has no other adverse drug reactions. A blood transfusion (2 bags) was performed, which led to an immediate increase of the hemoglobin level to 84 mg/dL, and linezolid was switched to 200 mg of tedizolid once a day. In May 2018, 9 months after the DAIR surgery and 4 months after the switch, the patient was perfectly fine, walked despite rupture of the right knee extensor apparatus (video S2), without any pain, without any local signs of relapse (Supplementary Figure S1C), without clinical signs of neuropathy, and he experienced a continuous increase of the hemoglobin to 14 mg/dL under tedizolid therapy. No other treatment was changed or introduced.
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