How <i>Staphylococcus aureus</i> and <i>Pseudomonas aeruginosa</i> Hijack the Host Immune Response in the Context of Cystic Fibrosis

Cystic fibrosis (CF) is a serious genetic disease that leads to premature death, mainly due to impaired lung function. CF lungs are characterized by ongoing inflammation, impaired immune response, and chronic bacterial colonization. Staphylococcus aureus (SA) and Pseudomonas aeruginosa (PA) are the two most predominant bacterial agents of these chronic infections. Both can colonize the lungs for years by developing host adaptation strategies. In this review, we examined the mechanisms by which SA and PA adapt to the host immune response. They are able to bypass the physical integrity of airway epithelia, evade recognition, and then modulate host immune cell proliferation. They also modulate the immune response by regulating cytokine production and by counteracting the activity of neutrophils and other immune cells. Inhibition of the immune response benefits not only the species that implements them but also other species present, and we therefore discuss how these mechanisms can promote the establishment of coinfections in CF lungs

Arthroscopic &quot;Debridement and Implant Retention&quot; 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 &gt;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

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

Evaluation of intraosteoblastic activity of dalbavancin against Staphylococcus aureus in an ex vivo model of bone cell infection

International audienceAbstract Objectives Long-acting lipoglycopeptides are promising therapeutic options in Staphylococcus aureus bone and joint infections (BJIs). This study evaluated the ability of dalbavancin to eradicate the intraosteoblastic reservoir of S. aureus, associated with BJI chronicity. Methods Osteoblastic cells were infected with a standardized inoculum of the S. aureus reference strain HG001 and incubated for 24 h with dalbavancin, vancomycin or rifampicin using the MIC, 10×MIC, 100×MIC and/or the intraosseous concentrations reached using standard therapeutic doses (i.e. vancomycin, 10 mg/L; rifampicin, 2 mg/L; and dalbavancin, 6 mg/L). The remaining intracellular bacteria were quantified by plating cell lysates. Results MICs of dalbavancin, vancomycin and rifampicin were 0.125, 1 and 0.004 mg/L, respectively. Dalbavancin significantly reduced the intracellular inoculum of S. aureus starting at a concentration equal to the MIC, with a significant dose effect, ranging from a reduction of 31.4% (95% CI = 17.6%–45.2%) at MIC to 51.6% (95% CI = 39.8%–63.4%) at 100×MIC compared with untreated cells. Of note, dalbavancin was the only molecule to significantly reduce the intraosteoblastic inoculum at low concentration (MIC). At intraosseous concentrations, dalbavancin reduced the intracellular inoculum by 49.6% (95% CI = 45.1%–54.1%) compared with untreated cells (P &lt; 0.001), with no significant difference compared with vancomycin (38.1%; 95% CI = 19.2%–57.0%; P = 0.646), and was less efficient than rifampicin (69.0%; 95% CI = 63.2-74.8; P &lt; 0.001). Conclusions Dalbavancin was able to decrease the intraosteoblastic S. aureus inoculum by 50% at intraosseous concentrations reached during standard human therapeutic dosing, with no difference compared with vancomycin, and remained less efficient than rifampicin. However, it was the only molecule significantly active at low concentration