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

Abstract

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.

Keywords: S. epidermidis; bacteriophage; lysin; prosthetic-joint infection; staphylococci; tedizolid.

Figure 1

Patient 1 was an 89-year-old woman with past history of recurrent lymphoma, splenectomy, and iterative prosthetic left knee revisions due to relapsing MDR S. epidermidis infection (04/02/2016). She had large constrained cemented prosthesis without loosening (A) and sinus tract (B). She experienced a relapse under SAT (pristinamycin plus doxycyclin) following open DAIR 1 year ago. She was treated according to the LysinDAIR procedure (C). The biofilm was visible at the surface of the implant during the DAIR procedure [08/11/2018; (D)]. She received daptomycin intravenously and linezolid orally, followed by tedizolid as SAT. At 6 months, still receiving tedizolid therapy, a new discharge occurred through the sinus tract (E).

Figure 2

Patient 2 was a 79-year-old man with history of severe ankylosing spondylitis under corticosteroids who presented a chronic left PKI due to S. hominis that was treated with a one-stage exchange. A postoperative infection occurred due to MDR S. epidermidis (02/12/3013) treated with open DAIR and SAT (minocycline followed by cotrimoxazole due to occurrence of a clinical relapse under minocycline therapy; 10/11/2013). He had a cementless revision prosthesis with long stem with no loosening (A) and clinical signs of septic arthritis (large joint effusion, pain during mobilization, skin inflammation without sinus tract) (B) and S. epidermidis grew from joint puncture (9/13/2018). He was treated according to the LysinDAIR procedure (08/11/2018), and a septic collection communicating with the joint was drained. He received daptomycin intravenously and linezolid orally and experienced eosinophilic pneumonia attributed to daptomycin and diarrhea attributed to linezolid. Then, tedizolid was prescribed as SAT, and the outcome was favorable with disappearance of the clinical signs of septic arthritis (C). At 12 months, as a mild joint effusion persisted, a joint puncture was performed, and surprisingly, S. epidermidis was still present in culture. At the time of writing (16 months of follow-up after the LysinDAIR procedure), the clinical outcome was still favorable under tedizolid therapy, and the patient was able to resume golf.

Figure 3

Patient 3 was an 88-year-old woman with a current history of active chronic myeloid leukemia under imatinib therapy requiring iterative blood perfusions. She also had chronic kidney disease with indication of dialysis that the patient refused. She also had chronic lymphoedema. She had a right-cemented revision prosthesis (A) following a two-stage exchange for PKI due to MDR S. epidermidis (04/02/2011). Unfortunately, S. epidermidis persistence was diagnosed (6/7/2018), and a sinus tract occurred (B). Cotrimoxazole as SAT was contraindicated due to the kidney disease. The patient received intermittent antimicrobial therapy with pristinamycin when skin and soft tissue inflammation occurred around the sinus tract (B). She was treated according to the LysinDAIR procedure (10/01/2019). She received daptomycin intravenously and linezolid orally and experienced severe thrombopenia (30 G/L) leading to discontinuation of linezolid and a switch to tedizolid. Unfortunately, at 6 months, under tedizolid therapy, a new discharge occurred trough the sinus tract (C).

Figure 4

Patient 4 was an 83-year-old man with a history of severe cardiomyopathy requiring anticoagulation, dyslipidemia, and diabetes. He had a left-cemented revision prosthesis (A) following a two-stage exchange for PKI due to Streptococcus spp. He experienced postoperative chronic septic arthritis due to S. epidermidis (5/23/2018), and he was treated by open DAIR, skin and soft tissue flap, and SAT (clindamycin plus levofloxacin followed by clindamycin plus cotrimoxazole). Under SAT, the patient experienced a relapse of the septic arthritis (B) due to MDR S. epidermidis (19/07/2018). He was treated according to the LysinDAIR procedure (10/01/2019) and received daptomycin intravenously and linezolid orally. He developed eosinophilic pneumonia attributed to daptomycin before the switch to tedizolid. During the follow-up, the clinical signs of septic arthritis totally disappeared. At the time of writing (14 months of follow-up after the LysinDAIR procedure), the clinical outcome was still favorable under tedizolid (C).