Bone and Joint Tissue Penetration of the Staphylococcus -Selective Antibiotic Afabicin in Patients Undergoing Elective Hip Replacement Surgery

Abstract

Afabicin (formerly Debio 1450, AFN-1720) is a prodrug of afabicin desphosphono (Debio 1452, AFN-1252), a novel antibiotic in development which targets the staphylococcal enoyl-acyl carrier protein reductase (FabI) and exhibits selective potent antibacterial activity against staphylococcal species, including methicillin-resistant Staphylococcus aureus. As part of clinical development in bone and joint infections, a distribution study in bone was performed in 17 patients who underwent elective hip replacement surgery. Patients received 3 doses of 240 mg afabicin orally (every 12 h) at various time points before surgery. Afabicin desphosphono concentrations were measured by liquid chromatography-tandem mass spectrometry in plasma, cortical bone, cancellous bone, bone marrow, soft tissue, and synovial fluid collected during surgery at 2, 4, 6, or 12 h after the third afabicin dose. The study showed good penetration of afabicin desphosphono into bone tissues, with mean area under the curve ratios for cortical bone-, cancellous bone-, bone marrow-, soft tissue-, and synovial fluid-to-total plasma concentrations of 0.21, 0.40, 0.32, 0.35, and 0.61, respectively. When accounting for the free fraction in plasma (2%) and synovial fluid (9.4%), the mean ratio was 2.88, which is indicative of excellent penetration and which showed that the afabicin desphosphono concentration was beyond the MIC90 of S. aureus over the complete dosing interval. These findings, along with preclinical efficacy data, clinical efficacy data for skin and soft tissue staphylococcal infection, the availability of both intravenous and oral formulations, and potential advantages over broad-spectrum antibiotics for the treatment of staphylococcal bone or joint infections, support the clinical development of afabicin for bone and joint infections. (This study has been registered at ClinicalTrials.gov under identifier NCT02726438.)

Antimicrobial activity of mesenchymal stem cells against Staphylococcus aureus

“…Long-term treatment with systemic antibiotics increases bacterial resistance through the selection of resistant strains. Bone penetration of many antibiotics has been studied [5][6][7][8][9][10], but the interpretation of results is difficult as the methodologies have not been standardized, and therefore, results have varied, but commonly used antibiotics such as vancomycin have poor bone penetration [2,7,11]. Recent attempts at local antibiotic delivery through an indwelling catheter in joint infections have only marginally improved outcomes [12][13][14].…”

Afabicin, a First-in-Class Antistaphylococcal Antibiotic, in the Treatment of Acute Bacterial Skin and Skin Structure Infections: Clinical Noninferiority to Vancomycin/Linezolid

“…The narrow spectrum of activity of afabicin is not only beneficial for the patient but also well aligned with antimicrobial stewardship, as it is believed that preservation of gut microbiota may also reduce spread of antibiotic resistance ( 35 ). Both the efficacy and safety data from this study support further development of afabicin for the treatment of ABSSSI and potentially pave the road for treatment of other types of staphylococcal infections such as bone and joint infections ( 36 ).…”

Critical analysis of antibacterial agents in clinical development

“…Preliminary studies have indicated that afabicin may not be prone to rapid emergence of resist ance, despite binding to a single target, possibly due to its high affinity binding 102 . It is currently being devel oped for the treatment of bone and joint infections 105 . Other FabI inhibitors are in preclinical development (for example, MUT056399) 106 .…”