Bone and Joint Tissues Penetration of the Staphylococcus-Selective Antibiotic Afabicin in Patients Undergoing Elective Hip Replacement Surgery [Clinical Therapeutics]

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 (q12h) at various time points before surgery. Afabicin desphosphono concentrations were measured by LC-MS/MS in plasma, cortical bone, cancellous bone, bone marrow, soft tissue and synovial fluid collected during surgery at 2, 4, 6, or 12 hours after the third afabicin dose.

The study showed good penetration of afabicin desphosphono into bone tissues with mean AUC ratios for cortical, cancellous, 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 showed that afabicin desphosphono concentration was beyond MIC90 of S. aureus over the complete dosing interval.

These findings, along with preclinical efficacy data, clinical efficacy data in skin and soft tissue staphylococcal infection, availability of both IV 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 in bone and joint infections.

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