Model-based quantification of immune response and anti-staphylococcal activity of afabicin in immunocompetent mouse thigh infections to enable predictions of clinical efficacy

This study aimed to describe the immune response and activity of the novel antibiotic afabicin against <i>Staphylococcus aureus</i> in an immunocompetent mouse thigh infection model using PKPD modeling and to predict the clinical efficacy of different afabicin dosing regimens in <i>Staphylococcus</i>-infected immunocompetent patients. Bacterial counts of five <i>Staphylococcus aureus</i> strains were determined over 74 h in an immunocompetent mouse thigh infection model. Afabicin doses of 0.011-150 mg/kg were administered intraperitoneally every 6 h. A PKPD model was developed to describe immune response and afabicin desphosphono (active moiety) activity. The model was used jointly with a human population PK model for afabicin to predict the efficacy of different clinical dosing regimens (intravenous 55 to 160 mg twice-daily or oral 80 to 240 mg twice-daily) in immunocompetent patients. The developed model included a saturable neutrophil-mediated phagocytosis process of bacteria. The afabicin desphosphono effect was characterized using a model structure previously developed based on <i>in vitro</i> time-kill and neutropenic mouse thigh infection data. A lower maximum killing rate constant (0.24 h^-1) and an 82% lower EC₅₀ were estimated for immunocompetent animals compared to <i>in vitro</i>. Predictions indicated that all tested afabicin regimens would achieve bacterial killing in immunocompetent patients infected with <i>S. aureus</i>. Afabicin activity against five <i>S. aureus</i> strains was adequately quantified in immunocompetent animals by the developed PKPD model. Predictions supported the efficacy of afabicin 55 mg intravenously twice daily, followed by an 80 mg oral twice-daily regimen in humans, which is currently tested in a clinical trial in bone and joint infections.