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

## TL;DR

This study uses a mouse model and PKPD modeling to evaluate afabicin's effectiveness against Staphylococcus aureus infections and predicts its clinical efficacy in humans.

## Contribution

A novel PKPD model integrating immune response and antibiotic activity in immunocompetent animals to predict clinical dosing regimens for afabicin.

## Key findings

- A model with saturable neutrophil-mediated phagocytosis was developed to describe immune response and afabicin activity.
- Afabicin regimens predicted to achieve bacterial killing in immunocompetent patients include 55 mg intravenous twice-daily followed by 80 mg oral twice-daily.
- The model showed an 82% lower EC50 and a lower maximum killing rate in immunocompetent animals compared to in vitro.

## Abstract

This study aimed to describe the immune response and activity of the novel antibiotic afabicin against Staphylococcus aureus in an immunocompetent mouse thigh infection model using PKPD modeling and to predict the clinical efficacy of different afabicin dosing regimens in Staphylococcus-infected immunocompetent patients. Bacterial counts of five Staphylococcus aureus 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 in vitro 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 in vitro. Predictions indicated that all tested afabicin regimens would achieve bacterial killing in immunocompetent patients infected with S. aureus. Afabicin activity against five S. aureus 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.