A mechanism-based model of immune status effects on antibiotic PK/PD targets in bacteremia

Abstract A key determinant of antibiotic dose selection is the pharmacokinetic/pharmacodynamic (PK/PD) target, typically determined using dose fractionation studies in preclinical infection models. However, such studies often do not consider the host immune response, despite its important role in bacterial infection. We therefore aimed to systematically characterize the potential contributions of the innate immune response on antibiotic PK/PD targets using a novel mathematical mechanism-based model, incorporating interactions between neutrophils, monocytes and bacterial pathogens. We parametrized the model using data from multiple in vitro host-pathogen interaction studies and calibrated using data from previous in vivo infection models. Key parameters included phagocytosis and digestion rates of neutrophils and monocytes, driven by immune cell concentrations and finite ingestion capacities. To describe data from immune competent rodent infection models, maximum phagocytosis rates required a 77% reduction relative to in vitro estimates for both cell types. The calibrated host-pathogen interaction model was then integrated with a pharmacodynamic model accounting for pathogen-drug interactions for four antibiotic modalities. We performed in silico dose fractionation studies for bacteremia thereby evaluating the impact of different types and magnitudes of immune deficiencies, e.g., neutropenia, monocytopenia, on PK/PD targets in humans. The combination of severe neutropenia and monocytopenia required up to 2.2-fold increase in target AUC/MIC for concentration-dependent antibiotics, and up to a 58% increase in T>MIC for time-dependent antibiotics, compared with immune competent individuals. In conclusion, this study provides general insights into the impact of neutrophil and monocyte suppression on PK/PD targets and associated dosage adjustments in case of immune suppression.