Pharmacokinetic-pharmacodynamic modeling to evaluate the relative impact of immune response and meropenem on bacterial killing in vivo

ABSTRACT In vivo antibiotic pharmacokinetic-pharmacodynamic (PKPD) properties are typically studied in neutropenic infection models, limiting the understanding of interactions between immune cells and antibiotics. This study aimed to characterize the impact of immune status on meropenem PKPD and dose-response in a mouse lung infection model, and to quantify the relative contribution of immune response and meropenem to bacterial killing. Meropenem PK was analyzed in plasma and epithelial lung fluid, and bacterial counts were monitored over 24 h following 40 or 300 mg/kg meropenem doses every 4 h in a mouse lung infection model with varying immunosuppression levels (neutropenic, intermediate, or immunocompetent). A PKPD model was developed to quantify bacterial killing by the immune response and meropenem over time. Dose-fractionation studies were simulated to investigate meropenem dose-response in different immune states. Observed differences in meropenem concentration-time profiles were explained by a higher volume of distribution in immunocompetent mice. The immune response was described by phagocytosis and digestion processes. The meropenem effect was best quantified based on plasma concentrations, with a maximal killing rate of 0.934 h −1 and EC 50 = 1.62 mg/L. The lower contribution of meropenem to bacterial killing in intermediate and immunocompetent conditions was explained as a lower fraction of bacteria being affected by meropenem. In simulations, the immune status impacted PKPD target derivation. The developed model characterized differences in meropenem PK between neutropenic and immunocompetent in vivo infection models and quantified the contributions of immune response and meropenem to bacterial killing, with a reduced effect of meropenem in immunocompetent systems.