A Model-Based Pharmacokinetic/Pharmacodynamic Analysis of the Combination of Amoxicillin and Monophosphoryl Lipid A Against S. pneumoniae in Mice

Abstract

Combining amoxicillin with the immunostimulatory toll-like receptor 4 agonist monophosphoryl lipid A (MPLA) represents an innovative approach for enhancing antibacterial treatment success. Exploiting pharmacokinetic and pharmacodynamic data from an infection model of Streptococcus pneumoniae infected mice, we aimed to evaluate the preclinical exposure-response relationship of amoxicillin with MPLA coadministration and establish a link to survival. Antibiotic serum concentrations, bacterial numbers in lung and spleen and survival data of mice being untreated or treated with amoxicillin (four dose levels), MPLA, or their combination were analyzed by nonlinear mixed-effects modelling and time-to-event analysis using NONMEM® to characterize these treatment regimens. On top of a pharmacokinetic interaction, regarding the pharmacodynamic effects the combined treatment was superior to both monotherapies: The amoxicillin efficacy at highest dose was increased by a bacterial reduction of 1.74 log10 CFU/lung after 36 h and survival was increased 1.35-fold to 90.3% after 14 days both compared to amoxicillin alone. The developed pharmacometric pharmacokinetic/pharmacodynamic disease-treatment-survival models provided quantitative insights into a novel treatment option against pneumonia revealing a pharmacokinetic interaction and enhanced activity of amoxicillin and the immune system stimulator MPLA in combination. Further development of this drug combination flanked with pharmacometrics towards the clinical setting seems promising.

Novel Pharmacokinetic/Pharmacodynamic Parameters Quantify the Exposure–Effect Relationship of Levofloxacin against Fluoroquinolone-Resistant Escherichia coli

“…As for all in vitro approaches, the direct transferability of the presented results to the in vivo situation is limited and serves as a first basis, as not all relevant processes are represented in the experimental setup. Importantly, the contribution of the human immune system to bacterial killing was not captured in the applied in vitro infection models [ 43 ]. Furthermore, the method used for bacterial quantification did not detect non-cultivable persister cells.…”

The Use of Translational Modelling and Simulation to Develop Immunomodulatory Therapy as an Adjunct to Antibiotic Treatment in the Context of Pneumonia

“…In the first one, ABIMMUNE, the lipopolysaccharide (LPS)-derived compound monophosphoryl lipid A (MPLA) was used in combination with amoxicillin (AMX) in order to treat mice infected with Streptococcus pneumoniae. This project is described in detail elsewhere [ 60 , 61 ], and the extensive pharmacometric analysis applied on the data can be found in a companion paper elsewhere in this issue [ 62 ].…”