Abstract
Temocillin is used for the treatment of various infections caused by Enterobacterales. The pharmacokinetic (PK)/pharmacodynamic (PD) index that is best correlated with the activity of beta-lactams is the percentage of time that the unbound concentration exceeds the MIC (%fT>MIC). However, the %fT>MIC needed for a bacteriostatic or killing effect of temocillin is unknown in thigh and lung infection models. In the present study, we studied the temocillin PK in plasma and epithelial lining fluid (ELF) of infected neutropenic mice and determined the plasma exposure-response relationships for Escherichia coli and Klebsiella pneumoniae. Neutropenic murine thigh and lung infection models were used. The bacterial loads in the thighs or lungs were determined. A sigmoid maximum-effect model was used to fit the plasma exposure-response relationship. A one-compartment model with first-order absorption best described temocillin PK (clearance [CL], 1.03 L/h/kg; volume of distribution [V], 0.457 L/kg). Protein binding was 78.2% ± 1.3% across different plasma concentrations. A static effect was achieved for all strains in both the thigh and lung infection models. However, the median %fT>MIC needed for a static effect was much lower in the lung infection model (27.8% for E. coli and 38.2% for K. pneumoniae) than in the thigh infection model (65.2% for E. coli and 64.9% for K. pneumoniae). A 1-log kill was reached for all strains in the lung infection model (median %fT>MIC values of 42.1% for E. coli and 44.1% for K. pneumoniae) and 7 out of 8 strains in the thigh infection model (median %fT>MIC values of 85.4% for E. coli and 74.5% for K. pneumoniae). These data support the use of temocillin in patients with pneumonia.