TY - JOUR
T1 - Variable temocillin protein binding and pharmacokinetics in different clinical conditions
T2 - Implications for target attainment
AU - Li, Letao
AU - Ngougni Pokem, Perrin
AU - Sassen, Sebastiaan D.T.
AU - Wittebole, Xavier
AU - Laterre, Pierre François
AU - Vervaeke, Steven
AU - Zeitlinger, Markus
AU - Van Bambeke, Françoise
AU - Muller, Anouk E.
N1 - Publisher Copyright:
© 2025 British Pharmacological Society.
PY - 2025/1/22
Y1 - 2025/1/22
N2 - Aims: The beta-lactam antibiotic temocillin is increasingly used to treat extended-spectrum beta-lactamase (ESBL-producing) strains; however, its protein binding is complex. This study aims to predict unbound temocillin concentrations in various participant groups to determine its impact on the probability of target attainment (PTA) and to improve dosing recommendations. Methods: The plasma pharmacokinetics were analysed using non-linear mixed-effects modelling. Data from individuals in four groups: healthy volunteers (HV), urinary tract infection patients (UTI), ventriculitis patients and sepsis-ICU patients were included. Simulations were performed to compare the PTA for different dosing regimens and participant-groups. Results: A two-compartment protein-binding model best fitted the 1085 concentrations (543 unbound, 542 total). Temocillin clearance was influenced by creatinine clearance, serum albumin (ALB) and C-reactive protein (CRP). For 2 g q8h intermittent infusion, the PTAs at an MIC of 16 mg/L were 2.3%, 39.5%, 10.0% and 72.5%, for HV, UTI, ventriculitis and sepsis-ICU patients, respectively. The effects of the covariates on the PTA were simulated for two example patients with intermittent infusion: the PTAs at an MIC of 8 mg/L for a sepsis-ICU patient (CRP 300 mg/L, albumin 15 g/L) and a mild-UTI patient (CRP 30 mg/L, albumin 35 g/L) were 94.3% and 62.4%, respectively. Continuous infusion consistently outperformed intermittent infusion in achieving the desired pharmacodynamic target (time above MIC).Conclusions: Our study underscores the significant variation in temocillin clearance and unbound fractions among different participant groups, challenging the efficacy of traditional 2 g q12h dosing. For patients with enhanced renal function and lower inflammation, continuous infusion emerges as a more effective strategy to achieve optimal target attainment.
AB - Aims: The beta-lactam antibiotic temocillin is increasingly used to treat extended-spectrum beta-lactamase (ESBL-producing) strains; however, its protein binding is complex. This study aims to predict unbound temocillin concentrations in various participant groups to determine its impact on the probability of target attainment (PTA) and to improve dosing recommendations. Methods: The plasma pharmacokinetics were analysed using non-linear mixed-effects modelling. Data from individuals in four groups: healthy volunteers (HV), urinary tract infection patients (UTI), ventriculitis patients and sepsis-ICU patients were included. Simulations were performed to compare the PTA for different dosing regimens and participant-groups. Results: A two-compartment protein-binding model best fitted the 1085 concentrations (543 unbound, 542 total). Temocillin clearance was influenced by creatinine clearance, serum albumin (ALB) and C-reactive protein (CRP). For 2 g q8h intermittent infusion, the PTAs at an MIC of 16 mg/L were 2.3%, 39.5%, 10.0% and 72.5%, for HV, UTI, ventriculitis and sepsis-ICU patients, respectively. The effects of the covariates on the PTA were simulated for two example patients with intermittent infusion: the PTAs at an MIC of 8 mg/L for a sepsis-ICU patient (CRP 300 mg/L, albumin 15 g/L) and a mild-UTI patient (CRP 30 mg/L, albumin 35 g/L) were 94.3% and 62.4%, respectively. Continuous infusion consistently outperformed intermittent infusion in achieving the desired pharmacodynamic target (time above MIC).Conclusions: Our study underscores the significant variation in temocillin clearance and unbound fractions among different participant groups, challenging the efficacy of traditional 2 g q12h dosing. For patients with enhanced renal function and lower inflammation, continuous infusion emerges as a more effective strategy to achieve optimal target attainment.
UR - http://www.scopus.com/inward/record.url?scp=85215666972&partnerID=8YFLogxK
U2 - 10.1111/bcp.16397
DO - 10.1111/bcp.16397
M3 - Article
C2 - 39840787
AN - SCOPUS:85215666972
SN - 0306-5251
JO - British Journal of Clinical Pharmacology
JF - British Journal of Clinical Pharmacology
ER -