Plasma Protein Binding and PK/PD of Total and Unbound Temocillin Non-ICU Patients
Status:
Unknown status
Trial end date:
2020-10-15
Target enrollment:
Participant gender:
Summary
Multidrug resistance towards Gram-negative pathogens makes essential the re-examination of
older compounds. Temocillin is a penicillin originally marketed in the 1980s but then largely
abandoned. It, however, shows a marked ß-lactamase stability (including most classical and
extended-spectrum TEM, SHV, CTX-M enzymes and AmpC ß-lactamase). Temocillin is approved for
the treatment of bacterial infections of the chest, the lungs, the kidney, the bladder, as
well as bacterial infections of the bloodstream and wound infections.
Temocillin efficacy depends primarily from the time interval during which the unbound plasma
concentration remains above the minimal inhibitory concentration (MIC) of the antibiotic
against the target organism(s). Unfortunately, no comprehensive pharmacokinetic data are
available in non-critically-ill patients.
The primary objective of the study is characterize the pharmacokinetics of total and unbound
temocillin in non-ICU patients, and, on this basis, to propose optimized dosage regimens in
this population. The secondary objectives are (i) to look for possible correlations between
the plasma protein profile and the unbound temocillin concentrations; (ii) to investigate the
impact of the level and nature of circulating plasma proteins on the unbound temocillin
concentration.
The study will be non-randomized, uncontrolled, prospective, open label, interventional, and
monocentric. It will include a population pharmacokinetic-pharmacodynamic analysis of the
data obtained. The study will enroll patients ≥ 18 years in need of a treatment with
temocillin for (i) complicated urinary tract infection and pyelonephritis (associated or not
with bacteremia), or (ii) lower respiratory tract infection, or (iii) abdominal infection,
and requiring ≥ 4 days of hospitalization. Blood samples will be obtained at day 0 (control)
and after 2 and 4 days of drug treatment (full pharmacokinetic evaluation over 8 to 12 h
post-administration). Total and unbound temocillin concentrations in plasma will be
quantified by a validated analytical method.
A population pharmacokinetic/pharmacodynamics model of plasma total and unbound
concentrations of temocillin will be obtained by Bayesian algorithms using Pmetrics software,
driven by the predicted plasma total and unbound concentration. The model will be used to
assess the probability of target attainment of temocillin.