Towards dose optimisation through pharcokinetic profiling of piperacillin/tazobactam in critically ill patients

Beta-lactams are the most prescribed group of antibiotics in critically ill
patients in Dutch intensive care units (ICUs). As suboptimal dosing is unwanted
both on an individual level in terms of outcome as well as on a larger scale
considering the emerging threat of antimicrobial resistance, ensuring an
optimal dosing strategy merits our utmost effort. Recent studies show that
conventional intermittent dosing of piperacillin-tazobactam (P/T), the most
frequently used β-lactam in our ICU, often leads to insufficient plasma
concentrations in the critical care setting. Considering the time-dependent
character of P/T, continuous dosing after a loading dose seems more logical,
with the potential of better target attainment and outcome. Literature
available in this field suggests this point. Given the unpredictable
pharmacokinetics of the critical care patient, building a robust
pharmacokinetic model on continuous dosing enabling reliable therapeutic drug
monitoring (TDM) will likely be of benefit.

Hypothesis: A reliable pharmacokinetic model can be made by assessing drug -
concentrations after starting treatment with P/T by continuous infusion in
critically ill patients. The purpose of this model will be, in a subsequent
study, to enable reliable real-time TDM of continuous P/T dosing in critically
ill patients to be introduced in our clinic optimizing treatment with P/T in
this patient category.

To assess piperacillin concentrations during continuous dosing of P/T in
critically ill patients; to determine PK variables, e.g. creatinine clearance,
leading to a predictive mathematical model enabling TDM and ideally
establishing better a priori dosing through tailoring; to assess
inter-individual variability in reaching a steady-state; to assess a
relationship between pharmacokinetic (PK) parameters and Acute Physiology and
Chronic Health Evaluation II (APACHE II) score; to assess target-attainment
based on concentration 4-5 times above a predefined Minimum Inhibitory
Concentration (MIC); to assess outcome in terms of ICU-mortality and mortality
at day 28; to assess outcome in terms of microbiological success (eradication
of P/T susceptible micro-organism) or failure (development of P/T resistence in
a priori susceptible micro-organism).

Prospective, Observational Single Center Cohort study.

Blood will be drawn on predefined time points after drug administration (t = 0,
t =20 min, 40 min, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours and every 12
hours onwards) at a quantity of 2 ml at a time through an arterial line placed
for reasons outside the study protocol. The patients are treated according to
the up-to-date standard of care on a recently proposed treatment protocol which
propagates the use of continuous infusion of P/T based on well established
pharmacokinetic and pharmacodynamic benefits, as alternative for intermittent
dosing. Its applicability, however, has not been unanimously adopted worldwide
possibly due to lack of evidence in clinical outcome studies; most studies in
this field are of small sample size, important case mix variation and resulting
poor level of evidence. All studies showed at least non-inferiority in the
continuous dosing treatment arm as compared to intermittent dosing. One study
showed better clinical outcome, as well as one using extended infusion dosing.
In the treatment group there is at least equipoise. For in-depth background
information we refer to addendum I, which is a review of available literature
in this field, and to chapter I of the protocol.