Hypotheses
The pharmacokinetics of benzylpenicillin, ceftriaxone, meropenem and
piperacillin/tazobactam are significantly different in ICU patients with pneumonia
when compared to those of non-ICU and non-infected patients.
Altered beta-lactam antibiotic dosing approaches, as opposed to "contemporary" or
"standard" dosing, are required for maximally effective blood (i.e., plasma) and
epithelial lining fluid beta-lactam exposures in ICU patients with pneumonia.
Beta-lactam antibiotic exposures in epithelial lining fluid influence levels of lung
inflammation in ICU patients with pneumonia.
Objective: The overall objective of this study is to characterise the plasma and
epithelial lining fluid pharmacokinetics of important antibiotics in ICU patients with
pneumonia to define optimal dosing regimens that maximise therapeutic outcomes.
Specific objectives
To describe the population pharmacokinetics of benzylpenicillin, ceftriaxone,
meropenem and piperacillin/tazobactam (in plasma, epithelial lining fluid and urine)
in ICU patients with pneumonia.
To design optimised dosing regimens for benzylpenicillin, ceftriaxone, meropenem and
piperacillin/tazobactam that maximise the achievement of effective epithelial lining
fluid exposures in ICU patients with pneumonia.
To characterise the effects of beta-lactam antibiotic (benzylpenicillin,
ceftriaxone, meropenem and piperacillin/tazobactam) exposures in epithelial lining
fluid on lung inflammation in ICU patients with pneumonia.
General design: This study is a prospective, open-labeled, multi-centre pharmacokinetic
study, which is designed to develop an individualised and optimal dosing regimen for
benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam in ICU patients with
pneumonia.
Patient recruitment: An ICU patient who is receiving either benzylpenicillin,
ceftriaxone, meropenem or piperacillin/tazobactam for confirmed/suspected
community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a
clinically diagnosed lung infection, who meets all the inclusion criteria and none of the
exclusion criteria will be considered for study participation.
Study antibiotics
The study antibiotics include:
Benzylpenicillin
Ceftriaxone
Meropenem
Piperacillin/tazobactam
Antibiotic dose and dosing interval will be determined by the treating clinician in
accordance to standard prescribing practices based on clinical assessment of the patient.
This study aims to recruit at least 20 participants per antibiotic.
Study procedures: For each antibiotic, samples of blood, epithelial lining fluid and
urine will be collected over one dosing interval (within the specified sampling times and
time-points) on two separate occasions; Occasion 1, between Days 1 - 3 of antibiotic
therapy and Occasion 2, between Days 3 - 6 of antibiotic therapy.
Blood sampling: During a single dosing interval, each participant will have 1 - 8 blood
samples taken for each antibiotic. Blood samples (3 mL each) will be drawn from an
existing arterial line or central venous catheter into heparinised tubes within the
specified sampling times and time-points, in accordance with the method of antibiotic
administration and dosing interval (i.e. intermittent infusion, extended infusion or
continuous infusion).
Epithelial lining fluid sampling: Epithelial lining fluid will be sampled using either a
bronchoalveolar lavage or mini-bronchoalveolar lavage technique, in accordance with the
preferred procedure in participating sites. Where possible, epithelial lining fluid
sampling will be performed on the same days and times as the blood sampling. Three
bronchoalveolar lavage or mini-bronchoalveolar lavage samples will be collected over the
two sampling occasions; Occasion 1, between Days 1 - 3 of antibiotic therapy and Occasion
2, between Days 3 - 6 of antibiotic therapy.
Urine sampling: The total urine volume over the duration of the dosing interval will be
collected on the two sampling occasions for a calculated urinary creatinine clearance
measurement.
Inflammatory cytokines/mediators in blood and epithelial lining fluid: Quantification of
systemic and lung inflammation by measuring inflammatory cytokines/mediators such as
C-reactive protein (CRP), interleukin-8 (IL-8), procalcitonin (PCT) and tumor necrosis
factor-α (TNF-α) in blood and epithelial lining fluid will occur on sampling Occasion 1
and then again on Occasion 2. These samples will be used to determine CRP, IL-8, PCT and
TNF-α, CRP and PCT levels.
Microbiological cultures: Bronchoalveolar lavage, blood or urine samples sent to the
microbiology laboratory for culture as part of routine clinical care will be used to
identify relevant causative organism(s) and drug susceptibility. Isolates of the
identified causative organism will be transferred to the reference microbiological
laboratory, University Queensland Centre for Clinical Research (UQCCR) at the University
of Queensland so that the organism's minimum inhibitory concentration (MIC) can be
determined using the broth microdilution and/or epsilometer test (Etest) methods,
depending on clinical usage at the time of analysis.
Bioanalysis: Total and free drug concentrations in epithelial lining fluid, plasma and
urine will be measured by a validated ultra-high performance liquid chromatography tandem
mass spectrometry (UHPLC-MS/MS) method on a Nexera2 UHPLC system coupled to a 8050 triple
quadruple mass spectrometer (Shimadzu Corporation, Kyoto, Japan). Bioanalysis will be
conducted in accordance with U.S FDA guidance for industry on bioanalysis. Inflammatory
cytokine/mediators will be measured by enzyme-linked immunosorbent assay (ELISA).
Bioanalysis of samples will be conducted by Central Bioanalysis Laboratory at UQCCR, the
University of Queensland.
Data collection: Data collection will be performed by trained personnel in the ICU and
the data will be entered into an electronic case report form. The following
parameters/variables will be collected from the patient medical record: (1) baseline
variables; (2) ICU-related variables; (3) microbiological data; and (4) post-ICU
variables (e.g. clinical cure on day of cessation of study antibiotic or at Day 14
post-enrolment).
Pharmacometric analysis plan Primary pharmacokinetic parameters (volume of distribution,
Vd and clearance, CL) will be estimated. An attempt will be made to correlate any
differences in these primary pharmacokinetics parameters between patients, with clinical
and demographic characteristics of the patient. Variability in antibiotic dosing,
infusion rates and sampling times will be accounted for by pharmacometric analyses and
the software used to perform the analysis. Different dosing regimens, with various
degrees of organ function and clinical characteristics, required to attain therapeutic
concentrations at the site of infection will be evaluated using Monte Carlo dosing
simulations.
