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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT04986254




Registration number
NCT04986254
Ethics application status
Date submitted
6/07/2021
Date registered
2/08/2021
Date last updated
2/08/2021

Titles & IDs
Public title
PNEUmonia DOSing in Critically Ill Patients (PNEUDOS)
Scientific title
A Multi-centre Study to Define Novel Individualised Dosing Regimens to Maximise Antibiotic Effectiveness for Treatment of Pneumonia in Intensive Care Units
Secondary ID [1] 0 0
PNEUDOS
Universal Trial Number (UTN)
Trial acronym
PNEUDOS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Condition category
Condition code
Respiratory 0 0 0 0
Other respiratory disorders / diseases
Infection 0 0 0 0
Other infectious diseases
Infection 0 0 0 0
Studies of infection and infectious agents

Intervention/exposure
Study type
Observational
Patient registry
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
Other interventions - Blood sampling
Other interventions - Epithelial lining fluid sampling
Other interventions - Urine sampling
Treatment: Drugs - Study antibiotics include benzylpenicillin, ceftriaxone, meropenem, and piperacillin/tazobactam

Benzylpenicillin - ICU patients receiving benzylpenicillin for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)

Ceftriaxone - ICU patients receiving ceftriaxone for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)

Meropenem - ICU patients receiving meropenem for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)

Piperacillin/tazobactam - ICU patients receiving piperacillin/tazobactam for confirmed/suspected community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically-diagnosed lung infection (n = 20)


Other interventions: 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. Blood samples will be collected on 2 separate occasions; Occasion 1, between Days 1 - 3 of antibiotic therapy and Occasion 2, between Days 3 - 6 of antibiotic therapy.

Other interventions: Epithelial lining fluid sampling
Epithelial lining fluid will be sampled using either a bronchoalveolar lavage (BAL) or mini-BAL technique, in accordance with the preferred procedure in participating sites. 3 BAL or mini-BAL samples will be collected over 2 separate occasions; Occasion 1, between Days 1 - 3 of antibiotic therapy and Occasion 2, between Days 3 - 6 of antibiotic therapy.

Other interventions: 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.

Treatment: Drugs: Study antibiotics include benzylpenicillin, ceftriaxone, meropenem, and 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.
Intervention code [1] 0 0
Other interventions
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Volume of distribution (Vd) of benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam in ICU patients with pneumonia
Timepoint [1] 0 0
Days 1 - 6 of antibiotic therapy
Primary outcome [2] 0 0
Drug clearance (CL) of benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam in ICU patients with pneumonia
Timepoint [2] 0 0
Days 1 - 6 of antibiotic therapy
Primary outcome [3] 0 0
Optimised dosing regimens for benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam that maximise the achievement of effective plasma exposure in ICU patients with pneumonia
Timepoint [3] 0 0
Days 1 - 6 of antibiotic therapy
Primary outcome [4] 0 0
Optimised dosing regimens for benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam that maximise the achievement of effective epithelial lining fluid exposure in ICU patients with pneumonia
Timepoint [4] 0 0
Days 1 - 6 of antibiotic therapy
Primary outcome [5] 0 0
The effect of lung inflammation on beta-lactam antibiotic exposures
Timepoint [5] 0 0
Days 1 - 6 of antibiotic therapy

Eligibility
Key inclusion criteria
1. Adult (=18 years old) ICU patients
2. Confirmed or suspected either community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically diagnosed lung infection
3. Patient has been prescribed or is receiving one of the study drugs (benzylpenicillin, ceftriaxone, meropenem, or piperacillin/tazobactam) for the treatment of pneumonia in the ICU
4. Patient is sedated and receiving mechanical ventilation
5. Patient has arterial line and urinary catheter in situ for blood and urine samplings
6. Informed consent to participate in the study
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Suspected or known hypersensitivity towards beta-lactam antibiotics (pre- or post-enrolment)
2. Receiving renal replacement therapy (RRT)
3. Pregnant patients or lactating mothers
4. Has received study antibiotic for more than 72 hours (at time of Occasion 1) during current infective episode.

Study design
Purpose
Duration
Selection
Timing
Prospective
Statistical methods / analysis

Recruitment
Recruitment status
UNKNOWN
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
17/10/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
31/12/2021
Actual
Sample size
Target
80
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
Recruitment hospital [1] 0 0
Royal Brisbane and Women's Hospital - Brisbane
Recruitment hospital [2] 0 0
The Alfred - Melbourne
Recruitment postcode(s) [1] 0 0
- Brisbane
Recruitment postcode(s) [2] 0 0
- Melbourne
Recruitment outside Australia
Country [1] 0 0
Belgium
State/province [1] 0 0
Ghent
Country [2] 0 0
France
State/province [2] 0 0
Nîmes
Country [3] 0 0
Hong Kong
State/province [3] 0 0
Hong Kong
Country [4] 0 0
Malaysia
State/province [4] 0 0
Kuala Lumpur

Funding & Sponsors
Primary sponsor type
Other
Name
The University of Queensland
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
Pneumonia is the most common infection in intensive care unit (ICU) patients and occurs in 10% of all ICU admissions. Unfortunately, ICU patient outcomes remain poor with a high mortality rate associated with pneumonia despite recent therapeutic advances.

Previous studies of antibiotics used in ICU patients, which includes ceftriaxone, meropenem and piperacillin/tazobactam, have quantified major differences in pharmacokinetics (PK) between ICU and non-ICU patients, with ICU patients displaying a unique spectrum of plasma concentration-time profiles. These PK differences can lead to suboptimal antibiotic concentrations in blood, which have been associated with a reduced likelihood of clinical cure for pneumonia. Furthermore, highlighting the importance of optimised dosing for pneumonia is that multi-drug resistant (MDR) pathogens emerge during antibiotic therapy in approximately half of the ICU patients, frequently emerging from the lung.

Previous work has highlighted how infection site concentrations determine patient outcome. For pneumonia, the infection site is best described as the epithelial lining fluid (ELF) in the lung.

Although optimal antibiotic therapy should be considered a priority for ICU patients with pneumonia to improve the persisting poor outcomes, the dosing regimens that can achieve therapeutic concentrations at the infection site (i.e., ELF) in ICU patients with pneumonia remain unknown.

The PNEUDOS study aims to address this significant knowledge gap by defining novel individualised dosing regimens that can maximise antibiotic efficacy by achieving therapeutic concentrations in the blood and ELF of ICU patients with pneumonia. These dosing regimens can then be validated in future clinical trials.
Trial website
https://clinicaltrials.gov/study/NCT04986254
Trial related presentations / publications
Abdul-Aziz MH, Alffenaar JC, Bassetti M, Bracht H, Dimopoulos G, Marriott D, Neely MN, Paiva JA, Pea F, Sjovall F, Timsit JF, Udy AA, Wicha SG, Zeitlinger M, De Waele JJ, Roberts JA; Infection Section of European Society of Intensive Care Medicine (ESICM); Pharmacokinetic/pharmacodynamic and Critically Ill Patient Study Groups of European Society of Clinical Microbiology and Infectious Diseases (ESCMID); Infectious Diseases Group of International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT); Infections in the ICU and Sepsis Working Group of International Society of Antimicrobial Chemotherapy (ISAC). Antimicrobial therapeutic drug monitoring in critically ill adult patients: a Position Paper. Intensive Care Med. 2020 Jun;46(6):1127-1153. doi: 10.1007/s00134-020-06050-1. Epub 2020 May 7.
Public notes

Contacts
Principal investigator
Name 0 0
Jason A. Roberts, PhD
Address 0 0
The University of Queensland
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Hafiz Abdul-Aziz, PhD
Address 0 0
Country 0 0
Phone 0 0
+61 7 334 65032
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/study/NCT04986254