PNEUmonia DOSing in Critically Ill Patients (PNEUDOS)

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.

Conditions

• Pneumonia

Interventions

OTHER

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

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

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.

DRUG

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.

Sponsors & Collaborators

• Royal Brisbane and Women's Hospital

  collaborator OTHER_GOV

• The Alfred

  collaborator OTHER

• University Hospital, Ghent

  collaborator OTHER

• Centre Hospitalier Universitaire de Nīmes

  collaborator OTHER

• Chinese University of Hong Kong

  collaborator OTHER

• University of Malaya

  collaborator OTHER

• International Islamic University Malaysia

  collaborator OTHER

• General Hospital of Larissa

  collaborator OTHER

• Central Hospital, Nancy, France

  collaborator OTHER

• Hospices Civils de Lyon

  collaborator OTHER

• The University of Queensland

  lead OTHER

Principal Investigators

• Jason A. Roberts, PhD · The University of Queensland

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2019-10-17

Primary Completion

2024-01-31

Completion

2024-01-31

FDA Drug

Yes

Countries

• Australia
• Belgium
• France
• Hong Kong
• Malaysia

Study Locations