PNEUmonia DOSing in Critically Ill Patients (PNEUDOS)

NCT04986254 | Completed FDA Drug

• 1 other identifier: PNEUDOS
• Study Type: observational
• Target: 179
• Locations: 5 countries
• Sites: 6

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.

Conditions

Pneumonia

Keywords

Pneumonia; Antibiotic dosing; Pharmacokinetic; Pharmacodynamic; Beta-lactam; Critically ill

Outcome Measures

Primary Outcomes (5)

• Volume of distribution (Vd) of benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam in ICU patients with pneumonia

  Population mean value of volume of distribution (Vd) in L/kg

  Days 1 - 6 of antibiotic therapy

• Drug clearance (CL) of benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam in ICU patients with pneumonia

  Population mean value of clearance (CL) in L/hr

  Days 1 - 6 of antibiotic therapy

• Optimised dosing regimens for benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam that maximise the achievement of effective plasma exposure in ICU patients with pneumonia

  Dosing regimens required to attain therapeutic concentrations in plasma will be evaluated using Monte Carlo dosing simulations. Therapeutic concentration is defined as concentrations above the minimum inhibitory concentration (MIC) of a pathogen for 100% of the dosing interval (100% T\>MIC) in plasma

  Days 1 - 6 of antibiotic therapy

• 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

  Dosing regimens required to attain therapeutic concentrations at the site of infection will be evaluated using Monte Carlo dosing simulations. Therapeutic concentration is defined as concentrations above the minimum inhibitory concentration (MIC) of a pathogen for 100% of the dosing interval (100% T\>MIC) in the epithelial lining fluid

  Days 1 - 6 of antibiotic therapy

• The effect of lung inflammation on beta-lactam antibiotic exposures

  To characterise the effects of beta-lactam (benzylpenicillin, ceftriaxone, meropenem and piperacillin/tazobactam) exposures in epithelial lining fluid on lung inflammation (using inflammatory cytokines/mediators) in ICU patients with pneumonia

  Days 1 - 6 of antibiotic therapy

Study Arms (4)

Benzylpenicillin

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

Other: Blood sampling; Other: Epithelial lining fluid sampling; Other: Urine sampling; Drug: Study antibiotics include benzylpenicillin, ceftriaxone, meropenem, and piperacillin/tazobactam

Ceftriaxone

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

Other: Blood sampling; Other: Epithelial lining fluid sampling; Other: Urine sampling; Drug: Study antibiotics include benzylpenicillin, ceftriaxone, meropenem, and piperacillin/tazobactam

Meropenem

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

Other: Blood sampling; Other: Epithelial lining fluid sampling; Other: Urine sampling; Drug: Study antibiotics include benzylpenicillin, ceftriaxone, meropenem, and piperacillin/tazobactam

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: Blood sampling; Other: Epithelial lining fluid sampling; Other: Urine sampling; Drug: Study antibiotics include benzylpenicillin, ceftriaxone, meropenem, and piperacillin/tazobactam

Interventions

Blood sampling OTHER

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.

Benzylpenicillin; Ceftriaxone; Meropenem; Piperacillin/tazobactam

Epithelial lining fluid sampling OTHER

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.

Benzylpenicillin; Ceftriaxone; Meropenem; Piperacillin/tazobactam

Urine sampling OTHER

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.

Benzylpenicillin; Ceftriaxone; Meropenem; Piperacillin/tazobactam

Study antibiotics include benzylpenicillin, ceftriaxone, meropenem, and piperacillin/tazobactam DRUG

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.

Benzylpenicillin; Ceftriaxone; Meropenem; Piperacillin/tazobactam

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

A critically ill patient in the ICU 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.

You may qualify if:

• Adult (≥18 years old) ICU patients
• Confirmed or suspected either community-acquired pneumonia, ventilator-associated pneumonia, aspiration pneumonia or a clinically diagnosed lung infection
• 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
• Patient is sedated and receiving mechanical ventilation
• Patient has arterial line and urinary catheter in situ for blood and urine samplings
• Informed consent to participate in the study

You may not qualify if:

• Suspected or known hypersensitivity towards beta-lactam antibiotics (pre- or post-enrolment)
• Receiving renal replacement therapy (RRT)
• Pregnant patients or lactating mothers
• Has received study antibiotic for more than 72 hours (at time of Occasion 1) during current infective episode.

Sponsors & Collaborators

• Royal Brisbane and Women's Hospital: collaborator
• University Hospital, Ghent: collaborator
• Centre Hospitalier Universitaire de Nīmes: collaborator
• General Hospital of Larissa: collaborator
• Central Hospital, Nancy, France: collaborator
• Hospices Civils de Lyon: collaborator
• The University of Queensland: lead
• The Alfred: collaborator
• Chinese University of Hong Kong: collaborator
• University of Malaya: collaborator
• International Islamic University Malaysia: collaborator

Study Sites (6)

Royal Brisbane and Women's Hospital

Brisbane, Australia

Location

The Alfred

Melbourne, Australia

Location

University Hospital, Ghent

Ghent, Belgium

Location

Centre Hospitalier Universitaire de Nimes

Nîmes, France

Location

Chinese University of Hong Kong

Hong Kong, Hong Kong

Location

University of Malaya

Kuala Lumpur, Malaysia

Location

Related Publications (1)

• 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.

  PMID: 32383061 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

For each participant, samples of blood, epithelial lining fluid, and urine will be collected over 1 dosing interval (within the specified sampling times and time-points) on two separate occasions

MeSH Terms

Conditions

Pneumonia; Critical Illness

Interventions

Blood Specimen Collection; Ceftriaxone; Meropenem; Piperacillin; Tazobactam

Condition Hierarchy (Ancestors)

Respiratory Tract Infections; Infections; Lung Diseases; Respiratory Tract Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques; Cefotaxime; Cephacetrile; Cephalosporins; beta-Lactams; Lactams; Amides; Organic Chemicals; Thiazines; Sulfur Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Thienamycins; Carbapenems; Ampicillin; Penicillin G; Penicillins; Penicillanic Acid; Sulfones

Study Officials

• Jason A. Roberts, PhD

  The University of Queensland

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 6, 2021
• First Posted: August 2, 2021
• Study Start: October 17, 2019
• Primary Completion: January 31, 2024
• Study Completion: January 31, 2024
• Last Updated: January 28, 2026

Record last verified: 2024-02

Locations

BE (1); FR (1); HK (1); AU (2); MY (1)