Defining Antibiotic Treatment Duration for Ventilator - Associated Lung Infection

• Status: Recruiting
• Trial end date: 2022-10-01
• Target enrollment: 0
• Participant gender: All

Summary

Intensive care units (ICUs), with high antibiotic consumption, are epicentres of antimicrobial resistance (AMR). Ventilator associated pneumonia (VAP) is the commonest hospital-acquired infection (HAI) in ICUs and is associated with a high morbidity and mortality in these vulnerable patients despite antibiotic therapy. No well-designed clinical trials studying antibiotic duration for VAP caused by predominantly non-fermenting Gram-negative bacteria have been conducted to date. Shortening antibiotic duration has the potential to improve individual patient outcomes and indirectly benefit other patients by reducing the selection pressure for multidrug resistant (MDR) bacteria within the ICU.

The study aims to demonstrate clinical non-inferiority-superiority of a short duration of antibiotics (up to 7 days) versus prolonged antibiotic therapy (as per physician preference) in adults with VAP in Asia. Patients who have been ventilated for more than 48 hours will be screened daily for signs and symptoms of VAP according to the US Centers for Disease Control and Prevention VAP criteria. Recruited patients will be reviewed daily for clinical signs of stability including temperature <38°C for 48 hours, systolic blood pressure >90mmHg without inotropes. Recruited patients will be randomised once they fulfill these clinical criteria of stability. In the intervention arm, antibiotics should be stopped within 7 days once the above criteria are fulfilled. In the control arm, antibiotics should be at least 7 days with the exact duration decided by the managing physicians.

The primary outcome of the study is a combined endpoint of mortality and VAP recurrence at day 60 of recruitment. The study hypothesis is that a shorter duration of treatment for VAP (7 days or less depending on clinical response) is not only noninferior, but may also be superior to a longer duration (8 days or more). The secondary outcomes of the study include clinical parameters such as rate of acquisition of MDRO hospital-acquired infections, duration of ventilation and hospitalization and days of antibiotics use. The study team will also characterise the microbiome changes in study participants according to the type and duration of antibiotics. MDROs collected will undergo whole genome sequencing for transmission dynamics study. The study is a multinational multicenter study involving hospitals in Asia.

• Phase: Phase 3
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Oxford
• Collaborators: Department for International Development, United Kingdom; Mahidol Oxford Tropical Medicine Research Unit; Medical Research Council
• Treatments: Anti-Bacterial Agents; Antibiotics, Antitubercular

Criteria

Inclusion Criteria:

1. Patients 18 years and older

2. Invasive mechanical ventilation ≥ 48 hours

3. Satisfy the US Centers for Disease Control and Prevention National Healthcare Safety Network VAP diagnostic criteria

• At least one of the following:

1. temperature > 38 °C

2. white blood cell count ≥ 12,000 cells/mm3 or ≤ 4,000 cells/mm3

3. altered mental status with no other causes in >70 year-olds; AND

• Two or more chest imaging tests demonstrating at least one of the following:

1. new and progressive OR progressive and persistent infiltrate

2. new and persistent OR progressive and persistent consolidation

3. new and persistent OR progressive and persistent cavitation, AND

• At least two of the following:

1. new onset of purulent sputum, or change in character of sputum, or increased respiratory secretions, or increased in suctioning requirements

2. new onset or worsening tachypnea or dyspnea

3. rales or bronchial breath sounds

4. worsening gas exchange defined by oxygen desaturations (e.g., PaO2/FiO2 <240), increased oxygen requirements or increased ventilation demand

Exclusion Criteria:

1. Poor likelihood of survival as defined by a Sepsis-related Organ Failure Assessment score (SOFA score) of >11 points

2. Immunocompromised patients (HIV with CD4 <200 cells/mm3, corticosteroids> 0.5 mg/kg per day for > 30 days, received chemotherapy in the past 3 months, solid organ or hematopoietic cell transplant)

3. Patients receiving antibiotic therapy for any other defined extra-pulmonary infections that warrant a duration of antibiotics longer than 7 days, or complications of pneumonia such as lung abscess or empyema, that warrant a duration of antibiotics longer than 7 days (excluding anti-tuberculosis treatment, antifungal medications, antibiotics meant for chronic suppression of chronic infections or chronic obstructive lung disease)

4. Patients who have been treated for VAP for more than 7 days from screening

5. Vulnerable population including prisoners and refugees