Pneumonia, Ventilator-Associated
Conditions
Keywords
Tobramycin, Inhaled Antibiotics, Antibiotic Prophylaxis, Ventilator-Associated Pneumonia, Multidrug-Resistant Bacteria, Invasive Mechanical Ventilation, Critically Ill Patients, Intensive Care Unit
Brief summary
The TOP-MDRVAP trial will test whether inhaled tobramycin can safely prevent pneumonia caused by multidrug-resistant bacteria in adults who need a breathing machine. Tobramycin is an antibiotic. Multidrug-resistant bacteria are bacteria that resist treatment with several types of antibiotics. Pneumonia that develops in patients receiving breathing support through a breathing tube is called ventilator-associated pneumonia (VAP). This study will evaluate tobramycin as a preventive treatment, rather than as treatment for existing VAP. The study plans to enroll 574 adults aged 18 years or older in intensive care units (ICUs) at several hospitals. Participants must have received breathing support through a tube for 72 to 96 hours and be expected to need this support for at least another 72 hours. They must have at least one risk factor for infection with multidrug-resistant bacteria and must not have suspected or confirmed VAP when entering the study. Participants will be assigned by chance to one of two groups, with an equal chance of entering either group. One group will receive tobramycin inhalation solution, 300 mg in 5 mL, twice daily for 3 consecutive days. The other group will receive 5 mL of 0.9% saline, a saltwater solution containing no antibiotic, on the same schedule. A nebulizer will turn the solution into a fine mist delivered through the breathing tube. Both groups will receive standard measures to prevent VAP. Participants, their representatives, the healthcare professionals providing their direct care, and the researchers assessing outcomes will not know which study treatment each participant receives. The main question is whether fewer participants develop VAP caused by multidrug-resistant bacteria within 28 days after assignment to a study group. Researchers will also compare the occurrence of VAP from any cause, antibiotic use, time receiving breathing support, time spent in the ICU and hospital, and deaths within 28 and 90 days. Participants will be monitored for possible side effects, including kidney problems, narrowing of the airways, and complications involving the breathing tube or equipment. Samples will be tested for bacteria and antibiotic resistance. Follow-up will continue for up to 90 days after assignment, using hospital records or telephone contact to assess survival and recovery milestones, including discharge and the end of breathing support.
Interventions
Tobramycin inhalation solution (300 mg/5 mL) is administered at a dose of 300 mg (5 mL) twice daily for 3 consecutive days, for a total of 6 planned doses. The ready-to-use solution is administered without additional dilution through the endotracheal tube using a vibrating mesh nebulizer connected to the ventilator circuit. Each nebulization continues until the nebulizer reservoir is empty. The intervention is administered to prevent multidrug-resistant ventilator-associated pneumonia (MDR-VAP), in addition to standard VAP prevention measures.
A 5 mL dose of 0.9% sodium chloride solution (normal saline) is administered as a placebo twice daily for 3 consecutive days, for a total of 6 planned doses. The solution is delivered through the endotracheal tube using the same type of vibrating mesh nebulizer, administration schedule, and nebulization procedure as the tobramycin intervention. Each nebulization continues until the nebulizer reservoir is empty. Participants also receive standard VAP prevention measures.
Sponsors
Second Affiliated Hospital, Zhejiang University, School of Medicine
First Affiliated Hospital of Zhejiang University
Sir Run Run Shaw Hospital
The Fourth Affiliated Hospital of Zhejiang University School of Medicine
Zhejiang Hospital
Zhejiang Provincial People's Hospital
Lishui Country People's Hospital
Jinhua People's Hospital
The First People's Hospital of Huzhou
Second Affiliated Hospital of Wenzhou Medical University
Ningbo Medical Center Lihuili Hospital
Qilu Hospital of Shandong University
Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University
Zhengzhou Central Hospital
Second Affiliated Hospital of Nanchang University
West China Hospital
Shanghai Tongji Hospital, Tongji University School of Medicine
Weifang People's Hospital
Huang Shan People's Hospital
Jinhua Central Hospital
RenJi Hospital
People's Hospital of Quzhou
Taizhou Hospital
the second people's of kaifeng
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Participants are randomized in a 1:1 ratio to one of two parallel groups: nebulized tobramycin or nebulized 0.9% saline placebo. Both study interventions are administered twice daily for 3 consecutive days.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age ≥18 years at enrollment. 2. Invasive mechanical ventilation through an endotracheal tube for ≥72 hours and ≤96 hours, measured from the time of intubation, with an anticipated requirement for at least another 72 hours of invasive mechanical ventilation, as assessed by the attending physician. 3. At least one of the following risk factors for multidrug-resistant (MDR) bacterial infection: 3.1 Exposure to systemic antibiotics for ≥24 hours within the 30 days before enrollment. 3.2 Current hospitalization for at least 120 hours before randomization. 3.3 Septic shock requiring vasoactive medication to maintain a mean arterial pressure ≥65 mmHg, with a blood lactate level \>2 mmol/L. 3.4 Moderate-to-severe acute respiratory distress syndrome (ARDS), according to the Berlin definition, with a PaO2/FiO2 ratio ≤200 mmHg and positive end-expiratory pressure (PEEP) ≥5 cm H2O. 3.5 Current renal replacement therapy, including continuous renal replacement therapy or intermittent hemodialysis. 3.6 A history of MDR bacterial colonization or infection within the previous 12 months, documented by clinical culture. 4. Written informed consent obtained from the patient or the patient's legally authorized representative.
Exclusion criteria
1. Suspected or confirmed ventilator-associated pneumonia (VAP) on the day of enrollment, based on the attending physician's clinical judgment. 2. Continuous invasive mechanical ventilation for more than 96 hours before enrollment. 3. Planned extubation within the next 24 hours. 4. Previous tracheostomy. 5. A history of allergy to tobramycin or any other aminoglycoside antibiotic. 6. Use of tobramycin within the 7 days before enrollment; ongoing treatment with any aminoglycoside antibiotic at enrollment; or a clinical indication for intravenous treatment with any aminoglycoside antibiotic at enrollment. 7. Chronic kidney disease (stages 4-5) with a baseline estimated glomerular filtration rate (eGFR) ≤30 mL/min/1.73 m², or acute kidney injury meeting the protocol-specified Kidney Disease: Improving Global Outcomes (KDIGO) stage 3 criteria: serum creatinine increased to three times baseline, serum creatinine \>353.6 μmol/L, urine output \<0.3 mL/kg/hour for more than 24 hours, or anuria for more than 12 hours. Patients currently receiving renal replacement therapy are exempt from this renal exclusion criterion. 8. Expected survival of no more than 48 hours, as assessed by the attending physician. 9. Pregnancy, indicated by a positive serum or urine human chorionic gonadotropin (hCG) test, or breastfeeding. 10. Concurrent participation in another interventional clinical study involving nebulized antibiotics or other ventilator-associated pneumonia prevention interventions.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 28-Day Cumulative Incidence of Multidrug-Resistant Ventilator-Associated Pneumonia | From randomization through Day 28. | Percentage of randomized participants with a first episode of multidrug-resistant ventilator-associated pneumonia (MDR-VAP), adjudicated by an independent blinded endpoint adjudication committee. VAP develops after 48 hours of mechanical ventilation, including within 48 hours after weaning or extubation. Diagnosis requires new or progressive infiltrates, consolidation, or ground-glass opacities on chest X-ray or CT plus at least two of: temperature \>38°C, purulent airway secretions, and white blood cell count \>10 x 10\^9/L or \<4 x 10\^9/L. MDR-VAP additionally requires a positive quantitative lower respiratory tract culture (tracheal aspirate ≥10\^5 CFU/mL; bronchoalveolar lavage ≥10\^4 CFU/mL; protected specimen brush ≥10\^3 CFU/mL) with a causative bacterium resistant to at least three antimicrobial classes. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence Density of Multidrug-Resistant Ventilator-Associated Pneumonia | From randomization through Day 28. | Number of first episodes of multidrug-resistant ventilator-associated pneumonia per 1,000 invasive mechanical ventilation days accumulated during the assessment period. |
| 28-Day Incidence of Ventilator-Associated Pneumonia From Any Cause | From randomization through Day 28. | 28-Day Incidence of Ventilator-Associated Pneumonia From Any Cause |
| Systemic Antibiotic Use Expressed as Antibiotic-Days | From randomization through Day 28. | Cumulative systemic antibiotic use during the assessment period, expressed as antibiotic-days. |
| Days of Exposure to Systemic Antibiotics | From randomization through Day 28. | Number of days on which a participant receives at least one systemic antibiotic during the assessment period. Each day with systemic antibiotic exposure is counted once, regardless of the number of antibiotics administered. |
| Duration of Mechanical Ventilation | From randomization through Day 28. | Total duration of invasive and noninvasive mechanical ventilation, measured in days, during the assessment period. |
| Intensive Care Unit Length of Stay | From randomization to ICU discharge, assessed up to Day 90. | Duration of intensive care unit stay, measured in days from randomization to ICU discharge, with follow-up through Day 90. |
| Hospital Length of Stay | From randomization to hospital discharge, assessed up to Day 90. | Duration of hospital stay, measured in days from randomization to hospital discharge, with follow-up through Day 90. |
| 28-Day All-Cause Mortality | From randomization through Day 28. | Percentage of participants who die from any cause within 28 days after randomization. |
| 90-Day All-Cause Mortality | From randomization through Day 90. | Percentage of participants who die from any cause within 90 days after randomization. Survival status is obtained from hospital records or telephone follow-up. |
| Incidence of Ventilator-Associated Pneumonia Caused by Tobramycin-Susceptible Gram-Negative Bacteria | From randomization through Day 28. | Percentage of participants who develop ventilator-associated pneumonia caused by gram-negative bacteria that are susceptible to tobramycin on in vitro antimicrobial susceptibility testing. |
| Incidence of Ventilator-Associated Events | From randomization through Day 28. | Percentage of participants who develop a ventilator-associated event, assessed using the protocol-specified 2023 Centers for Disease Control and Prevention/National Healthcare Safety Network definitions. Assessments include ventilator-associated conditions, infection-related ventilator-associated complications, and possible ventilator-associated pneumonia. |
| Incidence of New-Onset Acute Kidney Injury | From randomization through Day 28. | Percentage of participants without acute kidney injury at baseline who develop Kidney Disease: Improving Global Outcomes (KDIGO) stage 1 or higher acute kidney injury during the assessment period. |
| Daily Trajectory of the Clinical Pulmonary Infection Score | Assessed daily from randomization until extubation or Day 28, whichever occurs first. | Daily Clinical Pulmonary Infection Score (CPIS) values and their longitudinal changes during the assessment period, calculated using available clinical data. |
| Time to First Successful Spontaneous Breathing Trial | From randomization through Day 28. | Time, measured in days, from randomization to the first successful spontaneous breathing trial (SBT) during the assessment period. |
| Detection Rate of Tobramycin-Resistant Bacteria | From randomization through Day 28. | Rate of isolation of tobramycin-resistant bacteria from respiratory specimens or blood cultures during the assessment period. |
| Composite Incidence of Serious Nebulization-Related Adverse Effects | From randomization through Day 28. | Percentage of participants experiencing at least one serious adverse effect related to nebulization, including increased expiratory filter resistance, bronchospasm, or endotracheal tube obstruction. |
Countries
China
Contacts
CONTACTGensheng Zhang
CONTACTKai Zhang
Outcome results
None listed