Tobramycin Nebulization to Prevent Multidrug-Resistant Ventilator-Associated Pneumonia

NCT07856355 | Not Yet Recruiting Phase 4 DMC

• 1 other identifier: 2026-0634
• Study Type: interventional
• Target: 574
• Locations: 1 country
• Sites: 1

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.

Conditions

Pneumonia, Ventilator-Associated

Keywords

Tobramycin; Inhaled Antibiotics; Antibiotic Prophylaxis; Ventilator-Associated Pneumonia; Multidrug-Resistant Bacteria; Invasive Mechanical Ventilation; Critically Ill Patients; Intensive Care Unit

Outcome Measures

Primary Outcomes (1)

• 28-Day Cumulative Incidence of Multidrug-Resistant Ventilator-Associated Pneumonia

  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.

  From randomization through Day 28.

Secondary Outcomes (16)

• Incidence Density of Multidrug-Resistant Ventilator-Associated Pneumonia

  From randomization through Day 28.

• 28-Day Incidence of Ventilator-Associated Pneumonia From Any Cause

  From randomization through Day 28.

• Systemic Antibiotic Use Expressed as Antibiotic-Days

  From randomization through Day 28.

• Days of Exposure to Systemic Antibiotics

  From randomization through Day 28.

• Duration of Mechanical Ventilation

  From randomization through Day 28.

Other Outcomes (6)

• Longitudinal Changes in Respiratory Microbiome Alpha Diversity

  Protocol-specified Days 1, 4, 7, and 14, with additional sampling at VAP onset.

• Longitudinal Changes in Respiratory Microbiome Beta Diversity

  Protocol-specified Days 1, 4, 7, and 14, with additional sampling at VAP onset.

• Longitudinal Changes in Antibiotic Resistance Gene Abundance

  Protocol-specified Days 1, 4, 7, and 14, with additional sampling at VAP onset.

Study Arms (2)

Nebulized Tobramycin

EXPERIMENTAL

Participants receive tobramycin inhalation solution, 300 mg in 5 mL per dose, administered through the endotracheal tube using a vibrating mesh nebulizer twice daily for 3 consecutive days (6 planned doses). The intervention is administered to prevent multidrug-resistant ventilator-associated pneumonia (MDR-VAP). Participants also receive standard ventilator-associated pneumonia (VAP) prevention measures.

Drug: Tobramycin inhalation solution

Nebulized 0.9% Sodium Chloride Placebo

PLACEBO COMPARATOR

Participants receive 5 mL of 0.9% sodium chloride solution (normal saline) as a placebo, administered through the endotracheal tube using a vibrating mesh nebulizer twice daily for 3 consecutive days (6 planned doses). Participants also receive standard ventilator-associated pneumonia (VAP) prevention measures.

Drug: 0.9% Sodium Chloride Placebo

Interventions

Tobramycin inhalation solution DRUG

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.

Nebulized Tobramycin

0.9% Sodium Chloride Placebo DRUG

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.

Nebulized 0.9% Sodium Chloride Placebo

Eligibility Criteria

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

You may qualify if:

• Age ≥18 years at enrollment.
• 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.
• At least one of the following risk factors for multidrug-resistant (MDR) bacterial infection:
• Exposure to systemic antibiotics for ≥24 hours within the 30 days before enrollment.
• 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.
• 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.
• Current renal replacement therapy, including continuous renal replacement therapy or intermittent hemodialysis.
• A history of MDR bacterial colonization or infection within the previous 12 months, documented by clinical culture.
• Written informed consent obtained from the patient or the patient's legally authorized representative.

You may not qualify if:

• Suspected or confirmed ventilator-associated pneumonia (VAP) on the day of enrollment, based on the attending physician's clinical judgment.
• Continuous invasive mechanical ventilation for more than 96 hours before enrollment.
• Planned extubation within the next 24 hours.
• Previous tracheostomy.
• A history of allergy to tobramycin or any other aminoglycoside antibiotic.
• 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.
• Expected survival of no more than 48 hours, as assessed by the attending physician.
• Pregnancy, indicated by a positive serum or urine human chorionic gonadotropin (hCG) test, or breastfeeding.
• Concurrent participation in another interventional clinical study involving nebulized antibiotics or other ventilator-associated pneumonia prevention interventions.

Sponsors & Collaborators

• Zhejiang Hospital: collaborator
• Zhejiang Provincial People's Hospital: collaborator
• Lishui Country People's Hospital: collaborator
• Jinhua People's Hospital: collaborator
• Second Affiliated Hospital of Wenzhou Medical University: collaborator
• Ningbo Medical Center Lihuili Hospital: collaborator
• Qilu Hospital of Shandong University: collaborator
• Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University: collaborator
• Zhengzhou Central Hospital: collaborator
• Second Affiliated Hospital of Nanchang University: collaborator
• West China Hospital: collaborator
• Weifang People's Hospital: collaborator
• Jinhua Central Hospital: collaborator
• RenJi Hospital: collaborator
• Taizhou Hospital: collaborator
• Second Affiliated Hospital, Zhejiang University, School of Medicine: lead
• First Affiliated Hospital of Zhejiang University: collaborator
• Sir Run Run Shaw Hospital: collaborator
• The Fourth Affiliated Hospital of Zhejiang University School of Medicine: collaborator
• The First People's Hospital of Huzhou: collaborator
• Shanghai Tongji Hospital, Tongji University School of Medicine: collaborator
• Huang Shan People's Hospital: collaborator
• People's Hospital of Quzhou: collaborator
• the second people's of kaifeng: collaborator

Study Sites (1)

Second Affiliated Hospital of Zhejiang University School of Medicine

Hangzhou, Zhejiang, 310000, China

Location

MeSH Terms

Conditions

Pneumonia, Ventilator-Associated

Condition Hierarchy (Ancestors)

Healthcare-Associated Pneumonia; Cross Infection; Infections; Pneumonia; Respiratory Tract Infections; Lung Diseases; Respiratory Tract Diseases; Iatrogenic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Central Study Contacts

Gensheng Zhang

CONTACT

+86 18806812331; genshengzhang@zju.edu.cn

Kai Zhang

CONTACT

+86 15150686177; zhangkai1993@zju.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: September 23, 2026
• First Posted: October 2, 2026
• Study Start (Estimated): October 7, 2026
• Primary Completion (Estimated): October 31, 2028
• Study Completion (Estimated): January 29, 2029
• Last Updated: October 2, 2026

Record last verified: 2026-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: Data and supporting documents will be available beginning 6 months after publication of the primary trial results and ending 5 years after that publication.
• Access Criteria: Access will be available to qualified researchers who submit a methodologically sound proposal for secondary analyses or individual participant data meta-analyses. Requests should be submitted to the principal investigator through the study contact listed in the trial registry. The principal investigator and the study Executive Committee will review the scientific merit, feasibility, and data-protection safeguards of each request. Approved applicants must sign a data use agreement limiting use to the approved research, prohibiting participant re-identification and unauthorized onward sharing, and requiring secure data storage. Data will be provided by secure electronic transfer after any required institutional, ethics, or regulatory approvals have been obtained.

Locations

CN (1)