Colistin Methanesulfonate Sodium Inhalation for Prophylaxis of Ventilator-Associated Pneumonia (CIVAP): A Prospective, Multicentre, Double-Blind, Randomized, Placebo-Controlled Trial (CIVAP)

May 16, 2026 updated by: Wang Hao, Qilu Hospital of Shandong University
Previous studies have identified Acinetobacter baumannii (AB), Pseudomonas aeruginosa (PA), and Klebsiella pneumoniae (KP) as the predominant pathogens responsible for ventilator-associated pneumonia (VAP). The challenge of drug resistance, especially against carbapenem is intensifying, with variations noted across different regions. Multidrug-resistant organisms associated VAP (MDR-VAP) are increasing in frequency and are associated with significant morbidity, mortality, therefore imposes a heavy burden on the healthcare system. Colistin methanesulfonate sodium (CMS) has shown effectiveness against gram-negative bacteria, including carbapenem-resistant organisms (CRO) such as carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Pseudomonas aeruginosa (CRPA), and carbapenem-resistant Klebsiella pneumoniae (CRKP). This trial aims to evaluate the efficacy of a 3-day course of inhaled CMS in lowering the incidence of VAP among patients undergoing invasive mechanical ventilation for at least two days and at high risk of MDR-VAP.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

Detailed Description

Ventilator-Associated Pneumonia (VAP) is defined as pneumonia that develops 48-72 hours or more following the initiation of mechanical ventilation. It is a critical infection acquired in the Intensive Care Unit (ICU), significantly contributing to increased mortality rates, extended ICU stays, and elevated healthcare costs for patients on ventilators[1]. VAP is reported to affect 5-40% of patients receiving mechanical ventilation, with an average incidence of 20-25%. This proportion has been exacerbated in recent years by the COVID-19 pandemic[2-4]. A meta-analysis encompassing 195 studies found that the overall cumulative incidence of VAP in mainland China is 23.8% (95% CI 20.6-27.2%)[5].

Numerous risk factors, such as prolonged mechanical ventilation, advanced age, supine body position, prior antibiotic use, and various comorbidities, in addition to the endotracheal intubation itself, have been associated with the development of VAP[6, 7]. VAP results from the invasion of pulmonary parenchyma by pathogenic bacteria, which overwhelm the host's weakened defense capability. The primary sources of these bacteria include oropharyngeal colonization, secretions around the endotracheal tube cuff, and biofilm formation on the tracheal tube. The infectious process initiates at the time of intubation and progresses over several days. Reports indicate that the daily risk of VAP peaks between days 5 and 9 of incubation, underscoring the need for early preventive measures[8]. Despite decades of research highlighting interventions such as patient positioning adjustments, daily awakening and weaning protocols, oral decontamination, and systemic antibiotics to reduce VAP incidence, the burden remains unacceptably high.

Systemic antibiotics are commonly used for both treatment and prevention of VAP. However, the risk of resistant bacteria selection is a significant concern. A meta-analysis of six trials indicated that prophylactic antibiotics administered via nebulization effectively reduced VAP occurrence without increasing the risk of multidrug resistant (MDR) pathogen-related VAP[9]. Another Meta-Analysis consisting seven RCTs also confirmed that pro- phylactic antibiotics delivered via the respiratory tract reduced the risk of VAP, particularly for those treated with nebulized aminoglycosides[10]. Additionally, a short course of aerosolized ceftazidime significantly decreased VAP frequency in critically ill trauma patients without adversely affecting bacterial pathogen profiles and sensitivity patterns[11]. Recently, a study of 3-day course of inhaled amikacin was shown to effectively reduce the incidence of VAP[12, 13]. Stephan Ehrmann's team confirmed the possibility of inhaled amikacin to lessen the VAP burden during a 28-day follow-up period. This study provides us with excellent inspiration and suggests promising prospects for the use of nebulized antibiotics in preventing VAP. However, there are still more than 10% of patients who have amikacin resistance that can not be covered among all participants and the burden of MDR-VAP has becoming increasingly heavy with variations across different regions. Data from China Antimicrobial Surveillance Network (CHINET 2024) shows the resistance rates of Acinetobacter baumannii (AB), Klebsiella pneumoniae (KP), and Pseudomonas aeruginosa (PA) to amikacin are 49.5%, 15.5%, and 3.4%, respectively. In contrast, the resistance rates of carbapenem-resistant Acinetobacter baumannii (CRAB), carbapenem-resistant Klebsiella pneumoniae (CRKP), and carbapenem-resistant Pseudomonas aeruginosa (CRPA) to amikacin are as high as 77.4%, 67.1%, and 11.4%, respectively.

Given the effectiveness of CMS against gram-negative bacteria including carbapenem-resistant organisms (CRO), we are optimistic about the potential of nebulized CMS inhalation to prevent VAP. So we designed the study to evaluate the efficacy and safety of prophylactic CMS nebulization in preventing VAP among incubated patients at high risk of MDR-VAP. We hypothesize that administering a 3-day course of pre-emptive inhaled CMS after 2 days of ventilation will reduce the subsequent incidence of VAP.

Study Type

Interventional

Enrollment (Estimated)

508

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • China
    • Shandong
      • Jinan, Shandong, China, 250000
        • Recruiting
        • Qilu Hospital of Shandong University
        • Contact:
        • Principal Investigator:
          • Wang Hao associate professor

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

Participants will be enrolled if they meet the following criteria:

  1. Age ≥18 years;
  2. Mechanical ventilation for more than two consecutive days (48 hours);
  3. Patient has high-risk factors for multidrug-resistant bacterial infections, which meet any of the following criteria:

(1)History of antibiotic exposure within 30 days; (2)Hospitalization time>5 days (120 hours); (3)Septic shock; (4) ARDS; (5)Accept renal replacement therapy; (6)Previous colonization of multidrug-resistant bacteria; 4. Informed consent of the patient or a proxy was written.

Participants will be excluded in case of:

  1. Suspected or confirmed VAP at the inclusion day;
  2. Patient ventilated through an endotracheal tube for more than four consecutive days (96 hours);
  3. Expected that endotracheal intubation will be removed within the next 24 hours;
  4. Tracheostomy;
  5. Allergy to CMS;
  6. Patients has polymyxins medication history within 7 days or clinical indication for systemic CMS therapy at the inclusion day;
  7. Chronic kidney failure with baseline glomerular filtration ≤30 mL/min or Stage 3 classification AKI (KDIGO) (excluding patients undergoing renal replacement therapy);
  8. Expected survival time not exceeding 48 hours;
  9. Pregnancy or breastfeeding period;
  10. Patients previously included in this study or are using any inhaled antibiotics or are participating in other clinical studies within 30 days.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Prevention
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Quadruple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: CMS group
Participants were randomly assigned to receive either CMS (75mg caculated as colistin base activity(CBA), solubilized in 4 mL 0.9% saline) twice daily. Nebulization will be performed using a vibrating mesh nebulizer (Aeroneb solo, Aerogen, Galway, Ireland) placed in the inspiratory limb of the ventilator tubing, behind the Y-piece, and continued until the nebulizer deposit becomes dry for three consecutive days of mechanical ventilation. To ensure the experiment is conducted under blind conditions, the Nebulizer will be covered with an opaque protective cover. A filter will be placed on the expiratory limb to protect the ventilator.
Drug: Colistimethate sodium (CMS)
CMS (colistimethate sodium, 75mg, solubilized in 4 mL 0.9% saline), twice daily. Nebulization will be performed using a vibrating mesh nebulizer (Aeroneb solo, Aerogen, Galway, Ireland) placed in the inspiratory limb of the ventilator tubing, behind the Y-piece, and continued until the nebulizer deposit becomes dry for three consecutive days of mechanical ventilation. To ensure the experiment is conducted under blind conditions, the Nebulizer will be covered by stickers. A filter will be placed on the expiratory limb to protect the ventilator.
No Intervention: NS group
Participants were randomly assigned to receive equivalent volume of 0.9% saline (NS group), twice daily. Nebulization will be performed using a vibrating mesh nebulizer (Aeroneb solo, Aerogen, Galway, Ireland) placed in the inspiratory limb of the ventilator tubing, behind the Y-piece, and continued until the nebulizer deposit becomes dry for three consecutive days of mechanical ventilation. To ensure the experiment is conducted under blind conditions, the Nebulizer will be covered with an opaque protective cover. A filter will be placed on the expiratory limb to protect the ventilator.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The incidence of a first VAP episode from randomization to day 28
Time Frame: from randomization to day 28
calculated as the ratio of the number of patients diagnosed VAP divided by the number of randomized patients in each group
from randomization to day 28

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The number of days in the ICU and hospital from randomization to day 90
Time Frame: from randomization to day 90
the number of days in the ICU and the hospital
from randomization to day 90
incidence of a first MDR-VAP episode from randomization to day 28
Time Frame: from randomization to day 28
Calculated as the ratio of the number of patients diagnosed VAP divided by the number of randomized patients in each group
from randomization to day 28
Incidence density of adjudicated VAP from randomisation to day 28
Time Frame: from randomization to day 28
per 1000 patient-days of invasive mechanical ventilation
from randomization to day 28
Incidence of gram-negative bacteria-related VAP with in vitro susceptibility to CMS from randomisation to day 28
Time Frame: from randomization to day 28
the incidence of ventilator-associated pneumonia due to gram-negative bacteria with in vitro susceptibility to colistin
from randomization to day 28
The number of antibiotic-days from randomisation to day 28
Time Frame: from randomization to day 28
the sum of the number of systemic antibiotic treatments received each day
from randomization to day 28
The number of days of mechanical ventilation from randomization to day 28
Time Frame: from randomization to extubation or day 28, whichever occurs first
the number of days of mechanical ventilation
from randomization to extubation or day 28, whichever occurs first
Mortality at day 28 and 90
Time Frame: from randomization to day 28 and day 90
Mortality at 28- and 90-day after randomization
from randomization to day 28 and day 90
Evaluation of nebulization safety and side effects from randomisation to day 28
Time Frame: from randomization to day 28
Evaluation of nebulization safety and side effects: nephrotoxicity, neurotoxicity, and bronchospasm
from randomization to day 28
Incidence of CMS-resistant bacteria in tracheobronchial aspirate (TBA) or blood from randomisation to day 28
Time Frame: from randomization to day 28
incidence of colistin-resistant bacteria in tracheobronchial aspirate (TBA) or blood
from randomization to day 28
Incidence of ventilator-associated events from randomisation to extubation or day 28, whichever occurs first
Time Frame: from randomization to extubation or day 28, whichever occurs first
Incidence of ventilator-associated events， including ventilator-associated conditions (VACs), infection-related ventilator associated complications (IVACs), and possible VAP (PVAP).
from randomization to extubation or day 28, whichever occurs first
incidence of a first microbiologically confirmed VAP episode from randomization to day 28
Time Frame: from randomization to day 28
from randomization to day 28

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Qilu Hospital of Shandong University

Investigators

  • Study Director: Hao Wang, Professor, Qilu Hospital of Shandong University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 15, 2025

Primary Completion (Estimated)

September 1, 2026

Study Completion (Estimated)

December 1, 2026

Study Registration Dates

First Submitted

February 13, 2025

First Submitted That Met QC Criteria

February 13, 2025

First Posted (Actual)

February 19, 2025

Study Record Updates

Last Update Posted (Actual)

May 19, 2026

Last Update Submitted That Met QC Criteria

May 16, 2026

Last Verified

May 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Qilu Wang Hao

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Study protocol and informed consent form will be shared with other researchers when start this trial.

IPD Sharing Time Frame

Study protocol and ICF will be shared with other researchers when start this trial for five years.

IPD Sharing Access Criteria

Ever researchers can access our study protocol and ICF from the web of clinical trials.gov.

IPD Sharing Supporting Information Type

  • STUDY_PROTOCOL
  • ICF

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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