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

Not Applicable

Recruiting

• Conditions: Pneumonia, Ventilator-Associated
• Interventions: Drug: Colistimethate sodium (CMS)

• Registration Number: NCT06834971
• Lead Sponsor: Qilu Hospital of Shandong University

Brief Summary

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.

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 Timeline

• Study First Submitted: 2025-02-13
• Study First Submitted QC: 2025-02-13
• Study First Posted: 2025-02-19
• Status Verified: 2025-04
• Study Start: 2025-04
• Last Update Submitted: 2025-04-12
• Last Update Posted: 2025-04-16
• Primary Completion: 2025-12
• Study Completion: 2026-03

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 476

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
CMS group	Colistimethate sodium (CMS)	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. Participants are expected to complete the entire 3-day intervention unless they meet any of the following criteria: extubation; development of stage 3 AKI (KDIGO) and is not scheduled to begin receiving renal replacement therapy; the attending physician determined that the patient's condition requ

Primary Outcome Measures

Name	Time	Method
The incidence of a first VAP episode from randomization to day 28	at 28 - day after randomization or the day of ICU discharge/death	calculated as the ratio of the number of patients diagnosed VAP divided by the number of randomized patients in each group

Secondary Outcome Measures

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

Trial Locations

Locations (1)

Qilu Hospital of Shandong university; 🇨🇳 Jinan, Shandong, China