Clinical trial NCT06834971: Colistin Methanesulfonate Sodium Inhalation for Prophylaxis of Ventilator-Associated Pneumonia (CIVAP): A Prospective, Multicentre, Double-Blind, Randomized, Placebo-Controlled Trial
Official title: Colistin Methanesulfonate Sodium Inhalation for Prophylaxis of Ventilator-Associated Pneumonia (CIVAP): A Prospective, Multicentre, Double-Blind, Randomized, Placebo-Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Pneumonia, Ventilator-Associated
Keywords: colistin
prevention
nebulization
Lead sponsor: Qilu Hospital of Shandong University
Sponsor class: OTHER
First posted: 2025-02-19
Enrollment: 476
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

Eligibility criteria: 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 participating in other studies with inhaled or systemic antibiotics.

Primary outcomes:
measure: The incidence of a first VAP episode from randomization to day 28
timeFrame: at 28 - day after randomization or the day of ICU discharge/death
Secondary outcomes:
measure: incidence of a first MDR-VAP episode from randomization to day 28
timeFrame: at 28 - day after randomization or the day of ICU discharge/death
measure: Incidence density of adjudicated VAP from randomisation to day 28
timeFrame: at 28 - day after randomization or the day of ICU discharge/death
measure: Incidence of gram-negative bacteria-related VAP with in vitro susceptibility to CMS from randomisation to day 28
timeFrame: at 28 - day after randomization or the day of ICU discharge/death
measure: The number of antibiotic-days from randomisation to day 28
timeFrame: each day after after randomization or the day of ICU discharge/death
measure: The number of days of mechanical ventilation from randomization to day 28
timeFrame: at 28 - day after randomization or the day of ICU discharge/death
measure: The number of days in the ICU and hospital from randomization to day 90
timeFrame: from randomization to day 90
measure: Mortality at day 28 and 90
timeFrame: day 28- and day 90- after randomization or the day of ICU discharge/death
measure: Evaluation of nebulization safety and side effects, including nephrotoxicity, neurotoxicity, and bronchospasm from randomisation to day 28
timeFrame: at 28-day and 90-day after randomization
measure: Incidence of CMS-resistant bacteria in tracheobronchial aspirate (TBA) or blood from randomisation to day 28
timeFrame: at 28-day and 90-day after randomization
measure: Incidence of ventilator-associated events from randomisation to extubation or day 28, whichever occurs first
timeFrame: at 28 - day after randomization or the day of ICU discharge/death
Other outcomes:
Locations:
city: Jinan
country: China
facility: Qilu Hospital of Shandong university
state: Shandong
Study officials:
affiliation: Qilu Hospital of Shandong University
name: Wang Hao associate professor
role: STUDY_DIRECTOR
References:
citation: Wu Z, Zhang S, Cao Y, Wang Q, Sun K, Zheng X. Comparison of the clinical efficacy and toxicity of nebulized polymyxin monotherapy and combined intravenous and nebulized polymyxin for the treatment of ventilator-associated pneumonia caused by carbapenem-resistant gram-negative bacteria: a retrospective cohort study. Front Pharmacol. 2023 Aug 16;14:1209063. doi: 10.3389/fphar.2023.1209063. eCollection 2023.
citation: Povoa FCC, Cardinal-Fernandez P, Maia IS, Reboredo MM, Pinheiro BV. Effect of antibiotics administered via the respiratory tract in the prevention of ventilator-associated pneumonia: A systematic review and meta-analysis. J Crit Care. 2018 Feb;43:240-245. doi: 10.1016/j.jcrc.2017.09.019. Epub 2017 Sep 18.
citation: Lu Q, Luo R, Bodin L, Yang J, Zahr N, Aubry A, Golmard JL, Rouby JJ; Nebulized Antibiotics Study Group. Efficacy of high-dose nebulized colistin in ventilator-associated pneumonia caused by multidrug-resistant Pseudomonas aeruginosa and Acinetobacter baumannii. Anesthesiology. 2012 Dec;117(6):1335-47. doi: 10.1097/ALN.0b013e31827515de.
citation: Biswas S, Brunel JM, Dubus JC, Reynaud-Gaubert M, Rolain JM. Colistin: an update on the antibiotic of the 21st century. Expert Rev Anti Infect Ther. 2012 Aug;10(8):917-34. doi: 10.1586/eri.12.78.
citation: Yu Z, Qin W, Lin J, Fang S, Qiu J. Antibacterial mechanisms of polymyxin and bacterial resistance. Biomed Res Int. 2015;2015:679109. doi: 10.1155/2015/679109. Epub 2015 Jan 15.
citation: Zhang X, Cui X, Jiang M, Huang S, Yang M. Nebulized colistin as the adjunctive treatment for ventilator-associated pneumonia: A systematic review and meta-analysis. J Crit Care. 2023 Oct;77:154315. doi: 10.1016/j.jcrc.2023.154315. Epub 2023 Apr 28.
citation: Hu JN, Hu SQ, Li ZL, Bao C, Liu Q, Liu C, Xu SY. Risk factors of multidrug-resistant bacteria infection in patients with ventilator-associated pneumonia: A systematic review and meta-analysis. J Infect Chemother. 2023 Oct;29(10):942-947. doi: 10.1016/j.jiac.2023.06.008. Epub 2023 Jun 13.
citation: Ranzani OT, Niederman MS, Torres A. Ventilator-associated pneumonia. Intensive Care Med. 2022 Sep;48(9):1222-1226. doi: 10.1007/s00134-022-06773-3. Epub 2022 Jun 30. No abstract available.
citation: Xie J, Yang Y, Huang Y, Kang Y, Xu Y, Ma X, Wang X, Liu J, Wu D, Tang Y, Qin B, Guan X, Li J, Yu K, Liu D, Yan J, Qiu H. The Current Epidemiological Landscape of Ventilator-associated Pneumonia in the Intensive Care Unit: A Multicenter Prospective Observational Study in China. Clin Infect Dis. 2018 Nov 13;67(suppl_2):S153-S161. doi: 10.1093/cid/ciy692.
citation: Ding X, Ma X, Gao S, Su L, Shan G, Hu Y, Chen J, Ma D, Zhang F, Zhu W, Sun G, Meng X, Ma L, Zhou X, Liu D, Du B; China National Critical Care Quality Control Center Group. Effect of ICU quality control indicators on VAP incidence rate and mortality: a retrospective study of 1267 hospitals in China. Crit Care. 2022 Dec 29;26(1):405. doi: 10.1186/s13054-022-04285-6.
citation: Ehrmann S, Barbier F, Demiselle J, Quenot JP, Herbrecht JE, Roux D, Lacherade JC, Landais M, Seguin P, Schnell D, Veinstein A, Gouin P, Lasocki S, Lu Q, Beduneau G, Ferrandiere M, Plantefeve G, Dahyot-Fizelier C, Chebib N, Mercier E, Heuze-Vourc'h N, Respaud R, Gregoire N, Garot D, Nay MA, Meziani F, Andreu P, Clere-Jehl R, Zucman N, Azais MA, Saint-Martin M, Gandonniere CS, Benzekri D, Merdji H, Tavernier E; Reva and CRICS-TRIGGERSEP F-CRIN Research Networks. Inhaled Amikacin to Prevent Ventilator-Associated Pneumonia. N Engl J Med. 2023 Nov 30;389(22):2052-2062. doi: 10.1056/NEJMoa2310307. Epub 2023 Oct 25.
citation: Papazian L, Klompas M, Luyt CE. Ventilator-associated pneumonia in adults: a narrative review. Intensive Care Med. 2020 May;46(5):888-906. doi: 10.1007/s00134-020-05980-0. Epub 2020 Mar 10.
citation: Metersky ML, Kalil AC. Management of Ventilator-Associated Pneumonia: Guidelines. Infect Dis Clin North Am. 2024 Mar;38(1):87-101. doi: 10.1016/j.idc.2023.12.004.