Abstract
Background
Polymyxins are regarded as the last-resort antibiotics for treating resistant Gram-negative bacteria. Colistimethate sodium (CMS) is commonly used for carbapenem-resistant organism (CRO)-induced pulmonary infection. However, the polycationic/hydrophilic structure of intravenous injection (IV-CMS) limits its penetration into lung parenchyma, whereas aerosol inhalation (AER-CMS) has high alveolar penetration and minimal systemic dispersion. Currently, post-marketing monitoring of the clinical efficacy and safety of IV + AER CMS is limited. We aimed to evaluate the efficacy and safety of IV + AER CMS (Tianyun®; Chiatai Tianqing Pharma Jiangsu, China) in the treatment of CRO-induced pulmonary infections.
Methods
This is a multi-center retrospective study. Patients with CRO-induced pulmonary infection who received IV + AER CMS/IV-CMS alone between 2021 and 2023 were enrolled. The primary endpoint was clinical response rate, and secondary endpoints included clinical cure rate, length of stay, mortality, and incidence of adverse events (pigmentation, hypersensitivity, renal toxicity, neurotoxicity, and bronchospasm).
Results
There were 101 patients in IV + AER CMS group and 108 patients in IV-CMS group. The clinical response rate in IV + AER CMS group was significantly higher than that in IV-CMS group (78.57% vs. 60.00%, p = 0.017). There were no significant differences in clinical cure rate, length of stay and 28-day all-cause mortality between two groups. No significant differences in the incidence of adverse events were observed between two groups.
Conclusions
The clinical response rate of IV + AER CMS for CRO-induced pulmonary infection is higher than that of IV-CMS and no increased risk of renal toxicity, demonstrating good tolerability of AER-CMS in clinical practice.
Supplementary Information
The online version contains supplementary material available at https://doi.org/10.1186/s12941-026-00863-6.
Keywords: Colistimethate sodium, Carbapenem-resistant organism, Pulmonary infection, Polymyxins, Clinical response rate
Introduction
In recent years, the widespread use of broad-spectrum antibiotics in healthcare facilities and the inadequate implementation of effective measures to manage nosocomial infections have contributed to the growing problem of antimicrobial resistance in patients, particularly carbapenem resistance, which poses a significant challenge to global public health [1, 2]. According to the Centers for Disease Control and Prevention (CDC) in the United States, carbapenem-resistant organisms (CROs) are classified as “urgent threats” [3–5]. CROs, including carbapenem-resistant Enterobacterale (CRE), carbapenem-resistant Pseudomonas aeruginosa (CRPA), carbapenem-resistant Klebsiella pneumoniae (CRKP), and carbapenem-resistant Acinetobacter baumannii (CRAB), are prevalent in patients with hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) and have the highest incidence rates in intensive care unit (ICU) settings [6–10]. According to the “WHO Bacterial Priority Pathogens List 2024”, CRE and CRPA are identified as pathogens in the critical group with the highest threat to public health due to limited treatment options and high disease burden [11]. Therapeutic options for CROs are severely limited, with high levels of resistance observed against most carbapenems and other commonly used antibiotics [12, 13]. Currently available antibiotics include polymyxins, tigecycline and ceftazidime-avibactam, as well as some new drugs [14].
Colistimethate sodium (CMS), the prodrug of polymyxin E (colistin), represents a primary therapeutic approach for treating pulmonary infections caused by CROs [15, 16]. The intravenous injection of CMS (IV-CMS) may result in inadequate pulmonary tissue permeability [17–19]. Consequently, clinicians have explored various administration routes, with a particular focus on aerosolized colistimethate sodium (AER-CMS), to improve the efficacy and safety [20–22]. Several studies have shown that AER-CMS, either continuously or as a single drug, can improve the clinical response and microbial eradication rates in VAP/HAP patients without significantly affecting overall mortality [23, 24]. Currently, there are insufficient data on the clinical efficacy and safety of IV + AER CMS in Chinese patients, leading to a lack of consensus regarding the choice of treatment method.
The objective of this retrospective study was to enhance real-world clinical use data for CMS and reflect actual medication outcomes to provide empirical support for diverse medication approaches and the AER-CMS, thereby guiding rational drug utilization in clinical practice.
Methods
Participants and study design
Data were collected from patients receiving CMS treatment for carbapenem-resistant organism (CRO)-induced pulmonary infections, who were admitted to the ICU at Zhujiang Hospital of Southern Medical University, Nanfang Hospital of Southern Medical University, the First Affiliated Hospital of Soochow University, and the First Hospital of Hebei Medical University from December 2021 to December 2023. The inclusion criteria for this study were as follows: (1) patients aged 18–85 years (inclusive), with no gender restrictions; (2) patients admitted to the ICU; (3) patients suspected or confirmed to have pulmonary infections due to CRO admitted to the ICU (including CRAB, CRPA, CRKP, and carbapenem-resistant escherichia coli); and (4) patients who received IV + AER CMS/IV-CMS alone, with medication taken for at least 3 days. The exclusion criteria included the following: (1) patients who had estimated creatinine clearance < 30 ml/min; (2) patients who had Child‒Pugh liver function score of C grade; (3) β-2 receptor agonist was used before CMS inhalation; (4) patients who had primary lung cancers, such as small cell lung cancer and non-small cell lung cancer, or other malignant tumors that metastasized to the lungs or caused known bronchial obstruction; (5) patients who had severe bronchospasm; (6) patients who had a documented medical history of epilepsy or seizures; and (7) patients who had insufficient primary research data, including the absence of test data, baseline information on the sample, drug regimens, and records of drug adjustments.
The entire study employed a “two-stage” research design: the initial stage involved a descriptive analysis of the CMS, whereas the subsequent stage assessed the efficacy and safety of IV + AER CMS in treating CRO-induced pulmonary infections compared with IV-CMS alone. β-2 receptor agonists include salbutamol, terbutaline, salmeterol, formoterol, clenbuterol, and bambuterol. According to the treatment protocol, all eligible samples were allocated into two groups: Group A received combined IV + AER CMS treatment, whereas Group B received IV-CMS treatment alone. The treatment allocation was based on the clinical physician’s judgment according to the patient’s condition. For patients with sensitive airway responses or those who cannot tolerate local stimulation in the airway, IV-CMS treatment alone was used, while for other patients, IV + AER CMS treatment was used.
The type of nebulizer was compression nebulizer. The particle size was usually set at 2 μm. The loading dose of CMS was 300 mg, and the maintenance dose was 150 mg. The administration of nebulization: 150 mg of CMS was first reconstituted in 2 mL of sterile water for injection, and then 1 mL of the solution was extracted and added to 3 mL of 0.9% NaCl for patient use (equivalent to 75 mg per time). The nebulization frequency was twice a day. The median length of the treatment course was 12.00 (IQR 7.00–20.00) days. The dosing regimen was adjusted individually based on changes in the patient’s renal function (such as eGFR).
Ethics approval
This study was approved by the chief ethics committee (Zhujiang Hospital of Southern Medical University; Ethics No. 2024-KY-056-01) of all participating hospitals. The study was in accordance with the conditions for mutual recognition of ethics approval, and the participating hospitals recognized the ethics approval of the ethics committee of Zhujiang Hospital of Southern Medical University. The study was conducted in accordance with the Helsinki Declaration of 1964, study data were fully deidentified, and confidential information was deleted from patients in accordance with the World Health Organization International Ethical Guidelines for Health-related Research Involving Humans (2016), and requirement for informed consent was waived by the ethics committee of Zhujiang Hospital of Southern Medical University.
Data collection
The following data were extracted from medical records: gender, age, pathogens (CRAB, CRKP, CRPA, and carbapenem-resistant escherichia coli/others), inpatient days, drug days, basic chronic diseases (hypertension, diabetes, hyperlipidemia, and coronary heart disease), scheme grouping, tumors (malignant tumor), scores (acute physiology and chronic health evaluation II [APACHE II], sequential organ failure assessment [SOFA], and clinical pulmonary infection score evaluation [CPIS]), laboratory results (albumin, creatinine, C-reactive protein, procalcitonin, and white blood cell count), surgery, blood pressure (systolic pressure and diastolic blood pressure), combination drug therapy (ceftazidime-avibactam, tigecycline, and carbapenem), ICU days, and mechanical ventilation.
Definition
According to the “considerations and determination of the evaluation criterion for the clinical efficacy of antibacterial agents in China” [25], the assessment of therapeutic efficacy encompasses four graded standards: (1) clinical cure: all four parameters, including symptoms, physical signs, laboratory tests, and pathogenic examination results, have returned to normal; (2) markedly effective: the condition has significantly improved, albeit with one parameter not fully normalized; (3) effective: there is slight improvement in the condition postmedication, but not substantial; and (4) ineffective: the condition has shown no significant improvement or even worsened compared with pretreatment [25]. Cases showing “clinical response” encompasses “clinical cure”, “markedly effective” and “effective” cases.
The following symptoms can be utilized for safety assessment. Pigmentation: according to the von Luschan skin color chart, the skin color darkens by 2 levels or more; or clinically diagnosed as “pigmentation” [26]. Drug hypersensitivity reactions (DHR): drug-induced urticaria and generalized pruritus, alongside other associated symptoms [27, 28]. Neurotoxicity: dizziness, ataxia, facial flushing, somnolence, and peripheral paresthesia [29]. Renal toxicity: serum creatinine increased to ≥ 0.3 mg/dL (> 26.5 µmol/L) within 48 h; or serum creatinine increased to ≥ 1.5 times the baseline value within 7 days; or urine volume < 0.5 ml/kg/h for 6 h [30]. Bronchospasm: severe coughing, wheezing, and dyspnea [31].
Assessment of therapeutic efficacy and safety
The comparative analysis focused on the efficacy and safety of two treatment groups, with the primary endpoint being the clinical response rate (clinical response rate = “clinical cure” + “markedly effective” + “effective” cases / all cases). The secondary endpoints included the clinical cure rate, 28-day all-cause mortality rate, length of ICU stay, and adverse events (such as pigmentation, DHR, renal toxicity, neurotoxicity, and bronchospasm). Univariate logistic regression was used to analyze the relevant factors affecting the clinical response of the CMS.
Propensity score matching
Propensity score matching (PSM) is employed to address intergroup imbalances. The propensity score for each patient was estimated via logistic regression with preselected covariates, optimizing the receiver operating characteristic curve for the selection model. Cases in the IV + AER CMS group (Group A) were matched with cases in the IV-CMS group (Group B) via the propensity score at a ratio of 1:1, employing a greedy algorithm that considered the highest-ranked patients in the matching sequence until each case was matched. This process necessitates the use of the baseline characteristics of the patients. The control variables were gender, age, and the baseline APACHE II score.
Statistical analyses
If the quantitative indicators passed the normality test but did not adhere to a normal distribution, the comparison between two groups was conducted via the Wilcoxon rank sum test. If the indicators conformed to a normal distribution, comparisons between two groups were performed via Student’s t tests. The statistical descriptions included the mean, standard deviation, median, and upper and lower quartiles. Qualitative or categorical indicators were characterized in statistical terms by enumerating the frequency and percentage of each category. The comparison of disorder classification indicators was conducted via either the chi-square test or Fisher’s method. All the statistical tests were conducted via two-sided tests, and the test statistics along with the corresponding p-values were reported. In cases where Fisher’s method was employed, the p-value was directly provided. A p-value less than or equal to 0.05 was considered indicative of statistical significance for the tested difference. The statistical analysis was performed with the Statistical Package for Social Sciences version 26.0 (SPSS, Chicago, IL, USA).
Results
Baseline comparison
Following the inclusion and exclusion criteria, a total of 209 eligible samples were enrolled in this study (Fig. 1). In the IV + AER CMS group, 101 patients were included, whereas in the IV-CMS group, 108 patients were included. Differences in age and baseline APACHE II scores were compared via the Wilcoxon rank-sum test (Table 1). A significant difference was observed in the APACHE II score between two groups, but no statistically significant difference in age was observed. A chi-square test was used to compare the gender differences, and no statistically significant disparity was observed between two groups.
Fig. 1.
Patient enrollment. β-2 receptor agonists include salbutamol, terbutaline, salmeterol, formoterol, clenbuterol, and bambuterol. ICU intensive care unit; CRO carbapenem-resistant organisms; CRAB carbapenem-resistant Acinetobacter baumannii; CRPA carbapenem-resistant Pseudomonas aeruginosa; CRKP carbapenem-resistant Klebsiella pneumoniae; AER aerosol inhalation; IV intravenous injection; CMS colistimethate sodium
Table 1.
Baseline comparisons before and after matching
| Category | Before matching | After matching | ||||||
|---|---|---|---|---|---|---|---|---|
| IV + AER CMS (N = 101) |
IV-CMS alone (N = 108) |
Statistics | p-value | IV + AER CMS (N = 70) |
IV-CMS alone (N = 70) |
Statistics | p-value | |
| Age, median (IQR) | 56.00 (47.00–66.00) | 54.50 (40.75–68.25) | W = 5593.5 | 0.750 | 55.00 (45.25–64.00) | 52.00 (41.25–67.50) | W = 2432.5 | 0.943 |
| Gender (male), n (%) | 69 (69.00%) | 63 (58.88%) | χ²=2.236 | 0.135 | 43 (61.43%) | 45 (64.29%) | χ²=0.122 | 0.726 |
| APACHE II, median (IQR) | 22.00 (19.00–24.00) | 18.00 (15.00–21.00) | W = 7824.0 | < 0.001 | 20.00 (18.00–23.00) | 20.00 (17.25–21.00) | W = 2743.5 | 0.220 |
AER aerosol inhalation; IV intravenous injection; CMS colistimethate sodium; APACHE II acute physiology and chronic health evaluation II
To ensure baseline levels of the IV + AER CMS and the IV-CMS were consistent, we rematched them at a ratio of 1:1. After matching, 140 samples remained, comprising 70 patients in the IV + AER CMS group and 70 patients in the IV-CMS group (Table 1). Following PSM, there were no statistically significant differences in age, gender, or baseline APACHE II score between two groups. In supplemental Table S1, the balance of combined medication between the two groups after matching is displayed. There was no significant difference between the two groups in terms of patients who used a combination of tigecycline, avibactam sodium, and carbapenem (p > 0.05).
Efficacy evaluation
The chi-square test was used to assess differences in clinical cure rate and clinical response rate, whereas the Wilcoxon rank sum test was used to compare the disparities in inpatient days and ICU days (Table 2 & supplemental Fig. S1). The clinical response rate in IV + AER CMS group was significantly higher than that in IV-CMS group (78.57% vs. 60.00%, p = 0.017). There were no significant differences in inpatient days (38.50 d [IQR: 25.00–58.00] vs. 32.00 d [IQR:23.25–51.50], p = 0.228), or ICU days (25.00 d [IQR:13.00–49.25] vs. 24.00 d [IQR:14.25–37.50], p = 0.659) between two groups.
Table 2.
Comparison of efficacy between two groups
| Category | IV + AER CMS (N = 70) |
IV-CMS alone (N = 70) |
Statistics | p-value |
|---|---|---|---|---|
| Clinical response, n (%) | 55 (78.57%) | 42 (60.00%) | χ²=5.673 | 0.017 |
| Inpatient days, median (IQR) | 38.50 (25.00–58.00) | 32.00 (23.25–51.50) | W = 2740.0 | 0.228 |
| ICU days, median (IQR) | 25.00 (13.00–49.25) | 24.00 (14.25–37.50) | W = 2556.5 | 0.659 |
AER aerosol inhalation; IV intravenous injection; CMS colistimethate sodium; ICU intensive care unit
We employed the chi-square test to compare the mortality rates (32.86% vs. 34.29%, p = 0.858) and 28-day all-cause mortality rates (22.86% vs. 24.29%, p = 0.842) between two groups (Table 3 & supplemental Fig. S2) and found no statistically significant differences in terms of these measures.
Table 3.
Comparison of mortality between two groups
| Category | IV + AER CMS (N = 70) |
IV-CMS alone (N = 70) |
Statistics | p-value |
|---|---|---|---|---|
| Mortality, n (%) | 23 (32.86%) | 24 (34.29%) | χ²=0.032 | 0.858 |
| 28-day all-cause mortality, n (%) | 16 (22.86%) | 17 (24.29%) | χ²=0.040 | 0.842 |
AER aerosol inhalation; IV intravenous injection; CMS colistimethate sodium
Safety analyses
The chi-square test was used to compare the differences in adverse events between the IV + AER CMS and the IV-CMS groups. No statistically significant differences in the incidence of pigmentation (0.00% vs. 0.00%), DHR (8.57% vs. 10.00%, p = 0.771), neurotoxicity (10.00% vs. 12.86%, p = 0.595), renal toxicity (22.86% vs. 24.29%, p = 0.842), or bronchospasm (5.71% vs. 0.00%, p = 0.128) were observed between the two groups (Table 4). Both regimens demonstrated favorable safety profiles and that IV + AER administration did not lead to an increase in renal toxicity.
Table 4.
Comparison of safety between two groups
| Category | IV + AER CMS (N = 70) |
IV-CMS alone (N = 70) |
Statistics | p-value |
|---|---|---|---|---|
| Pigmentation | 0 (0.0%) | 0 (0.0%) | - | - |
| DHR | 6 (8.57%) | 7 (10.00%) | χ²=0.085 | 0.771 |
| Neurotoxicity | 7 (10.00%) | 9 (12.86%) | χ²=0.282 | 0.595 |
| Renal toxicity | 16 (22.86%) | 17 (24.29%) | χ²=0.040 | 0.842 |
| Bronchospasm | 4 (5.71%) | 0 (0.0%) | χ²=2.316 | 0.128 |
AER aerosol inhalation; IV intravenous injection; CMS colistimethate sodium; DHR drug hypersensitivity reaction
Analysis of factors affecting efficacy
Using clinical response as the dependent variable and various clinical characteristics as the independent variables, a univariate logistic regression analysis was performed (supplemental Table S2). The findings revealed that scheme grouping (OR = 2.44 [95% CI: 1.16–5.15], p = 0.019), malignant tumors (OR = 0.30 [95% CI: 0.11–0.82], p = 0.019), and ICU days (OR = 1.04 [95% CI: 1.02–1.07], p = 0.001) were significantly associated with clinical response. Subsequent multivariate logistic regression analysis of the independently related variables from the univariate analysis (supplemental Table S3) demonstrated that scheme grouping (OR = 2.22 [95% CI: 1.00-4.92], p = 0.050) and ICU days (OR = 1.04 [95% CI: 1.01–1.07], p = 0.002) were independently linked to clinical response. Specifically, for scheme grouping, IV + AER CMS was the protective factor for CRO-induced pulmonary infection.
Discussion
This study assessed the efficacy and safety of IV + AER CMS and IV-CMS for treating pulmonary infections caused by CRO using real-world data. The findings demonstrated that IV + AER CMS was significantly more effective in treating pulmonary infections than IV-CMS, without any increase in associated adverse events, indicating good tolerability of AER-CMS and providing real-world evidence for its rational clinical application.
CRO infections are associated with high morbidity and mortality. According to previous studies, the overall hospital mortality rate of CRE infection in China was 33.5%, and CRPA/CRAB prevalence reached 22.62% and 58.05% in hospitalized patients, respectively [32, 33]. Currently, CROs exhibit resistance to multiple available antibiotics [34, 35]. Polymyxin is one of the limited treatment options for CRO pneumonia, but the polycationic/hydrophilic structure of CMS hinders its penetration into the lung parenchyma via intravenous injection, leading to inadequate blood concentration of CMS in the lining fluid of lung epithelial cells [36]. After adding AER-CMS in the treatment regimen, the concentration of CMS in the epithelial lining fluid was significantly increased and the sterilization effect was significantly improved compared with IV-CMS alone [36]. Several guidelines recommend adjunctive AER-CMS for hospital-acquired or ventilator-associated pneumonia patients receiving IV-CMS treatment, thereby increasing the concentration in the target tissue and improving the efficacy [37, 38].
Previous studies on multi-drug resistant Gram-negative bacterial (MDR GNB) pneumonia proved the advantages of IV + AER polymyxin regimens. Maan et al. found that the combination regimen had better renal safety and faster bacterial clearance without reducing mortality [39]. Almangour et al. confirmed the combined regimen significantly improved clinical cure rate and microbial clearance rate with no increased nephrotoxicity [40]. When treating carbapenem-resistant Acinetobacter baumannii pneumonia, Kim et al. proposed aerosolized polymyxin alone as an alternative for patients at high risk of renal injury [41]. Lu and Mao’s meta-analysis further supported the clinical benefits and safety of the combined regimen [42]. Other research demonstrated that AER-CMS significantly enhances the clinical response and promoted bacterial clearance in patients with MDR GNB pneumonia [43–46]. These studies collectively indicate that combined IV + AER polymyxin increases lung drug concentration and clinical response rate with comparable or lower nephrotoxicity, which is consistent with our findings. Our multivariate analysis further confirmed that IV + AER CMS is an independent predictor of clinical response. We also found no significant difference in 28-day all-cause mortality (22.86% vs. 24.29%, p = 0.842) despite the higher clinical response rate, which is in line with Lu and Mao’s meta-analysis that adjunctive aerosol therapy improves clinical response and microbial clearance but has inconsistent benefits for overall mortality [42]. This is mainly because the enrolled patients were critically ill (median post-matching APACHE II score 20.00). Comorbidities and non-infectious factors have greater impacts on the outcome of carbapenem-resistant pneumonia, and infection control alone may not be sufficient in critically ill patients.
In terms of safety, the addition of AER-CMS did not significantly increase the incidence of adverse events (pigmentation, DHR, neurotoxicity, renal toxicity, and bronchospasm). In this study, both groups experienced renal toxicity (systemic toxicity). Renal toxicity is closely related to the plasma drug concentration, while bronchospasm is more dependent on the local microenvironment of the airway and individual sensitivity. These two factors form a dual safety monitoring dimension for the combined treatment plan. Bronchospasm, as a specific local adverse reaction of AER-CMS, remains a key clinical concern. Patients with CRAB pneumonia often have severe airway mucosal edema and reduced airway reserve, and bronchospasm may rapidly aggravate respiratory failure, which is consistent with the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guidelines that respiratory adverse events are the main limitation of aerosol antibiotic therapy [47]. Noteworthy, the non-significance of bronchospasm incidences between two groups may be due to the small sample size. Sample size estimation shows that at least 150 patients per group are required to detect a 5%-10% difference in bronchospasm incidence between the two groups (α = 0.05, β = 0.2).The current sample size is insufficient to capture the potentially small but meaningful differences that may exist in clinical practice. In future studies, we will include more samples to provide complete data comparison results.
In our initial analysis, baseline APACHE II scores were significantly different between the two groups. Kalin’s study had a similar baseline imbalance and adjusted it by excluding samples, while we adopted PSM to balance covariates, which is a more rigorous method for confounding control in real-world studies [48, 49]. After PSM, baseline characteristics were well balanced between groups, and no significant differences in mortality or safety outcomes were observed, which further validated the reliability of our results and was consistent with previous research [40, 42].
Several limitations exist in our study. First, it is retrospective and the sample size is relatively small, which is related to the short marketing time of CMS in China. Stratified analysis by pathogen type (CRAB, CRKP, CRPA) is also limited by small sample size (especially for the CRKP and Others groups with fewer cases) and lack of statistical power, leading to false negative results. Future large-scale studies are needed to evaluate pathogen-specific response of different anti-infective strategies. Second, extreme or abnormal data (variables with a ratio of positive samples to total samples less than 0.1 or a missing rate greater than 50%) were excluded from the database. Therefore, caution should be exercised when generalizing the study results to individuals with specific conditions. Third, AER-CMS is typically administered through conventional nebulizer, which lacks particle size control and thus does not allow accurate estimation the actual amount of drug delivered to the lungs. Last, the multicenter study utilized retrospective data collection, and not all centers followed strictly consistent nebulization procedures, which may lead to selection bias, the influence of unmeasured confounding factors (such as different treatment protocols among hospitals, differed ventilator parameters and unrecorded details of the severity of the clinical condition), and an underestimation of adverse event risks. Future studies will involve large-sample prospective randomized controlled trials, with blinded designs and standardized nebulization administration protocols to minimize bias, and the follow-up period will be extended to improve the relevant data.
Conclusion
This study provides additional real-world postmarketing data for CMS, offering valuable insights for the clinical management of CRO infection. This retrospective analysis reflects real-world drug utilization patterns and provides robust data to support the application of AER-CMS in clinical practice, thereby promoting rational drug use.
Supplementary Information
Below is the link to the electronic supplementary material.
Acknowledgements
Not applicable.
Author contributions
Conception and design: Ji Liu and Wei Wang. Administrative Support: Ji Liu and Wei Wang. Prepare study materials or patient data: Yong Wang, Shumei Sun, Ji Liu, Wei Wang, Xun Deng, Xiaoyu Lin, Xun Yu, Ran Fu. Data collection: Ji Liu, Wei Wang, Xun Deng, Xiaoyu Lin, Xun Yu, Ran Fu. Data analysis and interpretation: Ji Liu, Wei Wang, Xun Deng, Xiaoyu Lin. Manuscript writing and reviewing: all authors.
Funding
This work was supported by Guangdong Basic and Applied Basic Research Foundation of Department of Science and Technology of Guangdong Province (2022A1515111208) and Science and Technology Projects of Guangzhou Municipal Science and Technology Bureau (2024A04J3533) to Wei Wang.
Data availability
Data are available from the corresponding author on rational request.
Declarations
Ethics approval and consent to participate
This study was approved by the chief ethics committee (Zhujiang Hospital of Southern Medical University; Ethics No. 2024-KY-056-01) of all participating hospitals. The study was in accordance with the conditions for mutual recognition of ethics approval, and the participating hospitals recognized the ethics approval of the ethics committee of Zhujiang Hospital of Southern Medical University. The study was conducted in accordance with the Helsinki Declaration of 1964, study data were fully deidentified, and confidential information was deleted from patients in accordance with the World Health Organization International Ethical Guidelines for Health-related Research Involving Humans (2016), and requirement for informed consent was waived by the ethics committee of Zhujiang Hospital of Southern Medical University.
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ji Liu and Wei Wang have contributed equally to this work.
Contributor Information
Yong Wang, Email: yongwh2005@163.com.
Shumei Sun, Email: sunshumei99@126.com.
References
- 1.Livermore DM, Nicolau DP, Hopkins KL, Meunier D. Carbapenem-Resistant Enterobacterales, Carbapenem Resistant Organisms, Carbapenemase-Producing Enterobacterales, and Carbapenemase-Producing Organisms: Terminology Past its Sell-By Date in an Era of New Antibiotics and Regional Carbapenemase Epidemiology. Clin Infect Dis. 2020;71(7):1776–82. [DOI] [PubMed] [Google Scholar]
- 2.Chang K, Wang H, Zhao J, Yang X, Wu B, Sun W, Huang M, Cheng Z, Chen H, Song Y, et al. Polymyxin B/Tigecycline Combination vs. Polymyxin B or Tigecycline Alone for the Treatment of Hospital-Acquired Pneumonia Caused by Carbapenem-Resistant Enterobacteriaceae or Carbapenem-Resistant Acinetobacter baumannii. Front Med (Lausanne). 2022;9:772372. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Falagas ME, Tansarli GS, Karageorgopoulos DE, Vardakas KZ. Deaths attributable to carbapenem-resistant Enterobacteriaceae infections. Emerg Infect Dis. 2014;20(7):1170–5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.van Duin D, Doi Y. The global epidemiology of carbapenemase-producing Enterobacteriaceae. Virulence. 2017;8(4):460–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Morrill HJ, Pogue JM, Kaye KS, LaPlante KL. Treatment Options for Carbapenem-Resistant Enterobacteriaceae Infections. Open Forum Infect Dis. 2015;2(2):ofv050. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Zusman O, Altunin S, Koppel F, Dishon Benattar Y, Gedik H, Paul M. Polymyxin monotherapy or in combination against carbapenem-resistant bacteria: systematic review and meta-analysis. J Antimicrob Chemother. 2017;72(1):29–39. [DOI] [PubMed] [Google Scholar]
- 7.Xie J, Yang Y, Huang Y, Kang Y, Xu Y, Ma X, Wang X, Liu J, Wu D, Tang Y, et al. The Current Epidemiological Landscape of Ventilator-associated Pneumonia in the Intensive Care Unit: A Multicenter Prospective Observational Study in China. Clin Infect Dis. 2018;67(suppl2):S153–61. [DOI] [PubMed] [Google Scholar]
- 8.Farag AM, Tawfick MM, Abozeed MY, Shaban EA, Abo-Shadi MA. Microbiological profile of ventilator-associated pneumonia among intensive care unit patients in tertiary Egyptian hospitals. J Infect Dev Ctries. 2020;14(2):153–61. [DOI] [PubMed] [Google Scholar]
- 9.Chang Y, Jeon K, Lee SM, Cho YJ, Kim YS, Chong YP, Hong SB. The Distribution of Multidrug-resistant Microorganisms and Treatment Status of Hospital-acquired Pneumonia/Ventilator-associated Pneumonia in Adult Intensive Care Units: a Prospective Cohort Observational Study. J Korean Med Sci. 2021;36(41):e251. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Quartin AA, Scerpella EG, Puttagunta S, Kett DH. A comparison of microbiology and demographics among patients with healthcare-associated, hospital-acquired, and ventilator-associated pneumonia: a retrospective analysis of 1184 patients from a large, international study. BMC Infect Dis. 2013;13:561. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.WHO bacterial priority pathogens list. 2024: Bacterial pathogens of public health importance to guide research, development and strategies to prevent and control antimicrobial resistance: World Health Organization; 2024. [DOI] [PMC free article] [PubMed]
- 12.van Duin D, Kaye KS, Neuner EA, Bonomo RA. Carbapenem-resistant Enterobacteriaceae: a review of treatment and outcomes. Diagn Microbiol Infect Dis. 2013;75(2):115–20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Cai B, Echols R, Magee G, Arjona Ferreira JC, Morgan G, Ariyasu M, Sawada T, Nagata TD. Prevalence of Carbapenem-Resistant Gram-Negative Infections in the United States Predominated by Acinetobacter baumannii and Pseudomonas aeruginosa. Open Forum Infect Dis. 2017;4(3):ofx176. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Ben Lakhal H, M’Rad A, Naas T, Brahmi N. Antimicrobial Susceptibility among Pathogens Isolated in Early- versus Late-Onset Ventilator-Associated Pneumonia. Infect Dis Rep. 2021;13(2):401–10. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Gu WJ, Wang F, Tang L, Bakker J, Liu JC. Colistin for the treatment of ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria: a systematic review and meta-analysis. Int J Antimicrob Agents. 2014;44(6):477–85. [DOI] [PubMed] [Google Scholar]
- 16.Wang SH, Yang KY, Sheu CC, Chen WC, Chan MC, Feng JY, Chen CM, Wu BR, Zheng ZR, Chou YC, Peng CK. The necessity of a loading dose when prescribing intravenous colistin in critically ill patients with CRGNB-associated pneumonia: a multi-center observational study. Crit Care. 2022;26(1):91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Choe J, Sohn YM, Jeong SH, Park HJ, Na SJ, Huh K, Suh GY, Jeon K. Inhalation with intravenous loading dose of colistin in critically ill patients with pneumonia caused by carbapenem-resistant gram-negative bacteria. Ther Adv Respir Dis. 2019;13:1753466619885529. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Imberti R, Cusato M, Villani P, Carnevale L, Iotti GA, Langer M, Regazzi M. Steady-state pharmacokinetics and BAL concentration of colistin in critically Ill patients after IV colistin methanesulfonate administration. Chest. 2010;138(6):1333–9. [DOI] [PubMed] [Google Scholar]
- 19.Lim LM, Ly N, Anderson D, Yang JC, Macander L, Jarkowski A 3rd, Forrest A, Bulitta JB, Tsuji BT. Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing. Pharmacotherapy. 2010;30(12):1279–91. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Sweeney DA, Kalil AC. Why don’t we have more inhaled antibiotics to treat ventilator-associated pneumonia? Clin Microbiol Infect. 2019;25(10):1195–9. [DOI] [PubMed] [Google Scholar]
- 21.Wood GC, Swanson JM. An Update on Aerosolized Antibiotics for Treating Hospital-Acquired and Ventilator-Associated Pneumonia in Adults. Ann Pharmacother. 2017;51(12):1112–21. [DOI] [PubMed] [Google Scholar]
- 22.Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, Napolitano LM, O’Grady NP, Bartlett JG, Carratalà J, et al. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61–111. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Korkmaz Ekren P, Toreyin N, Sayiner A, Bacakoglu F. The Role of Aerolized Colistin in the Treatment of Hospital-Acquired Pneumonia: Experience of Multicenter From Turkey. Crit Care Med. 2016;44(5):e304. [DOI] [PubMed] [Google Scholar]
- 24.Valachis A, Samonis G, Kofteridis DP. The role of aerosolized colistin in the treatment of ventilator-associated pneumonia: a systematic review and metaanalysis. Crit Care Med. 2015;43(3):527–33. [DOI] [PubMed] [Google Scholar]
- 25.Xie SMZM, Yang JB, Li YJ, Zhao DH. Considerations and determination on the evaluation criterion for clinical efficacy of antibacterial agents in China. Chin J Clin Pharmacol. 2008;24(55):466–8. [Google Scholar]
- 26.Zhang X. Dermatovenereology (eighth edition). People’s Medical Publishing House; 2013.
- 27.Yosipovitch G, Bernhard JD. Clinical practice. Chronic pruritus. N Engl J Med. 2013;368(17):1625–34. [DOI] [PubMed] [Google Scholar]
- 28.Jia J, Chen S. Neurology. 8th ed. Beijing: People's Medical Publishing House; 2018.
- 29.Lin GWWJ, Ge JB. Practice of internal medicine. People’s Medical Publishing House; 2017.
- 30.Khwaja A. KDIGO Clinical Practice Guidelines for Acute Kidney Injury. Nephron Clin Pract. 2012;120(4):c179–84. [DOI] [PubMed] [Google Scholar]
- 31.Parsons JP, Hallstrand TS, Mastronarde JG, Kaminsky DA, Rundell KW, Hull JH, Storms WW, Weiler JM, Cheek FM, Wilson KC, Anderson SD. An official American Thoracic Society clinical practice guideline: exercise-induced bronchoconstriction. Am J Respir Crit Care Med. 2013;187(9):1016–27. [DOI] [PubMed] [Google Scholar]
- 32.Zhang Y, Wang Q, Yin Y, Chen H, Jin L, Gu B, Xie L, Yang C, Ma X, Li H, et al. Epidemiology of carbapenem-resistant enterobacteriaceae infections: report from the China CRE network. Antimicrob Agents Chemother. 2018;62(2):e01882-17. [DOI] [PMC free article] [PubMed]
- 33.Zhen X, Stålsby Lundborg C, Sun X, Zhu N, Gu S, Dong H. Economic burden of antibiotic resistance in China: a national level estimate for inpatients. Antimicrob Resist Infect Control. 2021;10(1):5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Xiao YH, Wang J, Li Y, Net MOHNARI. Bacterial resistance surveillance in China: a report from Mohnarin 2004–2005. Eur J Clin Microbiol Infect Dis. 2008;27(8):697–708. [DOI] [PubMed] [Google Scholar]
- 35.Hu FP, Guo Y, Zhu DM, Wang F, Jiang XF, Xu YC, Zhang XJ, Zhang CX, Ji P, Xie Y, et al. Resistance trends among clinical isolates in China reported from CHINET surveillance of bacterial resistance, 2005–2014. Clin Microbiol Infect. 2016;22(Suppl 1):S9–14. [DOI] [PubMed] [Google Scholar]
- 36.Boisson M, Jacobs M, Gregoire N, Gobin P, Marchand S, Couet W, Mimoz O. Comparison of intrapulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and colistin after aerosol delivery and intravenous administration of CMS in critically ill patients. Antimicrob Agents Chemother. 2014;58(12):7331–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Rello J, Solé-Lleonart C, Rouby JJ, Chastre J, Blot SI, Poulakou G, Luyt C-E, Riera J, Palmer LB, Pereira JM, et al. Use of nebulized antimicrobials for the treatment of respiratory infections in invasively mechanically ventilated adults: a position paper from the European Society of Clinical Microbiology and Infectious Diseases. Clin Microbiol Infect. 2017;23 9:629–39. [DOI] [PubMed] [Google Scholar]
- 38.Tsuji BT, Pogue JM, Zavascki AP, Paul M, Daikos GL, Forrest A, Giacobbe DR, Viscoli C, Giamarellou H, Karaiskos I, et al. International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). Pharmacotherapy. 2019;39(1):10–39. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Maan L, Anand N, Yadav G, Mishra M, Gupta MK. The Efficacy and Safety of Intravenous Colistin Plus Aerosolized Colistin Versus Intravenous Colistin Alone in Critically Ill Trauma Patients With Multi-Drug Resistant Gram-Negative Bacilli Infection. Cureus. 2023;15(11):e49314. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Almangour TA, Alruwaili A, Almutairi R, Alrasheed A, Alhifany AA, Eljaaly K, Alkofide H, Alhammad AM, Ghonem L, Alsharidi A. Aerosolized plus intravenous colistin vs intravenous colistin alone for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria: A retrospective cohort study. Int J Infect Dis. 2021;108:406–12. [DOI] [PubMed] [Google Scholar]
- 41.Kim YK, Lee JH, Lee HK, Chung BC, Yu SJ, Lee HY, Park JH, Kim S, Kim HK, Kiem S, Jang HJ. Efficacy of nebulized colistin-based therapy without concurrent intravenous colistin for ventilator-associated pneumonia caused by carbapenem-resistant Acinetobacter baumannii. J Thorac Dis. 2017;9(3):555–67. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Lu D, Mao W. Efficacy and safety of intravenous combined with aerosolised polymyxin versus intravenous polymyxin alone in the treatment of multidrug-resistant gram-negative bacterial pneumonia: A systematic review and meta-analysis. Heliyon. 2023;9(5):e15774. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Mubareka S, Rubinstein E. Aerosolized colistin for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria in patients without cystic fibrosis. Crit Care. 2005;9(1):29–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Michalopoulos A, Fotakis D, Virtzili S, Vletsas C, Raftopoulou S, Mastora Z, Falagas ME. Aerosolized colistin as adjunctive treatment of ventilator-associated pneumonia due to multidrug-resistant Gram-negative bacteria: a prospective study. Respir Med. 2008;102(3):407–12. [DOI] [PubMed] [Google Scholar]
- 45.Lin CC, Liu TC, Kuo CF, Liu CP, Lee CM. Aerosolized colistin for the treatment of multidrug-resistant Acinetobacter baumannii pneumonia: experience in a tertiary care hospital in northern Taiwan. J Microbiol Immunol Infect. 2010;43(4):323–31. [DOI] [PubMed] [Google Scholar]
- 46.Bao XL, Tao T, Tang N, Wang YZ, Liao XQ, Huang LL, Ji JJ, Chen X. Efficacy and safety of adjunctive nebulized colistin sulfate for multidrug-resistant Gram-negative bacteria pneumonia: a retrospective comparative cohort study. Ann Palliat Med. 2022;11(9):2939–51. [DOI] [PubMed] [Google Scholar]
- 47.Rello J, Solé-Lleonart C, Rouby JJ, Chastre J, Blot S, Poulakou G, Luyt CE, Riera J, Palmer LB, Pereira JM, et al. Use of nebulized antimicrobials for the treatment of respiratory infections in invasively mechanically ventilated adults: a position paper from the European Society of Clinical Microbiology and Infectious Diseases. Clin Microbiol Infect. 2017;23(9):629–39. [DOI] [PubMed] [Google Scholar]
- 48.Kalin G, Alp E, Coskun R, Demiraslan H, Gündogan K, Doganay M. Use of high-dose IV and aerosolized colistin for the treatment of multidrug-resistant Acinetobacter baumannii ventilator-associated pneumonia: do we really need this treatment? J Infect Chemother. 2012;18(6):872–7. [DOI] [PubMed] [Google Scholar]
- 49.Allan V, Ramagopalan SV, Mardekian J, Jenkins A, Li X, Pan X, Luo X. Propensity score matching and inverse probability of treatment weighting to address confounding by indication in comparative effectiveness research of oral anticoagulants. J Comp Eff Res. 2020;9(9):603–14. [DOI] [PubMed] [Google Scholar]
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Data Availability Statement
Data are available from the corresponding author on rational request.