Clinical outcomes and nephrotoxicity of colistin methanesulfonate in critically ill patients with carbapenem-resistant organisms infections: a retrospective study

Clinical outcomes and nephrotoxicity of colistin methanesulfonate in critically ill patients with carbapenem-resistant organisms infections: a retrospective study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical outcomes and nephrotoxicity of colistin methanesulfonate in critically ill patients with carbapenem-resistant organisms infections: a retrospective study Xindie Ren, Jun Xu, Hua Zhou, Hongliu Cai This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4978828/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Carbapenem resistant organisms (CRO) infection is one of the most common causes of high mortality among critically ill patients. Colistin methanesulfonate (CMS) represents a significant treatment option for CRO infections, yet the available data on CMS in the Chinese population remains limited. This study aimed to analyze the clinical outcomes and nephrotoxicity of CMS in treating critically ill patients with CRO infections in China. Methods A retrospective study was conducted from June 2022 to September 2023 in critically ill patients with CRO infections who received CMS treatment. The clinical outcomes were assessed by clinical effective, microbiological eradication, infection-related hospital mortality, the length of ICU stay, and total hospital stay. A sub-group analysis was conducted on patients with lung infection. The nephrotoxicity was assessed by the acute kidney injury (AKI). Results A total of 96 critically ill patients with CRO infections were enrolled in the study. The overall clinical effective, microbiological eradication and infection-related hospital mortality rates were 67.90%, 60.49% and 8.33%, respectively. The median length of ICU and total hospital stays was 28 and 32.5 days, respectively. In patients with lung infection, 70.31% and 61.19% achieved clinical effective and microbiological eradication, respectively. The younger patients (< 65 years old), patients who received intravenous combined nebulized CMS, and infections caused by CRE benefitted more from CMS treatment. The incidence of acute kidney injury (AKI) was 28 cases (30.43%), with the majority (82.14%) occurring in stage 1. Conclusions CMS treatment in Chinese critically ill patients with CRO infections achieved favorable outcomes, with acceptable nephrotoxicity, providing a promising option for this fatal disease. Carbapenem-resistant organisms Critically ill patients Colistin methanesulfonate Clinical outcomes Nephrotoxicity Background According to predictive statistical models, antibiotic resistance caused 1.27 million deaths in 2019, nearly twice the 700000 deaths reported in 2016 [ 1 ]. The incidence rate of carbapenem resistant organisms (CRO) infections is rising rapidly worldwide, which were listed as the highest priority category (i.e. critical) by the World Health Organization (WHO) [ 2 ]. Patients in the intensive care unit (ICU) are typically immunocompromised, with an infection rate of more than 50% [ 3 ]. Furthermore, due to the widespread adoption of carbapenems, the incidence of CRO infections in ICU patients has been significantly higher than in non-ICU settings, with an in-hospital mortality of up to 46.1% [ 4 – 6 ]. Therefore, the control of CRO infections has become a key issue to save ICU patients with severe infections. The clinical management of CRO infections is severely hampered by the extensively drug-resistant or pan-drug-resistant nature of CRO isolates [ 7 ]. Although extensive efforts have been made to identify new drugs that counteract the mechanisms underlying this phenomenon, most have been unsuccessful. Consequently, the reintroduction of old potent drugs into clinical practice may be a necessary effort [ 8 ]. Despite the cessation of polymyxins utilisation due to the elevated prevalence of adverse effects, including nephrotoxicity, its robust bactericidal efficacy and lowest resistance rate to multidrug-resistant Gram-negative bacterial infections render polymyxins the “last line of defence” for the treatment of CRO infections [ 9 ]. Currently, three injectable polymyxins are available in both domestic and international markets, including colistin methanesulfonate (CMS), polymyxin B sulfate (PBS), and polymyxin E sulfate (PES). As the earliest polymyxin launched internationally, CMS has the highest attention and lower nephrotoxicity than PBS [ 10 ]. CMS is a pro-drug of colistin, which has a high sensitivity rate against CRO infections [ 11 ]. Several clinical studies have confirmed that CMS is an effective antimicrobial agent for CRO infections, with acceptable nephrotoxicity [ 12 – 14 ]. In addition, there is growing evidence that critically ill patients with CRO infections also benefit from CMS treatment. A retrospective study from Vietnam of critically ill adult patients receiving intravenous colistin showed that 68% were clinically effective, with low nephrotoxicity (21%) [ 15 ]. Another study from Thailand proposed that, CMS was associated with better clinical outcomes in critically ill patients with CRO infection [ 16 ]. However, due to the late listing of CMS in China, there are currently limited studies on CMS for critically ill patients with CRO infection in China. Thus, we retrospectively investigated the clinical outcomes and nephrotoxicity of CMS in critically ill patients with CRO infection in China, aiming to provide a reference for the clinical application of CMS. Methods Study design This single-center, retrospective study was conducted to assess the clinical outcomes and safety in critically ill patients with CRO infections who received CMS treatment at the First Affiliated Hospital, Zhejiang University School of Medicine between June 2022 and September 2023. Adult patients aged of 18–90 years were included in the study if they were admitted to the ICU with positive cultures for CRO and received CMS treatment for three or more days. Patients were excluded if they had received other polymyxins treatment one week prior to enrollment, had a known allergy to CMS or its metabolites, pregnancy or lactation, severe liver and kidney dysfunction. The study was carried out in accordance with the Declaration of Helsinki and approved by the clinical research ethics committee of the first affiliated hospital, college of medicine, zhejiang university (IIT20230300B-R1). Written informed consent was waived owing to the retrospective nature of this investigation. The demographic, clinical, laboratory and microbiological characteristics of each enrolled patient were collected from baseline to the end of treatment. All causative organisms were identified by standard microbiological techniques. The Clinical and Laboratory Standards Institute (CLSI) method was used to evaluate the susceptibility of patients to antimicrobial agents [ 17 ]. CMS administration All enrolled patients were treated with CMS (Chia Tai Tianqing Pharmaceutical Group Co., Ltd, China). Patients receiving intravenous CMS were initially given a loading dose of 300 mg colistin base activity (CBA), followed by a maintenance dose of 2.5–5 mg of CBA/kg/ day[ 18 ]. Patients receiving nebulized CMS were given a dose of 75 mg CBA twice a day, and the vibrating mesh nebulizer was used for nebulization[ 19 ]. The nebulized CMS was prepared by mixing 75 mg CBA with 3–4 mL of normal saline immediately before nebulization. The specific dosage and duration of CMS was adjusted by clinical physicians based on the renal function of each patient, and the maximum daily dose is not more than 5 mg/kg. Clinical outcomes The primary outcomes evaluated in this study were clinical effective and microbiological eradication at the end of treatment. Clinical effective was defined as resolution or significant improvement of presenting symptoms and signs of CRO infection at the end of CMS treatment, or the non-microbiological indicators such as imaging all have returned to normal. Microbiological eradication was defined as the proportion of patients with eradication and presumed eradication in the total population. Eradication was defined as the failure to cultivate pathogenic bacteria from the original infected site of the specimen after treatment, and presumed eradication was defined as the disappearance of symptoms and signs making it impossible to obtain cultivable materials (such as sputum, skin pus, or secretions), or the method of obtaining specimens is too invasive for rehabilitation patients. Secondary outcomes included infection-related hospital mortality, the length of ICU stay and length of hospital stay. It was not considered that hospital death cases occurring after the improvement of infection symptoms were related to infection. The assessment of hospital and ICU stays did not include patients who died during the course of their hospitalization. Nephrotoxicity The nephrotoxicity was evaluated by the development of acute kidney injury (AKI), which was defined in accordance with the Kidney Disease Improving Global Outcomes (KDIGO) criteria based on serum creatinine (SCr) values at the end of treatment [ 20 ]. The stage of severity of AKI was also classified in accordance with the KDIGO criteria, as follows: 1) Stage 1, an increase in SCr by ≥ 26.5 µmol/L (0.3 mg/dL) or between 1.5 and 1.9 times the baseline value; 2) Stage 2, an increase in SCr by 2.0 to 2.9 times the baseline SCr value; 3) Stage 3, an increase in SCr by 353.6 µmol/L (4 mg/dL) or > 3.0 times the baseline SCr value, or commencement of renal replacement therapy. Statistical analysis All statistical analyses were conducted using the RStudio version 4.3.1. The descriptive statistics were employed to assess the baseline characteristics of patients. The distribution normality of the continuous variables was tested using the Shapiro-Wilk method. In the event that the variable was normally distributed, it was represented by the mean ± standard deviation (SD). Otherwise, the variable was represented by median (interquartile range, IQR). The categorical variables were represented by the corresponding number of cases and percentage. The Clopper-Pearson method was employed to calculate the 95% confidence interval (CI) for clinical efficacy, microbiological eradication, and other indicators. For patients with lung infection, a subgroup analysis was conducted based on age, medication method and causative organisms. Results Patient baseline characteristics A total of 96 critically ill patients with CRO infections who met the inclusion criteria were recruited for analysis. The characteristics of patient were presented in Table 1 . The mean age of all patients was 62.61 ± 17.28 years, with 73.96% being male. The majority of patients (83.33%) had a past medical history. Of these patients, 36 (37.50%) experienced sepsis, and 18 (18.75%) developed septic shock. The majority of patients (77/96, 80.2%) had a lung infection, and the most frequently causative organisms were carbapenem-resistant Acinetobacter baumannii (CRAB) (57/96, 59.38%), followed by carbapenem-resistant Enterobacteriaceae (CRE, 37/96, 38.54%), including 31 patients (32.29%) with carbapenem-resistant Klebsiella pneumonia . Most of patients (87/96, 90.62%) received mechanical ventilation, 33 patients (34.38%) received haemodialysis, and 52 patients (54.17%) were treated with vasoactive agents. All patients received CMS therapy, with 79.17% (76/96) of patients involving the prescription of this treatment in combination with other antimicrobial agents. Table 1 The demographic and clinical characteristics of patients Variables Total (n = 96) Age, years, mean ± SD 62.61 ± 17.28 Gender, male, no. (%) 71 (73.96) BMI, kg/m 2 , mean ± SD 23.08 ± 3.96 Past medical history, no. (%) 80 (83.33) Sepsis, no. (%) 36 (37.50) Septic shock, no. (%) 18 (18.75) SOFA score, mean ± SD 7.70 ± 4.18 APACHE II score, mean ± SD 18.03 ± 7.33 Charslon comorbidity index, mean ± SD 3.96 ± 2.59 Glasgow Coma Scale, mean ± SD 10.30 ± 5.41 Site of infection, no. (%) Lung 77 (80.2) Others 19 (19.79) Causative organisms, no. (%) Carbapenem-resistant Acinetobacter baumannii 57 (59.38) Carbapenem-resistant Enterobacteriaceae 37 (38.54) Carbapenem-resistant Pseudomonas aeruginosa 11 (11.46) Others 2 (2.08) Laboratory parameters, mean ± SD Serum creatinine, µmol/L 117.62 ± 89.18 C reactive protein, mg/L 97.76 ± 70.96 Procalcitonin, ng/mL 3.47 ± 7.25 Mechanical ventilation, no. (%) 87 (90.62) Hemodialysis, no. (%) 33 (34.38) Vasoactive agents, no. (%) 52 (54.17) Strategy of CMS use, no. (%) Monotherapy 20 (20.83) Combination therapy 76 (79.17) * Data are presented as mean ± SD, no. (%), median (IQR), where no. is the total number of patients with available data. SOFA, sequential organ failure assessment; APACHE II, acute physiology and chronic health evaluation II; CMS, Colistin methanesulfonate. The resistance profiles of the 5 common antimicrobial agents used for the treatment of CRO infections was shown in Table 2 . The antimicrobial non-susceptibility rates to meropenem and imipenem were both 96.84% (92/95). 71.25% (57/80) and 69.23% (27/39) of patients were susceptible to tigecycline and ceftazidime/avibactam, respectively. A total of 96.74% of patients exhibited intermediate resistance to colistin, with minimum inhibitory concentrations (MICs) of ≤ 2.0 mg/L (Table 2 ). Table 2 Susceptibility of patients to antimicrobial agents Antimicrobial agents Tested, no. Susceptibility no. (%) Intermediate no. (%) Resistance no. (%) Meropenem 95 3 (3.16) 0 92 (96.84) Imipenem 95 3 (3.16) 0 92 (96.84) Tigecycline 80 57 (71.25) 19 (23.75) 4 (5.00) Ceftazidime/avibactam 39 27 (69.23) 0 12 (30.77) Colistin 92 / 89 (96.74) 3 (3.26) Clinical outcomes analysis The clinical effective of CMS treatment was achieved in 55 patients (67.90%), and microbiological eradication was achieved in 49 patients (60.49%) (Table 3 ). The overall infection-related hospital mortality was 8.33% (8/96). The median length of ICU and hospital stays was 28 and 32.5 days, respectively. In patients with lung infection, 70.31% (45/77) and 61.19% (41/77) achieved clinical effective and microbiological eradication, respectively. Furthermore, the infection-related hospital mortality was 7.79% (6/77), with a median length of ICU and hospital stays of 29 and 33 days, respectively. Table 3 Clinical outcomes of patients treated with CMS Variables No. (%) or median (IQR) 95% CI Total (n = 96) Primary outcomes Clinical effective 55 (67.90) 56.60, 77.85 Microbiological eradication 49 (60.49) 49.01, 71.19 Secondary outcomes Infection-related hospital mortality 8 (8.33) 3.67, 15.76 Length of ICU stay (days) 28 (18.00, 51.75) 27, 41 Length of total hospital stay (days) 32.50 (20.50, 63.75) 35.50, 50.50 Lung infection (n = 77) Primary outcomes Clinical effective 45 (70.31) 57.58, 81.09 Microbiological eradication 41 (61.19) 48.50, 72.86 Secondary outcomes Infection-related hospital mortality 6 (7.79) 2.91, 16.19 Length of ICU stay (days) 29 (18.00, 50.50) 27.50, 42.00 Length of total hospital stay (days) 33 (24,62) 35.00, 50.50 Sub-group analysis Sub-group analysis based on age, medication method and causative organisms of patients with lung infection were presented in Table 4 . The younger patients (< 65 years old) demonstrated superior clinical efficiency (75% vs. 66.67%), lower infection-related hospital mortality (2.94% vs. 11.63%) and shorter ICU stay (24 vs. 31 days). Compared with patients who received intravenous alone, intravenous combined nebulized CMS achieved higher clinical efficacy (61.90% vs. 84.62%), microbiological eradication rate (56.82% vs. 78.57%), and lower infection-related hospital mortality rate (9.43% vs. 0). In the sub-groups defined by causative organisms, patients with CRE infections benefitted more from CMS treatment, with a clinical efficiency of 85.71%, a microbiological eradication of 64.29%, and an infection-related hospital mortality of 5.88%. Table 4 Subgroup analysis of clinical outcomes in patients with lung infection Variables, no. (%) or median (IQR) < 65 years (n = 34) ≥ 65 years (n = 43) Clinical effective 21 (75.00) 24 (66.67) / Microbiological eradication 16 (53.33) 25 (67.57) / Infection-related hospital mortality 1 (2.94) 5 (11.63) / Length of ICU stay (days) 24 (18, 56) 31 (19.00, 46.75) / Length of total hospital stay (days) 32 (19, 61) 33 (27.25, 61.75) / Intravenous Intravenous combined alone (n = 53) nebulized CMS (n = 14) / Clinical effective 26 (61.90) 11 (84.62) / Microbiological eradication 25 (56.82) 11 (78.57) / Infection-related hospital mortality 5 (9.43) 0 / Length of ICU stay (days) 27.50 (17.75, 44.00) 40 (24, 69) / Length of total hospital stay (days) 32 (18.75, 61.50) 40 (26, 93) / CRAB (n = 49) CRE (n = 17) CRPA (n = 6) Clinical effective 27 (65.85) 12 (85.71) 4 (66.67) Microbiological eradication 26 (59.09) 9 (64.29) 3 (50.00) Infection-related hospital mortality 2 (4.08) 1 (5.88) 2 (33.33) Length of ICU stay (days) 31.50 (19.00, 56.50) 27 (20, 41) 21 (17, 65) Length of total hospital stay (days) 32.50 (24.75, 64.50) 41 (25, 52) 82 (69, 113) CRAB, carbapenem-resistant Acinetobacter baumannii ; CRE, carbapenem-resistant Enterobacteriaceae ; CRPA, carbapenem-resistant Pseudomonas aeruginosa ; CMS, Colistin methanesulfonate. Nephrotoxicity analysis Nephrotoxicity that possibly or probably related to the use of CMS were presented in Table 5 . The incidence of AKI among patients received CMS treatment was 28 cases (30.43%), with 23 patients (82.14%) presenting with stage 1 AKI, 2 patients (7.14%) with stage 2 AKI, and 3 patients (10.71%) with stage 3 AKI. The median change in serum creatinine from baseline for patients was 4 µmol/L. Table 5 Nephrotoxicity possibly or probably related to the use of CMS Nephrotoxicity Total (n = 96) Acute kidney injury, no. (%) Yes 28 (30.43) No 64 (69.57) KDIGO criteria Stage 1 23 (82.14) Stage 2 2 (7.14) Stage 3 3 (10.71) Serum creatinine change from baseline (Δ), µmol/L, median (IQR) 4 (-31.00, 39.5) CMS, Colistin methanesulfonate; KDIGO, Kidney Disease Improving Global Outcomes. Discussion To the best of our knowledge, this was one of the first studies to describe the clinical outcomes of CMS use in Chinese critically ill patients. The overall clinical effective rate was 67.9%, the microbiological eradication rate was 60.49%, and the infection-related hospital mortality was 8.33%. Subgroup analysis demonstrated that younger patients (< 65 years old), patients who received intravenous combined nebulized CMS, and infections caused by CRE benefitted more from CMS treatment. 30.43% of patients developed AKI, and most (82.14%) of them were stage 1. In light of these findings, CMS treatment for Chinese critically ill patients with CRO infections achieved favorable outcomes, with acceptable nephrotoxicity. The increasing of mortality rate associated with CRO infections in critically ill patients has prompted the widespread adoption of CMS. A previous study in critically ill patients investigated the efficacy of CMS and found a clinical effective rate of 68% and a microbiological eradication rate of 62.5%. These findings are similar to those reported there [ 15 ]. Additionally, the findings of this study demonstrated that the infection-related hospital mortality rate was 8.33%, which was lower than that observed in previous studies [ 15 , 21 ]. It is plausible that the mortality in critically ill patients is influenced by factors beyond infectious control, such as disease severity and the presence of comorbidities. It should be noted that this study only counted infection-related hospital mortality, and hospital deaths that occurred after symptom improvement were considered unrelated to infection. Lung infection was the most common site of infection in critically ill patients [ 22 ], with 80% of patients with lung infections in our study. Consequently, an analysis of the clinical outcomes of patients with lung infections was condducted, which revealed that 70.31% of patients achieved clinical effective, 61.19% of patients achieved microbiological eradication, and the infection-related hospital mortality was 7.79%, which was comparable to those of the overall population. A 10-year prospective observational study conducted in China indicated that age ≥ 65 years was independent risk factor for in-hospital mortality among adult patients with lung infection [ 23 ]. The sub-group analysis of age < 65 years and ≥ 65 years revealed that younger patients exhibited a higher clinical effective rate and a lower infection-related hospital mortality. Similarly, a previous study has also demonstrated that the patients who responded to treatment were younger than patients who did not respond [ 15 ]. However, the microbiological eradication rate of younger patients in this study was slightly lower than that of older patients. It is postulated that this may be due to the fact that some younger patients with improved symptoms have not yet completed microbiological eradication. A previous study demonstrated that nebulized CMS enhanced clinical responses and diminished infection-related mortality [ 24 ]. Similarly, the sub-group analysis of medication method in this study demonstrated that, in comparison with patients who received intravenous therapy alone, those who received intravenous combined with nebulized CMS achieved higher clinical efficacy, microbiological eradication rate, and lower mortality rate. Our findings lend support to the combination of intravenous and nebulized CMS for lung infection caused by CRO, a recommendation also made by the most recent guidelines [ 8 ]. Prior research has demonstrated the efficacy of CMS in treating infections caused by CRAB, carbapenem-resistant Pseudomonas aeruginosa (CRPA), and CRE [ 25 – 27 ]. In accordance with the findings of this study, the clinical efficacy of CMS for the treatment of lung infections caused by various carbapenem-resistant organisms was consistently above 65%, with a microbial clearance rate was above 50%. It is noteworthy that the clinical effective rate in the CRE group reached 85%, indicating a greater benefit from CMS treatment. Nephrotoxicity represents one of the most prevalent and severe adverse effects observed in patients treated with CMS. Colistin has been demonstrated to increase the permeability of renal tubular epithelial cells, leading to cell swelling and lysis [ 28 ]. SCr is a key indicator for detecting renal filtration capacity, and the KDIGO criteria based on SCr are frequently employed to evaluate the nephrotoxicity of CMS[ 29 ]. The incidence of nephrotoxicity caused by polymyxins in previous reports ranged from 0–60% [ 30 – 32 ]. The discrepancies in reported incidence rates are likely attributable to variations in the study populations, colistin dosage and duration of treatment, as well as the concomitant use of other nephrotoxic drugs. In this study, 30.43% of patients receiving CMS treatment developed AKI, which is within the ranges reported previously in the literature. A recent systematic review identified a prevalence of approximately 34.7% for polymyxin-induced nephrotoxicity (KDIGO criteria), which is similar to the findings of this study [ 31 ]. Additionally, the majority of patients with AKI were classified as stage 1, with mild symptoms, indicating that CMS therapy is a safe treatment for the management of CRO infections in critically ill patients. The present study was subject to a number of limitations. Firstly, this single-center retrospective study is reliant on the record of events at the time of occurrence, which may result in a degree of bias in the interpretation of clinical response and toxicity. Secondly, the limited sample size and absence of a control group that did not receive CMS in this study restrict the scope for evaluating the true effect; a large-scale controlled study will be conducted to verify our findings. Thirdly, the majority of enrolled patients had lung infection, and therefore, the findings should be interpreted with caution when applied to other infection sites. Notwithstanding these limitations, our study has enhanced the efficacy and safety of CMS used in critically ill patients with CRO infections, thereby provides a reference for the clinical application of CMS. Conclusions Our findings corroborated CMS is a relatively safe and effective antimicrobial agent for critically ill patients with CRO infections. Subgroup analysis revealed that younger patients (< 65 years old), patients who received combined intravenous and nebulized CMS, and infections caused by CRE benefitted more from CMS treatment. Abbreviations CRO, Carbapenem resistant organisms CMS, Colistin methanesulfonate AKI, acute kidney injury WHO, World Health Organization PBS, polymyxin B sulfate PES, polymyxin E sulfate CLSI, Clinical and Laboratory Standards Institute CBA, colistin base activity KDIGO, Kidney Disease Improving Global Outcomes SCr, serum creatinine SD, standard deviation IQR, interquartile range CI, confidence interval CRAB, carbapenem-resistant Acinetobacter baumannii CRE, carbapenem-resistant Enterobacteriaceae MICs, minimum inhibitory concentrations CRPA, carbapenem-resistant Pseudomonas aeruginosa Declarations Ethics approval and consent to participate The study was conducted in accordance with the Declaration of Helsinki and approved by the clinical research ethics committee of the first affiliated hospital, college of medicine, zhejiang university (IIT20230300B-R1). Informed consent was obtained from all individual participants included in the study. Consent for publication Not applicable. Availability of data and materials All data generated or analyzed during this study are included in this published article. Competing interests The authors have no relevant financial or non-financial interests to disclose. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Authors' contributions All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; HC conceived and designed the study; XR and JX provided materials and samples for this study; XR and JX collected and assembled the data; HZ analyzed and interpreted the data. XR wrote the manuscript. Acknowledgement Not applicable. References Ma J, Song X, Li M, Yu Z, Cheng W, Yu Z, Zhang W, Zhang Y, Shen A, Sun H, et al. 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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;43:527–33. Chusri S, Sakarunchai I, Kositpantawong N, Panthuwong S, Santimaleeworagun W, Pattharachayakul S, Singkhamanan K, Doi Y. Outcomes of adjunctive therapy with intrathecal or intraventricular administration of colistin for post-neurosurgical meningitis and ventriculitis due to carbapenem-resistant acinetobacter baumannii. Int J Antimicrob Agents. 2018;51:646–50. Katip W, Uitrakul S, Oberdorfer P. A Comparison of Colistin versus Colistin Plus Meropenem for the Treatment of Carbapenem-Resistant Acinetobacter baumannii in Critically Ill Patients: A Propensity Score-Matched Analysis. Antibiot (Basel). 2020;9:647. Garcia RCL, Rodrigues RD, Garcia ECL, Rigatto MH. Comparison between Colistin and Polymyxin B in the Treatment of Bloodstream Infections Caused by Carbapenem-Resistant Pseudomonas aeruginosa and Acinetobacter baumannii-calcoaceticus Complex. Antibiot (Basel). 2023;12:1317. Ghlissi Z, Hakim A, Mnif H, Ayadi FM, Zeghal K, Rebai T, Sahnoun Z. Evaluation of colistin nephrotoxicity administered at different doses in the rat model. Ren Fail. 2013;35:1130–5. Moghnieh R, Husni R, Helou M, Abdallah D, Sinno L, Jadayel M, Diab K, Chami C, Al Rachid M, Awad DC, et al. The Prevalence and Risk Factors of Acute Kidney Injury during Colistin Therapy: A Retrospective Cohort Study from Lebanon. Antibiot (Basel). 2023;12:1183. Oliota AF, Penteado ST, Tonin FS, Fernandez-Llimos F, Sanches AC. Nephrotoxicity prevalence in patients treated with polymyxins: a systematic review with meta-analysis of observational studies. Diagn Microbiol Infect Dis. 2019;94:41–9. Wagenlehner F, Lucenteforte E, Pea F, Soriano A, Tavoschi L, Steele VR, Henriksen AS, Longshaw C, Manissero D, Pecini R et al. Systematic review on estimated rates of nephrotoxicity and neurotoxicity in patients treated with polymyxins. Clin Microbiol Infect. 2021: S1198-743X(20)30764-3. Eljaaly K, Bidell MR, Gandhi RG, Alshehri S, Enani MA, Al-Jedai A, Lee TC. Colistin Nephrotoxicity: Meta-Analysis of Randomized Controlled Trials. Open Forum Infect Dis. 2021;8:ofab026. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4978828","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":357944378,"identity":"9e6ccbbe-38bd-4d8a-af5a-f0f0e65d0ac6","order_by":0,"name":"Xindie Ren","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Xindie","middleName":"","lastName":"Ren","suffix":""},{"id":357944379,"identity":"1e9ecbc1-b146-4efc-a08a-baf518675911","order_by":1,"name":"Jun Xu","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jun","middleName":"","lastName":"Xu","suffix":""},{"id":357944381,"identity":"2dd81e66-b684-4082-817e-d9d6bca03be8","order_by":2,"name":"Hua Zhou","email":"","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Hua","middleName":"","lastName":"Zhou","suffix":""},{"id":357944382,"identity":"77aa9a14-44bc-4d97-bded-9f6c99fcce09","order_by":3,"name":"Hongliu Cai","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0ElEQVRIiWNgGAWjYBACNmbmww8SDCTkGBgOgLhEaOFjZ0sz+FBhYUy8Fjl+HgPJGWcqEhsglhLlMB4DY942ifT5jWcMGD6UHWbgn91ASAtbwWOgltzGhjMGjDPOHWaQuHOAkBbmDSBbcpsZzhgw87YdZjCQSCCkhcFAGuQwNpCWv8RpYQF5XyKBB6SFkTgt4ECWMJzBcKzgYM+5dB6JGwS0yPcfBkVlnbz8jMMbH/wos5bjn0FACwJIHABHJg+x6oGAv4EExaNgFIyCUTCiAADquz13E8UVDAAAAABJRU5ErkJggg==","orcid":"","institution":"Zhejiang University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Hongliu","middleName":"","lastName":"Cai","suffix":""}],"badges":[],"createdAt":"2024-08-26 14:51:36","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4978828/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4978828/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":86944917,"identity":"968cf4bf-a426-4793-ac0c-95752f7892f7","added_by":"auto","created_at":"2025-07-17 12:38:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":772017,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4978828/v1/c22056a2-2272-4ab5-9470-2179a813b4da.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical outcomes and nephrotoxicity of colistin methanesulfonate in critically ill patients with carbapenem-resistant organisms infections: a retrospective study","fulltext":[{"header":"Background","content":"\u003cp\u003eAccording to predictive statistical models, antibiotic resistance caused 1.27\u0026nbsp;million deaths in 2019, nearly twice the 700000 deaths reported in 2016 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The incidence rate of carbapenem resistant organisms (CRO) infections is rising rapidly worldwide, which were listed as the highest priority category (i.e. critical) by the World Health Organization (WHO) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Patients in the intensive care unit (ICU) are typically immunocompromised, with an infection rate of more than 50% [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Furthermore, due to the widespread adoption of carbapenems, the incidence of CRO infections in ICU patients has been significantly higher than in non-ICU settings, with an in-hospital mortality of up to 46.1% [\u003cspan additionalcitationids=\"CR5\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Therefore, the control of CRO infections has become a key issue to save ICU patients with severe infections.\u003c/p\u003e \u003cp\u003eThe clinical management of CRO infections is severely hampered by the extensively drug-resistant or pan-drug-resistant nature of CRO isolates [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Although extensive efforts have been made to identify new drugs that counteract the mechanisms underlying this phenomenon, most have been unsuccessful. Consequently, the reintroduction of old potent drugs into clinical practice may be a necessary effort [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Despite the cessation of polymyxins utilisation due to the elevated prevalence of adverse effects, including nephrotoxicity, its robust bactericidal efficacy and lowest resistance rate to multidrug-resistant Gram-negative bacterial infections render polymyxins the \u0026ldquo;last line of defence\u0026rdquo; for the treatment of CRO infections [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Currently, three injectable polymyxins are available in both domestic and international markets, including colistin methanesulfonate (CMS), polymyxin B sulfate (PBS), and polymyxin E sulfate (PES). As the earliest polymyxin launched internationally, CMS has the highest attention and lower nephrotoxicity than PBS [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCMS is a pro-drug of colistin, which has a high sensitivity rate against CRO infections [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Several clinical studies have confirmed that CMS is an effective antimicrobial agent for CRO infections, with acceptable nephrotoxicity [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In addition, there is growing evidence that critically ill patients with CRO infections also benefit from CMS treatment. A retrospective study from Vietnam of critically ill adult patients receiving intravenous colistin showed that 68% were clinically effective, with low nephrotoxicity (21%) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Another study from Thailand proposed that, CMS was associated with better clinical outcomes in critically ill patients with CRO infection [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, due to the late listing of CMS in China, there are currently limited studies on CMS for critically ill patients with CRO infection in China. Thus, we retrospectively investigated the clinical outcomes and nephrotoxicity of CMS in critically ill patients with CRO infection in China, aiming to provide a reference for the clinical application of CMS.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis single-center, retrospective study was conducted to assess the clinical outcomes and safety in critically ill patients with CRO infections who received CMS treatment at the First Affiliated Hospital, Zhejiang University School of Medicine between June 2022 and September 2023. Adult patients aged of 18\u0026ndash;90 years were included in the study if they were admitted to the ICU with positive cultures for CRO and received CMS treatment for three or more days. Patients were excluded if they had received other polymyxins treatment one week prior to enrollment, had a known allergy to CMS or its metabolites, pregnancy or lactation, severe liver and kidney dysfunction. The study was carried out in accordance with the Declaration of Helsinki and approved by the clinical research ethics committee of the first affiliated hospital, college of medicine, zhejiang university (IIT20230300B-R1). Written informed consent was waived owing to the retrospective nature of this investigation.\u003c/p\u003e \u003cp\u003eThe demographic, clinical, laboratory and microbiological characteristics of each enrolled patient were collected from baseline to the end of treatment. All causative organisms were identified by standard microbiological techniques. The Clinical and Laboratory Standards Institute (CLSI) method was used to evaluate the susceptibility of patients to antimicrobial agents [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eCMS administration\u003c/h2\u003e \u003cp\u003eAll enrolled patients were treated with CMS (Chia Tai Tianqing Pharmaceutical Group Co., Ltd, China). Patients receiving intravenous CMS were initially given a loading dose of 300 mg colistin base activity (CBA), followed by a maintenance dose of 2.5\u0026ndash;5 mg of CBA/kg/ day[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Patients receiving nebulized CMS were given a dose of 75 mg CBA twice a day, and the vibrating mesh nebulizer was used for nebulization[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The nebulized CMS was prepared by mixing 75 mg CBA with 3\u0026ndash;4 mL of normal saline immediately before nebulization. The specific dosage and duration of CMS was adjusted by clinical physicians based on the renal function of each patient, and the maximum daily dose is not more than 5 mg/kg.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eClinical outcomes\u003c/h2\u003e \u003cp\u003eThe primary outcomes evaluated in this study were clinical effective and microbiological eradication at the end of treatment. Clinical effective was defined as resolution or significant improvement of presenting symptoms and signs of CRO infection at the end of CMS treatment, or the non-microbiological indicators such as imaging all have returned to normal. Microbiological eradication was defined as the proportion of patients with eradication and presumed eradication in the total population. Eradication was defined as the failure to cultivate pathogenic bacteria from the original infected site of the specimen after treatment, and presumed eradication was defined as the disappearance of symptoms and signs making it impossible to obtain cultivable materials (such as sputum, skin pus, or secretions), or the method of obtaining specimens is too invasive for rehabilitation patients.\u003c/p\u003e \u003cp\u003eSecondary outcomes included infection-related hospital mortality, the length of ICU stay and length of hospital stay. It was not considered that hospital death cases occurring after the improvement of infection symptoms were related to infection. The assessment of hospital and ICU stays did not include patients who died during the course of their hospitalization.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eNephrotoxicity\u003c/h2\u003e \u003cp\u003eThe nephrotoxicity was evaluated by the development of acute kidney injury (AKI), which was defined in accordance with the Kidney Disease Improving Global Outcomes (KDIGO) criteria based on serum creatinine (SCr) values at the end of treatment [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The stage of severity of AKI was also classified in accordance with the KDIGO criteria, as follows: 1) Stage 1, an increase in SCr by \u0026ge;\u0026thinsp;26.5 \u0026micro;mol/L (0.3 mg/dL) or between 1.5 and 1.9 times the baseline value; 2) Stage 2, an increase in SCr by 2.0 to 2.9 times the baseline SCr value; 3) Stage 3, an increase in SCr by 353.6 \u0026micro;mol/L (4 mg/dL) or \u0026gt;\u0026thinsp;3.0 times the baseline SCr value, or commencement of renal replacement therapy.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll statistical analyses were conducted using the RStudio version 4.3.1. The descriptive statistics were employed to assess the baseline characteristics of patients. The distribution normality of the continuous variables was tested using the Shapiro-Wilk method. In the event that the variable was normally distributed, it was represented by the mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). Otherwise, the variable was represented by median (interquartile range, IQR). The categorical variables were represented by the corresponding number of cases and percentage. The Clopper-Pearson method was employed to calculate the 95% confidence interval (CI) for clinical efficacy, microbiological eradication, and other indicators. For patients with lung infection, a subgroup analysis was conducted based on age, medication method and causative organisms.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003ePatient baseline characteristics\u003c/h2\u003e \u003cp\u003eA total of 96 critically ill patients with CRO infections who met the inclusion criteria were recruited for analysis. The characteristics of patient were presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The mean age of all patients was 62.61\u0026thinsp;\u0026plusmn;\u0026thinsp;17.28 years, with 73.96% being male. The majority of patients (83.33%) had a past medical history. Of these patients, 36 (37.50%) experienced sepsis, and 18 (18.75%) developed septic shock. The majority of patients (77/96, 80.2%) had a lung infection, and the most frequently causative organisms were carbapenem-resistant \u003cem\u003eAcinetobacter baumannii\u003c/em\u003e (CRAB) (57/96, 59.38%), followed by carbapenem-resistant \u003cem\u003eEnterobacteriaceae\u003c/em\u003e (CRE, 37/96, 38.54%), including 31 patients (32.29%) with carbapenem-resistant \u003cem\u003eKlebsiella pneumonia\u003c/em\u003e. Most of patients (87/96, 90.62%) received mechanical ventilation, 33 patients (34.38%) received haemodialysis, and 52 patients (54.17%) were treated with vasoactive agents. All patients received CMS therapy, with 79.17% (76/96) of patients involving the prescription of this treatment in combination with other antimicrobial agents.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe demographic and clinical characteristics of patients\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;96)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e62.61\u0026thinsp;\u0026plusmn;\u0026thinsp;17.28\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender, male, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71 (73.96)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.08\u0026thinsp;\u0026plusmn;\u0026thinsp;3.96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePast medical history, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80 (83.33)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSepsis, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36 (37.50)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSeptic shock, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18 (18.75)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSOFA score, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7.70\u0026thinsp;\u0026plusmn;\u0026thinsp;4.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAPACHE II score, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e18.03\u0026thinsp;\u0026plusmn;\u0026thinsp;7.33\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCharslon comorbidity index, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.96\u0026thinsp;\u0026plusmn;\u0026thinsp;2.59\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGlasgow Coma Scale, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10.30\u0026thinsp;\u0026plusmn;\u0026thinsp;5.41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSite of infection, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e77 (80.2)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e19 (19.79)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCausative organisms, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCarbapenem-resistant \u003cem\u003eAcinetobacter baumannii\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e57 (59.38)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCarbapenem-resistant \u003cem\u003eEnterobacteriaceae\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37 (38.54)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCarbapenem-resistant \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (11.46)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOthers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (2.08)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLaboratory parameters, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum creatinine, \u0026micro;mol/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e117.62\u0026thinsp;\u0026plusmn;\u0026thinsp;89.18\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eC reactive protein, mg/L\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e97.76\u0026thinsp;\u0026plusmn;\u0026thinsp;70.96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eProcalcitonin, ng/mL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.47\u0026thinsp;\u0026plusmn;\u0026thinsp;7.25\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMechanical ventilation, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e87 (90.62)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemodialysis, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (34.38)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVasoactive agents, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52 (54.17)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStrategy of CMS use, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMonotherapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20 (20.83)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCombination therapy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76 (79.17)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003e\u003csup\u003e*\u003c/sup\u003eData are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, no. (%), median (IQR), where no. is the total number of patients with available data. SOFA, sequential organ failure assessment; APACHE II, acute physiology and chronic health evaluation II; CMS, Colistin methanesulfonate.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe resistance profiles of the 5 common antimicrobial agents used for the treatment of CRO infections was shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The antimicrobial non-susceptibility rates to meropenem and imipenem were both 96.84% (92/95). 71.25% (57/80) and 69.23% (27/39) of patients were susceptible to tigecycline and ceftazidime/avibactam, respectively. A total of 96.74% of patients exhibited intermediate resistance to colistin, with minimum inhibitory concentrations (MICs) of \u0026le;\u0026thinsp;2.0 mg/L (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSusceptibility of patients to antimicrobial agents\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntimicrobial agents\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTested,\u003c/p\u003e \u003cp\u003eno.\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSusceptibility\u003c/p\u003e \u003cp\u003eno. (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIntermediate\u003c/p\u003e \u003cp\u003eno. (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eResistance\u003c/p\u003e \u003cp\u003eno. (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMeropenem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (3.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e92 (96.84)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImipenem\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 (3.16)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e92 (96.84)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTigecycline\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57 (71.25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e19 (23.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4 (5.00)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCeftazidime/avibactam\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e39\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (69.23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e12 (30.77)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eColistin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e89 (96.74)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3 (3.26)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eClinical outcomes analysis\u003c/h2\u003e \u003cp\u003eThe clinical effective of CMS treatment was achieved in 55 patients (67.90%), and microbiological eradication was achieved in 49 patients (60.49%) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The overall infection-related hospital mortality was 8.33% (8/96). The median length of ICU and hospital stays was 28 and 32.5 days, respectively. In patients with lung infection, 70.31% (45/77) and 61.19% (41/77) achieved clinical effective and microbiological eradication, respectively. Furthermore, the infection-related hospital mortality was 7.79% (6/77), with a median length of ICU and hospital stays of 29 and 33 days, respectively.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical outcomes of patients treated with CMS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNo. (%) or median (IQR)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical effective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e55 (67.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e56.60, 77.85\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMicrobiological eradication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e49 (60.49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e49.01, 71.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecondary outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfection-related hospital mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (8.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.67, 15.76\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of ICU stay (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e28 (18.00, 51.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27, 41\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of total hospital stay (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32.50 (20.50, 63.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35.50, 50.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLung infection (n\u0026thinsp;=\u0026thinsp;77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical effective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e45 (70.31)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e57.58, 81.09\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMicrobiological eradication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41 (61.19)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e48.50, 72.86\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSecondary outcomes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfection-related hospital mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (7.79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.91, 16.19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of ICU stay (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29 (18.00, 50.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27.50, 42.00\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of total hospital stay (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33 (24,62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35.00, 50.50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eSub-group analysis\u003c/h2\u003e \u003cp\u003eSub-group analysis based on age, medication method and causative organisms of patients with lung infection were presented in Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e. The younger patients (\u0026lt;\u0026thinsp;65 years old) demonstrated superior clinical efficiency (75% \u003cem\u003evs.\u003c/em\u003e 66.67%), lower infection-related hospital mortality (2.94% \u003cem\u003evs.\u003c/em\u003e 11.63%) and shorter ICU stay (24 \u003cem\u003evs.\u003c/em\u003e 31 days). Compared with patients who received intravenous alone, intravenous combined nebulized CMS achieved higher clinical efficacy (61.90% \u003cem\u003evs.\u003c/em\u003e 84.62%), microbiological eradication rate (56.82% \u003cem\u003evs.\u003c/em\u003e78.57%), and lower infection-related hospital mortality rate (9.43% \u003cem\u003evs.\u003c/em\u003e 0). In the sub-groups defined by causative organisms, patients with CRE infections benefitted more from CMS treatment, with a clinical efficiency of 85.71%, a microbiological eradication of 64.29%, and an infection-related hospital mortality of 5.88%.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSubgroup analysis of clinical outcomes in patients with lung infection\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables, no. (%) or median (IQR)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;65 years (n\u0026thinsp;=\u0026thinsp;34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026ge;\u0026thinsp;65 years (n\u0026thinsp;=\u0026thinsp;43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical effective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21 (75.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24 (66.67)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMicrobiological eradication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (53.33)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25 (67.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfection-related hospital mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (2.94)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 (11.63)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of ICU stay (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24 (18, 56)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31 (19.00, 46.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of total hospital stay (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (19, 61)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e33 (27.25, 61.75)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIntravenous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIntravenous combined\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ealone (n\u0026thinsp;=\u0026thinsp;53)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003enebulized CMS (n\u0026thinsp;=\u0026thinsp;14)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical effective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (61.90)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (84.62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMicrobiological eradication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25 (56.82)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (78.57)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfection-related hospital mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (9.43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of ICU stay (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.50 (17.75, 44.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (24, 69)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of total hospital stay (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32 (18.75, 61.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e40 (26, 93)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCRAB (n\u0026thinsp;=\u0026thinsp;49)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCRE (n\u0026thinsp;=\u0026thinsp;17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCRPA (n\u0026thinsp;=\u0026thinsp;6)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eClinical effective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27 (65.85)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (85.71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4 (66.67)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMicrobiological eradication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (59.09)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9 (64.29)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 (50.00)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfection-related hospital mortality\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (4.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 (5.88)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2 (33.33)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of ICU stay (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e31.50 (19.00, 56.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27 (20, 41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e21 (17, 65)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLength of total hospital stay (days)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32.50 (24.75, 64.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e41 (25, 52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e82 (69, 113)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eCRAB, carbapenem-resistant \u003cem\u003eAcinetobacter baumannii\u003c/em\u003e; CRE, carbapenem-resistant \u003cem\u003eEnterobacteriaceae\u003c/em\u003e; CRPA, carbapenem-resistant \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e; CMS, Colistin methanesulfonate.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eNephrotoxicity analysis\u003c/h2\u003e \u003cp\u003eNephrotoxicity that possibly or probably related to the use of CMS were presented in Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e. The incidence of AKI among patients received CMS treatment was 28 cases (30.43%), with 23 patients (82.14%) presenting with stage 1 AKI, 2 patients (7.14%) with stage 2 AKI, and 3 patients (10.71%) with stage 3 AKI. The median change in serum creatinine from baseline for patients was 4 \u0026micro;mol/L.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eNephrotoxicity possibly or probably related to the use of CMS\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNephrotoxicity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTotal (n\u0026thinsp;=\u0026thinsp;96)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute kidney injury, no. (%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYes\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e28 (30.43)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNo\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e64 (69.57)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKDIGO criteria\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStage 1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23 (82.14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStage 2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2 (7.14)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eStage 3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3 (10.71)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSerum creatinine change from baseline (Δ),\u003c/p\u003e \u003cp\u003e\u0026micro;mol/L, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (-31.00, 39.5)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eCMS, Colistin methanesulfonate; KDIGO, Kidney Disease Improving Global Outcomes.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the best of our knowledge, this was one of the first studies to describe the clinical outcomes of CMS use in Chinese critically ill patients. The overall clinical effective rate was 67.9%, the microbiological eradication rate was 60.49%, and the infection-related hospital mortality was 8.33%. Subgroup analysis demonstrated that younger patients (\u0026lt;\u0026thinsp;65 years old), patients who received intravenous combined nebulized CMS, and infections caused by CRE benefitted more from CMS treatment. 30.43% of patients developed AKI, and most (82.14%) of them were stage 1. In light of these findings, CMS treatment for Chinese critically ill patients with CRO infections achieved favorable outcomes, with acceptable nephrotoxicity.\u003c/p\u003e \u003cp\u003eThe increasing of mortality rate associated with CRO infections in critically ill patients has prompted the widespread adoption of CMS. A previous study in critically ill patients investigated the efficacy of CMS and found a clinical effective rate of 68% and a microbiological eradication rate of 62.5%. These findings are similar to those reported there [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Additionally, the findings of this study demonstrated that the infection-related hospital mortality rate was 8.33%, which was lower than that observed in previous studies [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. It is plausible that the mortality in critically ill patients is influenced by factors beyond infectious control, such as disease severity and the presence of comorbidities. It should be noted that this study only counted infection-related hospital mortality, and hospital deaths that occurred after symptom improvement were considered unrelated to infection. Lung infection was the most common site of infection in critically ill patients [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], with 80% of patients with lung infections in our study. Consequently, an analysis of the clinical outcomes of patients with lung infections was condducted, which revealed that 70.31% of patients achieved clinical effective, 61.19% of patients achieved microbiological eradication, and the infection-related hospital mortality was 7.79%, which was comparable to those of the overall population.\u003c/p\u003e \u003cp\u003eA 10-year prospective observational study conducted in China indicated that age\u0026thinsp;\u0026ge;\u0026thinsp;65 years was independent risk factor for in-hospital mortality among adult patients with lung infection [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The sub-group analysis of age\u0026thinsp;\u0026lt;\u0026thinsp;65 years and \u0026ge;\u0026thinsp;65 years revealed that younger patients exhibited a higher clinical effective rate and a lower infection-related hospital mortality. Similarly, a previous study has also demonstrated that the patients who responded to treatment were younger than patients who did not respond [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. However, the microbiological eradication rate of younger patients in this study was slightly lower than that of older patients. It is postulated that this may be due to the fact that some younger patients with improved symptoms have not yet completed microbiological eradication. A previous study demonstrated that nebulized CMS enhanced clinical responses and diminished infection-related mortality [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Similarly, the sub-group analysis of medication method in this study demonstrated that, in comparison with patients who received intravenous therapy alone, those who received intravenous combined with nebulized CMS achieved higher clinical efficacy, microbiological eradication rate, and lower mortality rate. Our findings lend support to the combination of intravenous and nebulized CMS for lung infection caused by CRO, a recommendation also made by the most recent guidelines [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Prior research has demonstrated the efficacy of CMS in treating infections caused by CRAB, carbapenem-resistant \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e (CRPA), and CRE [\u003cspan additionalcitationids=\"CR26\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In accordance with the findings of this study, the clinical efficacy of CMS for the treatment of lung infections caused by various carbapenem-resistant organisms was consistently above 65%, with a microbial clearance rate was above 50%. It is noteworthy that the clinical effective rate in the CRE group reached 85%, indicating a greater benefit from CMS treatment.\u003c/p\u003e \u003cp\u003eNephrotoxicity represents one of the most prevalent and severe adverse effects observed in patients treated with CMS. Colistin has been demonstrated to increase the permeability of renal tubular epithelial cells, leading to cell swelling and lysis [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. SCr is a key indicator for detecting renal filtration capacity, and the KDIGO criteria based on SCr are frequently employed to evaluate the nephrotoxicity of CMS[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The incidence of nephrotoxicity caused by polymyxins in previous reports ranged from 0\u0026ndash;60% [\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. The discrepancies in reported incidence rates are likely attributable to variations in the study populations, colistin dosage and duration of treatment, as well as the concomitant use of other nephrotoxic drugs. In this study, 30.43% of patients receiving CMS treatment developed AKI, which is within the ranges reported previously in the literature. A recent systematic review identified a prevalence of approximately 34.7% for polymyxin-induced nephrotoxicity (KDIGO criteria), which is similar to the findings of this study [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Additionally, the majority of patients with AKI were classified as stage 1, with mild symptoms, indicating that CMS therapy is a safe treatment for the management of CRO infections in critically ill patients.\u003c/p\u003e \u003cp\u003eThe present study was subject to a number of limitations. Firstly, this single-center retrospective study is reliant on the record of events at the time of occurrence, which may result in a degree of bias in the interpretation of clinical response and toxicity. Secondly, the limited sample size and absence of a control group that did not receive CMS in this study restrict the scope for evaluating the true effect; a large-scale controlled study will be conducted to verify our findings. Thirdly, the majority of enrolled patients had lung infection, and therefore, the findings should be interpreted with caution when applied to other infection sites. Notwithstanding these limitations, our study has enhanced the efficacy and safety of CMS used in critically ill patients with CRO infections, thereby provides a reference for the clinical application of CMS.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eOur findings corroborated CMS is a relatively safe and effective antimicrobial agent for critically ill patients with CRO infections. Subgroup analysis revealed that younger patients (\u0026lt;\u0026thinsp;65 years old), patients who received combined intravenous and nebulized CMS, and infections caused by CRE benefitted more from CMS treatment.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCRO, Carbapenem resistant organisms\u003c/p\u003e \u003cp\u003eCMS, Colistin methanesulfonate\u003c/p\u003e \u003cp\u003eAKI, acute kidney injury\u003c/p\u003e \u003cp\u003eWHO, World Health Organization\u003c/p\u003e \u003cp\u003ePBS, polymyxin B sulfate\u003c/p\u003e \u003cp\u003ePES, polymyxin E sulfate\u003c/p\u003e \u003cp\u003eCLSI, Clinical and Laboratory Standards Institute\u003c/p\u003e \u003cp\u003eCBA, colistin base activity\u003c/p\u003e \u003cp\u003eKDIGO, Kidney Disease Improving Global Outcomes\u003c/p\u003e \u003cp\u003eSCr, serum creatinine\u003c/p\u003e \u003cp\u003eSD, standard deviation\u003c/p\u003e \u003cp\u003eIQR, interquartile range\u003c/p\u003e \u003cp\u003eCI, confidence interval\u003c/p\u003e \u003cp\u003eCRAB, carbapenem-resistant \u003cem\u003eAcinetobacter baumannii\u003c/em\u003e\u003c/p\u003e \u003cp\u003eCRE, carbapenem-resistant \u003cem\u003eEnterobacteriaceae\u003c/em\u003e\u003c/p\u003e \u003cp\u003eMICs, minimum inhibitory concentrations\u003c/p\u003e \u003cp\u003eCRPA, carbapenem-resistant \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki and approved by the clinical research ethics committee of the first affiliated hospital, college of medicine, zhejiang university (IIT20230300B-R1). Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; HC conceived and designed the study; XR and JX provided materials and samples for this study; XR and JX collected and assembled the data; HZ analyzed and interpreted the data. XR wrote the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eMa J, Song X, Li M, Yu Z, Cheng W, Yu Z, Zhang W, Zhang Y, Shen A, Sun H, et al. Global spread of carbapenem-resistant Enterobacteriaceae: Epidemiological features, resistance mechanisms, detection and therapy. Microbiol Res. 2023;266:127249.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNordmann P, Poirel L. Epidemiology and Diagnostics of Carbapenem Resistance in Gram-negative Bacteria. Clin Infect Dis. 2019;69:S521\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi Q, Zhou X, Yang R, Shen X, Li G, Zhang C, Li P, Li S, Xie J, Yang Y. Carbapenem-resistant Gram-negative bacteria (CR-GNB) in ICUs: resistance genes, therapeutics, and prevention - a comprehensive review. 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Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1). Crit Care. 2013;17:204.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFeng JY, Huang JR, Lee CC, Tseng YH, Pan SW, Chen YM, Yang KY. Role of nebulized colistin as a substitutive strategy against nosocomial pneumonia caused by CR-GNB in intensive care units: a retrospective cohort study. Ann Intensive Care. 2023;13:1.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbe T, Ogura H, Kushimoto S, Shiraishi A, Sugiyama T, Deshpande GA, Uchida M, Nagata I, Saitoh D, Fujishima S, et al. Variations in infection sites and mortality rates among patients in intensive care units with severe sepsis and septic shock in Japan. J Intensive Care. 2019;7:28.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYin Y, Zhao C, Li H, Jin L, Wang Q, Wang R, Zhang Y, Zhang J, Wang H. Clinical and microbiological characteristics of adults with hospital-acquired pneumonia: a 10-year prospective observational study in China. Eur J Clin Microbiol Infect Dis. 2021;40:683\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eValachis 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;43:527\u0026ndash;33.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChusri S, Sakarunchai I, Kositpantawong N, Panthuwong S, Santimaleeworagun W, Pattharachayakul S, Singkhamanan K, Doi Y. Outcomes of adjunctive therapy with intrathecal or intraventricular administration of colistin for post-neurosurgical meningitis and ventriculitis due to carbapenem-resistant acinetobacter baumannii. Int J Antimicrob Agents. 2018;51:646\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKatip W, Uitrakul S, Oberdorfer P. A Comparison of Colistin versus Colistin Plus Meropenem for the Treatment of Carbapenem-Resistant Acinetobacter baumannii in Critically Ill Patients: A Propensity Score-Matched Analysis. Antibiot (Basel). 2020;9:647.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGarcia RCL, Rodrigues RD, Garcia ECL, Rigatto MH. Comparison between Colistin and Polymyxin B in the Treatment of Bloodstream Infections Caused by Carbapenem-Resistant Pseudomonas aeruginosa and Acinetobacter baumannii-calcoaceticus Complex. Antibiot (Basel). 2023;12:1317.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGhlissi Z, Hakim A, Mnif H, Ayadi FM, Zeghal K, Rebai T, Sahnoun Z. Evaluation of colistin nephrotoxicity administered at different doses in the rat model. Ren Fail. 2013;35:1130\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMoghnieh R, Husni R, Helou M, Abdallah D, Sinno L, Jadayel M, Diab K, Chami C, Al Rachid M, Awad DC, et al. The Prevalence and Risk Factors of Acute Kidney Injury during Colistin Therapy: A Retrospective Cohort Study from Lebanon. Antibiot (Basel). 2023;12:1183.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOliota AF, Penteado ST, Tonin FS, Fernandez-Llimos F, Sanches AC. Nephrotoxicity prevalence in patients treated with polymyxins: a systematic review with meta-analysis of observational studies. Diagn Microbiol Infect Dis. 2019;94:41\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWagenlehner F, Lucenteforte E, Pea F, Soriano A, Tavoschi L, Steele VR, Henriksen AS, Longshaw C, Manissero D, Pecini R et al. Systematic review on estimated rates of nephrotoxicity and neurotoxicity in patients treated with polymyxins. Clin Microbiol Infect. 2021: S1198-743X(20)30764-3.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEljaaly K, Bidell MR, Gandhi RG, Alshehri S, Enani MA, Al-Jedai A, Lee TC. Colistin Nephrotoxicity: Meta-Analysis of Randomized Controlled Trials. Open Forum Infect Dis. 2021;8:ofab026.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Carbapenem-resistant organisms, Critically ill patients, Colistin methanesulfonate, Clinical outcomes, Nephrotoxicity","lastPublishedDoi":"10.21203/rs.3.rs-4978828/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4978828/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCarbapenem resistant organisms (CRO) infection is one of the most common causes of high mortality among critically ill patients. Colistin methanesulfonate (CMS) represents a significant treatment option for CRO infections, yet the available data on CMS in the Chinese population remains limited. This study aimed to analyze the clinical outcomes and nephrotoxicity of CMS in treating critically ill patients with CRO infections in China.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eA retrospective study was conducted from June 2022 to September 2023 in critically ill patients with CRO infections who received CMS treatment. The clinical outcomes were assessed by clinical effective, microbiological eradication, infection-related hospital mortality, the length of ICU stay, and total hospital stay. A sub-group analysis was conducted on patients with lung infection. The nephrotoxicity was assessed by the acute kidney injury (AKI).\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 96 critically ill patients with CRO infections were enrolled in the study. The overall clinical effective, microbiological eradication and infection-related hospital mortality rates were 67.90%, 60.49% and 8.33%, respectively. The median length of ICU and total hospital stays was 28 and 32.5 days, respectively. In patients with lung infection, 70.31% and 61.19% achieved clinical effective and microbiological eradication, respectively. The younger patients (\u0026lt;\u0026thinsp;65 years old), patients who received intravenous combined nebulized CMS, and infections caused by CRE benefitted more from CMS treatment. The incidence of acute kidney injury (AKI) was 28 cases (30.43%), with the majority (82.14%) occurring in stage 1.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eCMS treatment in Chinese critically ill patients with CRO infections achieved favorable outcomes, with acceptable nephrotoxicity, providing a promising option for this fatal disease.\u003c/p\u003e","manuscriptTitle":"Clinical outcomes and nephrotoxicity of colistin methanesulfonate in critically ill patients with carbapenem-resistant organisms infections: a retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-26 11:33:03","doi":"10.21203/rs.3.rs-4978828/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"224bf827-6c43-485d-8b57-ee8cbb119426","owner":[],"postedDate":"September 26th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-07-17T12:38:33+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-26 11:33:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4978828","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4978828","identity":"rs-4978828","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}