Efficacy and Safety of Three Colistin Regimens in the Treatment of Nosocomial Pneumonia Caused by Carbapenem-Resistant Organisms: A Single Centre, Open Label, Prospective Cohort Study

Efficacy and Safety of Three Colistin Regimens in the Treatment of Nosocomial Pneumonia Caused by Carbapenem-Resistant Organisms: A Single Centre, Open Label, Prospective Cohort 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 Efficacy and Safety of Three Colistin Regimens in the Treatment of Nosocomial Pneumonia Caused by Carbapenem-Resistant Organisms: A Single Centre, Open Label, Prospective Cohort Study Qiao-yi Wei, Xin-xing Chen, Feng Xu, Heng Fan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6911404/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 The optimal route of colistin administration for treating carbapenem-resistant organisms (CRO) nosocomial pneumonia remains unclear. The objective of this study was to assess the efficacy and safety of three distinct regimens that are based on colistin. Methods 98 patients with nosocomial pneumonia caused by CRO who received colistin treatment in the intensive care unit were included in this prospective cohort study. Based on the route of administration, patients were categorized into three groups: inhalation (IH), combined intravenous plus inhalation (IV + IH), and intravenous (IV). Clinical efficacy was the primary outcome at the end of the treatment. Secondary outcomes involved 28-day all-cause mortality, microbiological response, nephrotoxicity, and duration of hospital stay. Results The clinical efficacy rates were 70.0% for the IH group, 64.7% for the IV + IH group, and 64.3% for the IV group, with no significant differences observed ( P = 0.834). Patients in the IH group achieved significantly better microbiological outcomes compared to those in the IV group ( P = 0.009). However, no substantial differences were observed among the groups regarding 28-day all-cause mortality, duration of hospital stay, or incidence of acute kidney injury. Moreover, higher APACHE II scores, the existence of sepsis, and the occurrence of acute kidney injury were identified as factors related to clinical treatment failure. Conclusion In the treatment of nosocomial pneumonia caused by CRO, inhaled administration demonstrated non-inferior clinical efficacy compared to systemic administration and was associated with a higher incidence of microbiological eradication. Colistin Nosocomial pneumonia Inhaled Carbapenem-resistant Gram-negative bacteria Intravenous Figures Figure 1 Figure 2 Figure 3 Introduction Nosocomial pneumonia, including hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), remains a major challenge for critically ill patients. Studies show that 10–40% of individuals using mechanical ventilation for over 48 hours may develop VAP. Moreover, the probability of mortality in patients with HAP is 8.4 times higher compared to those without HAP, which is closely related to the profound pathophysiological alterations in critically ill patients—changes that can significantly affect the pharmacokinetics of antibiotics [ 1 ]. Additionally, refractory infections and multidrug-resistant pathogens are increasingly prevalent in intensive care units (ICUs), posing significant challenges to infection control [ 2 ]. Notably, carbapenem-resistant Gram-negative bacteria (GR-NGB), such as Acinetobacter baumannii and Enterobacterales , are linked to high mortality and have been designated as critical priority pathogens in the WHO’s 2024 Bacterial Priority Pathogens Lists, underscoring the urgent need for effective interventions [ 3 ]. Polymyxins, despite their known limitations, have played a pivotal role in the management of illnesses induced by resistant Gram-negative bacteria [ 4 ]. Discovered in the 1940s, these peptide antibiotics exert rapid bactericidal activity by disrupting the integrity of Gram-negative bacterial cell membranes. Although they were later replaced by newer antibiotics with more favourable toxicity profiles, the rise of multidrug-resistant bacteria has led to their re-emergence as a vital therapeutic option. Colistimethate sodium (CMS), a clinically prevalent formulation of colistin in practice, is an inactive prodrug that necessitates in vivo conversion to its active state, colistin, to manifest its antibacterial effects [ 5 ]. Although intravenous colistin has become an important salvage therapy, its high molecular weight and low solubility hinder effective penetration through the tightly bound cellular barriers of the lungs [ 6 ]. Previous studies have demonstrated that aerosolized administration of colistin results in significantly higher drug concentrations in the epithelial lining fluid relative to plasma. At 1, 3, and 5 hours post-administration, the median colistin concentrations in epithelial lining fluid were reported to be 614-fold, 408-fold, and 250-fold higher than those in plasma, respectively [ 7 ]. This marked pulmonary accumulation suggests that inhaled delivery has the potential to increase the therapeutic efficacy against pulmonary infections and reduce the risk of systemic toxicity by achieving high local drug concentrations at the site of infection while minimizing systemic distribution [ 8 , 9 ]. There is ongoing controversy regarding the optimal route of colistin administration for the treatment of nosocomial pneumonia [ 10 , 11 ], particularly concerning whether inhaled colistin should be used as an adjunct to or a substitute for intravenous colistin. Furthermore, the current body of evidence regarding its efficacy and safety remains insufficient [ 12 ]. Consequently, this study aims to assess and compare the clinical effectiveness and nephrotoxicity of three distinct administrative strategies for colistin — intravenous alone, inhaled alone, and the combination of both — in the management of nosocomial pneumonia induced by CR-GNB. Method Study design and setting This research was structured as a prospective, single-centre cohort study. It was conducted in the ICU of The First Affiliated Hospital of Ningbo University from January 1, 2023, to April 30, 2025. Approval for the study was granted by the Ethics Committee of The First Affiliated Hospital of Ningbo University [Approval No. 2024-R044-02]. The trial was registered in ClinicalTrials.gov (NCT06907069). We included patients aged ≥ 18 years who received colistin treatment for more than 72 hours and were diagnosed with nosocomial pneumonia (NP) caused by carbapenem-resistant organisms (CRO) and had respiratory isolates that were susceptible to colistin. Exclusion criteria were as follows: pregnancy or lactation, known allergy to colistin, missing essential clinical data, or participation in another clinical trial within the past three months. In this analysis, only the initial episode of colistin treatment was evaluated for individuals who received several treatments over the study period. Dosing and Administration Based on clinical status, patients received colistin therapy via intravenous administration (IV), inhalation (IH), or a combination of both (IV + IH). The intravenous dose of colistin ranged from 2.5 to 5 mg colistin base activity (CBA) per kilogram per day. In patients with renal impairment or those undergoing renal replacement treatment, the dose was adjusted based on the estimated glomerular filtration rate. For inhaled administration, 75 mg CBA was diluted in 3–5 mL of 0.9% sterile normal saline and administered every 8 or 12 hours using a vibrating mesh nebulizer. Data Collection All data were obtained from the electronic medical record system, with the day of colistin administration designated as Day 1 of treatment. A comprehensive range of potential confounding variables was collected, including demographic information, underlying disease, Charlson Comorbidity Index, Clinical Pulmonary Infection Score (CPIS). The laboratory parameters measured included inflammation-related markers, total protein, albumin, and serum creatinine. The Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores were also assessed pre-treatment and post-treatment. In addition, we also considered the patients' microbiological findings, details of antimicrobial therapy, clinical outcomes, microbiological outcomes, adverse drug reactions, and 28-day all-cause mortality. Definitions and Outcomes According to the Clinical Practice Guidelines for the Management of Adults with Hospital-acquired and Ventilator-associated Pneumonia jointly issued by the American Thoracic Society and the Infectious Diseases Society of America in 2016, HAP and VAP are defined as follows. HAP: pneumonia that occurs 48 hours or more after hospital admission, that was not present at the time of admission and is unrelated to mechanical ventilation. VAP: pneumonia that arises more than 48 hours after endotracheal intubation and initiation of mechanical ventilation [ 13 ]. The principal outcome was the clinical effectiveness at the end of treatment. Clinical efficacy was defined as the resolution or alleviation of pneumonia symptoms and signs after the conclusion of colistin treatment. Clinical failure was characterised by the persistence or exacerbation of pneumonia symptoms or signs at the end of colistin treatment. Cure or improvement was defined based on the patient’s alive, resolution of fever, reduced need for sputum suction, improvement or resolution of imaging findings, stabilization or improvement of PaO₂/FiO₂ ratio, and reduction or normalization of infection markers. Secondary clinical outcomes encompassed 28-day all-cause mortality, microbiological outcomes, nephrotoxicity, the duration of stay in the ICU and hospital. Sputum, endotracheal aspirates, or bronchoalveolar lavage fluid were the sources of all microbiological isolates. The absence of the original causative pathogen in cultures obtained from the primary site of infection after treatment has been defined as microbiological eradication. In cases where clinical resolution rendered specimen collection infeasible — such as the inability to expectorate sputum — or when obtaining specimens would require invasive procedures not justified in recovering patients, the outcome was considered presumed eradication. The microbiological eradication rate was determined using the formula: (number of eradications + number of presumed eradications) / total number of patients × 100%. Due to the sedated state of most ICU patients, neurological side effects could not be reliably assessed. In contrast, nephrotoxicity was more easily identifiable and had a higher incidence [ 14 ], making it the primary adverse effect of interest in this study. Nephrotoxicity was defined using the KDIGO criteria as the occurrence of acute kidney injury during colistin therapy, with at least one of the following conditions: (1) A serum creatinine increase of more than 26.5 µmol/L (0.3 mg/dL) within 48 hours; (2) A serum creatinine increase of more than 1.5 times the baseline within 7 days; (3) Urine output < 0.5 mL/(kg·h) [ 15 ]. Statistical analyses All statistical analyses were performed using SPSS (version 27.0, IBM Corporation, Armonk, NY, USA). Continuous variables with a normal distribution were characterised by mean ± standard deviation (SD), and analysis was conducted using ANOVA. For continuous variables that do not follow a normal distribution, data were presented as median with interquartile range (IQR) and analysed using the Kruskal-Wallis test for multiple independent samples. Categorical variables were represented as frequencies or proportions and analysed with the chi-square test or Fisher’s exact test. Post hoc pairwise comparisons were performed utilising the Bonferroni correction method. A P value of less than 0.05 was deemed statistically significant. Kaplan-Meier curves were constructed to compare 28-day cumulative survival among the IV, IH, and IV + IH groups. Variables linked to the primary outcome in univariate logistic regression analysis were used to determine independent predictors of clinical resolution. Result Patient characteristics and baseline clinical data This single-centre prospective study analysed 98 patients diagnosed with NP caused by CRO who received colistin treatment between January 2023 and April 2025. Figure 1 illustrates the flow diagram for patient inclusion and exclusion in this article. Among the enrolled patients, 50 patients received inhaled colistin therapy, 34 patients received a combination of intravenous and inhaled colistin, and 14 patients received intravenous colistin monotherapy. The study population included 71 male patients (72.4%) and 27 female patients (27.6%). Carbapenem-resistant Acinetobacter baumannii (57.1%) was the most common pathogen. There was no significant difference in microbial distribution among the groups ( P = 0.466). Regarding concomitant antibiotic therapy for CRO infections, meropenem (28.3%) and cefoperazone-sulbactam (28.3%) were the most frequently administered agents, followed by piperacillin-tazobactam (20.3%) and tigecycline (8.0%). No statistically significant variations in antibiotic utilization were detected among the three groups ( P > 0.05). There were no substantial differences among the three cohorts, including age, BMI, comorbidities, or baseline APACHE II, SOFA, and CPIS scores prior to treatment. However, a significant difference was detected in the baseline serum creatinine levels, with the intravenous group exhibiting lower levels compared to the inhalation group ( P = 0.019). Comprehensive demographic and clinical characteristics are characteristics in Table 1 (full table at the end of manuscript). Table 1 Demographic and clinical characteristic of study patients IH (n = 50) IV + IH (n = 34) IV (n = 14) P value Demographic Age, years 68.46 ± 15.33 72.21 ± 13.75 64.71 ± 10.96 0.180 Male, n (%) 40 (80.0) 25 (73.5) 6 (42.9) 0.022 BMI 23.58 ± 4.07 22.44 ± 4.44 23.21 ± 2.34 0.480 Charlson Comorbidity Index 4.02 ± 1.89 4.82 ± 1.70 3.86 ± 2.18 0.108 Underlying disease, n (%) Diabetes mellitus 12 (24.0) 14 (41.2) 2 (14.3) 0.102 Hypertension 26 (52.0) 22 (64.7) 6 (42.9) 0.336 Chronic cardiovascular disease 6 (12.0) 4 (11.8) 0 (0) 0.477 Chronic pulmonary disease 7 (14.0) 7 (20.6) 0 (0) 0.197 Cerebrovascular disease 6 (12.0) 5 (14.7) 0 (0) 0.422 Arrhythmia 7 (14.0) 4 (11.8) 3 (21.3) 0.672 Isolated pathogen at diagnosis, n (%) CRAB 32 (64.0) 18 (52.9) 10 (71.4) 0.446 CRPA 10 (20.0) 11 (32.4) 2 (14.3) 0.316 CRKP 8 (16.0) 5 (14.7) 3 (21.4) 0.864 Others 2 (4.0) 4 (11.8) 0 (0) 0.232 Polymyxins MIC distribution ≤ 0.5 mg/L, n (%) 31 (62.0) 17 (50.0) 5 (35.7) 0.183 Concomitant antibiotic therapy, n (%) Meropenem 17 (34.0) 14 (41.2) 8 (57.1) 0.313 Cefoperazone-Sulbactam 15 (30.0) 17 (50.0) 7 (50.0) 0.144 Piperacillin-Tazobactam 15 (30.0) 8 (23.5) 5 (35.7) 0.642 Tigecycline 9 (18.0) 2 (5.9) 0 (0) 0.122 Others 13 (26.0) 5 (14.7) 3 (21.4) 0.518 Pre-treatment APACHE II score 20.82 ± 5.19 22.06 ± 4.26 22.36 ± 5.27 0.407 SOFA score 7.00 ± 2.60 7.74 ± 3.21 8.36 ± 3.80 0.268 CPIS score 6.66 ± 1.66 7.12 ± 1.60 7.36 ± 2.13 0.289 PaO 2 /FiO 2 , mmHg 296.43 ± 111.32 251.00 ± 92.25 292.44 ± 114.07 0.149 T, °C 37.96 ± 0.76 37.92 ± 0.87 38.5 ± 0.86 0.066 White blood cell count, 10 9 /L 11.2 (8.60, 15.65) 9.95 (6.38, 15.50) 11.25 (6.55, 13.55) 0.507 CRP, mg/L 96.89 (65.61, 160.63) 92.32(41.84, 194.75) 48.44(25.71,170.05) 0.618 PCT, ng/mL 0.679(0.3, 1.794) 0.475(0.248, 3.173) 0.703(0.194, 8.112) 0.884 Total protein, g/L 59.04 ± 7.02 56.74 ± 6.01 55.95 ± 4.93 0.145 Albumin, g/L 29.83 ± 3.17 29.13 ± 3.62 29.44 ± 2.89 0.634 Serum creatinine, µmol/L 81.08 ± 36.14 66.31 ± 27.41 50.11 ± 25.59 0.019 CRAB: carbapenem-resistant Acinetobacter baumannii ; CRPA: carbapenem-resistant Pseudomonas aeruginosa ; CRKP: carbapenem-resistant Klebsiella pneumoniae ; CRP: C-reactive protein; PCT: procalcitonin. Assessment of inflammatory biomarkers and clinical severity scores Given that the mean duration of CMS therapy was 10.7 days, inflammatory biomarkers and disease severity scores were primarily evaluated on days 3, 7, and at the end of treatment. Prior to enrolment, 90.1% of patients required mechanical ventilation, and over two-thirds had concomitant respiratory failure. After 7 days of CMS therapy, the PaO₂/FiO₂ ratio showed an overall increasing trend with intermittent fluctuations (Fig. 2A), reaching a mean of 313.02 in the intravenous monotherapy group; however, no significant differences were observed ( P = 0.679). Furthermore, both APACHE II and SOFA scores exhibited a downward trend on days 3 and 7, with no significant variation observed among the three cohorts (all P > 0.05) (Table 2 ) (full table at the end of manuscript). Notably, the median PCT level peaked on the second day after treatment initiation and gradually declined thereafter (Fig. 2D). By the seventh day of treatment, total protein and albumin levels in the intravenous group were markedly lower than others (Fig. 2E, F). Upon conclusion of treatment, the SOFA score in the nebulization group [median 4 (IQR: 3–6)] was substantially lower than that of both the combination and intravenous groups ( P = 0.003). In addition, levels of inflammatory markers were reduced in the nebulization group relative to the combination group, including CRP (44.89 mg/L vs. 91.68 mg/L, P = 0.041) and PCT (0.300 ng/mL vs. 1.250 ng/mL, P = 0.004). Table 2 Inflammatory Markers and Severity Scores Across Treatment Timeline IH (n = 50) IV + IH (n = 34) IV (n = 14) P value On the third day of treatment APACHE II score 20 (17, 25) 22 (18, 23) 21 (20, 24) 0.509 SOFA score 6 (5, 8) 7 (5,10.25) 7.5 (5, 10.75) 0.227 PaO 2 /FiO 2 , mmHg 307.32 ± 99.11 263.20 ± 90.24 269.55 ± 101.79 0.102 T, °C 37.69 ± 0.54 37.95 ± 0.57 38.06 ± 0.84 0.049 CRP, mg/L 87.81(46.12, 144.91) 81.08 (50.96,143.01) 101.59 (35.31, 192.19) 0.603 PCT, ng/mL 0.845 (0.363, 1.520) 0.830 (0.280, 2.360) 2.305 (0.217, 6.938) 0.666 Total protein, g/L 58.66 ± 7.61 55.71 ± 5.11 56.24 ± 4.84 0.105 Albumin, g/L 28.82 ± 3.17 28.21 ± 2.96 29.44 ± 3.88 0.451 On the seventh day of treatment APACHE II score 20 (17.25, 22) 18.5 (15.25, 25.25) 22 (17, 24) 0.409 SOFA score 6 (5, 8) 6 (4.5, 8.5) 4.5 (4, 9.25) 0.471 PaO 2 /FiO 2 , mmHg 309.69 ± 87.2 286.57 ± 112.98 313.02 ± 90.06 0.679 T, °C 37.79 ± 0.60 37.69 ± 0.45 37.45 ± 0.46 0.094 CRP, mg/L 66.75 (42.93, 88.29) 61.39 (30.04, 134.17) 83.41 (35.95, 148.38) 0.673 PCT, ng/mL 0.638 (0.250, 1.468) 0.561 (0.176, 1.343) 0.650 (0.196, 1.280) 0.657 Total protein, g/L 59.50 (54.5, 66.70) 58.70 (53.75, 64.15) 51.70 (50.55, 53.70) 0.015 Albumin, g/L 28.70 (27.00, 31.00) 29.10 (27.75, 32.75) 26.00 (25.30, 28.00) 0.025 End of treatment APACHE II score 18 (14,23) 21 (16, 25) 22.5 (14.5, 26) 0.394 SOFA score 4 (3, 6) 6.5 (5, 9.5) 6 (4.25, 11.75) 0.003 PaO 2 /FiO 2 , mmHg 341.09 ± 117.58 308.31 ± 111.56 315.41 ± 77.16 0.261 T, °C 37.50 (37.13, 37.68) 37.30 (36.90, 38.00) 37.30 (36.80, 37.75) 0.606 CRP, mg/L 44.89 (22.06, 85.33) 91.68 (47.49, 160.01) 67.94 (16.19, 160,06) 0.037 PCT, ng/mL 0.300 (0.126, 0.628) 1.250 (0.374,5.660 0.484 (0.131, 2.085) 0.005 Total protein, g/L 61.94 ± 8.08 58.58 ± 6.65 57.60 ± 9.20 0.092 Albumin, g/L 30.05 ± 3.71 29.65 ± 3.92 30.70 ± 4.97 0.732 Therapeutic efficacy assessment In this study, out of 35 patients in the IH group, 70% achieved favourable clinical outcomes. In comparison, 64.7% of patients in the IV + IH group and 64.3% in the IV group had favourable clinical outcomes, with no significant difference observed ( P = 0.834). Patients who received nebulized antibiotic therapy demonstrated a markedly elevated rate of microbiological eradication. In the combination therapy cohort, 24 patients (70.6%) achieved negative culture results after treatment, compared to only 42.9% in the intravenous monotherapy group ( P = 0.025). In terms of prognosis, no statistically significant difference in 28-day all-cause mortality was observed among the groups ( P = 0.182) (Table 3 ). Furthermore, Kaplan-Meier survival analysis showed no significant difference in 28-day mortality between the three groups ( P = 0.180) (Fig. 3). After the exclusion of individuals who underwent renal replacement therapy previous to colistin administration (8 in the IH cohort, 3 in the combination cohort, and 5 in the IV cohort), the incidence of acute kidney injury was 31.0% in the IH cohort, 45.2% in the combination cohort, and 44.4% in the IV cohort ( P = 0.416). Table 3 Outcomes in patients receiving different administration IH (n = 50) IV + IH (n = 34) IV (n = 14) P value Clinical efficacy, n (%) 35 (70.0) 22 (64.7) 9 (64.3) 0.834 Microbiological eradication, n (%) 40 (80.0) 24 (70.6) 6 (42.9) 0.025 28-day mortality, n (%) 13 (26.0) 15 (44.1) 6 (42.9) 0.182 Length of hospital stay, days 30 (21, 43) 30 (24, 47.75) 23 (19.5, 35.5) 0.351 Length of ICU stay, days 28 (19, 39) 26 (20, 37) 18 (10.6, 23) 0.829 AKI, n (%) 13 (31.0) 14 (45.2) 4 (44.4) 0.416 KDIGO 1 6 (14.3) 5 (16.1) 2 (22.2) 0.755 KDIGO 2 5 (11.9) 2 (6.5) 2 (22.2) 0.341 KDIGO 3 2 (4.8) 7 (22.6) 0 (0) 0.043 Factors associated with clinical efficacy Univariate analysis of 98 patients revealed that those who experienced clinical improvement had significantly lower baseline APACHE II scores [odds ratio (OR) 0.91, 95% confidence interval (CI) 0.83–0.99], along with reduced risks of sepsis (OR 0.31, 95% CI 0.13–0.77) and acute kidney injury (OR 0.27, 95% CI 0.11–0.69) (Table 4 ) (full table at the end of manuscript). In the analysis of the relationship between AKI and treatment efficacy, patients who had undergone renal replacement therapy prior to drug administration were excluded. Notably, only 42 individuals had confirmed microbiological documentation, and no significant association was observed between pathogen clearance and clinical outcomes. Table 4 Univariate analysis of factors associated with clinical efficacy Clinical failure (n = 32) Clinical efficacy (n = 66) P value Demographic Age, years 75.7 (66.75, 81) 72 (58.75, 77) 0.067 Male, n (%) 23 (71.9) 48 (72.7) 0.929 BMI 23.17 ± 3.94 23.14 ± 3.79 0.966 Charlson Comorbidity Index 4 (4, 5) 4 (3, 5) 0.716 Underlying disease, n (%) Diabetes mellitus 7 (21.9) 21 (33.8) 0.310 Hypertension 16 (50.0) 38 (57.6) 0.480 Chronic cardiovascular disease 3 (9.4) 7 (10.6) 0.850 Chronic pulmonary disease 4 (12.5) 10 (15.2) 0.725 Cerebrovascular disease 4 (12.5) 7 (10.6) 0.781 Isolated pathogen at diagnosis, n (%) CRAB 17 (53.1) 43 (65.2) 0.254 CRPA 9 (28.1) 12 (18.2) 0.264 CRKP 5 (15.6) 7 (10.6) 0.480 Polymyxins MIC distribution ≤ 0.5 mg/L, n (%) 18 (56.3) 35 (53.0) 0.764 Concomitant antibiotic therapy, n (%) Meropenem 10 (31.3) 29 (43.9) 0.231 Cefoperazone-Sulbactam 14 (43.8) 25 (37.9) 0.578 Piperacillin-Tazobactam 7 (21.9) 21 (31.8) 0.310 Tigecycline 5 (15.6) 6(9.1) 0.342 Pre-treatment APACHE Ⅱ score 22.97 ± 4.77 20.76 ± 4.84 0.042 SOFA score 8 (5, 10) 7 (5, 9) 0.282 CIPS score 7 (6, 7.75) 7 (6, 8) 0.088 Others Sepsis, n (%) 21 (65.5) 25 (37.9) 0.011 Length of hospital stay, days 28 (18.75, 36) 33.5 (22, 42.25) 0.162 Length of ICU stay, days 24.5 (13, 31.25) 28.5 (21, 39.75) 0.097 Microbiological eradication, n (%) 10 (76.9) 23 (79.3) 0.682 AKI, n (%) 16 (55.2) 15 (25.9) 0.006 Discussion In this research, we assessed the effectiveness and nephrotoxicity of different administration routes for treating nosocomial pneumonia caused by CR-GNB. Compared to intravenous or inhaled monotherapy, combination therapy did not demonstrate superior clinical efficacy, lower 28-day all-cause mortality rate, or shorter length of hospital stay. In terms of bacterial eradication, the inhalation group showed higher eradication rates than the intravenous group ( P < 0.05). Notably, the addition of inhaled therapy to systemic intravenous administration was not associated with an increased risk of nephrotoxicity. A meta-analysis of 19 observational studies and 3 RCTs evaluated the efficacy of polymyxin-based regimens for multidrug-resistant Gram-negative pneumonia. The IV + IH regimen significantly reduced mortality (OR 0.67, 95% CI 0.50–0.88) and improved clinical cure rates (OR 1.90, 95% CI 1.20–3.00). This may be due to enhanced drug concentrations in both systemic and alveolar spaces [ 16 ]. However, in our study, the combination therapy group did not confer additional clinical benefits regarding treatment success or 28-day mortality. We also found that patients with elevated baseline APACHE II scores, concurrent sepsis, or developing AKI during treatment were more likely to experience treatment failure. A previous study reached similar conclusions, reporting that a higher mean Simplified Acute Physiology Score II ( P = 0.002), higher SOFA score ( P = 0.05), presence of septic shock ( P < 0.001), and the occurrence of AKI during polymyxin therapy ( P = 0.04) were all independently correlated with clinical failure [ 17 ]. In addition, the efficacy of aerosolized antibiotic therapy is influenced by multiple factors, including nebulizer performance, patient-specific conditions, and mechanical ventilation parameters [ 18 ]. In our study, many patients who underwent bronchoscopy exhibited thick airway secretions, which may have hindered alveolar drug deposition and affected treatment efficacy. Although a mesh nebulizer characterized by high pulmonary deposition efficiency, low residual volume, and short nebulization time was employed, the adequacy of the drug concentration in target lesion areas remains uncertain and requires further investigation [ 12 ]. In comparison to intravenous administration, aerosolized therapy has demonstrated a significantly higher rate of bacterial clearance ( P = 0.009). Several previous studies evaluating the efficacy of aerosolized administration have consistently reached the same conclusion [ 19 – 21 ]. The increased local drug concentration achieved via inhalation therapy may contribute to more effective bacterial clearance. However, a retrospective matched case-control study that included 43 patient pairs with VAP caused by multidrug-resistant Gram-negative bacteria, matched for age and APACHE Ⅱ, compared outcomes between individuals undergoing combination systemic and nebulized therapy versus intravenous therapy alone. The study found no statistically significant differences between the two groups in terms of pathogen eradication ( P = 0.679), clinical cure ( P = 0.100), or mortality ( P = 0.289) [ 22 ]. A similar study on multidrug-resistant Acinetobacter baumannii also reported no significant differences in outcomes [ 23 ]. These findings may reflect a limited understanding of drug penetration from the airway lumen to the infected tissue. In our study, although bacterial eradication was achieved, it was not associated with clinical outcomes (P = 0.682), consistent with findings from previous studies. A meta-analysis of 11 randomized controlled trials (n = 1,472) demonstrated that adjunctive inhaled antibiotic therapy significantly improved microbiological eradication rates compared to intravenous antibiotic therapy alone or intravenous therapy in combination with inhaled placebo (OR = 2.63, 95% CI: 1.36–5.09). Nonetheless, the study emphasized that microbiological eradication does not necessarily translate into clinical success [ 24 ]. Nephrotoxicity is a significant adverse effect of colistin, which often causes hesitation among clinicians regarding its use. In this study, clinicians carefully considered renal function during treatment and appeared more tolerant of elevated creatinine levels in patients receiving inhaled therapy alone. While the variations in AKI incidence among the three groups were not statistically significant, the AKI rate in the inhalation-only group appeared to be lower than that in the other two groups. The incidence of colistin-associated acute kidney injury ranges between approximately 20% and 60%. Studies have demonstrated that individuals administered breathed colistin exhibit a markedly reduced incidence of nephrotoxicity than those undergoing systemic administration [ 25 , 26 ]. Moreover, combined inhalation and intravenous therapy does not appear to significantly increase the risk of nephrotoxicity compared to intravenous therapy alone [ 19 ]. Additionally, a meta-analysis identified age > 65 years, hypoalbuminemia, sepsis or septic shock, and concurrent use of vancomycin or vasopressors as independent predictors for colistin-associated nephrotoxicity [ 27 ]. Although nephrotoxicity is commonly reported as an adverse effect of polymyxins, the associated increase in serum creatinine is generally mild. Since severe infections can lead to serious consequences, interruptions in colistin treatment due to nephrotoxicity are relatively rare in clinical practice. Previous studies have reported that AKI was reversible in 91.6% of people administered CMS and 79.0% of those receiving polymyxin B treatment [ 28 ]. However, the long-term renal impact of polymyxins, especially in elderly patients, is often overlooked. A retrospective cohort study involving patients who received intravenous polymyxin therapy for severe infections found that 40% of survivors (29/72) developed AKI during hospitalization. At the 6-month follow-up, 75% (22/29) of these AKI survivors progressed to chronic kidney disease, which was substantially higher than the 27% (16/58) recorded in a matched cohort of sepsis-associated AKI patients without polymyxin exposure ( P < 0.001). Further analysis identified polymyxin use (OR: 8.86; 95% CI: 2.8–27.8) and elderly status (OR: 1.04; 95% CI: 1.01–1.07) as independent risk factors for CKD progression [ 29 ]. These findings emphasize the critical need for careful and continuous renal monitoring, particularly in elderly patients, to prevent irreversible nephrotoxicity. Currently, several novel antibiotics, including aztreonam-avibactam, cefiderocol, and ceftazidime-avibactam, have emerged [ 10 , 30 ], while non-antibiotic therapies, such as phage therapy and nanomaterials are also rapidly developing [ 31 ]. However, due to economic constraints and other factors, colistin remains a valuable therapeutic option. Although its use is associated with multiple challenges, the incorporation of therapeutic drug monitoring into routine clinical practice may represent an effective strategy to optimize the benefit-risk ratio in critically ill patients [ 32 ]. This research has following limitations: Firstly, as a single-centre analysis, the relatively small sample size (particularly in the intravenous administration group) may introduce potential selection bias. Secondly, although the absence of statistically significant distinction in disease severity across the intravenous injection group and the nebulizer group, patients with better overall conditions tended to receive nebulized colistin alone. Thirdly, this study involved patients with varying ventilator settings, and we did not assess factors such as airway obstruction or lung consolidation, which could potentially affect the efficacy of inhaled colistin. Conclusion This prospective study compared the efficacy and nephrotoxicity of three different administration routes in the treatment of nosocomial pneumonia caused by CRO. The results indicated that combination therapy did not demonstrate superior clinical benefits compared to either inhaled or intravenous monotherapy. Notably, inhaled therapy was associated with a higher bacterial clearance rate and lower nephrotoxicity, suggesting its potential as a feasible alternative to intravenous administration. Given the limitations of this study, well-designed prospective clinical trials are warranted to further assess the efficacy and safety of different administration strategies. Abbreviations CRO carbapenem-resistant organisms NP nosocomial pneumonia AKI acute kidney injury HAP hospital-acquired pneumonia VAP ventilator-associated pneumonia CR-GNB carbapenem-resistant Gram-negative bacteria CRAB carbapenem-resistant Acinetobacter baumannii CRPA carbapenem-resistant Pseudomonas aeruginosa CRKP carbapenem-resistant Klebsiella pneumoniae CMS Colistimethate sodium CPIS Clinical Pulmonary Infection Score APACHE II Acute Physiology and Chronic Health Evaluation II SOFA Sequential Organ Failure Assessment Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of The First Affiliated Hospital of Ningbo University [No. 2024-R044-02]. All procedures were performed in accordance with the ethical principles outlined in the Declaration of Helsinki and relevant guidelines and regulations. Clinical Trial This study was retrospectively registered at ClinicalTrials.gov (NCT06907069) on December 9, 2024. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request. Competing interests The authors declare no competing interests. Funding This research was supported by the Project of Ningbo Key R&D Plan and “Unveiling and Leading” under Grant No.2023Z174, the Zhejiang Provincial Medical and Health Science Foundation of China under Grant No.2024KY312, the Ningbo Clinical Research Centre for Emergency and Critical Diseases under Grant No.2024L003. Authors’ details Qiao-yi Wei, MD., E-mail: [email protected] Xin-xing Chen, MD., E-mail: [email protected] Feng Xu, PhD., E-mail: [email protected] Heng Fan, PhD. Pro., E-mail: [email protected] Authors' contributions Qiao-yi Wei and Xin-xing Chen collected clinical data, interpreted of data and wrote the first draft of the manuscript. Feng Xu and Heng Fan participated in conception, design and providing critical revisions. All authors read and approved the final manuscript. Acknowledgements The authors would like to thank all the subjects, their families, and collaborating clinicians for their participation. References Zaragoza R, Vidal-Cortes P, Aguilar G, Borges M, Diaz E, Ferrer R, et al. Update of the treatment of nosocomial pneumonia in the ICU. Crit Care. 2020;24(1):383. Karaiskos I, Gkoufa A, Polyzou E, Schinas G, Athanassa Z, Akinosoglou K. High-Dose Nebulized Colistin Methanesulfonate and the Role in Hospital-Acquired Pneumonia Caused by Gram-Negative Bacteria with Difficult-to-Treat Resistance: A Review. Microorganisms. 2023;11(6). Collaborators GAR. Global burden of bacterial antimicrobial resistance 1990–2021: a systematic analysis with forecasts to 2050. Lancet. 2024;404(10459):1199–226. Bell TD, Park SC. Colistin - That Was Fun, But Now We're Done. NEJM Evid. 2023;2(1):EVIDe2200298. El-Sayed Ahmed MAE, Zhong LL, Shen C, Yang Y, Doi Y, Tian GB. Colistin and its role in the Era of antibiotic resistance: an extended review (2000–2019). Emerg Microbes Infect. 2020;9(1):868–85. Shi R, Fu Y, Gan Y, Wu D, Zhou S, Huang M. Use of polymyxin B with different administration methods in the critically ill patients with ventilation associated pneumonia: a single-center experience. Front Pharmacol. 2023;14:1222044. Lee DH, Kim SY, Kim YK, Jung SY, Jang JH, Jang HJ et al. Intrapulmonary and Systemic Pharmacokinetics of Colistin Following Nebulization of Low-Dose Colistimethate Sodium in Patients with Ventilator-Associated Pneumonia Caused by Carbapenem-Resistant Acinetobacter baumannii. Antibiot (Basel). 2024;13(3). Feng J-Y, Peng C-K, Sheu C-C, Lin Y-C, Chan M-C, Wang S-H, et al. Efficacy of adjunctive nebulized colistin in critically ill patients with nosocomial carbapenem-resistant Gram-negative bacterial pneumonia: a multi-centre observational study. Clin Microbiol Infect. 2021;27(10):1465–73. Feng JY, Huang JR, Lee CC, Tseng YH, Pan SW, Chen YM, et al. 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):1. Tamma PD, Heil EL, Justo JA, Mathers AJ, Satlin MJ, Bonomo RA. Infectious Diseases Society of America 2024 Guidance on the Treatment of Antimicrobial-Resistant Gram-Negative Infections. Clin Infect Dis. 2024. Rello J, Sole-Lleonart C, Rouby JJ, Chastre J, Blot S, Poulakou G, et al. Use of nebulized antimicrobials for the treatment of respiratory infections in invasively mechanically ventilated adults: a position paper from the European Society of Clinical Microbiology and Infectious Diseases. Clin Microbiol Infect. 2017;23(9):629–39. Rouby JJ, Sole-Lleonart C, Rello J. European Investigators Network for Nebulized Antibiotics in Ventilator-associated P. Ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria: understanding nebulization of aminoglycosides and colistin. Intensive Care Med. 2020;46(4):766–70. Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB, et al. Management of Adults With Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin Infect Dis. 2016;63(5):e61–111. Kilic I, Ayar Y, Ceylan I, Kaya PK, Caliskan G. Nephrotoxicity caused by colistin use in ICU: a single centre experience. BMC Nephrol. 2023;24(1):302. Kellum JA, Lameire. N, Group. ftKAGW. Diagnosis, evaluation, and management of acute kidney injury a KDIGO summary (Part 1). Crit Care. 2013;17(1):204. Zhou Y, Wang G, Zhao Y, Chen W, Chen X, Qiu Y, et al. Efficacy and safety of different polymyxin-containing regimens for the treatment of pneumonia caused by multidrug-resistant gram-negative bacteria: a systematic review and network meta-analysis. Crit Care. 2024;28(1):239. Tumbarello M, De Pascale G, Trecarichi EM, De Martino S, Bello G, Maviglia R, et al. Effect of aerosolized colistin as adjunctive treatment on the outcomes of microbiologically documented ventilator-associated pneumonia caused by colistin-only susceptible gram-negative bacteria. Chest. 2013;144(6):1768–75. Poulakou G, Siakallis G, Tsiodras S, Arfaras-Melainis A, Dimopoulos G. Nebulized antibiotics in mechanically ventilated patients: roadmap and challenges. Expert Rev Anti Infect Ther. 2017;15(3):211–29. Almangour TA, Alruwaili A, Almutairi R, Alrasheed A, Alhifany AA, Eljaaly K, et al. Aerosolized plus intravenous colistin vs intravenous colistin alone for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria: A retrospective cohort study. Int J Infect Dis. 2021;108:406–12. Choe J, Sohn YM, Jeong SH, Park HJ, Na SJ, Huh K, et al. Inhalation with intravenous loading dose of colistin in critically ill patients with pneumonia caused by carbapenem-resistant gram-negative bacteria. Ther Adv Respir Dis. 2019;13:1753466619885529. Maan L, Anand N, Yadav G, Mishra M, Gupta MK. The Efficacy and Safety of Intravenous Colistin Plus Aerosolized Colistin Versus Intravenous Colistin Alone in Critically Ill Trauma Patients With Multi-Drug Resistant Gram-Negative Bacilli Infection. Cureus. 2023;15(11):e49314. Kofteridis DP, Alexopoulou C, Valachis A, Maraki S, Dimopoulou D, Georgopoulos D, et al. Aerosolized plus intravenous colistin versus intravenous colistin alone for the treatment of ventilator-associated pneumonia: a matched case-control study. Clin Infect Dis. 2010;51(11):1238–44. Jang JY, Kwon HY, Choi EH, Lee WY, Shim H, Bae KS. Efficacy and toxicity of high-dose nebulized colistin for critically ill surgical patients with ventilator-associated pneumonia caused by multidrug-resistant Acinetobacter baumannii. J Crit Care. 2017;40:251–6. Sella N, Pettenuzzo T, De Cassai A, Zarantonello F, Congedi S, Bruni A, et al. Inhaled antibiotics for treating pneumonia in invasively ventilated patients in intensive care unit: a meta-analysis of randomized clinical trials with trial sequential analysis. Crit Care. 2024;28(1):387. Abdellatif S, Trifi A, Daly F, Mahjoub K, Nasri R, Ben Lakhal S. Efficacy and toxicity of aerosolised colistin in ventilator-associated pneumonia: a prospective, randomised trial. Ann Intensive Care. 2016;6(1):26. Xu P, Xu L, Ji H, Song Y, Zhang K, Ren X, et al. Analysis and comparison of adverse events of colistin administered by different routes based on the FAERS database. Sci Rep. 2025;15(1):10384. Wang JL, Xiang BX, Song XL, Que RM, Zuo XC, Xie YL. Prevalence of polymyxin-induced nephrotoxicity and its predictors in critically ill adult patients: A meta-analysis. World J Clin Cases. 2022;10(31):11466–85. Aysert-Yildiz P, Ozgen-Top O, Senturk AF, Kanik S, Ozger HS, Dizbay M. Polymyxin B vs. colistin: the comparison of neurotoxic and nephrotoxic effects of the two polymyxins. BMC Infect Dis. 2024;24(1):862. Meraz-Munoz A, Gomez-Ruiz I, Correa-Rotter R, Ramirez-Sandoval JC. Chronic kidney disease after acute kidney injury associated with intravenous colistin use in survivors of severe infections: A comparative cohort study. J Crit Care. 2018;44:244–8. Carmeli Y, Cisneros JM, Paul M, Daikos GL, Wang M, Torre-Cisneros J, et al. Aztreonam-avibactam versus meropenem for the treatment of serious infections caused by Gram-negative bacteria (REVISIT): a descriptive, multinational, open-label, phase 3, randomised trial. Lancet Infect Dis. 2025;25(2):218–30. Shariati A, Kashi M, Chegini Z, Hosseini SM. Antibiotics-free compounds for managing carbapenem-resistant bacteria; a narrative review. Front Pharmacol. 2024;15:1467086. Rychlickova J, Kubickova V, Suk P, Urbanek K. Challenges of Colistin Use in ICU and Therapeutic Drug Monitoring: A Literature Review. Antibiot (Basel). 2023;12(3). 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. 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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-6911404","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":486604620,"identity":"79446a7f-258e-4ac6-a2d3-d59876c7a4ec","order_by":0,"name":"Qiao-yi Wei","email":"","orcid":"","institution":"The First Affiliated Hospital of Ningbo University","correspondingAuthor":false,"prefix":"","firstName":"Qiao-yi","middleName":"","lastName":"Wei","suffix":""},{"id":486604621,"identity":"07ce95e7-44f1-41e8-9a1f-06868641b128","order_by":1,"name":"Xin-xing Chen","email":"","orcid":"","institution":"The First Affiliated Hospital of Ningbo University","correspondingAuthor":false,"prefix":"","firstName":"Xin-xing","middleName":"","lastName":"Chen","suffix":""},{"id":486604622,"identity":"b119e989-2781-466c-9143-fcbcbb770a93","order_by":2,"name":"Feng Xu","email":"","orcid":"","institution":"The First Affiliated Hospital of Ningbo University","correspondingAuthor":false,"prefix":"","firstName":"Feng","middleName":"","lastName":"Xu","suffix":""},{"id":486604623,"identity":"50f92dc8-93e3-47f2-85c2-5eac3cba79bf","order_by":3,"name":"Heng Fan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA70lEQVRIiWNgGAWjYBAC9gYGhg8MDAeATOYDzGChAwS08BxgYJwBUcaWQLIWHgMitUjkGDb83HFHzpx/zbfHhW0Mcnw3Ehg/FxDQ0th75pmx5Yy3241ntjEYS95IYJaegUeLvUSO+QPetsOJG26c3SbN28YAZCSwMfMQsuVv2+H6DTfOPANpqSdKSzPQlgSD8z1sIC0JBgS18DwrbJZtO2y44QabmfSMcxKGM888bJbGq4U9eWPj27bD8gbnDz+TLiizkec7nnzwMz4tDAIZBhCGRAKYBGLGBnwaGBj4jz+AMg7gVzgKRsEoGAUjFwAAkWtSwk1LI3kAAAAASUVORK5CYII=","orcid":"","institution":"The First Affiliated Hospital of Ningbo University","correspondingAuthor":true,"prefix":"","firstName":"Heng","middleName":"","lastName":"Fan","suffix":""}],"badges":[],"createdAt":"2025-06-17 07:23:34","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6911404/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6911404/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87357927,"identity":"071b8687-4ea7-4f6a-94a4-4086f493dda3","added_by":"auto","created_at":"2025-07-23 05:32:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":72818,"visible":true,"origin":"","legend":"\u003cp\u003eFlow chart of participant selection\u003c/p\u003e","description":"","filename":"OnlineFig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-6911404/v1/cb034ca173bc14cfabb66a7d.png"},{"id":87357935,"identity":"1041c5f0-8a49-4f88-854b-df0cea0f193c","added_by":"auto","created_at":"2025-07-23 05:32:31","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":206751,"visible":true,"origin":"","legend":"\u003cp\u003eDynamic profile of laboratory parameters and body temperature across the three groups. Each dot represents the median, and the error indicates the interquartile range (IQR). TP: total protein; ALB: albumin.\u003c/p\u003e","description":"","filename":"OnlineFig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-6911404/v1/17624a0bd86253a1f4b33d39.png"},{"id":87357928,"identity":"2fb0fbbc-ccae-4475-ac2e-4404ce798df6","added_by":"auto","created_at":"2025-07-23 05:32:31","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":48457,"visible":true,"origin":"","legend":"\u003cp\u003eSurvival analysis in each study groups\u003c/p\u003e","description":"","filename":"OnlineFig.3.png","url":"https://assets-eu.researchsquare.com/files/rs-6911404/v1/bd40f3179e33035a8b7979cd.png"},{"id":94620467,"identity":"9150fd58-9614-49c5-b5e9-28d77d16d0ac","added_by":"auto","created_at":"2025-10-29 04:03:28","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1452334,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6911404/v1/58a533b6-02e1-4745-90c8-c6210126609c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and Safety of Three Colistin Regimens in the Treatment of Nosocomial Pneumonia Caused by Carbapenem-Resistant Organisms: A Single Centre, Open Label, Prospective Cohort Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eNosocomial pneumonia, including hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP), remains a major challenge for critically ill patients. Studies show that 10\u0026ndash;40% of individuals using mechanical ventilation for over 48 hours may develop VAP. Moreover, the probability of mortality in patients with HAP is 8.4 times higher compared to those without HAP, which is closely related to the profound pathophysiological alterations in critically ill patients\u0026mdash;changes that can significantly affect the pharmacokinetics of antibiotics [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Additionally, refractory infections and multidrug-resistant pathogens are increasingly prevalent in intensive care units (ICUs), posing significant challenges to infection control [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Notably, carbapenem-resistant Gram-negative bacteria (GR-NGB), such as \u003cem\u003eAcinetobacter baumannii\u003c/em\u003e and \u003cem\u003eEnterobacterales\u003c/em\u003e, are linked to high mortality and have been designated as critical priority pathogens in the WHO\u0026rsquo;s 2024 Bacterial Priority Pathogens Lists, underscoring the urgent need for effective interventions [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e\u003cp\u003ePolymyxins, despite their known limitations, have played a pivotal role in the management of illnesses induced by resistant Gram-negative bacteria [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Discovered in the 1940s, these peptide antibiotics exert rapid bactericidal activity by disrupting the integrity of Gram-negative bacterial cell membranes. Although they were later replaced by newer antibiotics with more favourable toxicity profiles, the rise of multidrug-resistant bacteria has led to their re-emergence as a vital therapeutic option. Colistimethate sodium (CMS), a clinically prevalent formulation of colistin in practice, is an inactive prodrug that necessitates in vivo conversion to its active state, colistin, to manifest its antibacterial effects [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAlthough intravenous colistin has become an important salvage therapy, its high molecular weight and low solubility hinder effective penetration through the tightly bound cellular barriers of the lungs [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Previous studies have demonstrated that aerosolized administration of colistin results in significantly higher drug concentrations in the epithelial lining fluid relative to plasma. At 1, 3, and 5 hours post-administration, the median colistin concentrations in epithelial lining fluid were reported to be 614-fold, 408-fold, and 250-fold higher than those in plasma, respectively [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. This marked pulmonary accumulation suggests that inhaled delivery has the potential to increase the therapeutic efficacy against pulmonary infections and reduce the risk of systemic toxicity by achieving high local drug concentrations at the site of infection while minimizing systemic distribution [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThere is ongoing controversy regarding the optimal route of colistin administration for the treatment of nosocomial pneumonia [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], particularly concerning whether inhaled colistin should be used as an adjunct to or a substitute for intravenous colistin. Furthermore, the current body of evidence regarding its efficacy and safety remains insufficient [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Consequently, this study aims to assess and compare the clinical effectiveness and nephrotoxicity of three distinct administrative strategies for colistin \u0026mdash; intravenous alone, inhaled alone, and the combination of both \u0026mdash; in the management of nosocomial pneumonia induced by CR-GNB.\u003c/p\u003e"},{"header":"Method","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy design and setting\u003c/h2\u003e\u003cp\u003eThis research was structured as a prospective, single-centre cohort study. It was conducted in the ICU of The First Affiliated Hospital of Ningbo University from January 1, 2023, to April 30, 2025. Approval for the study was granted by the Ethics Committee of The First Affiliated Hospital of Ningbo University [Approval No. 2024-R044-02]. The trial was registered in ClinicalTrials.gov (NCT06907069).\u003c/p\u003e\u003cp\u003eWe included patients aged ≥ 18 years who received colistin treatment for more than 72 hours and were diagnosed with nosocomial pneumonia (NP) caused by carbapenem-resistant organisms (CRO) and had respiratory isolates that were susceptible to colistin. Exclusion criteria were as follows: pregnancy or lactation, known allergy to colistin, missing essential clinical data, or participation in another clinical trial within the past three months. In this analysis, only the initial episode of colistin treatment was evaluated for individuals who received several treatments over the study period.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eDosing and Administration\u003c/h3\u003e\n\u003cp\u003eBased on clinical status, patients received colistin therapy via intravenous administration (IV), inhalation (IH), or a combination of both (IV + IH). The intravenous dose of colistin ranged from 2.5 to 5 mg colistin base activity (CBA) per kilogram per day. In patients with renal impairment or those undergoing renal replacement treatment, the dose was adjusted based on the estimated glomerular filtration rate. For inhaled administration, 75 mg CBA was diluted in 3–5 mL of 0.9% sterile normal saline and administered every 8 or 12 hours using a vibrating mesh nebulizer.\u003c/p\u003e\n\u003ch3\u003eData Collection\u003c/h3\u003e\n\u003cp\u003eAll data were obtained from the electronic medical record system, with the day of colistin administration designated as Day 1 of treatment. A comprehensive range of potential confounding variables was collected, including demographic information, underlying disease, Charlson Comorbidity Index, Clinical Pulmonary Infection Score (CPIS). The laboratory parameters measured included inflammation-related markers, total protein, albumin, and serum creatinine. The Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA) scores were also assessed pre-treatment and post-treatment. In addition, we also considered the patients' microbiological findings, details of antimicrobial therapy, clinical outcomes, microbiological outcomes, adverse drug reactions, and 28-day all-cause mortality.\u003c/p\u003e\n\u003ch3\u003eDefinitions and Outcomes\u003c/h3\u003e\n\u003cp\u003e According to the Clinical Practice Guidelines for the Management of Adults with Hospital-acquired and Ventilator-associated Pneumonia jointly issued by the American Thoracic Society and the Infectious Diseases Society of America in 2016, HAP and VAP are defined as follows. HAP: pneumonia that occurs 48 hours or more after hospital admission, that was not present at the time of admission and is unrelated to mechanical ventilation. VAP: pneumonia that arises more than 48 hours after endotracheal intubation and initiation of mechanical ventilation [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe principal outcome was the clinical effectiveness at the end of treatment. Clinical efficacy was defined as the resolution or alleviation of pneumonia symptoms and signs after the conclusion of colistin treatment. Clinical failure was characterised by the persistence or exacerbation of pneumonia symptoms or signs at the end of colistin treatment. Cure or improvement was defined based on the patient’s alive, resolution of fever, reduced need for sputum suction, improvement or resolution of imaging findings, stabilization or improvement of PaO₂/FiO₂ ratio, and reduction or normalization of infection markers.\u003c/p\u003e\u003cp\u003eSecondary clinical outcomes encompassed 28-day all-cause mortality, microbiological outcomes, nephrotoxicity, the duration of stay in the ICU and hospital. Sputum, endotracheal aspirates, or bronchoalveolar lavage fluid were the sources of all microbiological isolates. The absence of the original causative pathogen in cultures obtained from the primary site of infection after treatment has been defined as microbiological eradication. In cases where clinical resolution rendered specimen collection infeasible — such as the inability to expectorate sputum — or when obtaining specimens would require invasive procedures not justified in recovering patients, the outcome was considered presumed eradication. The microbiological eradication rate was determined using the formula: (number of eradications + number of presumed eradications) / total number of patients × 100%. Due to the sedated state of most ICU patients, neurological side effects could not be reliably assessed. In contrast, nephrotoxicity was more easily identifiable and had a higher incidence [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], making it the primary adverse effect of interest in this study. Nephrotoxicity was defined using the KDIGO criteria as the occurrence of acute kidney injury during colistin therapy, with at least one of the following conditions: (1) A serum creatinine increase of more than 26.5 µmol/L (0.3 mg/dL) within 48 hours; (2) A serum creatinine increase of more than 1.5 times the baseline within 7 days; (3) Urine output \u0026lt; 0.5 mL/(kg·h) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eAll statistical analyses were performed using SPSS (version 27.0, IBM Corporation, Armonk, NY, USA). Continuous variables with a normal distribution were characterised by mean ± standard deviation (SD), and analysis was conducted using ANOVA. For continuous variables that do not follow a normal distribution, data were presented as median with interquartile range (IQR) and analysed using the Kruskal-Wallis test for multiple independent samples. Categorical variables were represented as frequencies or proportions and analysed with the chi-square test or Fisher’s exact test. Post hoc pairwise comparisons were performed utilising the Bonferroni correction method. A \u003cem\u003eP\u003c/em\u003e value of less than 0.05 was deemed statistically significant. Kaplan-Meier curves were constructed to compare 28-day cumulative survival among the IV, IH, and IV + IH groups. Variables linked to the primary outcome in univariate logistic regression analysis were used to determine independent predictors of clinical resolution.\u003c/p\u003e"},{"header":"Result","content":"\u003ch2\u003ePatient characteristics and baseline clinical data\u003c/h2\u003e\u003cp\u003eThis single-centre prospective study analysed 98 patients diagnosed with NP caused by CRO who received colistin treatment between January 2023 and April 2025. Figure\u0026nbsp;1 illustrates the flow diagram for patient inclusion and exclusion in this article. Among the enrolled patients, 50 patients received inhaled colistin therapy, 34 patients received a combination of intravenous and inhaled colistin, and 14 patients received intravenous colistin monotherapy. The study population included 71 male patients (72.4%) and 27 female patients (27.6%).\u003c/p\u003e\u003cp\u003eCarbapenem-resistant \u003cem\u003eAcinetobacter baumannii\u003c/em\u003e (57.1%) was the most common pathogen. There was no significant difference in microbial distribution among the groups (\u003cem\u003eP\u003c/em\u003e = 0.466). Regarding concomitant antibiotic therapy for CRO infections, meropenem (28.3%) and cefoperazone-sulbactam (28.3%) were the most frequently administered agents, followed by piperacillin-tazobactam (20.3%) and tigecycline (8.0%). No statistically significant variations in antibiotic utilization were detected among the three groups (\u003cem\u003eP\u003c/em\u003e \u0026gt; 0.05). There were no substantial differences among the three cohorts, including age, BMI, comorbidities, or baseline APACHE II, SOFA, and CPIS scores prior to treatment. However, a significant difference was detected in the baseline serum creatinine levels, with the intravenous group exhibiting lower levels compared to the inhalation group (\u003cem\u003eP\u003c/em\u003e = 0.019). Comprehensive demographic and clinical characteristics are characteristics in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e (full table at the end of manuscript).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv class=\"gridtable\"\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\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\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\u003eDemographic and clinical characteristic of study patients\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIH (n = 50)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIV + IH (n = 34)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIV (n = 14)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eDemographic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e68.46 ± 15.33\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e72.21 ± 13.75\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e64.71 ± 10.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.180\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40 (80.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25 (73.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (42.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.022\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23.58 ± 4.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22.44 ± 4.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e23.21 ± 2.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.480\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharlson Comorbidity Index\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.02 ± 1.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4.82 ± 1.70\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.86 ± 2.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.108\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eUnderlying disease, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes mellitus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 (24.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 (41.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (14.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.102\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertension\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26 (52.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22 (64.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (42.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.336\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChronic cardiovascular disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (12.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (11.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.477\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChronic pulmonary disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (14.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (20.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.197\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCerebrovascular disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (12.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (14.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.422\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eArrhythmia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (14.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (11.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (21.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.672\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eIsolated pathogen at diagnosis, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCRAB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e32 (64.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18 (52.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e10 (71.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.446\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCRPA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 (20.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e11 (32.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (14.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.316\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCRKP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (16.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (14.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (21.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.864\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 (4.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (11.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.232\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePolymyxins MIC distribution ≤ 0.5 mg/L, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e31 (62.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17 (50.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 (35.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.183\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eConcomitant antibiotic therapy, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMeropenem\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17 (34.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 (41.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8 (57.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.313\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCefoperazone-Sulbactam\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15 (30.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e17 (50.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7 (50.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.144\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePiperacillin-Tazobactam\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e15 (30.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8 (23.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 (35.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.642\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=\"left\" colname=\"c2\"\u003e\u003cp\u003e9 (18.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (5.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.122\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\u003e13 (26.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (14.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3 (21.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.518\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003ePre-treatment\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAPACHE II score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20.82 ± 5.19\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22.06 ± 4.26\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e22.36 ± 5.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.407\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSOFA score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.00 ± 2.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7.74 ± 3.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e8.36 ± 3.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.268\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCPIS score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.66 ± 1.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7.12 ± 1.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7.36 ± 2.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.289\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e, mmHg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e296.43 ± 111.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e251.00 ± 92.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e292.44 ± 114.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.149\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eT, °C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e37.96 ± 0.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e37.92 ± 0.87\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e38.5 ± 0.86\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.066\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWhite blood cell count, 10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11.2 (8.60, 15.65)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9.95 (6.38, 15.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e11.25 (6.55, 13.55)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.507\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCRP, mg/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e96.89 (65.61, 160.63)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e92.32(41.84, 194.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e48.44(25.71,170.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.618\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePCT, ng/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.679(0.3, 1.794)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.475(0.248, 3.173)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.703(0.194, 8.112)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.884\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal protein, g/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e59.04 ± 7.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e56.74 ± 6.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e55.95 ± 4.93\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.145\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlbumin, g/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e29.83 ± 3.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29.13 ± 3.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e29.44 ± 2.89\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.634\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSerum creatinine, µmol/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e81.08 ± 36.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e66.31 ± 27.41\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e50.11 ± 25.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.019\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eCRAB: carbapenem-resistant \u003cem\u003eAcinetobacter baumannii\u003c/em\u003e; CRPA: carbapenem-resistant \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e; CRKP: carbapenem-resistant \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e; CRP: C-reactive protein; PCT: procalcitonin.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003cbr\u003e\u003ch3\u003eAssessment of inflammatory biomarkers and clinical severity scores\u003c/h3\u003e\u003cp\u003eGiven that the mean duration of CMS therapy was 10.7 days, inflammatory biomarkers and disease severity scores were primarily evaluated on days 3, 7, and at the end of treatment. Prior to enrolment, 90.1% of patients required mechanical ventilation, and over two-thirds had concomitant respiratory failure. After 7 days of CMS therapy, the PaO₂/FiO₂ ratio showed an overall increasing trend with intermittent fluctuations (Fig.\u0026nbsp;2A), reaching a mean of 313.02 in the intravenous monotherapy group; however, no significant differences were observed (\u003cem\u003eP\u003c/em\u003e = 0.679). Furthermore, both APACHE II and SOFA scores exhibited a downward trend on days 3 and 7, with no significant variation observed among the three cohorts (all \u003cem\u003eP\u003c/em\u003e \u0026gt; 0.05) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) (full table at the end of manuscript). Notably, the median PCT level peaked on the second day after treatment initiation and gradually declined thereafter (Fig.\u0026nbsp;2D). By the seventh day of treatment, total protein and albumin levels in the intravenous group were markedly lower than others (Fig.\u0026nbsp;2E, F). Upon conclusion of treatment, the SOFA score in the nebulization group [median 4 (IQR: 3–6)] was substantially lower than that of both the combination and intravenous groups (\u003cem\u003eP\u003c/em\u003e = 0.003). In addition, levels of inflammatory markers were reduced in the nebulization group relative to the combination group, including CRP (44.89 mg/L vs. 91.68 mg/L, \u003cem\u003eP\u003c/em\u003e = 0.041) and PCT (0.300 ng/mL vs. 1.250 ng/mL, \u003cem\u003eP\u003c/em\u003e = 0.004).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv class=\"gridtable\"\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\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\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\u003eInflammatory Markers and Severity Scores Across Treatment Timeline\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIH (n = 50)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIV + IH (n = 34)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIV (n = 14)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eOn the third day of treatment\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAPACHE II score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20 (17, 25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22 (18, 23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e21 (20, 24)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.509\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSOFA score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (5, 8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (5,10.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e7.5 (5, 10.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.227\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e, mmHg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e307.32 ± 99.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e263.20 ± 90.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e269.55 ± 101.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.102\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eT, °C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e37.69 ± 0.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e37.95 ± 0.57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e38.06 ± 0.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.049\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCRP, mg/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e87.81(46.12, 144.91)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e81.08 (50.96,143.01)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e101.59 (35.31, 192.19)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.603\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePCT, ng/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.845 (0.363, 1.520)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.830 (0.280, 2.360)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2.305 (0.217, 6.938)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.666\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal protein, g/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e58.66 ± 7.61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e55.71 ± 5.11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e56.24 ± 4.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.105\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlbumin, g/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28.82 ± 3.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28.21 ± 2.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e29.44 ± 3.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.451\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eOn the seventh day of treatment\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAPACHE II score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e20 (17.25, 22)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e18.5 (15.25, 25.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e22 (17, 24)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.409\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSOFA score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (5, 8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6 (4.5, 8.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4.5 (4, 9.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.471\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e, mmHg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e309.69 ± 87.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e286.57 ± 112.98\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e313.02 ± 90.06\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.679\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eT, °C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e37.79 ± 0.60\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e37.69 ± 0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e37.45 ± 0.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.094\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCRP, mg/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e66.75 (42.93, 88.29)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e61.39 (30.04, 134.17)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e83.41 (35.95, 148.38)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.673\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePCT, ng/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.638 (0.250, 1.468)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.561 (0.176, 1.343)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.650 (0.196, 1.280)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.657\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal protein, g/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e59.50 (54.5, 66.70)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e58.70 (53.75, 64.15)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e51.70 (50.55, 53.70)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.015\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlbumin, g/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28.70 (27.00, 31.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29.10 (27.75, 32.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e26.00 (25.30, 28.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.025\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eEnd of treatment\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAPACHE II score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18 (14,23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21 (16, 25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e22.5 (14.5, 26)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.394\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSOFA score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (3, 6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6.5 (5, 9.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (4.25, 11.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.003\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePaO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e, mmHg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e341.09 ± 117.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e308.31 ± 111.56\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e315.41 ± 77.16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.261\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eT, °C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e37.50 (37.13, 37.68)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e37.30 (36.90, 38.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e37.30 (36.80, 37.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.606\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCRP, mg/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44.89 (22.06, 85.33)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e91.68 (47.49, 160.01)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e67.94 (16.19, 160,06)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.037\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePCT, ng/mL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.300 (0.126, 0.628)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.250 (0.374,5.660\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.484 (0.131, 2.085)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.005\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal protein, g/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e61.94 ± 8.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e58.58 ± 6.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e57.60 ± 9.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.092\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAlbumin, g/L\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30.05 ± 3.71\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29.65 ± 3.92\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e30.70 ± 4.97\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.732\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cbr\u003e\u003ch2\u003eTherapeutic efficacy assessment\u003c/h2\u003e\u003cp\u003eIn this study, out of 35 patients in the IH group, 70% achieved favourable clinical outcomes. In comparison, 64.7% of patients in the IV + IH group and 64.3% in the IV group had favourable clinical outcomes, with no significant difference observed (\u003cem\u003eP\u003c/em\u003e = 0.834). Patients who received nebulized antibiotic therapy demonstrated a markedly elevated rate of microbiological eradication. In the combination therapy cohort, 24 patients (70.6%) achieved negative culture results after treatment, compared to only 42.9% in the intravenous monotherapy group (\u003cem\u003eP\u003c/em\u003e = 0.025). In terms of prognosis, no statistically significant difference in 28-day all-cause mortality was observed among the groups (\u003cem\u003eP\u003c/em\u003e = 0.182) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Furthermore, Kaplan-Meier survival analysis showed no significant difference in 28-day mortality between the three groups (\u003cem\u003eP\u003c/em\u003e = 0.180) (Fig.\u0026nbsp;3). After the exclusion of individuals who underwent renal replacement therapy previous to colistin administration (8 in the IH cohort, 3 in the combination cohort, and 5 in the IV cohort), the incidence of acute kidney injury was 31.0% in the IH cohort, 45.2% in the combination cohort, and 44.4% in the IV cohort (\u003cem\u003eP\u003c/em\u003e = 0.416).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cdiv class=\"gridtable\"\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\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\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\u003eOutcomes in patients receiving different administration\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eIH (n = 50)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eIV + IH (n = 34)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eIV (n = 14)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eClinical efficacy, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e35 (70.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e22 (64.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e9 (64.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.834\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMicrobiological eradication, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e40 (80.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e24 (70.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (42.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.025\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e28-day mortality, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (26.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 (44.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e6 (42.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.182\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLength of hospital stay, days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e30 (21, 43)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e30 (24, 47.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e23 (19.5, 35.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.351\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 (19, 39)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e26 (20, 37)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e18 (10.6, 23)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.829\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAKI, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13 (31.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14 (45.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (44.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.416\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKDIGO 1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6 (14.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e5 (16.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (22.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.755\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKDIGO 2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (11.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2 (6.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e2 (22.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.341\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eKDIGO 3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (4.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (22.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0 (0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e\u003cp\u003e0.043\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e\u003cbr\u003e\u003ch2\u003eFactors associated with clinical efficacy\u003c/h2\u003e\u003cp\u003eUnivariate analysis of 98 patients revealed that those who experienced clinical improvement had significantly lower baseline APACHE II scores [odds ratio (OR) 0.91, 95% confidence interval (CI) 0.83–0.99], along with reduced risks of sepsis (OR 0.31, 95% CI 0.13–0.77) and acute kidney injury (OR 0.27, 95% CI 0.11–0.69) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e) (full table at the end of manuscript). In the analysis of the relationship between AKI and treatment efficacy, patients who had undergone renal replacement therapy prior to drug administration were excluded. Notably, only 42 individuals had confirmed microbiological documentation, and no significant association was observed between pathogen clearance and clinical outcomes.\u003c/p\u003e\u003cdiv class=\"gridtable\"\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\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\u003eUnivariate analysis of factors associated with clinical efficacy\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003c/colgroup\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eClinical failure (n = 32)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eClinical efficacy (n = 66)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eDemographic\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge, years\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e75.7 (66.75, 81)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e72 (58.75, 77)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.067\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23 (71.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e48 (72.7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.929\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e23.17 ± 3.94\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23.14 ± 3.79\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.966\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharlson Comorbidity Index\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (4, 5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e4 (3, 5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.716\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eUnderlying disease, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiabetes mellitus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (21.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21 (33.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.310\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHypertension\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 (50.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e38 (57.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.480\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChronic cardiovascular disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (9.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (10.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.850\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eChronic pulmonary disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (12.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (15.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.725\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCerebrovascular disease\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (12.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (10.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.781\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eIsolated pathogen at diagnosis, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCRAB\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17 (53.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e43 (65.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.254\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCRPA\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e9 (28.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e12 (18.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.264\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCRKP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (15.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (10.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.480\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePolymyxins MIC distribution ≤ 0.5 mg/L, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e18 (56.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e35 (53.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.764\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eConcomitant antibiotic therapy, n (%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMeropenem\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 (31.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e29 (43.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.231\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCefoperazone-Sulbactam\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e14 (43.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25 (37.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.578\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePiperacillin-Tazobactam\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (21.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e21 (31.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.310\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=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (15.6)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e6(9.1)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.342\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003ePre-treatment\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAPACHE Ⅱ score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22.97 ± 4.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e20.76 ± 4.84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.042\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSOFA score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (5, 10)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (5, 9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.282\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCIPS score\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (6, 7.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e7 (6, 8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.088\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eOthers\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSepsis, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e21 (65.5)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e25 (37.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.011\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLength of hospital stay, days\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e28 (18.75, 36)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e33.5 (22, 42.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.162\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\u003e24.5 (13, 31.25)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e28.5 (21, 39.75)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.097\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMicrobiological eradication, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 (76.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e23 (79.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.682\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAKI, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16 (55.2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 (25.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.006\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/table\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this research, we assessed the effectiveness and nephrotoxicity of different administration routes for treating nosocomial pneumonia caused by CR-GNB. Compared to intravenous or inhaled monotherapy, combination therapy did not demonstrate superior clinical efficacy, lower 28-day all-cause mortality rate, or shorter length of hospital stay. In terms of bacterial eradication, the inhalation group showed higher eradication rates than the intravenous group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05). Notably, the addition of inhaled therapy to systemic intravenous administration was not associated with an increased risk of nephrotoxicity.\u003c/p\u003e\u003cp\u003eA meta-analysis of 19 observational studies and 3 RCTs evaluated the efficacy of polymyxin-based regimens for multidrug-resistant Gram-negative pneumonia. The IV\u0026thinsp;+\u0026thinsp;IH regimen significantly reduced mortality (OR 0.67, 95% CI 0.50\u0026ndash;0.88) and improved clinical cure rates (OR 1.90, 95% CI 1.20\u0026ndash;3.00). This may be due to enhanced drug concentrations in both systemic and alveolar spaces [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. However, in our study, the combination therapy group did not confer additional clinical benefits regarding treatment success or 28-day mortality. We also found that patients with elevated baseline APACHE II scores, concurrent sepsis, or developing AKI during treatment were more likely to experience treatment failure. A previous study reached similar conclusions, reporting that a higher mean Simplified Acute Physiology Score II (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002), higher SOFA score (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.05), presence of septic shock (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and the occurrence of AKI during polymyxin therapy (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.04) were all independently correlated with clinical failure [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In addition, the efficacy of aerosolized antibiotic therapy is influenced by multiple factors, including nebulizer performance, patient-specific conditions, and mechanical ventilation parameters [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In our study, many patients who underwent bronchoscopy exhibited thick airway secretions, which may have hindered alveolar drug deposition and affected treatment efficacy. Although a mesh nebulizer characterized by high pulmonary deposition efficiency, low residual volume, and short nebulization time was employed, the adequacy of the drug concentration in target lesion areas remains uncertain and requires further investigation [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn comparison to intravenous administration, aerosolized therapy has demonstrated a significantly higher rate of bacterial clearance (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009). Several previous studies evaluating the efficacy of aerosolized administration have consistently reached the same conclusion [\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The increased local drug concentration achieved via inhalation therapy may contribute to more effective bacterial clearance. However, a retrospective matched case-control study that included 43 patient pairs with VAP caused by multidrug-resistant Gram-negative bacteria, matched for age and APACHE Ⅱ, compared outcomes between individuals undergoing combination systemic and nebulized therapy versus intravenous therapy alone. The study found no statistically significant differences between the two groups in terms of pathogen eradication (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.679), clinical cure (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.100), or mortality (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.289) [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. A similar study on multidrug-resistant \u003cem\u003eAcinetobacter baumannii\u003c/em\u003e also reported no significant differences in outcomes [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. These findings may reflect a limited understanding of drug penetration from the airway lumen to the infected tissue. In our study, although bacterial eradication was achieved, it was not associated with clinical outcomes (P\u0026thinsp;=\u0026thinsp;0.682), consistent with findings from previous studies. A meta-analysis of 11 randomized controlled trials (n\u0026thinsp;=\u0026thinsp;1,472) demonstrated that adjunctive inhaled antibiotic therapy significantly improved microbiological eradication rates compared to intravenous antibiotic therapy alone or intravenous therapy in combination with inhaled placebo (OR\u0026thinsp;=\u0026thinsp;2.63, 95% CI: 1.36\u0026ndash;5.09). Nonetheless, the study emphasized that microbiological eradication does not necessarily translate into clinical success [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eNephrotoxicity is a significant adverse effect of colistin, which often causes hesitation among clinicians regarding its use. In this study, clinicians carefully considered renal function during treatment and appeared more tolerant of elevated creatinine levels in patients receiving inhaled therapy alone. While the variations in AKI incidence among the three groups were not statistically significant, the AKI rate in the inhalation-only group appeared to be lower than that in the other two groups. The incidence of colistin-associated acute kidney injury ranges between approximately 20% and 60%. Studies have demonstrated that individuals administered breathed colistin exhibit a markedly reduced incidence of nephrotoxicity than those undergoing systemic administration [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Moreover, combined inhalation and intravenous therapy does not appear to significantly increase the risk of nephrotoxicity compared to intravenous therapy alone [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Additionally, a meta-analysis identified age\u0026thinsp;\u0026gt;\u0026thinsp;65 years, hypoalbuminemia, sepsis or septic shock, and concurrent use of vancomycin or vasopressors as independent predictors for colistin-associated nephrotoxicity [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eAlthough nephrotoxicity is commonly reported as an adverse effect of polymyxins, the associated increase in serum creatinine is generally mild. Since severe infections can lead to serious consequences, interruptions in colistin treatment due to nephrotoxicity are relatively rare in clinical practice. Previous studies have reported that AKI was reversible in 91.6% of people administered CMS and 79.0% of those receiving polymyxin B treatment [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. However, the long-term renal impact of polymyxins, especially in elderly patients, is often overlooked. A retrospective cohort study involving patients who received intravenous polymyxin therapy for severe infections found that 40% of survivors (29/72) developed AKI during hospitalization. At the 6-month follow-up, 75% (22/29) of these AKI survivors progressed to chronic kidney disease, which was substantially higher than the 27% (16/58) recorded in a matched cohort of sepsis-associated AKI patients without polymyxin exposure (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Further analysis identified polymyxin use (OR: 8.86; 95% CI: 2.8\u0026ndash;27.8) and elderly status (OR: 1.04; 95% CI: 1.01\u0026ndash;1.07) as independent risk factors for CKD progression [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. These findings emphasize the critical need for careful and continuous renal monitoring, particularly in elderly patients, to prevent irreversible nephrotoxicity.\u003c/p\u003e\u003cp\u003eCurrently, several novel antibiotics, including aztreonam-avibactam, cefiderocol, and ceftazidime-avibactam, have emerged [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], while non-antibiotic therapies, such as phage therapy and nanomaterials are also rapidly developing [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. However, due to economic constraints and other factors, colistin remains a valuable therapeutic option. Although its use is associated with multiple challenges, the incorporation of therapeutic drug monitoring into routine clinical practice may represent an effective strategy to optimize the benefit-risk ratio in critically ill patients [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis research has following limitations: Firstly, as a single-centre analysis, the relatively small sample size (particularly in the intravenous administration group) may introduce potential selection bias. Secondly, although the absence of statistically significant distinction in disease severity across the intravenous injection group and the nebulizer group, patients with better overall conditions tended to receive nebulized colistin alone. Thirdly, this study involved patients with varying ventilator settings, and we did not assess factors such as airway obstruction or lung consolidation, which could potentially affect the efficacy of inhaled colistin.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis prospective study compared the efficacy and nephrotoxicity of three different administration routes in the treatment of nosocomial pneumonia caused by CRO. The results indicated that combination therapy did not demonstrate superior clinical benefits compared to either inhaled or intravenous monotherapy. Notably, inhaled therapy was associated with a higher bacterial clearance rate and lower nephrotoxicity, suggesting its potential as a feasible alternative to intravenous administration. Given the limitations of this study, well-designed prospective clinical trials are warranted to further assess the efficacy and safety of different administration strategies.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCRO\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;carbapenem-resistant organisms\u003c/p\u003e\n\u003cp\u003eNP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;nosocomial pneumonia\u003c/p\u003e\n\u003cp\u003eAKI\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;acute kidney injury\u003c/p\u003e\n\u003cp\u003eHAP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;hospital-acquired pneumonia\u003c/p\u003e\n\u003cp\u003eVAP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;ventilator-associated pneumonia\u003c/p\u003e\n\u003cp\u003eCR-GNB\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;carbapenem-resistant Gram-negative bacteria\u003c/p\u003e\n\u003cp\u003eCRAB\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; carbapenem-resistant\u0026nbsp;\u003cem\u003eAcinetobacter baumannii\u003c/em\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCRPA\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;carbapenem-resistant\u0026nbsp;\u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eCRKP \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;carbapenem-resistant \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eCMS \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Colistimethate sodium\u003c/p\u003e\n\u003cp\u003eCPIS \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Clinical Pulmonary Infection Score\u003c/p\u003e\n\u003cp\u003eAPACHE II \u0026nbsp; \u0026nbsp; \u0026nbsp;Acute Physiology and Chronic Health Evaluation II\u003c/p\u003e\n\u003cp\u003eSOFA \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; Sequential Organ Failure Assessment\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of The First Affiliated Hospital of Ningbo\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUniversity [No. 2024-R044-02]. All procedures were performed in accordance with the ethical\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eprinciples outlined in the Declaration of Helsinki and relevant guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Trial\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was retrospectively registered at ClinicalTrials.gov (NCT06907069) on December 9, 2024.\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\u003eThe datasets used and/or analysed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was supported by the Project of Ningbo Key R\u0026amp;D Plan and \u0026ldquo;Unveiling and Leading\u0026rdquo; under Grant No.2023Z174, the Zhejiang Provincial Medical and Health Science Foundation of China under Grant No.2024KY312, the Ningbo Clinical Research Centre for Emergency and Critical Diseases under Grant No.2024L003.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; details\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQiao-yi Wei, MD., E-mail: [email protected]\u003c/p\u003e\n\u003cp\u003eXin-xing Chen, MD., E-mail: [email protected]\u003c/p\u003e\n\u003cp\u003eFeng Xu, PhD., E-mail: [email protected]\u003c/p\u003e\n\u003cp\u003eHeng Fan, PhD. Pro., E-mail: [email protected]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQiao-yi Wei and Xin-xing Chen collected clinical data, interpreted of data and wrote the first draft of the manuscript. Feng Xu and Heng Fan participated in conception, design and providing critical revisions. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank all the subjects, their families, and collaborating clinicians for their participation.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eZaragoza R, Vidal-Cortes P, Aguilar G, Borges M, Diaz E, Ferrer R, et al. Update of the treatment of nosocomial pneumonia in the ICU. 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Clin Infect Dis. 2016;63(5):e61\u0026ndash;111.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKilic I, Ayar Y, Ceylan I, Kaya PK, Caliskan G. Nephrotoxicity caused by colistin use in ICU: a single centre experience. BMC Nephrol. 2023;24(1):302.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKellum JA, Lameire. N, Group. ftKAGW. Diagnosis, evaluation, and management of acute kidney injury a KDIGO summary (Part 1). Crit Care. 2013;17(1):204.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eZhou Y, Wang G, Zhao Y, Chen W, Chen X, Qiu Y, et al. Efficacy and safety of different polymyxin-containing regimens for the treatment of pneumonia caused by multidrug-resistant gram-negative bacteria: a systematic review and network meta-analysis. Crit Care. 2024;28(1):239.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTumbarello M, De Pascale G, Trecarichi EM, De Martino S, Bello G, Maviglia R, et al. 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Int J Infect Dis. 2021;108:406\u0026ndash;12.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eChoe J, Sohn YM, Jeong SH, Park HJ, Na SJ, Huh K, et al. Inhalation with intravenous loading dose of colistin in critically ill patients with pneumonia caused by carbapenem-resistant gram-negative bacteria. Ther Adv Respir Dis. 2019;13:1753466619885529.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMaan L, Anand N, Yadav G, Mishra M, Gupta MK. The Efficacy and Safety of Intravenous Colistin Plus Aerosolized Colistin Versus Intravenous Colistin Alone in Critically Ill Trauma Patients With Multi-Drug Resistant Gram-Negative Bacilli Infection. Cureus. 2023;15(11):e49314.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKofteridis DP, Alexopoulou C, Valachis A, Maraki S, Dimopoulou D, Georgopoulos D, et al. Aerosolized plus intravenous colistin versus intravenous colistin alone for the treatment of ventilator-associated pneumonia: a matched case-control study. Clin Infect Dis. 2010;51(11):1238\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eJang JY, Kwon HY, Choi EH, Lee WY, Shim H, Bae KS. Efficacy and toxicity of high-dose nebulized colistin for critically ill surgical patients with ventilator-associated pneumonia caused by multidrug-resistant Acinetobacter baumannii. J Crit Care. 2017;40:251\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSella N, Pettenuzzo T, De Cassai A, Zarantonello F, Congedi S, Bruni A, et al. Inhaled antibiotics for treating pneumonia in invasively ventilated patients in intensive care unit: a meta-analysis of randomized clinical trials with trial sequential analysis. Crit Care. 2024;28(1):387.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAbdellatif S, Trifi A, Daly F, Mahjoub K, Nasri R, Ben Lakhal S. Efficacy and toxicity of aerosolised colistin in ventilator-associated pneumonia: a prospective, randomised trial. Ann Intensive Care. 2016;6(1):26.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eXu P, Xu L, Ji H, Song Y, Zhang K, Ren X, et al. Analysis and comparison of adverse events of colistin administered by different routes based on the FAERS database. Sci Rep. 2025;15(1):10384.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eWang JL, Xiang BX, Song XL, Que RM, Zuo XC, Xie YL. Prevalence of polymyxin-induced nephrotoxicity and its predictors in critically ill adult patients: A meta-analysis. World J Clin Cases. 2022;10(31):11466\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eAysert-Yildiz P, Ozgen-Top O, Senturk AF, Kanik S, Ozger HS, Dizbay M. Polymyxin B vs. colistin: the comparison of neurotoxic and nephrotoxic effects of the two polymyxins. BMC Infect Dis. 2024;24(1):862.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMeraz-Munoz A, Gomez-Ruiz I, Correa-Rotter R, Ramirez-Sandoval JC. Chronic kidney disease after acute kidney injury associated with intravenous colistin use in survivors of severe infections: A comparative cohort study. J Crit Care. 2018;44:244\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eCarmeli Y, Cisneros JM, Paul M, Daikos GL, Wang M, Torre-Cisneros J, et al. Aztreonam-avibactam versus meropenem for the treatment of serious infections caused by Gram-negative bacteria (REVISIT): a descriptive, multinational, open-label, phase 3, randomised trial. Lancet Infect Dis. 2025;25(2):218\u0026ndash;30.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eShariati A, Kashi M, Chegini Z, Hosseini SM. Antibiotics-free compounds for managing carbapenem-resistant bacteria; a narrative review. Front Pharmacol. 2024;15:1467086.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRychlickova J, Kubickova V, Suk P, Urbanek K. Challenges of Colistin Use in ICU and Therapeutic Drug Monitoring: A Literature Review. Antibiot (Basel). 2023;12(3).\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":"Colistin, Nosocomial pneumonia, Inhaled, Carbapenem-resistant Gram-negative bacteria, Intravenous","lastPublishedDoi":"10.21203/rs.3.rs-6911404/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6911404/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eThe optimal route of colistin administration for treating carbapenem-resistant organisms (CRO) nosocomial pneumonia remains unclear. The objective of this study was to assess the efficacy and safety of three distinct regimens that are based on colistin.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003e98 patients with nosocomial pneumonia caused by CRO who received colistin treatment in the intensive care unit were included in this prospective cohort study. Based on the route of administration, patients were categorized into three groups: inhalation (IH), combined intravenous plus inhalation (IV\u0026thinsp;+\u0026thinsp;IH), and intravenous (IV). Clinical efficacy was the primary outcome at the end of the treatment. Secondary outcomes involved 28-day all-cause mortality, microbiological response, nephrotoxicity, and duration of hospital stay.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eThe clinical efficacy rates were 70.0% for the IH group, 64.7% for the IV\u0026thinsp;+\u0026thinsp;IH group, and 64.3% for the IV group, with no significant differences observed (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.834). Patients in the IH group achieved significantly better microbiological outcomes compared to those in the IV group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009). However, no substantial differences were observed among the groups regarding 28-day all-cause mortality, duration of hospital stay, or incidence of acute kidney injury. Moreover, higher APACHE II scores, the existence of sepsis, and the occurrence of acute kidney injury were identified as factors related to clinical treatment failure.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eIn the treatment of nosocomial pneumonia caused by CRO, inhaled administration demonstrated non-inferior clinical efficacy compared to systemic administration and was associated with a higher incidence of microbiological eradication.\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of Three Colistin Regimens in the Treatment of Nosocomial Pneumonia Caused by Carbapenem-Resistant Organisms: A Single Centre, Open Label, Prospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-23 05:32:24","doi":"10.21203/rs.3.rs-6911404/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":"ae3f4cb3-1076-44ec-8560-7d71573f20d2","owner":[],"postedDate":"July 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-29T03:08:58+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-23 05:32:24","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6911404","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6911404","identity":"rs-6911404","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}