Clinical Outcomes and Safety of Polymyxin B in the Treatment of Carbapenem-resistant Gram-negative Bacterial Infections: a Real-world Multicenter Study

Clinical Outcomes and Safety of Polymyxin B in the Treatment of Carbapenem-resistant Gram-negative Bacterial Infections: a Real-world Multicenter Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical Outcomes and Safety of Polymyxin B in the Treatment of Carbapenem-resistant Gram-negative Bacterial Infections: a Real-world Multicenter Study Xiaojuan Zhang, Shaoyan Qi, Xiaoguang Duan, Bing Han, Shuguang Zhang, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-328922/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background: High morbidity and mortality due to carbapenem-resistant Gram-negative bacilli (CR-GNB) has led to the resurgence of polymyxin B (PMB) use in the last decade. The aim of our multicenter, real-world study was to evaluate the effectiveness and safety of PMB in the treatment of CR-GNB infections. Methods: The real-world study included patients treated with intravenous PMB for at least 7 days during the period of October 2018 through June 2019. Associations between these variables and 28-day mortality or all-cause hospital mortality were explored through univariate analyses and multivariable logistic regression. Results: The study included 100 patients. Many patients presented with combined chronic conditions, septic shock, mechanical ventilation, and the presence of Klebsiella pneumoniae . The mean duration of PMB therapy was 11 days (range 7–38 days). Temperature (38°C vs 37.1°C), white blood cells (14.13×10 9 /L vs 9.28×10 9 /L), C-reactive protein (103.55 ug/l vs 47.60 ug/l), procalcitonin (3.89 ng/ml vs 1.70 ng/ml) and APACHE Ⅱ levels (17.75 ± 7.69 vs 15.98 ± 7.95) were significantly decreased after PMB treatment. The bacteria eradication rate was 77.65%. The overall mortality at discharge was 15%, and 28-day mortality was 40%. Major adverse reactions occurred in 16 patients. Nephrotoxicity was observed in 7 patients (7%). Conclusions: Our results provide positive clinical and safety outcomes for PMB in the treatment of CR-GNB. Timely and appropriate use of PMB may be particularly useful in treating patients with sepsis in CR-GNB infections. Translational Medicine carbapenem-resistant Gram-negative bacilli infections Polymyxin B adverse effects 28-day mortality Figures Figure 1 Figure 2 Introduction In recent years, infections due to carbapenem-resistant Gram-negative bacilli (CR-GNB) have become an increasingly important cause of mortality and morbidity around the world[ 1 ]. The organisms most commonly identified in CR-GNB infections are Klebsiella pneumoniae , Acinetobacter baumannii , and Pseudomonas aeruginosa [ 2 – 4 ]. These bacteria can lead to bloodstream, respiratory tract, skin and soft tissue, urinary tract, intra-abdominal, and surgical infections [ 3 , 5 – 7 ]. They are responsible for nosocomial infections, particularly among critically ill patients hospitalized in intensive care units (ICUs)[ 8 ]. Mortality rates of greater than 47% have been reported for CR-GNB infections[ 5 , 9 – 13 ]. The decline in the development of newer antibiotics has created a challenge for clinicians treating CR-GNB infections[ 2 , 14 ]. As a result, physicians have sought solutions in the arsenal of older therapeutics. This has led to the re-introduction the polymyxins in the treatment of infections caused by CR-GNB, as polymyxins are one of the few antibiotics that remain effective against these organisms[ 3 ]. Two polymyxins in clinical use, polymyxin B (PMB) and colistin, had fallen out of favor due to nephrotoxicity and neurotoxicity reported during their use in the 1960s. However, due to multiple drug resistance among Gram-negative bacilli, physicians have been increasingly forced to rely on polymyxins for the treatment of infections caused by these pathogens. It has not been determined which of these agents is superior in terms of the cure rate or microbiological resolution[ 15 , 16 ]. A systematic review and meta-analysis summarized findings that included no significant difference in mortality between patients treated with these two polymyxins; this study also found a lower nephrotoxicity profile for PMB[ 15 ]. Additionally, recently published research demonstrated that PMB, unlike colistin, is not cleared renally and therefore, dosing of PMB should not be adjusted based on renal function[ 17 ]. The international consensus guidelines for the optimal use of polymyxins recommend that patients intravenous PMB should receive a dose of 1.25–1.5 mg/kg (equivalent to 12,500–15,000 IU/kg) PMB every 12 hours infused over 1 hour[ 16 ]. In one study, clinicians found that combination therapy with at least two in vitro active agents was associated with higher efficacy in treating bloodstream infections caused by CR-GNB[ 6 , 18 ]. Currently, there is a lack of data available on the efficacy, 28-day mortality, and adverse events for PMB in the treatment of CR-GNB infections. Here, we report on a multicenter, real-world study of patients receiving intravenous PMB to investigate the clinical outcomes of antimicrobial therapy in patients infected with CR-GNB. Methods Study Design and Patients This multicenter, real-world study was conducted at 14 hospitals in Henan province during the period of October 2018 through June 2019. The institutional research ethics committee of the First Affiliated Hospital of Zhengzhou University approved the study (SS-2019-015). Patients aged more than 14 years with CR-GNB infection who received PMB therapy for at least 7 days were included in the study. Patients with positive culture of CR-GNB, or the patients were infected with suspected CR-GNB from two experienced professors. The organisms identified in CR-GNB infections are Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa, Escherichia coli, and Stenotrophomonas maltophilia. Patients were excluded if they received intravenous PMB for fewer than 7 days. Data Collection Data was collected from electronic patient registration and follow-up. The database was generated by the clinician through a query of the electronic medical records. The following variables were recorded: age, gender, underlying disease, hospitalization date, dates of admission to and discharge from ICU, vital signs, Acute Physiology and Chronic Health Evaluation II (APACHEII) score, Sequential Organ Failure Assessment (SOFA) score, any major surgeries performed, ventilator care, site of isolation of organisms, exposure to antimicrobial therapies, clinical features, biochemical indices, and microbiological data on admission and on the day of introduction of PMB. The dose and duration of PMB therapy, renal function, clinical and microbiological outcomes, and adverse reactions to PMB were noted. Patients were followed up until the end of treatment at 28 days. Patient Diagnoses Diagnoses of infections were based on clinical features and the isolation of bacteria from areas that are normally sterile. The microbiologically documented infection was defined as positive cultures in sterile of localized, and absence of any bacterial pollution or colonization. Severe sepsis was defined as sepsis associated with organ dysfunction or hypoperfusion. Septic shock was defined as sepsis 3.0[19]. Pulmonary infection included hospital-associated pneumonia (HAP) and ventilator-associated pneumonia (VAP). HAP was defined as a pneumonia occurring 48h or more after admission. VAP was defined as a pneumonia developing 48h or more after tracheal intubation. Chronic diseases included heart disease, hypertension, stroke, cancer, diabetes mellitus, and chronic obstructive pulmonary disease. Microbiology The CR-GNB include Enterobacteriaceae, Acinetobacter spp., Pseudomonas aeruginosa, Stenotrophomonas maltophilia, and Burkholderia cepacia. All CR-GNB infections were identified in the microbiology laboratory. The biological samples included blood, vein catheter samples, urine, sputum, tracheal secretions, bronchial‐alveolar lavage fluid, intraperitoneal fluid, and pleural drainage fluid. Bacterial identification and drug sensitivity tests were performed using a Vitek® 2 automated system（France Biomerieux）. Susceptibility was interpreted according to Clinical and Laboratory Standards Institute criteria[20]. Enterobacteriaceae with a minimal inhibitory concentration(MIC) ≥ 4 µg/ml were considered resistance to carbapenem[20]. Pseudomonas aeruginosa and Acinetobacter spp. with a minimal inhibitory concentration (MIC) ≥ 8 µg/ml were considered resistance to carbapenem[20]. Burkholderia cepacia with a MIC ≥ 16 µg/ml were considered resistance to meropenem[20]. Isolates with a MIC ≤ 2 µg/ml were considered susceptible to PMB (colistin breakpoint for Enterobacteriaceae)[21]. The treating clinicians evaluated whether pathogens were the pathogenic bacteria according to the characteristics of pathogen distribution in the institution and their own experience. Treatment Regimen All patients were treated with intravenous PMB, to which all strains remained sensitive. The international consensus guidelines for the optimal use of polymyxins recommend that patients who require intravenous PMB receive a dose of 1.25~1.5 mg/kg (equivalent to 12,500~15,000 IU/kg) PMB every 12 hours infused over 1 hour[16]. Upon isolation of strains of CR-GNB that were resistant to carbapenem, an intravenous antibiotic regimen was initiated at the discretion of the attending physician. Outcomes The primary outcome of this analysis was 28-day mortality; the secondary outcomes included all-cause hospital mortality, ICU mortality, and the occurrence of adverse events during PMB therapy. The clinical outcomes of this study were based on the recovery of patients following PMB therapy. The measure of 28‐day mortality refers to patient deaths occurring within 28 days from the start of treatment, even if the death was related to other comorbidities that were not the infection. Clinical cure was defined as a combined outcome of survival and the complete disappearance or improvement of signs and symptoms of infection after day 7 of PMB therapy. Failure of treatment was defined as maintenance or worsening of signs and symptoms of disease or radiologic deterioration. Common adverse events included nephrotoxicity, neurotoxicity, skin hyperpigmentation, and eosinophil increase. Nephrotoxicity was defined as increase in serum creatinine (SCr) by ≥26.5 umol/L within 48 hours, or increase in SCr to ≥1.5 times baseline within 7 days, or urine volume ＜ 0.5 ml/Kg/hour for 6 hours[22]. Skin hyperpigmentation was evaluated based on changes of the skin of the face and neck during PMB therapy or four weeks after treatment completion. Neurotoxicity included any of the following: apnea, encephalopathy, paresthesia, or seizures. Statistical Analysis Statistical analyses were carried out using the statistical software package IBM SPSS Statistics 21.0 (SPSS, Chicago, IL). Descriptive analysis was performed to describe the distribution of the variables of interest. Categorical variables were presented as counts and percentages and were compared between survivors and non-survivors using Chi-squared test or Fisher’s exact test. Continuous variables of each group were presented as the mean ± SD or median with interquartile range (IQR) and were compared between survivors and non-survivors using Student’s t-test or Mann–Whitney U test, as appropriate. Paired t-test or Wilcoxon signed rank test was used to compare the continuous variables before and after therapy and categorical variables were compared using the McNemar test. Associations between these covariates and 28-day mortality or all-cause hospital mortality were explored through multivariable logistic regression. Kaplan-Meier curves were conducted to demonstrate the survival probability within 28 days and were compared using log-rank test between groups. A P -value < 0.05 was considered statistically significant. Results Data from 100 patients who received intravenous PMB between October 1, 2018 and June 30, 2019, were analyzed. The mean age of patients was 55.9 ± 17.1 years (range 17–91 years) and 79% were male. The mean length of hospitalization was 41.6 ± 26.42 days (range 7–130 days), and the mean residence time in the ICU was 26 days. Mechanical ventilation was given to 49% of patients in the study. There were 23 patients without chronic disease and 37 patients with one chronic illness; the remainder of patients had a combination of multiple chronic diseases. There were 39 patients who had septic shock at the beginning of therapy; an additional 10 patients later progressed to shock. The demographic and clinical features of patients who received intravenous PMB are summarized in Table 1 . For 85 patients, the pathogen culture was positive; 21 patients of these were infected with two bacteria species. In 35 cases, the patient had multi-site infection. The most patients received combination therapy with carbapenems, tigecycline, fosfomycin, or cefoperazone-sulbactam. There were 33 patients combined with meropenem, 27 patients combined with imipenem, 11 patients combined with biapenem. Only 3 patients were combined with doxycycline or amikacin. Table 1 Clinical Features and details of Patients Receiving Intravenous PMB Characteristic Mean ± SD, or n (%) Age (year) 55.91 ± 17.14 Male (%) 79 (79) ICU admission, n (%) 98 (98) Mechanical ventilation, n (%) 49 (49) Chronic medical conditions, n (%) Heart disease 14 (14) Hypertension 44 (44) Stroke 19 (19) Cancer 6 (6) Diabetes mellitus 15 (15) Chronic obstructive pulmonary disease 1 (1) Renal insufficiency, n (%) 27 (27) Septic shock, n (%) 39 (39) SOFA score, mean ± SD 7.76 ± 4.30 APACHE II, mean ± SD 17.61 ± 7.59 ICU stay before intravenous PMB, days, median (IQR) 8(3,14) MODS, n (%) 60 (60) PCT, ng/ml, median(IQR), 3.89(1.08,11.43) Bacterial, n (%) AB 33 (33) KP 48 (48) PA 16 (16) Other 9 (9) Unknown 15 (15) Infection sites, n (%) BSI 40 (40) Pulmonary infection 64 (64) Intraperitoneal infection 9 (9) Incision infection 6 (6) Others 18 (18) Concomitant antibiotic therapy Carbapenem 71 Tigecycline 47 Cefoperazone and sulbactam 16 Cefepime 8 Others 8 PMB: polymyxin B; ICU: intensive care unit; SOFA: Sequential Organ Failure Assessment; APACHE II: Acute Physiology and Chronic Health Evaluation II; MODS: multiple organ dysfunction syndrome; PCT: procalcitonin; KP: Klebsiella pneumoniae , AB: Acinetobacter baumannii ; PA: Pseudomonas aeruginosa ; BSI: bloodstream infection Overall, the condition of patients improved after the PMB treatment. Temperature, white blood cells, C-reactive protein (CRP), procalcitonin, and APACHE Ⅱ levels were significantly decreased among patients. Platelets were significantly increased ( P < 0.001). The number of patients with mechanical ventilation or shock significantly decreased after PMB treatment (Table 2 ). Table 2 Comparison of Patient Conditions Before and After Therapy Parameter Baseline After therapy P Heart rate, bpm, mean ± SD 92.02 ± 21.55 97.36 ± 20.35 0.895 Temperature,℃,median (IQR) 38(37.1,38.7) 37.1(36.7,37.6) < 0.001 WBC, ×10 9 , median (IQR) 14.13(10.08,20.02) 9.28(7.02,13.40) < 0.001 PLT, ×10 9 , mean ± SD 111.71 ± 97.68 190.95 ± 162.99 < 0.001 CRP, ug/l, median (IQR) 103.55(56.96,180.83) 47.6(13.08,102.58) < 0.001 PCT, ng/ml, median (IQR) 3.89(1.09,11.43) 1.695(0.46,5.41) < 0.001 SOFA, mean ± SD 7.74 ± 4.13 7.32 ± 4.41 0.282 APACHE Ⅱ, mean ± SD 17.75 ± 7.69 15.98 ± 7.95 0.007 Mechanical ventilation, n (%) 51 26 < 0.001 Septic shock, n (%) 49 26 < 0.001 WBC: white blood cell; CRP; C-reactive protein; PLT: platelet count; PCT: procalcitonin; SOFA: Sequential Organ Failure Assessment; APACHE II: Acute Physiology and Chronic Health Evaluation II. Microbiological eradication occurred in 66 (77.65%) out of 85 patients with electropositive germiculture. Serious adverse reactions occurred in 16 patients (16%). Seven patients experienced at least two adverse reactions. No patients had treatment discontinued because of an adverse reaction. Nephrotoxicity was manifested by transient creatinine and urea nitrogen elevations, and no patient required hemodialysis. Among 6 patients demonstrating neurotoxicity, 4 patients showed persistent drowsiness, transient irritability, paresthesia, fatigue, dizziness, or drowsiness, and the other 2 patients underwent invasive mechanical ventilation due to adverse reactions of respiratory depression. Transient adverse reactions included eosinophil increase. The outcomes of patients receiving intravenous PMB are shown in Table 3 . The 28-day mortality was 40%. More than 60% deaths occurred 7–14 days after enrollment, as shown in the Kaplan-Meier survival curve (Fig. 1 ). Table 3 Outcomes of Patients Receiving Intravenous PMB Outcomes n (%) Bacteria eradication rate, n (%) 66 (77.65) Treatment Duration, median (IQR) 11(9,13) Adverse events, n (%) 16 (16) Nephrotoxicity 7 (7) Neurotoxicity 6 (6) Skin hyperpigmentation 3 (3) Eosinophil increase 7 (7) ICU mortality, n (%) 12 (12) Hospital mortality, n (%) 15 (15) 28-day mortality, n (%) 40 (40) The survivors and nonsurviviors had similar characteristics (Table 4 ). Age, sex, and chronic medical conditions were similar in the two groups, and the types of adverse reactions were not notably different. Markers of infection, including white blood cell count, procalcitonin, and CRP, were also similar in the two groups. However, the platelet count in the nonsurvivors group was lower than in the survivor group ( P = 0.001). In terms of clinical characteristics, SOFA scores (6.77 ± 4.07 vs 9.25 ± 4.25, P = 0.004)༌APACHE II scores (16.17 ± 7.80 vs 19.7 8 ± 6.80, P = 0.016) and the number of patients on mechanical ventilation (21% vs 30%, P < 0.001) or having septic shock (17% vs 32%, P < 0.001) were lower in the survivor group than in the nonsurvivor group. There were no different therapeutic outcomes among the different combinations. The mortality among the 85 patients with identified pathogens was 38.82%, while the mortality among patients with negative pathogen culture results was 46.67% ( P = 0.58). During treatment, similar adverse reactions related to PMB were observed in the two groups. Table 4 Characteristics Associated With 28-Day Mortality Among Patients Who Received Intravenous PMB Parameter Value for: P Survivors (n = 60) Nonsurvivors (n = 40) Age, y, mean ± SD 54.65 ± 16.23 57.8 ± 18.45 0.370 Female, n (%) 47 (78.3) 32 (80.0) 0.840 WBC,×10 9 , median(IQR) 14.28(10.58,20.44) 13.84(9.55,19.65) 0.359 PLT, ×10 9 , mean ± SD 131.37 ± 101.96 71.15 ± 66.27 0.001 PCT, ng/ml, median (IQR) 2.30(0.70,10.07) 5.00(1.97,15.93) 0.062 CRP, ug/l, median (IQR) 100.15(50.70,174.33) 119.96(79.58,186.0) 0.624 SOFA, mean ± SD 6.77 ± 4.07 9.25 ± 4.25 0.004 APACHE Ⅱ, mean ± SD 16.17 ± 7.80 19.78 ± 6.80 0.016 Mechanical ventilation, n (%) 21 (35.0) 30 (75.0) < 0.001 Septic shock, n (%) 17 (28.3) 32 (80.0) < 0.001 Hospitalization before intravenous PMB, days, median (IQR) 12.00(5.25,20.75) 11.50(3.25,21.00) 0.882 ICU stay before intravenous PMB, days, median (IQR) 9.00(3.00,15.00) 5.00(1.00,14.00) 0.156 Treatment Duration, days, median (IQR) 11.00(9.00,13.00) 10.00(8.25,13.75) 0.697 Concomitant antibiotic therapy, n (%) Carbapenem 45(75) 26(65) 0.393 Tigecycline 28(46.67) 19(47.5) 0.935 Cefoperazone and sulbactam 9(15) 7(17.5) 0.956 Cefepime 3(5) 5(12.5) 0.328 Identify microorganisms, n (%) 52 (86.67) 33 (82.5) 0.580 KP, n (%) 32 (53.3) 16 (40.0) 0.191 AB, n (%) 19 (31.7) 14 (35) 0.728 Multisite infection, n (%) 20 (33. 3) 15 (37.5) 0.669 Pulmonary infection, n (%) 35 (58.3) 29 (72.5) 0.217 BSI, n (%) 26 (43.3) 14 (35.0) 0.405 Chronic medical conditions, n (%) 45 (75.0) 32 (80.0) 0.734 Nephrotoxicity, n (%) 13 (21.7) 13 (32.5) 0.251 Adverse reactions, n (%) 8 (13.3) 8 (20.0) 0.373 WBC: white blood cell; PLT: platelet count; PCT: procalcitonin; CRP: C-reactive protein; SOFA: Sequential Organ Failure Assessment; APACHEII: Acute Physiology and Chronic Health Evaluation II; PMB: polymyxin B; ICU: intensive care unit; KP: Klebsiella pneumoniae ; AB: Acinetobacter baumannii ; BSI: Bloodstream Infection. The factors demonstrating statistically significant differences in univariate analysis in Table 4 were analyzed by logistic regression (Table 5 ). Multivariate analysis showed that mechanical ventilation ( P = 0.023, odds ratio (OR) = 3.58; confidence interval (CI): 1.194–10.739) and septic shock ( P = 0.002, OR = 5.96; CI: 1.923–18.473) were independently associated with 28-day mortality in patients with sepsis due to CR-GNB. The 28-day mortality was 58.82% for patients on mechanical ventilation compared to 20.41% for patients who were not on mechanical ventilation. The 28-day mortality was 65.31% in patients with septic shock compared to 15.69% in patients who did not have septic shock. Survival of patients is shown in Fig. 2 . Table 5 Multivariate Analysis of Factors Associated With 28-Day Mortality Variable OR (95% CI) P -value PLT 1.578 (0.965–2.580) 0.069 Mechanical ventilation 3.580 (1.194–10.739) 0.023 Septic shock 5.960 (1.923–18.473) 0.002 APACHE II 1.013 (0.613–1.673) 0.960 SOFA 0.941 (0.553–1.601) 0.823 OR: odds ratio; CI: confidence interval; PLT: platelet count; APACHE II, Acute and Physiology and Chronic Health Evaluation; SOFA: Sequential Organ Failure Assessment. Discussion In this study, patients with CR-GNB infection treated with PMB had a bacteria eradication rate of 77.65%, ICU-related mortality of 12%, hospital mortality of 15%, and 28-day mortality of 40%. These results are favorable compared with those reported for studies of patients receiving different treatments for CR-GNB infections[ 23 ]. For example, in patients infected with carbapenem-resistant Acinetobacter baumannii who did not receive appropriate empirical antimicrobial therapy, the overall mortality rate was 86.1%[ 24 ]. In one retrospective study, the overall ICU mortality rate was 45.2% for critically ill patients infected with CR-GNB who received tigecycline therapy[ 25 ]. In another retrospective study, the in-hospital mortality rate for patients receiving tigecycline for the treatment of carbapenem-resistant Klebsiella pneumoniae bloodstream infections was 62.5%[ 26 ]. In a retrospective cohort study of the treatment of infections due to carbapenem-resistant Enterobacteriaceae, the 30-day mortality was 50% after ceftazidime-avibactam treatment[ 27 ]. Our results suggest that treatment with PMB may reduce the mortality of patients with CR-GNB. Our study found that after 7 days of PMB treatment, the temperature of patients with CR-GNB infection returned to normal, and the number of patients with septic shock or mechanical ventilation decreased. Moreover, the infection indicators of white blood cell, procalcitonin, and CRP were all significantly reduced. The symptoms of thrombocytopenia in patients with CR-GNB infection improved. APACHE Ⅱ scores were also lower than the initial sepsis. The mortality of PMB target therapy was 38.82%, while the mortality of patients with empiric therapy was 46.67% ( P = 0.580). Our results suggest that PMB may be a clinically effective treatment for patients infected with CR-GNB. Our results suggest that PMB therapy is safe for the treatment of infections caused by CR-GNB, as intravenous PMB was well tolerated in most patients. Serious adverse reactions occurred in 16 patients (16%), 7 patients had at least two adverse reactions, eight of whom had transient adverse reactions. Prior PMB population pharmacokinetic studies have made a contributions to optimizing the clinical use of this important last-line antibiotic in patients[ 17 ]. In our study, adverse effects related to nephrotoxicity occurred in 7 patients (7%) and were mild and reversible; none required renal replacement therapy. While the prevalence of nephrotoxicity was not lower in our study than in other observational studies (6–40.5%)[ 11 , 28 – 31 ], it was at the lower end of these reported ranges. Assessment of the contribution of PMB to renal impairment may be complicated by other factors such as infection, septic shock, multiple organ dysfunction syndrome (MODS), and concomitant use of other nephrotoxic drugs. Neurotoxicity of PMB is less common than nephrotoxicity, and it is usually mild and resolves after prompt discontinuation of therapy[ 11 , 28 ]. In a previous study on the use of PMB in patients, intravenous PMB was associated with neurotoxicity in 7% of cases, and no adverse reactions of respiratory depression were seen[ 11 ]. In another study, however, no cases of neurotoxicity complications occurred among 247 patients who were given PMB therapy [ 28 ]. In our study, among the 6 patients with neurotoxicity, 2 patients underwent invasive mechanical ventilation due to the adverse effects of respiratory depression. Neither patient used sedative analgesics. PMB therapy was not stopped in the patients with respiratory depression and the endotracheal tube was removed before the end of PMB treatment. In the present study, 3 cases (3%) developed skin hyperpigmentation in the face and neck. This incidence is lower than was reported in previous studies[ 28 ]. During treatment, there were no other adverse reactions such as rashes, itching, dermatitis, or fever. While our results support the use of PMB, the safety of polymyxin therapy requires further study. Mechanical ventilation and septic shock were independent factors associated with higher 28-day mortality risk in the present study. A previous study of a large US cohort found that most patients with culture-positive community onset sepsis did not have resistant bacteria [ 32 ], while a study of the epidemiology of sepsis in Chinese ICUs found that only 12% of culture-positive were multi-drug resistant organisms[ 33 ]. In our study, the mortality of patients with empiric PMB therapy was higher. This underscores the need for rapid identification of CR-GNB infection and an increased of judicious use of PMB for the treatment of sepsis, to avoid progression to mechanical ventilation or septic shock. In this regard, the optimization and validation of PMB-based combinations may have considerable clinical benefits. The present study has several limitations, including its retrospective, real-world design and lack of a control group or direct basis of comparison with other treatments. Another limitation was the relatively small number of patients included in the study. Serum PMB concentrations were not determined in the study. The decision to use additional antibiotics was made by individual clinicians, which may have introduced bias. Additionally, the concomitant use of other antibiotics with PMB makes it impossible to attribute treatment efficacy solely to PMB. Further, it was difficult to properly evaluate adverse effects attributable to PMB in view of the use of other drugs in seriously ill patients. Despite these limitations, our study represents a multicenter study evaluating a range of CR-GNB infections treated with PMB combination therapy. Conclusions In summary, the findings from our study suggest that timely and appropriate use of PMB may have a positive impact on clinical outcomes in the treatment of CR-GNB infections. These results underscore the need to more quickly identify patients with CR-GNB who may benefit from judicious use of PMB, in particular, patients with septic shock or on mechanical ventilation who may be at higher risk of mortality. Clinicians should apply strict protocols when using this antimicrobial agent to prevent the occurrence and spread of polymyxin resistance. Abbreviations CRGNB: carbapenem-resistant Gram-negative bacilli; PMB: polymyxin B; ICU: intensive care unit; APACHEII: Acute Physiology and Chronic Health Evaluation II; SOFA: Sequential Organ Failure Assessment; HAP: hospital-associated pneumonia; VAP: ventilator-associated pneumonia; PCT: procalcitonin; CRP: C-reactive protein; PLT: platelet count; MODS: Multiple organ dysfunction syndrome. Declarations Acknowledgements The authors would like to thank Chao Qin (The Fifth Affiliated Hospital of Zhengzhou University), Changyu Zhang (The Second Affiliated Hospital of Zhengzhou University), Xianrong Song (Henan Provincial Chest hospital), Ping Lou (The Medical Group of Zhengzhou First People’s Hospital), Yanqiu Gao (Zhengzhou Central Hospital), Ying Cai (Jinshui District General Hospital of Zhengzhou), Tiancai Wang (Nanshi Hospital of Nanyang), Xianfa Jiao (People’s Hospital of Zhengzhou), Yongmei Zhang (First Affiliated Hospital, Henan University of Science and Technology), Lin Guo (The Seventh People’s Hospital of Zhengzhou ), Jing Feng (Zhengzhou Yihe Hospital), Fengling Ju (Nanyang Second General Hospital)，Hong Liu (The First People’s Hospital of Pingdingshan) for their support with data collection. Authors’ contributions All authors were involved in the research concept and design. Zhang XJ, Qi SY, and Duan XG contributed to the data acquisition. Zhang XJ and Sun TW have reviewed and take responsibility for all of the data. Zhang XJ, Han B, Zhang SG, Liu SH, and Wang HX performed the analysis and interpretation of the data. Zhang XJ contributed to the writing of the first draft. Sun TW and Zhang HB reviewed this article and made necessary changes to improve it. All authors reviewed and approved the final manuscript. Funding This study was supported by the United Fund of National Natural Science Foundation of China (Grant No. U2004110), Leading Talents Fund in Science and Technology Innovation in Henan Province (Grant No.194200510017)；Science and Technology people-benefit project of Zhengzhou (2019KJHM0001)；The special fund for young and middle-aged medical research of China International Medical Exchange Foundation (Grant No. Z-2018-35); The integrated thinking research foundation of the China foundation for International Medical Exchange (Grant No. Z-2016-23-2001)；and the Overseas Training Program of Health Science and Technology Talents in Henan Province (HWYX2019008). Availability of data and materials The datasets used and/or analyzed in this study are not publicly available due to privacy issues but are available from the corresponding author upon reasonable request. Ethics approval and consent to participate The study was approved by the institutional research ethics committee of The First Affiliated Hospital of Zhengzhou University, and waived informed consent based on the real-world design and anonymization of patient identifiers before analysis. Consent for publication Not applicable. Competing interests The authors declare that they have no conflict of interest. References Patel G, Bonomo RA. "Stormy waters ahead": global emergence of carbapenemases . Front Microbiol. 2013; 4 : 48. Velkov T, Roberts KD, Nation RL, Thompson PE, Li J. Pharmacology of polymyxins: new insights into an 'old' class of antibiotics . Future Microbiol. 2013; 8(6) : 711-24. Gales AC, Jones RN, Sader HS. Contemporary activity of colistin and polymyxin B against a worldwide collection of Gram-negative pathogens: results from the SENTRY Antimicrobial Surveillance Program (2006-09) . J Antimicrob Chemother. 2011; 66(9) : 2070-4. 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Fridkin SK, Steward CD, Edwards JR, Pryor ER, Mcgowan JJ, Archibald LK, Gaynes RP, Tenover FC. Surveillance of antimicrobial use and antimicrobial resistance in United States hospitals: project ICARE phase 2. Project Intensive Care Antimicrobial Resistance Epidemiology (ICARE) hospitals . Clin Infect Dis. 1999; 29(2) : 245-52. Ismail B, Shafei MN, Harun A, Ali S, Omar M, Deris ZZ. Predictors of polymyxin B treatment failure in Gram-negative healthcare-associated infections among critically ill patients . J Microbiol Immunol Infect. 2018; 51(6) : 763-769. Bratu S, Landman D, Haag R, Recco R, Eramo A, Alam M, Quale J. Rapid spread of carbapenem-resistant Klebsiella pneumoniae in New York City: a new threat to our antibiotic armamentarium . Arch Intern Med. 2005; 165(12) : 1430-5. Sobieszczyk ME, Furuya EY, Hay CM, Pancholi P, Della-Latta P, Hammer SM, Kubin CJ. Combination therapy with polymyxin B for the treatment of multidrug-resistant Gram-negative respiratory tract infections . J Antimicrob Chemother. 2004; 54(2) : 566-9. Liang Q, Huang M, Xu Z. Early use of polymyxin B reduces the mortality of carbapenem-resistant Klebsiella pneumoniae bloodstream infection . Braz J Infect Dis. 2019; 23(1) : 60-65. Rigatto MH, Vieira FJ, Antochevis LC, Behle TF, Lopes NT, Zavascki AP. Polymyxin B in Combination with Antimicrobials Lacking In Vitro Activity versus Polymyxin B in Monotherapy in Critically Ill Patients with Acinetobacter baumannii or Pseudomonas aeruginosa Infections . Antimicrob Agents Chemother. 2015; 59(10) : 6575-80. Karaiskos I, Giamarellou H. Multidrug-resistant and extensively drug-resistant Gram-negative pathogens: current and emerging therapeutic approaches . Expert Opin Pharmacother. 2014; 15(10) : 1351-70. Vardakas KZ, Falagas ME. Colistin versus polymyxin B for the treatment of patients with multidrug-resistant Gram-negative infections: a systematic review and meta-analysis . Int J Antimicrob Agents. 2017; 49(2) : 233-238. Tsuji BT, Pogue JM, Zavascki AP, Paul M, Daikos GL, Forrest A, Giacobbe DR, Viscoli C, Giamarellou H, Karaiskos I, et al. International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP) . Pharmacotherapy. 2019; 39(1) : 10-39. Sandri AM, Landersdorfer CB, Jacob J, Boniatti MM, Dalarosa MG, Falci DR, Behle TF, Bordinhao RC, Wang J, Forrest A, et al. Population pharmacokinetics of intravenous polymyxin B in critically ill patients: implications for selection of dosage regimens . Clin Infect Dis. 2013; 57(4) : 524-31. Tan J, Yu W, Wu G, Shen J, Fang Y, Zhu H, Xiao Q, Peng W, Lan Y, Gong Y. A Real-World Study Comparing Various Antimicrobial Regimens for Bloodstream Infections Caused by Carbapenem-Resistant Gram-Negative Bacilli in a Tertiary Hospital, Shanghai, China, from 2010 to 2017 . Infect Drug Resist. 2020; 13 : 2453-2463. Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) . JAMA. 2016; 315(8) : 801-10. M100-S11, Performance standards for antimicrobial susceptibility testing . Clinical Microbiology Newsletter. 2001; 23(6) : 49. Testing ECOA. Breakpoint table for interpretation of MICs and zone diameters . , version 9.0. edition; 2019. Kellum JA, Lameire N. Diagnosis, evaluation, and management of acute kidney injury: a KDIGO summary (Part 1) . Crit Care. 2013; 17(1) : 204. Ngamprasertchai T, Boonyasiri A, Charoenpong L, Nimitvilai S, Lorchirachoonkul N, Wattanamongkonsil L, Thamlikitkul V. Effectiveness and safety of polymyxin B for the treatment of infections caused by extensively drug-resistant Gram-negative bacteria in Thailand . Infect Drug Resist. 2018; 11 : 1219-1224. Du X, Xu X, Yao J, Deng K, Chen S, Shen Z, Yang L, Feng G. Predictors of mortality in patients infected with carbapenem-resistant Acinetobacter baumannii: A systematic review and meta-analysis . Am J Infect Control. 2019; 47(9) : 1140-1145. Wu X, Zhu Y, Chen Q, Gong L, Lin J, Lv D, Feng J. Tigecycline Therapy for Nosocomial Pneumonia due to Carbapenem-Resistant Gram-Negative Bacteria in Critically Ill Patients Who Received Inappropriate Initial Antibiotic Treatment: A Retrospective Case Study . Biomed Res Int. 2016; 2016 : 8395268. Geng TT, Xu X, Huang M. High-dose tigecycline for the treatment of nosocomial carbapenem-resistant Klebsiella pneumoniae bloodstream infections: A retrospective cohort study . Medicine (Baltimore). 2018; 97(8) : e9961. Alraddadi BM, Saeedi M, Qutub M, Alshukairi A, Hassanien A, Wali G. Efficacy of ceftazidime-avibactam in the treatment of infections due to Carbapenem-resistant Enterobacteriaceae . Bmc Infect Dis. 2019; 19(1) : 772. Mattos K, Gouvea IR, Quintanilha J, Cursino MA, Vasconcelos P, Moriel P. Polymyxin B clinical outcomes: A prospective study of patients undergoing intravenous treatment . J Clin Pharm Ther. 2019; 44(3) : 415-419. Ouderkirk JP, Nord JA, Turett GS, Kislak JW. Polymyxin B nephrotoxicity and efficacy against nosocomial infections caused by multiresistant gram-negative bacteria . Antimicrob Agents Chemother. 2003; 47(8) : 2659-62. Nelson BC, Eiras DP, Gomez-Simmonds A, Loo AS, Satlin MJ, Jenkins SG, Whittier S, Calfee DP, Furuya EY, Kubin CJ. Clinical outcomes associated with polymyxin B dose in patients with bloodstream infections due to carbapenem-resistant Gram-negative rods . Antimicrob Agents Chemother. 2015; 59(11) : 7000-6. Cai Y, Leck H, Tan RW, Teo JQ, Lim TP, Lee W, Chlebicki MP, Kwa AL. Clinical Experience with High-Dose Polymyxin B against Carbapenem-Resistant Gram-Negative Bacterial Infections-A Cohort Study . Antibiotics (Basel). 2020; 9(8) : 451. Rhee C, Kadri SS, Dekker JP, Danner RL, Chen HC, Fram D, Zhang F, Wang R, Klompas M. Prevalence of Antibiotic-Resistant Pathogens in Culture-Proven Sepsis and Outcomes Associated With Inadequate and Broad-Spectrum Empiric Antibiotic Use . JAMA Netw Open. 2020; 3(4) : e202899. Xie J, Wang H, Kang Y, Zhou L, Liu Z, Qin B, Ma X, Cao X, Chen D, Lu W, et al. The Epidemiology of Sepsis in Chinese ICUs: A National Cross-Sectional Survey . Crit Care Med. 2020; 48(3) : e209-e218. Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 12 May, 2021 Editor assigned by journal 17 Mar, 2021 Reviewers invited by journal 17 Mar, 2021 First submitted to journal 14 Mar, 2021 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-328922","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":17501166,"identity":"04b7188b-5282-47b3-ba0b-2bda62e2340d","order_by":0,"name":"Xiaojuan Zhang","email":"","orcid":"","institution":"Zhengzhou University First Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaojuan","middleName":"","lastName":"Zhang","suffix":""},{"id":17501167,"identity":"c9813aee-3784-4e9e-a340-6e0c62129dfe","order_by":1,"name":"Shaoyan Qi","email":"","orcid":"","institution":"The Second Affiliated Hospital of Zhengzhou University","correspondingAuthor":false,"prefix":"","firstName":"Shaoyan","middleName":"","lastName":"Qi","suffix":""},{"id":17501168,"identity":"5a499e21-a1b9-49e6-a701-c144c77c2c6e","order_by":2,"name":"Xiaoguang Duan","email":"","orcid":"","institution":"Zhengzhou University First Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Xiaoguang","middleName":"","lastName":"Duan","suffix":""},{"id":17501169,"identity":"1b4258a6-646f-4be5-aa89-26008f762f2b","order_by":3,"name":"Bing Han","email":"","orcid":"","institution":"Zhengzhou University First Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Bing","middleName":"","lastName":"Han","suffix":""},{"id":17501170,"identity":"da9e245c-68b4-4daf-85a5-1521698ed875","order_by":4,"name":"Shuguang Zhang","email":"","orcid":"","institution":"Zhengzhou University First Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shuguang","middleName":"","lastName":"Zhang","suffix":""},{"id":17501171,"identity":"8ac6c7e7-d061-4e17-8708-2672a7251f98","order_by":5,"name":"Shaohua Liu","email":"","orcid":"","institution":"Zhengzhou University First Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shaohua","middleName":"","lastName":"Liu","suffix":""},{"id":17501172,"identity":"4ebc7c84-6ef0-40c1-8f5a-9dc19ace5157","order_by":6,"name":"Haixu Wang","email":"","orcid":"","institution":"Zhengzhou University First Affiliated Hospital","correspondingAuthor":false,"prefix":"","firstName":"Haixu","middleName":"","lastName":"Wang","suffix":""},{"id":17501173,"identity":"c795741c-e8de-4864-ab48-94301cd2a2b3","order_by":7,"name":"Haibo Zhang","email":"","orcid":"","institution":"University of Toronto","correspondingAuthor":false,"prefix":"","firstName":"Haibo","middleName":"","lastName":"Zhang","suffix":""},{"id":17501174,"identity":"54d1c136-d3e8-4b32-95b7-a6955f1a3948","order_by":8,"name":"Tongwen Sun","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYHAD5gMHPvwgTiljA4RmSzw4s4c0LTzGhznYiFAvPyP3+IOPO2oT+6V7Phxm4GGQ5xc7gF+LwY28xMaZZ44nzpxzdsPhAgsGw5mzEwhokcgxbOZtO5a74UbuhsMzeBgSDG4T0CI/A6pl/42cB4d52IjQwnADrKUmd4NEDgNxWgzOvDGcObPtQP2MG2kGwECWIOwX+fYcgw8f2+qM+WckP/7w4YeNPL80IYdBwGEYQ4Io5SBQR7TKUTAKRsEoGIEAAMF9S4As+5INAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-6536-3222","institution":"Zhengzhou University First Affiliated Hospital","correspondingAuthor":true,"prefix":"","firstName":"Tongwen","middleName":"","lastName":"Sun","suffix":""}],"badges":[],"createdAt":"2021-03-14 12:19:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-328922/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-328922/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":7242568,"identity":"f68d325a-cad9-47e7-be75-d894bc96aeae","added_by":"auto","created_at":"2021-03-22 20:58:12","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":13192,"visible":true,"origin":"","legend":"Survival analysis at 28 days: Kaplan-Meier curve.\nShown are survival curves from the receiving intravenous PMB to 28 days. The 28-day mortality was 40%. 25 patients died during their 7–14 days after enrollment.","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-328922/v1/587812c6f05bc32e2f1c9e9a.jpg"},{"id":7242217,"identity":"3afba67d-d70f-4fcc-a1ff-9dded91f94a9","added_by":"auto","created_at":"2021-03-22 20:55:12","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":103454,"visible":true,"origin":"","legend":"Kaplan-Meier 28-day survival curve comparing patients on mechanical ventilation or with septic shock.\n(A) 28-day mortality were 58.82% and 20.41% in patients on mechanical ventilation and not on mechanical ventilation, respectively (Log-rank, P \u003c 0.01). \n(B) 28-day mortality were 65.31% and 15.69% in patients with septic shock and without septic shock, respectively (Log-rank, P \u003c 0.01).","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-328922/v1/dcbd1e2694aabfb23c6808b1.jpg"},{"id":13681997,"identity":"f0dbe409-eedd-4c68-9654-5099a6230e59","added_by":"auto","created_at":"2021-09-17 11:54:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":441782,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-328922/v1/b786371e-ae1e-4ed9-8202-01438b1519a7.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eClinical Outcomes and Safety of Polymyxin B in the Treatment of Carbapenem-resistant Gram-negative Bacterial Infections: a Real-world Multicenter Study\u003c/p\u003e","fulltext":[{"header":"Introduction","content":" \u003cp\u003eIn recent years, infections due to carbapenem-resistant Gram-negative bacilli (CR-GNB) have become an increasingly important cause of mortality and morbidity around the world[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. The organisms most commonly identified in CR-GNB infections are \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e, \u003cem\u003eAcinetobacter baumannii\u003c/em\u003e, and \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e[\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. These bacteria can lead to bloodstream, respiratory tract, skin and soft tissue, urinary tract, intra-abdominal, and surgical infections [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan additionalcitationids=\"CR6\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. They are responsible for nosocomial infections, particularly among critically ill patients hospitalized in intensive care units (ICUs)[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMortality rates of greater than 47% have been reported for CR-GNB infections[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR10 CR11 CR12\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. The decline in the development of newer antibiotics has created a challenge for clinicians treating CR-GNB infections[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. As a result, physicians have sought solutions in the arsenal of older therapeutics. This has led to the re-introduction the polymyxins in the treatment of infections caused by CR-GNB, as polymyxins are one of the few antibiotics that remain effective against these organisms[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Two polymyxins in clinical use, polymyxin B (PMB) and colistin, had fallen out of favor due to nephrotoxicity and neurotoxicity reported during their use in the 1960s. However, due to multiple drug resistance among Gram-negative bacilli, physicians have been increasingly forced to rely on polymyxins for the treatment of infections caused by these pathogens. It has not been determined which of these agents is superior in terms of the cure rate or microbiological resolution[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. A systematic review and meta-analysis summarized findings that included no significant difference in mortality between patients treated with these two polymyxins; this study also found a lower nephrotoxicity profile for PMB[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Additionally, recently published research demonstrated that PMB, unlike colistin, is not cleared renally and therefore, dosing of PMB should not be adjusted based on renal function[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe international consensus guidelines for the optimal use of polymyxins recommend that patients intravenous PMB should receive a dose of 1.25\u0026ndash;1.5 mg/kg (equivalent to 12,500\u0026ndash;15,000 IU/kg) PMB every 12 hours infused over 1 hour[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In one study, clinicians found that combination therapy with at least two in vitro active agents was associated with higher efficacy in treating bloodstream infections caused by CR-GNB[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCurrently, there is a lack of data available on the efficacy, 28-day mortality, and adverse events for PMB in the treatment of CR-GNB infections. Here, we report on a multicenter, real-world study of patients receiving intravenous PMB to investigate the clinical outcomes of antimicrobial therapy in patients infected with CR-GNB.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy Design and Patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis multicenter, real-world study was conducted at 14 hospitals in Henan province during the period of October 2018 through June 2019. The institutional research ethics committee of the First Affiliated Hospital of Zhengzhou University approved the study (SS-2019-015).\u003c/p\u003e\n\u003cp\u003ePatients aged more than 14 years with CR-GNB infection who received PMB therapy for at least 7 days were included in the study. Patients with positive culture of CR-GNB, or the patients were infected with suspected CR-GNB from two experienced professors. The organisms identified in CR-GNB infections are \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e, \u003cem\u003eAcinetobacter baumannii\u003c/em\u003e, \u003cem\u003ePseudomonas aeruginosa, Escherichia coli, \u003c/em\u003eand \u003cem\u003eStenotrophomonas maltophilia. \u003c/em\u003ePatients were excluded if they received intravenous PMB for fewer than 7 days.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData Collection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData was collected from electronic patient registration and follow-up. The database was generated by the clinician through a query of the electronic\u0026nbsp;medical\u0026nbsp;records. The following variables were recorded: age, gender, underlying disease, hospitalization date, dates of admission to and discharge from ICU, vital signs, Acute Physiology and Chronic Health Evaluation II (APACHEII) score, Sequential Organ Failure Assessment (SOFA) score, any major surgeries performed, ventilator care, site of isolation of organisms, exposure to antimicrobial therapies, clinical features, biochemical\u0026nbsp;indices, and microbiological data on admission and on the day of introduction of PMB.\u003c/p\u003e\n\u003cp\u003eThe dose and duration of PMB therapy, renal function, clinical and microbiological outcomes, and adverse reactions to PMB were noted. Patients were followed up until the end of treatment at 28 days.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient Diagnoses\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDiagnoses of infections were based on clinical features and the isolation of bacteria from areas that are normally sterile. The microbiologically documented infection was defined as positive cultures in sterile of localized, and absence of any bacterial pollution or colonization. Severe sepsis was defined as sepsis associated with organ dysfunction or hypoperfusion. Septic shock was defined as sepsis 3.0[19]. Pulmonary\u0026nbsp;infection included hospital-associated pneumonia (HAP) and ventilator-associated pneumonia (VAP). HAP was defined as a pneumonia occurring 48h or more after admission. VAP was defined as a pneumonia developing 48h or more after tracheal intubation. Chronic diseases\u0026nbsp;included\u0026nbsp;heart disease,\u0026nbsp;hypertension, stroke,\u0026nbsp;cancer,\u0026nbsp;diabetes mellitus,\u0026nbsp;and\u0026nbsp;chronic obstructive pulmonary disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMicrobiology\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe CR-GNB include \u003cem\u003eEnterobacteriaceae,\u003c/em\u003e\u003cem\u003eAcinetobacter spp.,\u003c/em\u003e\u003cem\u003ePseudomonas aeruginosa, Stenotrophomonas maltophilia, \u003c/em\u003eand \u003cem\u003eBurkholderia cepacia. \u003c/em\u003eAll CR-GNB infections were identified in the microbiology laboratory. The biological samples included blood, vein\u0026nbsp;catheter samples, urine, sputum, tracheal secretions, bronchial‐alveolar lavage fluid, intraperitoneal fluid, and pleural drainage fluid. Bacterial identification and drug sensitivity tests were performed using a Vitek\u0026reg; 2 automated system（France Biomerieux）. Susceptibility was interpreted according to Clinical and Laboratory Standards Institute criteria[20]. \u003cem\u003eEnterobacteriaceae \u003c/em\u003ewith a minimal inhibitory concentration(MIC) \u0026ge; 4 \u0026micro;g/ml were considered resistance to carbapenem[20]. \u003cem\u003ePseudomonas aeruginosa \u003c/em\u003eand\u003cem\u003e Acinetobacter spp. \u003c/em\u003ewith a minimal inhibitory concentration (MIC) \u0026ge; 8 \u0026micro;g/ml were considered resistance to carbapenem[20]. \u003cem\u003eBurkholderia cepacia \u003c/em\u003ewith a MIC \u0026ge; 16 \u0026micro;g/ml were considered resistance to meropenem[20]. Isolates with a MIC \u0026le; 2 \u0026micro;g/ml were considered susceptible to PMB (colistin breakpoint for Enterobacteriaceae)[21]. The treating clinicians evaluated whether pathogens were the pathogenic bacteria according to the characteristics of pathogen distribution in the institution and their own experience.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTreatment Regimen\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll patients were treated with intravenous PMB, to which all strains remained sensitive. The international consensus guidelines for the optimal use of polymyxins recommend that patients who require intravenous PMB receive a dose of 1.25~1.5 mg/kg (equivalent to 12,500~15,000 IU/kg) PMB every 12 hours infused over 1 hour[16]. Upon isolation of strains of CR-GNB that were resistant to carbapenem, an intravenous antibiotic\u0026nbsp;regimen was initiated at the discretion of the attending physician.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary outcome of this analysis was 28-day mortality; the secondary outcomes included all-cause hospital mortality, ICU mortality, and the occurrence of adverse events during PMB therapy. The clinical outcomes of this study were based on the recovery of patients following PMB therapy. The measure of 28‐day mortality refers to patient deaths occurring within 28 days from the start of treatment, even if the death was related to other comorbidities that were not the infection.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Clinical cure was defined as a combined outcome of survival and the complete disappearance or improvement of signs and symptoms of infection after day 7 of PMB therapy. Failure of treatment was defined as maintenance or worsening of signs and symptoms of disease or radiologic deterioration.\u003c/p\u003e\n\u003cp\u003eCommon adverse\u0026nbsp;events\u0026nbsp;included nephrotoxicity, neurotoxicity, skin hyperpigmentation, and eosinophil increase. Nephrotoxicity was defined as increase in serum creatinine (SCr) by \u0026ge;26.5 umol/L within 48 hours, or increase in SCr to \u0026ge;1.5 times baseline within 7 days, or urine volume ＜ 0.5 ml/Kg/hour for 6 hours[22]. Skin hyperpigmentation was evaluated based on changes of the skin of the face and neck during PMB therapy or four weeks after treatment completion. Neurotoxicity included any of the following: apnea, encephalopathy, paresthesia, or seizures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStatistical analyses were carried out using the statistical software package IBM SPSS Statistics 21.0 (SPSS, Chicago, IL). Descriptive analysis was performed to describe the distribution of the variables of interest. Categorical variables were presented as counts and percentages and were compared between survivors and non-survivors using Chi-squared test or Fisher\u0026rsquo;s exact test. Continuous variables of each group were presented as the mean \u0026plusmn; SD or median with interquartile range (IQR) and were compared between survivors and non-survivors using Student\u0026rsquo;s t-test or Mann\u0026ndash;Whitney U test, as appropriate. Paired t-test or Wilcoxon signed rank test was used to compare the continuous variables before and after therapy and categorical variables were compared using the McNemar test. Associations between\u0026nbsp;these covariates\u0026nbsp;and\u0026nbsp;28-day mortality or all-cause hospital mortality were explored\u0026nbsp;through\u0026nbsp;multivariable\u0026nbsp;logistic\u0026nbsp;regression.\u0026nbsp;Kaplan-Meier curves were conducted to demonstrate the survival probability within 28 days and were compared using log-rank test between groups. A \u003cem\u003eP\u003c/em\u003e-value \u0026lt; 0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eData from 100 patients who received intravenous PMB between October 1, 2018 and June 30, 2019, were analyzed. The mean age of patients was 55.9\u0026thinsp;\u0026plusmn;\u0026thinsp;17.1 years (range 17\u0026ndash;91 years) and 79% were male. The mean length of hospitalization was 41.6\u0026thinsp;\u0026plusmn;\u0026thinsp;26.42 days (range 7\u0026ndash;130 days), and the mean residence time in the ICU was 26 days. Mechanical ventilation was given to 49% of patients in the study. There were 23 patients without chronic disease and 37 patients with one chronic illness; the remainder of patients had a combination of multiple chronic diseases. There were 39 patients who had septic shock at the beginning of therapy; an additional 10 patients later progressed to shock. The demographic and clinical features of patients who received intravenous PMB are summarized in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. For 85 patients, the pathogen culture was positive; 21 patients of these were infected with two bacteria species. In 35 cases, the patient had multi-site infection. The most patients received combination therapy with carbapenems, tigecycline, fosfomycin, or cefoperazone-sulbactam. There were 33 patients combined with meropenem, 27 patients combined with imipenem, 11 patients combined with biapenem. Only 3 patients were combined with doxycycline or amikacin.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab1\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eClinical Features and details of Patients Receiving Intravenous PMB\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eCharacteristic\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, or n (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge (year)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e55.91\u0026thinsp;\u0026plusmn;\u0026thinsp;17.14\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMale (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e79 (79)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eICU admission, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e98 (98)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMechanical ventilation, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49 (49)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChronic\u0026nbsp;medical conditions, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHeart disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (14)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHypertension\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e44 (44)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eStroke\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19 (19)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCancer\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (6)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eDiabetes mellitus\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (15)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChronic obstructive pulmonary disease\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1 (1)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eRenal insufficiency, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e27 (27)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSeptic\u0026nbsp;shock, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e39 (39)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSOFA score, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.76\u0026thinsp;\u0026plusmn;\u0026thinsp;4.30\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAPACHE II, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.61\u0026thinsp;\u0026plusmn;\u0026thinsp;7.59\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eICU stay before intravenous PMB, days, median (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8(3,14)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMODS, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e60 (60)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePCT, ng/ml, median(IQR),\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.89(1.08,11.43)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBacterial, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAB\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33 (33)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eKP\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e48 (48)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16 (16)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOther\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (9)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eUnknown\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (15)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eInfection\u0026nbsp;sites, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSI\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40 (40)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePulmonary\u0026nbsp;infection\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e64 (64)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIntraperitoneal\u0026nbsp;infection\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9 (9)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIncision infection\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (6)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOthers\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e18 (18)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eConcomitant antibiotic therapy\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCarbapenem\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e71\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTigecycline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCefoperazone\u0026nbsp;and sulbactam\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCefepime\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eOthers\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"2\"\u003ePMB: polymyxin B; ICU: intensive care unit; SOFA: Sequential\u0026ensp;Organ\u0026ensp;Failure\u0026ensp;Assessment; APACHE II: Acute Physiology and Chronic Health Evaluation II; MODS: multiple organ dysfunction syndrome; PCT: procalcitonin; KP: \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e, AB: \u003cem\u003eAcinetobacter baumannii\u003c/em\u003e; PA: \u003cem\u003ePseudomonas aeruginosa\u003c/em\u003e; BSI: bloodstream infection\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOverall, the condition of patients improved after the PMB treatment. Temperature, white blood cells, C-reactive protein (CRP), procalcitonin, and APACHE Ⅱ levels were significantly decreased among patients. Platelets were significantly increased (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The number of patients with mechanical ventilation or shock significantly decreased after PMB treatment (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab2\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eComparison of Patient Conditions Before and After Therapy\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eParameter\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eBaseline\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eAfter therapy\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHeart rate, bpm, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e92.02\u0026thinsp;\u0026plusmn;\u0026thinsp;21.55\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e97.36\u0026thinsp;\u0026plusmn;\u0026thinsp;20.35\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.895\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTemperature,℃,median (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e38(37.1,38.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e37.1(36.7,37.6)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWBC, \u0026times;10\u003csup\u003e9\u003c/sup\u003e, median (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14.13(10.08,20.02)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.28(7.02,13.40)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePLT, \u0026times;10\u003csup\u003e9\u003c/sup\u003e, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e111.71\u0026thinsp;\u0026plusmn;\u0026thinsp;97.68\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e190.95\u0026thinsp;\u0026plusmn;\u0026thinsp;162.99\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCRP, ug/l, median (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e103.55(56.96,180.83)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47.6(13.08,102.58)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePCT, ng/ml, median (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3.89(1.09,11.43)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e1.695(0.46,5.41)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSOFA, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.74\u0026thinsp;\u0026plusmn;\u0026thinsp;4.13\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7.32\u0026thinsp;\u0026plusmn;\u0026thinsp;4.41\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.282\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAPACHE Ⅱ, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17.75\u0026thinsp;\u0026plusmn;\u0026thinsp;7.69\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15.98\u0026thinsp;\u0026plusmn;\u0026thinsp;7.95\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.007\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMechanical ventilation, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e51\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSeptic\u0026nbsp;shock, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e49\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003eWBC: white blood cell; CRP; C-reactive protein; PLT: platelet count; PCT: procalcitonin; SOFA: Sequential\u0026ensp;Organ\u0026ensp;Failure\u0026ensp;Assessment; APACHE II: Acute Physiology and Chronic Health Evaluation II.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMicrobiological eradication occurred in 66 (77.65%) out of 85 patients with electropositive germiculture. Serious adverse reactions occurred in 16 patients (16%). Seven patients experienced at least two adverse reactions. No patients had treatment discontinued because of an adverse reaction. Nephrotoxicity was manifested by transient creatinine and urea nitrogen elevations, and no patient required hemodialysis. Among 6 patients demonstrating neurotoxicity, 4 patients showed persistent drowsiness, transient irritability, paresthesia, fatigue, dizziness, or drowsiness, and the other 2 patients underwent invasive mechanical ventilation due to adverse reactions of respiratory depression. Transient adverse reactions included eosinophil increase. The outcomes of patients receiving intravenous PMB are shown in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e. The 28-day mortality was 40%. More than 60% deaths occurred 7\u0026ndash;14 days after enrollment, as shown in the Kaplan-Meier survival curve (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab3\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eOutcomes of Patients Receiving Intravenous PMB\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOutcomes\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003en (%)\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBacteria eradication rate, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e66 (77.65)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTreatment Duration, median (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11(9,13)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAdverse events, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16 (16)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNephrotoxicity\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNeurotoxicity\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6 (6)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSkin hyperpigmentation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3 (3)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eEosinophil\u0026nbsp;increase\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7 (7)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eICU mortality, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12 (12)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHospital mortality, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (15)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28-day mortality, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e40 (40)\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe survivors and nonsurviviors had similar characteristics (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Age, sex, and chronic medical conditions were similar in the two groups, and the types of adverse reactions were not notably different. Markers of infection, including white blood cell count, procalcitonin, and CRP, were also similar in the two groups. However, the platelet count in the nonsurvivors group was lower than in the survivor group (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001). In terms of clinical characteristics, SOFA scores (6.77\u0026thinsp;\u0026plusmn;\u0026thinsp;4.07 vs 9.25\u0026thinsp;\u0026plusmn;\u0026thinsp;4.25,\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.004)༌APACHE II scores (16.17\u0026thinsp;\u0026plusmn;\u0026thinsp;7.80 vs 19.7 8\u0026thinsp;\u0026plusmn;\u0026thinsp;6.80, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.016) and the number of patients on mechanical ventilation (21% vs 30%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) or having septic shock (17% vs 32%, \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were lower in the survivor group than in the nonsurvivor group. There were no different therapeutic outcomes among the different combinations. The mortality among the 85 patients with identified pathogens was 38.82%, while the mortality among patients with negative pathogen culture results was 46.67% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.58). During treatment, similar adverse reactions related to PMB were observed in the two groups.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab4\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eCharacteristics Associated With 28-Day Mortality Among Patients Who Received Intravenous PMB\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003eParameter\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eValue for:\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n\u003cth rowspan=\"2\" align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eSurvivors (n\u0026thinsp;=\u0026thinsp;60)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cstrong\u003eNonsurvivors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(n\u0026thinsp;=\u0026thinsp;40)\u003c/strong\u003e\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAge, y, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e54.65\u0026thinsp;\u0026plusmn;\u0026thinsp;16.23\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e57.8\u0026thinsp;\u0026plusmn;\u0026thinsp;18.45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.370\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eFemale, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e47 (78.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32 (80.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.840\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eWBC,\u0026times;10\u003csup\u003e9\u003c/sup\u003e, median(IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14.28(10.58,20.44)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13.84(9.55,19.65)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.359\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePLT, \u0026times;10\u003csup\u003e9\u003c/sup\u003e, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e131.37\u0026thinsp;\u0026plusmn;\u0026thinsp;101.96\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e71.15\u0026thinsp;\u0026plusmn;\u0026thinsp;66.27\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePCT, ng/ml, median (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e2.30(0.70,10.07)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.00(1.97,15.93)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.062\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCRP, ug/l, median (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e100.15(50.70,174.33)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e119.96(79.58,186.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.624\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSOFA, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e6.77\u0026thinsp;\u0026plusmn;\u0026thinsp;4.07\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.25\u0026thinsp;\u0026plusmn;\u0026thinsp;4.25\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.004\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAPACHE Ⅱ, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16.17\u0026thinsp;\u0026plusmn;\u0026thinsp;7.80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19.78\u0026thinsp;\u0026plusmn;\u0026thinsp;6.80\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.016\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMechanical ventilation, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e21 (35.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e30 (75.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSeptic\u0026nbsp;shock, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e17 (28.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32 (80.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eHospitalization before intravenous PMB, days, median (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e12.00(5.25,20.75)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.50(3.25,21.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.882\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eICU stay before intravenous PMB, days, median (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9.00(3.00,15.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5.00(1.00,14.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.156\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTreatment Duration, days, median (IQR)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e11.00(9.00,13.00)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e10.00(8.25,13.75)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.697\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eConcomitant antibiotic therapy, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCarbapenem\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45(75)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26(65)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.393\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eTigecycline\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e28(46.67)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19(47.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.935\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCefoperazone\u0026nbsp;and sulbactam\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e9(15)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e7(17.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.956\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eCefepime\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e3(5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e5(12.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.328\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eIdentify microorganisms, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e52 (86.67)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e33 (82.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.580\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eKP, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32 (53.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e16 (40.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.191\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAB, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e19 (31.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (35)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.728\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMultisite infection, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e20 (33. 3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e15 (37.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.669\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePulmonary\u0026nbsp;infection, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e35 (58.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e29 (72.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.217\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eBSI, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e26 (43.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e14 (35.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.405\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eChronic\u0026nbsp;medical conditions, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e45 (75.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e32 (80.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.734\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eNephrotoxicity, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (21.7)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e13 (32.5)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.251\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAdverse reactions, n (%)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (13.3)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003e8 (20.0)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.373\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"4\"\u003eWBC: white blood cell; PLT: platelet count; PCT: procalcitonin; CRP: C-reactive protein; SOFA: Sequential\u0026ensp;Organ\u0026ensp;Failure\u0026ensp;Assessment; APACHEII: Acute Physiology and Chronic Health Evaluation II; PMB: polymyxin B; ICU: intensive care unit; KP: \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e; AB: \u003cem\u003eAcinetobacter baumannii\u003c/em\u003e; BSI: Bloodstream Infection.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe factors demonstrating statistically significant differences in univariate analysis in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e were analyzed by logistic regression (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e). Multivariate analysis showed that mechanical ventilation (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.023, odds ratio (OR)\u0026thinsp;=\u0026thinsp;3.58; confidence interval (CI): 1.194\u0026ndash;10.739) and septic shock (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.002, OR\u0026thinsp;=\u0026thinsp;5.96; CI: 1.923\u0026ndash;18.473) were independently associated with 28-day mortality in patients with sepsis due to CR-GNB. The 28-day mortality was 58.82% for patients on mechanical ventilation compared to 20.41% for patients who were not on mechanical ventilation. The 28-day mortality was 65.31% in patients with septic shock compared to 15.69% in patients who did not have septic shock. Survival of patients is shown in Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\n\u003ctable id=\"Tab5\" border=\"1\"\u003e\u003ccaption\u003e\n\u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e\n\u003cdiv class=\"CaptionContent\"\u003e\n\u003cp\u003eMultivariate Analysis of Factors Associated With 28-Day Mortality\u003c/p\u003e\n\u003c/div\u003e\n\u003c/caption\u003e\n\u003cthead\u003e\n\u003ctr\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eVariable\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003eOR (95% CI)\u003c/p\u003e\n\u003c/th\u003e\n\u003cth align=\"left\"\u003e\n\u003cp\u003e\u003cem\u003eP\u003c/em\u003e-value\u003c/p\u003e\n\u003c/th\u003e\n\u003c/tr\u003e\n\u003c/thead\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003ePLT\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.578 (0.965\u0026ndash;2.580)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.069\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eMechanical ventilation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e3.580 (1.194\u0026ndash;10.739)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.023\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSeptic shock\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e5.960 (1.923\u0026ndash;18.473)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.002\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eAPACHE II\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e1.013 (0.613\u0026ndash;1.673)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.960\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd align=\"left\"\u003e\n\u003cp\u003eSOFA\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.941 (0.553\u0026ndash;1.601)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd align=\"char\" char=\".\"\u003e\n\u003cp\u003e0.823\u003c/p\u003e\n\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003ctfoot\u003e\n\u003ctr\u003e\n\u003ctd colspan=\"3\"\u003eOR: odds ratio; CI: confidence interval; PLT: platelet count; APACHE II, Acute and Physiology and\u0026nbsp;Chronic Health Evaluation; SOFA: Sequential\u0026ensp;Organ\u0026ensp;Failure\u0026ensp;Assessment.\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tfoot\u003e\n\u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":" \u003cp\u003eIn this study, patients with CR-GNB infection treated with PMB had a bacteria eradication rate of 77.65%, ICU-related mortality of 12%, hospital mortality of 15%, and 28-day mortality of 40%. These results are favorable compared with those reported for studies of patients receiving different treatments for CR-GNB infections[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. For example, in patients infected with carbapenem-resistant \u003cem\u003eAcinetobacter baumannii\u003c/em\u003e who did not receive appropriate empirical antimicrobial therapy, the overall mortality rate was 86.1%[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. In one retrospective study, the overall ICU mortality rate was 45.2% for critically ill patients infected with CR-GNB who received tigecycline therapy[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. In another retrospective study, the in-hospital mortality rate for patients receiving tigecycline for the treatment of carbapenem-resistant \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e bloodstream infections was 62.5%[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. In a retrospective cohort study of the treatment of infections due to carbapenem-resistant Enterobacteriaceae, the 30-day mortality was 50% after ceftazidime-avibactam treatment[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Our results suggest that treatment with PMB may reduce the mortality of patients with CR-GNB.\u003c/p\u003e \u003cp\u003eOur study found that after 7 days of PMB treatment, the temperature of patients with CR-GNB infection returned to normal, and the number of patients with septic shock or mechanical ventilation decreased. Moreover, the infection indicators of white blood cell, procalcitonin, and CRP were all significantly reduced. The symptoms of thrombocytopenia in patients with CR-GNB infection improved. APACHE Ⅱ scores were also lower than the initial sepsis. The mortality of PMB target therapy was 38.82%, while the mortality of patients with empiric therapy was 46.67% (\u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.580). Our results suggest that PMB may be a clinically effective treatment for patients infected with CR-GNB.\u003c/p\u003e \u003cp\u003eOur results suggest that PMB therapy is safe for the treatment of infections caused by CR-GNB, as intravenous PMB was well tolerated in most patients. Serious adverse reactions occurred in 16 patients (16%), 7 patients had at least two adverse reactions, eight of whom had transient adverse reactions.\u003c/p\u003e \u003cp\u003ePrior PMB population pharmacokinetic studies have made a contributions to optimizing the clinical use of this important last-line antibiotic in patients[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. In our study, adverse effects related to nephrotoxicity occurred in 7 patients (7%) and were mild and reversible; none required renal replacement therapy. While the prevalence of nephrotoxicity was not lower in our study than in other observational studies (6\u0026ndash;40.5%)[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR29 CR30\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e], it was at the lower end of these reported ranges. Assessment of the contribution of PMB to renal impairment may be complicated by other factors such as infection, septic shock, multiple organ dysfunction syndrome (MODS), and concomitant use of other nephrotoxic drugs.\u003c/p\u003e \u003cp\u003eNeurotoxicity of PMB is less common than nephrotoxicity, and it is usually mild and resolves after prompt discontinuation of therapy[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In a previous study on the use of PMB in patients, intravenous PMB was associated with neurotoxicity in 7% of cases, and no adverse reactions of respiratory depression were seen[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In another study, however, no cases of neurotoxicity complications occurred among 247 patients who were given PMB therapy [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In our study, among the 6 patients with neurotoxicity, 2 patients underwent invasive mechanical ventilation due to the adverse effects of respiratory depression. Neither patient used sedative analgesics. PMB therapy was not stopped in the patients with respiratory depression and the endotracheal tube was removed before the end of PMB treatment.\u003c/p\u003e \u003cp\u003eIn the present study, 3 cases (3%) developed skin hyperpigmentation in the face and neck. This incidence is lower than was reported in previous studies[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. During treatment, there were no other adverse reactions such as rashes, itching, dermatitis, or fever. While our results support the use of PMB, the safety of polymyxin therapy requires further study.\u003c/p\u003e \u003cp\u003eMechanical ventilation and septic shock were independent factors associated with higher 28-day mortality risk in the present study. A previous study of a large US cohort found that most patients with culture-positive community onset sepsis did not have resistant bacteria [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e], while a study of the epidemiology of sepsis in Chinese ICUs found that only 12% of culture-positive were multi-drug resistant organisms[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In our study, the mortality of patients with empiric PMB therapy was higher. This underscores the need for rapid identification of CR-GNB infection and an increased of judicious use of PMB for the treatment of sepsis, to avoid progression to mechanical ventilation or septic shock. In this regard, the optimization and validation of PMB-based combinations may have considerable clinical benefits.\u003c/p\u003e \u003cp\u003eThe present study has several limitations, including its retrospective, real-world design and lack of a control group or direct basis of comparison with other treatments. Another limitation was the relatively small number of patients included in the study. Serum PMB concentrations were not determined in the study. The decision to use additional antibiotics was made by individual clinicians, which may have introduced bias. Additionally, the concomitant use of other antibiotics with PMB makes it impossible to attribute treatment efficacy solely to PMB. Further, it was difficult to properly evaluate adverse effects attributable to PMB in view of the use of other drugs in seriously ill patients. Despite these limitations, our study represents a multicenter study evaluating a range of CR-GNB infections treated with PMB combination therapy.\u003c/p\u003e "},{"header":"Conclusions","content":" \u003cp\u003eIn summary, the findings from our study suggest that timely and appropriate use of PMB may have a positive impact on clinical outcomes in the treatment of CR-GNB infections. These results underscore the need to more quickly identify patients with CR-GNB who may benefit from judicious use of PMB, in particular, patients with septic shock or on mechanical ventilation who may be at higher risk of mortality. Clinicians should apply strict protocols when using this antimicrobial agent to prevent the occurrence and spread of polymyxin resistance.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003eCRGNB: carbapenem-resistant Gram-negative bacilli; PMB: polymyxin B; ICU: intensive care unit; APACHEII: Acute Physiology and Chronic Health Evaluation II; SOFA: Sequential Organ Failure Assessment; HAP: hospital-associated pneumonia; VAP: ventilator-associated pneumonia; PCT: procalcitonin; CRP: C-reactive protein; PLT: platelet count; MODS: Multiple organ dysfunction syndrome.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors would like to thank Chao Qin (The Fifth Affiliated Hospital of Zhengzhou University), Changyu Zhang (The Second Affiliated Hospital of Zhengzhou University), Xianrong Song (Henan Provincial Chest hospital), Ping Lou (The Medical Group of Zhengzhou First People\u0026rsquo;s Hospital), Yanqiu Gao (Zhengzhou Central Hospital), Ying Cai (Jinshui District General Hospital\u0026nbsp;of\u0026nbsp;Zhengzhou), Tiancai Wang (Nanshi Hospital of Nanyang), Xianfa Jiao (People\u0026rsquo;s Hospital of Zhengzhou), Yongmei Zhang (First Affiliated Hospital, Henan University of Science and Technology), Lin Guo (The Seventh People\u0026rsquo;s Hospital of Zhengzhou ), Jing Feng (Zhengzhou Yihe Hospital), Fengling Ju (Nanyang Second General Hospital)，Hong Liu (The First People\u0026rsquo;s Hospital of Pingdingshan) for their support with data collection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors were involved in the research concept and design. Zhang XJ, Qi SY, and Duan XG contributed to the data acquisition. Zhang XJ and Sun TW have reviewed and take responsibility for all of the data. Zhang XJ, Han B, Zhang SG, Liu SH, and Wang HX performed the analysis and interpretation of the data. Zhang XJ contributed to the writing of the first draft. Sun TW and Zhang HB reviewed\u0026nbsp;this article\u0026nbsp;and made necessary changes\u0026nbsp;to improve it. All authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by the United Fund of National Natural Science Foundation of China (Grant No. U2004110), Leading Talents Fund in Science and Technology Innovation in Henan Province (Grant No.194200510017)；Science and Technology people-benefit project of Zhengzhou (2019KJHM0001)；The special fund for young and middle-aged medical research of China International Medical Exchange Foundation (Grant No. Z-2018-35); The integrated thinking research foundation of the China foundation for International Medical Exchange (Grant No. Z-2016-23-2001)；and the Overseas Training Program of Health Science and Technology Talents in Henan Province (HWYX2019008).\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 analyzed in this study are not publicly available due to privacy issues but are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was approved by the institutional research ethics committee of The First Affiliated Hospital of Zhengzhou University, and waived informed consent based on the real-world design and anonymization of patient identifiers before analysis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003ePatel G, Bonomo RA. \"Stormy waters ahead\": global emergence of carbapenemases\u003cstrong\u003e.\u003c/strong\u003e Front Microbiol. 2013; 4\u003cstrong\u003e:\u003c/strong\u003e48.\u003c/li\u003e\n\u003cli\u003eVelkov T, Roberts KD, Nation RL, Thompson PE, Li J. 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The Epidemiology of Sepsis in Chinese ICUs: A National Cross-Sectional Survey\u003cstrong\u003e.\u003c/strong\u003e Crit Care Med. 2020; 48(3)\u003cstrong\u003e:\u003c/strong\u003ee209-e218.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"journal-of-translational-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jtrm","sideBox":"Learn more about [Journal of Translational Medicine](http://translational-medicine.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/jtrm/default.aspx","title":"Journal of Translational Medicine","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"carbapenem-resistant Gram-negative bacilli, infections, Polymyxin B, adverse effects, 28-day mortality","lastPublishedDoi":"10.21203/rs.3.rs-328922/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-328922/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eHigh morbidity and mortality due to carbapenem-resistant Gram-negative bacilli (CR-GNB) has led to the resurgence of polymyxin B (PMB) use in the last decade. The aim of our multicenter, real-world study was to evaluate the effectiveness and safety of PMB in the treatment of CR-GNB infections.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThe real-world study included patients treated with intravenous PMB for at least 7 days during the period of October 2018 through June 2019. Associations between\u0026nbsp;these\u0026nbsp;variables and\u0026nbsp;28-day mortality or all-cause hospital mortality were explored\u0026nbsp;through univariate\u0026nbsp;analyses\u0026nbsp;and\u0026nbsp;multivariable\u0026nbsp;logistic\u0026nbsp;regression.\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eThe study included 100 patients. Many patients presented with combined chronic conditions, septic shock, mechanical ventilation, and the presence of \u003cem\u003eKlebsiella pneumoniae\u003c/em\u003e. The mean duration of PMB therapy was 11 days (range 7–38 days). Temperature (38°C vs 37.1°C), white\u0026nbsp;blood cells (14.13×10\u003csup\u003e9\u003c/sup\u003e/L vs 9.28×10\u003csup\u003e9\u003c/sup\u003e/L), C-reactive protein (103.55 ug/l vs 47.60 ug/l), procalcitonin (3.89 ng/ml vs 1.70 ng/ml) and APACHE Ⅱ levels (17.75 ± 7.69 vs 15.98 ± 7.95) were significantly decreased after PMB treatment. The bacteria eradication rate was 77.65%. The overall mortality at discharge was 15%, and 28-day mortality was 40%. Major adverse reactions occurred in 16 patients. Nephrotoxicity was observed in 7 patients (7%).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eOur results provide positive clinical and safety outcomes for PMB in the treatment of CR-GNB. Timely and appropriate use of PMB may be particularly useful in treating patients with sepsis in CR-GNB infections.\u003c/p\u003e","manuscriptTitle":"Clinical Outcomes and Safety of Polymyxin B in the Treatment of Carbapenem-resistant Gram-negative Bacterial Infections: a Real-world Multicenter Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2021-03-22 20:55:10","doi":"10.21203/rs.3.rs-328922/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2021-05-12T11:29:00+00:00","index":0,"fulltext":""},{"type":"editorAssigned","content":"","date":"2021-03-18T00:00:00+00:00","index":"","fulltext":""},{"type":"reviewersInvited","content":"","date":"2021-03-18T00:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Translational Medicine","date":"2021-03-14T08:19:13+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-translational-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"jtrm","sideBox":"Learn more about [Journal of Translational Medicine](http://translational-medicine.biomedcentral.com)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/jtrm/default.aspx","title":"Journal of Translational Medicine","twitterHandle":"@BioMedCentral","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b0b1d67d-5135-47c4-8265-ebacce40926a","owner":[],"postedDate":"March 22nd, 2021","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":3128978,"name":"Translational Medicine"}],"tags":[],"updatedAt":"2021-03-22T20:55:10+00:00","versionOfRecord":[],"versionCreatedAt":"2021-03-22 20:55:10","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-328922","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-328922","identity":"rs-328922","version":["v1"]},"buildId":"B-jG_2CBjPDmsCi4Wdhf-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}