Abstract
Objective
To compare the clinical efficacy and safety of intravenous polymyxin B versus the combination of intravenous and nebulized polymyxin B for treating carbapenem-resistant gram-negative bacilli hospital-acquired pneumonia (CRGNB-HAP), and to explore the risk factors affecting 28-day all-cause mortality.
Method
Our retrospective analysis was conducted on data from CRGNB-HAP patients treated in the intensive care unit (ICU) with either intravenous polymyxin B alone or in conjunction with nebulized polymyxin B between November 28, 2018 and May 6, 2024. The primary endpoint was 28-day all-cause mortality, while safety outcomes were also assessed. Logistic regression analysis was utilized to identify the risk factors associated with 28-day all-cause mortality.
Result
A total of 82 CRGNB-HAP patients were enrolled, including 38 patients in the intravenous plus nebulized (IV + NL) polymyxin B group and 44 patients in the intravenous (IV) polymyxin B group. The 28-day mortality rate of the IV + NL polymyxin B group was significantly lower than that of the IV polymyxin B group (23.7% vs 61.4%, p < 0.001), and there was no statistically significant difference in the incidence of acute kidney injury between the two groups. Multivariate logistic regression analysis indicated that IV + NL polymyxin B administration was a significant factor in reducing the 28-day mortality rate of CRGNB-HAP patients.
Conclusion
Our study found that intravenous combined with nebulized polymyxin B therapy is superior to intravenous monotherapy in the treatment of CRGNB-HAP, resulting in reduced 28-day mortality without increasing renal toxicity.
Keywords: Nebulized polymyxins, Polymyxin B, Carbapenem-resistant gram-negative bacilli, Hospital-acquired pneumonia, 28-day mortality
Introduction
Hospital-acquired pneumonia (HAP), particularly ventilator-associated pneumonia (VAP) which is a specific form of HAP, represents the most common nosocomial infection in intensive care units (ICUs). The risk of developing HAP is notably higher in mechanically ventilated patients, with an incidence rate approximately tenfold greater than that observed in non-ventilated patients [1]. The mortality rate of VAP can reach as high as 50%, with at least a quarter of fatalities directly attributed to the infection, which is primarily caused by drug-resistant Gram-negative bacteria [2]. The emergence of carbapenem-resistant gram-negative bacilli (CRGNB) in recent years has posed significant challenges to clinical treatment. Globally, it is estimated that around 1.3 million deaths were attributable to infections by drug-resistant bacteria in 2019, with projections indicating this number could rise to over 10 million deaths annually by 2050 [3]. In response to this crisis, the World Health Organization (WHO) has classified carbapenem-resistant Enterobacteriales (CRE), carbapenem-resistant Acinetobacter baumannii (CRAB), and carbapenem-resistant Pseudomonas aeruginosa (CRPA) as “critical” priorities for the research and development of new and effective antibiotic treatments [4]. Data from the China Antimicrobial Surveillance Network reveals a concerning trend of increasing isolation rates of CRGNB within China. Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa rank among the top five clinically isolated bacteria in hospitals nationwide. The proportion of carbapenem-resistant Klebsiella pneumoniae (CRKP) has escalated from 3% in 2005 to 23.1% in 2021, accounting for 60–90% of CRE infections. Meanwhile, the prevalence of CRAB has risen from 31.0% to 71.5% by 2021, while that of CRPA was as high as 23.0% [5]. According to 2023 data from Zhejiang Province, the carbapenem resistance rates of Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii were similar to the national data [6].
Polymyxins are the most important drugs for empirically treating CRGNB infections. Tigecycline demonstrates good sensitivity to CRE and CRAB, yet it lacks efficacy against CRPA [7]. Moreover, due to the annual increase in minimum inhibitory concentration (MIC) levels, tigecycline frequently necessitates double dosing, which significantly escalates the risk of adverse reactions. Additionally, owing to pharmacokinetic limitations, it is not recommended for treating infections in areas such as the bloodstream and central nervous system. Ceftazidime/avibactam exhibits good antibacterial activity against certain CRPA and non-metalloenzyme-producing CRE strains, but it is ineffective against CRAB [8]. Other effective antimicrobial agents, such as imipenem/cilastatin/relebactam, meropenem/vaborbactam, cefiderocol, ceftolozane/tazobactam, and sulbactam/dulrobactam, remain difficult to access in China [9]. Hence, given the grave landscape of drug resistance and paucity of therapeutic options, polymyxins, which demonstrate broad-spectrum activity against nearly all CRGNB, have emerged as the first-line agents for the clinically treatment of CRGNB infections [10].
Polymyxins include colistin and polymyxin B. Colistin is administered as the inactive prodrug colistin methanesulfonate (CMS), whereas polymyxin B is used in its active form. Following intravenous administration, polymyxins exhibit poor penetration into lung tissue, prompting the recommendation of nebulized polymyxins as an adjunctive therapy to intravenous administration when clinical efficacy is suboptimal [5, 11]. However, there is currently no specific formulation for polymyxins approved for nebulization in China. Most studies on nebulized polymyxins therapy for CRGNB-induced HAP (CRGNB-HAP) have focused on CMS, with limited and sometimes contradictory data available regarding the use of nebulized polymyxin B in this contex. This retrospective study aims to assess the clinical effectiveness and safety of combining intravenous with nebulized polymyxin B for the treatment of CRGNB-HAP, and to explore the risk factors associated with 28-day mortality rates.
Material and methods
Study design
This single-center, retrospective cohort study conducted at the Second Affiliated Hospital of Zhejiang Chinese Medical University in Hangzhou, China, a 1200-bed tertiary teaching hospital, spanning 3 ICUs from November 28, 2018, to May 6, 2024. Inclusion criteria include: age 18 years and above; confirmed diagnosis of HAP/VAP caused by CRGNB; treatment with intravenous polymyxin B, either alone or in combination with nebulized polymyxin B, for at least 72 h; exclusion criteria include: pregnant women; patients in the terminal stages of malignant tumors. The study protocol underwent review and was approved by the Ethics Review Committee of The Second Affiliated Hospital of Zhejiang Chinese Medical University (Approval No. ZJTCMU2AE2023R081-01), and informed consent was waived.
Eligible patients were divided into two groups: the intravenous plus nebulized (IV + NL) polymyxin B group and the intravenous (IV) polymyxin B group. For both groups, the initial intravenous dose of polymyxin B was administered at a rate of 2.0–2.5 mg/kg over 1 h, followed by a maintenance dose was 1.25–1.5 mg/kg every 12 h over 1 h. All ICUs adhered to the standard operating procedures for nebulized antimicrobial medications. Specifically, 25 mg of polymyxin B was dissolved in 5 ml of sterile water for injection and nebulized twice daily using a vibrating mesh nebulizer. The primary outcome was the 28-day mortality rate following initiation of polymyxin B treatment. Additionally, the study analyzed factors influencing 28-day all-cause mortality and evaluated safety profile of the treatments.
Definition and data collection
HAP is defined as pneumonia not incubating at the time of hospitalization and occuring at least 48 h after admission, while VAP refers to a pneumonia that develops following a minimum of 48 h after endotracheal intubation or tracheostomy [12]. Disease severity was assessed using the Acute Physiology and Chronic Health Evaluation II (APACHE II) score and Sequential Organ Failure Assessment (SOFA) score on the day of admission [13, 14]. The primary endpoint was 28 days following the initiation of polymyxin B administration. Safety evaluation focused on the incidence of acute kidney injury (AKI) following polymyxin B administration. AKI is defined as an increase in serum creatinine of 26 μmol/L or more within 48 h, a documented or suspected elevation in serum creatinine of 50% or more within the previous 7 days, or adult urine output falling below 0.5 ml/kg/h for more than 6 h [15]. All research data were retrospectively obtained from electronic health records, including patient demographics, clinical diagnoses, comorbidities, APACHE II score, SOFA score, infection sites, laboratory test results, microbial culture and sensitivity test results, CRGNB treatment regimens, polymyxin B administration protocols, and 28-day mortality rates.
Microbiology
Gram-negative bacteria were identified using the Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) system in China. Sensitivity testing for to meropenem, imipenem, colistin, and tigecycline was conducted using either the microbroth dilution method or disk diffusion method. If resistance to one or more carbapenems was detected, the Gram-negative bacteria were identified as carbapenem-resistant gram-negative Bacilli (CRGNB). The MIC breakpoints or disk diffusion interpretations for meropenem and imipenem were determined according to Clinical and Laboratory Standards Institute (CLSI) standards. For tigecycline and polymyxins, MIC breakpoints interpretations adhered to the standards set by the European Committee on Antimicrobial Susceptibility Testing (EUCAST).
Statistical analysis
We conducted statistical analysis using IBM SPSS Statistics 27 software (IBM Corp., Armonk, N.Y., USA). Continuous variables with a normal distribution were expressed as mean ± standard deviation and assessed using Student's t-test. Non-normally distributed continuous variables were presented as median (interquartile range, IQR) and analyzed using the Mann–Whitney U test. Categorical variables were presented as n (%) and differences were compared using the chi-square test or Fisher's exact test. Survival analysis was performed using the Kaplan–Meier method and compared using the log-rank test. Variables with a p-value ≤ 0.1 in univariate analysis were included in the logistic regression analysis. Multivariable logistic regression analysis was performed to identify factors associated with 28-day all-cause mortality. A p-value < 0.05 was considered statistically significant.
Results
Patients enrollment
During the study period, a total of 117 patients with CRGNB infections were treated with either IV + NL polymyxin B or IV polymyxin B. Among them, 35 patients were excluded: 14 did not meet the HAP/VAP diagnosis criteria and 21 had a treatment duration of less than 72 h. Ultimately, 82 eligible CRGNB-HAP cases were incorporated into the analysis. There were 38 patients assigned to the IV + NL polymyxin B group, receiving intravenous and nebulized polymyxin B treatments, and 44 patients allocated to the IV polymyxin B group, receiving intravenous polymyxin B treatments. The study patients enrollment is detailed in Fig. 1.
Fig. 1.
Patients enrollment. CRGNB, carbapenem-resistant gram-negative bacilli; HAP, hospital-acquired pneumonia; VAP, ventilator-associated pneumonia; IV, intravenous; NL, nebulized
A total of 106 strains of target CRGNB pathogens were isolated from sputum or bronchoalveolar lavage fluid of these 82 patients, with 48 strains in the IV + NL group and 58 strains in the IV group. The most commonly detected pathogen was CRKP, followed by CRPA, with CRAB being relatively less common. Notably, two CRGNB strains were cultured from the same respiratory specimen in 22 patients, and one patient had all three pathogens isolated from a single respiratory sample. All CRGNB strains exhibited resistance to meropenem but remained sensitive to polymyxins. There was no statistically significant variance in microbiology between the two groups. The distribution of microbiology in CRGNB-HAP patients is shown in Table 1.
Table 1.
Distribution of Microbiology in CRGNB-HAP Patients
| Infecting Bacteria (%) | Total (n = 106) |
IV + NL polymyxin B (n = 48) |
IV polymyxin B (n = 58) |
P-value |
|---|---|---|---|---|
| CRKP | 43(40.57%) | 20(41.67%) | 23(39.66%) | 1.000 |
| CRPA | 35(33.02%) | 14(29.17%) | 21(36.21%) | 0.375 |
| CRAB | 28(26.42%) | 14(29.17%) | 14(24.14%) | 0.649 |
Abbreviations: CRKP, carbapenem-resistant Klebsiella pneumoniae; CRPA, carbapenem-resistant Pseudomonas aeruginosa; CRAB, carbapenem-resistant Acinetobacter baumannii
Baseline features
We analyzed the demographic and clinical baseline characteristics of the enrolled patients. There were no statistically significant differences between the IV + NL polymyxin B group and the IV polymyxin B group in terms of age, gender, comorbidities, medical interventions, disease severity, laboratory tests, and concomitant medications. The most common combination therapy for treating CRGNB-HAP with polymyxin B involved its use in conjunction with carbapenems. The baseline characteristics of the enrolled patients are shown in Table 2.
Table 2.
Baseline Characteristics of Enrolled Patients
| Total (n = 82) |
IV + NL polymyxin B (n = 38) |
IV polymyxin B (n = 44) |
P-value | |
|---|---|---|---|---|
| Population Characteristics | ||||
| Age, mean years ± SD | 80 ± 13 | 81 ± 14 | 79 ± 13 | 0.363 |
| Male, n (%) | 59(71.95%) | 27(71.05%) | 32(72.73%) | 1.000 |
| Comorbidities, n(%) | ||||
| Hypertension | 49(59.76%) | 21(55.26%) | 28(63.64%) | 0.502 |
| Diabetes | 34(41.46%) | 16(42.11%) | 18(40.91%) | 1.000 |
| Cerebrovascular disease | 47(57.32%) | 26(68.42%) | 21(47.73%) | 0.075 |
| Chronic kidney disease | 16(19.51%) | 6(15.79%) | 10(22.73%) | 0.578 |
| Chronic pulmonary disease | 14(17.07%) | 7(18.42%) | 7(15.91%) | 0.777 |
| Coronary Heart Disease | 22(26.83%) | 12(31.58%) | 10(22.73%) | 0.456 |
| Heart failure | 41(50.00%) | 23(60.53%) | 18(40.91%) | 0.121 |
| Medical intervention, n(%) | ||||
| Tracheotomy | 31(37.80%) | 13(34.21%) | 18(40.91%) | 0.649 |
| Endotracheal intubation | 32(39.02%) | 14(36.84%) | 18(40.91%) | 0.821 |
| Mechanical Ventilation | 73(89.02%) | 33(86.84%) | 40(90.91%) | 0.726 |
| CRRT | 21(25.61%) | 6(15.79%) | 15(34.09%) | 0.077 |
| CVC or PICC | 69(84.15%) | 32(84.21%) | 37(84.09%) | 1.000 |
| Urinary catheter or Vesicostomy | 79(96.34%) | 37(97.37%) | 42(95.45%) | 1.000 |
| Nasogastric tube | 40(48.78%) | 20(52.63%) | 20(45.45%) | 0.658 |
| Nasoenteric tube | 34(41.46%) | 13(34.21%) | 21(47.73%) | 0.264 |
| Gastric fistula | 8(9.76%) | 5(13.16%) | 3(6.82%) | 0.462 |
| Severity level | ||||
| APACHE II score | 21 ± 5 | 20 ± 5 | 21 ± 6 | 0.673 |
| SOFA score | 7 ± 3 | 7 ± 2 | 7 ± 3 | 0.263 |
| Laboratory tests | ||||
| White blood cells, × 109/L | 12.47 ± 8.74 | 11.63 ± 5.94 | 13.20 ± 10.59 | 0.405 |
| Platelet, × 109/L | 162.18 ± 118.09 | 174.21 ± 107.23 | 151.80 ± 127.03 | 0.395 |
| C-reactive protein, mg/L | 94.21 ± 58.89 | 102.57 ± 54.00 | 87.00 ± 62.53 | 0.235 |
| Procalcitonin, ng/mL | 5.11 ± 15.17 | 3.78 ± 11.72 | 6.25 ± 17.68 | 0.466 |
| Glutamic-pyruvic transaminase, U/L | 39.93 ± 68.47 | 33.00 ± 60.87 | 45.91 ± 74.59 | 0.398 |
| Total bilirubin, μmol/L | 37.35 ± 60.23 | 34.14 ± 56.60 | 40.12 ± 63.71 | 0.657 |
| Creatinine, μmol/L | 138.41 ± 117.20 | 127.86 ± 126.00 | 147.53 ± 109.69 | 0.452 |
| Concomitant medication | ||||
| Carbapenems | 52(63.41%) | 23(60.53%) | 29(65.91%) | 0.651 |
| β-Lactams | 19(23.17%) | 12(31.58%) | 7(15.91%) | 0.119 |
| Novel tetracyclines | 7(8.54%) | 1(2.63%) | 6(13.64%) | 0.116 |
| Carbapenems and novel tetracyclines | 2(2.44%) | 1(2.63%) | 1(2.27%) | 1.000 |
| No combination | 2(2.44%) | 1(2.63%) | 1(2.27%) | 1.000 |
Abbreviations: CRRT, continuous renal replacement therapy; CVC, central venous cathete; PICC, peripherally inserted central catheter; Carbapenems, meropenem, imipenem/cilastatin; β-Lactams, piperacillin/tazobactam, cefoperazone/sulbactam, ceftazidime/avibactam; Novel tetracyclines, tigacycline, omadacycline
Efficacy assessment
On the 28th day post-initiation of polymyxin B therapy in all patients with CRGNB-HAP, the effectiveness of polymyxin B was assessed. The 28-day mortality rates in the IV + NL polymyxin B group and the IV polymyxin B group were 23.7% and 61.4%, respectively. Survival analysis revealed that the IV + NL polymyxin B group exhibited a significantly lower 28-day mortality rate compared to the IV polymyxin B group (χ2 = 11.364, p < 0.001). Comparison of Kaplan–Meier survival curves is shown in Fig. 2.
Fig. 2.
Comparison of Kaplan–Meier survival curves
Factors influencing 28-day all-cause mortality
We analyzed data from 82 patients with CRGNB-HAP included in the study. Based on the 28-day outcome, these patients were categorized into the Survivor group (n = 46) and Non-survivor group (n = 36). The distribution of microbiology in two groups is shown in Table 3. The overall 28-day all-cause mortality rate was 43.9% (36/82). Table 4 outlines the univariate examination of demographic and clinical factors linked to 28-day all-cause mortality. Variables that exhibited statistically significant variances between the Survivor group and Non-survivor group included receipt of CRRT, baseline total bilirubin levels prior to polymyxin B administration, IV + NL polymyxin B administration, combination of polymyxin B with carbapenems, and combination of polymyxin B with β-lactams.
Table 3.
Distribution of Microbiology in Survivor group and Non-survivor group
| Infecting Bacteria (%) | Total (n = 106) | Survivor (n = 58) | Non-survivor (n = 48) | P-value |
|---|---|---|---|---|
| CRKP | 43(40.57%) | 22(37.93%) | 21(43.75%) | 0.380 |
| CRPA | 35(33.02%) | 19(32.76%) | 16(33.33%) | 0.824 |
| CRAB | 28(26.42%) | 17(29.31%) | 11(22.92%) | 0.641 |
Abbreviations: CRKP, carbapenem-resistant Klebsiella pneumoniae; CRPA, carbapenem-resistant Pseudomonas aeruginosa; CRAB, carbapenem-resistant Acinetobacter baumannii
Table 4.
Univariate examination of factors associated with 28-day all-cause mortality
| Total (n = 82) |
Survivor (n = 46) |
Non-survivor (n = 36) |
P-value | |
|---|---|---|---|---|
| Population Characteristics | ||||
| Age, mean years ± SD | 80 ± 13 | 81 ± 13 | 78 ± 13 | 0.250 |
| Male, n (%) | 59(71.95%) | 33(71.74%) | 26(72.22%) | 1.000 |
| Comorbidities, n(%) | ||||
| Hypertension | 49(59.76%) | 28(60.87%) | 21(58.33%) | 0.825 |
| Diabetes | 34(41.46%) | 16(34.78%) | 18(50.00%) | 0.183 |
| Cerebrovascular disease | 47(57.32%) | 29(63.04%) | 18(50.00%) | 0.267 |
| Chronic kidney disease | 16(19.51%) | 8(17.39%) | 8(22.22%) | 0.589 |
| Chronic pulmonary disease | 14(17.07%) | 8(17.39%) | 6(16.67%) | 1.000 |
| Coronary Heart Disease | 22(26.83%) | 12(26.09%) | 10(27.78%) | 1.000 |
| Heart failure | 41(50.00%) | 20(43.48%) | 21(58.33%) | 0.266 |
| Medical intervention, n(%) | ||||
| Tracheotomy | 31(37.80%) | 19(41.30%) | 12(33.33%) | 0.499 |
| Endotracheal intubation | 32(39.02%) | 14(30.43%) | 18(50.00%) | 0.110 |
| Mechanical Ventilation | 73(89.02%) | 41(89.13%) | 32(88.89%) | 1.000 |
| CRRT | 21(25.61%) | 6(13.04%) | 15(41.67%) | 0.005 |
| CVC or PICC | 69(84.15%) | 38(82.61%) | 31(86.11%) | 0.766 |
| Urinary catheter or Vesicostomy | 79(96.34%) | 44(95.65%) | 35(97.22%) | 1.000 |
| Nasogastric tube | 40(48.78%) | 22(47.83%) | 18(50.00%) | 1.000 |
| Nasoenteric tube | 34(41.46%) | 18(39.13%) | 16(44.44%) | 0.658 |
| Gastric fistula | 8(9.76%) | 6(13.04%) | 2(5.56%) | 0.456 |
| Severity level | ||||
| APACHE II score | 21 ± 5 | 21 ± 5 | 21 ± 6 | 0.785 |
| SOFA score | 7 ± 3 | 7 ± 3 | 7 ± 3 | 0.358 |
| Laboratory tests | ||||
| White blood cells, × 109/L | 12.47 ± 8.74 | 11.97 ± 7.81 | 13.11 ± 9.87 | 0.559 |
| Platelet, × 109/L | 162.18 ± 118.09 | 180.22 ± 100.09 | 139.14 ± 135.71 | 0.133 |
| C-reactive protein, mg/L | 94.21 ± 58.89 | 84.56 ± 52.30 | 106.55 ± 65.05 | 0.094 |
| Procalcitonin, ng/mL | 5.11 ± 15.17 | 2.68 ± 8.33 | 8.20 ± 20.64 | 0.138 |
| Glutamic-pyruvic transaminase, U/L | 39.93 ± 68.47 | 36.00 ± 58.36 | 44.94 ± 80.15 | 0.560 |
| Total bilirubin, μmol/L | 37.35 ± 60.23 | 24.47 ± 27.32 | 53.81 ± 83.30 | 0.049 |
| Creatinine, μmol/L | 138.41 ± 117.20 | 139.95 ± 135.12 | 136.46 ± 91.15 | 0.895 |
| Polymyxin B Sulfate | ||||
| IV + NL | / | 29(63.04%) | 9(25.00%) | < 0.001 |
| Concomitant medication | ||||
| Carbapenems | 52(63.41%) | 24(52.17%) | 28(77.78%) | 0.021 |
| β-Lactams | 19(23.17%) | 15(32.61%) | 4(11.11%) | 0.034 |
| Novel tetracyclines | 7(8.54%) | 4(8.70%) | 3(8.33%) | 1.000 |
| Carbapenems and novel tetracyclines | 2(2.44%) | 1(2.17%) | 1(2.78%) | 1.000 |
| No combination | 2(2.44%) | 2(4.35%) | 0(0.00%) | 0.501 |
Abbreviations: CRRT, continuous renal replacement therapy; CVC, central venous cathete; PICC, peripherally inserted central catheter; Carbapenems, meropenem, imipenem/cilastatin; β-Lactams, piperacillin/tazobactam, cefoperazone/sulbactam, ceftazidime/avibactam; Novel tetracyclines, tigacycline, omadacycline
We further analyzed conducted logistic regression analysis on variables with a p-value < 0.1, and the findings are detailed in Table 5. The results indicated that receipt of CRRT (OR = 0.210, p = 0.005), IV + NL polymyxin B administration (OR = 0.195, p < 0.001), combination of polymyxin B with carbapenems (OR = 0.312, p = 0.019), and combination of polymyxin B with β-lactams (OR = 3.871, p = 0.028) independently affected the 28-day mortality rate of CRGNB-HAP patients. The multivariable regression analysis revealed that the administration of polymyxin B via both intravenous and nebulized routes was associated with a reduced 28-day mortality rate in CRGNB-HAP patients (OR = 0.222, p = 0.006), as shown in Table 6.
Table 5.
Univariate logistic regression analysis of 28-day all-cause mortality
| Survivor (n = 46) |
Non-survivor (n = 36) |
P-value | OR | 95%CI | |
|---|---|---|---|---|---|
| CRRT | 6(13.04%) | 15(41.67%) | 0.005 | 0.210 | 0.071–0.621 |
| Baseline C-reactive protein, mg/L | 84.56 ± 52.30 | 106.55 ± 65.05 | 0.102 | 0.993 | 0.985–1.001 |
| Baseline Total bilirubin, μmol/L | 24.47 ± 27.32 | 53.81 ± 83.30 | 0.070 | 0.989 | 0.978–1.001 |
| IV + NL polymyxin B | 29(63.04%) | 9(25.00%) | < 0.001 | 0.195 | 0.075–0.512 |
| Combined carbapenems | 24(52.17%) | 28(77.78%) | 0.019 | 0.312 | 0.117–0.827 |
| Combined β-lactams | 15(32.61%) | 4(11.11%) | 0.028 | 3.871 | 1.156–12.962 |
Abbreviations: CRRT, continuous renal replacement therapy; Carbapenems, meropenem, imipenem/cilastatin; β-Lactams, piperacillin/tazobactam, cefoperazone/sulbactam, ceftazidime/avibactam
Table 6.
Multivariable logistic regression analysis of 28-day all-cause mortality
| P-value | OR | 95%CI | |
|---|---|---|---|
| CRRT | 0.073 | 0.314 | 0.089–1.115 |
| Baseline Total bilirubin, μmol/L | 0.285 | 0.992 | 0.981–1.003 |
| IV + NL polymyxin B | 0.006 | 0.222 | 0.076–0.650 |
| Combined carbapenems | 0.391 | 0.211 | 0.030–1.473 |
| Combined β-lactams | 0.611 | 1.573 | 0.188–13.128 |
Abbreviations: CRRT, continuous renal replacement therapy; Carbapenems, meropenem, imipenem/cilastatin; β-Lactams, piperacillin/tazobactam, cefoperazone/sulbactam, ceftazidime/avibactam
Safety assessment
We conducted a safety assessment of patients included in the study based on the incidence of AKI following polymyxin B administration. Twenty-one patients who underwent CRRT were excluded, comprising 6 patients from the IV + NL polymyxin B group and 15 patients from the IV polymyxin B group. As shown in Table 7, a total of 61 patients were included in the final analysis, with 32 in the IV + NL polymyxin B group and 29 in the IV polymyxin B group. There were no statistically significant differences between the two groups in terms of baseline APACHE II scores and SOFA scores. Six patients experienced AKI, including 4 in the IV + NL polymyxin B group and 2 in the IV polymyxin B group. None of the AKI patients in either group were concomitantly using other nephrotoxic drugs, such as vancomycin or amikacin. The incidence of AKI did not differ significantly between the two groups.
Table 7.
Incidence of AKI after the administration of polymyxin B
| Total (n = 61) |
IV + NL polymyxin B (n = 32) |
IV polymyxin B (n = 29) |
P-value | |
|---|---|---|---|---|
| APACHE II score | 21 ± 5 | 20 ± 5 | 21 ± 6 | 0.781 |
| SOFA score | 6 ± 3 | 6 ± 2 | 7 ± 3 | 0.380 |
| AKI | 6(9.84%) | 4(12.50%) | 2(6.90%) | 0.674 |
Abbreviations: APACHE II, Acute Physiology and Chronic Health Evaluation II; SOFA, Sequential Organ Failure Assessment
Discussion
The emergence and spread of CRGNB represents a significant public health issue, with CRGNB-HAP posing a clinical challenge. Epidemiological data on 2,827 adult Chinese HAP patients showed that 64.9% of patients tested positive for multidrug-resistant strains, which were more prevalent in patients with VAP than in non-VAP cases. This resistance has led to limited treatment options, resulting in higher mortality rates and increased healthcare costs [16]. Polymyxins were introduced in the 1950 s but gradually fell out of clinical use due to safety concerns such as nephrotoxicity [17]. However, it wasn't until the 1980 s, amid the rapid rise of multidrug-resistant bacteria and a slowdown in new drug development, that polymyxins re-emerged as a crucial therapeutic option due to their unique antimicrobial mechanism. To date, the clinical value of polymyxins in treating CRGNB infections remains irreplaceable. Previous studies [18–20] have shown that intravenous administration of polymyxins results in very low concentrations in sputum, whereas inhalation achieves much higher concentrations in the epithelial lining fluid (ELF) compared to plasma (100 to 1000 times higher), with minimal systemic exposure. This makes nebulized polymyxins a potentially safer choice for treating critically ill patients with HAP/VAP. However, most clinical research and meta-analyses on nebulized polymyxins have mainly focused on CMS [21–24], with fewer studies specifically addressing nebulized polymyxin B for HAP. The findings from these studies are contradictory. For instance, a real-world study [25] indicated that combined intravenous and nebulized therapy with polymyxin B improved clinical outcomes in HAP caused by carbapenem-resistant microorganisms. The clinical success group had a higher likelihood of being treated with combination therapy (p = 0.012). Hasan et al. [26] demonstrated better microbial clearance and reduced mortality in VAP patients with multidrug-resistant Klebsiella pneumoniae when treated with both intravenous and nebulized polymyxin B compared to intravenous polymyxin B alone, but these improvements did not reach statistical significance. A randomized control trial [27] showed no significant difference in treatment success rates between polymyxin B plus high-dose nebulized colistin and intravenous polymyxin B alone in ICU patients with extensively drug-resistant gram-negative bacteria (XDR-GNB)-induced HAP, although microbial clearance was higher in the combined therapy group. In our study, no statistically significant variances were observed in demographic and clinical baseline characteristics between the IV + NL polymyxin B group and the IV polymyxin B group. Survival analysis and multivariable logistic regression analysis revealed that the 28-day mortality rate in the IV + NL polymyxin B group was significantly lower than in IV polymyxin B group (p < 0.001). This finding indicates the potential superiority of IV + NL polymyxin B as a treatment strategy for CRGNB-HAP, offering a therapeutic option to improve patient outcomes in this challenging clinical scenario.
Nephrotoxicity is the most common adverse reaction of polymyxins, and its mechanism of occurrence is related to cell death mediated by megalin and PEPT2 transporters leading to the accumulation of polymyxins in renal tubules [18]. While CMS is mainly eliminated renally, colistin and polymyxin B are predominantly cleared via non-renal pathways. Despite this, previous studies have observed nephrotoxicity following parenteral application of colistin and polymyxin B. A meta-analysis [28] revealed that the overall incidence of nephrotoxicity caused by intravenous colistin was approximately 48%, higher than that of polymyxin B (38%). A retrospective study by Wu et al. [29] reported a significantly higher incidence of AKI in patients receiving combination therapy with nebulized and intravenous polymyxin B compared to those treated with nebulized polymyxin B alone, likely due to increased drug exposure and subsequent renal burden. It is noteworthy that nebulized polymyxin B monotherapy may still pose a risk of AKI. Another study [26] calculated that the rate of nephrotoxic adverse drug events after intravenous combined with nebulized polymyxin B was 5.2%, compared to 4.6% for intravenous polymyxin B alone, with no statistical difference between the two groups. In our study, upon excluding patients receipt of CRRT, no statistically significant difference was observed in the incidence of AKI between the two groups. Additionally, none of the AKI patients in either group were co-administered with other nephrotoxic drugs, suggesting that nebulized polymyxin B may have a certain level of safety. However, further research is still needed to confirm these observations, so we still recommend careful monitoring of renal function in patients receiving polymyxin B treatment.
Furthermore, recent research data [30] suggest that polymyxins, when combined with other antibiotics, exhibit synergistic effects against multiple drug-resistant gram-negative bacteria (MDR-GNB) and XDR-GNB in vitro. However, the combination of polymyxins and carbapenems for treating CRGNB remains controversial [5]. An RCT study [31] revealed that colistin-meropenem combination therapy was superior to colistin monotherapy for HAP/VAP caused by multidrug-resistant Klebsiella pneumoniae, significantly reducing mortality rates in the combination therapy group. Conversely, in ICU patients with CRAB-HAP, a regimen combining polymyxin B and sulbactam was significantly associated with a reduced risk of mortality, while the polymyxin B plus carbapenem regimen was significantly linked to an increased mortality rate [32]. The ESCMID guidelines [33] recommend using polymyxin-carbapenem combination therapy for CRE infections when the meropenem MIC is ≤ 8 mg/L, alongside increasing the meropenem dosage and prolonging the infusion time. In our study, polymyxin B was most frequently combined with carbapenems. Univariate regression analysis found that the combination therapy of polymyxin B with carbapenems for treating CRGNB-HAP was associated with an increased 28-day mortality rate (p = 0.019). Notably, carbapenems were administered using a prolonged infusion regimen. In contrast, the combination of polymyxin B with β-lactams, such as piperacillin/tazobactam, cefoperazone/sulbactam, and ceftazidime/avibactam, was associated with a reduced the 28-day mortality rate (p = 0.028).
This study has some limitations. Firstly, the relatively small sample size of the study may have introduced potential biases in the results. However, this was a real-world study, and its data reflect actual clinical practice. Secondly, as a retrospective study, potential confounding factors and missing data may preclude the analysis of certain outcomes, particularly the differences in bacteriological clearance rates between IV + NL polymyxin B and IV polymyxin B. Thirdly, some cases used the disk diffusion method for meropenem susceptibility testing, resulting in a lack of MIC values for meropenem. The absence of MIC data hindered further analysis of the carbapenem susceptibility of CRGNB isolates and the evaluation of its impact on treatment strategies. Lastly, most patients were in a state of tracheostomy or endotracheal intubation, limiting our ability to observe adverse reactions such as bronchospasm following nebulized polymyxin B administration. Additionally, there was insufficient data on skin pigmentation changes, another potential side effect of polymyxin therapy.
Conclusion
In conclusion, our study found that the combination of intravenous and nebulized polymyxin B is superior to intravenous monotherapy for treating CRGNB-HAP, resulting in a lower 28-day mortality rate with no difference in nephrotoxicity. Future research should include larger randomized controlled trials to confirm these findings.
Acknowledgements
We wish to thank all the authors for completing this study in their spare time after busy work.
Author contributions
Conceptualization, YZ and YD; Methodology, YZ, JC and YD; Validation, JC, LF, MW and YD; Formal Analysis, LF, MW and WZ; Data Curation, YZ, JC, MW and WZ; Writing – Original Draft, YZ, JC and YD; Writing – Review & Editing, YZ, LF, MW, WZ and YD; Visualization, LF and MW.
Funding
The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethical approval
The study protocol was approved by the Ethics Review Committee of The Second Affiliated Hospital of Zhejiang Chinese Medical University (Approval No. ZJTCMU2AE2023R081-01).
Competing interests
The authors declare no competing interests.
Footnotes
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Ye Zhang, Jiangtao Chen, Lexin Fang and Min Wangcontributed equally to the work.
References
- 1.Miron M, Blaj M, Ristescu AI, Iosep G, Avadanei AN, Iosep DG et al (2024) Hospital-acquired pneumonia and ventilator-associated pneumonia: a literature review. Microorganisms 12. 10.3390/microorganisms12010213 [DOI] [PMC free article] [PubMed]
- 2.Ranzani OT, Niederman MS, Torres A (2022) Ventilator-associated pneumonia. Intens Care Med 48:1222–1226. 10.1007/s00134-022-06773-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Huemer M, Mairpady Shambat S, Brugger SD, Zinkernagel AS (2020) Antibiotic resistance and persistence-Implications for human health and treatment perspectives. EMBO Rep 21:e51034. 10.15252/embr.202051034 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.World Health Organisation (2017) Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics. https://www.infobioquimica.com/new/wp-content/uploads/2017/02/WHO-PPL-Short_Summary_25Feb-ET_NM_WHO.pdf. [Accessed 2 July 2024]
- 5.Zeng M, Xia J, Zong Z, Shi Y, Ni Y, Hu F et al (2023) Guidelines for the diagnosis, treatment, prevention and control of infections caused by carbapenem-resistant gram-negative bacilli. J Microbiol Immunol Infect 56:653–671. 10.1016/j.jmii.2023.01.017 [DOI] [PubMed] [Google Scholar]
- 6.China Antimicrobial Resistance Surveillance System (2024) 2023 national report on antimicrobial resistance surveillance. https://www.carss.cn/Report/Details/978. [Accessed 23 June 2025]
- 7.Yaghoubi S, Zekiy AO, Krutova M, Gholami M, Kouhsari E, Sholeh M et al (2021) Tigecycline antibacterial activity, clinical effectiveness, and mechanisms and epidemiology of resistance: narrative review. Eur J Clin Microbiol Infect Dis 41:1003–1022. 10.1007/s10096-020-04121-1 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Zhen S, Wang H, Feng S (2022) Update of clinical application in ceftazidime-avibactam for multidrug-resistant Gram-negative bacteria infections. Infection 50:1409–1423. 10.1007/s15010-022-01876-x [DOI] [PubMed] [Google Scholar]
- 9.Tamma PD, Heil EL, Justo JA, Mathers AJ, Satlin MJ, Bonomo RA (2024) Infectious diseases society of America 2024 guidance on the treatment of antimicrobial-resistant gram-negative infections. Clin Infect Dis. 10.1093/cid/ciae403 [DOI] [PubMed] [Google Scholar]
- 10.Rabanal F, Cajal Y (2017) Recent advances and perspectives in the design and development of polymyxins. Nat Prod Rep 34:886–908. 10.1039/c7np00023e [DOI] [PubMed] [Google Scholar]
- 11.Tsuji BT, Pogue JM, Zavascki AP, Paul M, Daikos GL, Forrest A et al (2019) 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 39:10–39. 10.1002/phar.2209 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Kalil AC, Metersky ML, Klompas M, Muscedere J, Sweeney DA, Palmer LB et al (2016) Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the infectious diseases society of America and the American thoracic society. Clin Infect Dis 63:e61–e111. 10.1093/cid/ciw353 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.LeGall JRLP (1986) Alpérovitch A APACHE II–a severity of disease classification system. Crit Care Med 14:754–764. 10.1097/00003246-198608000-00027 [DOI] [PubMed] [Google Scholar]
- 14.Lambden S, Laterre PF, Levy MM, Francois B (2019) The SOFA score-development, utility and challenges of accurate assessment in clinical trials. Crit Care 23:374. 10.1186/s13054-019-2663-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.London (2023) Acute kidney injury_prevention, detection andmanagement. https://www.niceorguk/guidance/ng148/chapter/Recommendations#assessing-risk-of-acute-kidney-injury. Accessed 2 Jul 2024
- 16.Yin Y, Zhao C, Li H, Jin L, Wang Q, Wang R et al (2021) Clinical and microbiological characteristics of adults with hospital-acquired pneumonia: a 10-year prospective observational study in China. Eur J Clin Microbiol Infect Dis 40:683–690. 10.1007/s10096-020-04046-9 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Poirel L, Jayol A, Nordmann P (2017) Polymyxins: antibacterial activity, susceptibility testing, and resistance mechanisms encoded by plasmids or chromosomes. Clin Microbiol Rev 30:557–596. 10.1128/CMR.00064-16 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Tran TB, Velkov T, Nation RL, Forrest A, Tsuji BT, Bergen PJ et al (2016) Pharmacokinetics/pharmacodynamics of colistin and polymyxin B: are we there yet? Int J Antimicrob Agents 48:592–597. 10.1016/j.ijantimicag.2016.09.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Boisson M, Gregoire N, Cormier M, Gobin P, Marchand S, Couet W et al (2017) Pharmacokinetics of nebulized colistin methanesulfonate in critically ill patients. J Antimicrob Chemother 72:2607–2612. 10.1093/jac/dkx167 [DOI] [PubMed] [Google Scholar]
- 20.Benitez-Cano A, de Antonio-Cusco M, Luque S, Sorli L, Carazo J, Ramos I et al (2019) Systemic pharmacokinetics and safety of high doses of nebulized colistimethate sodium in critically ill patients with hospital-acquired and ventilator-associated pneumonia. J Antimicrob Chemother 74:3268–3273. 10.1093/jac/dkz356 [DOI] [PubMed] [Google Scholar]
- 21.Feng JY, Peng CK, Sheu CC, Lin YC, Chan MC, Wang SH et al (2021) Efficacy of adjunctive nebulized colistin in critically ill patients with nosocomial carbapenem-resistant gram-negative bacterial pneumonia: a multi-centre observational study. Clin Microbiol Infect 27:1465–1473. 10.1016/j.cmi.2021.01.020 [DOI] [PubMed] [Google Scholar]
- 22.Almangour TA, Alruwaili A, Almutairi R, Alrasheed A, Alhifany AA, Eljaaly K et al (2021) Aerosolized plus intravenous colistin vs intravenous colistin alone for the treatment of nosocomial pneumonia due to multidrug-resistant Gram-negative bacteria: a retrospective cohort study. Int J Infect Dis 108:406–412. 10.1016/j.ijid.2021.06.007 [DOI] [PubMed] [Google Scholar]
- 23.Lu D, Mao W (2023) Efficacy and safety of intravenous combined with aerosolised polymyxin versus intravenous polymyxin alone in the treatment of multidrug-resistant gram-negative bacterial pneumonia: a systematic review and meta-analysis. Heliyon 9:e15774. 10.1016/j.heliyon.2023.e15774 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Vardakas KZ, Mavroudis AD, Georgiou M, Falagas ME (2018) Intravenous plus inhaled versus intravenous colistin monotherapy for lower respiratory tract infections: a systematic review and meta-analysis. J Infect 76:321–327. 10.1016/j.jinf.2018.02.002 [DOI] [PubMed] [Google Scholar]
- 25.Tang T, Li Y, Xu P, Zhong Y, Yang M, Ma W et al (2023) Optimization of polymyxin B regimens for the treatment of carbapenem-resistant organism nosocomial pneumonia: a real-world prospective study. Crit Care 27:164. 10.1186/s13054-023-04448-z [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Hasan MJ, Rabbani R, Anam AM, Santini A, Huq SMR (2021) The susceptibility of MDR-K. Pneumoniae to polymyxin B plus its nebulised form versus polymyxin B alone in critically Ill South Asian patients. J Crit Care Med (Targu Mures) 7:28–36. 10.2478/jccm-2020-0044 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Ghosh S, Polymyxin B (2024) Plus aerosolized colistin vs polymyxin B alone in hospital-acquired pneumonia (“AEROCOL” Study): a feasibility study. Indian J Crit Care Med 28:792–795. 10.5005/jp-journals-10071-24767 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Sisay M, Hagos B, Edessa D, Tadiwos Y, Mekuria AN (2021) Polymyxin-induced nephrotoxicity and its predictors: a systematic review and meta-analysis of studies conducted using RIFLE criteria of acute kidney injury. Pharmacol Res 163:105328. 10.1016/j.phrs.2020.105328 [DOI] [PubMed] [Google Scholar]
- 29.Wu Z, Zhang S, Cao Y, Wang Q, Sun K, Zheng X (2023) Comparison of the clinical efficacy and toxicity of nebulized polymyxin monotherapy and combined intravenous and nebulized polymyxin for the treatment of ventilator-associated pneumonia caused by carbapenem-resistant gram-negative bacteria: a retrospective cohort study. Front Pharmacol 14:1209063. 10.3389/fphar.2023.1209063 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Ardebili A, Izanloo A, Rastegar M (2023) Polymyxin combination therapy for multidrug-resistant, extensively-drug resistant, and difficult-to-treat drug-resistant gram-negative infections: is it superior to polymyxin monotherapy? Expert Rev Anti Infect Ther 21:387–429. 10.1080/14787210.2023.2184346 [DOI] [PubMed] [Google Scholar]
- 31.Abdelsalam MFA, Abdalla MS, El-Abhar HSE (2018) Prospective, comparative clinical study between high-dose colistin monotherapy and colistin-meropenem combination therapy for treatment of hospital-acquired pneumonia and ventilator-associated pneumonia caused by multidrug-resistant Klebsiella pneumoniae. J Glob Antimicrob Resist 15:127–135. 10.1016/j.jgar.2018.07.003 [DOI] [PubMed] [Google Scholar]
- 32.Qiao LZW, Yang Y, Liu X, Wang Q, Yu J, Wu J, Xu T, Jiang J, Zhang B, Long Y (2023) Clinical outcomes and safety of intravenous polymyxin B-based treatment in critically ill patients with carbapenem-resistant acinetobacter baumannii nosocomial pneumonia. Int J Antimicrob Agents 62:106880. 10.1016/j.ijantimicag.2023.106880 [DOI] [PubMed] [Google Scholar]
- 33.Paul M, Carrara E, Retamar P, Tangden T, Bitterman R, Bonomo RA et al (2022) European society of clinical microbiology and infectious diseases (ESCMID) guidelines for the treatment of infections caused by multidrug-resistant Gram-negative bacilli (endorsed by European society of intensive care medicine). Clin Microbiol Infect 28:521–547. 10.1016/j.cmi.2021.11.025 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
No datasets were generated or analysed during the current study.