Colistin sulfate is effective and safe in the treatment of severe pneumonia patients with CRE resistance: a retrospective cohort study

doi:10.21203/rs.3.rs-4916931/v1

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Colistin sulfate is effective and safe in the treatment of severe pneumonia patients with CRE resistance: a retrospective cohort study

https://doi.org/10.21203/rs.3.rs-4916931/v1

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Objective

Severe pneumonia is difficult to treat and with a high mortality. The increasing drug resistance problem increased the difficulties to treat, so we estimated whether colistin sulfate reduces the mortality of severe pneumonia patients with suspicious CRO infection.

Method

A retrospective cohort study was conducted on the patients consecutively admitted for pneumonia to the Second Affiliated Hospital of Chongqing Medical University from Jan 2022 to Feb 2023. Data were recorded.

Results

We found that the 28-day mortality after discharge of severe pneumonia patients with suspected MDR bacterial infections in our cohort study is also high (42/84, 50%). The 28-day mortality of discharge in tigecycline (TC) group is a bit lower than that of colistin combined with other antibiotics (OC) group (18/46, 39.1% vs. 24/38, 63.2%, P = 0.048). Further multivariate analysis revealed that positive sputum culture was significantly associated with the 28-day discharge mortality rate with different treatment regimens (OR 0.073, 95% CI 0.006–0.882, P = 0.040). And no significant differences were founded before and after the use of colistin sulfate for the white blood count (WBC), platelet count, level of CRP, PCT, ALT, and creatinine.

Conclusion

Colistin sulfate is effective and safe in the treatment of severe pneumonia patients with CRE resistance.

Biological sciences/Drug discovery/Drug safety

Health sciences/Health care/Therapeutics

Colistin sulfate

severe pneumonia

CRE resistance

efficiency

safety

Hospital acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are common hospital acquired infections (HAI) worldwide. Both are difficult to diagnose and treat, and have a high mortality rate. In European and American, HAP ranks second in HAIs. It is the main cause of critical patients’ death, with an incidence rate of 0.5%~2% [1]. The risk of VAP is time-dependent, VAP mortality rate and ICU discharge are competing endpoints, research has found attributed mortality rate is 10%. And in patients with brain injury and trauma, the incidence of VAP can be very high, reaching 50% [2]. In China, the incidence of HAIs is 3.22%~5.22%. Incidence of HAP range from 1.76%~1.94% [3–4]. The clinical survey results of HAP in 13 large teaching hospitals show that the average incidence rate of HAP in Respiratory Wards and Respiratory Intensive Care Units (RICUs) is 1.4%, with RICU being 15.3%, and in general wards 0.9%. The average all-cause mortality rate of HAP is 22.3%, among which of VAP is 34.5% [4]. Among 17358 ICU residents in 46 hospitals in China, the total days of intubation is 91 448 days, and the incidence rate of VAP is 8.9/1000 days of mechanical ventilation, the incidence rate of VAP was 9.7%~48.4%, Or (1.3–28.9)/1000 mechanical ventilation days, with a mortality rate of 21.2–43.2% [1].

The composition of the HAP pathogen spectrum in China differs greatly from that of European and American countries, with Gram-negative bacteria being the main pathogens. Among them, Acinetobacter baumannii accounted for the most, about 16.2%~35.8%. Pseudomonas aeruginosa accounted for 16.9%~22.0%. Staphylococcus aureus accounted for 8.9%~16.0%, and Klebsiella pneumoniae accounted for 8.3%~15.4%. VAP patients in China are mainly seen in ICUs, with a slightly different pathogen spectrum from HAP [5]. The isolation rate of Acinetobacter baumannii is as high as 35.7%~50.0%, followed by Pseudomonas aeruginosa and Staphylococcus aureus, with similar proportions (12.5%~27.5% and 6.9%~21.4%) [6]. In addition, according to the data from the China Surveillance Network for Bacterial Resistance (CHINET) and the Chinese Antibiotic Resistance Survey of Nosocomial Infection (CARES) in China's multicenter bacterial resistance monitoring network, the separation rate of carbapenem-resistant Acinetobacter baumannii (CRAB) and carbapenem-resistant Pseudomonas aeruginosa (CRPA) in various specimens (blood, urine, sputum, etc.) is as high as 60%~70% and 20% ~40%, respectively. The isolation rates of Klebsiella pneumoniae and Escherichia coli producing extended-spectrum β Amide like enzymes (ELBLs) were 25%~35% and 45%~60%, respectively [7]. More serious, the CARES data on HAP/VAP resistance from 2007 to 2013 showed an upward trend in carbapenem-resistant organisms (CRO), represented by multi-drug resistant (MDR) Acinetobacter baumannii and carbapenem-resistant enterobacteriaceae (CRE). The increasing problem of drug resistance has brought great difficulties to the treatment of clinical doctors and the prognosis of patients.

How to improve the survival rate of patients with severe pneumonia, especially those with suspectable CRO infections, is an important issue needs clinical doctors’ consideration. Choosing a safe and effective antibiotic is an undoubtedly crucial issue. In fact, colistin sulfate is an important drug to treat CRE, but there is still a lack of important evidence-based medicine evidence for its efficacy and safety in patients with severe pneumonia. In this study, we collected information of patients admitted to hospital with severe pneumonia. We aimed to estimate whether colistin sulfate reduces the mortality of severe pneumonia patients with suspicious CRO infection.

Patients and Methods

Our retrospective cohort study was conducted on the medical record of patients who consecutively admitted for pneumonia to the Second Affiliated Hospital of Chongqing Medical University from Jan 2022 to Feb 2023. For each patient, data including gender, age, clinical history (e.g., comorbidities), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TB), creatine, complete blood cell count, C reactive protein (CRP), procalcitonin (PCT), oxygenation index, imaging data, clinical outcomes, and treatments were collected. Inclusion criteria: a) CT imaging findings met the standard of pneumonia, b) patients’ condition met the diagnostic criteria for severe pneumonia [8], c) used intravenous colistin sulfate in the treatment. Exclusion criteria: a) age < 18 years, b) information is not complete. Some patients received other treatments following with doctors’ judgement such as systemic corticosteroids, budesonide, supplemental oxygen, non-invasive mechanical ventilation (NIV), and invasive mechanical ventilation (IMV), which were all be collected. The study was approved by the Research Ethics Commission of the Second Affiliated Hospital of Chongqing Medical University.

Statistical analysis

Variables conformed to a Gaussian distribution were expressed as means standard deviations (SD). Continuous variables were reported as median with interquartile range (IQR), and categorical variables were expressed as frequency and percentages (%). The categorical variables were analyzed by the Pearson Chi-square test. Statistically significant was considered if P-values < 0.05 (two-tailed). To estimate the association between risk factors and 28-day disease-related mortality after discharge, we used the univariate and multivariate adjusted logistic regression models to analysis odds ratio (OR) and 95% confidence interval (95% CI). Statistical analyses and figures were done using IBM SPSS Statistics (Version 26.0) and GraphPad Prism software (Version 9.0).

A total of 85 patients with a diagnosis of severe pneumonia who treated with intravenous colistin sulfate were recruited. Then following the exclusion criteria, 1 patient was excluded because of incomplete information. Finally, 84 cases were included in our cohort study. And based on different treatment schemes, two groups were divided: colistin combined with tigecycline group (TC) (46 cases) and colistin combined with other antibiotics group (OC) (38 cases) (Fig. 1).

The clinical characteristics of patients with different colistin treatment schemes in the cohort are shown in Table 1. For the basic clinical characteristics, there were no significant differences in the mean age, gender, percentage of most combinations (eg. chronic pulmonary disease, malignancy, neurological disease, diabetes and extrapulmonary infections), and detection rate of pathogenic microorganisms in the TC and OC group. However, the frequency for the combination of chronic kidney disease in the TC group is significantly higher than that of OC group (14/46, 30.4% vs. 4/38, 10.5%, P = 0.034). For the treatment patients received in hospital, there were no significant differences in the percentage of systemic corticosteroids using, antiviral drugs using, colistin dosage choosing (percentage of 75000u) and atomize colistin. However, the frequency of antifungal drugs using in the TC group is significantly higher than that of OC group (36/46, 78.3% vs. 21/38, 55.3%, P = 0.035). For the clinical outcomes, there were no significant differences in the CT imaging improvement and hospitalization days. However, the mortality with 28 days of discharge in the TC group is a bit significantly lower than that of OC group (18/46, 39.1% vs. 24/38, 63.2%, P = 0.048).

Table 1

Clinical characteristics of patients with different colistin schemes.
	Colistin + Tigecycline (TC) n = 46	Colistin + other antibiotics (OC) n = 38	P-value
Age, years (mean ± SD) Gender, male Chronic pulmonary disease Malignancy Neurological disease Diabetes Chronic kidney disease Other chronic disease With extrapulmonary infection Laboratory tests Positive sputum smear Positive sputum culture Respiratory pathogen test positive GM test Treatment received in hospital Systemic corticosteroids Antiviral Antifungal Colistin dosage (75000u, %) Atomize Colistin (Venous + nebulization, %) Outcomes CT image improvement Hospitalization days (mean ± SD) Mortality within 28 days of discharge	66.8 ± 14.9 13(28.3%) 14(30.4%) 9(19.6%) 14(30.4%) 1(2.2%) 14(30.4%) 31(67.4%) 28(60.9%) 5(10.9%) 33(71.7%) 13(28.3%) 4(8.7%) 9(19.6%) 1(2.2%) 36(78.3%) 15(32.6%) 11(23.9%) 21(80.8%) 34.6 ± 27.8 18(39.1%)	67.2 ± 14.9 10(26.3%) 17(44.7%) 9(23.7%) 5(13.2%) 4(10.5%) 4(10.5%) 34(89.5%) 26(68.4%) 2(5.3%) 22(57.9%) 11(28.9%) 2(5.3%) 7(18.4%) 0(0%) 21(55.3%) 6(15.8%) 6(15.8%) 12(63.2%) 34.9 ± 38.9 24(63.2%)	P = 0.919 P = 1.000 P = 0.256 P = 0.790 P = 0.071 P = 0.171 P = 0.034 P = 0.019 P = 0.502 P = 0.449 P = 0.249 P = 1.000 P = 0.685 P = 1.000 P = 1.000 P = 0.035 P = 0.084 P = 0.421 P = 0.306 P = 0.968 P = 0.048

Then we did a univariate and multivariate analysis about different colistin sulfate regimens and the 28-day mortality after discharge (Table 2). For overall population, there were significant differences between the sputum culture results and 28-day mortality after discharge, no matter in the univariate (OR 0.375, 95% CI 0.155–0.910, P = 0.030) or multivariate analysis (OR 0.180, 95%CI 0.040–0.813, P = 0.026). However, in the univariate analysis, no statistical difference was observed both in the sputum culture positive and negative patients. Further multivariate analysis, it was revealed that positive sputum culture was significantly associated with the 28-day discharge mortality rate of patients with different treatment regimens (OR 0.073, 95% CI 0.006–0.882, P = 0.040).

Table 2

Univariate and multivariate analysis of different treatment regimens and 28-day disease-related mortality after discharge.
	Univariate analysis				Multivariate analysis
Mortality within 28 days of discharge	OR	Lower.95	Upper.95	P-value	OR	Lower.95	Upper.95	P-value
Overall (n = 84) Positive sputum culture (n = 55) Negative sputum culture (n = 29)	0.375 0.233 0.907	0.155 0.074 0.208	0.910 0.739 3.952	P = 0.030 P = 0.013 P = 0.897	0.180 0.073 0.090	0.040 0.006 0.000	0.813 0.882 16.712	P = 0.026 P = 0.040 P = 0.367

Later we compared the changes in biochemical indicators such as liver function, kidney function and blood routine before and after the use of colistin sulfate in the recruited patients (Table 3). No significant differences were founded before and after the use of colistin sulfate for the white blood count (WBC), neutrophil count, lymphocyte count, platelet count, level of CRP, PCT, ALT, AST, and creatinine. But the level of TB after using colistin sulfate is significantly higher than that of before (11.4 umoul/L vs. 15.1 umol/L, P = 0.030).

Table 3

Comparison of blood biochemical indicators before and after the use of colistin.
Laboratory tests	Before Colistin (n = 84)	After Colistin (n = 84)	P-value
WBC (median ± IQR) ×10⁹ Neutrophil percentage (median ± IQR) Lymphocyte percentage (median ± IQR) Platelet count (median ± IQR) ×10⁹ CRP (median ± IQR) – mg/dL PCT (median ± IQR) – ng/mL ALT (median ± IQR) – U/mL AST (median ± IQR) – U/mL Total bilirubin (median ± IQR) – umol/L Creatinine, male (median ± IQR) – umol/L Creatinine, female (median ± IQR) – umol/L	9.3 (5.2–14.3) 86.7 (76.6–92.1) 7.8 (3.6–13.3) 164 (90–241) 100.3 (28.6-163.7) 0.5 (0.2–2.7) 36.0 (18.0–54.0) 40.0 (24.0–61.0) 11.4 (7.2–16.3) 81.3 (54.6-128.6) 53.0 (38.0-80.3)	9.6 (5.6–14.2) 86.4 (74.8–92.6) 7.7 (3.9–12.3) 145.5 (74.8-292.5) 90.6 (31.4-156.5) 1.3 (0.1–5.4) 33.0 (16.0–54.0) 35.0 (25.0-57.8) 15.1 (8.0-22.5) 75.5 (54.7-171.5) 41.4 (31.0-64.4)	P = 0.697 P = 0.773 P = 0.793 P = 0.965 P = 0.763 P = 0.521 P = 0.704 P = 0.823 P = 0.030 P = 0.882 P = 0.149

Finally, we evaluated the impacts of other factors on the 28-day mortality after discharge (Fig. 2). It was found that there were no significant differences in the 28-day mortality after discharge, whether using glucocorticoids or not, using antifungal drugs or not, using big or routine dosage of colistin sulfate, whether it was combined with nebulization or not, or whether the patient had extrapulmonary infections or not.

Severe pneumonia is a serious condition of lower respiratory infection. In addition to common symptom of pneumonia like fever and cough, patients with severe pneumonia also have symptoms of respiratory failure and obvious involvement of other systems [9]. According to different environments obtained, it can be divided into severe community-acquired pneumonia (SCAP) and severe hospital-acquired pneumonia (SHAP). SCAP development rapidly. Even with sufficient anti-infection treatment, its mortality can be as high as 28.8% [10–12]. And some research reported that its mortality can even be 50% [13]. The mortality of SHAP is even higher, as the prevalence of drug-resistant bacteria is becoming increasingly severe [4].

Since 20th century, the increasing bacterial resistance rate has become an important threat to human health, especially CRE, CRAB, and CRPA. These strains have high resistance to common antibiotics and limited options for therapeutic drugs. Polymyxin was recommended by both domestic and international guidelines as an important therapeutic drug for carbapenem-resistant Gram-negative bacterial infections [1, 2]. Polymyxin belongs to the class of peptide antibiotics, clinically including polymyxin B sulfate, colistin sulfate, and colistin methane-sulfonate (CMS). CMS is a precursor drug that is converted into the active ingredient colistin after entering the human body to exert its effects [14]. Both polymyxin B sulfate and colistin sulfate directly enter the bloodstream in an active form and exerted similarly high bactericidal activity when administered topically [15, 16]. While colistin sulfate showed less nephrotoxicity, little has been reported on the bactericidal effect of colistin sulfate in patients with severe pneumonia [16, 17]. After the relaunch of colistin sulfate in May 2019 in China, we organized this study to estimate the anti-bacterial effect and safety of colistin sulfate in severe pneumonia patients.

At present, there is lack of high-quality, large-sample clinical research for severe pneumonia patients, especially the one with MDR bacterial infections. Some studies have shown that HAP is the direct cause of death in critically ill patients, with related mortality ranging from 15.5% − 38.2% [18, 19]. The clinical survey results of 13 large teaching hospitals in China show that the average all-cause mortality of HAP is 22.3%, of which VAP is 34.5% [20]. Another survey in China showed that among 17,358 ICU inpatients in 46 hospitals, the mortality of VAP in mechanically ventilated patients was 21.2% -43.2% [20, 21]. And it had been proved that if the pathogen is MDR or pan-drug resistant (PXD), the attributed mortality can reach as high as 38.8% − 60% [21, 22]. In our retrospective cohort study, we can see that the 28-day mortality after discharge of severe pneumonia patients with suspected MDR bacterial infections included in our cohort study is also high (42/84, 50%), which is consistent with the results of other relative studies.

We divided the patients recruited in our study into two groups based on different colistin sulfate treatment schemes. The basic clinical characteristics of patients in the two groups were comparable, no matter with their age, gender, complication, and detection of pathogens (Table 1). Further study showed clinical outcomes including CT image improvement and hospitalization days, were also comparable between the two groups, except the 28-day mortality after discharge. For patients in TC group, the 28-day mortality is significantly lower than that of the OC group (18/46, 39.1% vs. 24/38, 63.2%, P = 0.048). At present, there is still lack of clinical research on the efficacy of colistin and tigecycline in the treatment of CRE pneumonia, and the results of some existing observational clinical studies are inconsistent [23–24]. A meta-analysis which included 14 studies involving 1163 patients, compared the efficacy and safety of polymyxin E and tigecycline monotherapy or combination therapy for multidrug-resistant/extensively-resistant Gram-negative bacterial infections. The monotherapy with tigecycline significantly reduced the 30-day mortality (OR = 0.35, 95% CI 0.16–0.75, P = 0.007), while the monotherapy with polymyxin E significantly reduced the in-hospital mortality rate (OR = 2.27, 95% CI 1.24–4.16, P = 0.008) [23]. While combined the use of tigecycline and polymyxin E, there is no significant difference in clinical efficacy and mortality. Compared with polymyxin E, tigecycline has a lower incidence of renal injury, whether it is monotherapy or combination therapy. Kimberly et al. retrospectively compared the efficacy of polymyxin E and tigecycline in the treatment of CRAB and/or CRE infections. And the results showed that receiving polymyxin E alone, patients treated with the combination of colistin E and tigecycline have a higher mortality (33/90 37% vs. 0/16 0%, P = 0.002) and a longer hospital stay [29.5 (37.7 ± 30.3) vs 23.3 (23.5 ± 14.0), P = 0.004] than those treated with tigecycline alone [24]. Researchers analyze that it may be due to the higher severity of acute disease in patients receiving polymyxin E treatment, and a significant delay in initiating effective of antibacterial treatment (P < 0.001). Chang et al. conducted a multicenter retrospective study comparing the clinical efficacy of polymyxin B combined with tigecycline, and polymyxin B or tigecycline combined with other drugs in the treatment of HAP caused by CRO [25]. The results showed that the 28-day all-cause mortality of the combination regimen based on polymyxin B was 28.3% (28/99), significantly lower than 39.3% (68/173) of the combination regimen based on tigecycline or 48.9% (45/92) of the polymyxin B combined with tigecycline group (P = 0.014), which is quite consisted with the results in our study. Researchers analyze the reasons and believe that tigecycline has certain limitations in treating pulmonary infections, partly due to the limitations of tigecycline is an antibacterial agent rather than a fungicide. On the other hand, tigecycline has a steady-state distribution volume of about 7–10 L/kg and is widely distributed in human tissues, while the drug concentration in plasma is relatively low [25]. However, it should be noted that Chang et al. did not mention the dosage of tigecycline administered to the included patients in their study [25].

Further we found that sputum culture results were significantly associated with the 28-day mortality after discharge both through the univariate (OR 0.375, 95% CI 0.155–0.910, P = 0.030) and multivariate analysis (OR 0.180, 95%CI 0.040–0.813, P = 0.026). The positive sputum culture results were especially associated with the 28-day mortality after discharge of severe pneumonia patients (univariate analysis: OR 0.233, 95% CI 0.074–0.739, P = 0.013; multivariate analysis: OR 0.073, 95% CI 0.006–0.882, P = 0.040). This suggests the important role of pathogen detection in guiding antibiotic selection, which is consistent with previous research findings [23–25].

Finally, we estimated the safety of colistin sulfate using in patients with severe pneumonia. And found that there were no significant differences before and after the use of colistin sulfate for the white blood count (WBC), neutrophil count, lymphocyte count, platelet count, level of CRP, PCT, ALT, AST, and creatinine, so it will not increase the burden on the liver, kidneys, and blood system. In fact, colistin sulfate exert its effect directly after entering the body, mainly eliminated through non-renal or non-hepatic pathways [26].

To summary, in this study, we confirmed the effectiveness and safety of colistin therapy through a retrospective study of severe pneumonia patients who were considered to have CRE infection in our hospital. Of course, some lacking existed. One thing is that this study is a single center study with a small sample size, which may have significant bias. In addition, prospective studies with large samples and multiple centers are needed for further validation.

Table Legend

Table 1. Clinical characteristics of patients with different colistin schemes.

Table 2. Univariate and multivariate analysis of different treatment regimens and 28-day disease-related mortality after discharge.

Table 3. Comparison of blood biochemical indicators before and after the use of colistin.

Data availability statement

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding author.

Author contributions

LSY and HP conceived and designed the study and took responsibility for the integrity of the data and the accuracy of the data analysis. All authors collected the data and had full access to all the data in the study. All authors critically revised the manuscript for important intellectual content and gave final approval for the version to be published.

Fundings

This work was supported by the Chongqing Talents Project (cstc2021ycjh-bgzxm0150), the General Program of Chongqing Natural Science Foundation (CSTB2022NSCQ-MSX0901, China), the Chongqing Medical Scientific Research Project（Grant No.2024WSJK011）and Kuanren Talents Program of the Second Affiliated Hospital of Chongqing Medical University (kryc-yq-2204, China).

Ethic statement

This study was approved by the Ethics Committee of the second affiliated hospital of Chongqing Medical University in accordance with the principles stated in the Declaration of Helsinki. And written informed consent was provided by the patient to have the case details included in this article.

Conflicts of interest

The authors have declared no conflict of interest.

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Tables 1 to 4 are available in the Supplementary Files section.

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Colistin sulfate is effective and safe in the treatment of severe pneumonia patients with CRE resistance: a retrospective cohort study

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