Clinical Efficacy and Safety of Colistin Sulfate in the Treatment of Carbapenem-Resistant Organism Infections in Patients with Hematological Diseases

This observational, retrospective, single-center clinical study was performed at the Hospital of Suzhou Hongci Hematology, Suzhou, Jiangsu Province, China. Data concerning patients treated with colistin sulfate in our hospital between April 2022 and January 2023 were reviewed. This study was approved by the Ethics Committee of the Hospital of Suzhou Hongci Hematology and was exempt from informed consent because of its observational nature. Furthermore, the study was implemented in accordance with the Declaration of Helsinki (as revised in 2013).

The primary outcomes of the study were clinical efficacy, microbial response, 30-day all-cause mortality, and the incidence of adverse events at discontinuation. Secondary outcomes were factors associated with the therapeutic efficacy of colistin sulfate.

Adult patients were considered eligible if they: (1) were diagnosed with a hematological disease (including malignant hematology and aplastic anemia); (2) had a positive culture for CRO or high suspicion of CRO infection. The diagnosis of CRO infection was made by two clinicians based on culture of CRO from sterile or eligible specimens and high suspicion of CRO infection based on the patient’s clinical symptoms, signs, and laboratory findings, such as fever pattern and inflammatory indicators, despite the absence of positive pathogenic bacterial culture results; (3) had completed clinical data; (4) had received colistin sulfate treatment for ≥ 72 h, either alone or in combination with other antimicrobials. Patients were excluded if they were: (1) under 18 years of age; (2) allergic to the study drug; (3) co-infected with any gram-positive bacteria; (4) died within 48 h after treatment; (5) had incomplete clinical data; (6) had severe organ damage (renal and/or hepatic dysfunction grade > 2 according to the Common Terminology Criteria for Adverse Events [version 5.0]).

Patient data collection was based on the electronic medical record system of our hospital. It mainly includes basic demographic characteristics: age, gender, type of hematological disease, hematopoietic stem cell transplantation status, site of infection, distribution of pathogens, infection index, exposure to antimicrobial therapy, clinical and microbiological responses, adverse reactions, and survival status, etc.

All patients in this study were treated with intravenous colistin sulfate (colistin sulfate for injection, Shanghai SPH New Asia Pharmaceutical Co. Ltd., Shanghai, China) for ≥ 72 h at a dose of 1.0–1.5 million IU per day, divided into 2–3 intravenous doses. Clinicians administered colistin sulfate in accordance with the drug package insert, the national consensus on the optimal clinical use of the polymyxins in China [24], as well as adverse reactions and in the context of the patient’s disease progression.

The clinical effectiveness of colistin sulfate treatment was evaluated by clinical and microbiological criteria at the time of drug discontinuation. Patients received multiple courses of colistin sulfate treatment, whereas only the first course of therapy was evaluated. Clinical efficacy was defined as the recovery from symptoms and signs at the end of colistin sulfate treatment, while clinical failure was defined as the aggravation or persistence of symptoms and signs during treatment.

CRO strains were isolated from body fluid specimens of enrolled patients, including sputum, alveolar lavage fluid, and blood. The pathogenic bacteria were extracted and identified through matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. In addition, when there was clinical suspicion of infection in a critically or seriously ill patient, or when empirical treatment had not been effective for 3 days, pathogen metagenomic next-generation sequencing (mNGS) was used for bacterial identification and detection of drug resistance genes in pathogens [25]. In vitro antimicrobial susceptibility testing was performed according to the Clinical and Laboratory Standards Institute (CLSI) guidelines (M100), using the micro-broth dilution method. The results for carbapenems, aminoglycosides, quinolones, fosfomycin, tigecycline, and aztreonam were interpreted according to CLSI breakpoints. Clinical breakpoint reference for colistin susceptibility testing was according to the United States Committee on Antimicrobial Susceptibility Testing (USCAST) (S ≤ 2 mg/l, R ≥ 4 mg/l) [26, 27]. Bacterial clearance was considered a clinically favorable outcome. However, the absence of the above microbiological responses or persistent detection of the same causative pathogens was defined as invalid.

Adverse events associated with colistin sulfate were closely monitored, including nephrotoxicity, hepatotoxicity, and neurotoxicity. The renal and liver functions were evaluated on the day before and after treatment with colistin sulfate. Increased creatinine (Cr) was calculated by subtracting the creatinine level prior to the commencement of colistin sulfate treatment from the post-treatment creatinine level. Renal impairment was assessed according to the Kidney Disease: Improving Global Outcomes (KDIGO) criteria [28]. Neurotoxicity was evaluated according to CTCAE (version 5.0).

SPSS22.0 software was used for statistical analyses (IBM Corp. in Armonk, NY, USA). Data are presented as n (%), mean ± SD, or median (range). Student’s t-tests were performed for continuous variables between groups. The χ² or Fisher’s exact tests were performed for categorical variables. Variables with a p-value < 0.05 in the univariate analysis were enrolled in the multivariate logistic regression model for further analysis. The Kaplan-Meier curve was used to demonstrate the survival probability. A two-tailed p-value < 0.05 indicates a significant difference.

Patients who received colistin sulfate treatment between April 2022 and January 2023 were enrolled. Of 193 patients screened for eligibility, 118 were included in the final analysis based on the inclusion and exclusion criteria (Fig. 1). We summarized the patient demographic and clinical characteristics to describe the overall population. The mean age of these patients was 43.92 ± 15.82 years, including 52 (44.1%) females and 66 (55.9%) males. The most common hematological disease was acute myeloid leukemia (49.2%), followed by acute lymphoblastic leukemia (22.0%), myelodysplastic syndrome (18.6%), and aplastic anemia (10.2%). Among them, 81 (68.6%) patients received allogeneic hematopoietic stem cell transplantation, and 37 (31.4%) received chemotherapy.

All patients were diagnosed with CRO infections, and the most common site of infection was the lung (58.5%), followed by bloodstream (39.8%) and intestinal tract (15.3%). Among them, multiple sites of infection were seen in 21 (17.8%) of the patients. CRKP (28%) was the most commonly monitored CRO in sterile specimens, followed by CRAB (25.4%) and CRPA (20.3%). In addition, there were other CRE (33.1%) infections such as Enterobacter cloacae and Escherichia coli. Of the 118 patients, 33.1% were infected with more than one CRO pathogens.

Overall, 118 patients received colistin sulfate at doses of 1.0–1.5 million IU/day for a mean treatment duration of 12.75 ± 5.91 (range 4–30) days. The total mean cumulative dose was 17.58 ± 8.70 million IU. Only nine (7.6%) patients were treated with a loading dosage of colistin sulfate at 1.5 million IU. Twenty-one (17.8%) patients received colistin sulfate treatment for no more than 7 days, 61 (51.7%) for 8–14 days, and 36 (30.5%) for > 14 days. Only nine (7.6%) patients received colistin sulfate monotherapy. Forty (33.9%) patients received colistin sulfate combined with one other antibacterial agent, 55 patients (46.6%) with 2, and 14 patients (11.9%) with 3 or more other antibacterial agents. Antibacterial agents used in combination with colistin sulfate included carbapenems, aminoglycosides, quinolones, fosfomycin, tigecycline, aztreonam, etc. (Table 1).

Based on the clinical response outcomes after colistin sulfate treatment, all patients and relevant variables were categorized into clinically effective and ineffective groups. The key demographic and clinical characteristics and clinical outcomes of these patients are presented below in Table 1. Overall, clinical response was achieved by 88 (74.6%) patients, and 30 (25.4%) patients were considered treatment failure. There were no significant differences between the clinically effective and ineffective groups (all p > 0.05) in terms of age, weight, gender, hematopoietic disease type, hematopoietic stem cell transplantation status, infection sites, and CRO types. Compared to the ineffective group, patients in the clinically effective group had a significantly longer course of treatment (13.73 vs. 9.90 days; p = 0.005) and received a higher cumulative dose of colistin sulfate (18.58 ± 7.89 vs. 14.67 ± 10.35 million IU, p = 0.033). A daily dose of 1.5 million IU/day was significantly more likely with favorable efficacy than that of 1.0 million IU/day (60.2% vs. 39.8%, p = 0.029). Compared to those treated for ≤ 7 days, a longer duration of > 7 days had a significantly higher efficacy rate (88.4% vs. 11.4, p  = 0.002). Multiple comparisons of subgroups with different treatment durations showed that a treatment duration of 8–14 days or > 14 days was more advantageous in efficacy than that of a treatment duration of > 7 days (all p < 0.05). However, there was no significant difference in efficacy between treatments with a duration of 8–14 days and > 14 days (Fig. 2A). Compared with the clinically ineffective group, patients in the clinically effective group who were treated with colistin sulfate in combination with other antibiotics had a significantly higher clinical response rate than that of monotherapy (p = 0.016). Multiple comparisons of subgroups with different medications showed that the efficacy of colistin sulfate in combination with one or two antibacterial agents was superior to that of colistin sulfate monotherapy, but it was not when combined with three antibacterial agents (Fig. 2B).

The changes in clinical parameters were evaluated before and after colistin sulfate treatment. Overall, all monitored clinical infection-associated indicators were improved after colistin sulfate treatment, with neutrophil counts and platelet levels significantly increased (p < 0.05), and C-reaction protein (CRP) and procalcitonin (PCT) levels significantly decreased (p < 0.05). Compared to baseline, an increase in creatinine (Cr) was observed after colistin sulfate administration, suggesting that colistin sulfate treatment might impair renal function. However, the level of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) did not change significantly, suggesting that colistin sulfate did not affect liver function (p > 0.1) (Fig. 3).

Multivariate logistic regression was used to analyze all above variables that showed significant differences and potentially affected the colistin treatment efficacy. The treatment course (p = 0.031; OR = 2.980; 95% CI 1.107–8.019) and combination with other antibacterial agents (p = 0.012; OR = 3.009; 95% CI 1.276–7.095) were identified factors that were significantly associated with the treatment effectiveness of colistin sulfate. These suggest that the treatment duration of colistin sulfate and co-medication with other antibacterial agents, rather than the daily dose of colistin sulfate and transplant status, might affect the curative effect (Fig. 4).

Twenty-seven patients died within 30 days, with an overall 30-day all-cause mortality of 22.9%. Compared to the ineffective group, patients in the clinically effective group had significantly lower 30-day mortality (8.0% vs. 66.7%, χ² = 43.71, p < 0.001) (Fig. 5).

Overall, nephrotoxicity was observed in nine (7.6%) cases and neurotoxicity in three cases (2.5%). The incidence of these adverse events was comparable between the clinically effective and ineffective groups, with incidences of nephrotoxicity of 5.7% and 13.3% (p = 0.221) and neurotoxicity of 5.7% and 13.3% (p = 0.159), respectively (Table 1). These nine patients developed renal impairment within 4–7 days after drug administration, of which seven patients experienced a gradual decrease in creatinine after discontinuation of colistin sulfate and two died the next day of acute renal failure caused by septic shock. Three patients with neurotoxicity were relieved 2 days after discontinuation of colistin sulfate (not shown in Table 1). Treatment with colistin sulfate was safe and well tolerated.