A pilot clinical risk model to predict polymyxin-induced nephrotoxicity: a real-world, retrospective cohort study.

OBJECTIVES: Polymyxin-induced nephrotoxicity (PIN) is a major safety concern and challenge in clinical practice, which limits the clinical use of polymyxins. This study aims to investigate the risk factors and to develop a scoring tool for the early prediction of PIN. METHODS: Data on critically ill patients who received intravenous polymyxin B or colistin sulfate for over 24 h were collected. Logistic regression with the least absolute shrinkage and selection operator (LASSO) was used to identify variables that are associated with outcomes. The eXtreme Gradient Boosting (XGB) classifier algorithm was used to further visualize factors with significant differences. A prediction model for PIN was developed through binary logistic regression analysis and the model was assessed by temporal validation and external validation. Finally, a risk-scoring system was developed based on the prediction model. RESULTS: Of 508 patients, 161 (31.6%) patients developed PIN. Polymyxin type, loading dose, septic shock, concomitant vasopressors and baseline blood urea nitrogen (BUN) level were identified as significant predictors of PIN. All validation exhibited great discrimination, with the AUC of 0.742 (95% CI: 0.696-0.787) for internal validation, of 0.708 (95% CI: 0.605-0.810) for temporal validation and of 0.874 (95% CI: 0.759-0.989) for external validation, respectively. A simple risk-scoring tool was developed with a total risk score ranging from -3 to 4, corresponding to a risk of PIN from 0.79% to 81.24%. CONCLUSIONS: This study established a prediction model for PIN. Before using polymyxins, the simple risk-scoring tool can effectively identify patients at risk of developing PIN within a range of 7% to 65%.

Acute kidney injury with intravenous colistin sulfate compared with polymyxin B in critically ill patients: A real-world, retrospective cohort study.

BACKGROUND: Polymyxins have re-emerged as a last-resort therapeutic option for infections caused by carbapenem-resistant gram-negative bacteria. Nephrotoxicity induced by polymyxins is a significant limitation of its use in the clinic. Polymyxin B and colistin sulfate are two widely used active formulations of polymyxins. However, there is a lack of studies conducting a comparative assessment of nephrotoxicity between the two formulations. This study aimed to compare the nephrotoxicity of polymyxin B and colistin sulfate in critically ill patients. METHODS: We conducted a retrospective cohort study among critically ill patients who received intravenous polymyxin B or colistin sulfate for over 48 h from January 2017 to January 2024. The primary outcome was the incidence of acute kidney injury (AKI) associated with polymyxins, and the secondary outcome was 30-day all-cause mortality. Additionally, the risk factors of polymyxins-induced AKI and 30-day all-cause mortality were identified by Cox proportional hazard regression analysis. RESULTS: A total of 473 patients were included in this study. The overall incidence of AKI was significantly higher in patients who received polymyxin B compared to those who received colistin sulfate in the unmatched cohort (20.8% vs. 9.0%, p = 0.002) and in the propensity score matching cohort (21.1% vs. 7.0%, p = 0.004), respectively. However, there was no significant difference in 30-day all-cause mortality between the two groups. Polymyxin type, septic shock, and concomitant use of vasopressors were identified as independent risk factors for polymyxin-induced AKI. CONCLUSIONS: The prevalence of AKI was higher among patients who received polymyxin B compared to those treated with colistin sulfate. However, there was no significant difference in 30-day all-cause mortality between the two groups. Further prospective, multicenter studies with larger sample sizes are needed to validate these findings.

Polymyxin B-induced Bartter syndrome.

Bartter syndrome is a genetic disorder characterised by chloride-unresponsive metabolic alkalosis, hypokalaemia, hypomagnesaemia and hypercalciuria. While it commonly presents antenatally or in early infancy, sometimes, drugs can induce a state similar to Bartter syndrome in any age group, called acquired Bartter syndrome. Polymyxins and aminoglycosides are the most commonly implicated drugs. Polymyxin B and polymyxin E (popularly known as colistin) are the two chemically similar polymyxins that are commonly used clinically. While colistin is frequently associated with nephrotoxicity, polymyxin B is generally considered less nephrotoxic. This difference is due to the way these two drugs are handled by the kidneys. In this case report, we discuss a middle-aged male who developed Bartter syndrome due to polymyxin B, which resolved on discontinuation of the drug, and re-appeared after its re-introduction later. This case exemplifies the nephrotoxicity caused by polymyxin B and the need for vigilance when using this drug.

Acute kidney injury associated with colistin sulfate vs. polymyxin B sulfate therapy: A real-world, retrospective cohort study.

OBJECTIVE: To compare the incidence of acute kidney injury (AKI) in patients treated with colistin sulfate (CS) and polymyxin B sulfate (PMB). METHODS: Sociodemographic and laboratory measures of adult patients who received intravenous CS or PMB for at least 72 h for the first time at the study hospital from October 2021 to November 2022 were collected retrospectively. The primary outcome was the incidence of AKI, defined by the Kidney Diseases Improving Global Outcomes criteria. The secondary outcome was 30-day mortality. RESULTS: In total, 109 patients were included in the CS cohort and 176 patients were included in the PMB cohort. The incidence of AKI was significantly higher in the PMB cohort compared with the CS cohort (50.6% vs. 18.3%; P<0.001). On multi-variate analysis, CS therapy [hazard ratio (HR) 0.275; P<0.001] was an independent protective factor for AKI, along with higher estimated glomerular filtration rate. Nevertheless, 30-day mortality was similar in the PMB and CS cohorts (21.6% vs. 13.8%; P=0.099). Multi-variate analyses revealed that CS therapy was not associated with 30-day mortality (HR 0.968; P=0.926), while intensive care unit admission, combination with meropenem, Charlson score and stage 3 AKI were independent risk factors for 30-day mortality. After balancing the baseline characteristics of patients using propensity score matching, the main results were unchanged. CONCLUSION: The incidence of AKI was significantly lower in the CS cohort compared with the PMB cohort. However, 30-day mortality was similar in the two cohorts.

Battle of polymyxin induced nephrotoxicity: Polymyxin B versus colistin.

OBJECTIVES: Nephrotoxicity is the most serious and common adverse effect that limits the use of polymyxins. This study compared polymyxin E (colistin) and polymyxin B regarding drug-related nephrotoxicity. METHODS: This study was conducted as a retrospective cohort study in a university hospital between January 2020 and July 2022. Patients older than 18 years and who received colistin or polymyxin B were identified using electronic hospital records. Kidney disease improving global outcome criteria were used for assessing nephrotoxicity. RESULTS: A total of 190 patients, 95 in both groups, were evaluated. The incidence of acute kidney injury during the treatment was higher in the colistin group [52.6% (n = 50) and 34.7% (n = 33), P = 0.013]. In patients who were exposed to high-dose, the rate of nephrotoxicity was higher in patients receiving colistin [25% (n = 3) vs. 76.9% (n = 10); P = 0.017]. Nephrotoxicity was reversible in 64.4% (n = 38) of patients and the reversibility rate was similar (70% and 52.6% for colistin and polymyxin; P = 0.248). In the multivariable analysis, colistin treatment [odds ratio (OR): 3.882, 95% confidence interval (95% CI) = (1.829-8.241)], concomitant vasopressor use (OR = 2.08, CI: 1.036-4.179), and age (OR=1.036, CI: 1.014-1.058) were found to be independent markers of nephrotoxicity. CONCLUSION: Nephrotoxicity was more common in patients receiving high-dose colistin than polymyxin B. Therefore, the use of appropriate doses of colistin is important in terms of preventing nephrotoxicity. In addition, advancing age and concomitant use of vasopressors contribute to polymyxin-related nephrotoxicity.

Efficacy and nephrotoxicity of polymyxin B in elderly patients with carbapenem resistant bacterial infection.

BACKGROUND: To study the efficacy and nephrotoxicity of polymyxin B in the treatment of elderly patients with carbapenem-resistant organism (CRO) infection. METHODS: The clinical and microbiological data of patients with CRO-infected sepsis treated with polymyxin B were retrospectively analyzed. The effective rate, bacterial clearance, incidence and recovery rate of acute renal injury (AKI) and prognosis-related indicators in AKI at different stages were compared. RESULTS: The effective rate of 215 elderly patients with CRO infection treated with polymyxin was 50.7%. The total bacterial clearance rate was 44.2%, the total incidence of AKI was 37.2%, the recovery rate of AKI was 35%, and the incidence range of polymyxin B-related AKI was 10.2-37.2%. Logistic multivariate regression analysis showed that the predictors of AKI in elderly patients were high APACHE II score, long duration of polymyxin, chronic renal insufficiency and ineffective outcome; the ROC curve showed that the cutoff value for predicting AKI was a serum creatinine concentration of 73 mmol/L before polymyxin B use, and the AUC was 0.931. CONCLUSIONS: Rational use of polymyxin B is safe and effective in elderly patients with CRO infection, and its effective outcome can improve the recovery rate of AKI.

Hyperpigmentation on head and neck caused by polymyxin B: A rare case.

Polymyxin B was widely used to treat drug-resistant gram-negative bacteria and showed a better antibacterial effect. However, it is associated with some side effects. It should be remembered that polymyxin B may cause hyperpigmentation, albeit rare. This is a case report of a 68-year-old male patient who developed hyperpigmentation following treatment of a chest infection with polymyxin B. He was a known patient with chronic kidney diasease and chronic obstructive pulmonary disease followed up in the intensive care unit due to acute exacerbation of COPD. Later, polymyxin B treatment was started due to the development of pneumonia caused by the multidrug-resistant Acinetobacter baumannii. On the second day of polymyxin B treatment, hyperpigmentation developed in the face and neck region. The fact that the patient had chronic kidney disease possibly facilitated the development of skin hyperpigmentation due to the cumulative effect of polymyxin B. Hyperpigmentation which a rare side effect of polymyxin B may occur in those with underlying kidney disease.

Colistin versus polymyxin B: A pragmatic assessment of renal and neurological adverse effects and effectiveness in multidrug-resistant Gram-negative bacterial infections.

OBJECTIVES: Our study aimed to evaluate the real-world data on renal and neurological adverse effects and effectiveness of colistimethate sodium (CMS) and polymyxin B (PMB). MATERIALS AND METHODS: An observational prospective study was performed on inpatients receiving CMS and PMB for multidrug-resistant Gram-negative bacterial infections. CMS dose was titrated to renal function, and serum creatinine was assessed daily. The incidence of nephrotoxicity, the primary outcome, was evaluated based on an increase in serum creatinine from baseline as well as by the Risk, Injury, Failure, Loss of kidney function, and End-stage renal disease criteria. Neurological adverse effects were assessed based on clinical signs and symptoms, and the causality and severity were assessed by the Naranjo scale and modified Hartwig-Siegel scale, respectively. The effectiveness of polymyxin therapy was ascertained by a composite of microbiological eradication of causative bacteria and achievement of clinical cure. Thirty-day all-cause mortality was also determined. RESULTS: Between CMS and PMB, the incidence of nephrotoxicity (59.3% vs. 55.6%, P = 0.653) or neurotoxicity (8.3% vs. 5.6%, P = 0.525) did not significantly differ. However, reversal of nephrotoxicity was significantly more with patients receiving CMS than PMB (48.4% vs. 23.3%, P = 0.021). Favorable clinical outcomes (67.6% vs. 37%, P < 0.001) and microbiological eradication of causative bacteria (73.1% vs. 46.3%, P = 0.001) were significantly more with CMS than PMB. Patients treated with CMS had lower all-cause mortality than those with PMB treatment (19.4% vs. 42.6%, P = 0.002). CONCLUSION: There is no significant difference in the incidence of renal and neurotoxic adverse effects between CMS and PMB when CMS is administered following renal dose modification. CMS shows better effectiveness and lower mortality compared to PMB.

Mid-dosing interval concentration is important for polymyxin B exposure and acute kidney injury in critically ill patients.

This study aimed to evaluate the association between polymyxin B (PMB) exposure and acute kidney injury (AKI) and analyze the risk factors for PMB-induced AKI in critically ill patients. Plasma concentrations of PMB were determined using an ultraperformance liquid chromatography-tandem mass spectrometer in intensive care unit patients who were administered PMB. Univariate and multivariate analyses were conducted to identify risk factors. A receiver operating characteristic curve was constructed to assess the discriminant power of the factors and to identify the cutoff value for AKI. The white blood cell count and estimated area under the concentration-time curve (AUC) of patients administered PMB were independent risk factors for PMB-induced AKI, where AUC were calculated using a first-order pharmacokinetic equation based on the mid-dosing interval concentration (C1/2t ) and peak concentration. The area under the receiver operating characteristic curve of the final model was 0.805 (95% confidence interval, 0.690-0.921). The cutoff value for the combined predictor was 0.57. Alternatively, when using C1/2t , which was strongly correlated with AUC, as the only independent risk factor, the analysis showed that the 3.47 µg/ml threshold provides favorable differentiation between the AKI and non-AKI groups. These results provide insightful information for therapeutic drug monitoring-guiding PMB dosing in clinical practice.

Zileuton ameliorates aminoglycoside and polymyxin-associated acute kidney injury in an animal model.

OBJECTIVES: Aminoglycosides and polymyxins are antibiotics with in vitro activity against MDR Gram-negative bacteria. However, their clinical use is hindered by dose-limiting nephrotoxicity. The objective of this project was to determine if zileuton can reduce nephrotoxicity associated with amikacin and polymyxin B in a rat model of acute kidney injury. METHODS: Sprague Dawley rats (n = 10, both genders) were administered either amikacin (300 mg/kg) or polymyxin B (20 mg/kg) daily for 10 days. Zileuton (4 and 10 mg/kg) was delivered intraperitoneally 15 min before antibiotic administration. Blood samples were collected at baseline and daily to determine serum creatinine concentration. Nephrotoxicity was defined as a ≥2× elevation of baseline serum creatinine. Time-to-event analysis and log rank test were used to compare the onset of nephrotoxicity in different cohorts. Histopathological analysis was also conducted to characterize the extent of kidney injury. RESULTS: Animals receiving amikacin or polymyxin B alone had nephrotoxicity rates of 90% and 100%, respectively. The overall rate was reduced to 30% in animals receiving adjuvant zileuton. The onset of nephrotoxicity associated with amikacin and polymyxin B was also significantly delayed by zileuton at 4 and 10 mg/kg, respectively. Histopathology confirmed reduced kidney injury in animals receiving amikacin concomitant with zileuton. CONCLUSIONS: Our pilot data suggest that zileuton has the potential to attenuate nephrotoxicity associated with last-line antibiotics. This would allow these antibiotics to treat MDR Gram-negative bacterial infections optimally without dose-limiting constraints. Further studies are warranted to optimize drug delivery and dosing in humans.

[Efficacy and safefy of Polymyxin B treatment for neutropenic patients suffering from refractory Gram-negative bacterial bloodstream infection].

Objective: To assess the efficacy and safety of polymyxin B in neutropenic patients with hematologic disorders who had refractory gram-negative bacterial bloodstream infection. Methods: From August 2021 to July 2022, we retrospectively analyzed neutropenic patients with refractory gram-negative bacterial bloodstream infection who were treated with polymyxin B in the Department of Hematology of the First Affiliated Hospital of the Soochow University between August 2021 to July 2022. The cumulative response rate was then computed. Results: The study included 27 neutropenic patients with refractory gram-negative bacterial bloodstream infections. Polymyxin B therapy was effective in 22 of 27 patients. The median time between the onset of fever and the delivery of polymyxin B was 3 days [interquartile range (IQR) : 2-5]. The median duration of polymyxin B treatment was 7 days (IQR: 5-11). Polymyxin B therapy had a median antipyretic time of 37 h (IQR: 32-70). The incidence of acute renal dysfunction was 14.8% (four out of 27 cases), all classified as "injury" according to RIFLE criteria. The incidence of hyperpigmentation was 59.3%. Conclusion: Polymyxin B is a viable treatment option for granulocytopenia patients with refractory gram-negative bacterial bloodstream infections.

Population pharmacokinetics of polymyxin B in patients with liver dysfunction.

AIMS: Polymyxin B (PMB) is widely used to treat infections caused by multidrug-resistant Gram-negative pathogens. Currently, the pharmacokinetic data of PMB in patients with liver dysfunction are limited. This study aimed to develop a population pharmacokinetic (PopPK) model of PMB in patients with liver dysfunction and identify the factors affecting PMB pharmacokinetics. METHODS: We conducted a retrospective pharmacokinetic study involving 136 adults with different levels of liver function. Nonlinear mixed effects modelling was used to develop a PopPK model of PMB. Monte Carlo simulation was used to design PMB dosage schedules across various liver and renal functions. RESULTS: PMB pharmacokinetic analyses included 401 steady-state concentrations in 136 adult patients. A one-compartment pharmacokinetic model with first-order absorption and elimination was used to describe the data. The typical population value of PMB clearance was 2.43 L/h and the volume of distribution was 23.11 L. This study revealed that creatinine clearance (CrCL) and Child-Pugh class were significantly associated with PMB pharmacokinetic parameters; however, clinically relevant variations of dose-normalized drug exposure were not significant. For patients with a minimum inhibitory concentration of ≤0.5 mg/L, the appropriate dose was 40-75 mg/12-h. When the dose exceeded 100 mg/12-h, the risk of nephrotoxicity increased significantly. CONCLUSIONS: This study provided PMB pharmacokinetic information for patients with liver dysfunction. Patients with renal and liver dysfunctions may not require an initial dose adjustment. Rather than PopPK-guided dose adjustment, therapeutic drug monitoring of PMB plays a more direct role in optimizing dosing regimens based on its therapeutic window.

Polymyxin B-related neurotoxicity: a brief case report.

Polymyxin B and colistin are considered the last therapeutic option to treat infections caused by highly drug-resistant bacteria. However, their administration may lead to various adverse effects such as nephrotoxicity, neurotoxicity, and allergic reactions. The current case report presents the clinical manifestation of polymyxin B-associated neurotoxicity in a female patient with no chronic illness history. The patient was rescued from under rubble during an earthquake. She was diagnosed with an intra-abdominal infection caused by Acinetobacter baumannii (A. baumannii) After the initiation of the polymyxin B infusion, the patient developed numbness and tingling sensations in her hands, face, and head. On discontinuing polymyxin B and starting colistimethate, the patient's symptoms improved. Therefore, healthcare professionals should be aware of the potential risk factors associated with neurotoxicity in patients receiving polymyxin B. On identifying such symptoms treatment should be discontinued promptly to prevent further neurological damage.

Clinical outcomes and safety of intravenous polymyxin B-based treatment in critically ill patients with carbapenem-resistant Acinetobacter baumannii nosocomial pneumonia.

OBJECTIVES: Polymyxin B (PMB)-based therapy is one of the most important treatments for patients with nosocomial pneumonia caused by carbapenem-resistant Acinetobacter baumannii (CRAB). However, the optimal PMB-based combination regimen has not been well documented. METHODS: In this retrospective study, 111 critically ill patients in the intensive care unit with CRAB nosocomial pneumonia who received intravenous PMB-based therapy between 1 January 2018 and 1 June 2022 were included. The primary outcome was all-cause mortality within 28 days. Cox proportional hazards regression was used to explore risk factors for mortality in the enrolled patients treated with PMB-based regimens and the three most frequent combination regimens. RESULTS: PMB + sulbactam (SB) regimen was significantly associated with a decreased risk of mortality (aHR = 0.10, 95% CI 0.03-0.39; P = 0.001). The proportion of low-dose PMB in PMB + SB regimen (79.2%) was higher than in PMB + carbapenem (61.9%) or tigecycline (50.0%) regimens. In contrast, PMB + carbapenem regimen significantly increased mortality (aHR = 3.27, 95% CI 1.47-7.27; P = 0.004). Although the proportion of high-dose PMB in PMB + tigecycline (17.9%) was higher than in the other two regimens, mortality remained highest (42.9%) and serum creatinine increased significantly. CONCLUSIONS: PMB in combination with SB may be a promising treatment option for patients with CRAB-induced nosocomial pneumonia, as mortality was significantly reduced with low-dose PMB and no increased risk of nephrotoxicity was observed.

Comparative study of polymyxin B and colistin sulfate in the treatment of severe comorbid patients infected with CR-GNB.

BACKGROUND: With the difficulties in choosing colistin sulfate and polymyxin B sulfate (PBS) for carbapenem-resistant gram-negative bacteria (CR-GNB), we compared the efficacy and safety of these two old polymyxins in treatment of critically ill patients infected with CR-GNB infection. METHODS: One hundred four patients infected with CR-GNB in ICU were retrospectively grouped by PBS (68 patients) or colistin sulfate (36 patients). Clinical efficacy including symptoms, inflammatory parameters, defervescence, prognosis and microbial efficacy were analyzed. Hepatotoxicity, nephrotoxicity, and hematotoxicity were evaluated by TBiL, ALT, AST, creatinine, and thrombocytes. RESULTS: Demographic characteristics between colistin sulfate and PBS were not significantly different. Most of the CR-GNB were cultured in respiratory tract (91.7% vs 86.8%), and almost all were polymyxin-sensitive (98.2% vs 100%, MIC ≤ 2 µg/ml). The microbial efficacy in colistin sulfate (57.1%) was significantly higher than PBS (30.8%) (p = 0.022), however, no significant difference in clinical success was seen in both groups (33.8% vs 41.7%), as well as mortality, defervescence, imaging remission, days in the hospital, microbial reinfections, and prognosis, and almost all patients defervesce within 7 days (95.6% vs 89.5%). CONCLUSIONS: Both polymyxins can be administrated in critically ill patients infected with CR-GNB and colistin sulfate is superior to PBS in microbial clearance. These results highlight the necessity of identifying CR-GNB patients who may benefit from polymyxin and who are at higher risk of mortality.

Melatonin for prevention of acute kidney injury in patients treated with intravenous polymyxin B: a double-blind, placebo-controlled randomized clinical trial.

OBJECTIVES: To evaluate the effect of melatonin versus placebo on the incidence of acute kidney injury (AKI) in patients treated with polymyxin B. METHODS: We performed a single-centre, double-blind, randomized clinical trial (NCT03725267) of 30-mg oral melatonin versus placebo for patients treated with intravenous polymyxin B. Patients aged ≥18 years receiving polymyxin B for ≤48 hours were eligible. Melatonin or placebo pills were administered until the end of polymyxin B treatment or for a maximum of 14 days. The main outcome was any level of AKI. RESULTS: Eighty-eight patients were randomized: 44 in the melatonin group and 44 in the placebo group. The study ended prematurely because of polymyxin B shortage during the COVID-19 pandemic. The patients' mean age was 63.6 ± 17.3 years, and 60.2% of the patients were men. Forty-six (52.3%, 23 in each group) patients developed AKI during the follow-up period. The incidence rate of AKI was 81.9/1000 and 77.4/1000 patients per day in melatonin and placebo groups, respectively (hazard ratio, 1.09; 95% CI, 0.61-1.94; p 0.78). Renal failure and 30-day mortality were similar between the groups. Moreover, the incidence of AKI was not different in pre-specified sub-groups. DISCUSSION: Melatonin initiated in the first 48 hours of therapy did not reduce the incidence of AKI in patients treated with polymyxin B.