Inhibition of ABI2 ubiquitination-dependent degradation suppresses TNBC cell growth via down-regulating PI3K/Akt signaling pathway.

Triple negative breast cancer (TNBC) is a type of cancer that lacks receptor expression and has complex molecular mechanisms. Recent evidence shows that the ubiquitin-protease system is closely related to TNBC. In this study, we obtain a key ubiquitination regulatory substrate-ABI2 protein by bioinformatics methods, which is also closely related to the survival and prognosis of TNBC. Further, through a series of experiments, we demonstrated that ABI2 expressed at a low level in TNBC tumors, and it has the ability to control cell cycle and inhibit TNBC cell migration, invasion and proliferation. Molecular mechanism studies proved E3 ligase CBLC could increase the ubiquitination degradation of ABI2 protein. Meanwhile, RNA-seq and IP experiments indicated that ABI2, acting as a crucial factor of tumor suppression, can significantly inhibit PI3K/Akt signaling pathway via the interaction with Rho GTPase RAC1. Finally, based on TNBC drug target ABI2, we screened and found that FDA-approved drug Colistimethate sodium(CS) has significant potential in suppressing the proliferation of TNBC cells and inducing cell apoptosis, making it a promising candidate for impeding the progression of TNBC.

The first spectrofluorimetric approach for quantification of colistin sulfate and its prodrug colistimethate sodium in pharmaceutical dosage form and human plasma.

A new, accurate, nonextractive, and sensitive fluorimetric approach was proposed and validated for the first time estimation of colistin sulfate and its inactive prodrug colistimethate sodium in its bulk form, pharmaceutical formulations, and human plasma. The approach relied on condensation between acetylacetone/formaldehyde and the primary amino moiety of nonfluorescent colistin in Teorell and Stenhagen buffer (pH 2.8) by the Hantzsch reaction to form a highly fluorescent dihydropyridine derivative. The fluorescent product was measured at 460 nm (λex  = 402 nm). A plot of relative fluorescence intensity (RFI) versus concentration was rectilinear over the range 200-4000 ng ml-1 with excellent correlation (r) and determination (r2 ) coefficients of 0.9999 and 0.9998, respectively. The limit of detection (LOD) and limit of quantitation (LOQ) were 40.91 and 123.99 ng ml-1 , respectively. The present procedure was useful for determination of colistin sulfate either in powder form for suspension or in its parenteral prodrug colistimethate sodium in vial formulation. The investigated approach was applied for in vitro quantification of this drug in spiked human plasma, with a per cent mean recovery of 98.24 ± 1.34. The proposed method is reliable, selective, and does not require tedious sample pretreatment steps, expensive instrumentation, or harmful reagents, all of which make it ideally suited for use in quality control laboratories.

Assessment of colistimethate sodium (COLOBREATHE) risk minimization measures implemented in the European Union: A cross-sectional study.

PURPOSE: To assess the effectiveness of additional risk minimization measures (aRMMs) implemented in Europe for colistimethate sodium (CMS) among healthcare professionals (HCPs) and patients/caregivers following safety concerns regarding incorrect use of CMS delivered via Turbospin inhaler. METHODS: A cross-sectional study was conducted among HCPs and patients/caregivers in Austria, Denmark, France, Germany, The Netherlands, and the United Kingdom between September 2016 and March 2018. Knowledge of the educational materials was assessed regarding common side effects, correct use of CMS and Turbospin inhaler, and capsule breakage. Awareness, receipt, and utilization of the aRMMs were also evaluated. RESULTS: Among 124 HCPs surveyed, the majority acknowledged awareness (86.2%), receipt (91.0%), and utilization (81.6%) of the CMS educational materials and were knowledgeable about the common CMS side effects (93.2%). Most HCPs correctly answered most questions regarding the proper use of CMS (>90%), yet only half knew how to correctly use the Turbospin inhaler (53.2%). Knowledge about capsule breakage was moderate (67.5%). Of the 29 patients/caregivers surveyed, almost half were aware of the educational materials (48.1%); of these, 69.2% received and used the materials. Most patients/caregivers were knowledgeable about the common CMS side effects (81.5%) and proper CMS use (>85%); however, knowledge about correct Turbospin inhaler use and potential for capsule breakage was moderate to low (48.1% and 37.9%, respectively). CONCLUSIONS: HCPs and patients/caregivers have good knowledge about the common side effects associated with CMS. However, knowledge of correct use of the Turbospin inhaler and capsule breakage was moderate to low.

Clinical and subclinical acute kidney injury in multidrug-resistant septic patients treated with colistimethate sodium: Incidence and clinical outcomes.

AIM: Colistimethate sodium (CMS) has been postulated as the principal cause of high incidence of clinical acute kidney injury (AKI) in multidrug-resistance (MDR) septic patients with normal baseline serum creatinine (sCr) who were treated with CMS. This prospective observational study was conducted to examine the incidence and clinical outcomes of clinical and subclinical AKI in MDR septic patients receiving CMS. METHODS: Forty-two MDR septic patients with normal sCr who required CMS were included. Clinical AKI was diagnosed by increased sCr levels according to the KDIGO2012 criteria while subclinical AKI was identified by elevated levels of urinary neutrophil gelatinase-associated lipocalin (uNGAL > 150 ng/mL) or urinary liver-type fatty-acid-binding protein (uL-FABP > 10.5 ng/mL). RESULTS: Clinical AKI was noted in 47.6% of patients on day 5 and 38.1% on day 7 after initiating CMS. By using uL-FABP, subclinical AKI was observed in 45.2% and 54.8% on day 5 and 7, respectively. At baseline prior to CMS treatment, subclinical AKI was already present in 90%. The baseline uL-FABP was superior to the baseline uNGAL in early prediction of clinical AKI on day 5. The subclinical AKI patients had comparable worse outcomes as clinical AKI patients. CONCLUSION: The incidence of subclinical AKI in MDR septic patients before CMS treatment was extremely high. The baseline uL-FABP provided the best predictive capacity of clinical AKI. The causes of clinical AKI might include the persistence of sepsis process, subclinical AKI and CMS nephrotoxicity. Proper management of subclinical AKI patients before CMS initiation should be concerned to prevent further renal damage and improve patient and renal outcomes.

Dry powder inhaler of colistimethate sodium for lung infections in cystic fibrosis: optimization of powder construction.

Colistimethate sodium (CMS) for treatment of lung infections in cystic fibrosis patient was transformed into a dry powder for inhalation by spray drying. Design of Experiment was applied for understanding the role of the spray-drying process parameters on the critical quality attributes of the CMS spray-dried (SD) powders and agglomerates thereof. Eleven experimental SD microparticle powders were constructed under different process conditions according to a central composite design. The SD microparticles were then agglomerated in soft pellets. Eleven physico-chemical characteristics of SD CMS microparticle powders or agglomerates thereof were selected as critical quality attributes. The yield of SD process was higher than 75%. The emitted fraction of agglomerates from RS01 inhaler was 75-84%, and the fine particle fraction (particles <5 µm) was between 58% and 62%. The quality attributes of CMS SD powders and respective agglomerates that were significantly influenced by spray-drying process parameters were residual solvent and drug content of the SD microparticles as well as bulk density and respirable dose of the agglomerates. These attributes were also affected by the combination of the process variables. The air aspiration rate was found as the most positively influential on drug and solvent content and respirable dose. The residual solvent content significantly influenced the powder bulk properties and aerodynamic behavior of the agglomerates, i.e. quality attributes that govern drug metering in the device and the particles lungs deposition. Agglomerates of CMS SD microparticles, in combination with RS01 DPI, showed satisfactory results in terms of dose emitted and fine particle fraction.

Interaction of Bacterial Phenazines with Colistimethate in Bronchial Epithelial Cells.

Multidrug-resistant bacterial infections are being increasingly treated in clinics with polymyxins, a class of antibiotics associated with adverse effects on the kidney, nervous system, or airways of a significant proportion of human and animal patients. Although many of the resistant pathogens display enhanced virulence, the hazard of cytotoxic interactions between polymyxin antibiotics and bacterial virulence factors (VFs) has not been assessed, to date. We report here the testing of paired combinations of four Pseudomonas aeruginosa VF phenazine toxins, pyocyanin (PYO), 1-hydroxyphenazine (1-HP), phenazine-1-carboxylic acid (PCA), and phenazine-1-carboxamide (PCN), and two commonly prescribed polymyxin drugs, colistin-colistimethate sodium (CMS) and polymyxin B, in three human airway cell lines, BEAS-2B, HBE-1, and CFT-1. Cytotoxicities of individual antibiotics, individual toxins, and their combinations were evaluated by the simultaneous measurement of mitochondrial metabolic, total transcriptional/translational, and Nrf2 stress response regulator activities in treated cells. Two phenazines, PYO and 1-HP, were cytotoxic at clinically relevant concentrations (100 to 150 µM) and prompted a significant increase in oxidative stress-induced transcriptional activity in surviving cells. The polymyxin antibiotics arrested cell proliferation at clinically achievable (<1 mM) concentrations as well, with CMS displaying surprisingly high cytotoxicity (50% effective dose [ED50] = 180 µM) in BEAS-2B cells. The dose-response curves were probed by a median-effect analysis, which established a synergistically enhanced cytotoxicity of the PYO-CMS combination in all three airway cell lines; a particularly strong effect on BEAS-2B cells was observed, with a combination index (CI) of 0.27 at the ED50 PCA, PCN, and 1-HP potentiated CMS cytotoxicity to a smaller extent. The cytotoxicity of CMS could be reduced with 10 mM N-acetyl-cysteine. Iron chelators, while ineffective against the polymyxins, could rescue all three bronchial epithelial cell lines treated with lethal PYO or CMS-PYO doses. These findings suggest that further evaluations of CMS safety are needed, along with a search for means to moderate potentially cytotoxic interactions.

Microbiota in Exhaled Breath Condensate and the Lung.

The lung microbiota is commonly sampled using relatively invasive bronchoscopic procedures. Exhaled breath condensate (EBC) collection potentially offers a less invasive alternative for lung microbiota sampling. We compared lung microbiota samples retrieved by protected specimen brushings (PSB) and exhaled breath condensate collection. We also sought to assess whether aerosolized antibiotic treatment would influence the lung microbiota and whether this change could be detected in EBC. EBC was collected from 6 conscious sheep and then from the same anesthetized sheep during mechanical ventilation. Following the latter EBC collection, PSB samples were collected from separate sites within each sheep lung. On the subsequent day, each sheep was then treated with nebulized colistimethate sodium. Two days after nebulization, EBC and PSB samples were again collected. Bacterial DNA was quantified using 16S rRNA gene quantitative PCR. The V2-V3 region of the 16S rRNA gene was amplified by PCR and sequenced using Illumina MiSeq. Quality control and operational taxonomic unit (OTU) clustering were performed with mothur. The EBC samples contained significantly less bacterial DNA than the PSB samples. The EBC samples from anesthetized animals clustered separately by their bacterial community compositions in comparison to the PSB samples, and 37 bacterial OTUs were identified as differentially abundant between the two sample types. Despite only low concentrations of colistin being detected in bronchoalveolar lavage fluid, PSB samples were found to differ by their bacterial compositions before and after colistimethate sodium treatment. Our findings indicate that microbiota in EBC samples and PSB samples are not equivalent.IMPORTANCE Sampling of the lung microbiota usually necessitates performing bronchoscopic procedures that involve a hospital visit for human participants and the use of trained staff. The inconvenience and perceived discomfort of participating in this kind of research may deter healthy volunteers and may not be a safe option for patients with advanced lung disease. This study set out to evaluate a less invasive method for collecting lung microbiota samples by comparing samples taken via protected specimen brushings (PSB) to those taken via exhaled breath condensate (EBC) collection. We found that there was less bacterial DNA in EBC samples compared with that in PSB samples and that there were differences between the bacterial communities in the two sample types. We conclude that while EBC and PSB samples do not produce equivalent microbiota samples, the study of the EBC microbiota may still be of interest.

Efficacy and Safety of a Colistin Loading Dose, High-Dose Maintenance Regimen in Critically Ill Patients With Multidrug-Resistant Gram-Negative Pneumonia.

INTRODUCTION: Emergence of multidrug-resistant (MDR) gram-negative (GN) pathogens and lack of novel antibiotics have increased the use of colistin, despite unknown optimal dosing. This study aimed to evaluate the safety and efficacy of a colistin loading dose, high-dose (LDHD) maintenance regimen in patients with MDR-GN pneumonia. METHODS: A retrospective cohort analysis was performed comparing critically ill patients with MDR-GN pneumonia pre- and postimplementation of a colistin LDHD guideline with a primary outcome of clinical cure. Safety was assessed using incidence of acute kidney injury (AKI) based on RIFLE (risk, injury, failure, loss, end-stage renal disease) criteria. RESULTS: Seventy-two patients met the inclusion criteria (42 preimplementation and 30 postimplementation). Clinical cure was achieved in 23 (55%) patients in the preimplementation group and 20 (67%) patients in the postimplementation group ( P = .31). AKI occurred in 50% of the patients during the preimplementation period and 58% during the postimplementation period ( P = .59) with no difference in initiation rates of renal replacement therapy. CONCLUSION: The increased clinical cure rate after implementation of the colistin LDHD guideline did not reach statistical significance. The LDHD guideline, however, was not associated with an increased incidence of AKI, despite higher intravenous colistin doses. Opportunity exists to optimize colistin dosage while balancing toxicity, but larger studies are warranted.

The 21st-century challenge to neurocritical care: the rise of the superbug Acinetobacter baumannii. A meta-analysis of the role of intrathecal or intraventricular antimicrobial therapy in reduction of mortality.

OBJECTIVE Neurosurgical infections due to multidrug-resistant organisms have become a nightmare that neurosurgeons are facing in the 21st century. This is the dawn of the so-called postantibiotic era. There is an urgent need to review and evaluate ways to reduce the high mortality rates due to these infections. The present study evaluates the efficacy of combined intravenous plus intrathecal or intraventricular (IV + IT) therapy versus only intravenous (IV) therapy in treating postneurosurgical Acinetobacter baumannii infections. METHODS The authors performed a meta-analysis of all peer-reviewed studies from the PubMed, Cochrane Library database, ScienceDirect, and EMBASE in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Five studies were finally included in the present analysis: 126 patients were studied who had postneurosurgical A. baumannii infection. The Cochrane collaboration tool was used to evaluate risk of bias, and a test of heterogeneity was performed. The I2 statistic was calculated. The patients were divided into 2 groups: the IV group received only intravenous therapy and the IV + IT group received both intravenous and intrathecal or intraventricular antimicrobial therapy. The outcome was mortality attributed specifically to A. baumannii infection in postneurosurgical cases. The pooled data were analyzed using the Cochran-Mantel-Haenszel method in a fixed-effects model. RESULTS The total number of patients in the IV-only group was 73, and the number of patients in the IV + IT group was 53. The mean duration of intravenous therapy was 27 days. The mean duration of intrathecal colistin was 21 days. The intravenous dose of colistin ranged from 3.75 to 8.8 MIU per day. The dose of intrathecal colistin ranged between 125,000 and 250,000 IU per day. The overall calculated odds ratio for mortality for the IV + IT group after pooling the data was 0.16 (95% CI 0.06-0.40, p < 0.0001). The patients who received IV + IT therapy had an 84% lower risk of dying due to the infection compared with those who received only IV therapy. CONCLUSIONS There is an 84% lower risk of mortality in patients who have been treated with combined intrathecal or intraventricular plus intravenous antimicrobial therapy versus those who have been treated with intravenous therapy alone. The intrathecal or intraventricular route should be strongly considered when dealing with postneurosurgical multidrug-resistant A. baumannii infections.

Colistin-associated Acute Kidney Injury in Severely Ill Patients: A Step Toward a Better Renal Care? A Prospective Cohort Study.

BACKGROUND: Critically ill patients with severe sepsis or septic shock may need relatively high colistin daily doses for efficacy against multidrug-resistant and extensively drug-resistant gram-negative rods. However, acute kidney injury (AKI) may represent a major dose-limiting adverse effect of colistin. We sought to determine AKI occurrence and to identify factors influencing AKI risk in severely ill patients receiving colistin according to a recently proposed dosing strategy. METHODS: A prospective, observational, cohort study involving patients with severe sepsis or septic shock who received colistin was performed. AKI was defined according to Acute Kidney Injury Network criteria. Colistin administration was driven by a modified pharmacokinetics-pharmacodynamics (PK/PD)-based dosing approach. RESULTS: Of 70 patients who received colistin at a median daily dose of 9 million IU (MIU; interquartile range, 5.87-11.1 MIU), 31 (44%) developed AKI. In univariate analysis, age, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA), score and baseline renal impairment were significantly associated with AKI. Moreover, patients with AKI were less frequently treated with adjuvant ascorbic acid (P = .003). In multivariate analysis, independent predictors of AKI were baseline renal impairment (adjusted hazard ratio, 4.15; 95% confidence interval, 1.9-9.2; P < .001) and age (1.03; 1.0-1.05; P = .028), whereas a strong independent renal-protective role emerged for ascorbic acid (0.27; .12-.57; P < .001). CONCLUSIONS: In severely ill patients receiving colistin according to a PK/PD-driven dosing approach, baseline renal impairment and older age strongly predict AKI occurrence, but concomitant administration of ascorbic acid markedly reduces AKI risk, allowing safer use of colistin.

Radiolabeling and preclinical evaluation of technetium-99m labeled colistin.

INTRODUCTION: Antibiotic resistance is a burden on the healthcare system. In present study, we have labeled an antibiotic named Colistimethate sodium (CMS) with technetium-99m (99mTc) to develop a SPECT based imaging tracer. METHODS: We standardised the labeling using 0.5-2 mg of CMS (in water) using stannous chloride dihydrate as a reducing agent followed by addition of 370 ± 74 MBq of 99mTc. A group of mice were injected intravenously (in tail vein) with 4-6 MBq of [99mTc]Tc-CMS diluted with saline and euthanized at various time intervals. microSPECT Imaging (ϒ-eye) was acquired to study the biodistribution in the healthy mice. RESULTS: We standardised the labeling using 0.5 mg of colistin in 0.5 ml of saline with addition of 30 µg stannous chloride dihydrate. The retention factor value was 0.1-0.3 as compared to 0.9-1.0 for free 99mTc by TLC and retention time was found to be 14.2 ± 1.3 min as evaluated by HPLC. The biodistribution data showed uptake in lungs, spleen, and liver at 30 min but the uptake decreased in lung at 60 min. The imaging data corroborated with the biodistribution data. CONCLUSIONS: We could successfully label [99mTc]Tc-CMS 99mTc and we could study its biodistribution in healthy mice.

Colistin utilization at a tertiary hospital in South Africa: an opportunity for antimicrobial stewardship practices.

Introduction. Colistin (polymyxin E) has emerged as a last-resort treatment option for multidrug-resistant infections.Hypothesis/Gap Statement. Studies on the use, safety and efficacy of colistin in South Africa are limited.Aim. This study aims to describe the use of colistin and its clinical outcomes at a tertiary public hospital in South Africa.Methodology. We conducted a retrospective review of adult and paediatric patients who received parenteral colistin between 2015 and 2019.Results. A total of 69 patients (26 adults, 13 children and 30 neonates) were reviewed. Acinetobacter baumannii was the most common causative pathogen isolated (70.1 %). Colistin was predominately used to treat septicaemia (75.4 %). It was primarily administered as definitive therapy (71.0 %) and as monotherapy (56.5 %). It was used in 11.5 % of adults with infections susceptible to other antibiotics. Loading doses of intravenous colistin were administered in only 15 (57.7 %) adult patients. Neurotoxicity and nephrotoxicity occurred in 5.8 % and 43.5 % of patients, respectively. Clinical cure was achieved in 37 (53.6 %) patients. On multivariate logistic regression analysis, adults [adjusted odds ratio (aOR), 25.54; 95 % CI, 2.73-238.65; P < 0.01] and children (aOR, 8.56; 95 % CI, 1.06-69.10; P < 0.05) had higher odds of death than neonates.Conclusion. The study identified significant stewardship opportunities to improve colistin prescription and administration. Achieving optimal patient outcomes necessitates a multidisciplinary approach and vigilant monitoring of colistin use.

Ceftazidime/avibactam combined with colistimethate sodium successfully cures carbapenem-resistant Pseudomonas aeruginosa-induced brain abscess in a child post-craniotomy: a case report.

The treatment of brain abscess induced by carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a clinical challenge around the world. Apart from novel ß-lactam/ß-lactamase inhibitors and polymyxins, there are few sufficiently powerful antibiotics that are effective against CRPA-induced infections. Considering the blood-brain barrier factor, there are even fewer drugs that can be used to treat intracranial CRPA-induced infections. In this article, we reported a case of CRPA-induced brain abscess that was successfully treated with intravenous ceftazidime/avibactam and intrathecal colistimethate sodium in a child after intracranial tumor resection.

Efficacy of Tamoxifen Metabolites in Combination with Colistin and Tigecycline in Experimental Murine Models of Escherichia coli and Acinetobacter baumannii.

This study aimed to evaluate the potential of tamoxifen and N-desmethyltamoxifen metabolites as therapeutic agents against multidrug-resistant Escherichia coli and Acinetobacter baumannii, using a repurposing approach to shorten the time required to obtain a new effective treatment against multidrug-resistant bacterial infections. Characterisation and virulence studies were conducted on E. coli (colistin-susceptible C1-7-LE and colistin-resistant MCR-1+) and A. baumannii (tigecycline-susceptible Ab#9 and tigecycline-resistant Ab#186) strains. The efficacy of the metabolite mix (33.3% each) and N-desmethyltamoxifen in combination with colistimethate sodium (CMS) or tigecycline was evaluated in experimental models in mice. In the pneumonia model, N-desmethyltamoxifen exhibited significant efficacy against Ab#9 and both E. coli strains, especially E. coli MCR-1+ (-2.86 log10 CFU/g lungs, -5.88 log10 CFU/mL blood, and -50% mortality), and against the Ab#186 strain when combined with CMS (-2.27 log10 CFU/g lungs, -2.73 log10 CFU/mL blood, and -40% mortality) or tigecycline (-3.27 log10 CFU/g lungs, -4.95 log10 CFU/mL blood, and -50% mortality). Moreover, the metabolite mix in combination with both antibiotics decreased the bacterial concentrations in the lungs and blood for both A. baumannii strains. In the sepsis model, the significant efficacy of the metabolite mix was restricted to the colistin-susceptible E. coli C1-7-LE strain (-3.32 log10 CFU/g lung, -6.06 log10 CFU/mL blood, and -79% mortality). N-desmethyltamoxifen could be a new therapeutic option in combination with CMS or tigecycline for combating multidrug-resistant GNB, specifically A. baumannii.

Intrapulmonary and Systemic Pharmacokinetics of Colistin Following Nebulization of Low-Dose Colistimethate Sodium in Patients with Ventilator-Associated Pneumonia Caused by Carbapenem-Resistant Acinetobacter baumannii.

Colistimethate sodium (CMS) nebulization is associated with reduced systemic toxicity compared to intravenous injection, with potentially enhanced clinical efficacy. This study aimed to assess the pharmacokinetic (PK) properties of colistin during low-dose CMS nebulization in patients with ventilator-associated pneumonia (VAP) caused by carbapenem-resistant Acinetobacter baumannii. A nonlinear mixed-effects modeling approach was applied to develop population PK models for colistin in both epithelial lining fluid (ELF) and plasma. Twenty patients participated, and 80 ELF and 100 plasma samples were used for model development. Median colistin concentrations measured in ELF were 614-fold, 408-fold, and 250-fold higher than in plasma at 1, 3, and 5 h, respectively. Time courses in both ELF and plasma were best described by a one-compartment model with a Weibull absorption process. When the final model was simulated, the maximum free concentration and area under the free colistin concentration-time curve at steady state over 24 h in the plasma were approximately 1/90 and 1/50 of the corresponding values in ELF at steady state, respectively. For an A. baumannii MIC of 1 mg/L, inhaling 75 mg of CMS at 6 h intervals was deemed appropriate, with dose adjustments needed for MICs exceeding 2 mg/L. Using a nebulizer for CMS resulted in a notably higher exposure of colistin in the ELF than plasma, indicating the potential of nebulization to reduce systemic toxicity while effectively treating VAP.

Higher incidence of acute kidney injury with intravenous colistimethate sodium compared with polymyxin B in critically ill patients at a tertiary care medical center.

Nephrotoxicity was assessed in 173 critically ill patients receiving intravenous colistin or polymyxin B; it occurred in 60.4% and 41.8%, respectively. Further investigation is necessary to elucidate the reason for the difference in nephrotoxicity observed between the groups and to assess the impact of severity of illness and dosing/administration.

The Prevalence and Risk Factors of Acute Kidney Injury during Colistin Therapy: A Retrospective Cohort Study from Lebanon.

INTRODUCTION: The current study aimed to determine the prevalence, risk factors, and stages of severity of acute kidney injury (AKI) caused by colistimethate sodium (CMS) treatment in patients diagnosed with systemic antibiotic-resistant Gram-negative bacterial infections. The predictors of all-cause mortality in this patient population were also examined. METHODS: This retrospective cohort study included patients who were admitted to a university-affiliated hospital and acute tertiary care referral center in Beirut, Lebanon between January 2015 and December 2018 and underwent CMS treatment for a period of 48 h or more. RESULTS: The study sample included 298 adult patients, of which 46.3% (n = 138/298) developed AKI (assessed using the Kidney Disease Improving Global Outcomes (KDIGO) criteria). Of these, 37.7% (n = 51/138) were diagnosed with stage 1 AKI, 23.9% with stage 2 (n = 33/138), and 38.4% with stage 3 (n = 53/138). Nephrotoxicity was reversed in 87.5% of AKI patients who survived until hospital discharge. Independent risk factors for AKI included patient age ≥ 75 years (aOR = 1.854; 95% CI: 1.060-3.241; p-value = 0.03); underlying chronic kidney disease (aOR = 4.849; 95% CI: 2.618-9.264; p-value < 0.0001); and concomitant use of vasopressors (aOR = 4.305; 95% CI: 2.517-7.456; p-value < 0.0001). Multivariate analysis showed that the predictors of severe AKI (stage 2 or 3) included baseline hypoalbuminemia (aOR = 2.542; 95% CI: 1.000-6.564; p-value = 0.05); concomitant use of vasopressors (aOR = 6.396; 95% CI: 2.741-15.87; p-value < 0.0001); and CMS days of therapy (DOT) prior to development of AKI ≥ 7 days (aOR = 4.728; 95% CI: 2.069-11.60; p-value < 0.0001). All-cause mortality was recorded in 51.3% of patients (n = 153/298), and this was significantly higher in patients with AKI (76.8%; n = 106/138) compared to those without (29.4%; n = 47/160; OR = 7.964; 95% CI: 4.727-13.417; p-value < 0.0001). Independent predictors of all-cause mortality included a baseline Charlson comorbidity index score ≥5 (aOR = 4.514; 95% CI: 2.443-8.530; p-value < 0.0001); concomitant use of vasopressors (aOR = 7.76; 95% CI: 4.238-14.56; p-value < 0.0001); and CMS-induced AKI (aOR = 4.117; 95% CI: 2.231-7.695; p-value < 0.0001). CONCLUSIONS: The findings of this study suggest that old age, history of chronic kidney disease, and concomitant vasopressor treatment are all independent predictors of CMS-induced AKI. The risk of developing severe AKI significantly increases with CMS DOT. Understanding the risk factors of nephrotoxicity is essential for improving prognosis and treatment outcomes.

Colistin treatment in older adults: why should we know more?

OBJECTIVES: We aimed to investigate the risk factors of colistin-associated nephrotoxicity in patients older than 65 years treated in the palliative care unit. METHODS: 119 palliative care patients who received intravenous colistimethate for at least 7 days were included in the study. The estimated glomerular filtration rate (GFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) 2021 equation. Data were obtained from the hospital information system. RESULTS: The mean age of the participants was 76.7 ± 9.9 years and 49.4% were female. Of the 119 patients, 57 had colistin-induced nephropathy (CIN) according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria. The rate of CIN was higher in women than in men. The baseline phosphate level was higher in the CIN (+) group than in the CIN (-) group. The lower GFR values in patients with pneumonia persisted at days 14 and 30, whereas the lower GFR in patients without pneumonia did not. According to multivariate logistic regression, female gender and baseline phosphate level ≥ 4.5 mg/dl were found as independent variables for the development of nephropathy. CONCLUSIONS: The creatinine levels of the patients with pneumonia and CIN did not improve after nephrotoxicity, whereas the creatinine levels of the other patients without pneumonia and CIN did. Female gender and baseline phosphate were independent risk factors for CIN. Prolonged kidney failure may lead to a more difficult clinical follow-up process for clinicians. Therefore, clinicians should be aware of persistent renal insufficiency in older patients with pneumonia receiving colistimethate.

Prevention of colistin-induced neurotoxicity: a narrative review of preclinical data.

Polymyxin E or colistin is an effective antibiotic against MDR Gram-negative bacteria. Due to unwanted side effects, the use of this antibiotic has been limited for a long time, but in recent years, the widespread of MDR Gram-negative bacteria infections has led to its reintroduction. Neurotoxicity and nephrotoxicity are the significant dose-limiting adverse effects of colistin. Several agents with anti-inflammatory and antioxidant properties have been used for the prevention of colistin-induced neurotoxicity. This study aims to review the preclinical studies in this field to prepare guidance for future human studies. The data was achieved by searching PubMed, Scopus, and Google Scholar databases. All eligible pre-clinical studies performed on neuroprotective agents against colistin-induced neurotoxicity, which were published up to September 2023, were included. Finally, 16 studies (ten in vitro and eight in vivo) are reviewed. Apoptosis (in 13 studies), inflammatory (in four studies), and oxidative stress (in 14 studies) pathways are the most commonly reported pathways involved in colistin-induced neurotoxicity. The assessed compounds include non-herbal (e.g., ascorbic acid, rapamycin, and minocycline) and herbal (e.g., curcumin, rutin, baicalein, salidroside, and ginsenoside) agents. Besides these compounds, some other measures like transplantation of mitochondria and the use of nerve growth factor and mesenchymal stem cells could be motivating subjects for future research. Based on the data from experimental (in vitro and animal) studies, a combination of colistin with neuroprotective agents could prevent or decrease colistin-induced neurotoxicity. However, well-designed randomized clinical trials and human studies are essential for demonstrating efficacy.

Ceftazidime-Avibactam versus Colistin for the Treatment of Infections Due to Carbapenem-Resistant Enterobacterales: A Multicenter Cohort Study.

BACKGROUND: The aim of this study was to compare the safety and effectiveness of ceftazidime-avibactam (CAZ-AVI) to colistin-based regimen in the treatment of infections caused by carbapenem-resistant Enterobacterales (CRE). METHODS: This was a retrospective, multicenter, observational cohort study of inpatients who received either CAZ-AVI or intravenous colistin for treatment of infections due to CRE. The study was conducted in 5 tertiary care hospitals in Saudi Arabia. Main study outcomes included in-hospital mortality, clinical cure at end of treatment, and acute kidney injury (AKI). Univariate analysis and multivariate logistic regression model were conducted to assess the independent impact of CAZ-AVI on the clinical outcome. RESULTS: A total of 230 patients were included in this study: 149 patients received CAZ-AVI and 81 patients received colistin-based regimen. Clinical cure (71% vs 52%; P = 0.004; OR, 2.29; 95% CI, 1.31-4.01) was significantly more common in patients who received CAZ-AVI. After adjusting the difference between the two groups, treatment with CAZ-AVI is independently associated with clinical cure (adjusted OR, 2.75; 95% CI, 1.28-5.91). In-hospital mortality (35% vs 44%; P = 0.156; OR, 0.67; 95% CI, 0.39-1.16) was lower in patients who received CAZ-AVI but the difference was not significant. AKI (15% vs 33%; P = 0.002; OR, 0.37; 95% CI, 0.19-0.69) was significantly less common in patients who received CAZ-AVI. CONCLUSION: CAZ-AVI is associated with higher rate of clinical cure and lower rate of AKI compared to colistin. Our findings support the preferential use of CAZ-AVI over colistin-based regimen for treating these infections.