Colistin-induced Nephrotoxicity Research Articles

The power of trans-sodium crocetinate: exploring its renoprotective effects in a rat model of colistin-induced nephrotoxicity.

Colistin, a multidrug-resistant gram-negative bacterial infection medication, has been associated with renal impairment and failure. Trans-sodium crocetinate (TSC), a saffron-derived chemical recognized for its antioxidant and nephroprotective properties, was studied in this study to determine its potential to alleviate the nephrotoxic effects of colistin. Forty-two male Wistar rats were randomly classified into seven groups (n = 6): (1) control (normal saline, 12 days, i.p.), (2) colistin (22 mg/kg, 7 days, i.p.), (3-5) colistin + TSC (25, 50, and 100 mg/kg, 12 days, i.p., starting from 5 days before colistin), (6) TSC (100 mg/kg, 12 days, i.p.), (7) colistin + vitamin E (100 IU/kg, 12 days, i.p). On day 13, the rats were euthanized and the serum content of creatinine, BUN, Na+, and K+, as well as oxidative stress (GSH, MDA, SOD, CAT), inflammatory (IL-1β), apoptotic (Bax, Bcl-2, caspase-3, 8, 9), and autophagy (Beclin-1, LC3) markers, NGAL, and histopathological changes in the kidney were measured. Colistin significantly increased serum creatinine, BUN, MDA, IL-1β, caspase-3,8,9, Bax, Beclin-1, LC3, and NGAL levels in kidney tissue. It also caused inflammation, focal necrosis of tubular epithelial cells, protein cast, and acute tubular necrosis. Furthermore, colistin decreased SOD, CAT, GSH, and Bcl-2 levels. TSC and vitamin E administration along with colistin restored most of the alterations induced by colistin. Overall, it could be concluded that colistin induces oxidative stress, inflammation, autophagy, and apoptosis, which can cause kidney injury. However, TSC can also be used as a therapeutic agent to reduce injuries caused by colistin.

Machine learning algorithms to predict colistin-induced nephrotoxicity from electronic health records in patients with multidrug-resistant Gram-negative infection

ObjectivesColistin-induced nephrotoxicity prolongs hospitalisation and increases mortality. The study aimed to construct machine learning models to predict colistin-induced nephrotoxicity in patients with multidrug-resistant Gram-negative infection. MethodsPatients receiving colistin from three hospitals in the Clinical Research Database were included. Data were divided into a derivation cohort (2011–2017) and a temporal validation cohort (2018–2020). Fifteen machine learning models were established by categorical boosting, light gradient boosting machine and random forest. Classifier performances were compared by the sensitivity, F1 score, Matthews correlation coefficient (MCC), area under the receiver operating characteristic (AUROC) curve, and area under the precision-recall curve (AUPRC). SHapley Additive exPlanations plots were drawn to understand feature importance and interactions. ResultsThe study included 1392 patients, with 360 (36.4%) and 165 (40.9%) experiencing nephrotoxicity in the derivation and temporal validation cohorts, respectively. The categorical boosting with oversampling achieved the highest performance with a sensitivity of 0.860, an F1 score of 0.740, an MCC of 0.533, an AUROC curve of 0.823, and an AUPRC of 0.737. The feature importance demonstrated that the days of colistin use, cumulative dose, daily dose, latest C-reactive protein, and baseline haemoglobin were the most important risk factors, especially for vulnerable patients. A cutoff colistin dose of 4.0 mg/kg body weight/d was identified for patients at higher risk of nephrotoxicity. ConclusionsMachine learning techniques can be an early identification tool to predict colistin-induced nephrotoxicity. The observed interactions suggest a modification in dose adjustment guidelines. Future geographic and prospective validation studies are warranted to strengthen the real-world applicability.

Genetic predisposition and high exposure to colistin in the early treatment period as independent risk factors for colistin-induced nephrotoxicity.

Colistin is known to cause nephrotoxicity due to its extensive reabsorption and accumulation in renal tubules. Invitro studies have identified the functional role of colistin transporters such as OCTN2, PEPT2, megalin, and P-glycoprotein. However, the role of these transporter gene variants in colistin-induced nephrotoxicity has not been studied. Utilizing targeted next-generation sequencing, we screened for genetic polymorphisms covering the colistin transporters (SLC15A1, SLC15A2, SLC22A5, LRP2, and ABCB1) in 42 critically ill patients who received colistimethate sodium. The genetic variants rs2257212 ((NM_021082.4):c.1048C>G) and rs13397109 ((NM_004525.3):C.7626C > T) were identified as being associated with an increased incidence of acute kidney injury (AKI) on Day 7. Colistin area under the curve (AUC) was predicted using a previously published pharmacokinetic model of colistin. Using logistic regression analysis, the predicted 24-h AUC of colistin was identified as an important contributor for increased odds of AKI on Day 7. Among 42 patients, 4 (9.5%) were identified as having high predisposition to colistin-induced AKI based on the presence of predisposing genetic variants. Determination of the presence of the abovementioned genetic variants and early therapeutic drug monitoring may reduce or prevent colistin-induced nephrotoxicity and facilitate dose optimization of colistimethate sodium.

Risk factors and prognosis for the development of acute kidney injury in patients using colistin in the intensive care unit: A retrospective cohort study.

Colistin, an antibiotic of polymyxin group, has recently been increasingly used in the treatment of multidrug resistant gram-negative bacteria. However, it has serious adverse effects such as acute kidney injury (AKI). We aimed to determine the factors affecting the development of AKI due to colistin, which has serious adverse effects, such as nephrotoxicity and neurotoxicity. We retrospectively analyzed the data of patients who received colistin for multidrug resistant gram-negative sepsis in adult intensive care units between January 2020 and December 2022. Demographic data, blood test results, concomitant drug use, need for renal replacement therapy, and mortality were recorded. Kidney damage was assessed according to the Kidney Disease Improving Global Outcomes criterion. We obtained data from 103 patients, 45 (43.7%) of whom were women. The most common comorbidity was a neurological disorder. Renal damage developed in 59.2% of patients. Renal replacement was required in 50.8% of the patients. Among patients who received colistin, 64.1% died. The use of vasopressors, diuretics, nephrotoxic agents with colistin, advanced age, and hypoalbuminemia were more common in patients with renal injury. Multivariate regression analysis showed that vasopressor use, prior creatinine elevation, and diuretic use were independent risk factors for colistin-induced AKI. Vasoactive agent use, previous kidney injury, and furosemide use were independent risk factors for colistin-induced nephrotoxicity. Considering these factors may be instructive for better monitoring of patients when colistin is required in intensive care units.

Renoprotective effects of crocin against colistin-induced nephrotoxicity in a rat model.

Colistin is used to treat multidrug-resistant gram-negative bacterial infections. It increases the membrane permeability of kidney cells, leading to kidney toxicity. Crocin, a carotenoid found in saffron, has anti-oxidant and nephroprotective properties. The present study aimed to explore the potential renoprotective effects of crocin against colistin-induced nephrotoxicity. Six groups of male Wistar rats were utilized: 1- Control (0.5 ml of normal saline, 10 days, IP); 2- Crocin (40 mg/kg, 10 days, IP); 3-Colistin (23 mg/kg, 7 days, IP); 4-6 Colistin (23 mg/kg, 7 days, IP)+ crocin (10, 20, 40 mg/kg, 10 days, IP). On day 11, rats were sacrificed and their blood and kidney samples were collected to measure creatinine, blood urea nitrogen (BUN), glutathione (GSH) levels, malondialdehyde (MDA), and histopathological alterations. Colistin caused a significant increase in BUN, creatinine, and MDA, and a decrease in GSH compared to the control group. It also led to congested blood vessels, glomerular shrinkage, and medullary tubular degeneration. Co-administration of crocin with colistin resulted in a significant decrease in BUN and creatinine, increased GSH levels, and ameliorated the histopathological alterations compared to the colistin group. No significant difference was found between the control group and the crocin (40 mg/kg) group. It might be suggested that colistin can induce kidney damage by inducing oxidative stress. However, crocin shows protective effects against colistin-induced renal injury by acting as an anti-oxidant. Hence, crocin can be used as a supplement to reduce tissue and biochemical damage caused by colistin injection.

Prostaglandin F2α analogue, bimatoprost ameliorates colistin-induced nephrotoxicity

Colistin (polymyxin E) is an antibiotic that is effective against multidrug-resistant gram-negative bacteria. However, the high incidence of nephrotoxicity caused by colistin limits its clinical use. To identify compounds that might ameliorate colistin-induced nephrotoxicity, we obtained 1707 compounds from the Korea Chemical Bank and used a high-content screening (HCS) imaging-based assay. In this way, we found that bimatoprost (one of prostaglandin F2α analogue) ameliorated colistin-induced nephrotoxicity. To further assess the effects of bimatoprost on colistin-induced nephrotoxicity, we used in vitro and in vivo models. In cultured human proximal tubular cells (HK-2), colistin induced dose-dependent cytotoxicity. The number of terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL)-positive cells, indicative of apoptosis, was higher in colistin-treated cells, but this effect of colistin was ameliorated by cotreatment with bimatoprost. The generation of reactive oxygen species, assessed using 2,7-dichlorodihydrofluorescein diacetate, was less marked in cells treated with both colistin and bimatoprost than in those treated with colistin alone. Female C57BL/6 mice (n = 10 per group) that were intraperitoneally injected with colistin (10 mg/kg/12 hr) for 14 days showed high blood urea nitrogen and serum creatinine concentrations that were reduced by the coadministration of bimatoprost (0.5 mg/kg/12 hr). In addition, kidney injury molecule-1 (KIM1) and Neutrophil gelatinase-associated lipocalin (NGAL) expression also reduced by bimatoprost administration. Further investigation in tubuloid and kidney organoids also showed that bimatoprost attenuated the nephrotoxicity by colistin, showing dose-dependent reducing effect of KIM1 expression. In this study, we have identified bimatoprost, prostaglandin F2α analogue as a drug that ameliorates colistin-induced nephrotoxicity.

Oral Melatonin for Colistin-induced Nephrotoxicity Reduction in Intensive Care Unit: A Randomized Placebo Controlled Clinical Trial

Background: Colistin is a drug of choice against multidrug-resistance (MDR) bacteria. The most important side effect of colistin is nephrotoxicity, observed in 20 - 54% of patients. According to the studies that examined its antioxidant effect, it can reduce the kidney toxicity of various drugs, including colistin. Objectives: This study aimed to investigate melatonin's effect on reducing colistin-induced kidney toxicity to use this drug with fewer complications. Methods: This double-blind, randomized clinical trials with two groups involved 56 critically ill adults infected by MDR bacteria. The intervention group received 3 mg of oral melatonin simultaneously with intravenous colistin, which continued until the end of the treatment. The control group received placebo orally with IV colistin. We measured urine volume, blood creatinine, and blood urea nitrogen (BUN) daily and determined the patients with renal failure using the KDIGO guideline. STATA software analyzed data with a P-value of less than 0.05 as the significance level. Results: Data obtained from recipients were analyzed for age (P-value = 0.357), gender (P-value = 0.945), weight (P-value = 0.438), APACHE score (P-value = 0.162). We did not observe significant difference in acute kidney injury (AKI) criteria between the two groups. Compared to the control group, melatonin did not decrease blood creatinine (P-value = 0.110) and BUN (P-value = 0.567) and, made no change of urinary volume (P-value = 0.913). There was no decrease in kidney failure in the intervention group compared to the control group. As a result, we did not find a significant difference in outcome of the two groups. Conclusions: We did not reveal any significant difference in the AKI criteria including blood creatinine, BUN, and daily urine volume with the addition of melatonin in participants receiving colistin; However, no complication was observed in the intervention group who received melatonin.

Comprehensive Assessment of Colistin Induced Nephrotoxicity: Incidence, Risk Factors and Time Course.

In recent years, the emergence of multidrug-resistant (MDR) microorganisms had caused the resurgence of colistin use after it was previously abandoned due to its side effects, nephrotoxicity in particular. However, the specific incidence of colistin-induced nephrotoxicity varies in reports with different populations. This study aims to assess the incidence of colistin-associated nephrotoxicity and the associated risk factors. This study was on 178 patients who received colistin for more than 48 hours during the years 2019-2022, who were followed up for 14 days after the initiation of colistin, and demographic and clinical data were gained from medical reports. Logistic regression was used to assess the relationship between nephrotoxicity and study variables. The incidence of nephrotoxicity was 44.9% (95% confidence interval (CI); 37% to 53%), and the overall mortality was 33%, with a significantly higher level among patients with nephrotoxicity. The significant risk factors for nephrotoxicity after adjustment were; higher weights (OR = 1.1, 95% CI; 0.03-1.2), P-value: 0.006, and the combination with carbapenem showed a significant protective effect (OR = 0.09, 95% CI; 0.01-0.8), P-value: 0.03. The severity, according to KDIGO classification, was stage 1 (47%), stage 2 (21%), and stage 3 (31%). Higher stages had earlier onset acute kidney injury, a lower percentage of returning to baseline, and exposure to a higher colistin dose. Colistin-induced nephrotoxicity was a frequent issue associated with higher weights, mitigated by the combination with carbapenems. While higher colistin dosages, and earlier onset AKI, were linked to the progression to higher AKI stages and the need for dialysis.

An Investigation on The Use of Colistin in Critically Ill Patients at A Teaching Hospital in Ho Chi Minh City

Colistin is reintroduced into therapeutic protocols as one of the last resort antibiotics against multidrug-resistant (MDR) pathogens. In February 2019, the International Consensus Guidelines (ICG 2019) on optimizing the administration of colistin has for the first time stipulated an official recommendation for higher colistin dosing regimen based on pharmacokinetic/pharmacodynamic (PK/PD) modeling data. This study aimed at assessing the current dosing of colistin at University Medical Center (UMC) of Ho Chi Minh City (HCMC) and to identify rates and risk factors of colistin-induced nephrotoxicity. A cross sectional study was conducted on patients admitted to Intensive Care Unit (ICU), being treated for severe infection with at least 5 days of colistin IV administration from April 2018 to April 2019. KDIGO criteria were used to evaluate nephrotoxicity during treatment. Colistin-resistance was detected in 4 cases during the study period. The majority (n=104, 87.4%) of patients was diagnosed with pneumonia due to mainly Acinetobacter baumannii. Rational dosing according to PK/PD approach, EMA, FDA was observed in 33 cases (27.8%), 39 cases (32,8%), and 44 cases (38,2%), respectively. 85 cases (71,4%) were evaluated as rational dosing in accordance with at least one of the three guidelines. Clinical efficacy was recorded in 59 infected patients (49.6%). Lower average maintenance dose was observed in patients with treatment failure (p = 0.002). KDIGO-defined acute kidney injury (AKI) developed in 70 patients (58,8%). Multivariate analysis showed that concomitant administration of vasopressors (OR = 16.52; 95% CI 5.3750.83; p = 0.001), furosemide (OR = 5.24; 95% CI 1.89–14.55; p = 0.001) and hypoalbuminemia (< 25 g/l) (OR = 6.24; 95% CI 2.17–17.93; p = 0.001) were significantly associated with nephrotoxicity. Consistent with previous studies, due to a very modest clinical cure rate with a high frequency of colistin-induced AKI and the development of colistin-resistant strains, alternative agents such as new beta-lactam/beta-lactamase inhibitor combinations with favourable safety data are strongly preferred for the treatment of carbapenem-resistant infection.

Modulation of miR-205/ EGLN2 by rosuvastatin mitigates colistin-induced nephrotoxicity in rats: Involvement of ATF4/ CHOP and Nrf2 pathways

Although the beneficial role of microRNA has been investigated thoroughly, the reno-protective role of microRNA-205 (miR-205) against colistin-induced nephrotoxicity has not yet been tackled. Hence, our study sought to study the possible modulatory effect of rosuvastatin on miR-205 and its downstream target, Egl-9 family hypoxia-inducible factor 2 (EGLN2) to combat oxidative and endoplasmic reticulum (ER) stresses as pivotal contributors to colistin-associated renal injury. Rats were randomly divided into four groups; normal, colistin (300 000 IU/Kg/day; i.p), colistin pretreated with rosuvastatin (10 mg/kg; p.o) and colistin pretreated with rosuvastatin (20 mg/kg; p.o) for 6 successive days. Pretreatment with rosuvastatin attenuated renal injury induced by colistin and enhanced kidney function with a marked reduction in renal injury markers, neutrophil gelatinase-associated lipocalin, and kidney injury molecule-1. Besides, rosuvastatin upregulated renal miR-205 expression and suppressed gene expression of EGLN2. In addition, it downregulated ER stress-related genes (activation transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP)) along with caspases 12 and 3. It also induced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) as detected by immunohistochemical examination besides increased renal antioxidants, reduced glutathione, and superoxide dismutase. In conclusion, rosuvastatin triggered a series of protective mechanisms against colistin-induced nephrotoxicity through modulating miR-205 and EGLN2 expression. Rosuvastatin suppressed ATF4/ CHOP trajectory and activated the Nrf2 pathway to substantiate its antioxidant and anti-apoptotic capacities.

Incidence and Risk Factors of Colistin-Induced Nephrotoxicity Associated with The International Consensus Guidelines for the Optimal Use of the Polymyxins: A Retrospective Study in a Tertiary Care Hospital, Saudi Arabia.

Background: Colistin is an effective therapy against multidrug-resistant gram-negative bacteria. However, nephrotoxicity is a major issue with its use. Objective: We aimed to evaluate the incidence and the potential risk factors of nephrotoxicity in colistin-treated patients. Methods: A retrospective cohort study was conducted. All adult patients aged 18 years and older who received colistin for ≥72 h were included in the study, while end-stage kidney disease patients requiring dialysis or had renal transplants were excluded. The incidence and severity of acute kidney injury (AKI) were assessed based on the Kidney Disease Improving Global Outcomes (KDIGO). Result: Out of 128 patients who received colistin, 51.56% of them have experienced AKI. The incidence was increased among oldest patients (above 80) and those who did not receive the appropriate dose (p-value = 0.0003). In addition, the median time until the AKI occurred was 10 days after receiving the colistin treatment. Rates of AKI in patients with previous AKI (71.7%) were three times higher than patients who did not previously experience AKI (HR = 2.97, 95% CI [1.8-4.8]). Conclusions: Nephrotoxicity is a significant issue among patients who receive colistin in the hospital, especially among older patients and those who did not receive the appropriate dose. As a result, healthcare providers should play a major role in colistin dosing, especially among the older adult population.

Prevalence of polymyxin-induced nephrotoxicity and its predictors in critically ill adult patients: A meta-analysis.

Polymyxin-induced nephrotoxicity is a major safety concern in clinical practice due to long-term adverse outcomes and high mortality. To conducted a systematic review and meta-analysis of the prevalence and potential predictors of polymyxin-induced nephrotoxicity in adult intensive care unit (ICU) patients. PubMed, EMBASE, the Cochrane Library and Reference Citation Analysis database were searched for relevant studies from inception through May 30, 2022. The pooled prevalence of polymyxin-induced nephrotoxicity and pooled risk ratios of associated factors were analysed using a random-effects or fixed-effects model by Stata SE ver. 12.1. Additionally, subgroup analyses and meta-regression were conducted to assess heterogeneity. A total of 89 studies involving 12234 critically ill adult patients were included in the meta-analysis. The overall pooled incidence of polymyxin-induced nephrotoxicity was 34.8%. The pooled prevalence of colistin-induced nephrotoxicity was not higher than that of polymyxin B (PMB)-induced nephrotoxicity. The subgroup analyses showed that nephrotoxicity was significantly associated with dosing interval, nephrotoxicity criteria, age, publication year, study quality and sample size, which were confirmed in the univariable meta-regression analysis. Nephrotoxicity was significantly increased when the total daily dose was divided into 2 doses but not 3 or 4 doses. Furthermore, older age, the presence of sepsis or septic shock, hypoalbuminemia, and concomitant vancomycin or vasopressor use were independent risk factors for polymyxin-induced nephrotoxicity, while an elevated baseline glomerular filtration rate was a protective factor against colistin-induced nephrotoxicity. Our findings indicated that the incidence of polymyxin-induced nephrotoxicity among ICU patients was high. It emphasizes the importance of additional efforts to manage ICU patients receiving polymyxins to decrease the risk of adverse outcomes.

The potential role of adjunctive ascorbic acid in the prevention of colistin-induced nephrotoxicity in critically ill patients: A retrospective study

BackgroundColistin is considered a valuable and last-resort therapeutic option for MDR gram-negative bacteria. Nephrotoxicity is the most clinically pertinent adverse effect of colistin. Vivo studies suggest that administering oxidative stress-reducing agents, such as ascorbic acid, is a promising strategy to overcome colistin-induced nephrotoxicity (CIN). However, limited clinical data explores the potential benefit of adjunctive ascorbic acid therapy for preventing CIN. Therefore, this study aims to assess the potential nephroprotective role of ascorbic acid as adjunctive therapy against CIN in critically ill patients. MethodThis was a retrospective cohort study at King Abdulaziz Medical City (KAMC) for all critically ill adult patients who received IV colistin. Eligible patients were classified into two groups based on the ascorbic acid use as concomitant therapy within three days of colistin initiation. The primary outcome was CIN odds after colistin initiation, while the secondary outcomes were 30-day mortality, in-hospital mortality, ICU, and hospital LOS. Propensity score (PS) matching was used (1:1 ratio) based on the patient’s age, SOFA score, and serum creatinine. ResultsA total of 451 patients were screened for eligibility; 90 patients were included after propensity score matching based on the selected criteria. The odds of developing CIN after colistin initiation were similar between patients who received ascorbic acid (AA) as adjunctive therapy compared to patients who did not (OR (95 %CI): 0.83 (0.33, 2.10), p-value = 0.68). In addition, the 30-day mortality, in-hospital mortality, ICU, and hospital LOS were similar between the two groups. ConclusionAdjunctive use of Ascorbic acid during colistin therapy was not associated with lower odds of CIN. Further studies with a larger sample size are required to confirm these findings.

Efficacy of stem cell-based therapies for colistin-induced nephrotoxicity

The increase in infections with multidrug resistant bacteria has forced to return to the use of colistin, antibiotic with known nephrotoxicity. Mesenchymal stem cells (MSCs) are being extensively investigated for their potential in regenerative medicine. This study aimed to investigate the possible protective mechanisms of the MSCs against kidney injury induced by colistin. Forty adult female albino rats were randomly classified into 4 equal groups; the control group, the MSC-treated group (a single dose of 1 ×106 /ml MSCs through the tail vein), the colistin-treated group (36 mg/kg/day colistin was given for 7 days), and the both colistin and MSC group (36 mg/kg/day colistin and 1 ×106 /ml MSCs). Main outcome measures were histopathological alterations, kidney malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT) and immunohistological autophagy evaluation. MSC repressed the progression of colistin-induced kidney injury as evidenced by the improvement of histopathological alterations and the substantial increase MDA, and decrease SOD and CAT in serum levels. Moreover, MSC resulted in a profound reduction in oxidative stress as manifested by decreased MDA and increased SOD in serum. Notably, MSC suppressed colistin-induced autophagy; it reduced renal levels of Beclin-1, P62 and LC3A/B. Furthermore, MSC decreased renal levels of eNOS. Lastly, MSC efficiently decreased expression of the TUNEL positive cell number. MSC confers protection against colistin-induced kidney injury by alleviating oxidative stress, nitric oxide synthase besides modulating reducing autophagy and apoptosis.

Omeprazole Prevents Colistin-Induced Nephrotoxicity in Rats: Emphasis on Oxidative Stress, Inflammation, Apoptosis and Colistin Accumulation in Kidneys.

The clinical value of colistin, a polymyxin antibiotic, is limited by its nephrotoxicity. Omeprazole is a commonly prescribed proton pump inhibitor. The current study aimed to evaluate the effects of the concomitant administration of omeprazole on colistin-induced nephrotoxicity in rats. Omeprazole significantly ameliorated colistin nephrotoxicity as evidenced by prevention in the rise in the serum level of creatinine, urea and cystactin C as well as urinary N-acetylglucosamine activity. This was confirmed by histological studies that indicated a decreased incidence of interstitial nephritis, degenerative cortical changes and collagen deposition. This was accompanied by the prevention of oxidative stress as omeprazole significantly inhibited the lipid peroxidation, glutathione depletion and enzymatic exhaustion of superoxide dismutase as well as catalase. Additionally, omeprazole inhibited the expression of interleukin-6 and tumor necrosis factor-α. Further, omeprazole inhibited the colistin-induced rise in Bax and the down-regulation of Bcl2 mRNA expression. An assessment of the serum levels of colistin revealed that omeprazole had no significant impact. However, it was observed that omeprazole significantly inhibited the accumulation of colistin in kidney tissues. In conclusion, omeprazole protects against colistin-induced nephrotoxicity. This can be attributed to, at least partly, omeprazole’s anti-oxidant, anti-inflammatory and anti-apoptotic activities in addition to its ability to prevent the toxic accumulation of colistin in kidneys.

Pharmacological agents for the prevention of colistin-induced nephrotoxicity

BackgroundColistin is a polymyxin antibiotic which has been used for treatment of Gram-negative infections, but it was withdrawn due to its nephrotoxicity. However, colistin has gained its popularity in recent years due to the reemergence of multidrug resistant Gram-negative infections and drug-induced toxicity is considered as the main obstacle for using this valuable antibiotic.ResultsIn total, 30 articles, including 29 animal studies and one clinical trial were included in this study. These compounds, including aged black garlic extract, albumin fragments, alpha lipoic acid, astaxanthin, baicalein, chrysin, cilastatin, colchicine, curcumin, cytochrome c, dexmedetomidine, gelofusine, grape seed proanthocyanidin extract, hesperidin, luteolin, lycopene, melatonin, methionine, N-acetylcysteine, silymarin, taurine, vitamin C, and vitamin E exhibited beneficial effects in most of the published works.ConclusionsIn this review, the authors have attempted to review the available literature on the use of several compounds for prevention or attenuation of colistin-induced nephrotoxicity. Most of the studied compounds were potent antioxidants, and it seems that using antioxidants concomitantly can have a protective effect during the colistin exposure.

Nephroprotective potential of Panduratin A against colistin-induced renal injury via attenuating mitochondrial dysfunction and cell apoptosis

Colistin is a last-resort polypeptide antibiotic widely used to treat against multidrug-resistant Gram-negative bacterial infections. However, this treatment is associated with nephrotoxicity. The aim of this study was to examine the potential protective effect of panduratin A, a bioactive compound of Boesenbergia rotunda, on colistin-induced nephrotoxicity in both in vivo and in vitro models. Intraperitoneal injection of 15 mg/kg colistin for 7 days markedly promoted renal tubular degeneration, increased blood urea nitrogen (BUN) levels, and upregulated the expression of renal injury biomarker and apoptosis proteins. In addition, treatment with colistin increased oxidative stress and apoptosis in mice kidney tissues. Interestingly, these defects were attenuated when co-administered of colistin with panduratin A (2.5 or 25 mg/kg). The underlying mechanisms of panduratin A attenuating colistin toxicity was investigated in human renal proximal tubular cells (RPTEC/TERT1). The mechanisms by which colistin-triggered cytotoxicity was determined by analysis of cell death, reactive oxygen species (ROS) levels, mitochondria function as well as the expression of proteins related to apoptosis pathway. Colistin treatment (200 µg/ml) significantly increased cell apoptosis, elevated ROS production, reduced mitochondrial membrane potential, and decreased anti-apoptotic protein (Bcl-2) expression. These effects were notably suppressed by co-treatment with panduratin A (5 μM). Collectively, panduratin A exerts as a novel nephroprotective agent to protect against colistin-induced renal injury by attenuating mitochondrial damage and renal cell apoptosis.

Delineation of the molecular mechanisms underlying Colistin-mediated toxicity using metabolomic and transcriptomic analyses

The mechanisms underlying colistin-induced toxicity are not fully understood. This study used untargeted metabolomics and transcriptomics to elucidate the molecular processes occurring in the liver and kidney of rats after treatment with colistin methanesulfonate (CMS). Rats were treated with 50 mg/kg CMS (high-dose), 25 mg/kg CMS (low-dose), or vehicle control, either as a single dose or once daily for 1 or 4 weeks. We found that metabolic alterations were dose- and treatment duration-dependent in the kidney, whereas mild changes were noted in the liver. Metabolic profiles in the high-dose, low-dose, and control groups of both tissues could be classified using partial least-squares discriminant analysis. Metabolic alterations were associated with the citric acid cycle and related processes, disrupted balance between pro-oxidants and antioxidants, inflammatory responses, and amino acid and nucleic acid metabolism. Gene expression profiles further showed that high-dose treatment was associated with disrupted metabolism, oxidative stress, and proinflammatory signals in the kidney. The expression levels of genes related to the cell cycle, DNA replication, and programmed cell death were also predominantly upregulated. These findings suggested that high-dose treatment was associated with a dramatic increase in cellular kidney injury, while only minor effects were observed in the low-dose group. Almost no significant gene expression was changed in the liver, even with high-dose CMS. In conclusion, untargeted metabolomics and transcriptomics provided better insights into the biological mechanisms underlying colistin-induced nephrotoxicity.

Investigation of the nephroprotective effect of dexmedetomidine on colistin-induced nephrotoxicity in rats.

There are very few studies in the literature focusing on whether dexmedetomidine exerts a protective effect on colistin nephrotoxicity. Our study aims to investigate the nephroprotective effect of dexmedetomidine in an experimental model of nephrotoxicity in rats. The control group was administered saline (SF) intraperitoneally twice a day. The colistin group received an intraperitoneal (ip) injection of 10 mg/kg of colistin twice a day. The DX10 group received 10 mg/kg of colistin 20 minutes after the intraperitoneal injection of 10 mcg/kg of dexmedetomidine. The DX20 group received 10 mg/kg of colistin 20 minutes after the intraperitoneal injection of 20 mcg/kg of dexmedetomidine. Applications were continued for 7 days, twice a day. All rats were sacrificed on the 8th day after blood and kidney tissue samples were taken. BUN, Creatine, KIM-1 and Endothelin-1 were studied in blood samples. There was a significant difference in the median values of Urea, BUN and Creatine between the groups (p<0.001, p<0.001, p<0.001, respectively). There was a significant difference in the median values of KIM-1 and Endothelin-1 between the groups (p=0.009, p=0.001, respectively). A significant difference was observed between the histopathological scores of the groups (p<0.001). Dexmedetomidine significantly decreased the elevated levels of BUN, Creatinine, KIM-1, and Endothelin-1 induced by colistin. Dexmedetomidine, at both doses, histopathologically prevented apoptosis and reduced the number of necrotic cells in the kidneys. Dexmedetomidine provides renoprotective effects, therefore it is a valuable sedation agent for clinicians working in intensive care units (Tab. 2, Fig. 4, Ref. 19). Text in PDF www.elis.sk Keywords: rat, colistin, nephrotoxicity, dexmedetomidine.

Implementing the First Outpatient Parenteral Antimicrobial Therapy (OPAT) Program to Utilize Disposable Elastomeric Pumps in the Gulf Region: Results From a Tertiary Teaching Hospital in the Kingdom of Saudi Arabia.

ObjectivesTo describe the implementation process, safety, and efficacy outcomes, as well as cost-effectiveness, of the first outpatient parenteral antimicrobial therapy (OPAT) program to utilize disposable elastomeric pumps in the Kingdom of Saudi Arabia and the entire Gulf region.MethodsThis OPAT program was initiated in May 2018 and was administered through a multidisciplinary team that included the home medicine department, pharmacy department, nursing department, and the infectious diseases service. The device used was the Intermate® (Baxter, Deerfield, Illinois) elastomeric pump. After consultation with an infectious diseases physician, eligible patients were discharged home to complete the remainder of their antimicrobial treatment, which was self-administered via the elastomeric devices.ResultsFrom May 2018 to December 2019, 47 patients received 55 courses of OPAT via the new program. A total of 2,869 pumps were used during that period to provide 927 days of antimicrobial therapy in the home setting. Most patients completed the program successfully with no reported significant OPAT-related complications such as catheter-related infections. Four patients were re-admitted for relapse of infections and one patient was re-admitted for colistin-induced nephrotoxicity. No mortality was reported for any patient during OPAT treatment and 30 days after program completion.ConclusionsThe implementation of this novel OPAT program was safe, effective, and offered significant cost-savings to our institution. The entire process was very dynamic and was centered around proper patient selection and education as well as excellent communication between patients and the entire multidisciplinary team involved in the program. We hope that these results will encourage other institutions in the region to implement similar OPAT programs to alleviate the existing bed crisis due to the ongoing COVID-19 pandemic.