colistin and Kidney-Diseases

Colistin (polymyxin E) is a mainly concentration-dependent bactericidal antimicrobial active against multidrug-resistant Gram-negative bacteria. After being abandoned over the past 30 years due to its neuro- and nephrotoxicity, colistin has been reintroduced recently as a last-resort drug for the treatment of multidrug-resistant Gram-negative bacteria infections in combination with other antimicrobials. Unfortunately, although renal toxicity is a well-known dose-related adverse effect of colistin, relatively few studies are currently available on its peculiar pharmacodynamic/pharmacokinetic properties in clinical settings at high risk for drug accumulation, such as acute or chronic kidney disease. In these specific contexts, the risk for underdosing is also substantial because colistin can be easily removed by dialysis/hemofiltration, especially when the most efficient modalities of renal replacement therapy (RRT) are used in critically ill patients. For this reason, recent recommendations in patients undergoing RRT have shifted toward higher dosing regimens, and therapeutic drug monitoring is advised. This review aims to summarize the main issues related to chemical structure, pharmacodynamics/pharmacokinetics, and renal toxicity of colistin. Moreover, recent data and current recommendations concerning colistin dosing in patients with reduced kidney function, with special regard to those receiving RRT such as dialysis or hemofiltration, are also discussed.

Topics: Acute Kidney Injury; Anti-Bacterial Agents; Colistin; Drug Monitoring; Humans; Kidney; Kidney Diseases; Practice Guidelines as Topic; Renal Insufficiency, Chronic; Renal Replacement Therapy

Colistin is an antibiotic that was introduced many years ago and was withdrawn because of its nephrotoxicity. Nowadays, reemergence of this antibiotic for multi-drug resistant Gram-negative infections, and a new high dosing regimen recommendation increases concern about its nephrotoxicity. This review attempts to give a view on colistin nephrotoxicity, its prevalence especially in high doses, the mechanism of injury, risk factors, and prevention of this kidney injury.. The data collection was done in PubMed, Scopus and Cochrane databases. The keywords for search terms were "colistin", "nephrotoxicity", "toxicity", "renal failure", "high dose", and "risk factor". Randomized clinical trials and prospective or retrospective observational animal and human studies were included. In all, 60 articles have been reviewed.. Colistin is a nephrotoxic antibiotic; a worldwide increase in nosocomial infections has led to an increase in its usage. Nephrotoxicity is the concerning adverse effect of this drug. The mechanism of nephrotoxicity is via an increase in tubular epithelial cell membrane permeability, which results in cation, anion and water influx leading to cell swelling and cell lysis. There are also some oxidative and inflammatory pathways that seem to be involved in colistin nephrotoxicity. Risk factors of colistin nephrotoxicity can be categorized as dose and duration of colistin therapy, co-administration of other nephrotoxic drugs, and patient-related factors such as age, sex, hypoalbuminemia, hyperbilirubinemia, underlying disease and severity of patient illness.

Topics: Animals; Anti-Bacterial Agents; Colistin; Drug Administration Schedule; Drug Dosage Calculations; Humans; Incidence; Kidney; Kidney Diseases; Prognosis; Risk Assessment; Risk Factors

Colistin has re-emerged as an essential antibiotic for the treatment of carbapenem-resistant Gram-negative infections. Unfortunately, its utility is limited by high rates of nephrotoxicity, even at potentially therapeutic concentrations, and an overall lack of understanding on how to optimally administer the agent. In this review, recent advancements in the understanding of the safety and efficacy of colistin are discussed and strategies and suggestions on how to balance the two are described.

Topics: Anti-Bacterial Agents; Carbapenems; Colistin; Drug Resistance; Gram-Negative Bacteria; Humans; Kidney Diseases

Although a worldwide increasing incidence of bacterial infections with panresistant pathogens may need innovative antiinfective agents, no breakthrough developments can be expected in the near future. As a consequence, well-tried antibiotics like aztreonam, fosfomycin and colistin, are experiencing a clinical revival, particularly if they are used in an improved manner. Even penicillin G with its narrow spectrum of antimicrobial activity remains an important considerable agent of first choice in special indications compared to broad spectrum antiinfectives.

Topics: Anti-Bacterial Agents; Aztreonam; Bacterial Infections; Colistin; Fosfomycin; Humans; Kidney Diseases; Penicillin G

Topics: Anti-Bacterial Agents; Cephalosporins; Chloramphenicol; Colistin; Drug Hypersensitivity; Enterobacteriaceae Infections; Erythromycin; Female; Gonorrhea; Humans; Kidney Diseases; Mycoplasma Infections; Pelvic Inflammatory Disease; Salpingitis; Staphylococcal Infections; Streptococcal Infections; Streptomycin; Tetracycline; Thrombophlebitis; Tuberculosis, Female Genital; Wound Infection

Topics: Biological Assay; Bordetella; Colistin; Creatinine; Humans; Injections, Intramuscular; Kidney Diseases; Metabolic Clearance Rate; Peritoneal Dialysis; Renal Dialysis; Urea

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.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Cell Line; Chalcones; Colistin; Epithelial Cells; Humans; Kidney; Kidney Diseases; Male; Mice; Mice, Inbred C57BL; Mitochondria; Oxidative Stress; Protective Agents; Proto-Oncogene Proteins c-bcl-2; Reactive Oxygen Species; Zingiberaceae

Colistin is an antimicrobial agent that is used in resistant gram-negative infections. Its most common dose-limiting adverse effect is nephrotoxicity. The objective of our study was to explore the possible effects of each of taxifolin and dapagliflozin alone and in combination on colistin-induced nephrotoxicity in rats. Sixty male rats were randomized into six groups: Control; colistin; colistin + taxifolin; colistin + dapagliflozin; colistin + carboxymethyl cellulose (CMC) and colistin + taxifolin + dapagliflozin. Dapagliflozin, taxifolin, and CMC were given daily for 7 days, 4 hours before colistin injection. Kidney weight/body weight ratio and renal function tests were determined. Renal tissue nerve growth factor-β (NGF-β), transforming growth factor beta 1 (TGF-β1), proinflammatory cytokines, nuclear factor (erythroid-derived 2)-like 2 (Nrf2), toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB) p65, signal transducer and activator of transcription 3 (STAT3), oxidative stress parameters, beclin-1 and c-Jun NH2-terminal kinase (JNK) activities were measured. Kidneys were examined histopathologically and immunohistochemically. Taxifolin and/or dapagliflozin induced significant improvement in the renal functions and oxidative stress parameters with significant increase in tissue Nrf2, STAT3 and NGF-β accompanied with significant decrease in kidney weight/body weight ratio, tissue proinflammatory cytokines, TGF-β1, NF-κB (p65), TLR4, beclin-1 and JNK activities and improved the histopathological picture when compared to rats treated with colistin alone. This improvement was significant with taxifolin/dapagliflozin combination compared to rats treated with each of these agents alone. So, we concluded that the combined use of taxifolin and dapagliflozin may confer a therapeutic tool for attenuation of colistin-induced nephrotoxicity.

Topics: Animals; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Beclin-1; Benzhydryl Compounds; Colistin; Drug Combinations; Gene Expression Regulation; Glucosides; Kidney Diseases; Male; MAP Kinase Kinase 4; Quercetin; Random Allocation; Rats; Sodium-Glucose Transporter 2 Inhibitors

Acinetobacter baumannii has emerged as an important nosocomial pathogen worldwide. In Thailand, the incidence and mortality rate of carbapenem-resistant A. baumannii (CRAB) is continuously increasing. This organism is a common pathogen that can cause HAP and VAP. CRAB tends to be susceptible to only colistin, so colistin would be the last line of treatment for CRAB. The recent data from in-vitro studies found that colistin and meropenem combination therapy could exert synergistic effects. However, some in-vivo studies have shown no significant difference in antibacterial effect between colistin monotherapy and colistin plus meropenem. Moreover, the clinical data are recently limited and not clear. Thus, the objective of this study was to compare clinical outcome, microbiological response, mortality rate and nephrotoxicity between loading dose (LD) colistin monotherapy and LD colistin-meropenem for treatment of infection caused by CRAB in Maharaj Nakorn Chiang Mai Hospital.. This study is a retrospective analytical study. The data were collected from patients who received LD colistin monotherapy or LD colistin plus meropenem combination therapy for treatment of CRAB from 1 January 2013 to 31 August 2017 at Maharaj Nakorn Chiang Mai Hospital. A total of 324 patients met the inclusion criteria. The data were analyzed by descriptive statistics and inferential statistics, and were adjusted for confounding factors by logistic regression analysis.. The adjusted OR of good clinical outcome of patients who received LD colistin plus meropenem was 1.05 times that of patients who received loading dose colistin monotherapy (95%CI 0.62-1.74, p=0.860). Patients who received LD colistin plus meropenem had 0.93 times (adjusted OR) mortality rate at the end of treatment compared to patients who received LD colistin monotherapy (95%CI=0.51-1.71, p=0.935). In addition, microbiological response was defined as eradication of pre-treatment isolated pathogens in post-treatment cultures. Patients who received LD colistin plus meropenem could eradicate pathogens 1.28 times more than LD colistin monotherapy (95% CI=0.74-2.20, p=0.371). Also there was no significant difference in nephrotoxicity (adjusted OR=0.84, 95% CI 0.52-1.36, p=0.492) between LD colistin monotherapy and LD colistin plus meropenem.. There were no significant differences in effectiveness and nephrotoxicity of LD colistin monotherapy versus LD colistin plus meropenem for treatment of CRAB infection, so colistin combination therapy was not necessary for the management of infection caused by CRAB.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Aged; Anti-Bacterial Agents; Carbapenems; Colistin; Drug Resistance, Bacterial; Drug Therapy, Combination; Female; Humans; Kidney; Kidney Diseases; Male; Meropenem; Middle Aged; Retrospective Studies; Thailand

Colistin (COL) belongs to the polymixin class of antibiotics used as the last line antibiotic against drug-resistant infections. However, nephrotoxicity is the major deleterious and dose-limiting side effect associated with COL therapy. Oxidative stress and mitochondrial impairment are suspected mechanisms involved in COL-induced nephrotoxicity. Taurine is one of the most abundant amino acids in the human body with antioxidant and mitochondria protecting properties. The current study was designed to evaluate the potential nephroprotective properties of taurine against COL-associated nephrotoxicity. Mice were treated with COL (15 mg/kg/day, i.v, for 7 consecutive days) alone or in combination with taurine (500 and 1000 mg/kg, i.p). Plasma biomarkers of nephrotoxicity in addition of kidney tissue markers of oxidative stress were evaluated. Additionally, kidney mitochondria were isolated, and several mitochondrial indices were assessed. The COL-associated renal injury was evident by a significant increase in plasma markers of renal injury including creatinine (Cr), and blood urine nitrogen (BUN). COL treatment also caused a significant increase in kidney reactive oxygen species (ROS) and lipid peroxidation (LPO). Renal GSH reservoirs and antioxidant capacity were also decreased in COL-treated animals. Mitochondrial parameters including mitochondrial dehydrogenase activity, membrane potential, GSH, and ATP were significantly decreased while mitochondrial LPO, permeabilization, and GSSG content were increased in the kidney of COL-treated mice. It was found that taurine (500 and 1000 mg/kg, i.p) treatment alleviated COL-induced oxidative stress and mitochondrial dysfunction in the kidney tissue. The data obtained from the current study suggest mitochondrial dysfunction and oxidative stress as fundamental mechanisms of renal injury induced by COL. On the other hand, taurine supplementation protected kidney through decreasing oxidative stress and regulating mitochondrial function.

Topics: Animals; Anti-Bacterial Agents; Antioxidants; Colistin; Dose-Response Relationship, Drug; Kidney Diseases; Lipid Peroxidation; Male; Mice; Mice, Inbred BALB C; Mitochondria; Oxidative Stress; Reactive Oxygen Species; Taurine

The alarming rise in the rate of multi drug resistant, life threatening gram negative infections has brought renaissance in the use of Colistin for last two decades. The major constraint in its utilization is its nephrotoxicity. Therefore it is being underused which is favoring the development of resistance. This study assesses the prevention of nephrotoxicity associated with high and low toxic doses of Colistin by alpha-tocopherol. Thirty rabbits were randomly divided into five groups. Baseline serum urea, creatinine and electrolytes were estimated. A loading dose of colistin was given in the form of infusion followed by I.M injections for six days. In the preventive groups α-tocopherol was additionally given orally for two weeks. Rabbits were sacrificed 24 hours after the last dose. The kidney slides graded and statistically analyzed using "chi square". The results of serum analysis were compared using one way analysis of variance followed by post hoc tukey test. There was marked nephrotoxicity in high toxic group where as in low toxic group mild nephrotoxicity was evident. Alpha-tocopherol attenuated the renal insult in both the toxic groups. As damage induced by colistin is oxidative in nature, thus it was concluded that the protection offered by α- tocopherol is due to its antioxidant activity.

Topics: alpha-Tocopherol; Animals; Colistin; Creatinine; Dose-Response Relationship, Drug; Female; Kidney Diseases; Male; Protective Agents; Rabbits; Urea

Nephrotoxicity is the major adverse effect patients experience during colistin therapy. The development of effective nephroprotective agents that can be co-administered during polymyxin therapy remains a priority area in antimicrobial chemotherapy.. To investigate the nephroprotective effect of baicalein, a component of the root of Scutellaria baicalensis, against colistin-induced nephrotoxicity using a mouse model.. C57BL/6 mice were randomly divided into the following groups: control, baicalein 100 mg/kg/day (administered orally), colistin (18 mg/kg/day administered intraperitoneally) and colistin (18 mg/kg/day) plus baicalein (25, 50 and 100 mg/kg/day). After 7 day treatments, histopathological damage, the markers of renal functions, oxidative stress and inflammation were examined. The expressions of Nrf2, HO-1 and NF-κB mRNAs were also further examined using quantitative RT-PCR examination.. Baicalein co-administration markedly attenuated colistin-induced oxidative and nitrative stress, apoptosis, the infiltration of inflammatory cells, and caused decreases in IL-1β and TNF-α levels (all P < 0.05 or 0.01) in the kidney tissues. Baicalein co-administration up-regulated expression of Nrf2 and HO-1 mRNAs and down-regulated the expression of NF-κB mRNA, compared with those in the colistin alone group.. To the best of our knowledge, this is the first study demonstrating the protective effect of baicalein on colistin-induced nephrotoxicity and apoptosis by activating the antioxidant defence mechanism in kidneys and down-regulating the inflammatory response. Our study highlights that oral baicalein could potentially ameliorate nephrotoxicity in patients undergoing polymyxin therapy.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Colistin; Down-Regulation; Flavanones; Inflammation; Kidney; Kidney Diseases; Kidney Function Tests; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Protective Agents; Real-Time Polymerase Chain Reaction; Up-Regulation

Colistin loading dose (LD) has been postulated as an advance in therapy. The clinical, microbiological effectiveness and nephrotoxicity of adding an LD to systemic colistin in ventilator-associated pneumonia (VAP) caused by multidrug-resistant (MDR) Acinetobacter baumannii remain unknown. In this quasi experimental study, the efficacy, outcomes and nephrotoxicity in 30 adults who received intravenous colistin with LD for MDR A. baumannii ventilator associated pneumonia were compared with 22 in absence of LD. Adding LD, the clinical cure rate at 14 days of therapy increased from 47.6% to 56.7% (p>0.397). No significant differences in bacteriological clearance (80 vs 81%), ICU mortality (50% vs 54.2%) or ICU length of stay (median: 32 vs 36 days) were identified. Mortality increased (76.2% vs 35.5%, p=0.004) in patients with nephrotoxicity, with age (median 67.0 vs. 50.0 years, p=0.002) being the only risk factor for nephrotoxicity. The nephrotoxicity rate increased from 27.3% in absence of LD to 35.3% with LD and SOFA <8, and 69.2% (p= 0.065) with LD and SOFA >7. Overall, nephrotoxicity was more severe in the LD group according to RIFLE criteria (p=0.015). Adding LD to systemic colistin for MDR A. baumannii VAP had no significant effect on clinical cure rates, bacteriologic clearance or pre-defined outcomes. However, the nephrotoxicity rate increased with LD, with special risk in adults with high organ failure development or advanced age. Further evidence regarding the risks and benefits of LD is required. The development of newer agents and strategies is urgently needed.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adolescent; Adult; Aged; Aged, 80 and over; Colistin; Drug Resistance, Multiple, Bacterial; Female; Humans; Kidney Diseases; Male; Middle Aged; Pneumonia, Ventilator-Associated; Retrospective Studies; Sepsis; Young Adult

Although once a common antibiotic, polymyxin E fell out of favor after reports of its nephrotoxicity. However, recent concerns with gram-negative bacteria, which are resistant to multiple antibiotics, have resulted in increased interest in polymyxin E. Silybin is a known antihepatotoxic drug and may have potential for protecting the kidney from polymyxin E. Therefore, the aim of the current study was to evaluate whether silybin affected the damages produced by polymyxin E on the rat kidney.. Four groups of rats with 10 rats per group were included in the study: control (no treatment, group I), vehicle (control vehicle treatment, group II), polymyxin E treatment (group III), and polymyxin E and silybin treatment (group IV). Groups II-IV received intravenous treatment twice a day for 7 days. All rats were euthanized after 7 days. Histological, ultrastructural, and morphometric analyses were performed on the rats' kidney tissues.. Analysis of tissues from group III showed differences from groups I and II, such as glomerular and tubular affection and changes in morphometric measures. Results for group IV were more similar to those of groups I and II than those of group III.. Our results suggested that administering silybin with polymyxin E alleviated polymyxin E-induced nephrotoxicity in the rat kidney. Future biochemical studies should investigate whether silybin could ameliorate the nephrotoxicity caused by polymyxin E in rats and whether concomitant administration of silybin could be an effective clinical pharmacological strategy to protect against polymyxin E-induced insult in human kidneys.

Topics: Animals; Colistin; Kidney; Kidney Diseases; Male; Protective Agents; Rats; Rats, Sprague-Dawley; Silybin; Silymarin

Colistin has a narrow therapeutic window with nephrotoxicity being the major dose-limiting adverse effect. Currently, the optimal doses and therapeutic plasma levels are unknown.. Prospective observational cohort study, including patients infected by colistin-susceptible P. aeruginosa treated with intravenous colistimethate sodium (CMS). Clinical data and colistin plasma levels at steady-state (C. In this series of patients with infections caused by XDR P. aeruginosa infections, C

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Biological Availability; Colistin; Drug Resistance, Multiple, Bacterial; Female; Humans; Kidney Diseases; Male; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Risk Factors; Treatment Outcome; Young Adult

Topics: Anti-Bacterial Agents; Ascorbic Acid; Colistin; Humans; Kidney; Kidney Diseases

Colistin is a polypeptide antibiotic that effectively treats infections caused by multidrug-resistant Gram-negative bacteria, but its clinical use is limited due to nephrotoxicity. The purpose of the present study was to identify biomarkers of colistin-induced nephrotoxicity and to further characterize the mechanisms underlying this process by analyzing urinary metabolites using untargeted metabolomic approach. Rats receiving intraperitoneal administration of colistin sodium methanesulfonate (CMS) (25 or 50mg/kg) exhibited histopathological changes in the kidney and increased blood urea nitrogen levels. Additionally, the levels of phenylalanine, tryptophan, and tyrosine in the urine of the CMS-treated group were significantly higher than those of the control group, suggesting that colistin caused proximal tubular damage. Urinary acetylcarnitine and butyrylcarnitine levels also increased after CMS treatment, but the levels of purine metabolites and metabolites related to the tricarboxylic acid cycle were reduced. The most significant increase in the CMS-treated groups was observed in creatine levels. CMS-induced selective nephrotoxicity may be attributed to relatively high tissue concentrations of colistin in the kidney. Taken together, our results indicate that high levels of colistin in the kidney caused perturbations in the tricarboxylic acid cycle, amino acid metabolism, creatine metabolism, and purine metabolism and ultimately led to kidney injury.

Topics: Amino Acids; Animals; Anti-Bacterial Agents; Biomarkers; Chromatography, High Pressure Liquid; Colistin; Creatinine; Kidney Diseases; Male; Metabolomics; Multivariate Analysis; Rats, Sprague-Dawley; Tandem Mass Spectrometry; Tissue Distribution

To study the protective, preventive effect of luteolin from colistin-induced nephrotoxicity.. Four different treatment options were tested on rats: colistin, luteolin, and a combination of colistin and luteolin, intraperitoneally as two doses a day, for seven days. Another group of rats were used as the control and treated with sterile saline. Serum creatinine levels were measured before and after treatment. Histological changes and colistin-induced apoptosis (Insitu BrdU-red DNA Fragmentation Assay Kit) of the renal tissues were examined after the scarification procedure.. In the Colistin Group, post-treatment creatinine levels were statistically higher than the pretreatment levels (p = .001). In the remaining groups, no significant changes were observed. Cells that undergo apoptosis were counted and it was shown that all groups except the colistin-treated group had a similar number of apoptotic cells, whereas the colistin-treated group had statistically higher number of apoptotic cells compared to other groups (p = .0001). Renal histological damage was also measured and the score of the colistin treated group was higher as compared to other groups.. The results obtained from this study demonstrated us that luteolin was capable of preventing colistin-induced nephrotoxicity and that this effect was significant at histopathological level.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Colistin; Creatinine; Disease Models, Animal; Kidney; Kidney Diseases; Luteolin; Male; Oxidative Stress; Rats; Rats, Wistar

Nephrotoxicity is the major dose-limiting factor for the clinical use of colistin against multidrug-resistant (MDR) Gram-negative bacteria. This study aimed to investigate the protective effect of lycopene on colistin-induced nephrotoxicity in a mouse model. Fifty mice were randomly divided into 5 groups: the control group (saline solution), the lycopene group (20 mg/kg of body weight/day administered orally), the colistin group (15 mg/kg/day administered intravenously), the colistin (15 mg/kg/day) plus lycopene (5 mg/kg/day) group, and the colistin (15 mg/kg/day) plus lycopene (20 mg/kg/day) group; all mice were treated for 7 days. At 12 h after the last dose, blood was collected for measurements of blood urea nitrogen (BUN) and serum creatinine levels. The kidney tissue samples were obtained for examination of biomarkers of oxidative stress and apoptosis, histopathological assessment, and quantitative reverse transcription-PCR (qRT-PCR) analysis. Colistin treatment significantly increased concentrations of BUN and serum creatinine, tubular apoptosis/necrosis, lipid peroxidation, and heme oxygenase 1 (HO-1) activity, while the treatment decreased the levels of endogenous antioxidant biomarkers glutathione (GSH), catalase (CAT), and superoxide dismutase (SOD). Notably, the changes in the levels of all biomarkers were attenuated in the kidneys of mice treated with colistin by lycopene (5 or 20 mg/kg). Lycopene treatment, especially in the colistin plus lycopene (20 mg/kg) group, significantly downregulated the expression of NF-κB mRNA (P < 0.01) but upregulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and HO-1 mRNA (both P < 0.01) in the kidney compared with the results seen with the colistin group. Our data demonstrated that coadministration of 20 mg/kg/day lycopene can protect against colistin-induced nephrotoxicity in mice. This effect may be attributed to the antioxidative property of lycopene and its ability to activate the Nrf2/HO-1 pathway.

Topics: Animals; Anti-Bacterial Agents; Blood Urea Nitrogen; Carotenoids; Colistin; Disease Models, Animal; Female; Heme Oxygenase-1; Kidney; Kidney Diseases; Lycopene; Membrane Proteins; Metabolic Networks and Pathways; Mice, Inbred Strains; NF-E2-Related Factor 2; NF-kappa B; Oxidative Stress; Protective Agents

Despite six decades of clinical experience with the polymyxin class of antibiotics, their dose-limiting nephrotoxicity remains difficult to predict due to a paucity of sensitive biomarkers. Here, we evaluate the performance of standard of care and next-generation biomarkers of renal injury in the detection and monitoring of polymyxin-induced acute kidney injury in male Han Wistar rats using colistin (polymyxin E) and a polymyxin B (PMB) derivative with reduced nephrotoxicity, PMB nonapeptide (PMBN). This study provides the first histopathological and biomarker analysis of PMBN, an important test of the hypothesis that fatty acid modifications and charge reductions in polymyxins can reduce their nephrotoxicity. The results indicate that alterations in a panel of urinary kidney injury biomarkers can be used to monitor histopathological injury, with Kim-1 and α-GST emerging as the most sensitive biomarkers outperforming clinical standards of care, serum or plasma creatinine and blood urea nitrogen. To enable the prediction of polymyxin-induced nephrotoxicity, an in vitro cytotoxicity assay was employed using human proximal tubule epithelial cells (HK-2). Cytotoxicity data in these HK-2 cells correlated with the renal toxicity detected via safety biomarker data and histopathological evaluation, suggesting that in vitro and in vivo methods can be incorporated within a screening cascade to prioritize polymyxin class analogs with more favorable renal toxicity profiles.

Topics: Animals; Anti-Bacterial Agents; Biomarkers; Cell Line; Cell Survival; Colistin; Data Interpretation, Statistical; Dose-Response Relationship, Drug; Early Diagnosis; Kidney Diseases; Male; Polymyxin B; Prognosis; Rats; Rats, Wistar

Increasing evidence suggests that colistin monotherapy is suboptimal at currently recommended doses. We hypothesized that front-loading provides an improved dosing strategy for polymyxin antibiotics to maximize killing and minimize total exposure. Here, we utilized an in vitro pharmacodynamic model to examine the impact of front-loaded colistin regimens against a high bacterial density (10(8) CFU/ml) of Pseudomonas aeruginosa. The pharmacokinetics were simulated for patients with hepatic (half-life [t1/2] of 3.2 h) or renal (t1/2 of 14.8 h) disease. Front-loaded regimens (n=5) demonstrated improvement in bacterial killing, with reduced overall free drug areas under the concentration-time curve (fAUC) compared to those with traditional dosing regimens (n=14) with various dosing frequencies (every 12 h [q12h] and q24h). In the renal failure simulations, front-loaded regimens at lower exposures (fAUC of 143 mg · h/liter) obtained killing activity similar to that of traditional regimens (fAUC of 268 mg · h/liter), with an ∼97% reduction in the area under the viable count curve over 48 h. In hepatic failure simulations, front-loaded regimens yielded rapid initial killing by up to 7 log10 within 2 h, but considerable regrowth occurred for both front-loaded and traditional regimens. No regimen eradicated the high bacterial inoculum of P. aeruginosa. The current study, which utilizes an in vitro pharmacodynamic infection model, demonstrates the potential benefits of front-loading strategies for polymyxins simulating differential pharmacokinetics in patients with hepatic and renal failure at a range of doses. Our findings may have important clinical implications, as front-loading polymyxins as a part of a combination regimen may be a viable strategy for aggressive treatment of high-bacterial-burden infections.

Topics: Anti-Bacterial Agents; Colistin; Humans; In Vitro Techniques; Kidney Diseases; Liver Diseases; Models, Biological; Pseudomonas Infections

We evaluated the effect of astaxanthin (ASX) and vitamin E (vit E) on colistin methanesulfonate (CMS) induced-nephrotoxicity in rats.. Animals were treated with sterile saline, 300000 or 450 000 IU/kg/day of CMS, CMS + ASX (20 mg/kg), CMS + vit E (100 mg/kg), or CMS + 1 ml/kg olive oil (OO) for 7 days. The plasma/urine creatinine (Cr) level, urine γ-glutamyl-transferase (GGT) level, and renal tissue activities in malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and reductase (GSH), as well as renal histology were performed.. CMS induced a tubular damage, increased the GGT and MDA levels, and decreased the activities of SOD, CAT, GPx and GSH. Co-treatment with ASX or vit E restored all biochemical parameters cited above and improved the histopathological damage.. Nephrotoxicity induced by CMS might be due to oxidative damage. The improvement by ASX or vit E seems to be related to their antioxidant properties.

Topics: Animals; Anti-Bacterial Agents; Antioxidants; Catalase; Colistin; Creatinine; gamma-Glutamyltransferase; Glutathione Peroxidase; Glutathione Reductase; Kidney; Kidney Diseases; Male; Malondialdehyde; Rats, Wistar; Superoxide Dismutase; Vitamin E; Xanthophylls

We describe a 51-year-old man who developed renal and neural toxicity after the administration of colistin. He developed respiratory apnoea, neuromuscular blockade and severe comatose encephalopathy with the lack of brainstem reflexes. After discontinuation of the antibiotic, he made a prompt recovery to his baseline neurological function. The case illustrates the importance of recognising the toxicities associated with colistin. Although recent literature details its nephrotoxicity, current data have been discordant with the rare cases of respiratory apnoea or neuromuscular blockade once cited over 30 years ago. Additionally, no cases have ever described the profound encephalopathy with lack of brainstem function described here. The awareness of colistin's potentially fatal effects must be kept in mind when administering this antibiotic. Vigilance of the encephalopathic picture can also facilitate the diagnosis of colistin-mediated neurotoxicity in a patient with altered mental status of otherwise unknown aetiology.

Topics: Anti-Bacterial Agents; Apnea; Brain Stem; Colistin; Coma; Humans; Kidney Diseases; Male; Middle Aged; Neuromuscular Diseases; Neurotoxicity Syndromes

To evaluate the association between the administration of intravenous (IV) colistin and the emergence of renal dysfunction.. A retrospective medical record review.. A tertiary care academic medical center.. A total of 174 critically ill patients who received at least one dose of IV colistin between 2004 and 2007.. The primary outcome was development of renal dysfunction, defined as an increase in serum creatinine of 50% or more during therapy or the initiation of renal replacement therapy (RRT), in patients who received at least one dose of colistin and were not already on RRT. The severity of renal dysfunction was further categorized by the RIFLE criteria. Demographic and clinical characteristics were analyzed by logistic regression for association with new renal dysfunction. A total of 174 patients were evaluated for renal dysfunction. Of these patients, 84 (48%) experienced renal dysfunction on colistin. On multivariate analysis, age in years (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01-1.05) and receipt of concurrent nephrotoxin(s) (OR 3.35, 95% CI 1.34-8.36) significantly increased the risk of developing renal dysfunction.. In this critically ill population, renal dysfunction occurred frequently and was associated with older age and receipt of nephrotoxins.

Topics: Adult; Age Factors; Aged; Anti-Bacterial Agents; APACHE; Colistin; Confidence Intervals; Creatinine; Critical Illness; Female; Humans; Injections, Intravenous; Kidney Diseases; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Renal Replacement Therapy; Retrospective Studies; Risk; Tertiary Healthcare; Treatment Outcome

Colistin is an old antibiotic used in the treatment of Gram-negative infections. It was once suspended because of its nephrotoxic effect but has since been reintroduced due to multidrug-resistant bacterial infections. The pathogenesis of colistin-associated nephropathy has not been clarified, and there is currently no effective therapeutic or prophylactic agent available. The aim of this study was to investigate the roles of caspase-associated apoptosis and caspase 1, calpain 1, inducible nitric oxide synthase (iNOS), and endothelial nitric oxide synthase (eNOS) expression in the pathogenesis of colistin-associated nephrotoxicity and the effect of grape seed proanthocyanidin extract (GSPE) in preventing it. Twenty-four rats were divided into three groups: control, colistin, and colistin plus GSPE (colistin+GSPE). Colistin-associated nephropathy was induced by the administration of 300,000 IU/kg of body weight/day colistin intraperitoneally for 7 days. The experiment was discontinued on the seventh day. Blood was collected for measurements of blood urea nitrogen (BUN) and creatinine levels. Histopathological examination of kidney tissue and caspase 1 and 3, iNOS, eNOS, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL), and calpain 1 staining was also performed. Significant increases in BUN levels; creatinine levels; renal histopathological scores; and TUNEL, caspase 1 and 3, calpain 1, iNOS, and eNOS staining were observed for the colistin group compared to the control group. Significant decreases in BUN levels; creatinine levels; renal histopathological scores; and TUNEL, caspase 1 and 3, calpain 1, iNOS, and eNOS staining were observed in the colistin+GSPE group compared to the colistin group. Our study shows, for the first time in the literature, that caspase-mediated apoptosis, iNOS, caspase 1, and calpain 1 are involved in the pathogenesis of colistin-associated nephropathy. GSPE had a renoprotective effect, as shown by the lowered levels of these mediators.

Topics: Animals; Apoptosis; Blood Urea Nitrogen; Calpain; Caspases; Colistin; Gene Expression Regulation, Enzymologic; Grape Seed Extract; In Situ Nick-End Labeling; Kidney; Kidney Diseases; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Phytotherapy; Proanthocyanidins; Rats; Rats, Sprague-Dawley; Vitis

This study evaluated the usefulness of plasma Cystatin C (pCysC) along with urinary neutrophil gelatinase-associated lipocalin (NGAL), γ-glutamyltransferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), aspartate (AST) and alanine (ALT) aminotransferase to monitor colistin nephrotoxicity.. Male rats were given intramuscular (i.m.) injections of colistin in doses of 150,000 (G1), 300,000 (G2) and 450,000 IU/kg/day (G3) or normal saline (Control), every 12 h for 7 days. After the 14th injection, animals were placed in metabolic cages and urine samples were collected in the next 12 h. Thereafter, animals were euthanized, blood samples were collected and kidneys were removed for histological assessment.. Nephrotoxicity was completely dose-dependent according to pathologic findings. The major insults were acute tubular necrosis in the tubules of G3. No significant change in pCr was observed in all treated groups, but pCysC increased in the G3 compared to the control. In urinary markers, uNGAL level showed a dose dependant increase with significant change in the G2 and G3 groups compared to the control. However, there was no significant change in the AST, ALT, LDH or ALP activities but only GGT increased in the G3 compared to the control.. Based on colistin doses used in our experimental study on rat model, histopathologic assessment remains the most accurate way to diagnose colistin nephrotoxicity. pCysC appears to be more reliable than pCr, and uNGAL seems to be the most sensitive factor of colistin nephrotoxicity.

Topics: Acute-Phase Proteins; Alanine Transaminase; Alkaline Phosphatase; Animals; Anti-Bacterial Agents; Aspartic Acid; Colistin; Cystatin C; Disease Models, Animal; Dose-Response Relationship, Drug; gamma-Glutamyltransferase; Kidney Diseases; L-Lactate Dehydrogenase; Lipocalin-2; Lipocalins; Male; Proto-Oncogene Proteins; Rats; Rats, Wistar

Data regarding the most efficacious and least toxic schedules for the use of colistin are scarce. The aim of this study was to determine the incidence and the potential risk factors of colistin-associated nephrotoxicity including colistin plasma levels.. A prospective observational cohort study was conducted for over one year in patients receiving intravenous colistin methanesulfonate sodium (CMS). Blood samples for colistin plasma levels were collected immediately before (Cmin) and 30 minutes after CMS infusion (Cmax). Renal function was assessed at baseline, on day 7 and at the end of treatment (EOT). Severity of acute kidney injury (AKI) was defined by the RIFLE (risk, injury, failure, loss, and end-stage kidney disease) criteria.. One hundred and two patients met the inclusion criteria. AKI related to CMS treatment on day 7 and at the end of treatment (EOT) was observed in 26 (25.5%) and 50 (49.0%) patients, respectively. At day 7, Cmin (OR, 4.63 [2.33-9.20]; P < 0.001) was the only independent predictor of AKI. At EOT, the Charlson score (OR 1.26 [1.01-1.57]; P = 0.036), Cmin (OR 2.14 [1.33-3.42]; P = 0.002), and concomitant treatment with ≥ 2 nephrotoxic drugs (OR 2.61 [1.0-6.8]; P = 0.049) were independent risk factors for AKI. When Cmin was evaluated as a categorical variable, the breakpoints that better predicted AKI were 3.33 mg/L (P < 0.001) on day 7 and 2.42 mg/L (P < 0.001) at EOT.. When using the RIFLE criteria, colistin-related nephrotoxicity is observed in a high percentage of patients. Cmin levels are predictive of AKI. Patients who receive intravenous colistin should be closely monitored and Cmin might be a new useful tool to predict AKI.

Topics: Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Female; Gram-Negative Bacterial Infections; Humans; Kidney Diseases; Male; Middle Aged; Prospective Studies; Risk Factors; Spain

A rapid increase in multidrug-resistant Gram-negative infections has led to a reemergence of colistin use globally. Although it is well described among adults, colistin use and its associated toxicities in children are poorly understood. We report findings from the largest case series of pediatric colistin use to date.. We queried pediatric infectious diseases specialists from the Emerging Infections Network to identify members who had prescribed intravenous colistin within the past 7 years. We collected relevant demographic and clinical data. Bivariate analyses and multivariable logistic regression were performed.. Two hundred twenty-nine pediatric infectious diseases specialists completed the survey (84% response); 22% had prescribed colistin to children. Among respondents, 92 cases of colistin use from 25 institutions were submitted. The most commonly targeted organisms were multidrug-resistant Pseudomonas (67.4%), multidrug-resistant Acinetobacter -baumanii (11.9%), carbapenemase-producing Enterobacteriaceae (13.0%) and extended-spectrum β-lactamase producing Enterobacteriaceae (5.4%). Development of resistance to colistin was observed in 20.5% of patients. Additional antimicrobial therapy was administered to 84% of patients, and 22% of children experienced nephrotoxicity (not associated with dosage or interval of colistin prescribed). Renal function returned to baseline in all patients. Children aged ≥13 years had approximately 7 times the odds of developing nephrotoxicity than younger children, even after controlling for receipt of additional nephrotoxic agents (odds ratio 7.16; 95% confidence interval: 1.51-14.06; P = 0.013). Four children exhibited reversible neurotoxicity.. Most pediatric infectious diseases specialists have no experience prescribing colistin. Colistin use in children has been associated primarily with nephrotoxicity and, to a lesser extent, neurotoxicity, both of which are reversible. Emergence of resistance to colistin is concerning.

Topics: Administration, Intravenous; Adolescent; Analysis of Variance; Anti-Bacterial Agents; Bacterial Infections; Child; Child, Preschool; Colistin; Drug Resistance, Bacterial; Humans; Infant; Kidney Diseases; Logistic Models; Practice Patterns, Physicians'; Retrospective Studies; Treatment Outcome; United States

Acquired Bartter-like syndrome (BLS), characterized by hypokalemic metabolic alkalosis, hypomagnesemia, hypocalcemia, and normal kidney function, can be induced by diuretics or antibiotics. It is a very rare condition and only anecdotal cases mostly in adults were reported. Although tubulopathy associated with colistin was reported in adults, to the best of our knowledge, colistin-associated BLS neither in adults nor in children has been reported in the literature. We here report a-28-week, 740 g female preterm infant who developed BLS just after colistin treatment for Acinetobacter baumannii infection and recovered few days after the drug cessation, and discuss the possible association of colistin and tubulopathy. More research on colistin pharmacokinetics and pharmacodynamics in critically ill patients and preterm infants is needed to guide adequate colistin dosing at the least toxicity.

Topics: Adult; Anti-Bacterial Agents; Bartter Syndrome; Colistin; Enterocolitis, Necrotizing; Female; Humans; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases; Kidney Diseases; Pregnancy

The use of colistin in the treatment of life-threatening Gram-negative infections is associated with a high rate of nephrotoxicity that is dose limiting. This study aimed to examine the nephroprotective effect of ascorbic acid against colistin-induced nephrotoxicity.. Rats were treated intravenously twice daily with saline, colistin (cumulative dose of 36.5 mg/kg), a combination of ascorbic acid (50 or 200 mg/kg) and colistin, or ascorbic acid (200 mg/kg) over 7 days. Colistin-induced apoptosis was examined in rats over 5 days and in vitro using rat renal proximal tubular cells NRK-52E over 24 h with and without ascorbic acid. The effect of co-administered ascorbic acid on colistin pharmacokinetics was investigated.. The 24 h urinary excretion of N-acetyl-β-D-glucosaminidase, a sensitive marker for tubular damage, was significantly lower (P < 0.0001) in the colistin/ascorbic acid 200 mg/kg group. Significant histological abnormalities (P < 0.01) were detected only in the kidneys of the colistin group, which also had the highest percentage (30.6 ± 7.8%) of apoptotic cells (P < 0.005). In the cell culture studies, the percentage of apoptotic cells was significantly higher in the presence of 0.1 mM colistin alone (51.8 ± 2.0%; P < 0.0001) than in the presence of ascorbic acid, which decreased the apoptotic effect in a concentration-dependent manner. Ascorbic acid (200 mg/kg) altered colistin pharmacokinetics, as the total body clearance decreased from 3.78 ± 0.36 mL/min/kg (colistin group) to 2.46 ± 0.57 mL/min/kg (P = 0.0024).. This is the first study demonstrating the protective effect of ascorbic acid against colistin-induced nephrotoxicity and tubular apoptosis. Co-administration of ascorbic acid has the potential to increase the therapeutic index of colistin.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Ascorbic Acid; Cells, Cultured; Colistin; Injections, Intravenous; Kidney Diseases; Male; Rats; Rats, Sprague-Dawley; Vitamins

Gram-negative bacteria susceptible only to colistin (COS) are emerging causes of severe nosocomial infections, reviving interest in the use of colistin. However, consensus on the most effective way to administer colistin has not yet been reached.. All patients who had sepsis due to COS gram-negative bacteria or minimally susceptible gram-negative bacteria and received intravenous colistimethate sodium (CMS) were prospectively enrolled. The CMS dosing schedule was based on a loading dose of 9 MU and a 9-MU twice-daily fractioned maintenance dose, titrated on renal function. For each CMS course, clinical cure, bacteriological clearance, daily serum creatinine clearance, and estimated creatinine clearance were recorded.. Twenty-eight infectious episodes due to Acinetobacter baumannii (46.4%), Klebsiella pneumoniae (46.4%), and Pseudomonas aeruginosa (7.2%) were analyzed. The main types of infection were bloodstream infection (64.3%) and ventilator-associated pneumonia (35.7%). Clinical cure was observed in 23 cases (82.1%). Acute kidney injury developed during 5 treatment courses (17.8%), did not require renal replacement therapy, and subsided within 10 days from CMS discontinuation. No correlation was found between variation in serum creatinine level (from baseline to peak) and daily and cumulative doses of CMS, and between variation in serum creatinine level (from baseline to peak) and duration of CMS treatment.. Our study shows that in severe infections due to COS gram-negative bacteria, the high-dose, extended-interval CMS regimen has a high efficacy, without significant renal toxicity.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Cohort Studies; Colistin; Critical Illness; Cross Infection; Female; Gram-Negative Bacterial Infections; Humans; Kidney Diseases; Male; Middle Aged; Prospective Studies; Sepsis; Treatment Outcome

In this study we aimed to assess the safety and efficacy of high-dose IV colistin (COL) and aerosolized COL for the treatment of Acinetobacter baumannii ventilator-associated pneumonia (VAP). Critically ill adult patients who received IV COL for multidrug-resistant A. baumannii VAP were evaluated retrospectively. A total of 45 patients were evaluated [15 patients with high-dose COL (2.5 mg/kg every 6 h), 20 patients with normal dose (2.5 mg/kg every 12 h), and 10 patients with low dose, determined according to creatine clearance]. Aerosolized COL was used in 29 patients treated with parenteral COL and 16 patients received only parenteral COL. The clinical response rates on the fifth day were 50, 30, and 27 % with the normal, low, and high doses, respectively. However, the clinical response rates at the end of the therapy had declined to 30, 30, and 7 % with the normal, low, and high doses, respectively. The bacteriological clearance rates at the end of the therapy were 65, 75, and 64 %, with the normal, low, and high doses, respectively. With the aerosolized COL, the clinical response rates on the fifth day and at the end of the therapy were 35 and 14 %, whereas these rates were 44 and 38 % without the aerosolized COL. Bacteriological clearance rates with and without the aerosolized COL were 76 and 69 %, respectively. The nephrotoxicity rate was 40 % for the high-dose COL, whereas it was 35 % for the normal dose, and 20 % for the low-dose COL. In conclusion, higher doses of COL and aerosolized COL had no advantages over lower doses in alleviating multidrug-resistant A. baumannii VAP. Moreover, the higher doses and the aerosolized COL increased the nephrotoxicity risk and seemed not to be safe.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Administration, Inhalation; Administration, Intravenous; Adult; Aerosols; Aged; Anti-Bacterial Agents; Chi-Square Distribution; Colistin; Drug Resistance, Multiple, Bacterial; Female; Humans; Kidney Diseases; Male; Middle Aged; Pneumonia, Bacterial; Pneumonia, Ventilator-Associated; Retrospective Studies; Statistics, Nonparametric; Turkey

The protective effect of N-acetylcysteine (NAC) on nephrotoxicity due to contrast nephropathy and reperfusion-induced ischemia has been reported in experimental models. However, its efficacy on colistin-induced nephrotoxicity has not been elucidated yet. The primary aim of this study was to evaluate the nephrotoxic effect of colistin and to investigate the possible protective effect of NAC on colistin-induced nephrotoxicity. The secondary aim was to research the systemic effects of nephrotoxicity-induced oxidative stress on the lung.. Eighteen female Sprague-Dawley rats were randomly assigned and were given (a) 1 ml/kg sterile saline, (b) 300,000 IU/kg/day colistin, and (c) 300,000 IU/kg/day colistin and 150 mg/kg NAC for six consecutive days.. Plasma blood urea nitrogen (BUN), creatinine, urinary creatinine, urinary protein, plasma TNF-alpha levels, renal tissue superoxide dismutase (SOD) and malondialdehyde (MDA) activity and immunocytochemical findings were evaluated. Colistin exerted nephrotoxicity and achieved a significant increase in plasma BUN and creatinine levels and renal tissue SOD levels. NAC exhibited no significant effect on biochemical parameters but reduced renal tissue SOD level and reversed immunocytochemical staining of inducible nitric oxide synthase (i-NOS) and neurotrophin-3. Increased oxidative stress in the lung tissue of the rats treated with colistin has also been documented. Additionally, NAC significantly reduced the immunostaining of endothelial NOS (e-NOS) and i-NOS in the lung tissue.. Colistin-induced renal toxicity may be attributable to oxidative damage. The combined treatment of colistin plus NAC seems to have a beneficial role in restoration of the oxidant injury which may be related to its antioxidant effect.

Topics: Acetylcysteine; Animals; Anti-Bacterial Agents; Colistin; Female; Kidney Diseases; Lung; Oxidative Stress; Rats; Rats, Sprague-Dawley

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Child; Colistin; Creatinine; Drug Resistance, Multiple, Bacterial; Female; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Risk Factors; Thailand

Colistin, originally abandoned due to high rates of nephrotoxicity, has been recently reintroduced due to activity against carbapenem-resistant Gram-negative organisms. Recent literature, largely obtained from outside the United States, suggests a lower rate of nephrotoxicity than historically reported.. A retrospective cohort of all patients who received colistin for ≥ 48 hours at the Detroit Medical Center over a 5-year period was performed to determine the rate of colistin-associated nephrotoxicity as defined by the RIFLE criteria.. Fifty-four (43%) patients in the cohort developed nephrotoxicity. Patients who experienced nephrotoxicity after colistin administration were in the Risk (13%), Injury (17%), or Failure (13%) categories per RIFLE criteria. Patients who developed nephrotoxicity received significantly higher mean doses than those who did not (5.48 mg/kg per day vs 3.95 mg/kg per day; P < .001), and the toxicity occurred in a dose-dependent fashion. Independent predictors for nephrotoxicity were a colistin dose of ≥ 5.0 mg/kg per day of ideal body weight (odds ratio [OR], 23.41; 95% confidence interval [CI], 5.3-103.55), receipt of concomitant rifampin (OR, 3.81; 95% CI, 1.42-10.2), and coadministration of ≥ 3 concomitant nephrotoxins (OR, 6.80; 95% CI, 1.42-32.49).. In this retrospective cohort, nephrotoxicity (as defined by RIFLE criteria) occurred among 43% of treated patients in a dose-dependent manner. Higher colistin doses, similar to those commonly used in the United States, led to a relatively high rate of nephrotoxicity. These data raise important questions regarding the safe use of colistin in the treatment of multidrug-resistant pathogens.

Topics: Academic Medical Centers; Adult; Aged; Anti-Bacterial Agents; Cohort Studies; Colistin; Female; Humans; Incidence; Kidney Diseases; Male; Middle Aged; Retrospective Studies; Risk Factors; United States

To determine the frequency of nephrotoxicity associated with colistin therapy by using a standardized definition and to identify risk factors for colistin-induced nephrotoxicity in critically ill patients.. Single-center, retrospective cohort analysis.. University-affiliated tertiary care center.. Forty-nine adults admitted to an intensive care unit who received intravenous colistin for at least 48 hours between July 2007 and July 2009.. Nephrotoxicity was determined by using the standardized RIFLE criteria: risk, injury, failure, loss, and end-stage renal disease. Patients who had end-stage renal disease or required renal replacement therapy before initiation of colistin were excluded. Of the 49 patients included in the analysis, 15 (31%) developed nephrotoxicity, and only two patients (4%) had irreversible cases. Patients with chronic kidney disease (40% in the group with nephrotoxicity vs 3% in the group without nephrotoxicity, p=0.002) and hypertension (87% vs 56%, p=0.037) at baseline had a higher risk of developing nephrotoxicity. In addition, patients with nephrotoxicity were more likely to have received intravenous contrast material (33% vs 0%, p=0.002). The risk of developing nephrotoxicity was 6.5 times higher in patients who had been given at least two concomitant nephrotoxic agents compared with no other nephrotoxic agents (p=0.034).. The frequency and severity of colistin-induced nephrotoxicity in critically ill patients was consistent with previous reports in non-critically ill patients. Most cases of nephrotoxicity demonstrated in this study were mild and reversible. Patients receiving colistin therapy who have hypertension or chronic kidney disease should be monitored closely, and administration of additional nephrotoxic agents should be avoided in all patients when possible. Large, prospective trials are warranted to confirm these results.

Topics: Adult; Aged; Anti-Bacterial Agents; Cohort Studies; Colistin; Critical Illness; Female; Humans; Hypertension; Injections, Intravenous; Intensive Care Units; Kidney Diseases; Male; Middle Aged; Retrospective Studies; Risk Factors; Severity of Illness Index

Multidrug-resistant (MDR) bacterial infections are increasing in Taiwan hospitals, prompting the common use of colistin. In this study, the safety and efficacy of intravenous (i.v.) colistin was assessed. The medical records of patients receiving colistin for treatment of MDR Gram-negative bacterial infections between January 2006 and September 2008 at a Taiwan medical centre were reviewed retrospectively. Demographics, clinical presentation, causative organism, adverse events and outcomes were recorded. Of the 115 patient records analysed, 74 patients (64%) were treated in the Intensive Care Unit. Common underlying diseases were hypertension (49%), chronic pulmonary disease (46%), chronic kidney disease (33%) and malignancy (31%). Lower respiratory tract infections were most common (71%), followed by primary bloodstream infections (12%), urinary tract infections (8.7%) and others (7.8%). Successful treatment with i.v. colistin against MDR Gram-negative bacterial infections occurred in 59 patients (51%). Multivariate analysis showed that a higher Acute Physiology and Chronic Health Evaluation (APACHE) II score (odds ratio=1.14; 95% confidence interval 1.02-1.28; P=0.02) was independently associated with a poor clinical response. Overall, 12 (14%) of 84 patients presented nephrotoxicity and 4 patients (3.5%) had neurotoxicity. In conclusion, colistin is an effective antimicrobial agent for severe infections caused by MDR Gram-negative bacteria. Clinical outcomes are associated with the severity of infection and underlying diseases. Compared with previous reports, this study showed a lower incidence of nephrotoxicity and neurotoxicity.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Central Nervous System; Central Nervous System Diseases; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Kidney; Kidney Diseases; Male; Middle Aged; Retrospective Studies; Taiwan; Treatment Outcome

In recent reports polymyxins have been considered an effective and safe treatment option for the management of multidrug-resistant (MDR) Gram-negative bacterial infections. Here we report our clinical experience with the use of intravenous colistin sulfate in critically ill patients hospitalized from January 2006 to October 2008, as a last treatment resort in China, and assess its effectiveness and adverse effects. Fifteen patients who suffered from severe infections caused by MDR or pandrug-resistant (PDR) Gram-negative bacteria (13 isolates of Acinetobacter baumannii, 4 isolates of Pseudomonas aeruginosa and 2 isolates of Klebsiella pneumoniae), unresponsive to the initial empirical regimens, were treated with colistin sulfate (daily dose of 1.28 +/- 0.25 million IU and duration of 22.3 +/- 6.2 days), based on sensitivity results. The treatment resulted in a good clinical response in 73.3%, microbiological clearance in 60% and mortality in 20%. Possible nephrotoxicity occurred in 1 patient and no patients developed neurotoxicity. In conclusion, intravenous colistin sulfate is a safe and viable alternative for the treatment of severe infections due to sensitive MDR Gram-negative bacteria.

Topics: Adult; Aged; Anti-Bacterial Agents; Central Nervous System Diseases; China; Colistin; Critical Illness; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; Humans; Injections, Intravenous; Kidney; Kidney Diseases; Male; Middle Aged; Retrospective Studies; Treatment Outcome

Colistimethate sodium (CMS) was recently re-introduced into clinical practice as a last resort for the treatment of nosocomial infections caused by multiresistant bacteria. This retrospective cohort study was designed to identify predictors of acute kidney injury (AKI) associated with intravenous (i.v.) CMS treatment. From March 2007 to July 2008, 71 adult patients receiving CMS for > or = 72h were enrolled. AKI was defined using Risk, Injury, Failure, Loss and End-stage kidney disease (RIFLE) criteria according to serum creatinine. The median total dose of CMS was 54.3mg/kg (range 27.5-94.5mg/kg). AKI developed in 38 patients (53.5%). Cox regression analysis based of cumulative CMS dose (mg/kg) identified four independent predictors of AKI: male sex [hazard ratio (HR)=3.55, 95% confidence interval (CI), 1.47-8.55]; concomitant use of a calcineurin inhibitor (HR=6.74, 95% CI 2.49-18.24); hypoalbuminaemia (serum albumin level <2.0g/dL) (HR=6.29, 95% CI 2.04-19.39); and hyperbilirubinaemia (total bilirubin level >5mg/dL) (HR=3.53, 95% CI 1.17-10.71). In conclusion, AKI was a common complication of i.v. CMS treatment. Male sex, concomitant use of calcineurin inhibitors, hypoalbuminaemia and hyperbilirubinaemia were independent predictors of AKI. The effect of AKI on patient outcomes was not determined.

Topics: Aged; Anti-Bacterial Agents; Bacterial Infections; Cohort Studies; Colistin; Creatinine; Cross Infection; Female; Humans; Infusions, Intravenous; Kidney; Kidney Diseases; Male; Middle Aged; Retrospective Studies; Risk Factors

Topics: Anti-Bacterial Agents; Bacterial Infections; Colistin; Humans; Kidney Diseases

To describe the clinical and microbiological outcomes of patients infected with multidrug-resistant Pseudomonas aeruginosa (MDRP) treated with colistin (colistimethate sodium) and the adverse events observed with this treatment.. Retrospective study of MDRP infections treated with colistin from 1997 to 2006.. 121 episodes were identified. The median daily intravenous dose was 240 mg/day; 28.9% of patients received intravenous and nebulized colistin. Clinical outcome was favorable in ten cases of bacteremia (62.5%, n = 16), 43 cases of bronchial infection (72.9%, n = 59), 13 cases of pneumonia (65%, n = 20), 11 cases of urinary infection (84.6%, n = 13), eight cases of skin and soft tissues (72.7%, n = 11), and in the one case of arthritis and one case of otitis. Eradication was achieved in 31 (34.8%) of the 89 patients with available bacteriologic data. Factors associated with bacteriological failure were smoking, chronic obstructive pulmonary disease (COPD), and previous infection with P. aeruginosa. Nephrotoxicity occurred in ten cases (8.3%), with the associated factors being previous chronic renal insufficiency, diabetes mellitus, and aminoglycoside use. Crude mortality was 16.5%, and related MDRP was 12.4%, and was higher in patients with pneumonia or bacteremia (36.1%) than in other types of infections (8.2%).. Colistin is a safe option for the treatment of MDRP infections, with acceptable clinical outcomes. However, bacteriological eradication is difficult to achieve, especially in COPD patients.

Topics: Administration, Inhalation; Aged; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Female; Humans; Injections, Intravenous; Kidney Diseases; Male; Middle Aged; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Treatment Outcome

We retrospectively assessed the renal toxicity associated with the use of intravenous colistin. Fifty-four patients with multidrug-resistant Acinetobacter infections were included. At the end of therapy 6/54 patients (11%) suffered renal impairment. Renal impairment associated with the use of colistin is less frequent than initially reported.

Topics: Acinetobacter Infections; Adult; Anti-Bacterial Agents; Colistin; Creatinine; Humans; Injections, Intravenous; Kidney Diseases; Kidney Function Tests; Microbial Sensitivity Tests; Retrospective Studies; Statistics, Nonparametric

Since multidrug-resistant gram-negative organisms have been increasing, polymyxin E (colistin) has been reintroduced despite its nephrotoxicity. A case-control study was performed to investigate the incidence, clinical characteristics and risk factors of colistin-induced nephrotoxicity. From August 2006 to June 2008, 47 cases receiving at least one defined daily dose (DDD) of intravenous colistin were included; 15 (31.9%) of the 47 cases developed nephrotoxicity with preserved urine output, 3 (20%) of whom underwent renal replacement therapy. The mean dosage of colistimethate sodium was 2.25 g (22.5 DDD; range 0.6-8.7 g) at the time of nephrotoxicity. Of 10 patients who were re-assessed for renal function after 1 month, 9 (90%) recovered their renal function. In the univariate analysis, site of infection, hypoalbuminaemia and cumulative dosage of the second-generation fluoroquinolones, aminoglycosides and non-steroidal anti-inflammatory drugs (NSAIDs) co-administered during colistin treatment as well as concomitant use of NSAIDs were risk factors for nephrotoxicity. However, in the logistic regression hypoalbuminaemia and the use of NSAIDs were significant risk factors for increased nephrotoxicity during colistin administration, suggesting that free colistin might cause renal toxicity. In conclusion, colistin-induced nephrotoxicity occurred at a high rate, and hypoalbuminaemia and concomitant use of NSAIDs were significant risk factors.

Topics: Adult; Aged; Anti-Bacterial Agents; Anti-Inflammatory Agents, Non-Steroidal; Case-Control Studies; Colistin; Female; Gram-Negative Bacterial Infections; Humans; Hypoalbuminemia; Incidence; Kidney; Kidney Diseases; Male; Middle Aged; Risk Factors

The relative nephro- and neurotoxicity of colistin methanesulfonate (CMS) was investigated with rats during 7 days of intravenous administration in regimens mimicking twice- and once-daily dosing of a clinically relevant dose for humans. Histological examination revealed more-severe renal lesions with the regimen corresponding to once-daily dosing, indicating that the potential for renal toxicity may be greater with extended-interval dosing.

Topics: Animals; Anti-Bacterial Agents; Behavior, Animal; Colistin; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Injections, Intravenous; Kidney; Kidney Diseases; Mesylates; Motor Activity; Rats; Rats, Sprague-Dawley

Topics: Colistin; Drug Resistance, Multiple, Bacterial; Gram-Negative Bacterial Infections; Humans; Kidney Diseases; Polymyxin B

The prospective case series study presented here was conducted to assess the outcome of patients with infections caused by polymyxin-only-susceptible (POS) gram-negative bacteria managed with intravenous colistin. Between July 2003 and April 2005 a total of 27 patients were infected with a POS gram-negative bacterium and received intravenous colistin at a dose of 2 million international units (MIU) (160 mg or 66.7 mg colistin base) every 8 h for a mean (+/-SD) duration of 13.9 (+/-7.5) days. Nine patients had ventilator-associated pneumonia and received, in addition to the intravenous colistin therapy, 1 MIU (80 mg or 33.3 mg colistin base) aerosolized colistin every 12 h for a mean (+/-SD) duration of 13 (+/-6.5) days. The predominant pathogens were Pseudomonas aeruginosa (n = 17) and Acinetobacter baumannii (n = 12); in two patients both pathogens were isolated from one clinical specimen. In-hospital mortality and clinical response were 15% and 85%, respectively. Colistin-associated nephrotoxicity was observed in two of the 27 patients. POS gram-negative pathogens represent a major threat for hospitalized patients. Colistin appears to be an effective and safe treatment, even in patients with severe underlying diseases.

Topics: Acinetobacter baumannii; Acinetobacter Infections; Adult; Aged; Aged, 80 and over; Anti-Bacterial Agents; Colistin; Drug Resistance, Multiple, Bacterial; Female; Gram-Negative Bacterial Infections; Humans; Infusions, Intravenous; Kidney Diseases; Male; Middle Aged; Pneumonia, Ventilator-Associated; Prospective Studies; Pseudomonas aeruginosa; Treatment Outcome

Topics: Acinetobacter Infections; Anti-Bacterial Agents; Colistin; Drug Resistance, Bacterial; Humans; Kidney Diseases

The authors test antibiotic strategies aimed at either mitigating bacterial translocation from the gut or delivering antibiotics specifically concentrated by the pancreas for prevention of early secondary infection after acute necrotizing pancreatitis.. Infection currently is the principal cause of death after severe pancreatitis. The authors have shown that the risk of bacterial infection correlates directly with the degree of tissue injury in a rodent model of pancreatitis. Bacteria most likely arrive by translocation from the colon.. Severe acute necrotizing pancreatitis was induced in rats by a combination of low-dose controlled intraductal infusion of glycodeoxycholic acid superimposed on intravenous cerulein hyperstimulation. At 6 hours, animals were randomly allocated to five treatment groups: controls, selective gut decontamination (oral antibiotics and cefotaxime), oral antibiotics alone, cefotaxime alone, or imipenem. At 96 hours, surviving animals were killed for quantitative bacterial study of the cecum, pancreas, and kidney.. The 96-hour mortality (35%) was unaffected by any treatment regimen. Cecal gram-negative bacteria were significantly reduced only by the oral antibiotics. Pancreatic infection was significantly reduced by full-gut decontamination and by imipenem, but not by oral antibiotics or by cefotaxime alone. Renal infection was reduced by both intravenous antibiotics.. Early pancreatic infection after acute necrotizing pancreatitis can be reduced with a full-gut decontamination regimen or with an antibiotic concentrated by the pancreas (imipenem) but not by unconcentrated antibiotics of similar spectrum (cefotaxime) or by oral antibiotics alone. These findings suggest that 1) both direct bacterial translocation from the gut and hematogenous seeding interplay in pancreatic infection while hematogenous seeding is dominant at extrapancreatic sites and 2) imipenem may be useful in clinical pancreatitis.

Topics: Acute Disease; Administration, Oral; Amphotericin B; Animals; Bacteria; Bacterial Infections; Bacterial Physiological Phenomena; Cecal Diseases; Cefotaxime; Colistin; Disease Models, Animal; Drug Therapy, Combination; Imipenem; Injections, Intravenous; Kidney Diseases; Male; Necrosis; Pancreas; Pancreatic Diseases; Pancreatitis; Rats; Rats, Sprague-Dawley; Survival Rate; Tobramycin

Topics: Ampicillin; Child, Preschool; Chloramphenicol; Colistin; Diagnosis, Differential; Drug Eruptions; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Electroencephalography; Erythromycin; Female; Fever; Humans; Hydrocortisone; Infections; Kanamycin; Kidney Diseases; Male; Middle Aged; Penicillins; Pericarditis; Pertussis Vaccine; Pleural Diseases; Recurrence; Salicylates; Tetracycline; Tonsillectomy

Topics: Aminohippuric Acids; Animals; Colistin; Dogs; Glomerular Filtration Rate; Glucose; Inulin; Kidney; Kidney Concentrating Ability; Kidney Diseases; Kidney Tubules; Mesylates; Nitrates; Polymyxins; Sulfates; Time Factors

Topics: Aged; Aniline Compounds; Biopsy, Needle; Carbuncle; Colistin; Humans; Kidney Diseases; Klebsiella Infections; Male; Sulfamethizole; Sulfathiazoles; Ultrasonography

Topics: Cephalothin; Colistin; Drug Synergism; Gentamicins; Humans; Kidney; Kidney Diseases

Topics: Anti-Bacterial Agents; Anuria; Colistin; Gentamicins; Glomerular Filtration Rate; Half-Life; Humans; Kidney; Kidney Diseases; Rolitetracycline; Streptomycin; Tetracycline; Vancomycin

Topics: Aged; Animals; Bordetella; Colistin; Dogs; Female; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Polymyxins; Urinary Tract Infections

Topics: Adult; Colistin; Diabetes Complications; Female; Humans; Kidney Diseases; Neurologic Manifestations; Paralysis

Topics: Acute Disease; Animals; Colistin; Kidney; Kidney Diseases; Male; Mannitol; Potentiometry; Rabbits

Topics: Abscess; Colistin; Female; Fistula; Humans; Kidney Diseases; Middle Aged; Postoperative Complications; Salmonella Infections

Topics: Acute Kidney Injury; Adolescent; Adult; Age Factors; Aged; Apnea; Body Weight; Colistin; Drug Hypersensitivity; Female; Follow-Up Studies; Humans; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Nausea; Nervous System Diseases; Paresthesia; Pneumonia; Prospective Studies; Pyelonephritis; Respiratory Insufficiency; Sepsis; Sex Factors; Statistics as Topic; Time Factors; Vomiting

Topics: Adolescent; Basement Membrane; Colistin; Cytoplasm; Endoplasmic Reticulum; Epithelium; Humans; Kidney; Kidney Diseases; Kidney Glomerulus; Kidney Tubules; Leukemia, Lymphoid; Male; Microscopy, Electron; Plasma Cells; Pseudomonas Infections; Rhinitis; Streptomycin

Topics: Colistin; Diuretics; Gold; Humans; Kanamycin; Kidney Diseases; Mercury; Methicillin; Nitrofurans; Phenindione; Phenylbutazone; Streptomycin; Sulfonamides

Topics: Colistin; Humans; Kidney Diseases; Nephritis; Nephritis, Interstitial; Nervous System Diseases; Toxicology

Topics: Blood; Colistin; Humans; Injections, Intramuscular; Kidney; Kidney Diseases; Kidney Function Tests; Kidneys, Artificial; Renal Insufficiency; Toxicology

Topics: Colistin; Drug Resistance; Drug Resistance, Microbial; Kidney Diseases; Mice; Pathology; Polymyxin B; Polymyxins; Pseudomonas; Pseudomonas Infections; Research; Toxicology

Topics: Animals, Newborn; Colistin; Dogs; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Kidney Diseases; Mesylates; Methane; Pseudomonas Infections; Research; Toxicology; Urea

Topics: Colistin; Drug Resistance; Drug Resistance, Microbial; Humans; Kidney Diseases; Polymyxin B; Polymyxins; Pseudomonas Infections; Toxicology

Topics: Blood; Body Fluids; Colistin; Kidney Diseases; Kidney Function Tests; Toxicology; Urinary Tract Physiological Phenomena; Urine

Topics: Blood Chemical Analysis; Chemical and Drug Induced Liver Injury; Colistin; Diverticulitis; Diverticulitis, Colonic; Escherichia coli Infections; Hepatitis A; Intestinal Perforation; Kidney Diseases; Pathology; Sepsis; Toxicology

Topics: Anti-Bacterial Agents; Antibiotics, Antitubercular; Ataxia; Colistin; Dermatologic Agents; Humans; Kidney Diseases; Neurologic Manifestations

Topics: Anti-Bacterial Agents; Colistin; Escherichia coli Infections; Humans; Kidney; Kidney Diseases; Urinary Tract Infections