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Roger L Nation - One of the best experts on this subject based on the ideXlab platform.
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Nephrotoxicity of Polymyxins: Is There Any Difference between Colistimethate and Polymyxin B?
Antimicrobial agents and chemotherapy, 2017Co-Authors: Alexandre P. Zavascki, Roger L NationAbstract:ABSTRACT Nephrotoxicity is a common adverse effect of the clinically used polymyxins, colistin and polymyxin B. This adverse effect is dose limiting for both polymyxins, as the plasma polymyxin concentrations associated with renal damage overlap those required for antibacterial effect. Since development of acute kidney injury (AKI) during therapy is highly undesirable, it is extremely important to know whether there is any difference between the nephrotoxic potential of colistin (administered as its inefficient prodrug, Colistimethate) and polymyxin B (administered as the active form). Both polymyxins are cytotoxic to renal tubular cells and are prone to cause nephrotoxicity in vivo because of the renal handling mechanisms that facilitate accumulation of these compounds in these cells, processes that are reviewed in this article. Also reviewed are the emerging data that strongly suggest significantly higher rates of AKI in patients treated with Colistimethate compared to patients treated with polymyxin B. This finding may be due to differences in pharmacokinetics and renal handling mechanisms of Colistimethate and formed colistin versus polymyxin B, and consequently the relative amount of polymyxin material delivered to tubular cells. A lower risk of AKI with polymyxin B is one of several potential advantages over Colistimethate. The relative safety and efficacy of the two agents require closer examination in well-designed clinical studies.
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dosing guidance for intravenous colistin in critically ill patients
Clinical Infectious Diseases, 2016Co-Authors: Roger L Nation, Samira M Garonzik, Visanu Thamlikitkul, Evangelos J Giamarellosbourboulis, Alan Forrest, David L Paterson, Fernanda P SilveiraAbstract:Background. Intravenous colistin is difficult to use because plasma concentrations for antibacterial effect overlap those causing nephrotoxicity, and there is large interpatient variability in pharmacokinetics. The aim was to develop dosing algorithms for achievement of a clinically desirable average steady-state plasma colistin concentration (Css,avg) of 2 mg/L. Methods. Plasma concentration-time data from 214 adult critically ill patients (creatinine clearance, 0-236 mL/min; 29 receiving renal replacement therapy [RRT]) were subjected to population pharmacokinetic analysis. Development of an algorithm for patients not receiving RRT was based on the relationship between the dose of Colistimethate that would be needed to achieve a desired Css,avg and creatinine clearance. The increase in colistin clearance when patients were receiving RRT was determined from the population analysis and guided the supplemental dosing needed. To balance potential antibacterial benefit against risk of nephrotoxicity the algorithms were designed to achieve target attainment rates of >80% for Css,avg ≥2 and 80% of patients with creatinine clearance 80% with the proposed supplemental dosing. In all categories of patients, <30% of patients attained Css,avg ≥4 mg/L. Conclusions. The project has generated clinician-friendly dosing algorithms and pointed to circumstances in which intravenous monotherapy may be inadequate.
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Pharmacokinetics of four different brands of Colistimethate and formed colistin in rats
2016Co-Authors: Roger L Nation, Brian T Tsuji, Jovan Jacob, Gong Chen, Hee Ji Lee, Philip E. Thompson, Kade Roberts, Tony VelkovAbstract:Objectives: Very different labelling conventions are employed by different products of Colistimethate (CMS), an in-active prodrug of colistin that is used as a last-line defence against Gram-negative ‘superbugs’. This study exam-ined the chemical composition and pharmacokinetics in rats of four commercial parenteral products of CMS. Methods: Contents per vial of four brands of CMS from three different continents were weighed (n3). Elemental analysis and HPLC examination were conducted. The pharmacokinetics of CMS and formed colistin were investi-gated for each product after intravenous administration in rats (28.1 mg/kg CMS; n4). Blood was collected over 180 min, and concentrations of CMS and colistin were measured followed by pharmacokinetic analysis. Results: X-GEN, Paddock and Atlantic products, labelled with 150 mg ‘colistin base activity’, contained 366.8+0.80
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defining the dosage units for colistin methanesulfonate urgent need for international harmonization
Antimicrobial Agents and Chemotherapy, 2006Co-Authors: Roger L Nation, John D TurnidgeAbstract:In a recent letter in Antimicrobial Agents and Chemotherapy , Falagas and Kasiakou ([2][1]) made reference to the difference in the contents of and recommended dosage regimens for different parenteral colistin methanesulfonate (CMS, also known as Colistimethate) products available in various parts
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Comment on: Pharmacokinetics of inhaled colistin in patients with cystic fibrosis
2006Co-Authors: Roger L NationAbstract:Ratjen et al.1 recently published an important paper in JAC reporting the pharmacokinetics of colistin after inhalation of colistin methanesulphonate in patients with cystic fibrosis (CF). HPLC was used to measure the concentrations of the formed colistin. The paper raises a number of important issues that deserve comment. It is important not to use the terms colistin and colistin metha-nesulphonate (sodium salt, or Colistimethate-Na in the paper1) interchangeably. The chemistry, pharmacokinetics, pharmacody-namics and toxicity of these two entities are substantially differ-ent;2–5 most importantly, colistin is formed from colistin methanesulphonate both in vitro6 and in vivo.7,8 Even though some manufacturers (such as Grünenthal, Germany) label the content of injection vials of colistin methanesulphonate with ‘158 mg colistin methanesulphonate is equal to 66 m
Visanu Thamlikitkul - One of the best experts on this subject based on the ideXlab platform.
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dosing guidance for intravenous colistin in critically ill patients
Clinical Infectious Diseases, 2016Co-Authors: Roger L Nation, Samira M Garonzik, Visanu Thamlikitkul, Evangelos J Giamarellosbourboulis, Alan Forrest, David L Paterson, Fernanda P SilveiraAbstract:Background. Intravenous colistin is difficult to use because plasma concentrations for antibacterial effect overlap those causing nephrotoxicity, and there is large interpatient variability in pharmacokinetics. The aim was to develop dosing algorithms for achievement of a clinically desirable average steady-state plasma colistin concentration (Css,avg) of 2 mg/L. Methods. Plasma concentration-time data from 214 adult critically ill patients (creatinine clearance, 0-236 mL/min; 29 receiving renal replacement therapy [RRT]) were subjected to population pharmacokinetic analysis. Development of an algorithm for patients not receiving RRT was based on the relationship between the dose of Colistimethate that would be needed to achieve a desired Css,avg and creatinine clearance. The increase in colistin clearance when patients were receiving RRT was determined from the population analysis and guided the supplemental dosing needed. To balance potential antibacterial benefit against risk of nephrotoxicity the algorithms were designed to achieve target attainment rates of >80% for Css,avg ≥2 and 80% of patients with creatinine clearance 80% with the proposed supplemental dosing. In all categories of patients, <30% of patients attained Css,avg ≥4 mg/L. Conclusions. The project has generated clinician-friendly dosing algorithms and pointed to circumstances in which intravenous monotherapy may be inadequate.
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randomized controlled trial of nebulized Colistimethate sodium as adjunctive therapy of ventilator associated pneumonia caused by gram negative bacteria
Journal of Antimicrobial Chemotherapy, 2010Co-Authors: Pinyo Rattanaumpawan, Jintana Lorsutthitham, Puangpaka Ungprasert, Nasikarn Angkasekwinai, Visanu ThamlikitkulAbstract:Background: Cases of ventilator-associated pneumonia (VAP) due to multidrug-resistant (MDR) Acinetobacter baumannii and Pseudomonas aeruginosa are common in hospitalized patients at Siriraj Hospital, Bangkok, Thailand. Parenteral Colistimethate sodium (CMS) has been used for therapy of VAP caused by MDR A. baumannii and P. aeruginosa at Siriraj Hospital over the past few years, with modest favourable outcomes. Objectives: To determine whether nebulized CMS as adjunctive therapy of Gram-negative VAP was safe and beneficial. Methods: This was a randomized controlled study in 100 adults who developed Gram-negative VAP (clinical trial registration number: NCT00920270). All patients received systemic antibiotics according to the decisions of their responsible physicians. The patients were randomized to receive an additional 4 mL of nebulized sterile normal saline (NSS) (n= 49 ) or nebulized CMS equivalent to 75 mg of colistin base in 4 mL of NSS (n= 51 ) every 12 h until systemic antibiotic therapy of VAP was ended. Results: The baseline characteristics of the patients and conventional therapy of VAP in both groups were comparable. Most of the cases of VAP were caused by MDR A. baumannii and/or P. aeruginosa. All isolates of Gram-negative bacteria were susceptible to colistin. Favourable clinical outcome was 51.0% in the CMS group and 53.1% in the control group (P=0.84). Patients in the CMS group had significantly more favourable microbiological outcome when compared with patients in the control group (60.9% versus 38.2%, P= 0 . 03 ). Bronchospasm was observed in 7.8% of patients in the CMS group and in 2.0% of patients in the control group (P=0.36). Renal impairment was observed in 25.5% of patients in the CMS group and in 22.4% of patients in the NSS group (P=0.82). Conclusions: Nebulized CMS as adjunctive therapy of Gram-negative VAP seems to be safe. However, a beneficial effect on clinical outcomes of adjunctive nebulized CMS for therapy of Gram-negative VAP was not ascertained.
Dimitrios P. Kontoyiannis - One of the best experts on this subject based on the ideXlab platform.
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antifungal activity of colistin against mucorales species in vitro and in a murine model of rhizopus oryzae pulmonary infection
Antimicrobial Agents and Chemotherapy, 2010Co-Authors: Ronen Benami, Dimitrios P. Kontoyiannis, Russell E. Lewis, Jeffrey J Tarrand, Konstantinos LeventakosAbstract:In immunosuppressed hosts, mucormycosis is a life-threatening infection with few treatment options. We studied the activity of colistin (polymyxin E) against Mucorales species in vitro and in a murine model of pulmonary Rhizopus oryzae infection. Colistin exhibited fungicidal activity in vitro against Mucorales spores and mycelia. At the colistin MIC, initial R. oryzae hyphal damage was followed by rapid regrowth; however, regrowth was prevented by combining colistin with a subinhibitory concentration of amphotericin B. Using electron microscopy and FM4-64 staining, we demonstrated that colistin disrupts R. oryzae cytoplasmic and vacuolar membranes, resulting in the leakage of intracellular contents. The prophylactic intranasal treatment of immunosuppressed mice with Colistimethate significantly reduced the mortality rate and pulmonary fungal burden resulting from inhalational challenge with R. oryzae spores, whereas intraperitoneal Colistimethate treatment had no effect. We conclude that colistin has modest in vitro and in vivo fungicidal activity against Mucorales spp. Further studies are warranted to assess the use of this drug in the prevention and treatment of mucormycosis.
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Antifungal Activity of Colistin against Mucorales Species In Vitro and in a Murine Model of Rhizopus oryzae Pulmonary Infection
2009Co-Authors: Ronen Ben-ami, Konstantinos Leventakos, Russell E. Lewis, Jeffrey Tarr, Dimitrios P. KontoyiannisAbstract:In immunosuppressed hosts, mucormycosis is a life-threatening infection with few treatment options. We studied the activity of colistin (polymyxin E) against Mucorales species in vitro and in a murine model of pulmonary Rhizopus oryzae infection. Colistin exhibited fungicidal activity in vitro againstMucorales spores and mycelia. At the colistin MIC, initial R. oryzae hyphal damage was followed by rapid regrowth; however, regrowth was prevented by combining colistin with a subinhibitory concentration of amphotericin B. Using electron microscopy and FM4-64 staining, we demonstrated that colistin disrupts R. oryzae cytoplasmic and vacuolar membranes, resulting in the leakage of intracellular contents. The prophylactic intranasal treatment of immuno-suppressedmice with Colistimethate significantly reduced themortality rate and pulmonary fungal burden resulting from inhalational challenge with R. oryzae spores, whereas intraperitoneal Colistimethate treatment had no effect. We conclude that colistin has modest in vitro and in vivo fungicidal activity against Mucorales spp. Further studies are warranted to assess the use of this drug in the prevention and treatment of mucormycosis. During the past decade, pulmonary mucormycosis (PMM) has emerged as an important life-threatening opportunistic infection in severely immunocompromised patients, such as those with prolonged neutropenia and recipients of allogenei
Preeti Mehta - One of the best experts on this subject based on the ideXlab platform.
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pharmacokinetics of colistin in critically ill patients with multidrug resistant gram negative bacilli infection
European Journal of Clinical Pharmacology, 2013Co-Authors: Niteen D Karnik, Kannan Sridharan, Sonali Jadhav, Prashant P Kadam, Raghu K Naidu, Rahul Namjoshi, Vishal Gupta, Mangesh S Gore, Pallavi Surase, Preeti MehtaAbstract:Colistin, which had not been used widely because of nephrotoxicity and neurotoxicity, has gained clinical importance in recent times due to the resurgence of multidrug-resistant Gram-negative bacilli. Very few studies, especially pharmacokinetic studies, have been performed with intravenous Colistimethate sodium, and none in India. The aim of our study was to study the single-dose and steady-state pharmacokinetics of colistin in patients with multidrug-resistant Gram-negative bacilli infections. This was a prospective open-label pharmacokinetic study done in an intensive care unit in a tertiary care hospital on 15 critically ill patients with proven multidrug-resistant Gram-negative bacilli infection. Colistimethate sodium was injected as intermittent intravenous infusions in accordance with the recommendations on the package insert. For patients weighing ≥60 kg with a normal renal function or with a creatinine clearance (CLCR) of between 20 and 50 ml/min, the drug was administered at 2 million international units (MIU) every 8 h; for those with a CLCR of 10–20 ml/min, the dose was 2 MIU every 12 h. Those patients who weighed 8 was achieved in seven of nine patients after the single dose and in seven of eight patients at steady-state. For those patients whose cultures grew Pseudomonas spp, only one patient after the single dose and one patient at steady-state achieved a Cmax/MIC ratio of >8. A significant association was noted between dose and survival, and a trend was observed with patients weighing ≤60 kg (who received 50,000 IU/kg/day instead of 6 MIU/day for those >60 kg) having an increased mortality. The pharmacokinetic parameters of colistin were comparable to those reported in previous studies in critically ill patients. However, the recommended dose may be inadequate to maintain the Cmax/MIC ratio to an optimal level—at least in patients infected with Pseudomonas spp. The dose recommendation should be based only on creatinine clearance and not body weight.
Robert P Rapp - One of the best experts on this subject based on the ideXlab platform.
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polymyxin b sulfate and colistin old antibiotics for emerging multiresistant gram negative bacteria
Annals of Pharmacotherapy, 1999Co-Authors: Martin E Evans, David J Feola, Robert P RappAbstract:BACKGROUND:Polymyxin B sulfate and colistin, also known as Colistimethate, have not been used for many years because less toxic antimicrobials are available. Gram-negative bacteria that are resistant to the aminoglycosides, β-lactams, and fluoroquinolones are becoming more common. These bacteria are often susceptible to the polymyxins.OBJECTIVE:To present a review of the chemistry, antibacterial spectrum, dosing, pharmacokinetics, toxicity, and indications for polymyxin B sulfate and colistin.DATA SOURCE:A MEDLINE search (1966–1998) of the English-language literature was performed to identify primary literature on the polymyxins. Older citations (1949–1965) were identified through the bibliographies of these articles.STUDY SELECTION:All available reports of in vitro antibacterial activity, animal and clinical trials, and case reports were reviewed.DATA SYNTHESIS:The polymyxins are amphipathic molecules that interact with lipopolysaccharide in the bacterial outer membrane. They have potent antiendotoxic pr...