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    Colistin in Multidrug Resistant Bacteria

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    tummalapalli venkateswara rao
    Polymyxins are a class of antibiotics that work by disrupting the structure of the bacterial cell membrane of gram-negative bacteria through interaction with phospholipids and neutralizing endotoxins. While polymyxins like colistin are effective against multidrug-resistant bacteria, they can cause nephrotoxicity and neurotoxicity, especially in patients with impaired kidney function, so careful monitoring is required with their use. Recent increasing antimicrobial resistance has led to renewed interest in polymyxins as treatments for difficult infections despite their toxicities.

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    Colistin in Multidrug Resistant Bacteria

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    tummalapalli venkateswara rao
    128 views29 pages
    Polymyxins are a class of antibiotics that work by disrupting the structure of the bacterial cell membrane of gram-negative bacteria through interaction with phospholipids and neutralizing endotoxins. While polymyxins like colistin are effective against multidrug-resistant bacteria, they can cause nephrotoxicity and neurotoxicity, especially in patients with impaired kidney function, so careful monitoring is required with their use. Recent increasing antimicrobial resistance has led to renewed interest in polymyxins as treatments for difficult infections despite their toxicities.

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    Colistin in Multidrug Resistant Bacteria

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    Polymyxins are a class of antibiotics that work by disrupting the structure of the bacterial cell membrane of gram-negative bacteria through interaction with phospholipids and neutralizing endotoxins. While polymyxins like colistin are effective against multidrug-resistant bacteria, they can cause nephrotoxicity and neurotoxicity, especially in patients with impaired kidney function, so careful monitoring is required with their use. Recent increasing antimicrobial resistance has led to renewed interest in polymyxins as treatments for difficult infections despite their toxicities.

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    128 views29 pages

    Colistin in Multidrug Resistant Bacteria

    Uploaded by

    tummalapalli venkateswara rao
    Polymyxins are a class of antibiotics that work by disrupting the structure of the bacterial cell membrane of gram-negative bacteria through interaction with phospholipids and neutralizing endotoxins. While polymyxins like colistin are effective against multidrug-resistant bacteria, they can cause nephrotoxicity and neurotoxicity, especially in patients with impaired kidney function, so careful monitoring is required with their use. Recent increasing antimicrobial resistance has led to renewed interest in polymyxins as treatments for difficult infections despite their toxicities.

    Copyright:

    Attribution Non-Commercial (BY-NC)
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    of 29

    Dr.T.V.

    Rao MD

    POLYMYXINS
    Polymyxins are antibiotics, with a general structure consisting of a cyclic peptide with a long hydrophobic tail. They disrupt the structure of the bacterial cell membrane by interacting with its phospholipids. They are produced by the Gram-positive bacterium Bacillus polymyxa and are selectively toxic for Gram-negative bacteria due to their specificity for the lipopolysaccharide molecule that exists within many Gramnegative outer membranes.

    Introduction
    Polymyxin E First isolated in Japan 1949 & available for clinical use in 1959 IM for gram (-) infection Fell out of favor after aminoglycosides usage Aerosolized form for cystic fibrosis IV for pan resistant nosocomial infections (Pseudomonas & Acinetobacter spp.)

    Colistin A Polymyxin
    Colistin is a cationic polypeptide antibiotic from the polymyxin family that was first introduced in 1962 but abandoned in the early 1970s because of initial reports of severe toxicities. However, a recent increase in the prevalence of multidrug resistant (MDR) Pseudomonas aeruginosa and the lack of novel agents in development calls for a need to re-examine the role of colistin therapy in patients with cystic fibrosis.

    What is Colistin
    Colistin (also called polymyxin E) belongs to the polymyxin group of antibiotics . It was first isolated in Japan in 1949 from Bacillus polymyxa var. colistinus and became available for clinical use in 1959 . Colistin was given as an intramuscular injection for the treatment of gram-negative infections, but fell out of favor after aminoglycosides became available because of its significant side effects. It was later used as topical therapy as part of selective digestive tract decontamination and is still used in aerosolized form for patients with cystic fibrosis.

    Structure of Polymyxins
    Polymyxin B Sulfate is one of a group of basic polypeptide antibiotics derived from B polymyxa (B aero porous). Polymyxin B sulfate is the sulfate salt of Polymyxins B1 and B2, which are produced by the growth of Bacillus polymyxa (Prazmowski) Migula (Fam. Bacillacea)

    Colistin
    The target of antimicrobial activity of colistin is the bacterial cell membrane Colistin has also potent anti-endotoxin activity
    The endotoxin of G-N bacteria is the lipid A portion of LPS molecules, and colistin binds and neutralizes LPS
    7

    Mechanism of Action
    Bactericidal Bind to lipopolysaccharides(LPS) & phospholipids in the outer cell membrane of G(-) bacteria Neutralize LPS & prevent pathophysiologic effects of endotoxin Resistance is uncommon Disk diffusion method cannot be used

    Spectrum of Activity
    Pseudomonas & A. baumannii E. coli, Enterobacter H. influenza Bordetella pertussis Legionella, Klebsiella spp. Salmonella spp., Shigella spp. Stenotrophomonas maltophilia

    Pharmacokinetics
    Colistin sulfate, colistin methanesulfonate Not absorbed from GI tract Hydrolized after IV administration to colistin Half life 251 minutes Excreted in the urine, no biliary excretion

    Mechanism of action
    After binding to lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria, polymyxins disrupt both the outer and inner membranes. The hydrophobic tail is important in causing membrane damage, suggesting a detergent-like mode of action. Removal of the hydrophobic tail of polymyxin B yields polymyxin nonapeptide, which still binds to LPS but no longer kills the bacterial cell. However, it still detectably increases the permeability of the bacterial cell wall to other antibiotics, indicating that it still causes some degree of membrane disorganization

    Clinical Uses of Polymyxins


    Only polymyxins B and E are used clinically; the others damage the kidneys. Polymyxin B can also cause kidney damage and therefore can only be applied topically to treat infections such as those of the eye, ear, skin, and urinary bladder. Polymyxin E, also known as colistin, is used frequently for diarrhea in children. The chief therapeutic use of the polymyxins is treating infections of gram-negative bacteria that are resistant to penicillin and other broad-spectrum antibiotics.

    Clinical uses
    Polymyxins antibiotics are relatively neurotoxic and nephrotoxic and are usually only used as a last resort if modern antibiotics are ineffective or are contraindicated. Typical uses are for infections caused by strains of multi-drug resistant Pseudomonas aeruginosa or carbapenemase-producing Enterobacteriaceae.

    NEWER APPLICATIONS
    Polymyxins B and E (also known as colistin) are used in the treatment of Gramnegative bacterial infections. The global problem of advancing antimicrobial resistance has led to a renewed interest in their use recently.

    Colistin:
    Re-emerging antibiotic for multidrug-resistant Gram-negative bacterial infections.
    Increasing multidrug resistance in Gram-negative bacteria, in particular Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae, presents a critical problem. Limited therapeutic options have forced infectious disease clinicians and microbiologists to reappraise the clinical application of colistin, a polymyxin antibiotic discovered more than 50 years ago

    Colistin of Active .
    Active:
    Acinetobacter species, Pseudomonas aeruginosa, Enterobacteriace ae
    16

    Emerging Problem
    MDR-Acinetobacter
    MDR Acinetobacter (definition per Johns Hopkins) MDR Acinetobacter = an isolate that is susceptible to no more than one class of Antibiotic (excluding Colistin). In reality, MDR is typically resistant to commonly prescribed antibiotics or are susceptible to only the Aminoglycoside class.

    MDR-Acinetobacter Treatment
    Carbapenems (Meropenam& Imipenem)

    Colistin
    PolymyxinB Amikacin Rifampin Minocycline Tigecycline

    How Colistin Works


    Colistin is a bactericidal drug that binds to lipopolysaccharides and phospholipids in the outer cell membrane of gramnegative bacteria. It competitively displaces divalent cations from the phosphate groups of membrane lipids, which leads to disruption of the outer cell membrane, leakage of intracellular contents, and bacterial death

    Experimental uses of Polymyxins


    Polymyxins are used to neutralize or absorb LPS contaminating samples that are intended for use in e.g. immunological experiments. Minimization of LPS contamination can be important because LPS can evoke strong reactions from immune cells and therefore distort experimental results. By increasing permeability of the bacterial membrane system, polymyxin is also used to experimentally increase release of secreted toxins, such as Shiga toxin from Escherichia coli[7].

    Colistin can Neutralize Endotoxins


    In addition to its bactericidal effect, colistin can bind and neutralize lipopolysaccharide (LPS) and prevent the pathophysiologic effects of endotoxin in the circulation .

    Adverse Reaction
    Nephrotoxicity Acute tubular necrosis 27% Normal renal function patient (mean inc. 0.9 mg/dL serum creatine) 58% impaired renal function patient (mean inc. 1.5 mg/dL serum creatine)

    Minimal data on long term use

    Adverse Reaction
    Neurotoxicity 7% Facial & peripheral paresthesia Dizziness, weakness, vertigo, visual disturbance, confusion, ataxia, neuromuscular blockade Benign & reversible

    Caution with Polymyxins


    Caution: when this drug is given intramuscularly, intravenously and/or intrathecally, it should be given only to hospitalized patients, so as to provide constant supervision by a physician. Renal function should be carefully determined and patients with renal damage and nitrogen retention should have reduced dosage. Patients with nephrotoxicity due to polymyxin b sulfate usually show albuminuria, cellular casts, and azotemia. Diminishing urine output and a rising bun are indications for discontinuing therapy with this drug. .

    Polymyxin Can Cause Toxicity


    Neurotoxic reactions may be manifested by irritability, weakness, drowsiness, ataxia, perioral paresthesia, numbness of the extremities, and blurring of vision. These are usually associated with high serum levels found in patients with impaired renal function and/or nephrotoxicity.

    Colistin continues to be option


    MDR gram ve bacteria
    Because few, if any, new antibiotics with activity against multidrug-resistant Gramnegative bacteria will be available within the next several years, it is essential that Colistin is used in ways that maximize its antibacterial efficacy and minimize toxicity and development of resistance. Recent developments have improved use of Colistin in the 21st century.

    Polymyxins too Develop Resistance


    The gram-negative bacteria can develop resistance to polymyxins through various modifications of the LPS structure that inhibit the binding of polymyxins to LPS

    Colistin too becoming resistant


    The Colistin-resistant bacteria, A. baumanii is the most common, followed by K. pneumonia and P. aeruginosa. Resistance to Colistin can occur through mechanisms of mutation or adaptation , leading to bacterial cell membrane changes such as a decrease in the content of lipopolysaccharides, specific outer membrane proteins and Mg 2+ and Ca 2+ content

    Use the drug with caution and clinical adjustment

    Created by Dr.T.V.Rao MD for e-learning resources for Medical and Paramedical Students in Developing world

    Email
    [email protected]

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