colistin in multidrug resistant bacteria

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    Dr.T.V.Rao MDDr.T.V.Rao MD

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    Polymyxins are antibiotics, with a general

    structure consisting of a cyclic peptide with a

    long hydrophobic tail. They disrupt thestructure of the bacterial cell membrane byinteracting with its phospholipids. They areproduced by the Gram-positive bacterium

    Bacillus polymyxa and are selectively toxicfor Gram-negative bacteria due to theirspecificity for the lipopolysaccharidemolecule that exists within many Gram-negative outer membranes.

    POLYMYXINS

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    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 nosocomialinfections (Pseudomonas &Acinetobacter spp.)

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    Colistin is a cationic polypeptide antibiotic

    from the polymyxin family that was firstintroduced in 1962 but abandoned in theearly 1970s because of initial reports of severetoxicities. However, a recent increase in the

    prevalence of multidrug resistant (MDR)Pseudomonas aeruginosa and the lack ofnovel agents in development calls for a needto re-examine the role of colistin therapy in

    patients with cystic fibrosis.

    Colistin A Polymyxin

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    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 andbecame available for clinical use in 1959 . Colistin wasgiven as an intramuscular injection for the treatment ofgram-negative infections, but fell out of favor afteraminoglycosides became available because of its

    significant side effects. It was later used as topical therapyas part of selective digestive tract decontamination and isstill used in aerosolized form for patients with cysticfibrosis.

    Whatis

    Colistin

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    Structure of Polymyxins Polymyxin B Sulfate is

    one of a group of basic

    polypeptide antibioticsderived from B polymyxa(B aero porous).Polymyxin B sulfate is thesulfate salt of PolymyxinsB1 and B2, which are

    produced by the growthof Bacillus polymyxa(Prazmowski) Migula(Fam. Bacillacea)

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    7

    Colistin

    The target ofantimicrobial activity ofcolistin is the bacterial

    cell membrane Colistin has also potent

    anti-endotoxin activity The endotoxin of G-N

    bacteria is the lipid Aportion of LPSmolecules, and colistinbinds and neutralizesLPS

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    Mech

    anism of Action Bactericidal

    Bind to lipopolysaccharides(LPS) &phospholipids in the outer cell membrane of G(-)bacteria

    Neutralize LPS & prevent pathophysiologiceffects of endotoxin

    Resistance is uncommon

    Disk diffusion method cannot be used

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    Spectrum of Activity Pseudomonas & A. baumannii

    E. coli, Enterobacter H. influenza

    Bordetella pertussis

    Legionella, Klebsiella spp.

    Salmonella spp., Shigella spp.

    Stenotrophomonas maltophilia

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    Ph

    armacokinetics Colistin sulfate, colistin

    methanesulfonate Not absorbed from GI tract

    Hydrolized after IV administration tocolistin

    Half life 251 minutes

    Excreted in the urine, no biliaryexcretion

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    After binding to lipopolysaccharide (LPS) in the outer

    membrane of Gram-negative bacteria, polymyxins disrupt

    both the outer and inner membranes. The hydrophobictail 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 nolonger kills the bacterial cell. However, it still detectablyincreases the permeability of the bacterial cell wall toother antibiotics, indicating that it still causes somedegree of membrane disorganization

    Mechanism of action

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    Only polymyxins B and E are used clinically; the

    others damage the kidneys. Polymyxin B can also

    cause kidney damage and therefore can only beapplied topically to treat infections such as those ofthe eye, ear, skin, and urinary bladder. Polymyxin E,also known as colistin, is used frequently for

    diarrhea in children. The chief therapeutic use of thepolymyxins is treating infections of gram-negativebacteria that are resistant to penicillin and otherbroad-spectrum antibiotics.

    Clinical Uses of

    Polymyxins

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    Polymyxins antibiotics are relatively

    neurotoxic and nephrotoxic and are usuallyonly used as a last resort if modernantibiotics are ineffective or arecontraindicated. Typical uses are for

    infections caused by strains of multi-drugresistant Pseudomonas aeruginosa orcarbapenemase-producingEnterobacteriaceae.

    Clinical uses

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    NEW

    ER APPLIC

    ATIONS Polymyxins B and E

    (also known as colistin)

    are used in thetreatment of Gram-negative bacterialinfections. The globalproblem of advancing

    antimicrobial resistancehas led to a renewedinterest in their userecently.

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    Colistin:Re-emerging antibiotic for multidrug-resistant

    Gram-negative bacterial infections. Increasing multidrug resistance

    in Gram-negative bacteria, inparticular Pseudomonas

    aeruginosa, Acinetobacterbaumannii, and Klebsiellapneumoniae, presents a criticalproblem. Limited therapeuticoptions have forced infectiousdisease clinicians and

    microbiologists to reappraisethe clinical application ofcolistin, a polymyxin antibioticdiscovered more than 50 yearsago

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    16

    Colistin of Active .

    Active:

    Acinetobacterspecies,

    Pseudomonas

    aeruginosa, Enterobacteriaceae

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    MDR Acinetobacter (definition per Johns

    Hopkins) MDR Acinetobacter = an isolate that is

    susceptible to no more than one class ofAntibiotic (excluding Colistin).

    In reality, MDR is typically resistant tocommonly prescribed antibiotics or aresusceptible to only the Aminoglycosideclass.

    EmergingProblem

    MDR-Acinetobacter

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    Carbapenems (Meropenam& Imipenem)

    Colistin PolymyxinB

    Amikacin

    Rifampin

    Minocycline

    Tigecycline

    MDR-Acinetobacter Treatment

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    H

    owC

    olistinW

    orks Colistin is a bactericidal

    drug that binds tolipopolysaccharides and

    phospholipids in the outercell membrane of gram-negative bacteria. Itcompetitively displacesdivalent cations from thephosphate groups ofmembrane lipids, which

    leads to disruption of theouter cell membrane,leakage of intracellularcontents, and bacterial death

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    Polymyxins are used to neutralize or absorb LPS

    contaminating samples that are intended for use in e.g.

    immunological experiments. Minimization of LPScontamination can be important because LPS can evokestrong reactions from immune cells and therefore distortexperimental results.

    By increasing permeability of the bacterial membranesystem, polymyxin is also used to experimentally increaserelease of secreted toxins, such as Shiga toxin fromEscherichia coli[7].

    Experimental uses of

    Polymyxins

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    Colistin canNeutralize

    Endotoxins

    In addition to its

    bactericidal effect,colistin can bindand neutralizelipopolysaccharide

    (LPS) and preventthepathophysiologiceffects of endotoxin

    in the circulation .

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    Adverse ReactionNephrotoxicity

    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 longterm use

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    Neurotoxicity

    7%

    Facial & peripheral paresthesia

    Dizziness, weakness, vertigo, visualdisturbance, confusion, ataxia,

    neuromuscular blockade Benign & reversible

    Adverse Reaction

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    Caution: when this drug is given intramuscularly,

    intravenously and/or intrathecally, it should begiven only to hospitalized patients, so as to provideconstant supervision by a physician.

    Renal function should be carefully determined andpatients with renal damage and nitrogen retentionshould have reduced dosage. Patients with

    nephrotoxicity due to polymyxin b sulfate usuallyshow albuminuria, cellular casts, and azotemia.Diminishing urine output and a rising bun areindications for discontinuing therapy with this drug.

    Caution withPolymyxins

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    PolymyxinCanCause

    Toxicity Neurotoxic reactions may

    be manifested byirritability, weakness,drowsiness, ataxia,perioral paresthesia,numbness of theextremities, and blurringof vision. These areusually associated with

    high serum levels foundin patients with impairedrenal function and/ornephrotoxicity.

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    Because few, if any, new antibiotics with

    activity against multidrug-resistant Gram-

    negative bacteria will be available within thenext several years, it is essential that Colistinis used in ways that maximize itsantibacterial efficacy and minimize toxicity

    and development of resistance. Recentdevelopments have improved use of Colistinin the 21st century.

    Colistin continues to be option

    MDR gram ve bacteria

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    Polymyxinstoo Develop

    Resistance

    The gram-negativebacteria can develop

    resistance topolymyxins throughvarious modificationsof the LPS structure

    that inhibit the bindingof polymyxins to LPS

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    The Colistin-resistant bacteria,A.baumanii is the

    most common, followed by K. pneumonia and P.aeruginosa. Resistance to Colistin can occur throughmechanisms of mutation or adaptation , leading tobacterial cell membrane changes such as a decreasein the content of lipopolysaccharides, specific outermembrane proteins and Mg 2+ and Ca 2+ content

    Use the drug with caution and clinicaladjustment

    Colistintoo becoming resistant

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    Created by Dr.T.V.Rao MD for e-learning

    resources for Medical and ParamedicalStudentsin Developing world

    Email

    [email protected]