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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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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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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