Dr.T.V.Rao MD

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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 nosocomial infections (Pseudomonas & Acinetobacter spp.)

�� 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 Gram-negative outer membranes.

POLYMYXINS

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Structure of Polymyxin

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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). It has a potency of not less than 6000 polymyxin B units per mg, calculated on the anhydrous basis.

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STRUCTURE OF POLYMYXIN

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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

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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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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

��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 of Polymyxins

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NEWER APPLICATIONS

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

�� 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

Mechanism of action

��Polymyxins antibiotics are relatively neurotoxic

and nephrotoxic[6] 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.

Clinical uses

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Colistin: the 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 (also called polymyxin E) belongs to the polymyxin

group of antibiotics [1]. It was first isolated in Japan in 1949 from Bacillus polymyxa var. colistinus and became available for clinical use in 1959 [2,3]. 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.

What is Colistin

��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.

Colistin – A Polymyxin

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How Colistin Works

� Colistin is a bactericidal drug that binds to lipopolysaccharides and phospholipids in the outer cell membrane of gram-negative 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

�� Polymyxin B forInjection is in powder form suitable for

preparation of sterile solutions for intramuscular, intravenous drip, intrathecal, or ophthalmic use.

� In the medical literature, dosages have frequently been given in terms of equivalent weights of pure polymyxin B base.Each milligram of pure polymyxin B base is equivalent to 10,000 units of polymyxin B and each microgram of pure polymyxin B base is equivalent to 10 units of polymyxin B.

How Polymyxins are Dispensed

�� 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].

Experimental uses of Polymyxins

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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 .

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Dosing & Administration

�Optimal dose & dosing interval are unknown

Systemic administration

�U.S. 2.5~5 mg/kg per day, in 2~4 doses

�U.K. 4~6 mg/kg per day, in 3 doses

Inhaled administration

�Not FDA approved

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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

�Neurotoxicity

�7%

�Facial & peripheral paresthesia

�Dizziness, weakness, vertigo, visual disturbance, confusion, ataxia, neuromuscular blockade

�Benign & reversible

Adverse Reaction

�� 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.

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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.

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Caution with Polymyxins

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Summary

�Bactericidal, binding to LPS & phospholipids

�Disk diffusion method cannot be performed

�IV for pan resistant nosocomial infections (Pseudomonas & Acinetobacter spp.)

�Adverse effects (nephrotoxicity, neurotoxicity)

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Polymyxins 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 is structurally and pharmacologically related to

polymyxin B, the other commercially available drug from the polymyxin class. Colistin is bactericidal in nearly all strains of gram-negative bacilli. As with all antibiotics, resistance is of paramount concern. Resistance to colistin has not been frequently documented. Colistin must be administered parenterally, as it is not absorbed from the gastrointestinal tract, mucous membranes, or intact or denuded skin. Parenteral colistin has been replaced by less-toxic antibiotics and should be reserved for life-threatening infections caused by organisms resistant to preferred drugs

Summary – Colistin Use

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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

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�Created by Dr.T.V.Rao MD for “e-learning” resources for Medical and Paramedical

Students in Developing world�Email

�doctortvrao@gmail.com