Detailed Drug review Colistin sulphate.pptx

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1. DRUG REVIEW- COLISTIN SULPHATE

2. Introduction Colistin is produced from a strain of the species Bacillus polymyxa and B.colistinus PolymyxinE It acts specifically on gram-negative bacteria and has a rapid bactericidal effect on both resting cells and growing cells. First isolated in Japan 1949 & available for clinical use in 1959 Fell out of favor after aminoglycosides usage Aerosolized form for cystic fibrosis IV for pan resistant nosocomialinfections (Pseudomonas & Acinetobacter spp.)

3. 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 Gram negative outer membranes.

4. Mechanism of Action Bactericidal Bind to lipopolysaccharides (LPS) & phospholipids in the outer cell membrane of G(-) bacteria Neutralize LPS & prevent pathophysiologic effects of endotoxin

5. 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. 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

6. Pharmacokinetics Colistin sulfate, colistin methanesulfonate Not absorbed from GI tract Prodrug ; Hydrolized after IV administration to colistin Half life about 2-3 hours (with normal renal function) Excreted in the urine, no biliary excretion Modification of the dose is generally required in patients with impaired renal function.

7. Antimicrobial Activity The antimicrobial activities of polymyxin B and colistin are similar and restricted to gram-negative bacteria, primarily aerobes. Most Pseudomonas, Acinetobacter , and Enterobacteriaceae are susceptible, except for Proteus and Serratia spp. Stenotrophomonas and Burkholderia are usually resistant

8. Spectrum of Activity Active against gram negative bacteria Pseudomonas & Acinetobacter baumannii E. coli, Enterobacter H. influenza Bordetella pertussis Legionella , Klebsiella spp. Salmonella spp., Shigella spp.

9. Adverse Effects The primary toxicity of polymyxins is dose-related nephrotoxicity . Neurological reactions include muscle weakness, apnea, paresthesias , vertigo, and slurred speech. Given orally – occasional nausea, vomiting, diarrhea Polymyxin B applied to intact or denuded skin or mucous membranes produces no systemic reactions because of its almost complete lack of absorption from these sites. Hypersensitivity reactions are uncommon

10. Uses- Systemic Uses Polymyxins are used systemically only for serious infections due to pathogens resistant to other effective therapies. They have been used for treatment of a variety of infections, including bacteremia , pneumonia, bone/joint infections, burns, cellulitis , cystic fibrosis, endocarditis , gynecologic infections, meningitis, and ventriculitis

11. Topical Use Polymyxin B sulfate is available for ophthalmic, ear, and topical use in combination with a variety of other compounds. Colistin is available as ear drops. Infections of the skin, mucous membranes, eye, and ear due to polymyxin B–sensitive microorganisms respond to local application of the antibiotic in solution or ointment. External otitis , frequently due to Pseudomonas, may be cured by the topical use of the drug. Pseudomonas aeruginosa is a common cause of infection of corneal ulcers; local application or subconjunctival injection of polymyxin B often is curative.

12. Dosing- In normal Renal function Usual dose: 5 to 8 mg/kg/DAY (to a maximum of 450mg DAILY) In three divided doses. Reconstitute each 150mg vial with 2mL of water for injection to give a final concentration of 75mg/ mL (negligible powder volume). This should be swirled gently (not shaken) to avoid frothing Can be given as slow IV injection over 3-5 minutes or as IV infusion

13. Dosage- For Renal impairment eGFR > 80 = normal dosing eGFR 50 to 79 = 2.5 to 3.8mg/kg/DAY in two divided doses eGFR 30 to 49 = 2.5mg/kg/DAY in one OR two divided doses eGFR 10 to 29 = 1.5mg/kg/dose 36 hourly eGFR < 10 = avoid use. eGFR =0.413 x ht(cm)/ S.Cr ml/min/1.73m 2

14. Resistance Resistance to polymyxins is rare, Emergence of resistance while on treatment has been documented Among extensively drug-resistant Acinetobacter and Klebsiella .

15. resistance The Colistin -resistant bacteria, A. baumanii is the most common, followed by K. pneumonia and P. aeruginosa . Resistance 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 Mg 2+ and Ca 2+ content

16. Colistin sulphate oral preparations As colistin is not absorbed in the intestinal tract, the syrup is reserved for treatment of gastrointestinal infections.

17. Indications Infections caused by susceptible gram-negative bacteria. Gastroenteritis and enterocolitis (also in the new born, including premature babies and infants) caused by gram-negative strains. Bacillary dysentery.

18. Dose Colistin sulfate 5-8 mg/kg/day q 6 to 8 hr oral Adult dose: 25-100 mg q 8 hr. Adverse effects: Nephrotoxicity , and neurotoxicity ( Walamycin , colistop , colistin susp 12.5 mg per 5ml, walamycin -DS, colistop -DS susp 25 mg per 5 ml).

19. Colistimethate sodium 50,000 to 75,000 iu /kg/day q 8 hr IV 1 vial = 150mg Colistin =4.5mil.units 1mIU( colistimehate sodium) =33.33mg colistin base For treatment of Gram-negative Pseudomonas aeruginosa , Enterobacter , and Klebsiella . ( Inj xylistin , promistin , colymonas , remergin 1 million iu per vial)

20. REFERENCES 1- Childrens Antimicrobial Management Program – Govt. of Western Australia Child and Adolescent Health Services 2- Goodman & Gillman -Pharmacology 3- K D Thripathi – Pharmacology 4- Meharban Singh Drug dosage

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