4. Antibiotics - Polymyxins (Polypeptides )

1. 4.Antibiotics - Polymyxins(Polypeptides) Pharma II Dr/ AbdulazizSaeedan Pharmacy College

2. Polymyxins (Polypeptides) • Polymyxins(Polypeptides) are a group of bactericidal antibiotics that interfere with the permeability of bacterial membrane and are particularly active against Gram-negative bacteria. • Polymyxinsare consists of 5 different compounds (Polymyxin A-E). • Only polymyxins B and E have been used in clinical practice because they are the least toxic members of the polymixingroup. • Polymyxin A, C and D are highly toxic for human as they damage the kidneys. • The use of polymyxins is limited due to: 1- Their potential toxicity (nephrotoxicity and neurotoxicity). 2- The availability of other less toxic antibiotics.

3. Classification • Polymyxinsare produced from Bacillusspp. They include: 1- PolymyxinB . • Used in the form of polymyxin B sulfate. • It is stable. • Aqueous solutions of polymyxin B may be stored up to 12 months without significant loss of potency if kept under refrigeration. 2- Polymyxin E (Colistin). • Colistin is available in 2 forms: a- Colistin sulfate: • It is administered orally, applied topically, or by inhalation. b- Colistimethate sodium : • Colistimethate sodium is not stable. • It is readily hydrolyzed to form sulfomethylated derivatives and colistin. • Until colistin is formed, colistimethate sodium has no antibacterial activity SO it is considered an inactive pro-drug of colistin. • It is administered by injection (IV, IM) or by inhalation.

4. Polymyxins: Pharmacokinetics 1- Absorption • Oral: • Polymyxins are not absorbed from the GIT. • For systemic infections, they must be given by injection or by inhalation. • Injections - IM & I/V : • PolymyxinB: It has an irritant effect SO induces severe pain at the injection sites. • Colistimethatesodium: It is less irritant SO induces less pain at the injection sites compared to polymyxin B. • Inhalation: • Both types of colistin may be given by inhalation as in case of lung infections. • Topical: • Polymyxin B and colistin sulfate are used topically. NOTE: • The dose of polymyxin B sulfate is dissolved in 2 mL of procaine hydrochloride 1% to reduce pain sensation after IM injection.

5. 2- Distribution • Injectable polymyxins are widely distributed in the body but penetration into CNS is poor. • The safety of polymyxinsduring pregnancy has not been confirmed. 3- Elimination • Injectable polymyxinsare excreted mainly by the kidneys. • Antimicrobial spectrum • Polymyxins are narrow spectrum antimicrobial drugs. • They are active against gram-negative bacteria such as E. coli, Salmonella, Shigellas and Pseudomonas aeruginosa. • All gram-positive bacteria and fungi are resistant.

6. Action & Mechanism of action • Polymyxins are bactericidal drugs. The main site of action of polymyxins is the bacterial membrane. • The bacterial membrane has a certain permeability that control and protect the internal composition of the bacterial cell. • Polymyxins binds to lipopolysaccharideand phospholipids in the outer cell membrane of Gram-negative bacteria. They displaces divalent cations(calcium and magnesium) from the phosphate groups of membrane lipids. • This displacement leads to disruption of the outer cell membrane, leakage of the cell contents and subsequently bacterial lysisand death. NOTE: • Polymyxins are very toxic to human as there is little differences between human and bacterial cell membranes. ► So, they are used as the last option.

7. Side Effects • The main side effects following systemic treatment are nephrotoxicity (damage to the kidneys) and neurotoxicity (damage to the nerves),which observed by the use of very high doses. 1- Nephrotoxicity: • Polymyxins can cause a direct toxic effect to kidneys that results in acute tubular necrosis and renal failure. • Nephrotoxicityismanifested by increase in serum levels of urea and creatinine. 2- Neurotoxicity: • The neurotoxic effects include oral and perioral paresthesia, headache, vertigo, blurred vision, numbness in the arms or legs. • Other possible side effects: 1- Allergic reactions (rash, itching). 2- Overgrowth of non-susceptible organisms, including fungi.

8. Clinical Uses: • The main therapeutic use of polymyxins is the treatment of infections by gram-negative bacteria that are resistant to other available antibiotics like Pseudomonas aeruginosa. • Injection: 1- Polymyxin B is a drug of choice in the treatment of infections of the urinary tract caused by Pseudomonasaeruginosa. 2- Colistimethatesodiumused mainly for lung infections due to Pseudomonas aeruginosaespecially in people with cystic fibrosis. • Inhalation: • Both types of colistin are used for lung infections due to Pseudomonas aeruginosaespecially in people with cystic fibrosis. • Oral:PolymyxinB & Colistin sulfate • Used for treatment of intestinal infections or to suppress bacteria from the bowel before surgery. • Topical: PolymyxinB & Colistin sulfate • Used topically for treatment of infections of the eye, the ear and skin caused by Pseudomonasaeruginosa.