4. Antibiotics - Polymyxins (Polypeptides) Pharma II Dr/ Abdulaziz Saeedan Pharmacy College

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. Polymyxins are 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 polymixin group. 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.

Classification Polymyxins are produced from Bacillus spp. They include: 1- Polymyxin B . 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.

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 : Polymyxin B: It has an irritant effect SO induces severe pain at the injection sites. Colistimethate sodium: 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.

2- Distribution Injectable polymyxins are widely distributed in the body but penetration into CNS is poor. The safety of polymyxins during pregnancy has not been confirmed. 3- Elimination Injectable polymyxins are 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.

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 lipopolysaccharide and 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 lysis and 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.

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. Nephrotoxicity is manifested 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.

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 Pseudomonas aeruginosa. 2- Colistimethate sodium used mainly for lung infections due to Pseudomonas aeruginosa especially in people with cystic fibrosis. Inhalation: Both types of colistin are used for lung infections due to Pseudomonas aeruginosa especially in people with cystic fibrosis. Oral: Polymyxin B & Colistin sulfate Used for treatment of intestinal infections or to suppress bacteria from the bowel before surgery. Topical: Polymyxin B & Colistin sulfate Used topically for treatment of infections of the eye, the ear and skin caused by Pseudomonas aeruginosa.