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Colistimethate Sodium

Colistin (polymyxin E) is an antibiotic that is structurally and pharmacologically related to polymyxin B.

Uses

Gram-negative Aerobic Bacterial Infections

Colistimethate sodium is used in the treatment of acute or chronic infections caused by susceptible strains of certain gram-negative bacteria (e.g., Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa). Other more effective and less toxic anti-infectives (e.g., fluoroquinolones, aminoglycosides, third generation cephalosporins, extended-spectrum penicillins) usually are drugs of choice for most gram-negative bacterial infections, and colistimethate sodium should be used in the treatment of infections caused by susceptible gram-negative bacteria only when other more effective and less toxic anti-infectives are contraindicated or are ineffective. However, colistimethate sodium may be useful for the treatment of infections caused by multiple-drug resistant gram-negative bacteria, such as respiratory tract infections in cystic fibrosis patients caused by multiple-drug resistant Ps. aeruginosa.

Colistimethate Sodium

Colistimethate sodium is not indicated for infections caused by Proteus or Neisseria. Colistin sulfate (no longer commercially available in the US for oral use) has been used in infants and children for the treatment of diarrhea caused by susceptible strains of enteropathogenic E. coli. However, anti-infective therapy is generally ineffective in the treatment of diarrhea caused by enteropathogenic E. coli and treatment is usually limited to replacement of fluids and electrolytes. Colistin sulfate (no longer commercially available in the US for oral use) also has been used in the treatment of gastroenteritis caused by Shigella; however, substantial evidence of effectiveness is lacking and other anti-infectives (e.g., tetracycline, ampicillin, co-trimoxazole) are generally preferred if anti-infective therapy is indicated in the treatment of these infections.

Dosage and Administration

Reconstitution and Administration

Colistimethate sodium is administered by IM or IV injection. Colistimethate sodium sterile powder is reconstituted by adding 2 mL of sterile water for injection to a vial labeled as containing 150 mg of colistin; the vial should be swirled gently to avoid frothing. The resultant solution contains 75 mg of colistin per mL. For direct intermittent IV administration, one-half of the total daily dose should be injected directly into a vein over a 3- to 5-minute period every 12 hours. For continuous IV infusion, one-half of the total daily dose should be injected directly into a vein over a 3- to 5-minute period; the remaining one-half of the total daily dose should be added to a compatible IV solution and administered 1-2 hours later (over the next 22-23 hours) by slow IV infusion. The infusion rate should be 5-6 mg/hour in patients with normal renal function. For patients with impaired renal function, the infusion rate should be reduced depending on the degree of renal impairment. The specific IV solution and volume of the solution used should be based on the patient’s fluid and electrolyte requirements.

Dosage

Dosage of colistimethate sodium is expressed in terms of colistin. The usual IM or IV dosage of colistimethate for adults and children with normal renal function is 2.5-5 mg/kg daily given in 2-4 divided doses, depending on the severity of the infection. The maximum daily dose is 5 mg/kg. The manufacturer recommends that dosage of colistimethate sodium be based on an estimate of ideal body weight in obese patients. In patients with renal impairment, the dose and frequency of administration of colistimethate should be decreased in proportion to the degree of renal impairment. The manufacturer recommends that patients with mild renal impairment (serum creatinine of 1.3-1.5 mg/dL) receive 2.5-3.8 mg/kg daily given in 2 divided doses; patients with moderate renal impairment (serum creatinine of 1.6-2.5 mg/dL) receive 2.5 mg/kg daily in a single dose or in 2 divided doses; and patients with considerable renal impairment (serum creatinine of 2.6-4 mg/dL) receive 1.5 mg/kg every 36 hours.

Cautions

Adverse effects reported with colistimethate sodium are similar to those reported with polymyxin B sulfate. Nephrotoxicity and neurotoxicity are the most serious adverse effects of colistimethate sodium and are most likely to occur when the drug is used in higher than recommended dosages or in patients with impaired renal function.

Renal Effects

Nephrotoxicity, manifested as decreased urine output, increased serum concentrations of BUN and creatinine, proteinuria, hematuria, and casts in the urine, has been reported in patients receiving usual dosage of colistimethate sodium. Acute tubular necrosis has been reported with colistimethate sodium and was not necessarily preceded by progressive renal impairment. Nephrotoxicity is generally reversible when colistimethate sodium is discontinued; however, additional increases in concentrations of serum creatinine have frequently occurred for 1-2 weeks following discontinuance of the drug. The manufacturer states that administration of colistimethate sodium in doses that exceed the renal excretory capacity will lead to high serum concentrations of the drug which can result in further impairment of renal function.

GI Effects

GI disturbance has been reported in patients receiving colistimethate sodium. Because Clostridium difficile-associated diarrhea and colitis (also known as antibiotic-associated pseudomembranous colitis) caused by overgrowth of toxin-producing clostridia has been reported with the use of many anti-infective agents, it should be considered in the differential diagnosis of patients who develop diarrhea during anti-infective therapy. Clostridium difficile-associated diarrhea and colitis may range in severity from mild to life-threatening. Mild cases of colitis may respond to discontinuance of the drug alone, but management of moderate to severe cases should include treatment with fluid, electrolyte, protein supplementation, and appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin).

Nervous System Effects

Transient nervous system effects, including circumoral or peripheral paresthesia or numbness, tingling or formication of the extremities or tongue, dizziness, vertigo, giddiness, ataxia, blurred vision, and slurred speech, have been reported in patients receiving colistimethate sodium. If these adverse nervous system effects occur, they generally appear within the first 4 days of therapy and disappear when the drug is discontinued. If adverse nervous system effects occur, colistimethate sodium therapy does not necessarily have to be discontinued, but the patient should be monitored closely; some of these adverse nervous system effects may be alleviated by reducing dosage of the drug. More severe neurotoxic effects including mental confusion, coma, psychosis, and seizures also have been reported with colistimethate sodium, especially in patients receiving high dosage or in patients with renal impairment. Neuromuscular blockade, which may result in respiratory arrest, can occur in patients receiving colistimethate sodium, especially when the drug is used in patients with neuromuscular disease such as myasthenia gravis or in patients who are receiving neuromuscular blocking agents, general anesthetics, or other drugs with neuromuscular blocking potential. Apnea and neuromuscular blockade have been reported most frequently when colistimethate sodium was used in patients with impaired renal function and dosage of the drug was not reduced in proportion to the degree of renal impairment. If apnea occurs during therapy with colistimethate sodium, respiration should be assisted and calcium chloride injections and oxygen should be administered if appropriate. Neuromuscular blockade induced by colistimethate sodium is noncompetitive and is not reversed by neostigmine.

Other Adverse Effects

Generalized pruritus or urticaria, rash, and drug fever have been reported in patients receiving colistimethate sodium. Dysphonia and pain at the site of injection have also been reported. Although a causal relationship has not been definitely established, leukopenia, granulocytopenia, and hepatotoxicity have been reported rarely with colistimethate sodium.

Precautions and Contraindications

Because transient neurologic disturbances may occur during therapy with colistimethate sodium (see Cautions: Nervous System Effects), patients should be warned that the drug may impair their ability to perform hazardous activities requiring mental alertness or physical coordination (e.g., operating machinery, driving a motor vehicle). Renal function should be monitored in patients receiving colistimethate sodium, since adverse renal effects may occur regardless of the dosage of the drug. If diminishing urine output or increasing concentrations of BUN or serum creatinine occur, colistimethate sodium should be discontinued immediately. Colistimethate sodium should be used with caution in patients in whom the possibility of renal impairment exists (e.g., geriatric patients). Administration of colistimethate sodium in dosages in excess of renal excretory capacity will lead to high serum concentrations of the drug which can result in further impairment of renal function and possibly acute renal insufficiency, renal shutdown, and neuromuscular blockade. If colistimethate sodium is used in patients with renal impairment, extreme caution should be exercised and dosage and frequency of administration reduced in proportion to the degree of impairment. Prolonged use of colistimethate sodium may result in overgrowth of nonsusceptible organisms (e.g., Proteus). If suprainfection or superinfection occurs during therapy with colistimethate sodium or colistin sulfate, appropriate anti-infective therapy should be instituted. Colistimethate sodium is contraindicated in individuals who are hypersensitive to the drugs or any ingredient in its formulation.

Pediatric Precautions

Colistimethate sodium has been administered to neonates, infants, children, and adolescents. The adverse effect profile in pediatric patients appears to be similar to that in adults; however, subjective symptoms of toxicity may not be reported by pediatric patients and therefore, close monitoring of these patients is recommended.

Mutagenicity and Carcinogenicity

Long-term studies in animals have not been performed to date to evaluate the carcinogenic potential of colistimethate sodium.

Pregnancy, Fertitlity and Lactation

Safe use of colistimethate sodium during pregnancy has not been established. When colistimethate sodium was given to rabbits during organogenesis in an IM dosage of 4.15 or 9.3 mg/kg (0. or 0.55 times, respectively, the maximum daily human dosage based on mg/mm3), talipes varus occurred in 2.6 or 2.9% of fetuses, respectively. In addition, increased resorption occurred at the 9.2 mg/kg dosage. Colistimethate was not teratogenic when the same dosages were used in rats (0. or 0.3 times the maximum daily human dosage, respectively, based on mg/mm3). There are no adequate and controlled studies to date using colistimethate sodium in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus. There was no evidence of adverse effects on fertility or reproduction when colistimethate was given to rats at dosages of 9.3 mg/kg daily (0. times the maximum daily dosage based on mg/mm3). It is not known whether colistimethate sodium is distributed into milk, but colistin sulfate has been detected in milk. Therefore, colistimethate sodium should be used with caution in nursing women.

Drug Interactions

Since nephrotoxic and/or neurotoxic effects may be additive, concurrent or sequential use of colistimethate sodium and other drugs with similar toxic potentials (e.g., aminoglycosides, amphotericin B, capreomycin, methoxyflurane, polymyxin B sulfate, vancomycin) should be avoided, if possible. Neuromuscular blocking agents (e.g., tubocurarine, succinylcholine, gallamine [no longer commercially available in the US], decamethonium) potentiate neuromuscular blockade induced by colistimethate sodium and these drugs should be used with caution in patients receiving colistimethate sodium.

Acute Toxcicity

Overdosage of colistimethate sodium can cause neuromuscular blockade characterized by paresthesia, lethargy, confusion, dizziness, ataxia, nystagmus, disorders of speech, and apnea. Respiratory muscle paralysis may lead to apnea, respiratory arrest, and death. Overdosage of the drug may also cause acute renal failure, manifested as decreased urine output and increases in serum concentrations of BUN and creatinine. If overdosage of colistimethate sodium occurs, the drug should be discontinued and general supportive measures initiated. It is not known whether colistimethate sodium is removed by hemodialysis or peritoneal dialysis. Mechanism of Action Colistimethate sodium is inactive until hydrolyzed to colistin; this hydrolysis occurs in vitro in aqueous solutions of the drug and in vivo. Colistin is usually bactericidal in action. The mechanism of action of colistin is similar to that of polymyxin B. Colistin acts like a cationic detergent and binds to and damages the bacterial cytoplasmic membrane of susceptible bacteria. Damage to the bacterial cytoplasmic membrane alters the osmotic barrier of the membrane and causes leakage of essential intracellular metabolites and nucleosides. Spectrum Colistin has a spectrum of activity that is similar to that of polymyxin B. Colistin is active in vitro against many gram-negative bacteria; however, the drug is inactive against gram-positive bacteria, fungi, and viruses.

Gram-negative Bacteria

Colistin is active in vitro against many strains of Acinetobacter, Citrobacter, Escherichia coli, Enterobacter, Haemophilus influenzae, Klebsiella pneumoniae, Pseudomonas aeruginosa, Salmonella, Shigella, and some strains of Bordetella and Vibrio. Most strains of Proteus, Providencia, Serratia, Neisseria gonorrhoeae, N. meningitidis, and Bacteroides fragilis are resistant to colistin. In vitro, colistin concentrations of 0.01-4 mcg/mL inhibit most susceptible strains of E. coli, E. aerogenes, H. influenzae, K. pneumoniae, Salmonella, and Shigella and concentrations of 0.8-8 mcg/mL inhibit most susceptible strains of Ps. aeruginosa. Resistance Resistance to colistin has been induced in vitro in strains originally susceptible to the drug, but such resistance may be reversible when the antibiotic is withdrawn. Resistance to colistin has developed only rarely during therapy with colistimethate sodium or colistin sulfate. Complete cross-resistance occurs between colistin and polymyxin B; however, cross-resistance with other anti-infectives has not been reported to date.

Pharmacokinetics

Absorption

Colistimethate sodium is not absorbed from the GI tract and must be given parenterally. Colistin sulfate (no longer commercially available in the US for oral use) is not appreciably absorbed from the GI tract following oral administration, although some GI absorption of the drug reportedly occurs in infants. Colistimethate sodium and colistin sulfate do not appear to be absorbed from mucous membranes or intact or denuded skin. Following IM administration of 150 mg of colistin as colistimethate sodium, peak serum concentrations of antimicrobial activity are attained within 2 hours and average 5-7.5 mcg/mL; serum concentrations of antimicrobial activity may be detectable 12 hours after the dose. Following IV administration of colistimethate sodium, peak serum concentrations of antimicrobial activity are higher but decline more rapidly than those achieved with IM administration of the drug.

Distribution

Following IM or IV administration of colistimethate sodium, the drug is widely distributed into body tissues, but only negligible concentrations of antimicrobial activity are attained in synovial, pleural, or pericardial fluids. Animal studies indicate that colistin, like polymyxin B sulfate, reversibly binds to and persists in body tissues such as the liver, kidneys, lung, heart, and muscle. Colistin is reportedly more than 50% bound to serum proteins.

Colistimethate Sodium

Only minimal concentrations of antimicrobial activity are generally attained in CSF following IM or IV administration of colistimethate sodium in patients with normal or inflamed meninges. Colistin crosses the placenta and is reportedly distributed into milk.

Elimination

The plasma half-life of antimicrobial activity following IM or IV administration of colistimethate sodium is reportedly 1.5-8 hours in adults with normal renal function. Serum concentrations of antimicrobial activity following administration of colistimethate sodium appear to decline more rapidly in children than in adults. Serum concentrations are higher and the half-life is prolonged in patients with impaired renal function. In patients with creatinine clearances less than 20 mL/minute, the half-life of colistin ranges from 10-20 hours.

Following administration of colistimethate sodium in a few anuric patients, half-life of antimicrobial activity reportedly ranged up to 2-3 days. Colistimethate sodium is hydrolyzed in vivo to colistin and possibly other metabolites with fewer substituted amino groups; however, the rate and extent of hydrolysis as well as the specific metabolites and their antibacterial activities have not been determined to date. Colistimethate sodium and metabolites of the drug are excreted mainly by the kidneys via glomerular filtration. Antimicrobial activity in urine is generally higher than antimicrobial activity in serum. Following IM or IV administration of a single 150-mg dose of colistin as colistimethate sodium in patients with normal renal function, antimicrobial concentrations in urine reportedly range from 200-270 mcg/mL 2 hours after the dose to 15-25 mcg/mL 8 hours after the dose. It is not known whether colistimethate sodium is removed by hemodialysis or peritoneal dialysis.

Chemistry and Stability

Chemistry

colistimethate sodium Colistin is a polymyxin antibiotic obtained from cultures of Bacillus polymyxa var. colistinus. Colistin, which also is known as polymyxin E, is structurally and pharmacologically related to polymyxin B. Colistin is commercially available as colistimethate sodium (the sulfamethyl derivative of colistin) for parenteral administration. Colistin also has been available as colistin sulfate for oral administration; however, oral colistin sulfate is no longer commercially available in the US. Colistimethate sodium occurs as a white to slightly yellow, fine powder and is freely soluble in water. Following reconstitution with sterile water for injection, colistimethate sodium solutions have a pH of 7-8.

Stability

Colistimethate sodium powder for injection should be stored at 15-30°C. Following reconstitution with sterile water for injection, colistimethate sodium injection should be stored at 2-8°C or 15-30°C and used within 7 days. Colistimethate sodium is physically and chemically compatible with the following IV solutions: 0.9% sodium chloride, 5% dextrose, 5% dextrose and 0.225%, 0.45%, or 0.9% sodium chloride, lactated Ringer’s, or 10% invert sugar. The manufacturer states that reconstituted solutions of colistimethate sodium which have been further diluted with one of the above IV solutions should be used within 24 hours. Colistimethate sodium is potentially physically and/or chemically incompatible with some drugs, but the compatibility depends on several factors (e.g., concentrations of the drugs, specific diluents used, resulting pH, temperature). Specialized references should be consulted for specific compatibility information.

Preparations

Colistimethate Sodium Parenteral For injection 150 mg (of colistin) Coly-Mycin® M Parenteral, Monarch Colistin sulfate is commercially available in combination with neomycin sulfate and hydrocortisone acetate for otic use.

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