VA Class:AM900
Colistimethate sodium is a prodrug of colistin.134, 140, 141, 142 Colistin (also known as polymyxin E) is a polymyxin antibiotic structurally and pharmacologically related to polymyxin B.134
Gram-negative Aerobic Bacterial Infections
Colistimethate sodium is used parenterally for the treatment of acute or chronic infections caused by certain susceptible gram-negative bacteria (e.g., Enterobacter aerogenes , Escherichia coli , Klebsiella pneumoniae , Pseudomonas aeruginosa ).100 Other more effective and less toxic anti-infectives (e.g., fluoroquinolones, aminoglycosides, third generation cephalosporins, extended-spectrum penicillins, carbapenems) usually are drugs of choice for most gram-negative bacterial infections.108, 134 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 alone or in conjunction with other anti-infectives 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 .106, 119, 121, 122, 135 Colistimethate sodium is not indicated for infections caused by Proteus or Neisseria .100
Colistin sulfate (no longer commercially available in the US) has been used orally for the treatment of gastroenteritis caused by susceptible Shigella ; however, substantial evidence of effectiveness is lacking and other anti-infectives (e.g., fluoroquinolones, azithromycin, ampicillin, co-trimoxazole) generally are preferred if anti-infective therapy is indicated in the treatment of these infections. Colistin sulfate also has been used orally for the treatment of diarrhea caused by susceptible strains of enteropathogenic E. coli ; however, use of anti-infectives for treatment of diarrhea caused by enteropathogenic E. coli is controversial and management usually involves replacement of fluids and electrolytes.
Colistimethate sodium has been administered by oral inhalation via nebulization† for early treatment of Ps. aeruginosa respiratory tract infections in adult and pediatric cystic fibrosis patients and for suppressive therapy in cystic fibrosis patients colonized with Ps. aeruginosa .109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126 Safety and efficacy of such treatment have not been established, and colistimethate sodium is not labeled by the US Food and Drug Administration (FDA) for administration via nebulization.109, 110 Adverse respiratory effects (e.g., bronchoconstriction) have occurred with this route,119, 130, 131 and there has been at least one fatality in a patient who self-administered a nebulizer treatment using a premixed solution of the drug.109, 110 (See Cautions: Respiratory Effects.)
There is some evidence from a randomized study and observational studies that early initiation of a treatment regimen that includes colistimethate sodium administered by oral inhalation† (usually given in conjunction with oral ciprofloxacin) in addition to standard therapy for cystic fibrosis may prevent or delay chronic colonization in some adult and pediatric cystic fibrosis patients with Ps. aeruginosa respiratory tract infections.113, 114, 115, 116, 117 A review of anti-infective strategies for eradicating Ps. aeruginosa in patients with cystic fibrosis that analyzed results of studies involving tobramycin or colistimethate sodium administered by oral inhalation concluded that there is some evidence that such anti-infective treatment of early Ps. aeruginosa infection in cystic fibrosis patients results in short-term eradication, but it remains uncertain whether there is an associated clinical benefit.127
Results of a randomized study of colistimethate sodium or tobramycin administered by oral inhalation in adult and pediatric cystic fibrosis patients chronically infected with Ps. aeruginosa indicate that either treatment reduced the bacterial load, but only nebulized tobramycin significantly improved lung function as measured by FEV1.111 Results of a randomized study of colistimethate sodium administered by oral inhalation in adult and pediatric cystic fibrosis patients with chronic Ps. aeruginosa lung infections indicate that such therapy may be a useful supplement to IV antipseudomonal anti-infectives.112 A review of use of nebulized antipseudomonal anti-infectives in patients with cystic fibrosis concluded that such treatment may have a beneficial effect on lung function and may reduce exacerbations of respiratory infections, but that more research is needed to determine the duration of benefit, risk of emergence of resistant Ps. aeruginosa , and optimal drug and dosage regimens.128
Reconstitution and Administration
Colistimethate sodium is administered by IM injection, IV injection, or continuous IV infusion.100 The drug also has been administered by oral inhalation via nebulization†.109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126
Dispensing and Dosage and Administration Precautions
The Institute for Safe Medication Practices (ISMP) alerted healthcare professionals about the risk of serious and potentially fatal medication errors related to dosage of colistimethate sodium.139
Colistimethate sodium is a prodrug of colistin and is inactive until hydrolyzed in vivo to colistin.139, 140, 141, 142 In the US, vials and carton packaging of colistimethate sulfate are labeled as colistimethate for injection; however, strength and dosage of the drug are expressed in terms of colistin base activity (colistin).100, 139 This dosage convention must be considered when prescribing, preparing, and dispensing colistimethate sodium.139
Healthcare professionals should be aware that, in the US, colistimethate sodium must only be prescribed in terms of colistin.139 If the drug is prescribed as colistimethate or colistimethate sodium, the prescriber should be contacted to verify the dosage in terms of colistin.139 At least 1 fatality related to acute renal failure and other complications occurred when colistimethate sodium was prescribed in terms of the prodrug (instead of colistin), resulting in administration of a dosage approximately 2.5 times greater than it should have been.139
Healthcare professionals also should be aware that strength and dosage of colistimethate sodium preparations commercially available in some other countries may be expressed in terms of colistimethate sodium, in terms of colistin, or as international units.111, 112, 113, 114, 115, 116, 117, 118, 121, 129, 139, 140, 141 (See Dosage and Administration: Dosage.)
Any medication errors involving colistimethate sodium should be reported to the ISMP National Medication Error Reporting Program and the FDA MedWatch program.139
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.100 The resultant solution contains 75 mg of colistin per mL.100
Reconstituted solutions of colistimethate sodium should be used within 7 days, but final solutions for continuous IV infusion should be freshly prepared and used within 24 hours.100 (See Chemistry and Stability: Stability)
For IM injection, the appropriate dose (as reconstituted solution) should be given by deep IM injection into a large muscle mass (e.g., gluteal muscle or lateral part of the thigh).100
For direct intermittent IV administration, one-half of the total daily dose (as reconstituted solution) should be injected directly into a vein over a 3- to 5-minute period every 12 hours.100
For continuous IV infusion, one-half of the total daily dose (as reconstituted solution) should be injected directly into a vein over a 3- to 5-minute period; the remaining one-half of the total daily dose (as reconstituted solution) should be added to a compatible IV solution (see Chemistry and Stability: Stability) and administered 1-2 hours later (over the next 22-23 hours) by slow IV infusion.100
The specific IV solution and volume of the solution used should be based on the patient's fluid and electrolyte requirements.100
For oral inhalation via nebulization†, an isotonic solution of colistimethate sodium has been prepared by diluting the appropriate dose in 2-4 mL of preservative-free 0.9% sodium chloride injection, sterile water, or a mixture of 0.9% sodium chloride injection and sterile water.110, 111, 112, 114, 115, 121, 126, 131
Solutions of colistimethate sodium for oral inhalation via nebulization† should be used promptly after being prepared.109 A fatality has been reported in a cystic fibrosis patient who self-administered a nebulizer treatment using a premixed solution of the drug.109, 110 (See Cautions: Respiratory Effects.)
Dosage of colistimethate sodium commercially available in the US is expressed in terms of colistin.100
Dosage of colistimethate sodium preparations commercially available in some other countries (e.g., United Kingdom, Greece) may be expressed in terms of colistimethate sodium, in terms of colistin, or as international units.111, 112, 113, 114, 115, 116, 117, 118, 121, 129, 140 The fact that dosages reported in published clinical studies or case reports may vary depending on the country of origin and the preparation used should be considered. 120, 129, 140, 141
Although not the dosage convention in the US,100, 139 it has been suggested that dosage of colistimethate sodium should preferably be expressed in terms of international units to avoid confusion.129, 135, 140 When expressed in terms of international units, each mg of colistin base has a potency of 30,000 international units129, 134, 140 and each mg of colistimethate sodium has a potency of 12,500 international units.129
The usual IM or IV dosage of colistimethate sodium for adults and children with normal renal function is 2.5-5 mg/kg of colistin daily given in 2-4 divided doses, depending on the severity of the infection.100
The maximum IM or IV dosage of colistimethate sodium recommended by the manufacturer for patients with normal renal function is 5 mg/kg of colistin daily.100
The manufacturer recommends that dosage for obese patients should be based on an estimate of ideal body weight.100
For early treatment of Pseudomonas aeruginosa respiratory tract infections in adult and pediatric cystic fibrosis patients or for suppressive therapy in adult or pediatric cystic fibrosis patients colonized with Ps. aeruginosa , colistimethate sodium has been given by oral inhalation via nebulization† in a dosage of 33.33-66.66 mg of colistin 2 or 3 times daily.111, 112, 113, 114, 115, 116, 117, 128 This corresponds to a dosage of 1-2 million international units 2 or 3 times daily.111, 112, 113, 114, 115, 116, 117, 121, 128
In patients with renal impairment, dosage of colistimethate sodium should be decreased in proportion to the degree of renal impairment.100
Creatinine Clearance (mL/minute) | IM or IV Dosage (of Colistin) |
|---|---|
80 or greater | 2.5-5 mg/kg daily given in 2-4 divided doses |
50-79 | 2.5-3.8 mg/kg daily given in 2 divided doses |
30-49 | 2.5 mg/kg daily given as a single dose or in 2 divided doses |
10-29 | 1.5 mg/kg given once every 36 hours |
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.100
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. 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.100 (See Cautions: Precautions and Contraindications.)
GI disturbance has been reported in patients receiving colistimethate sodium.100
Clostridium difficile -associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) has been reported with nearly all anti-infectives, including colistimethate sodium, and may range in severity from mild diarrhea to fatal colitis.100 CDAD should be considered in the differential diagnosis of patients who develop diarrhea during or after anti-infective therapy.100 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, appropriate anti-infective therapy (e.g., oral metronidazole or vancomycin), and surgical evaluation when clinically indicated.100, 101, 102, 103, 104, 105 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.100
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.100 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.100
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. (See Drug Interactions.) 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.
Bronchoconstriction has been reported in adult and pediatric cystic fibrosis patients who received colistimethate sodium by oral inhalation via nebulization†.119, 130, 131 Bronchoconstriction has occurred almost immediately after initiation of nebulization and can last for more than 30 minutes in some patients.119 It has been suggested that premedication with bronchodilators may reduce the potential for development of bronchoconstriction in patients receiving the drug by nebulization.119, 120, 122, 130, 131 Pre- and post-treatment pulmonary function tests have been recommended to identify patients who may be predisposed to bronchoconstriction.119 In young children who are unable to perform pulmonary function tests, bronchodilator premedication has been recommended.131
Respiratory distress that progressed over several days to acute respiratory failure, multi-organ system failure, and death has been reported in a patient who received colistimethate sodium by oral inhalation via nebulization†.109, 110 This patient self-administered the nebulizer treatment using a solution of colistimethate sodium that had been prepared by a pharmacy and dispensed in premixed unit dose ready-to-use vials.109, 110 The patient developed respiratory distress within hours of the nebulization treatment and died about 19 days later.109, 110 It has been suggested that this fatality may have been related to the fact that a premixed solution of colistimethate sodium was used in the nebulizer.109, 110 After colistimethate sodium is mixed with water and buffer, it undergoes spontaneous hydrolysis to colistin.110 A component of colistin (polymyxin E1) has been shown to cause pulmonary inflammatory reactions in animals and may contribute to such local toxicity in humans.109, 110, 119 (See Cautions: Precautions and Contraindications.)
Generalized pruritus, urticaria, rash, and fever have been reported in patients receiving colistimethate sodium.100 Anaphylaxis has also been reported.100
Although a causal relationship has not been definitely established, leukopenia, granulocytopenia, and hepatotoxicity have been reported rarely with colistimethate sodium.
Precautions and Contraindications
Colistimethate sodium is contraindicated in individuals who are hypersensitive to the drug or any ingredient in its formulation.100
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).100
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.100
Colistimethate sodium should be used with caution in patients in whom the possibility of renal impairment exists (e.g., geriatric patients).100 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.100 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.100
Adults and children who receive colistimethate sodium by oral inhalation via nebulization† may be at risk of bronchoconstriction.130, 131 Premedication with bronchodilators may reduce the potential for development of bronchoconstriction in patients receiving the drug by nebulization.119, 120, 122, 130, 131 The FDA states that healthcare providers who choose to prescribe colistimethate sodium for administration by oral inhalation via nebulization† should be familiar with the chemistry of the drug and aware of the potential for serious and life-threatening side effects from inhalation of premixed, ready-to-use liquid preparations of the drug.109, 110 If colistimethate sodium is administered via a nebulizer, the solution should be used promptly after being mixed.109, 110 Premixing colistimethate sodium into an aqueous solution and storing it for longer than 24 hours results in increased concentrations of colistin in the solution and increases the potential for lung toxicity if the premixed solution is administered via nebulization.110 Patients should be advised not to use any premixed, ready-to-use liquid preparations of colistimethate sodium for nebulization and to discard any unused vials of premixed, ready-to-use liquid preparations of the drug that they may have in their possession.109, 110
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, appropriate anti-infective therapy should be instituted.
To reduce development of drug-resistant bacteria and maintain effectiveness of colistimethate sodium and other antibacterials, the drug should be used only for the treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.100 When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.100 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.100
Because Clostridium difficile -associated diarrhea and colitis has been reported with colistimethate sodium, it should be considered in the differential diagnosis of patients who develop diarrhea during or after therapy.100 Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued; however, they should contact a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.100
Patients should be advised that antibacterials (including colistimethate sodium) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).100 Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with colistimethate or other antibacterials in the future.100
Colistimethate sodium has been used in neonates, infants, children, and adolescents.100 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 close monitoring of these patients is recommended.100
Clinical studies of colistimethate sodium did not include sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger patients.100 While other clinical experience has not revealed age-related differences in response, dosage generally should be selected carefully for geriatric patients, usually initiating therapy at the low end of the dosage range.100 The greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly also should be considered.100
Since the drug is substantially eliminated by the kidney, the risk of adverse effects may be greater in patient with impaired renal function.100 The greater frequency of decreased renal function observed in the elderly should be considered and dosage should be selected carefully in geriatric patients; monitoring renal function may be useful in these patients.100
Mutagenicity and Carcinogenicity
Long-term studies in animals have not been performed to date to evaluate the carcinogenic potential of colistimethate sodium.100
Pregnancy, Fertility, and Lactation
Safe use of colistimethate sodium during pregnancy has not been established.100 When colistimethate sodium was given to rabbits during organogenesis in an IM dosage of 4.15 or 9.3 mg/kg (0.25 or 0.55 times, respectively, the maximum daily human dosage based on mg/m2), talipes varus occurred in 2.6 or 2.9% of fetuses, respectively.100 In addition, increased resorption occurred at the 9.3 mg/kg dosage.100 The drug was not teratogenic when the same dosages were used in rats (0.13 or 0.3 times the maximum daily human dosage, respectively, based on mg/mm2).100 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.100
There was no evidence of adverse effects on fertility or reproduction when colistimethate sodium was given to rats at dosages of 9.3 mg/kg daily (0.3 times the maximum daily dosage based on mg/m2).100
It is not known whether colistimethate sodium is distributed into milk, but colistin sulfate has been detected in milk.100 Therefore, colistimethate sodium should be used with caution in nursing women.100
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 [no longer commercially available in the US], polymyxin B sulfate, vancomycin) should be avoided, if possible.
Neuromuscular blocking agents (e.g., tubocurarine, succinylcholine, ether, decamethonium [no longer commercially available in the US], gallamine [no longer commercially available in the US], decamethonium) and other drugs (e.g., sodium citrate) potentiate neuromuscular blockade induced by colistimethate sodium and these drugs should be used with extreme caution in patients receiving colistimethate sodium.100
Overdosage of colistimethate sodium can cause neuromuscular blockade characterized by paresthesia, lethargy, confusion, dizziness, ataxia, nystagmus, disorders of speech, and apnea.100 Respiratory muscle paralysis may lead to apnea, respiratory arrest, and death.100 Overdosage of the drug may also cause acute renal failure, manifested as decreased urine output and increases in serum concentrations of BUN and creatinine.100
If overdosage of colistimethate sodium occurs, the drug should be discontinued and general supportive measures initiated.100 Colistimethate sodium may be removed by hemodialysis and, to a lesser extent, by peritoneal dialysis.134
Colistimethate sodium is a prodrug and is inactive until hydrolyzed to colistin;140, 141, 142 this hydrolysis occurs in vivo and in vitro in aqueous solutions of the drug.
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.
Colistin (the active metabolite of colistimethate sodium) 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.
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 to colistin (the active metabolite of colistimethate sodium) has been induced in vitro in strains originally susceptible to the drug; in some cases, resistance may be reversible when the antibiotic is withdrawn. Resistance to colistin has developed rarely during therapy with colistimethate sodium or colistin sulfate.
Pseudomonas aeruginosa resistant to colistin have been reported rarely, including in some patients who received long-term treatment with colistimethate sodium administered by oral inhalation via nebulization†.122, 134Acinetobacter baumannii 136Enterobacter cloacae ,138 and Klebsiella pneumoniae 137, 138 resistant to colistin also have been reported rarely.
Complete cross-resistance occurs between colistin and polymyxin B;134 however, cross-resistance with other anti-infectives has not been reported to date.
Colistimethate sodium, a prodrug of colistin,140, 141, 142 is not absorbed from the GI tract and must be given parenterally. Colistimethate sodium does not appear to be absorbed from mucous membranes or intact or denuded skin.
Following IM administration of colistimethate sodium in a dosage of 150 mg of colistin, 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 in a dosage of 5-7 mg/kg of colistin daily given in 3 equally divided doses (maximum 70-100 mg every 8 hours) in cystic fibrosis patients 14-53 years of age, mean peak serum concentrations were 21.4 mcg/mL after the first dose and 23 mcg/mL at steady state.133 Mean 8-hour trough concentrations were 2.8 mcg/mL after the first dose and 4.5 mcg/mL at steady state.133 Peak serum concentrations of antimicrobial activity are higher, but decline more rapidly than those achieved with IM administration of the drug.
Following oral inhalation via nebulization† of colistimethate sodium in a dosage of 66.66 mg of colistin (2 million international units) in cystic fibrosis patients 12-48 years of age, mean peak serum concentrations were 0.17 mcg/mL132 and were attained in 1.5 hours.132
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.
In cystic fibrosis patients 14-53 years of age receiving IV colistimethate sodium in a dosage of 5-7 mg/kg of colistin daily given in 3 equally divided doses, the volume of distribution at steady state was 0.09 L/kg.133
Following oral inhalation via nebulization† of colistimethate sodium in a dosage of 66.66 mg of colistin (2 million international units) in cystic fibrosis patients 12-48 years of age, sputum concentrations peaked 1 hour after inhalation and remained greater than 4 mcg/mL for up to 12 hours in most patients.132
Colistin is reportedly more than 50% bound to serum proteins.
Only minimal concentrations of antimicrobial activity are attained in CSF following IM or IV administration of colistimethate sodium in patients with normal or inflamed meninges.
Colistin crosses the placenta and is distributed into milk.
Colistimethate sodium is hydrolyzed in vivo to colistin and possibly other metabolites with fewer substituted amino groups. The rate and extent of hydrolysis as well as the specific metabolites and their antibacterial activities have not been determined to date.
The plasma half-life of antimicrobial activity following IM or IV administration of colistimethate sodium is 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.
The mean plasma half-life in cystic fibrosis patients 14-53 years of age who received IV colistimethate sodium in a dosage of 5-7 mg/kg of colistin daily given in 3 equally divided doses was 3.4 hours after the first dose and 3.5 hours at steady state.133
The plasma half-life following oral inhalation via nebulization† of colistimethate sodium in a dosage of 66.66 mg of colistin (2 million international units) in cystic fibrosis patients 12-48 years of age was 4.1-4.5 hours.132
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 are 200-270 mcg/mL at 2 hours after the dose and 15-25 mcg/mL at 8 hours after the dose.
Colistimethate sodium may be removed by hemodialysis and, to a lesser extent, by peritoneal dialysis.134
Colistimethate sodium is the sulfamethyl derivative (methane sulfonate) of colistin.134 Colistimethate sodium is a prodrug that is inactive until hydrolyzed in vivo and in vitro to colistin.110, 121, 141, 142 Colistin (also known as polymyxin E) is a polymyxin antibiotic obtained from cultures of Bacillus polymyxa var. colistinus and is structurally and pharmacologically related to polymyxin B.134
Colistin may be commercially available as colistin sulfate for oral administration in other countries; 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.
Colistimethate sodium powder for injection should be stored at 20-25°C.100
Following reconstitution with sterile water for injection, colistimethate sodium solutions containing 75 mg of colistin per mL should be stored at 2-8°C or 20-25°C and used within 7 days.100 However, reconstituted solutions that have been further diluted with a compatible IV solution should be used within 24 hours.100
Solutions of colistimethate sodium prepared extemporaneously for oral inhalation via nebulization† should be used promptly after being mixed.109 (See Cautions: Respiratory Effects.)
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.100
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.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | For injection | 150 mg (of colistin)* | Colistimethate Sodium for Injection | |
Coly-Mycin® M Parenteral |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
100. Par Pharmaceutical. Coly-mycin® M parenteral (colistimethate) for injection, USP prescribing information. Chestnut Ridge, NY; 2017.
101. Johnson S, Gerding DN. Clostridium difficile -associated diarrhea. Clin Infect Dis . 1998; 26:1027-36. [PubMed 9597221]
102. Gerding DN, Johnson S, Peterson LR et al for the Society for Healthcare Epidemiology of American. Position paper on Clostridium difficile -associated diarrhea and colitis. Infect Control Hosp Epidemiol . 1995; 16:459-77. [PubMed 7594392]
103. Fekety R for the American College of Gastroenterology Practice Parameters Committee. Guidelines for the diagnosis and management of Clostridium difficile -associated diarrhea and colitis. Am J Gastroenterol . 1997; 92:739-50 (IDIS 386628) [PubMed 9149180]
104. American Society of Health-System Pharmacists Commission on Therapeutics. ASHP therapeutic position statement on the preferential use of metronidazole for the treatment of Clostridium difficile -associated disease. Am J Health-Syst Pharm . 1998; 55:1407-11. [PubMed 9659970]
105. Wilcox MH. Treatment of Clostridium difficile infection. J Antimicrob Chemother . 1998; 41(Suppl C):41-6. [PubMed 9630373]
106. Evans ME, Feola DJ, Rapp RP. Polymyxin B sulfate and colistin: old antibiotics for emerging multiresistant gram-negative bacteria. Ann Pharmacol . 1999; 33:960-7.
108. Anon. The choice of antibacterial drugs. Med Lett Drugs Ther . 2001; 43:69-78. [PubMed 11518876]
109. Food and Drug Administration. Public health advisory on colistimethate (marketed as Coly-Mycin M and generic products). Rockville, MD; June 28 2007. From FDA website. [Web]
110. Food and Drug Administration. Information for healthcare professionals on colistimethate (marketed as Coly-Mycin M and generic products). Rockville, MD; June 28 2007. From FDA website. [Web]
111. Hodson ME, Gallagher CG, Govan JRW. A randomised clinical trial of nebulised tobramycin or colistin in cystic fibrosis. Eur Respir J . 2002;20:658-64. [PubMed 12358344]
112. JensenT, Pederson SS, Garne S et al. Colistin inhalation therapy in cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection. J Antimicrob Chemother . 1987;19:831-8.
113. Valerius NH, Koch C, Hoiby N. Prevention of chronic Pseudomonas aeruginosa colonisation in cystic fibrosis by early treatment. Lancet . 1991;338:725-6. [PubMed 1679870]
114. Hoiby N, Frederiksen B, Pressler T. Eradication of early Pseudomonas aeruginosa infection. J Cystic Fibro . 2005; 4:49-54.
115. Frederiksen B, Koch C, Hoiby N. Antibiotic treatment of initial colonisation with Pseudomonas aeruginosa postpones chronic infection and prevents deterioration of pulmonary function in cystic fibrosis. Pediatr Pulmonol . 1997;23:330-5. [PubMed 9168506]
116. Littlewood JM, Miller MG, Ghoneim AT et al. Nebulised colomycin for early pseudomonas colonisation in cystic fibrosis (letter). Lancet . 1985;1:865. [PubMed 2858720]
117. Taccetti G, Campana S, Festini F et al. Early eradication therapy against Pseudomonas aeruginosa in cystic fibrosis patients. Eur Resp J . 2005; 26:458-61.
118. Marchetti F, Giglio L, Candusso M et al. Early antibiotic treatment of pseudomonas aeruginosa colonisation in cystic fibrosis: a critical review of the literature. Eur J Clin Pharmacol . 2004; 60:67-74. [PubMed 15004732]
119. Beringer P. The clinical use of colistin in patients with cystic fibrosis. Curr Opin Pulm Med . 2001; 7: 434-40. [PubMed 11706322]
120. Shirk M, Donahue K, Shirvani J. Unlabeled uses of nebulized medications. Am J Health Syst Pharm . 2006;63:1704-16 [PubMed 16960254]
121. Falagas M, Kasiakou S. Colistin: the revival of polymyxins for the management of multidrug-resistant gram-negative bacterial infections. Clin Infect Dis . 2005;40:1333-41. [PubMed 15825037]
122. Littlewood J, Koch C, Lambert PA, et al. A ten year review of colomycin. Respir Med . 2000;94:632-40. [PubMed 10926333]
123. Gibson RL, Burns JL, Ramsey BW. Pathophysiology and management of pulmonary infections in cystic fibrosis. Am J Respir Crit Care Med . 2003;168:918-51 [PubMed 14555458]
124. Boyle MP. Adult cystic fibrosis. JAMA . 2007; 298:1787-93. [PubMed 17940235]
125. Mukhopadhyay S, Singh M, Cater J et al. Nebulised antipseudomonal antibiotic therapy in cystic fibrosis: a meta-analysis of benefits and risks. Thorax . 1996;51:364-8. [PubMedCentral][PubMed 8733486]
126. Webb AK, Dodd ME. Nebulised antibiotics for adults with cystic fibrosis. Thorax . 1997;52 Suppl 2:S69-71. [PubMed 9155856]
127. Wood DM, Smyth AR. Antibiotic strategies for eradicating Pseudomonas aeruginosa in people with cystic fibrosis. Cochrane Database Syst Rev . 2006. 25;(1):CD004197.
128. Ryan G, Mukhopadhyay S, Singh M. Nebulised anti-pseudomonal antibiotics for cystic fibrosis. Cochrane Database Syst Rev . 2003;(3):CD001021. [PubMed 12917897]
129. Falagas ME, Kasiakou SK. Use of international units when dosing colistin will help decrease confusion related to various formulations of the drug around the world. Antimicrob Agents Chemother . 2006;50:2274-5 [PubMedCentral][PubMed 16723606]
130. Alothman G, Ho B, Alsaadi MM et al, Bronchial constriction and inhaled colistin in cystic fibrosis. Chest . 2005;127:522-9.
131. Cunningham S, Prasad A, Collyer L et al. Bronchoconstriction following nebulised colistin in cystic fibrosis. Arch Dis Child . 2001;84:432-3 . [PubMedCentral][PubMed 11316693]
132. Ratjen F, Rietschel E, Kasel D et al. Pharmacokinetics of inhaled colistin in patients with cystic fibrosis. J Antimicrob Chemother . 2006;57:306-11. [PubMed 16396919]
133. Reed MD, Stern RC, O'Riordan MA et al. The pharmacokinetics of colistin in patients with cystic fibrosis. J Clin Pharmacol . 2001;41:645-54. [PubMed 11402633]
134. Kucers A, Crowe S, Grayson ML et al, eds. The use of antibiotics. A clinical review of antibacterial, antifungal, and antiviral drugs. 5th ed. Jordan Hill, Oxford: Butterworth-Heinemann; 1997: 667-75.
135. Falagas ME, Kasiakou SK, Tsiodras S et al. The use of intravenous and aerosolized polymyxins for the treatment of infections in critically ill patients: a review of the recent literature. Clin Med Res . 2006; 4:138-46. [PubMedCentral][PubMed 16809407]
136. Li J, Rayner CR, Nation RL. Heteroresistance to colistin in multidrug-resistant Acinetobacter baumanii . Antimicrob Agents Chemother . 2006; 50:2946-50. [PubMedCentral][PubMed 16940086]
137. Antoniadou A, Kontopidou F, Poulakou G et al. Colistin-resistant isolates of Klebsiella pneumoniae emerging in intensive care unit patients: first report of a multiclonal cluster. J Antimicrob Chemother . 2007; 59:786-90. [PubMed 17307769]
138. Paolino K, Erwin D, Padharia V et al. In vitro activity of colistin against multidrug-resistant gram-negative bacteria isolated at a major army hospital during the military campaigns in Iraq and Afghanistan. Clin Infect Dis . 2007; 45:140-2. [PubMed 17554723]
139. Institute for Safe Medication Practices (ISMP). NAN alert regarding risk of serious or fatal medication error: Dosing confusion with colistimethate for injection. 2011 Jun 29.
140. Colistin Sulfate and Colistimethate Sodium. In: Brayfield A, ed. Martindale: The Complete Drug Reference [online], London: Pharmaceutical Press. Accessed 2017 Mar 22.
141. Lim LM, Ly N, Anderson D et al. Resurgence of colistin: a review of resistance, toxicity, pharmacodynamics, and dosing. Pharmacotherapy . 2010; 30:1279-91. [PubMedCentral][PubMed 21114395]
142. Bergen PJ, Li J, Rayner CR et al. Colistin methanesulfonate is an inactive prodrug of colistin against Pseudomonas aeruginosa. Antimicrob Agents Chemother . 2006; 50:1953-8. [PubMedCentral][PubMed 16723551]