Colistimethate (Monograph)

Brand name: Coly-Mycin M
Drug class: Polymyxins
VA class: AM900
CAS number: 8068-28-8

Medically reviewed by Drugs.com on Mar 21, 2024. Written by ASHP.

Introduction

Antibacterial; prodrug of colistin (a polymyxin antibiotic structurally and pharmacologically related to polymyxin B).

Uses for Colistimethate

Gram-negative Aerobic Bacterial Infections

Treatment of acute or chronic infections caused by certain susceptible gram-negative bacteria (e.g., Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa).

Used only when the causative agent is susceptible and other more effective and less toxic anti-infectives are contraindicated or ineffective.

May be useful alone or in conjunction with other anti-infectives for 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.

Not indicated for infections caused by Proteus or Neisseria.

Respiratory Tract Infections

Administered by oral inhalation via nebulization^{† [off-label]} in adult and pediatric cystic fibrosis patients for early treatment of Ps. aeruginosa respiratory tract infections and for suppressive therapy in those colonized with Ps. aeruginosa.

Safety and efficacy not established and the drug is not labeled by FDA for administration via nebulization^{† [off-label]}. Adverse respiratory effects (e.g., bronchoconstriction) have occurred with this route and there has been at least one fatality in a patient who self-administered a nebulizer treatment using a premixed solution of the drug. (See Respiratory Effects under Cautions.)

Colistimethate Dosage and Administration

Administration

Administer by IM injection, IV injection, or continuous IV infusion. Also has been administered by oral inhalation via nebulization^{† [off-label]}.

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.

Colistimethate is a prodrug of colistin and is inactive until hydrolyzed in vivo to colistin. In the US, vials and carton packaging are labeled as colistimethate for injection; however, strength and dosage of the drug are expressed in terms of colistin base activity (colistin). This dosage convention must be considered when prescribing, preparing, and dispensing colistimethate.

In the US, colistimethate must only be prescribed in terms of colistin. If the drug is prescribed as colistimethate or colistimethate sodium, contact the prescriber to verify the dosage in terms of colistin. At least 1 fatality occurred as the result of acute renal failure and other complications when colistimethate was prescribed in terms of the prodrug (instead of colistin), resulting in administration of dosage approximately 2.5 times greater than it should have been.

Strength and dosage of colistimethate preparations commercially available in some other countries may be expressed in terms of colistimethate, in terms of colistin, or as international units. (See Dosage under Dosage and Administration.)

Report any medication errors involving colistimethate to the ISMP National Medication Error Reporting Program and the FDA MedWatch program.

IM Administration

Give appropriate dose (as reconstituted solution) by deep IM injection into a large muscle mass (e.g., gluteal muscle or lateral part of thigh).

Reconstitution

Reconstitute colistimethate sterile powder by adding 2 mL of sterile water for injection to a vial labeled as containing 150 mg of colistin; swirl gently to avoid frothing. The resultant solution contains 75 mg of colistin per mL.

IV Injection

Reconstitution

Reconstitute colistimethate sterile powder by adding 2 mL of sterile water for injection to a vial labeled as containing 150 mg of colistin; swirl gently to avoid frothing. Resultant solution contains 75 mg of colistin per mL.

Rate of Administration

Inject the appropriate dose (as reconstituted solution) directly into a vein over 3–5 minutes.

IV Infusion

For solution and drug compatibility information, see Compatibility under Stability.

Reconstitution and Dilution

Reconstitute colistimethate sterile powder by adding 2 mL of sterile water for injection to a vial labeled as containing 150 mg of colistin; swirl gently to avoid frothing. Resultant solution contains 75 mg of colistin per mL.

Add one-half of the total daily dose (as reconstituted solution) to a compatible IV solution. (See Compatibility under Stability.)

Rate of Administration

Inject one-half of the total daily dose (as reconstituted solution) directly into a vein over 3–5 minutes, then administer the dilution containing the remaining one-half of the total daily dose by slow IV infusion over 22–23 hours beginning 1–2 hours after the injection.

Oral Inhalation† [off-label]

For oral inhalation via nebulization^{† [off-label]}, an isotonic solution 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.

Extemporaneously prepared solutions for nebulization^† should be used promptly after being prepared. A fatality has been reported in a cystic fibrosis patient who self-administered a nebulizer treatment using a premixed solution of the drug. (See Respiratory Effects under Cautions.)

Bronchoconstriction has occurred almost immediately after initiation of nebulization^†; premedication with bronchodilators can be used to reduce the potential for bronchoconstriction. (See Respiratory Effects under Cautions.)

Dosage

Available as colistimethate sodium.

Dosage of colistimethate sodium commercially available in the US is expressed in terms of colistin.

Dosage of colistimethate sodium preparations commercially available in some other countries (e.g., United Kingdom, Greece) may be expressed in terms of colistimethate, in terms of colistin, or as international units. Consider that dosages reported in published clinical studies or case reports may vary depending on the country of origin and the preparation used.

Although not the US dosage convention, it has been suggested that dosage of colistimethate should preferably be expressed in terms of international units to avoid confusion. When expressed in terms of international units, each mg of colistin has a potency of 30,000 international units and each mg of colistimethate sodium has a potency of 12,500 international units.

Dosage is identical for either IV or IM administration.

Pediatric Patients

General Dosage for Infants and Children

IM or IV Injection

2.5–5 mg/kg of colistin daily given in 2–4 divided doses, depending on the severity of the infection.

Continuous IV Infusion

2.5–5 mg/kg of colistin daily, depending on the severity of the infection. Give the first half of the dose by direct IV injection and the second half of the dose by slow IV infusion over 22–23 hours beginning 1–2 hours after the injection.

Pseudomonas aeruginosa Infections in Cystic Fibrosis Patients

Oral Inhalation†

33.33–66.66 mg of colistin 2 or 3 times daily. This corresponds to 1–2 million international units 2 or 3 times daily.

Adults

General Adult Dosage

IM or IV Injection

2.5–5 mg/kg of colistin daily given in 2–4 divided doses, depending on the severity of the infection.

Continuous IV Infusion

2.5–5 mg/kg of colistin daily, depending on the severity of the infection. Give the first half of the dose by direct IV injection and the second half of the dose by slow IV infusion over 22–23 hours beginning 1–2 hours after the injection.

Pseudomonas aeruginosa Infections in Cystic Fibrosis Patients†

Oral Inhalation†

33.33–66.66 mg of colistin 2 or 3 times daily. This corresponds to 1–2 million international units 2 or 3 times daily.

Prescribing Limits

Pediatric Patients

IM or IV

Maximum of 5 mg/kg of colistin daily in those with normal renal function.

Adults

IM or IV

Maximum of 5 mg/kg of colistin daily in those with normal renal function.

Special Populations

Hepatic Impairment

No specific dosage recommendations at this time.

Renal Impairment

Decrease dosage in proportion to the degree of renal impairment. (See Table.)

Geriatric Patients

Select IM or IV dosage with caution, usually initiating therapy at the low end of the dosage range. Consider the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy observed in the elderly.

Obese Patients

Base dosage on ideal body weight.

Cautions for Colistimethate

Contraindications

• Hypersensitivity to colistimethate or any ingredient in the formulation.

Warnings/Precautions

Warnings

Nephrotoxicity

Nephrotoxicity (decreased urine output, increased BUN and S_cr, proteinuria, hematuria, casts in the urine) reported with usual dosage. Acute tubular necrosis has been reported and was not necessarily preceded by progressive renal impairment.

Nephrotoxicity generally reversible when the drug is discontinued. Additional increases in S_cr frequently occur for 1–2 weeks following discontinuance of the drug.

Monitor renal function. Nephrotoxicity probably is dose-dependent, but adverse renal effects may occur regardless of dosage.

Use with caution in patients in whom the possibility of renal impairment exists (e.g., geriatric patients).

Discontinue drug immediately if diminishing urine output, increasing BUN or S_cr, or decreased Cl_cr occur. If colistimethate must be reinstated, dosage should be adjusted after plasma concentrations of the drug have declined. (See Renal Impairment under Dosage and Administration.)

Neurotoxicity

Transient neurologic effects reported, including circumoral or peripheral paresthesia or numbness, tingling, or formication of the extremities or tongue, generalized pruritus, dizziness, vertigo, giddiness, ataxia, blurred vision, and slurred speech.

If neurologic effects occur, they generally appear within the first 4 days of therapy and disappear upon discontinuing the drug.

More severe neurotoxic effects (e.g., mental confusion, coma, psychosis, seizures) also reported, especially when high dosage was used or renal function was impaired.

The drug does not necessarily have to be discontinued if neurologic effects occur, but monitor patient closely; some of these effects may be alleviated by reducing dosage.

Patients should not drive vehicles or use hazardous machinery while receiving colistimethate.

Neuromuscular Blockade

Neuromuscular blockade (which may result in respiratory arrest) can occur, especially when used in patients who have neuromuscular disease such as myasthenia gravis or are receiving neuromuscular blocking agents, general anesthetics, or other drugs with neuromuscular blocking potential. (See Specific Drugs under Interactions.)

Apnea and neuromuscular blockade reported most frequently when dosage was not reduced in proportion to the degree of renal impairment.

If apnea occurs, respiration should be assisted, and calcium chloride injections and oxygen administered if appropriate.

Neuromuscular blockade induced by colistimethate is noncompetitive and is not reversed by neostigmine.

Respiratory Effects

Administration by oral inhalation via nebulization^† has caused bronchoconstriction in adult and pediatric cystic fibrosis patients. Bronchoconstriction has occurred almost immediately after initiation of nebulization and can last for >30 minutes.

Premedication with bronchodilators may reduce the potential for bronchoconstriction.

Pre- and posttreatment pulmonary function tests recommended to identify patients who may be predisposed to bronchoconstriction. Bronchodilator premedication recommended in young children who are unable to perform pulmonary function tests.

Respiratory distress progressing over several days to acute respiratory failure, multi-organ system failure, and death was reported in a patient who received colistimethate by oral inhalation via nebulization^†. This patient self-administered the nebulizer treatment using a colistimethate solution prepared by a pharmacy and dispensed in premixed unit dose ready-to-use vials. This fatality may have been related to the fact that a premixed solution of colistimethate was used in the nebulizer.

Extemporaneously prepared solutions of colistimethate should be used promptly. After colistimethate is mixed with water and buffer, it undergoes spontaneous hydrolysis to colistin. 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.

Respiratory arrest reported following IM administration.

Clostridium difficile-associated Diarrhea and Colitis

Treatment with anti-infectives may permit overgrowth of Clostridium difficile. C. 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, and may range in severity from mild diarrhea to fatal colitis.

Consider CDAD if diarrhea develops during or after therapy and manage accordingly. 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.

If CDAD is suspected or confirmed, discontinuance of the anti-infective may be necessary. Some mild cases may respond to discontinuance alone. Manage moderate to severe cases with fluid, electrolyte, and protein supplementation, anti-infective therapy active against C. difficile (e.g., oral metronidazole or vancomycin), and surgical evaluation when clinically indicated.

Sensitivity Reactions

Generalized pruritus, urticaria, rash, and fever reported in patients receiving colistimethate; anaphylaxis also reported.

General Precautions

Superinfection

Prolonged use may result in overgrowth of nonsusceptible organisms (e.g., Proteus). If suprainfection or superinfection occurs during therapy, appropriate anti-infective therapy should be instituted.

Selection and Use of Anti-Infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of colistimethate and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.

When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing. In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.

Specific Populations

Pregnancy

Category C.

Lactation

Not know whether colistimethate is distributed into milk; colistin is distributed into milk. Use with caution.

Pediatric Use

Used in neonates, infants, children, and adolescents. Adverse effect profile in pediatric patients appears to be similar to that in adults; however, monitor closely since subjective symptoms of toxicity may not be reported by pediatric patients.

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. Other clinical experience has not revealed age-related differences in response.

Select dosage with caution, usually starting at the low end of the dosage range, because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Substantially eliminated by kidneys; risk of toxicity may be greater in those with impaired renal function. Consider monitoring renal function because of age-related decreases in renal function. (See Renal Impairment under Dosage and Administration.)

Renal Impairment

Use with caution in patients in whom the possibility of renal impairment exists (e.g., geriatric patients).

If used in patients with renal impairment, reduce dosage and frequency of administration in proportion to the degree of impairment. (See Renal Impairment under Dosage and Administration.)

Dosage that exceeds 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.

Discontinue drug immediately if diminishing urine output, increasing concentrations of BUN or S_cr, or decreased Cl_cr occur.

Common Adverse Effects

Renal effects, nervous system effects.

Drug Interactions

Neurotoxic or Nephrotoxic Drugs

Concomitant or sequential use with other drugs that have neurotoxic and/or nephrotoxic effects may result in additive toxicity and should be avoided, if possible.

Specific Drugs

Colistimethate Pharmacokinetics

Absorption

Bioavailability

Not absorbed orally; must be given parenterally.

Following IM administration, peak serum concentrations of antibacterial activity attained within 2 hours.

Special Populations

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 after first dose and at steady state are 21.4 mcg/mL and 23 mcg/mL, respectively; mean 8-hour trough concentrations after first dose and at steady state are 2.8 mcg/mL and 4.5 mcg/mL, respectively.

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, peak serum concentrations of 0.17 mcg/mL are attained in 1.5 hours.

Distribution

Extent

Widely distributed into body tissues following IV or IM administration. Negligible concentrations attained in synovial, pleural, or pericardial fluids.

Minimal concentrations attained in CSF following IV or IM administration in patients with normal or inflamed meninges.

Crosses placenta.

Not known whether colistimethate is distributed into milk; colistin is distributed into milk.

Plasma Protein Binding

>50% bound.

Special Populations

Following IV administration in cystic fibrosis patients 14–53 years of age, steady state volume of distribution is 0.09 L/kg.

Following oral inhalation via nebulization^† in cystic fibrosis patients 12–48 years of age, sputum concentrations peaked in 1 hour and remained >4 mcg/mL for up to 12 hours in most patients.

Elimination

Metabolism

Prodrug of colistin; hydrolyzed in vivo to colistin and possibly other metabolites with fewer substituted amino groups. Rate and extent of hydrolysis as well as the specific metabolites and their antibacterial activities have not been determined to date.

Elimination Route

Excreted mainly by the kidneys via glomerular filtration. Antimicrobial activity in urine generally higher than in serum.

May be removed by hemodialysis and, to a lesser extent, by peritoneal dialysis.

Half-life

1.5–8 hours in adults with normal renal function.

Special Populations

Children: Serum concentrations decline more rapidly than in adults.

Impaired renal function: Serum concentrations are higher and the half-life prolonged. Half-life ranges from 10–20 hours in patients with Cl_cr <20 mL/minute. In a few anuric patients, half-life of antimicrobial activity ranged from 2–3 days.

Cystic fibrosis patients 14–53 years of age receiving IV colistimethate: Half-life is 3.4 hours after the first dose and 3.5 hours at steady state.

Cystic fibrosis patients 12–48 years of age receiving colistimethate by oral inhalation via nebulization^†: Half-life is 4.1–4.5 hours.

Stability

Storage

Parenteral

Powder for Injection

20–25°C.

Following reconstitution, store at 2–8°C or 20–25°C and use within 7 days.

Reconstituted solutions further diluted with a compatible IV solution should be used within 24 hours.

Extemporaneously prepared solutions for oral inhalation via nebulization^† should be used promptly after being mixed. (See Respiratory Effects under Cautions.)

Compatibility

Parenteral

Solution Compatibility

Drug Compatibility

Actions and Spectrum

• Colistimethate, the sulfamethyl derivative (methane sulfonate) of colistin, is a prodrug that is inactive until hydrolyzed to colistin; hydrolysis occurs in vivo and in vitro in aqueous solutions.

• Usually bactericidal.

• Acts like a cationic detergent and binds to and damages bacterial cytoplasmic membrane of susceptible bacteria causing alteration of the osmotic barrier and leakage of essential intracellular metabolites and nucleosides.

• In vitro spectrum of activity of colistin (active metabolite of colistimethate) includes certain gram-negative bacteria. Inactive against gram-positive bacteria, fungi, and viruses.

• Gram-negative bacteria: Active in vitro against 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.

• Resistance to colistin (active metabolite of colistimethate) has been induced in vitro in strains originally susceptible. Resistance may be reversible when drug is withdrawn. Resistance developed rarely during therapy.

• Resistant Ps. aeruginosa reported rarely, including in some patients receiving long-term treatment with colistimethate administered by oral inhalation via nebulization^†.

• Resistant Acinetobacter baumannii, Enterobacter cloacae, and Klebsiella pneumoniae reported rarely.

• Complete cross-resistance occurs between colistin and polymyxin B; cross-resistance with other anti-infectives has not been reported to date.

Advice to Patients

• Advise patients that antibacterials (including colistimethate) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).

• Importance of completing full course of therapy, even if feeling better after a few days.

• Advise patients that skipping doses or not completing the full course of 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.

• Importance of informing clinician if there is evidence of neurotoxicity (e.g., paresthesia, lethargy, confusion, dizziness, ataxia, nystagmus, speech disorders, apnea) or nephrotoxicity (e.g., decreased urine output).

• 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).

• Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued. Importance of contacting 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.

• Patients should be advised not to use any premixed, ready-to-use liquid preparations of colistimethate 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.

• Importance of informing clinician of existing or contemplated therapy, including prescription and OTC drugs, and any concomitant illnesses.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of advising patients of other important precautionary information. (See Cautions.)

Preparations

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.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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