Colistimethate Sodium

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).100

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

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.106 119 121 122 135

Not indicated for infections caused by Proteus or Neisseria.100

Respiratory Tract Infections

Administered by oral inhalation via nebulization† 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.109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126

Safety and efficacy not established and the drug is not labeled by FDA for administration via nebulization†.109 110 Adverse respiratory effects (e.g., bronchoconstriction) have occurred with this route119 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 Respiratory Effects under Cautions.)

Contraindications

• Hypersensitivity to colistimethate or any ingredient in the formulation.100

Warnings/Precautions

Warnings

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

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

Monitor renal function.a Nephrotoxicity probably is dose-dependent,100 but adverse renal effects may occur regardless of dosage.a

Use with caution in patients in whom the possibility of renal impairment exists (e.g., geriatric patients).100

Discontinue drug immediately if diminishing urine output, increasing BUN or Scr, or decreased Clcr occur.100 If colistimethate must be reinstated, dosage should be adjusted after plasma concentrations of the drug have declined.100 (See Renal Impairment under Dosage and Administration.)

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.100 a

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

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

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.100 a

Patients should not drive vehicles or use hazardous machinery while receiving colistimethate.100

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.a (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.a

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

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

Administration by oral inhalation via nebulization† has caused bronchoconstriction in adult and pediatric cystic fibrosis patients.119 130 131 Bronchoconstriction has occurred almost immediately after initiation of nebulization and can last for >30 minutes.119

Premedication with bronchodilators may reduce the potential for bronchoconstriction.119 120 122 130 131

Pre- and posttreatment pulmonary function tests recommended to identify patients who may be predisposed to bronchoconstriction.119 Bronchodilator premedication recommended in young children who are unable to perform pulmonary function tests.131

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†.109 110 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.109 110 This fatality may have been related to the fact that a premixed solution of colistimethate was used in the nebulizer.109 110

Extemporaneously prepared solutions of colistimethate should be used promptly.109 After colistimethate 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

Respiratory arrest reported following IM administration.100

Treatment with anti-infectives may permit overgrowth of Clostridium difficile.100 101 102 103 104 105 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.100 101 102 103 104 105

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

If CDAD is suspected or confirmed, discontinuance of the anti-infective may be necessary.100 101 102 103 104 105 Some mild cases may respond to discontinuance alone.100 101 102 103 104 105 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.100 101 102 103 104 105

Sensitivity Reactions

Generalized pruritus, urticaria, rash, and fever reported in patients receiving colistimethate;100 anaphylaxis also reported.100

General Precautions

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

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.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

Specific Populations

Category C.100

Not know whether colistimethate is distributed into milk;100 colistin is distributed into milk.100 Use with caution.100

Used in neonates, infants, children, and adolescents.100 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.100

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults.100 Other clinical experience has not revealed age-related differences in response.100

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.100

Substantially eliminated by kidneys; risk of toxicity may be greater in those with impaired renal function.100 Consider monitoring renal function because of age-related decreases in renal function.100 (See Renal Impairment under Dosage and Administration.)

Use with caution in patients in whom the possibility of renal impairment exists (e.g., geriatric patients).100

If used in patients with renal impairment, reduce dosage and frequency of administration in proportion to the degree of impairment.100 (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.100

Discontinue drug immediately if diminishing urine output, increasing concentrations of BUN or Scr, or decreased Clcr occur.100

Common Adverse Effects

Renal effects, nervous system effects.100

Absorption

Bioavailability

Not absorbed orally;a must be given parenterally.a

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

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;133 mean 8-hour trough concentrations after first dose and at steady state are 2.8 mcg/mL and 4.5 mcg/mL, respectively.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, peak serum concentrations of 0.17 mcg/mL are attained in 1.5 hours.132

Distribution

Extent

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

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

Crosses placenta.100

Not known whether colistimethate is distributed into milk; colistin is distributed into milk.100

Plasma Protein Binding

>50% bound.a

Following IV administration in cystic fibrosis patients 14–53 years of age, steady state volume of distribution is 0.09 L/kg.133

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.132

Elimination

Metabolism

Prodrug of colistin;140 141 142 hydrolyzed in vivo to colistin and possibly other metabolites with fewer substituted amino groups.a Rate and extent of hydrolysis as well as the specific metabolites and their antibacterial activities have not been determined to date.a

Elimination Route

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

May be removed by hemodialysis and, to a lesser extent, by peritoneal dialysis.134

Half-life

1.5–8 hours in adults with normal renal function.a

Special Populations

Children: Serum concentrations decline more rapidly than in adults.a

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

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.133

Cystic fibrosis patients 12–48 years of age receiving colistimethate by oral inhalation via nebulization†: Half-life is 4.1–4.5 hours.132

• 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).100

• Importance of completing full course of therapy, even if feeling better after a few days.100

• 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.100

• 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).a

• 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).a

• Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued.100 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.100

• 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.109 110

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

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

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