Colistimethate (colistin (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 sodium, in terms of colistin, or as international units. 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.

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

In patients with renal impairment, dosage of colistimethate sodium should be decreased in proportion to the degree of renal impairment.

Dosage for Adults with Renal Impairment

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

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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.

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Antibiotics/Fecal Microbiota

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota is a suspension of live bacteria, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota. Antibacterial treatment should be completed for 24 to 72 hours before initiating treatment with fecal microbiota. Do not use antibiotics for up to 8 weeks after fecal microbiota.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota.

Antibiotics/Fecal Microbiota Spores

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Fecal microbiota spores is a suspension of live bacterial spores, which may be compromised by concurrent use of antibiotics.(1)

CLINICAL EFFECTS: Antibiotics may decrease the effectiveness of fecal microbiota spores.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Antibiotics should not be used concurrently with fecal microbiota spores. Antibacterial treatment should be completed for 2 to 4 days before initiating treatment with fecal microbiota spores.(1)

DISCUSSION: Antibiotics may compromise the effectiveness of fecal microbiota spores.

Antimicrobials/Live Typhoid Vaccine

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: The antimicrobial may be active against the organism in the live-vaccine. Antimicrobial therapy may prevent the vaccine organism from replicating enough to trigger an immune response.(1)

CLINICAL EFFECTS: Vaccination may be ineffective.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Do not give oral typhoid vaccine until 72 hours after the last dose of antimicrobial. If possible, to optimize vaccine effectiveness, do not start antibacterial drugs for 72 hours after the last dose of oral typhoid vaccine. A longer interval should be considered for long-acting antimicrobials, such as azithromycin.(3)

DISCUSSION: Because antimicrobial therapy may prevent sufficient vaccine-organism replication to generate an immune response, the manufacturer of live-attenuated typhoid vaccine and the Centers for Disease Control (CDC) state that the vaccine should not be administered to patients receiving antimicrobial therapy.(1-3)

Selected Nephrotoxic Agents/Bacitracin

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Bacitracin may cause renal failure due to glomerular and tubular necrosis. Concurrent administration of other nephrotoxic agents may result in additive renal toxicity.(1-3)

CLINICAL EFFECTS: Concurrent use of bacitracin with other potentially nephrotoxic agents may result in renal toxicity.(1-3)

PREDISPOSING FACTORS: Dehydration and high-dose bacitracin may predispose to adverse renal effects.(1)

PATIENT MANAGEMENT: Health Canada states that bacitracin is contraindicated in patients with renal impairment, including those taking other nephrotoxic drugs.(1) The Canadian and US manufacturers of bacitracin state that concomitant use of bacitracin with other potentially nephrotoxic agents should be avoided.(2,3)

DISCUSSION: Renal impairment is a major toxicity of bacitracin. Cases of nephrotoxicity have been reported when bacitracin was used off-label.(1-3)

Selected Nephrotoxic Agents/Polymyxin B

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Polymyxin B can cause nephrotoxicity with a slight degree of tubular damage. Concurrent administration of other nephrotoxic agents may result in an increased risk of nephrotoxicity.(1)

CLINICAL EFFECTS: Concurrent use of polymyxin B with other nephrotoxic agents may result in additive nephrotoxic effects. Polymyxin B nephrotoxicity is characterized by albuminuria, cellular casts, azotemia, diminished urine output, elevated BUN and rising blood levels usually after about 4 days of therapy.(1,2)

PREDISPOSING FACTORS: Factors predisposing to nephrotoxicity include higher cumulative doses and longer duration of therapy of polymyxin B and exposure to multiple nephrotoxins.(2)

PATIENT MANAGEMENT: Concurrent or sequential use of potentially nephrotoxic agents with polymyxin B should be avoided. If concurrent use is necessary, it should be undertaken with great caution. Check renal function at baseline and monitor renal function and polymyxin B blood levels frequently during therapy.(1)

DISCUSSION: Polymyxin B is associated with high rates of nephrotoxicity. Concurrent use with other nephrotoxins may increase the risk of nephrotoxicity.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Colistimethate/Selected Nephrotoxic Agents

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Colistimethate can cause nephrotoxicity.(1,2) Concurrent administration of other nephrotoxic agents may result in an increased risk of nephrotoxicity.(1) It is suspected that cephalothin interferes with the excretion of colistimethate resulting in enhanced nephrotoxicity.(2,3)

CLINICAL EFFECTS: Concurrent use of colistimethate with other nephrotoxic agents may result in additive nephrotoxic effects.

PREDISPOSING FACTORS: Factors predisposing to nephrotoxicity include higher cumulative doses of colistimethate, longer treatment duration, hypovolemia, and critical illness.

PATIENT MANAGEMENT: Concurrent use of potentially nephrotoxic agents with colistimethate should be avoided.(1,2) If concurrent use is necessary, it should be undertaken with great caution.(1)

DISCUSSION: In a case control study of 42 patients on intravenous colistimethate sodium, NSAIDs were identified as an independent risk factor for nephrotoxicity (OR 40.105, p=0.044).(4) In 4 case reports, patients developed elevated serum creatinine and blood urea nitrogen following concurrent colistimethate and cephalothin (3 patients) or when colistimethate followed cephalothin therapy (1 patient).(3) A literature review found that individual nephrotoxic agents, including aminoglycosides, vancomycin, amphotericin, IV contrast, diuretics, ACE inhibitors, ARBs, NSAIDs, and calcineurin inhibitors, were not consistently associated with additive nephrotoxicity when used with colistimethate. However, when multiple agents (at least 2 additional potential nephrotoxins) were used concurrently, there was a significant correlation to colistimethate nephrotoxicity.(5)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Polypeptide Antibiotics/Neuromuscular Blocking Agents

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Synergistic pharmacologic activity. Polymyxin B affects neuromuscular transmission by blocking acetylcholine receptors. Its action is thus post-synaptic and the neuromuscular block has no antagonists. Polymyxin B causes neostigmine resistance to d-tubocurarine blockade and calcium resistance to the blockade evoked by aminoglycoside antibiotics (1,2,3,4). A pre-synaptic mechanism may also be involved with decreased release of acetylcholine.

CLINICAL EFFECTS: May see an increase in the neuromuscular blocking effects, including profound sedation, respiratory depression, coma, and/or death.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If it is necessary to administer these drugs concurrently, do so with extreme caution. Monitor neuromuscular function and adjust the dose of the neuromuscular blocking agent accordingly. If concurrent use is necessary, monitor patients for unusual dizziness or lightheadedness, extreme sleepiness, slowed or difficult breathing, or unresponsiveness.

DISCUSSION: Concomitant administration of polypeptide antibiotics and neuromuscular blocking agents has been shown to produce synergism of the effects on skeletal muscles. Concurrent administration of these drugs has been associated with prolonged respiratory depression, respiratory paralysis, and apnea. This interaction has been documented with colistimethate, polymyxin B, bacitracin, and vancomycin.

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There are no contraindication contraindications for this drug.

• Clostridioides difficile infection
• Kidney disease with reduction in glomerular filtration rate (GFr)
• Myasthenia gravis

• Neuromuscular blockade

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Less Frequent

• Paresthesia

Rare or Very Rare

• Acute respiratory distress syndrome
• Anaphylaxis
• Apnea
• Bronchospastic pulmonary disease
• Clostridioides difficile infection
• Nephrotoxicity
• Neuromuscular blockade
• Pseudo-bartter syndrome
• Respiration changes
• Seizure disorder
• Slurred speech
• Urticaria

More Frequent

• Cough
• Vertigo

Less Frequent

• Dizziness
• Fever
• Gastrointestinal irritation
• Pruritus of skin
• Skin rash

Rare or Very Rare

• Oliguria

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No enhanced messaging available.

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 (0.25 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. In addition, increased resorption occurred at the 9.3 mg/kg dosage. 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). 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.

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.

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