Inhalation/Respiratory Chronic pulmonary infections due to Pseudomonas aeruginosa
Adult: In patients with cystic fibrosis: Doses are expressed in IU of colistimethate sodium (CMS). As powder for nebuliser solution: 1-2 MIU bid or tid; Max: 6 MIU daily. As inhalation powder in hard capsule: 1.6625 MIU bid. All doses are given using the inhalation delivery system provided (refer to specific product guidelines). Dosing recommendations may vary among individual products and between countries (refer to specific product guidelines). Child: As powder for nebuliser solution: <2 years 0.5-1 MIU bid; Max: 2 MIU daily. ≥2 years Same as adult dose. As inhalation powder in hard capsule: ≥6 years Same as adult dose. Dosing recommendations may vary among individual products and between countries (refer to specific product guidelines).
Intramuscular, Intravenous Severe Gram-negative infections
Adult: For selected gram-negative pathogens wherein patients have limited treatment options (e.g. commonly prescribed antibiotics are ineffective or inappropriate): Doses are expressed in IU of colistimethate sodium (CMS) and colistin base activity (CBA). Maintenance dose: 9 MIU CMS daily in 2-3 divided doses. In critically ill patients: Loading dose: 9 MIU CMS. Doses to be given via slow IV infusion over 30-60 minutes. Alternatively, 2.5-5 mg/kg CBA daily, to be given in 2-4 divided doses via slow IV inj, continuous IV infusion or deep IM inj. Dosing recommendations and methods of administration may vary among individual products and between countries (refer to specific product guidelines). Child: ≤40 kg: 75,000-150,000 IU CMS/kg daily in 3 divided doses. >40 kg: Maintenance dose: 9 MIU CMS daily in 2-3 divided doses. In critically ill patients: Loading dose: 9 MIU CMS. Doses to be given via slow infusion over 30-60 minutes. Alternatively, 2.5-5 mg/kg CBA daily, to be given in 2-4 divided doses via slow IV inj, continuous IV infusion or deep IM inj. Dosing recommendations and methods of administration may vary among individual products and between countries (refer to specific product guidelines).
Renal Impairment
Intravenous; Intramuscular Severe Gram-negative infections: Haemodialysis patients: Non-haemodialysis days: 2.25 MIU CMS daily via slow IV infusion. Haemodialysis days: 3 MIU CMS daily on haemodialysis days, to be given post haemodialysis session via slow IV infusion. Doses are given in 2 divided doses.
CrCl (mL/min)
Dosage
<10
3.5 MIU CMS daily in 2 divided doses via slow IV infusion.
10-<30
4.5-5.5 MIU CMS daily in 2 divided doses via slow IV infusion.
30-<50
5.5-7.5 MIU CMS daily in 2 divided doses via slow IV infusion.
Dosing recommendations may vary among individual products and between countries (refer to specific product guidelines).
Reconstitution
IV infusion: Reconstitute with water for inj or NaCl 0.9% inj, then further dilute with appropriate amount of NaCl 0.9% inj or dextrose 5% inj to prepare the desired concentration. Swirl gently to avoid frothing during reconstitution. Powder for nebuliser solution: Reconstitute with appropriate volume of NaCl 0.9% solution to prepare desired concentration, then carefully transfer it to the medication reservoir. Avoid vigorous shaking. Instructions for reconstitution may vary among individual products and between countries (refer to specific product guidelines).
Contraindications
Hypersensitivity to colistimethate sodium, colistin or other polymyxins.
Special Precautions
Patient with myasthenia gravis, porphyria, hypovolaemia; hyperactive airways (inhalation). Colistimethate and colistin based strengths are not interchangeable. Renal and hepatic impairment. Children (particularly infants <1 year). Pregnancy and lactation.
Adverse Reactions
Significant: Nephrotoxicity (dose-dependent); neurotoxicity (e.g. facial, mouth or perioral paraesthesia, headache, muscle weakness); respiratory arrest; bronchospasm, cough, sore throat or mouth (inhalation). Ear and labyrinth disorders: Tinnitus (inhalation). Gastrointestinal disorders: Dysgeusia, nausea, vomiting (inhalation). General disorders and administration site conditions: Inj site reaction (IV/IM); balance disorder, fever, asthenia, fatigue (inhalation). Investigations: Decreased forced expiratory volume (inhalation). Musculoskeletal and connective tissue disorders: Arthralgia. Renal and urinary disorders: Acute renal failure. Respiratory, thoracic and mediastinal disorders: Pharyngolaryngeal pain or discomfort, dyspnoea, wheezing, shortness of breath, apnoea, dysphonia, throat irritation, haemoptysis, asthma, chest discomfort, lower respiratory tract infection (inhalation). Skin and subcutaneous tissue disorders: Pruritus. Potentially Fatal:Clostridium difficile-associated diarrhoea, pseudomembranous colitis; hypersensitivity reactions (e.g. skin rash, angioedema).
This drug may cause neurological disturbances (e.g. dizziness, confusion, visual disturbances), if affected, do not drive or operate machinery.
Monitoring Parameters
Perform culture and susceptibility tests; consult local institutional recommendations before treatment initiation due to antibiotic resistance risks. Evaluate renal function (e.g. serum creatinine, BUN, urine output) before and during the treatment regularly. Assess FEV1 before and after treatment regularly. Monitor colistin serum concentrations; signs of neurotoxicity, nephrotoxicity; bronchospasm (inhalation).
Overdosage
Symptoms: Paraesthesia of the perioral region and extremities, confusion states, temporospatial disorientation; renal insufficiency or failure, visual disturbances, psychosis, slurred speech, vertigo, apnoea, muscle weakness, vasomotor instability, respiratory paralysis. Management: Supportive and symptomatic treatment. May administer mannitol to induce osmotic diuresis. Perform peritoneal dialysis or prolonged haemodialysis. Provide assisted breathing if necessary.
Drug Interactions
Increased risk of nephrotoxicity with nephrotoxic drugs (e.g. iodinated contrast agents, aminoglycosides antibiotics, organoplatinum compounds, high-dose methotrexate, certain antiviral agents, pentamidine, ciclosporin, tacrolimus, cephalosporin antibiotics). May prolong effects of non-depolarising and depolarising muscle relaxants (e.g. suxamethonium), inhalation narcotics (e.g. ether, halothane).
Action
Description: Colistimethate sodium, an inactive prodrug, is hydrolysed into colistin which acts as a cationic detergent and damages the cytoplasmic membrane of the bacteria, thereby resulting in the leaking of intracellular substances and cell death. Pharmacokinetics: Absorption: Time to peak plasma concentration: IV: Colistin 2 hours; range: 1-4 hours (healthy volunteers); approx 7 hours (critically ill). Distribution: Minimal penetration into the CSF. Crosses the placenta and enters breast milk. Volume of distribution: IV: 8.92 L (colistimethate); 12.4 L (colistin). Plasma protein binding: 50%. Metabolism: Undergoes hydrolysis to the active substance colistin. Excretion: Mainly via urine (as unchanged drug). Elimination half-life: IM/IV: 2-3 hours (colistimethate).
Chemical Structure
Colistimethate sodium Source: National Center for Biotechnology Information. PubChem Database. Colistimethate, CID=216258, https://pubchem.ncbi.nlm.nih.gov/compound/Colistimethate (accessed on Jan. 22, 2020)
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