Kolistimetatnatrium Noridem: Uses, Dosage & Side Effects

What Is Kolistimetatnatrium Noridem and What Is It Used For?

Kolistimetatnatrium Noridem contains the active substance colistimethate sodium (also known as colistin methanesulfonate or CMS), which belongs to the polymyxin class of antibiotics. Polymyxins were first discovered in 1947 from the soil bacterium Paenibacillus polymyxa and were introduced into clinical practice in the late 1950s. However, they fell out of widespread use in the 1970s and 1980s due to concerns about nephrotoxicity and neurotoxicity, and because safer alternative antibiotics were available. The resurgence of interest in colistin over the past two decades has been driven by the alarming global rise of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria, for which polymyxins are often the only remaining effective treatment option.

Colistimethate sodium is itself microbiologically inactive; it functions as a prodrug that undergoes hydrolysis in vivo (in the body and in aqueous solutions at physiological pH) to release colistin, the pharmacologically active compound. Colistin exerts its bactericidal activity through a unique mechanism of action: the positively charged colistin molecule binds electrostatically to the negatively charged lipid A component of lipopolysaccharides (LPS) in the outer membrane of Gram-negative bacteria. This interaction displaces the divalent cations (calcium and magnesium) that normally stabilize the LPS layer, leading to disruption of the outer membrane structure. The resulting increase in membrane permeability causes leakage of intracellular contents, osmotic imbalance, and ultimately rapid bacterial cell death. This mechanism explains why colistin is selectively active against Gram-negative bacteria (which possess an LPS-containing outer membrane) and has no activity against Gram-positive bacteria, anaerobes, or fungi.

The spectrum of activity of colistin includes many clinically important Gram-negative pathogens, most notably Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Escherichia coli, Enterobacter species, Citrobacter species, and Haemophilus influenzae. Notably, certain Gram-negative species are intrinsically resistant to colistin, including Proteus species, Providencia species, Morganella morganii, Serratia marcescens, Burkholderia cepacia, and Neisseria species. Acquired resistance to colistin, mediated through chromosomal mutations or plasmid-borne mcr genes that modify the lipid A portion of LPS, is an emerging global concern that further underscores the need for judicious use of this antibiotic.

Kolistimetatnatrium Noridem is indicated for the treatment of serious infections caused by aerobic Gram-negative organisms in patients with limited treatment options. The principal clinical indications include:

• Nosocomial pneumonia including ventilator-associated pneumonia (VAP) caused by MDR Pseudomonas aeruginosa or Acinetobacter baumannii
• Bloodstream infections (bacteremia) caused by carbapenem-resistant Gram-negative bacteria
• Urinary tract infections caused by MDR organisms when other antibiotics have failed
• Respiratory tract infections in cystic fibrosis patients colonized or infected with Pseudomonas aeruginosa (via nebulization)
• Intra-abdominal infections and other deep-seated infections caused by XDR Gram-negative pathogens
• Central nervous system infections (via intrathecal or intraventricular administration in selected cases of MDR meningitis or ventriculitis)

The World Health Organization (WHO) classifies polymyxins, including colistin, as “critically important antimicrobials” in its AWaRe classification system, placing them in the Reserve category. This means that colistin should be used only as a last-resort treatment when all other alternatives have been exhausted. The WHO, IDSA (Infectious Diseases Society of America), and ESCMID (European Society of Clinical Microbiology and Infectious Diseases) all emphasize that polymyxins should be reserved for infections caused by organisms resistant to all other available antibiotics, and that their use should ideally be guided by antimicrobial susceptibility testing and, where possible, therapeutic drug monitoring.

What Should You Know Before Taking Kolistimetatnatrium Noridem?

Contraindications

Colistimethate sodium is contraindicated in patients with a known hypersensitivity to colistimethate sodium, colistin sulfate, or any other polymyxin antibiotic. Cross-reactivity between polymyxin B and polymyxin E (colistin) is well established, so patients with a documented allergy to one polymyxin should not receive the other. Additionally, colistimethate sodium is generally contraindicated in patients with myasthenia gravis due to its potential to exacerbate neuromuscular weakness and precipitate myasthenic crisis. In clinical practice, however, this absolute contraindication may be reconsidered in life-threatening infections where no other effective antibiotic exists, provided that close neuromuscular monitoring is in place.

Warnings and Precautions

Several important warnings and precautions must be considered before and during treatment with colistimethate sodium. The two most clinically significant toxicities are nephrotoxicity and neurotoxicity, both of which are dose-dependent and generally reversible upon dose reduction or discontinuation.

Nephrotoxicity: Acute kidney injury (AKI) is the most common serious adverse effect of colistimethate sodium, reported in approximately 20–60% of patients depending on the definition used, the dose administered, the duration of treatment, and the patient’s baseline renal function. The mechanism of nephrotoxicity involves direct tubular damage, particularly to the proximal tubular epithelial cells. Risk factors for colistin-induced nephrotoxicity include pre-existing renal impairment, concomitant use of other nephrotoxic agents (aminoglycosides, vancomycin, NSAIDs, amphotericin B, ciclosporin), hypovolemia, hypotension, older age, and higher cumulative doses. Renal function should be assessed prior to initiating therapy and monitored every 2–3 days throughout treatment, using serum creatinine, blood urea nitrogen (BUN), and estimated glomerular filtration rate (eGFR). Dose adjustment is required for patients with impaired renal function.

Neurotoxicity: Neurological adverse effects of colistin include paraesthesia (tingling or numbness, particularly of the face and extremities), dizziness, vertigo, visual disturbances, confusion, slurred speech, and rarely neuromuscular blockade that can progress to respiratory paralysis. The neurotoxic effects are believed to result from colistin’s interaction with neuronal cell membranes and its effects on calcium ion flux at neuromuscular junctions. Patients with pre-existing neurological conditions, renal impairment (leading to drug accumulation), or those receiving concurrent neurotoxic medications or neuromuscular blocking agents are at increased risk. If signs of neurotoxicity develop, the dose should be reduced or the drug discontinued.

Superinfection: As with all antibiotics, prolonged use of colistimethate sodium may result in overgrowth of non-susceptible organisms, including fungi. Patients should be monitored for signs of superinfection, and appropriate measures taken if it occurs.

Pregnancy and Breastfeeding

There are limited clinical data on the use of colistimethate sodium in pregnant women. Animal studies have shown that colistin crosses the placenta, and animal reproduction studies have demonstrated potential for fetal toxicity at high doses, although the relevance to human therapeutic doses is uncertain. Colistimethate sodium should only be used during pregnancy if the potential benefit clearly justifies the potential risk to the fetus, and only when no safer alternative antibiotic is available. The decision should be made by an infectious disease specialist or clinical microbiologist in consultation with the treating physician and the patient.

Colistin is excreted in small amounts in human breast milk. Due to the potential for serious adverse effects in breastfed infants (including effects on intestinal flora and potential for selection of resistant organisms), breastfeeding is not recommended during treatment with colistimethate sodium. If treatment is essential, breastfeeding should be discontinued for the duration of therapy and for at least 24 hours after the last dose.

Renal Impairment

Colistimethate sodium is primarily eliminated by the kidneys, and dose adjustment is essential in patients with impaired renal function. In patients with creatinine clearance below 80 mL/min, the maintenance dose must be reduced according to the degree of renal impairment. The loading dose, however, should generally remain the same regardless of renal function, as this is critical for achieving adequate initial plasma concentrations. In patients undergoing renal replacement therapy (hemodialysis, continuous renal replacement therapy), supplemental dosing after dialysis sessions is typically required, as colistin is significantly removed by these procedures. Therapeutic drug monitoring (TDM) of colistin plasma concentrations is strongly recommended in these patients to optimize dosing and minimize toxicity.

How Does Kolistimetatnatrium Noridem Interact with Other Drugs?

Colistimethate sodium has several important drug interactions that can increase the risk of its major toxicities. Because colistin is not metabolized by hepatic cytochrome P450 enzymes, traditional pharmacokinetic drug-drug interactions are not a concern. Instead, the clinically relevant interactions are primarily pharmacodynamic in nature, involving additive or synergistic toxicity when colistimethate sodium is combined with other nephrotoxic or neurotoxic agents.

Major Interactions

Minor Interactions

NSAIDs (e.g., ibuprofen, diclofenac): Non-steroidal anti-inflammatory drugs may reduce renal blood flow and exacerbate colistin-induced nephrotoxicity, particularly in patients who are dehydrated or hemodynamically unstable. While the interaction is considered moderate rather than major, it is prudent to avoid NSAIDs during colistimethate sodium therapy where possible and use paracetamol (acetaminophen) as an alternative for fever and pain management.

Loop diuretics (furosemide, bumetanide): High-dose loop diuretics may theoretically increase the risk of colistin nephrotoxicity through volume depletion and reduced renal perfusion. However, in critically ill patients requiring both diuresis and colistin therapy, the benefit of appropriate fluid management generally outweighs this risk. Close attention to fluid balance and renal function is recommended.

Inhalational anesthetics: Some inhalational anesthetic agents (such as ether and halothane) have muscle-relaxant properties that could theoretically be enhanced by colistin’s neuromuscular blocking effects. Modern anesthetic agents (sevoflurane, desflurane) have a lower risk, but anesthetists should be informed of concurrent colistin therapy.

What Is the Correct Dosage of Kolistimetatnatrium Noridem?

Dosing of colistimethate sodium is complex and has been the subject of considerable evolution over the past decade. The 2019 International Consensus Guidelines on the Optimal Use of Polymyxins provide the most current evidence-based recommendations. It is critically important to understand that colistimethate sodium can be expressed in different units depending on the manufacturer and the country: International Units (IU) and milligrams of colistin base activity (mg CBA). Kolistimetatnatrium Noridem is labeled in International Units, where approximately 12,500 IU = 1 mg CBA, and 1 million IU ≈ 80 mg CBA ≈ 240 mg colistimethate sodium (CMS).

Adults

Children

In children with normal renal function, the recommended intravenous dose of colistimethate sodium is 75,000–150,000 IU/kg/day, divided into three equal doses (every 8 hours). In neonates, lower doses of 75,000 IU/kg/day in two to three divided doses are generally recommended, owing to the immature renal function in this population. For nebulization in children with cystic fibrosis, doses of 0.5–1 million IU two to three times daily are typically used, adjusted according to the child’s age and weight. Pediatric dosing should always be determined by a specialist in pediatric infectious diseases.

Elderly

Elderly patients are at increased risk of colistin-induced nephrotoxicity and neurotoxicity due to age-related decline in renal function and reduced physiological reserve. Dosing in elderly patients should be based on estimated creatinine clearance (using the Cockcroft-Gault equation or similar methods) rather than serum creatinine alone, which may underestimate the degree of renal impairment in this population. More frequent monitoring of renal function (every 24–48 hours) is recommended, and dose adjustments should be made promptly if renal function deteriorates.

Missed Dose

Colistimethate sodium is administered in a hospital setting by healthcare professionals, so missed doses are rare. If a dose is inadvertently omitted, it should be given as soon as possible, and the regular dosing schedule resumed. The timing of subsequent doses should be adjusted to maintain appropriate intervals. Do not administer a double dose to compensate for a missed dose, as this could increase the risk of nephrotoxicity and neurotoxicity.

Overdose

Overdose of colistimethate sodium may result in severe nephrotoxicity, neuromuscular blockade (which can lead to respiratory failure), and neurological symptoms including paraesthesia, muscle weakness, dizziness, vertigo, confusion, and seizures. There is no specific antidote for colistin overdose. Treatment is supportive and symptomatic, including immediate cessation of the drug, supportive care for respiratory and cardiovascular function, and hemodialysis or continuous renal replacement therapy, which can remove significant amounts of colistin from the circulation. Neuromuscular blockade may respond to calcium gluconate or neostigmine, although evidence for these interventions is limited to case reports.

What Are the Side Effects of Kolistimetatnatrium Noridem?

The adverse effect profile of colistimethate sodium is well characterized from decades of clinical use and numerous observational studies and meta-analyses. The frequency and severity of adverse effects depend on the route of administration, the dose used, the duration of treatment, the patient’s renal function, and the presence of other risk factors. The side effects listed below are categorized according to their frequency as reported in clinical studies and post-marketing surveillance.

Nephrotoxicity is the most clinically significant and well-studied adverse effect of colistimethate sodium. The mechanism involves direct toxicity to proximal tubular epithelial cells, leading to tubular necrosis, increased membrane permeability, and mitochondrial dysfunction. Risk factors include high cumulative dose, prolonged duration of treatment, pre-existing renal impairment, hypovolemia, concomitant nephrotoxic drugs, and older age. A meta-analysis published in Clinical Infectious Diseases (2017) reported a pooled incidence of AKI of approximately 33.6% in patients receiving intravenous colistimethate sodium, though rates vary widely depending on the definition of AKI used. Importantly, colistin-induced nephrotoxicity is generally reversible upon discontinuation of the drug, with the majority of patients recovering renal function within days to weeks.

Neurotoxicity is less common than nephrotoxicity but can be clinically significant, particularly in patients with impaired renal function (leading to drug accumulation). Paraesthesia (typically described as tingling around the mouth, face, and extremities) is the most common neurological complaint and may occur within the first few days of treatment. More severe neurotoxic effects, including neuromuscular blockade and respiratory depression, are rare with current dosing regimens but have been reported historically when higher doses were used. Patients who develop any neurological symptoms during treatment should be assessed promptly, and dose reduction or discontinuation should be considered.

Inhalation-specific side effects: When colistimethate sodium is administered by nebulization, local airway irritation is common. Bronchospasm can occur, particularly in patients with reactive airway disease, and pre-treatment with a short-acting bronchodilator (such as salbutamol) is recommended. A sensation of chest tightness, cough, and unpleasant taste in the mouth are also frequently reported. These local effects are generally mild and do not necessitate discontinuation of therapy.

How Should You Store Kolistimetatnatrium Noridem?

Proper storage of Kolistimetatnatrium Noridem is important to ensure the stability, potency, and safety of the medication. The unreconstituted powder for solution for injection/infusion should be stored at a temperature not exceeding 25°C (77°F). The vials should be kept in their original carton to protect the contents from light and moisture. Like all medications, Kolistimetatnatrium Noridem should be stored out of the sight and reach of children.

Once reconstituted, the solution should be used promptly. Chemical and physical in-use stability has been demonstrated for up to 24 hours when stored in a refrigerator at 2–8°C. However, from a microbiological perspective, the product should ideally be used immediately after reconstitution. If not used immediately, in-use storage times and conditions are the responsibility of the healthcare professional and should normally not exceed 24 hours at 2–8°C, unless reconstitution has taken place in controlled and validated aseptic conditions. The reconstituted solution should not be frozen.

The reconstituted solution should be inspected visually before administration. It should be a clear, colorless to slightly yellow solution. Do not use if the solution is discolored, turbid, or contains visible particles. Any unused portion of the reconstituted solution should be discarded in accordance with local institutional guidelines for pharmaceutical waste disposal.

Do not use Kolistimetatnatrium Noridem after the expiry date stated on the vial label and outer carton. The expiry date refers to the last day of that month. In the hospital setting, pharmacy staff are responsible for ensuring that expired products are identified and removed from use.

What Does Kolistimetatnatrium Noridem Contain?

Kolistimetatnatrium Noridem is formulated as a sterile lyophilized (freeze-dried) powder for reconstitution. Each vial contains:

• Active substance: Colistimethate sodium 1 million IU (equivalent to approximately 80 mg of colistin base activity)

The product does not contain any additional excipients, preservatives, or other inactive ingredients. Colistimethate sodium is the sodium salt of the methanesulfonate derivative of colistin, a cyclic polypeptide antibiotic originally derived from Paenibacillus polymyxa var. colistinus. The sulfomethylation process converts colistin to its less toxic prodrug form, colistimethate sodium, which has significantly reduced direct toxicity compared to colistin sulfate while maintaining the ability to regenerate the active colistin moiety in vivo.

For reconstitution, the powder should be dissolved in the appropriate diluent as specified in the product information. For intravenous or intramuscular administration, reconstitute with 2 mL of Water for Injections or 0.9% Sodium Chloride solution. For intravenous infusion, the reconstituted solution should be further diluted with 0.9% Sodium Chloride or 5% Glucose solution to a suitable volume (typically 50–100 mL) and administered over 30–60 minutes. For nebulization, reconstitute with 2–4 mL of 0.9% Sodium Chloride or Water for Injections, and administer using a suitable jet nebulizer.

The product is supplied as a single-dose vial. The glass vial contains a white to off-white lyophilized cake or powder. After reconstitution, the solution should be clear and colorless to pale yellow. Discard any unused solution. The product does not contain latex in the vial stopper.