Colistimethate sodium

Colistimethate sodium is an Antibiotic agent belonging to the pharmacological class of Polymyxin .

Colistimethate sodium has been approved to relieve symptoms and also for the treatment and maintenance of Bronchiectasis, pulmonary colonization/infection with susceptible organisms in cystic fibrosis and noncystic fibrosis patient, Meningitis and ventriculitis, Pulmonary infection due to multidrug-resistant gram-negative bacilli, Systemic infections, Urinary tract infection due to multidrug-resistant gram-negative bacilli.

Colistimethate sodium exhibits very poor absorption from the gastrointestinal tract, and information regarding its volume of distribution and protein binding is not available. Regarding metabolism, approximately 80% of the administered dose is excreted unchanged in the urine, indicating minimal biliary excretion. The remaining portion of the drug is presumed to undergo inactivation in the tissues, although the specific mechanism behind this process remains unknown.

The common side effects involved in using Colistimethate sodium are Nephrotoxicity (kidney damage), Neurotoxicity (nerve damage), Ototoxicity (ear damage), Gastrointestinal disturbances (nausea, vomiting, abdominal pain, diarrhea), Hypersensitivity reactions (allergic reactions), Injection site reactions (pain, redness, swelling), Rarely, blood disorders such as agranulocytosis or thrombocytopenia.

Colistimethate sodium is available in the form of Powder for injection.

Colistimethate sodium is approved in Germany, Japan, Malaysia, India, the U.K., the U.S., and China.

Colistimethate sodium belonging to the pharmacological class of Polymyxin is an Antibiotic agent.

Colistimethate sodium acts as a surface-active agent that enters and disrupts the bacterial cell membrane. It possesses polycationic properties and contains hydrophobic and lipophilic components. By interacting with the bacterial cytoplasmic membrane, it alters its permeability, resulting in a bactericidal effect. Additionally, there is evidence suggesting that polymyxins, including Colistimethate sodium, enter the bacterial cell and cause the precipitation of cytoplasmic components, particularly ribosomes.

Colistimethate sodium has been approved to relieve symptoms and also for the treatment and maintenance of Bronchiectasis, pulmonary colonization/infection with susceptible organisms in cystic fibrosis and noncystic fibrosis patient, Meningitis and ventriculitis, Pulmonary infection due to multidrug-resistant gram-negative bacilli, Systemic infections, Urinary tract infection due to multidrug-resistant gram-negative bacilli.

The average length of time Colistimethate sodium was administered was 17.9 days, with a range of 10 to 22 days between the lower and upper quartiles. In 79.1% of patients, the infection was successfully cured.

Colistimethate sodium is found to be available in the form of Powder for injection.

Colistimethate sodium can be used in the following treatment:

• Bronchiectasis, pulmonary colonization/infection with susceptible organisms in cystic fibrosis and non-cystic fibrosis patients
• Meningitis and ventriculitis
• Pulmonary infection due to multidrug-resistant gram-negative bacilli
• Systemic infections
• Urinary tract infection due to multidrug-resistant gram-negative bacilli

Colistimethate sodium can help to relieve symptoms and also for the treatment and maintenance of Bronchiectasis, pulmonary colonization/infection with susceptible organisms in cystic fibrosis and noncystic fibrosis patient, Meningitis and ventriculitis, Pulmonary infection due to multidrug-resistant gram-negative bacilli, Systemic infections, Urinary tract infection due to multidrug-resistant gram-negative bacilli.

Colistimethate sodium is approved for use in the following clinical indications:

• Bronchiectasis, pulmonary colonization/infection with susceptible organisms in cystic fibrosis and non-cystic fibrosis patients
• Meningitis and ventriculitis
• Pulmonary infection due to multidrug-resistant gram-negative bacilli
• Systemic infections
• Urinary tract infection due to multidrug-resistant gram-negative bacilli

Bronchiectasis, pulmonary colonization/infection with susceptible organisms in cystic fibrosis and non-cystic fibrosis patients:

• Off-label use/route: Inhalation of Colistimethate sodium.
• Recommended dosing: 30 to 150 mg or 1 - 5 IU of Colistimethate sodium base activity (CBA) via nebulizer, 1 to 2 times daily. The maximum dose is 150 mg CBA twice daily.
• The optimal dosing regimen has not been determined and may vary among studies. Lower doses have been used in non-cystic fibrosis patients with bronchiectasis. It should be used in addition to systemic antibiotics.

Meningitis and ventriculitis:

• Adjunct to systemic therapy, using a preservative-free preparation.
• Off-label route: Intrathecal/intraventricular administration.
• Recommended dosing: 4.2 mg CBA per day (equivalent to 10 mg Colistimethate sodium methanesulfonate [CMS] per day).
• The dose ranges from 0.7 to 8.3 mg CBA per day in 1 or 2 divided doses, administered with concomitant systemic antimicrobial therapy.
• When administered via a ventricular drain, the drain should be clamped for 15 to 60 minutes after administration to allow equilibration in the cerebrospinal fluid (CSF).
• Intraventricular administration is typically reserved for patients who fail parenteral therapy despite CSF shunt removal or when CSF shunt cannot be removed.

Pulmonary infection due to multidrug-resistant gram-negative bacilli:

• Adjunctive agent (off-label route): Inhalation for nebulization.
• Recommended dosing is not well defined but ranges from 75 to 150 mg or 2.5 or 5 IU CBA every 12 hours.
• Higher doses, up to 167 mg every 8 hours, have been described. Doses are typically rounded to the nearest vial size.
• It should be used in combination with systemic antimicrobial therapy.

Systemic infections:

• Alternative agent for systemic infections caused by multidrug-resistant gram-negative bacilli.
• Polymyxin B is preferred over Colistimethate sodium due to variability in pharmacokinetics, slower attainment of desired plasma concentrations, and increased risk of nephrotoxicity with Colistimethate sodium.
• Intravenous (IV) dosing: A loading dose of 300 mg or 10 IU CBA followed by maintenance doses of 150 to 180 mg or 5-6 IU CBA twice daily, starting 12 hours after the loading dose.
• Combination therapy with other antibiotics is recommended to minimize the development of resistance.

Urinary tract infection due to multidrug-resistant gram-negative bacilli:

• Colistimethate sodium is preferred over polymyxin B for lower urinary tract infections due to higher urinary concentrations.
• It may be used in combination with other antibiotics based on susceptibilities.
• IV dosing: A loading dose of 300 mg CBA or 10 IU followed by maintenance doses of 150 to 180 mg or 5-6 IU CBA twice daily, starting 12 hours after the loading dose. The dosing aims to achieve an average Colistimethate sodium steady-state plasma concentration of 2 mg/L, especially in critically ill patients.

Powder for injection: 150mg/vial

Powder for injection

Dosage Adjustments in Kidney Patients:

• When the creatinine clearance (CrCl) is greater than 80 mL/min, no adjustment in dosage is necessary.
• For patients with a CrCl ranging from 50 to 79 mL/min, the recommended dosage is 2.5-3.8 mg/kg/day, given intravenously or intramuscularly, divided into two doses every 12 hours.
• If the CrCl is between 30 and 49 mL/min, the recommended dosage is 2.5 mg/kg/day administered intravenously or intramuscularly, either once daily or divided into two doses every 12 hours.
• In patients with a CrCl of 10-29 mL/min, the recommended dosage is 1.5 mg/kg administered intravenously or intramuscularly every 36 hours.

Dosage Adjustments in Hepatic Impairment Patients:

No dosage adjustments are necessary.

Dosage Adjustments in Pediatric Patients:

CNS infection, multidrug-resistant:

• Infants and Children: Limited data available. Intraventricular/Intrathecal administration: Reported range: 1 to 4.2 mg of Colistimethate sodium base activity (CBA) per dose once daily in combination with systemic antibiotics. Doses should be individualized based on culture/susceptibility, minimum inhibitory concentration (MIC), tolerability, patient size, and cerebrospinal fluid volume. Case reports in patients aged 2 months to 4 years have described a titration regimen starting with 1 mg CBA on day 1, followed by 2 mg CBA once daily for 1 to 2 days, and then 4 mg CBA once daily for a total of 8 to 18 days of therapy. In other case reports, patients aged 1 month to 5 years received intrathecal or intraventricular Colistimethate sodium without titration at a dose of 4.2 mg CBA once daily for 5 to 9 days. Higher doses, up to 10 mg CBA (after titration), have been reported in infants to treat multidrug-resistant Acinetobacter baumannii.
• Adolescents: Limited data available. Intraventricular/Intrathecal administration: 4.2 mg CBA per day (equivalent to 10 mg Colistimethate sodium methanesulfonate (CMS) per day). Reported range: 2 to 8.3 mg CBA per day in 1 or 2 divided doses, with a duration of 10 to 14 days most commonly reported. Some reports used a titration regimen starting at 2.1 mg CBA once daily and increasing to 4.2 mg CBA once daily.

Cystic fibrosis, pulmonary infection:

• IV: Children ≥5 years and Adolescents: Usual reported range: 3 to 5 mg CBA per kilogram of body weight per day divided every 8 hours, with a maximum dose of 100 mg CBA per dose. Higher doses (up to 8 mg CBA per kilogram of body weight per day) have been described, but they are associated with more severe toxicity. Treatment duration varies and depends on patient-specific factors, with a typical duration of 10 to 21 days.
• Inhaled: Children and Adolescents: Usual dose: 75 to 150 mg CBA via nebulizer every 12 hours. Reported range: 33 to 150 mg CBA per dose. Doses ≤66 mg have been reported as frequently as every 8 hours. Duration depends on the specific use (maintenance therapy vs eradication therapy) and should be individualized.

Pulmonary infection due to multidrug-resistant gram-negative bacilli:

• Infants: Inhalation: 4 mg/kg per dose via nebulizer every 12 hours, with a maximum dose of 75 mg per dose.
• Children and Adolescents: Inhalation: 75 to 150 mg CBA or 2.5-5 IU via nebulizer every 12 hours. Reported range: 30 to 150 mg or 1-5 IU CBA per dose every 12 hours.

Systemic infections due to multidrug-resistant gram-negative bacilli:

• Infants, Children, and Adolescents: IM, IV: Loading dose of 2.5 to 5 mg CBA per kilogram of body weight once (maximum dose: 300 mg CBA or 10 IU per dose), followed by 5 mg CBA per kilogram of body weight per day divided every 8 to 12 hours (maximum dose: 180 mg per dose). Population pharmacokinetic studies suggest that higher doses may be necessary for severe/critical illness, with doses of approximately.

There are no specific dietary restrictions associated with the use of Colistimethate sodium. However, it is always advisable to follow a balanced and healthy diet while taking any medication to support overall well-being and optimize the body's response to treatment.

Colistimethate sodium may be contraindicated under the following conditions:

• Patients with a known hypersensitivity to Colistimethate for Injection USP should not receive the medication due to contraindications.

• The maximum recommended daily dose of Colistimethate for Injection USP should not exceed 5 mg/kg/day in individuals with normal renal function.
• Occupational hazards: Temporary neurological disturbances may occur, including tingling or numbness around the mouth, tingling or crawling sensation in the extremities, generalized itching, dizziness, vertigo, and slurred speech. Patients should be cautioned against driving or operating machinery while undergoing treatment.
• Reducing the dosage may alleviate these symptoms. Therapy does not necessarily need to be discontinued, but patients should be closely monitored. Overdosing can lead to renal insufficiency, muscle weakness, and difficulty breathing.
• The safety of sodium colistimethate during pregnancy has not been established.
• Due to its primarily renal excretion, caution should be exercised when using sodium colistimethate in patients with impaired renal function. Aging-related decline in renal function should be taken into account.
• In cases of actual renal impairment, sodium colistimethate can be used, but with extreme caution and dosage adjustment based on the level of impairment. Exceeding the renal excretory capacity can lead to elevated serum levels, further impairment of renal function, and toxic levels of the antibiotic in the body. This can result in muscle weakness, breathing difficulties, and interference with nerve transmission.
• Signs of impaired renal function include reduced urine output, elevated blood urea nitrogen (BUN), and serum creatinine levels. If these signs are present, sodium colistimethate therapy should be discontinued immediately.
• In life-threatening situations, therapy may be resumed at a lower dosage once blood levels have decreased.
• The concurrent use of certain antibiotics (kanamycin, streptomycin, dihydrostreptomycin, polymyxin, neomycin) with sodium colistimethate should be approached cautiously due to their potential interference with nerve transmission. Antibiotics with a gram-positive antimicrobial spectrum (e.g., penicillin, tetracycline, sodium cephalothin) are not reported to interfere with nerve transmission and would not be expected to enhance this effect of sodium colistimethate.
• Other drugs, including curariform muscle relaxants (ether, tubocurarine, succinylcholine, gallamine, decamethonium, and sodium citrate), can potentiate the neuromuscular blocking effect and should be used with extreme caution in patients receiving sodium colistimethate treatment.
• If apnea occurs, it can be managed with assisted respiration, administration of oxygen, and calcium chloride injections.
• Prescribing Colistimethate for Injection USP without a confirmed or strongly suspected bacterial infection is unlikely to benefit the patient and increases the risk of developing drug-resistant bacteria.

There is no specific warning against consuming alcohol while using Colistimethate sodium. However, it is generally recommended to avoid alcohol when taking antibiotics as it can potentially interfere with the effectiveness of the medication and may also increase the risk of side effects. Alcohol consumption can strain the liver and impair its ability to metabolize drugs, which can affect how Colistimethate sodium is processed in the body. Furthermore, both Colistimethate sodium and alcohol can individually cause gastrointestinal side effects, and consuming alcohol may exacerbate these symptoms.

The excretion of Colistimethate sodium in human breast milk is currently unknown. However, it is known that Colistimethate sodium sulfate is excreted in human breast milk. As a result, caution should be exercised when administering Colistimethate sodium to nursing women.

Pregnancy Category C

In rabbits, the administration of Colistimethate sodium via intramuscular injection during organogenesis at doses of 4.15 and 9.3 mg/kg resulted in talipes varus in 2.6% and 2.9% of fetuses, respectively. These doses are equivalent to 0.25 and 0.55 times the maximum daily human dose when adjusted for body surface area. Additionally, an increase in resorption was observed at the dose of 9.3 mg/kg. However, in rats, Colistimethate sodium at doses of 4.15 and 9.3 mg/kg did not show teratogenic effects. These doses are equivalent to 0.13 and 0.30 times the maximum daily human dose when adjusted for body surface area. There is a lack of sufficient and well-controlled studies in pregnant women. Given that Colistimethate sodium crosses the placental barrier in humans, its use during pregnancy should only be considered if the potential benefit justifies the potential risk to the fetus.

There are no specific food warnings related to the use of Colistimethate sodium. However, it is generally recommended to take Colistimethate sodium on an empty stomach, as food may interfere with its absorption. This means that Colistimethate sodium should be taken at least one hour before or two hours after meals.

The adverse reactions related to Colistimethate sodium can be categorized as follows:

Common

• Nephrotoxicity (kidney damage)
• Neurotoxicity (nerve damage)
• Ototoxicity (hearing loss or impairment)
• Neuromuscular blockade (muscle weakness or paralysis)
• Allergic reactions (such as rash, itching, or hives)
• Gastrointestinal disturbances (nausea, vomiting, diarrhea)

Less common

• Hypersensitivity reactions (severe allergic reactions)
• Respiratory complications (breathing difficulties)
• Electrolyte disturbances (such as changes in potassium or magnesium levels)
• Hematological abnormalities (changes in blood cell counts)
• Liver function abnormalities

Rare

• Neurological disorders (such as seizures or peripheral neuropathy)
• Cardiac arrhythmias (abnormal heart rhythms)
• Pancreatitis (inflammation of the pancreas)
• Superinfection (infection caused by resistant organisms)
• Disseminated intravascular coagulation (excessive blood clotting)

Other antibiotics, such as aminoglycosides and polymyxin, have been reported to affect nerve transmission at the neuromuscular junction. Therefore, caution should be exercised when administering them concurrently with Colistimethate sodium Parenteral. Muscle relaxants with curariform activity (e.g., tubocurarine) and other drugs like ether, succinylcholine, gallamine, decamethonium, and sodium citrate can enhance the neuromuscular blocking effect and should be used with great care in patients receiving Colistimethate sodium Parenteral. The use of sodium cephalothin along with Colistimethate sodium Parenteral may increase the risk of nephrotoxicity, and thus, their concomitant use should be avoided.

The following are the side effects involving Colistimethate sodium:

• Nephrotoxicity
• Neurotoxicity
• Ototoxicity
• Respiratory effects
• Gastrointestinal effects
• Allergic reactions
• Hematologic effects
• Nausea
• Vomiting

Pregnancy:

Pregnancy Category C

In rabbits, the administration of Colistimethate sodium via intramuscular injection during organogenesis at doses of 4.15 and 9.3 mg/kg resulted in talipes varus in 2.6% and 2.9% of fetuses, respectively. These doses are equivalent to 0.25 and 0.55 times the maximum daily human dose when adjusted for body surface area. Additionally, an increase in resorption was observed at the dose of 9.3 mg/kg. However, in rats, Colistimethate sodium at doses of 4.15 and 9.3 mg/kg did not show teratogenic effects. These doses are equivalent to 0.13 and 0.30 times the maximum daily human dose when adjusted for body surface area. There is a lack of sufficient and well-controlled studies in pregnant women. Given that Colistimethate sodium crosses the placental barrier in humans, its use during pregnancy should only be considered if the potential benefit justifies the potential risk to the fetus.

Lactation:

The excretion of Colistimethate sodium in human breast milk is currently unknown. However, it is known that Colistimethate sodium sulfate is excreted in human breast milk. As a result, caution should be exercised when administering Colistimethate sodium to nursing women.

Pediatric:

During clinical studies, Colistimethate sodium was administered to pediatric patients, including neonates, infants, children, and adolescents. While adverse reactions seem to be comparable between adults and pediatric populations, it is worth noting that pediatric patients may not always report subjective symptoms of toxicity. Therefore, it is advised to closely monitor pediatric patients clinically to ensure their safety and well-being.

Geriatric Use:

The clinical studies conducted on Colistimethate sodium did not include an adequate number of participants aged 65 and above, making it difficult to determine if their response differs from younger individuals. However, based on other reported clinical experiences, no notable differences in responses have been observed between elderly and younger patients. When prescribing this medication to elderly individuals, caution should be exercised in selecting the dosage, typically starting at the lower end of the recommended range. This approach takes into consideration the higher likelihood of decreased hepatic, renal, or cardiac function, as well as the presence of concurrent illnesses or other drug therapies. Since this drug is primarily eliminated by the kidneys, the risk of toxic reactions may be increased in patients with impaired renal function. Given that elderly patients are more prone to decreased renal function, careful dose selection is advised, and monitoring of renal function may be beneficial.

Physicians should be knowledgeable as well as vigilant about the treatment and identification of overdosage of Colistimethate sodium.

In the case of a suspected drug overdose, it is important to seek immediate assistance from your local Poison Control Centre for proper management. Symptoms that may be experienced include dizziness, ataxia, speech disturbances, generalized muscular weakness, apnea, and elevated blood urea nitrogen (BUN) levels. The recommended treatment involves following the standard medical protocol for addressing decreased urine output (oliguria) or absence of urine production (anuria). In severe cases of overdose, dialysis may be considered, especially if a significant amount of the drug was taken shortly after administration.

Pharmacodynamics

Colistimethate sodium, classified as a polymyxin antibiotic, belongs to a group of cationic polypeptides that disrupt the bacterial cell membrane using a mechanism similar to that of detergents. Initially, the use of parenteral polymyxins diminished as safer alternatives like extended-spectrum penicillins and cephalosporins became available, except in cases of treating multidrug-resistant pulmonary infections in cystic fibrosis patients. However, due to the emergence of multidrug-resistant gram-negative bacteria, such as Pseudomonas aeruginosa and Acinetobacter baumannii, combined with the lack of new antimicrobial agents, the utilization of polymyxins has been revitalized.

Pharmacokinetics

• Absorption:

Absorption from the gastrointestinal tract is extremely limited.

• The volume of distribution:

The volume of distribution has not been determined or reported.

• Protein binding:

Information regarding protein binding is not available.

• Metabolism:

Based on the fact that 80% of the dose is excreted unchanged in the urine and there is no biliary excretion, it can be inferred that the drug undergoes inactivation in the tissues. However, the specific mechanism of metabolism remains unknown.

• Route of elimination:

Details about the route of elimination are not available.

1. https://pdf.hres.ca/dpd_pm/00047891.PDF
2. https://go.drugbank.com/drugs/DB00803
3. https://reference.medscape.com/drug/colistimethate-sodium-coly-mycin-m-Colistimethate sodium-342578
4. https://elifesciences.org/articles/65836
5. https://www.unmc.edu/intmed/divisions/id/asp/protected-antimicrobials/Colistimethate sodium.html
6. https://www.merckmanuals.com/en-ca/professional/infectious-diseases/bacteria-and-antibacterial-drugs/polypeptide-antibiotics-bacitracin,-Colistimethate sodium,-polymyxin-b
7. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050108s026lbl.pdf
8. https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=5524
9. https://pch.health.wa.gov.au/~/media/Files/Hospitals/PCH/General-documents/Health-professionals/ChAMP-Monographs/Colistimethate-Sodium.pdf