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Composition:


active ingredient: colistimethate;


1 vial contains sodium colistimethate, sterile 1,000,000 IU or 2,000,000 IU;


1 bottle of the drug contains sodium of at least 1 mmol (23 mg).


Dosage form. Powder for solution for injection or infusion.


Basic physical and chemical properties: white or almost white powder.


Pharmacotherapeutic group.


Antibacterial agents for systemic use. ATX code J01X B01.


Pharmacological properties.


Pharmacodynamics.


Mechanism of action


Sodium colistimethate is a cyclic polypeptide antibiotic derived from Bacillus polymyxa var. colistinus and belongs to the polymyxin group. Polymyxin antibiotics are cationic agents that act by damaging cell membranes. As a result, their physiological effects are fatal to bacteria. Polymyxins act selectively on Gram-negative bacteria that have a hydrophobic outer membrane.


Resistance


Resistant bacteria are characterized by modification of phosphate groups of lipopolysaccharides, which are replaced by ethanolamine or aminoarabinose. Naturally resistant Gram-negative bacteria, such as Proteus mirabilis and Burkholderia cepacia, completely replace their lipid phosphate with ethanolamine or aminoarabinose.


Cross-resistance


Cross-resistance between sodium colistimethate and polymyxin B. Since the mechanism of action of polymyxins differs from the mechanism of action of other antibiotics, resistance to colistin and polymyxin by the above mechanism does not imply resistance to other groups of drugs. 


Control points


The proposed total minimum inhibitory concentration (mic) for identifying bacteria sensitive to sodium colistimethate is ≤ 4 mg/l.


Bacteria for which the mic of sodium colistimethate is ≥ 8 mg/L are considered resistant.


Sensitivity


The prevalence of acquired resistance may vary depending on the geographical location and time of the selected bacterial species, and therefore it is desirable to obtain local information about resistance, especially in the treatment of severe infections. If necessary, if the local predominance of resistance is such that the benefits of the drug for certain types of infections are questionable, you should seek professional advice.


Most sensitive species: Acinetobacter * spp., Citrobacter spp., Escherichia coli, Haemophilus influenzae, Pseudomonas aeruginosa.


Species for which acquired resistance may be a problem: Enterobacter spp., Klebsiella spp.


The most resistant microorganisms are Brucella species, Burkholderia cepacia and related species, Neisseria spp., Proteus spp., Providencia spp., Serratia spp.


Anaerobes: all Gram-positive microorganisms.


* In vitro results may not correlate with clinical efficacy in the case of Acinetobacter spp.


Pharmacokinetics.


Absorption from the digestive tract in healthy individuals occurs only to a small extent.


Distribution


In patients with cystic fibrosis, after taking 7.5 mg/kg/day of the drug in separate doses, administered by 30-minute intravenous infusions until stabilization, the maximum concentration (Cmax) was 23±6 mg/L, and the minimum concentration (Cmin) after 8 hours was 4.5±4 mg/l. cmin-2.76 mg/l (1-6.2 mg/l). In healthy volunteers who received a 150 mg bolus injection (approximately 2 million units), the maximum plasma concentration of 18 mg/l was observed 10 minutes after the injection.


Binding to blood proteins is insignificant. Polymyxins accumulate in the liver, kidneys, brain, heart, and muscles.


In studies in patients with cystic fibrosis, the steady-state volume of distribution was 0.09 l/kg.


In vivo, sodium colistimethate is converted to a base. Since 80% of the dose can be detected in the urine unchanged, and the drug is not excreted in the bile, it can be assumed that the remaining drug is inactivated in the tissues. The mechanism of inactivation is unknown.


The main route of elimination of the drug after parenteral administration is renal excretion. 40% of the parenteral dose is detected in the urine within 8 hours and approximately 80% – after 24 hours. Since sodium colistimethate is largely excreted in the urine, patients with renal insufficiency need to reduce the dose to prevent accumulation of the drug.


After intravenous administration to healthy adult volunteers, the Half-Life of the drug is approximately 1.5 hours. In a study where patients with cystic fibrosis were given a single 30-minute intravenous infusion, the elimination half-life was 3.4±1.4 hours.


The kinetics of sodium colistimethate is similar in children and adults, including the elderly, provided that renal function is normal. Although data on the use of the drug in infants are limited, it is assumed that the kinetics of the drug in infants is similar to the kinetics in children and adults, but the possibility of higher maximum serum concentrations and a longer Half-Life in such patients should be taken into account, and therefore it is necessary to monitor the levels of the drug in the blood serum.


Clinical characteristics.


Indications.


Treatment of some severe infections caused by Gram-negative bacteria, including lower respiratory tract and urinary tract infections, when more widely used systemic antibacterial agents are contraindicated or ineffective due to the development of bacterial resistance.


Contraindications.


Hypersensitivity to sodium colistimethate (colistin) or polymyxin B.


The patient has myasthenia gravis.


Interactions with other drugs and other types of interactions.


Concomitant use of sodium colistimethate with other drugs that have a neurotoxic and/or nephrotoxic effect should be avoided. These include aminoglycoside antibiotics such as gentamicin, amikacin, netilmycin, and tobramycin. When used concomitantly with cephalosporin antibiotics, the risk of nephrotoxicity may increase.


Neuromuscular blockers and diethyl ether should be used with extreme caution in patients receiving sodium colistimethate.

Application features.


Special care should be taken when using the drug in patients with porphyria.


If the recommended parenteral dose is exceeded, nephrotoxicity or neurotoxicity may occur.


Caution should be exercised when using the drug in patients with impaired renal function. In moderate to severe renal impairment, the excretion of sodium colistimethate slows down, so the dose and interval between doses should be adjusted to prevent accumulation of the drug.


It is recommended to evaluate renal function at the beginning of treatment and monitor it during treatment. It is also necessary to monitor the concentration of sodium colistimethate in the blood plasma.


Against the background of the use of almost all antibacterial drugs, including colistimethate, diarrhea associated with Clostridium difficile may occur, from mild to fatal colitis. Antibacterial drugs alter the normal flora of the large intestine, which leads to excessive growth of Clostridium difficile. Clostridium difficile produces toxins A and B, which contribute to the development of diarrhea associated with Clostridium difficile. Clostridium difficile strains that overproduce toxins cause increased morbidity and mortality, as these infections may be resistant to antimicrobials and require colectomy. Diarrhea associated with Clostridium difficile should be excluded in all patients with the use of antibiotics. It is necessary to collect a detailed medical history, since diarrhea associated with Clostridium difficile can occur within two months after the end of the use of antibacterial agents.


If diarrhea associated with Clostridium difficile is suspected or confirmed, antibiotic therapy that does not affect Clostridium difficile should be discontinued. For clinical indications, appropriate amounts of fluids and electrolytes, protein supplements, antibiotic therapy to which Clostridium difficile is sensitive, and surgical examination should be prescribed. Antiperistaltic drugs are contraindicated in such cases.


Use during pregnancy or lactation.


There are insufficient data on the use of sodium colistimethate in pregnant women. Studies of single doses in pregnant women have shown that sodium colistimethate penetrates the placental barrier, so there may be a risk of fetotoxicity if repeated doses are prescribed to pregnant women.


Data on the possible genotoxicity of the drug are limited, and there are no data on the carcinogenicity of sodium colistimethate. Sodium colistimethate has been shown to cause chromosomal abnormalities in human lymphocytes in vitro. This effect may be due to a decrease in the mitotic index, which was also observed.


Sodium colistimethate can only be used during pregnancy when the benefit to the woman exceeds the potential risk to the fetus.


Sodium colistimethate in small concentrations penetrates into breast milk, so it is better to stop breastfeeding during treatment with the drug.


Ability to influence the reaction rate when driving vehicles or other mechanisms.


Dizziness, confusion, and visual disturbances may occur during treatment with sodium colistimethate. Patients should be advised to avoid driving vehicles or working with other mechanisms.


Do not violate the rules for using the drug, it can harm your health.


Dosage and administration.


The dose of the drug depends on the severity and type of infection, as well as on the patient's age, body weight and renal function. If the clinical or bacteriological effectiveness of the drug is delayed, the dose can be increased depending on the patient's condition.


Patients with impaired renal function, newborns and patients with cystic fibrosis are recommended to monitor the concentration of the drug in blood plasma. Concentrations of 10-15 mg/l (approximately 125-200 IU/mL) of sodium colistimethate should be sufficient to treat most infections. Usually, treatment is recommended for at least 5 days.


Children and adults (including the elderly)


With a body weight of up to 60 kg: 50,000-75,000 IU/kg/day. The total daily dose is divided into 3 injections, the interval between which is approximately 8 hours. The maximum daily dose is 75,000 IU/kg/day.


With a body weight of more than 60 kg: 1000000-2000000 IU 3 times a day. The maximum daily dose is 6,000,000 IU.

Overdose.


An overdose of the drug can cause Neuromuscular blockage, which in turn can lead to muscle weakness, apnea, and respiratory arrest. Overdose can cause acute renal failure, which is characterized by a decrease in urination and an increase in the concentration of ASA and creatinine in blood plasma.


There is no specific antidote. Maintenance therapy is recommended. The following measures can be taken to increase the rate of colistin elimination: forced diuresis using mannitol, prolonged hemodialysis or peritoneal hemodialysis – but their effectiveness is unknown.


Adverse reactions.


Adverse renal effects usually occurred after taking doses that exceeded the recommended ones in patients with normal renal function or due to an insufficiently reduced dose of the drug in patients with renal insufficiency, or as a result of concomitant use of other nephrotoxic drugs. These reactions are usually reversible upon discontinuation of treatment.


High serum concentrations of sodium colistimethate, which may be associated with overdose or inability to reduce the dose in patients with renal insufficiency, have been reported to lead to neurotoxic effects such as paresthesia, muscle weakness, dizziness, unintelligible speech, vasomotor instability, visual impairment, confusion, psychosis or apnea.


Concomitant use of non-depolarizing muscle relaxants or antibiotics with similar neurotoxic effects can also lead to neurotoxicity. Reducing the dose may relieve these symptoms.


Hypersensitivity reactions have been reported, including skin rashes or angioedema. In case of these phenomena, treatment with the drug should be discontinued.


Immune system disorders: hypersensitivity reactions such as skin rashes and angioedema.


Nervous system disorders: neurotoxicity (facial and oral paresthesia), headache, muscle weakness, dizziness, ataxia.


From the skin: itching.


From the urinary system: impaired renal function caused by an increase in blood creatinine and/or urea and/or a decrease in creatinine clearance; renal failure.


General disorders and reactions at the injection site: reactions at the injection site.


Incompatibility.


Mixed infusions and injections containing sodium colistimethate should be avoided.

Tags: Sodium Colistimethate