Cefotaxime, 1 g

Pharmacodynamics

A III generation cephalosporin antibiotic for parenteral administration. It acts bactericidally by disrupting synthesis of mucopeptide of the cell wall of microorganisms. It has a wide spectrum of action. Cefotaxime is usually sensitive to: Aeromonas hydrophila; Bacillus subtilis; Bordetella pertussis; Borrelia burgdorferi; Moraxella catarrhalis; Citrobacter diversus*; Citrobacter freundii*; Clostridium perfringens; Corynebacterium diphtheriae; Esherichia coli; Enterobacter spp.*; Erysipelothrix insidiosa; Eubacterium spp.; Haemophillus spp. (penicillinase-producing and non-producing strains, including ampicillin-resistant strains); Klebsiella pneumoniae; Klebsiella oxytoca; Staphylococcus spp. (methicillin-sensitive, including penicillinase-producing and nonproducing strains); Morganella morganii; Neisseria gonorrhoea (including penicillinase-producing and nonproducing strains); Neisseria meningitidis; Propionibacterium spp.Proteus mirabilis; Proteus vulgaris; Providencia spp.; Streptococcus spp. (including Streptococcus pneumoniae); Salmonella spp.; Serratia spp.*; Shigella spp.; Veillonella spp.; Yersinia spp.*; Pseudomonas spp. (except Pseudomonas aeruginosa, Pseudomonas cepacia).

* – sensitivity depends on epidemiological data and on the level of resistance in each specific country.

The following are resistant to cefotaxime: Acinetobacter baumanii; Bacteroides fragilis; Clostridium difficile; Enterococcus spp.; Gram-negative anaerobes; Listeria monocytogenes; Staphylococcus spp. (methicillin-resistant strains); Pseudomonas aeruginosa; Pseudomonas cepacia; Stenotrophomonas maltophilia.

Pharmacokinetics

In adults – 5 minutes after a single intravenous (IV) injection of 1 g of cefotaxime the maximum concentration (Cmax) in blood plasma is 100 µg/ml. After intramuscular (i/m) injection of cefotaxime at the same dose, Cmax in plasma is reached after 0.5 hours and is 20-30 mcg/ml. Bioavailability of cefotaxime when administered intravenously is 100%, when administered intravenously – 90-95%.

The half-life (T1/2) of cefotaxime is 1 hour in intravenous and 1-1.5 hours in perinatal administration.

The binding to plasma proteins (predominantly albumins) is on average 25-40%.

It is metabolized in the liver with the formation of the active metabolite deacetylcephotaxime (M1), which has antibacterial activity, and inactive metabolites (M2, M3).

About 90% of the administered dose is excreted by the kidneys: 50% unchanged, about 15-25% as the deacetylcephotaxime metabolite and 15-30% as inactive metabolites (M2+M3). 10% of the administered dose is excreted by the intestine.

In elderly patients over 80 years old the T1/2 of cefotaxime is increased up to 2.5 h. The volume of distribution (Vd) does not change compared to young healthy volunteers.

In adults with impaired renal function, Vd is unchanged and the T1/2 does not exceed 2.5 h, even in the last stages of renal failure.

In children the plasma concentration of cefotaxime and Vd are similar to those in adults receiving the same dose of the drug in mg/kg of weight. The T1/2 is 0.75 to 1.5 h.

In newborns and prematurely born children the plasma concentration of cefotaxime and Vd are similar to those in children. Mean T1/2 of cefotaxime is 1.4 to 6.4 h.

Indications

Infections caused by microorganisms sensitive to the drug:

– infections of the central nervous system, including meningitis (with the exception of listeria);

– respiratory tract infections;

– infections of the genitourinary system (including gonorrhea);

– infections of bones and joints;

– infections of the skin and soft tissues;

– intra-abdominal infections (including peritonitis);

– septicemia, bacteremia;

– endocarditis.

Prevention of infections after surgical operations (including urological, obstetric-gynecological, gastrointestinal tract).

Pharmacological effect

Pharmacodynamics

III generation cephalosporin antibiotic for parenteral administration. It acts bactericidal, disrupting the synthesis of mucopeptide in the cell wall of microorganisms. Has a wide spectrum of action. The following are usually sensitive to cefotaxime: Aeromonas hydrophila; Bacillus subtilis; Bordetella pertussis; Borrelia burgdorferi; Moraxella catarrhalis; Citrobacter diversus*; Citrobacter freundii*; Clostridium perfringens; Corynebacterium diphtheriae; Escherichia coli; Enterobacter spp.*; Erysipelothrix insidiosa; Eubacterium spp.; Haemophillus spp. (penicillinase-producing and non-penicillinase-producing strains, including ampicillin-resistant); Klebsiella pneumoniae; Klebsiella oxytoca; Staphylococcus spp. (methicillin-sensitive, including penicillinase-producing and non-penicillinase-producing strains); Morganella morganii; Neisseria gonorrhoea (including penicillinase-producing and non-penicillinase-producing strains); Neisseria meningitidis; Propionibacterium spp.; Proteus mirabilis; Proteus vulgaris; Providencia spp.; Streptococcus spp. (including Streptococcus pneumoniae); Salmonella spp.; Serratia spp.*; Shigella spp.; Veillonella spp.; Yersinia spp.*; Pseudomonas spp. (except Pseudomonas aeruginosa, Pseudomonas cepacia).

* – sensitivity depends on epidemiological data and the level of resistance in each specific country.

Resistant to cefotaxime: Acinetobacter baumanii; Bacteroides fragilis; Clostridium difficile; Enterococcus spp.; gram-negative anaerobes; Listeria monocytogenes; Staphylococcus spp. (methicillin-resistant strains); Pseudomonas aeruginosa; Pseudomonas cepacia; Stenotrophomonas maltophilia.

Pharmacokinetics

In adults, 5 minutes after a single intravenous (IV) administration of 1 g of cefotaxime, the maximum concentration (Cmax) in blood plasma is 100 mcg/ml. After intramuscular (IM) administration of cefotaxime at the same dose, Cmax in blood plasma is reached after 0.5 hours and ranges from 20-30 mcg/ml. The bioavailability of cefotaxime with intravenous administration is 100%, with intramuscular administration – 90-95%.

The half-life (T1/2) of cefotaxime is 1 hour with intravenous administration and 1-1.5 hours with intramuscular administration.

Binding to plasma proteins (mainly albumin) averages 25-40%.

Metabolized in the liver to form the active metabolite desacetylcefotaxime (M1), which has antibacterial activity, and inactive metabolites (M2, M3).

About 90% of the administered dose is excreted by the kidneys: 50% unchanged, about 15-25% as a metabolite of desacetylcefotaxime and 15-30% as inactive metabolites (M2 + M3). 10% of the administered dose is excreted by the intestines.

In elderly patients over 80 years of age, T1/2 of cefotaxime increases to 2.5 hours. The volume of distribution (Vd) does not change compared to young healthy volunteers.

In adults with impaired renal function, Vd does not change, and T1/2 does not exceed 2.5 hours, even in the last stages of renal failure.

In children, the plasma concentrations of cefotaxime and Vd are similar to those in adults receiving the same dose of the drug in mg/kg body weight. T1/2 ranges from 0.75 to 1.5 hours.

In newborns and prematurely born children, the plasma concentrations of cefotaxime and Vd are similar to those in children. The average T1/2 of cefotaxime ranges from 1.4 to 6.4 hours.

Special instructions

Anaphylactic reactions

The prescription of cephalosporins requires the collection of an allergic history (allergic diathesis, hypersensitivity reactions to β-lactam antibiotics).

If the patient develops a hypersensitivity reaction, treatment should be discontinued.

The use of cefotaxime is contraindicated in patients with a history of immediate hypersensitivity reaction to cephalosporins. If there is any doubt, the presence of a doctor during the first administration of the drug is mandatory, due to a possible anaphylactic reaction.

Cross-allergy between cephalosporins and penicillins is known, which occurs in 5-10% of cases. Anaphylactic reactions that develop in this situation can be serious and even fatal.

In patients with a history of allergy to penicillins, the drug is used with extreme caution. The patient’s condition should be carefully monitored when the drug is first administered due to a possible anaphylactic reaction.

If the first symptoms and signs of anaphylactic shock develop, you should immediately stop administering the drug. The patient should remain in a supine position with legs elevated. Slow intravenous administration of 0.1 mg (1 ml) of epinephrine (Adrenaline) solution is indicated under control of pulse and blood pressure, as well as intravenous administration of plasma expanders, human albumin or balanced electrolyte solutions; subsequently – intravenous administration of glucocorticosteroids (for example, 250-1000 mg of hydrocortisone), once or, if necessary, repeatedly. Supportive therapeutic measures should be carried out: artificial ventilation, oxygen inhalation, administration of antihistamines.

Diseases caused by Clostridium difficile (eg, pseudomembranous colitis)

Diarrhea, especially severe and/or prolonged, developing during treatment or in the first weeks after the end of treatment with various antibiotics, especially broad-spectrum antibiotics, may be a symptom of a disease caused by Clostridium difficile, the most severe form of which is pseudomembranous colitis. The diagnosis of this rare but possibly fatal disease is confirmed endoscopically and/or histologically. The most important method for confirming the diagnosis of pseudomembranous colitis is the identification of Clostridium difficile toxins in the stool. If a diagnosis of pseudomembranous colitis is suspected, cefotaxime should be discontinued immediately and appropriate antibiotic therapy (eg, oral vancomycin or metronidozole) should be started immediately. Drugs that inhibit intestinal motility are contraindicated.

Use of lidocaine as a solvent

When using lidocaine as a solvent, it is necessary to take into account the information presented in the “Contraindications” section.

Injection rate

The rate of administration of the drug should be monitored (see section “Method of administration and dosage”).

Kidney failure

In case of renal failure, the dose should be adjusted depending on creatinine clearance (see section “Dosage and Administration”).

Caution should be exercised when using cefotaxime and aminoglycosides simultaneously.

Renal function should be monitored in all cases of combined use of cefotaxime with aminoglycosides, other nephrotoxic drugs, in elderly patients or with renal impairment.

Sodium content In patients requiring sodium restriction, the sodium content of cefotaxime sodium salt (48.2 mg/g) should be taken into account.

Hematopoietic disorders

During treatment with cefotaxime, leukopenia, neutropenia and, more rarely, bone marrow hematopoietic failure, pancytopenia and agranulocytosis may develop. If the course of treatment lasts more than 10 days, the number of blood cells should be monitored. If these blood parameters deviate from the norm, the drug should be discontinued.

Laboratory tests

During therapy with cephalosporins, a positive Coombs test may occur.

It is recommended to use glucose oxidase methods for determining the concentration of glucose in the blood, due to the development of false positive results when using nonspecific reagents.

Impact on the ability to drive vehicles and machinery

If a side effect such as dizziness develops, the ability to concentrate and react may be impaired. In this case, patients should refrain from driving vehicles and operating machinery.

Active ingredient

Cefotaxime

Composition

Active substance:

Cefotaxime sodium in terms of cefotaxime – 1.0 g.

Pregnancy

Pregnancy

Cefotaxime penetrates the placental barrier. Studies conducted on animals did not reveal the teratogenic or fetotoxic effects of the drug. However, the safety of cefotaxime during pregnancy in humans has not been established, so the drug should not be used during pregnancy.

Breastfeeding period

Cefotaxime passes into breast milk, so if you need to use the drug, breastfeeding should be discontinued.

Contraindications

– hypersensitivity to cefotaxime and other cephalosporins.

For forms containing lidocaine as a solvent:

– hypersensitivity to lidocaine or other amide-type local anesthetic;

– intracardiac blockade without an established pacemaker;

– severe heart failure;

– intravenous administration;

– children up to 2.5 years of age (for intramuscular administration).

With caution

– in patients with a history of allergies to penicillins (risk of developing cross-allergic reactions) (see section “Special instructions”);

– when used simultaneously with aminoglycosides (see sections “Special instructions” and “Interaction with other drugs”);

– for renal failure (see section “Method of administration and dosage”).

Side Effects

Classification of undesirable side reactions by frequency of development, according to WHO recommendations: very often (≥10%); often (≥1% and <10%); uncommon (≥0.1% and <1%); rare (≥0.01% and <0.1%); very rare (<0.01%); frequency unknown (it is impossible to estimate the frequency of side effects based on the available data).

Infectious and parasitic diseases:

Frequency not known: superinfections. As with the prescription of other antibiotics, the use of cefotaxime, especially long-term, can lead to excessive growth of non-susceptible microorganisms. The patient’s condition should be monitored regularly. If superinfection occurs during cefotaxime therapy, appropriate measures should be taken.

Immune system disorders:

Uncommon: Jarisch-Herxheimer reaction. As with the use of other antibiotics, when treating borreliosis, the development of a Jarisch-Herxheimer reaction is possible during the first days of therapy. There are reports of the occurrence of one or more symptoms after a few weeks of treatment for borreliosis: skin rash, itching, fever, leukopenia, increased activity of liver enzymes, difficulty breathing, discomfort in the joints.

Frequency unknown: anaphylactic reactions, angioedema, bronchospasm, anaphylactic shock.

Nervous system disorders:

Uncommon: convulsions.

Frequency unknown: headache, dizziness, encephalopathy (eg, impaired consciousness, impaired motor activity).

Skin disorders:

Uncommon: rash, itching, urticaria.

Frequency unknown: acute generalized exanthematous pustulosis, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis.

Urinary system disorders:

Uncommon: decreased renal function/increased creatinine concentration, especially when combined with aminoglycosides.

Frequency unknown: interstitial nephritis, acute renal failure.

Digestive system disorders:

Uncommon: diarrhea.

Frequency unknown: nausea, vomiting, abdominal pain, pseudomembranous colitis. Disorders of the liver and biliary tract:

Uncommon: increased activity of liver enzymes (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, gamma-glutamyltransferase, alkaline phosphatase) and/or bilirubin concentration. These laboratory abnormalities (which can also be explained by the presence of infection), in rare cases exceed the upper limit of normal by 2 times and indicate liver damage, manifested by cholestasis and often asymptomatic.

Frequency unknown: hepatitis (sometimes with jaundice).

Disorders of the hematopoietic organs:

Uncommon: leukopenia, eosinophilia, thrombocytopenia.

Frequency unknown: hemolytic anemia, neutropenia, agranulocytosis, bone marrow hematopoietic failure, pancytopenia.

Cardiovascular system disorders:

Not known: Arrhythmias following rapid bolus administration through a central venous catheter.

General disorders and disorders at the injection site:

Often: pain at the injection site (with intramuscular injection).

Uncommon: fever, inflammatory reactions at the injection site, including phlebitis/thrombophlebitis.

Frequency unknown: with intramuscular administration, if lidocaine is used as a solvent, systemic reactions associated with lidocaine may develop.

Interaction

Probenecid delays excretion and increases the concentration of cephalosporins in the blood plasma.

As with other cephalosporins, cefotaxime may enhance the nephrotoxic effect of drugs that have nephrotoxic effects (such as furosemide, aminoglycosides).

Compatibility Notes

Cefotaxime should not be mixed with other antibiotics (including aminoglycosides), either in the same syringe or in the same infusion solution.

The following solutions can be used for infusions (cefotaxime concentration 1 g/250 ml): water for injection; 0.9% sodium chloride solution; 5% dextrose solution; lactated Ringer’s solution; Yonosteril.

Overdose

Symptoms: convulsions, encephalopathy (in case of large doses, especially in patients with renal failure), tremor, neuromuscular irritability.

Treatment: symptomatic, no specific antidote

Storage conditions

Store at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Store in original packaging.

Shelf life

2 years.

Manufacturer

Lecco CJSC, Russia