Cefotaxime, 1 g

Pharmacotherapeutic group: Antibiotic-cephalosporin

ATX code: J01DD01

Pharmacokinetics

Absorption and distribution

In adults 5 min 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 h and is 20 to 30 mcg/ml. Bioavailability of cefotaxime when administered intravenously is 100%, when administered intravenously – 90-95%.

Binding to plasma proteins (mainly albumin) is on average 25-40%.

Metabolism

Metabolized in the liver with the formation of the active metabolite desacetylcephotaxime (Ml), 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 metabolite deacetylcephotaxime and 15-30% as inactive metabolites (M2-M3). 10% of the administered dose is excreted by the intestine. The half-life (T1/2) of cefotaxime is 1 h when administered by IV and 1-1.5 h when administered by IV/m.

In elderly patients over 80 years old the T1/2 of cefotaxime is increased 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 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 weight. T1/2 of cefotaxime 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. The average T1/2 of cefotaxime is 1.4 to 6.4 h.

Pharmacodynamics

A semi-synthetic antibiotic of the group of III generation cephalosporins. Cefotaxime acts bactericidally by disrupting the synthesis of the bacterial wall. It is also resistant to the action of most β-lactamases.

The following bacteria are usually sensitive to cefotaxime: Aeromonas hydrophila; Bacillus subtilis; Bordetella pertussis; Borrelia burgdorferi; Moraxella (Branhamella) catarrhalis; Citrobacter diversus*; Citrobacter freundii*; Clostridium perfringens; Corynebacterium diphtheriae; Escherichia coli; Enterobacter spp.*; Erysipelothrix insidiosa; Eubacterium spp.; Haemophilus 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 morgcinii; Neisseria gonorrhoeae (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.

Indications

Cefotaxime is intended for the treatment of infections caused by microorganisms sensitive to the drug:

– respiratory tract infections;

– urinary tract infections;

– septicemia bacteremia;

– endocarditis;

– intra-abdominal infections (including peritonitis);

– meningitis (except listeriosis) and other central nervous system infections;

– skin and soft tissue infections;

– bone and joint infections.

The prevention of infections after gastrointestinal surgical operations of the urological and obstetric and gynecological operations.

Active ingredient

Composition

1 vial contains:

The active ingredient

Cefotaxime sodium (in terms of cefotaxime) – 1 g.

How to take, the dosage

Intravenously or intramuscularly. The dose, method and frequency of administration should be determined by the severity of the infection, the sensitivity of the pathogen and the patient’s condition. Treatment may be initiated before the results of the sensitivity test have been obtained.

Adults and children over 12 years of age and with body weight 50 kg or more: In infections of mild to moderate severity – 1000 mg every 12 hours. The dose may vary depending on the severity of infection, the sensitivity of the pathogen and the patient’s condition. In severe infections, the dose may be increased to 12,000 mg per day divided into 3 or 4 injections. In infections caused by Pseudomonasspp. the daily dose should be more than 6000 mg. Children under 12 years of age and those weighing less than 50 kg: the usual dose is 100-150 mg/kg/day divided into 2 to 4 injections. In very severe infections, the dose may be increased to 200 mg/kg/day. Infants: 50 mg/kg/day divided into 2-4 injections. In severe infections, the dose is 150-200 mg/kg/day divided into 2-4 injections.

In gonorrhea: 1000 mg once intravenously or intramuscularly.

In order to prevent infections before surgery (30 to 90 minutes before surgery), administer 1000 mg intramuscularly or intravenously.

In case of caesarean section, at the moment of application of clamps on the umbilical vein, 1000 mg of the drug is administered intravenously followed by 1000 mg intravenously or intramuscularly again after 6 and 12 hours.

In case of renal failure: in cases where creatinine clearance is less than 10 ml/min, the dose should be reduced. After the initial single dose, the daily dose should be halved without changing the frequency of administration, i.e., instead of 1000 mg every 12 h – 500 mg every 12 h instead of 1000 mg every 8 h – 500 mg every 8 h instead of 2000 mg every 8 h – 1000 mg every 8 h, etc. Further dose adjustments may be necessary depending on the course of the infection and the patient’s general condition.

Rules for preparation of solutions: for intravenous injection, water for injection is used as a solvent (500 mg diluted in 2 ml of solvent 1000 mg in 4 ml); during intravenous injection, the solution should be injected within 3 to 5 minutes. For intravenous infusion, 09% NaCl solution or 5% dextrose solution (1-2 g diluted in 40-100 ml of solvent) is used as solvent. Ringer’s lactate solution can also be used. Infusion duration is 20-60 minutes. For intramuscular injection use water for injection or 1% lidocaine solution (500 mg diluted in 2 ml of solvent 1000 mg in 4 ml).

Interaction

Probenecid delays excretion and increases plasma concentrations of cephalosporins.

As with other cephalosporins cefotaxime may increase nephrotoxic effect of drugs with nephrotoxic effect (such as furosemide aminoglycosides).

Prompts for compatibility: cefotaxime should not be mixed with other antibiotics (including aminoglycosides) both in the same syringe and in the same infusion solution.

For infusion the following solutions may be used (cefotaxime concentration 1 g / 250 ml): water for injection 09% sodium chloride solution 5% dextrose solution Ringer’s lactate Ionosteril solution.

Special Instructions

Anaphylactic reactions

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

If a patient develops a hypersensitivity reaction then treatment must be discontinued.

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

Cross-allergy between cephalosporins and penicillins is known to occur in 5-10% of cases. Anaphylactic reactions developing in this situation can be serious or even fatal.

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

In case of the first symptoms and signs of anaphylactic shock the drug administration should be stopped immediately. The patient should remain in the supine position with elevated legs. Slow intravenous injection of 01 mg (1 ml) of epinephrine (adrenaline) solution under control of pulse and blood pressure is indicated, as well as intravenous injection of human albumin plasma substitutes or balanced electrolyte solutions; subsequently, intravenous injection of glucocorticosteroids (e.g. 250- 1000 mg hydrocortisone) once or repeatedly if necessary.

Therapeutic supportive measures should be taken: artificial lung ventilation oxygen inhalation administration of antihistamine medications.

Diseases caused by Clostridium difficile (e.g. pseudomembranous colitis)

Diarrhea particularly severe and/or prolonged during treatment or in the first weeks after therapy with various antibiotics, especially broad-spectrum antibiotics, may be a symptom of disease caused by Clostridium difficile and the most severe form is pseudomembranous colitis. The diagnosis of this rare but possibly fatal disease is confirmed endoscopically and/or histologically. The most important method of confirming the diagnosis of pseudomembranous colitis is the detection of Clostridium difficile toxins in the feces. If the diagnosis of pseudomembranous colitis is suspected, cefotaxime should be stopped immediately and appropriate specific antibiotic therapy (e.g. oral vancomycin or metronidazole) started immediately. Drugs that inhibit intestinal peristalsis are contraindicated.

Encephalopathy

The use of beta-lactam antibiotics including cefotaxime increases the risk of encephalopathy (which may manifest as seizures confusion, impaired consciousness and motor disturbances) especially in case of overdose or renal failure.

The use of lidocaine as a solvent

When using lidocaine as a solvent, the information under “Contraindications” must be noted.

The rate of administration

The rate of administration must be controlled (See “Administration and Doses”).

Renal failure

The dose should be adjusted according to creatinine clearance if there is renal failure (See “Dosage and administration”).

Caution should be exercised when concomitant use of cefotaxime and aminoglycosides. Renal function should be monitored in all cases of combined use of cefotaxime with aminoglycosides other nephrotoxic drugs in elderly patients or patients with renal impairment.

The sodium content of cefotaxime sodium salt (482 mg/g) should be taken into account in patients requiring sodium restriction.

Hematopoietic disorders

Leukopenia neutropenia and more rarely pancytopenia and agranulocytosis may develop during treatment with cefotaxime.

The number of blood cells should be monitored if the treatment course lasts more than 10 days. If these blood counts deviate from the normal range, the drug should be discontinued.

Laboratory tests

A positive Coombs test may occur during therapy with cephalosporins. The use of glucose oxidase methods of determining blood glucose concentration is recommended due to the development of false-positive results when using nonspecific reagents.

Contraindications

– Hypersensitivity to cefotaxime and other cephalosporins.

– For forms containing lidocaine as a solvent:

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

– Intracardiac blockages without an established pacemaker;

– severe heart failure;

– intravenous administration;

In patients with a history of allergy to penicillins (risk of cross-allergic reactions);

In concurrent use with aminoglycosides;

In renal failure.

Side effects

Classification of adverse reactions by frequency of development according to the recommendations of the World Health Organization: very common (≥10%); common (≥1 % and < 10%); infrequent (≥01% and < 1%); rare (≥001% and < 01%); very rare (< 001%); frequency is unknown (based on available data it is impossible to estimate the frequency of side effects).

Infectious and parasitic diseases: frequency unknown: superinfections. As with the administration of other antibiotics, the use of cefotaxime especially long-term may lead to an overgrowth of insensitive microorganisms. The patient’s condition should be monitored regularly. If superinfection develops during therapy with cefotaxime appropriate measures should be taken.

Blood and lymphatic system disorders: infrequent: leukopenia eosinophilia thrombocytopenia. Frequency unknown: insufficiency of medullary hematopoiesis pancytopenia neutropenia agranulocytosis hemolytic anemia.

Immune system disorders: infrequent: Jarisch-Herxheimer reaction. As with the use of other antibiotics in the treatment of borreliosis during the first days of therapy it is possible to develop a Jarisch-Herxheimer reaction. There are reports of one or more symptoms occurring after a few weeks of treatment with borreliosis: skin rash itching fever leukopenia increased “liver” enzyme activity difficult breathing discomfort in the joints. It should be kept in mind that to a certain extent these manifestations are consistent with the symptoms of the underlying disease for which the patient is receiving treatment. Frequency is unknown: anaphylactic reactions angioedema bronchospasm anaphylactic shock.

Nervous system disorders: infrequent: seizures. Frequency unknown: encephalopathy (e.g., impaired consciousness impaired motor activity) headache dizziness.

Cardiac disorders: frequency unknown: arrhythmias (due to rapid bolus injection through a central venous catheter).

Gastrointestinal disorders: infrequent: diarrhea. Frequency unknown: nausea vomiting abdominal pain pseudomembranous colitis.

Hepatic and biliary tract disorders: infrequent: increased activity of “hepatic” enzymes (alanine aminotransferase (ALT) aspartate aminotransferase (ACT) lactate dehydrogenase (LDH) gamma-glutamyl transferase (gamma-GT) alkaline phosphatase (ALP)) and/or concentration of bilirubin. These abnormal laboratory values (which can also be explained by the presence of infection) rarely exceed the upper limit of the norm by a factor of 2 and indicate liver damage manifested by cholestasis and often asymptomatic. Frequency unknown: hepatitis (sometimes with jaundice).

Skin and subcutaneous tissue disorders: infrequent: rash pruritus urticaria. Frequency unknown: erythema multiforme Stevens-Johnson syndrome toxic epidermal necrolysis acute generalized exanthematous pustulosis.

Renal and urinary tract disorders: infrequent: decreased renal function/ increased creatinine concentration especially when combined with aminoglycosides. Frequency unknown: acute renal failure interstitial nephritis.

General disorders and disorders at the injection site: frequently: pain at the injection site (when administered intramuscularly). Infrequent: fever inflammatory reactions at the injection site including phlebitis/thrombophlebitis. Infrequent: in intramuscular injection if lidocaine is used as a solvent, systemic reactions associated with lidocaine may develop, especially in cases of inadvertent intravenous injection of the drug into highly vascularized tissues or in case of overdose.

Overdose

Pregnancy use

Pregnancy

Cefotaxime penetrates the placental barrier. Studies conducted on animals have not revealed teratogenic or fetotoxic effects of the drug. However, the safety of cefotaxime use in humans has not been established; therefore, the drug should not be used during pregnancy.

Breast-feeding period

Cefotaxime penetrates into the breast milk; therefore, if it is necessary to prescribe the drug, breast-feeding should be interrupted.

Similarities