Cefazolin, 1 g

Pharmacotherapeutic group: Antibiotic of cephalosporin group

ATC code: J01DB04

Pharmacodynamics

Semi-synthetic cephalosporin antibiotic of the first generation for parenteral use. It acts bactericidally by blocking penicillin-binding proteins (e.g., transpeptidases), disrupts cell wall synthesis of microorganisms. It has a wide spectrum of action. The prevalence of acquired resistance may vary geographically and also change over time, local information should be considered, especially in the case of treatment of severe infections.

Microorganisms susceptible to cefazolin

Gram-positive aerobes: Staphylococcus aureus (sensitive to methicillin), Staphylococcus saprophyticus, Streptococcus pneumoniae, Streptococcus agalactiae, Streptococcus pyogenes, Corynebacterium diphtheria, Bacillus anthracis.

Gram-negative microorganisms: Neisseria meningitidis, Neisseria gonorrhoeae, Shigella spp., Salmonella spp., Treponema spp., Leptospira spp.

Microorganisms moderately sensitive to cefazolin

Gram-positive aerobes: Staphylococcus aureus, Staphylococcus epidermidis*, Staphylococcus haemolyticus*, Staphylococcus hominis*, Steptococcus pneumoniae* (moderately sensitive to penicillins);

Gram-negative aerobes: Escherichia coli, Haemophilus influenzae**, Klebsiella oxytoca***, Klebsiella pneumoniae, Proteus mirabilis.

Microorganisms with natural resistance to cefazolin

Gram-positive aerobes: Enterococcus spp., Staphylococcus aureus (resistant to methicillin), Staphylococcus pneumoniae (resistant to penicillin).

Gram-negative aerobes: Acinetobacter baumanii, Citrobacter freundii, Enterobacter spp.; Morganella morganii, Moraxella catarrhalis, Proteus vulgaris, Pseudomonas aeruginosa, Serratia marcescens, Stenotrophomonas maltophilia.

Anaerobes: Bacteroides fragilis.

Other microorganisms: Chlamydia spp., Chlamydophila spp., Legionella spp., Mycoplasma spp.

Penicillin-resistant Streptococcus pneumoniae, due to the presence of cross-resistance to cephalosporins, are insensitive to cephalosporins, including cefazolin.

* In some regions, the rate of microbial resistance may exceed 50%;

** current data on the prevalence of resistance are not available, studies (more than 5 years old) have reported a rate of microbial resistance of >50%.

Pharmacokinetics

Intake

Cefazolin is not absorbed when taken orally, so it is only used parenterally. After intramuscular (i.m.) injection, cefazolin is quickly absorbed from the injection site. Compared with most other cephalosporins, the concentration of cefazolin in blood plasma is higher and lasts longer.

Distribution

The binding of cefazolin to plasma proteins is 70-90%. Cefazolin penetrates well into various organs and tissues, including lungs, liver, skin and soft tissues, joints, heart, peritoneum, middle ear, tonsils, gallbladder wall, appendix, as well as into bodily fluids. Very high concentrations of the drug are created in the kidneys – after administration of 1 g of cefazolin its concentration in the urine reaches 4000 mcg/ml.

In absence of biliary obstruction, 90-120 minutes after administration of the drug, cefazolin is found in bile at higher concentration than in blood plasma. It should be taken into account that in patients with impaired patency of the biliary tract, concentration of the drug in bile may be significantly lower than the plasma concentration.

The drug penetrates through the placental barrier and is detected in breast milk. It penetrates into the cerebrospinal fluid (CSF) in small amounts; against the background of inflammation of the dura mater the concentration of the drug in the CSF is 0-0.4 µg/ml.

Cefazolin passes through capillary membranes in bone and reaches bactericidal concentrations in both healthy and affected bones with osteomyelitis. The concentration of cefazolin in joint fluid is comparable with that in blood plasma. In therapeutic concentrations it is found in ascitic and pleural fluid, inflammatory exudate.

Metabolism

Cefazolin is not metabolized in humans.

Elimation

Most of the administered cefazolin is excreted by the kidneys through glomerular filtration and tubular secretion in a microbiologically active form. During the first 6 hours after administration the kidneys excrete 60-90% of cefazolin, during the day – 70-95% of the administered dose. A small part of cefazolin is excreted with bile.

Half-life period in patients with impaired renal function may be prolonged up to 20-40 hours.

Indications

Bacterial infections caused by cefazolin-sensitive microorganisms:

– respiratory tract infections;

– urinary and genital tract infections;

– infections of the biliary tract;

– infections of the skin, soft tissues, bones and joints,

– Bacterial endocarditis, sepsis;

– intraoperative prevention of the development of infections (prophylactic use of cefazolin may reduce the likelihood of infection in the postoperative period).

The in vitro sensitivity of antibiotics varies by geographic region and over time, so local resistance information should be considered when choosing antibiotic therapy. If possible, antimicrobial sensitivity testing of the pathogen should be performed. Therapy may be initiated empirically, prior to antibiotic sensitivity test results.

Active ingredient

Composition

Active ingredient:

Sodium cefazolin converted to cefazolin – 1.0 g

The active ingredient:

Cefazolin sodium in terms of cefazolin – 1.0 g

How to take, the dosage

Cefazolin is intended for parenteral administration only – the drug should be administered intravenously (by stream or dropwise) or deeply intravenously. Doses of the drug and duration of treatment are determined individually taking into account severity of course and localization of infection as well as potential sensitivity of the pathogen.

Average daily dose for adults is 1-4 g; number of times of administration is 3-4 times a day. Maximal daily dose is 6 g. Average duration of treatment is 7-10 days.

In accordance with the principles of antibiotic therapy, the course of treatment should be continued for at least 2-3 days after resolution of fever or until confirmation of eradication of the pathogen.

Prevention of intraoperative infections

The initial dose of cefazolin, 1 g, should be given 30 min-1 h before surgery by IV or IM. In case of prolonged operations (2 hours and longer) 0.5 g-1 g of the drug should be administered directly during the operation. Doses and times of administration depend on the type and duration of surgery. Within 24 hours after surgery we administer 0.5 g – 1 g of the drug by IV or IM with an interval of 6-8 hours.

If the possibility of infection poses a great danger to the patient (e.g., after cardiac surgery or major orthopedic surgery such as total joint replacement), it is recommended that the drug be continued for 3-5 days. It is important to adhere to the above timescales so that sufficient concentrations of the antibiotic are already present in the serum and tissues at the time of the surgical incision. If there is an increased risk of anaerobic infection (e.g., after colorectal surgery), additional use of a drug active against anaerobes is recommended.

Elderly patients

There is no need for dose adjustment.

Administration in children from 1 month to 18 years

For treatment of most infections of mild to moderate severity, a daily dose of 25-50 mg/kg divided into 3-4 injections is sufficient.

In case of severe infections the daily dose can be increased to the maximum recommended dose of 100 mg/kg. The safety of using the drug in infants has not been established.

Dose adjustment in children with impaired renal function

In children whose CKR is 70-40 ml/min/1.73 m2, 60% of the average daily dose of cefazolin is administered after 12 hours. In children whose CKR is 39-20 ml/min/1.73 m2, 25% of the average daily dose of the drug is administered 12 hours later.

In children with a CK of 19-5 ml/min/1.73 m2, 10% of the average daily dose of cefazolin is administered at 24-hour intervals.

All recommended doses are administered after the initial dose corresponding to the severity of the infection.

Preparing the solution

For the intravenous administration, 1 g is dissolved in 4 ml of water for injection or 0.5% lidocaine solution. The maximum single dose for I/m injection is 1 g and the drug should be injected into large muscles only.

The solution containing lidocaine should not be administered intravenously.

Doses up to 1 g can be administered by slow IV injection, larger doses of the drug should be administered by IV infusion.

For intravenous injection, a single dose of the drug is diluted in 10 ml of water for injection, then injected slowly over 3-5 minutes.

For intravenous drip administration the drug is diluted in 50-100 ml of 5% dextrose solution or 0.9% sodium chloride solution. During dilution vials are shaken vigorously until complete dissolution. The infusion is carried out for 20-30 minutes (infusion rate 60-80 drops per minute).

The following solvents can be used to prepare the infusion solution:

– 0.9% sodium chloride solution;

– 5% dextrose solution;

– 5% dextrose solution with 0.9% sodium chloride solution;

– Ringer’s solution;

– 10% dextrose solution in Ringer’s solution;

– Ringer’s solution with 0.9% sodium chloride solution;

– 5% or 10% fructose solution in sterile water for injection;

– 5% sodium hydrogen carbonate solution.

Freshly prepared and clear solutions should be used. However, if necessary, prepared solutions can be stored, provided that they remain sterile, in a light-proof place at 2-8 °C for not more than 24 hours.

Possible yellowish discoloration, which appears after dissolution of the powder, is not an indication of any change in the properties of the medicinal product or of any difference in its therapeutic effectiveness.

Interaction

Cefazolin may decrease the effectiveness of oral contraceptives. For this reason, additional contraceptive measures should be used during treatment with the drug.

Cefazolin should not be used together with other antibacterial drugs with bacteriostatic effect (e.g., tetracyclines, sulfonamides, erythromycin, chloramphenicol), because in in vitro studies antagonism between these drugs has been revealed.

In co-administration with cefazolin nephrotoxic properties of other antibacterial agents (e.g., aminoglycosides, colistin, polymyxin B); iodine-containing contrast agents may be increased; high doses of methotrexate; some antiviral drugs (e.g., acyclovir, foscarnet); pentamidine; cyclosporine; tacrolimus; platinum-containing drugs and diuretics (e.g., furosemide). If it is necessary to combine them with cefazolin, renal function should be carefully monitored.

Concomitant use with “loop” diuretics (e.g., furosemide) leads to blockade of tubular secretion of cefazolin, which leads to increased plasma concentrations. For this reason, co-administration of these drugs should be avoided.

When co-administration of cefazolin and probenecid the renal clearance of cefazolin is decreased, which leads to increased elimination time of cefazolin and increased plasma concentrations.

In rare cases cephalosporins can cause coagulation disorders. If coadministration with oral anticoagulants is necessary, especially in high doses, coagulogram parameters should be monitored.

Some cephalosporin antibiotics, such as cefamandole, cefotetan and cefazolin, by inhibiting intestinal microflora can disrupt metabolism of vitamin K, which reduces its formation in the body, especially in patients with baseline deficiency. Administration of vitamin K preparations may be required. Concomitant use with drugs that reduce platelet aggregation (e.g., nonsteroidal anti-inflammatory drugs) increases the risk of bleeding.

Cefazolin may cause disulfiram-like reactions when used concomitantly with ethanol.

Cefazolin is pharmaceutically incompatible with antibiotics of the group of aminoglycosides (gentamicin, kanamycin, amikacin, etc.); tetracyclines (oxytetracycline, tetracycline, etc.); colistimethate sodium; polymyxin B; erythromycin (in the form of glucoheptonate salt); barbiturate derivatives (amobarbital, pentobarbital); bleomycin; calcium salts (calcium glucoheptonate, calcium gluconate); cimetidine; ascorbic acid.

Special Instructions

Hypersensitivity reactions

An allergologic history should be taken before starting cefazolin administration due to the possibility of cross-sensitivity between cephalosporins and other beta-lactam antibiotics. Severe, including fatal, allergic reactions have been described during cephazolin therapy. In case of severe hypersensitivity reactions it is necessary to cancel cefazolin, prescribe appropriate symptomatic therapy. The drug is contraindicated in patients with severe hypersensitivity reactions to cephalosporins or any other beta-lactam antibiotics in history.

Patients with a predisposition to allergic reactions (allergic rhinitis, bronchial asthma) should be monitored particularly closely, since the risk of hypersensitivity reactions increases with these conditions.

Diarrhea associated with antibiotic use

The development of severe and persistent diarrhea during treatment and in the first weeks after therapy may be a manifestation of pseudomembranous colitis caused by Clostridium difficile. Since this condition is life-threatening, cefazolin should be withdrawn immediately and specific antibacterial therapy (e.g., vancomycin or metronidazole) should be prescribed. Symptomatic supportive therapy is indicated, including correction of water-electrolyte balance, nutritional disorders. The use of drugs inhibiting intestinal peristalsis is contraindicated. In particularly severe cases, if the infection is resistant to the ongoing antibiotic therapy, colectomy may be required. Careful attention should be paid to the patient’s medical history, since there have been cases of pseudomembranous colitis within two months of antibiotic therapy.

Renal dysfunction

With regard to the cumulation of the drug in the body, in patients with reduced renal function the dose of the drug should be adjusted to the severity of renal failure (see also section “Dosage and administration”). Although the use of cefazolin rarely causes renal dysfunction and development of renal failure, it is recommended to assess renal function during the use of the drug, especially in patients in severe condition, when using high doses of the drug and/or other nephrotoxic drugs (e.g., aminoglycosides, “loop” diuretics).

The development of bacterial resistance and superinfections

Long-term use of cefazolin may provoke the emergence of resistant strains of bacteria. Patients should be closely monitored for the possibility of superinfection and appropriate measures should be taken if this occurs.

Decreased blood clotting and bleeding

In rare cases during the use of cefazolin decreased blood clotting is possible. Risk factors include vitamin K deficiency, parenteral nutrition, renal and/or hepatic thrombocytopenia, anticoagulant therapy. In addition, diseases such as hemophilia, gastric and/or duodenal mucosal ulceration may cause the development or increase the severity of bleeding. Therefore, it is necessary to monitor coagulogram values in patients with the known presence of these diseases. If a decrease in blood clotting is detected, therapy with vitamin K (10 mg/week) should be prescribed.

Preventive therapy in children

Cefazolin should not be used in premature and newborn children within 1 month of life since to date there are no data to confirm its safety in this patient population.

The sodium content

1 g of cefazolin contains approximately 48 mg of sodium, which must be considered when using the drug in patients on a sodium-restricted diet.

Impact on laboratory parameters

False positive reactions of urine glucose concentration determination using Benedict or Fehling reagent, as well as false positive results of direct and indirect Coombs test are possible during use of cefazolin.

Peripheral blood counts should be monitored with long-term use of the drug.

Ethanol administration during treatment

At the potential for disulfiram-like reactions with cefazolin, patients should refrain from drinking alcohol during treatment.

Intrathecal administration

Cefazolin should not be administered intrathecally due to the possibility of severe toxic effects on the central nervous system (including seizures).

Influence on ability to drive vehicles and mechanisms

There has been no effect of cefazolin on the ability to drive vehicles and operate mechanisms. Nevertheless, since with the use of cefazolin such side effects as nausea, vomiting, dizziness, and seizures may occur, caution should be exercised while performing these activities and abstain from them in case of the above mentioned adverse events.

Contraindications

– hypersensitivity to cephazolin;

– history of severe hypersensitivity reactions (e.g., anaphylactoid reactions) to cephalosporins or any other beta-lactam antibiotics (penicillins, monobactams, carbapenems);

– period of newborn infancy up to 1 month, including premature infants.

When using lidocaine solution as a solvent – see the lidocaine instructions for use.

With caution

– co-administration of other nephrotoxic drugs;

– history of non-serious hypersensitivity reactions to penicillins;

– chronic renal failure;

– intestinal diseases (including colitis in the history of

– bowel disease (including a history of colitis);

– childhood age from 1 to 12 months.

Side effects

According to the classification of the World Health Organization (WHO), adverse reactions are presented according to their frequency of occurrence: Very common (>1/10); common (>1/100, < 1/10), infrequent (>1/1000, < 1/100), rare (>1/10000, < 1/1000) and very rare (< 1/10000), frequency unknown – the incidence could not be determined from available data.

Infections and parasitic infestations

Infrequent: oral candidiasis (with long-term use);

Rare: genital candidiasis, vaginitis.

Blood and lymphatic system disorders

Rarely: leukopenia, granulocytopenia, neutropenia, thrombocytopenia, leukocytosis, granulocytosis, monocytosis, lymphocytosis, thrombocytosis, lymphocytopenia, basophilia, eosinophilia. As a rule, these adverse events are transient and reversible;

Very rarely: bleeding disorders and, as a consequence, increased bleeding, anemia, agranulocytosis, aplastic anemia, pancytopenia, hemolytic anemia.

Immune system disorders

Infrequent: fever, arthralgia;

Very rare: Anaphylactic shock (development of laryngeal edema with narrowing of the airway lumen, increased heart rate^, shortness of breath, decreased blood pressure, tongue swelling, facial edema, anal and/or genital itching).

Metabolic and nutritional disorders

Rarely: hyperglycemia or hypoglycemia.

Nervous system disorders

Infrequent: development of seizures (in patients with impaired renal function when the drug is used in high doses if the dosing regimen is not followed);

Rarely: Dizziness, malaise, general weakness, nightmares, vertigo, hyperactivity, nervousness or anxiety, insomnia or drowsiness, impaired color vision, confusion, increased seizure activity of the brain.

Vascular disorders

Rarely: “hot flashes”.

Respiratory system, chest and mediastinum disorders

Rarely: pleural effusion, chest pain, bronchospasm, dyspnea, cough, development of acute respiratory distress syndrome, rhinitis.

Gastrointestinal disorders

Often: loss of appetite, diarrhea, nausea, vomiting, abdominal pain.

Very rare: development of pseudomembranous colitis. This condition requires immediate initiation of treatment (see also section “Special Precautions”).

Liver and biliary tract disorders

Rarely: transient increase in the activity of “hepatic” transaminases: alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase, gamma-glutamyltransferase, lactate dehydrogenase, increased plasma bilirubin concentration, transient hepatitis, cholestatic jaundice.

Skin and subcutaneous tissue disorders

Often: rash;

Infrequent: erythema, exudative (polymorphic) erythema, urticaria, pruritus, angioedema (Quincke’s edema);

Rarely: toxic epidermal necrolysis (Lyell’s syndrome), malignant exudative erythema (Stevens-Johnson syndrome).

Rarely: interstitial nephritis, proteinuria, transient increase of urea concentration in plasma (usually in patients treated with other nephrotoxic agents), nephropathy unspecified and other manifestations of nephrotoxicity.

Impact on the results of laboratory and instrumental studies

Prevalence unknown: false positive Coombs reaction, hypercreatininemia, increased prothrombin time, false positive urine glucose reaction.

General disorders and reactions at the injection site

Often: pain at the injection site after IUI, sometimes with the development of thickening;

Infrequent: thrombophlebitis and phlebitis when IUI.

Overdose

Symptoms

Headache, vertigo, paresthesia, agitation, myoclonias, seizures.

Laboratory signs: increased plasma creatinine and urea concentrations, increased “hepatic” transaminase activity and bilirubin concentrations, positive Coombs reaction, thrombocytopenia or thrombocytosis, eosinophilia, leukopenia and increased prothrombin time.

Treatment

In case of seizures cefazolin should be withdrawn immediately, vital signs should be carefully monitored, symptomatic therapy should be administered if necessary, anticonvulsants may need to be prescribed if seizures develop. In case of severe overdose and ineffectiveness of other methods of treatment hemodialysis may be performed. Peritoneal dialysis is not effective.

Pregnancy use

Pregnancy

Cefazolin penetrates through the placenta. Preclinical studies of cefazolin in animals have shown no direct or indirect reproductive toxicity. However, since there are insufficient data on the safety of cefazolin, the use of cefazolin in pregnancy is acceptable only if the expected benefit to the mother exceeds the potential risk to the fetus.

Breastfeeding

Cefazolin penetrates into breast milk in very small amounts; when cefazolin is used in therapeutic doses, the effect on the newborn is unlikely. If a breastfed infant develops diarrhea or candidiasis symptoms, the decision should be made whether to stop breastfeeding or to discontinue the drug.