Cefazolin, 1 g

Pharmacotherapeutic group: cephalosporin antibiotic.

To be sure to use the following medicines.

Pharmacological properties

Pharmacodynamics

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

Microorganisms sensitive 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: Veisseria meningitides, Neisserria gonorrhoeae, Shigella spp., Salmonella spp., Treponema spp., Leptospira spp.

Microorganisms that are moderately sensitive to cefazolin.

Gram-positive aerobes: Staphylococcus aus, Staphylococcus epidermidis, Staphylococcus haemolyticus*, Staphylococcus hominis*, Streptococcus pneumonia* (moderately sensitive to penicillins).

Gram-negative aerobes: Escherichia coli, Haemophilus influenza**, 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 cross-resistance to cephalosporins are insensitive to cephalosporins, including cefazolin.

Pharmacokinetics

In oral administration cefazolin is not absorbed; therefore, the drug is used only parenterally. After intramuscular (i.m.) administration cefazolin is quickly absorbed from the injection site compared to most other cephalosporins, plasma concentrations of the drug are higher and remain longer. After a 1.0 g injection or intravenous (IV) injection, plasma concentrations of the drug are altered.

The drug’s binding to plasma proteins is 70-90%. Cefazolin penetrates well into various organs and tissues, including lungs, liver, skin and soft tissue, joints, heart, peritoneum, middle ear, tonsils, gall bladder wall, appendix as well as into body fluids. Very high concentrations of the drug are created in the kidneys – after administration of 1.0 g of cefazolin its concentration in the urine reaches 4000 mcg/ml. In absence of biliary obstruction, 90-120 minutes after drug administration, cefazolin is detected 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 in plasma.

The drug penetrates through the placental barrier and is detected in breast milk. It penetrates into cerebrospinal fluid (CSF) in small amounts; against inflammation of the dura mater the concentration of the drug in CSF is 0 – 0.4 µg/ml. The drug passes through capillary membranes in the bones and reaches bactericidal concentrations in both healthy and affected bones with osteomyelitis.

The drug concentration in joint fluid is comparable to that in blood plasma. In therapeutic concentrations it is found in ascitic and pleural fluid, inflammatory exudate.
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*In some regions the resistance rate of microorganisms may exceed 50%
**actual data on the prevalence of resistance are not available, in studies (older than 5 years) reported on the resistance rate of microorganisms > 50%
***in outpatient settings, the prevalence of resistance is less than 10%

Cefazolin is not metabolized in humans. Most of the administered drug is excreted with urine by glomerular filtration and tubular secretion in microbiologically active form. During the first 6 hours after administration, 60-90% of the drug is excreted with urine, during the day – 70-95% of the administered dose. A small part of the drug is excreted with bile. The elimination half-life in patients with renal dysfunction (T1/2) may be prolonged to 20-40 hours.

Indications

Tonsillitis, Osteomyelitis, Biliary tract infections, Otitis media, Purulent wounds, Lung inflammation (pneumonia), Inflammation of the female genitalia, Bronchitis, Skin infections, Urinary tract infections, Guillotine, Burns

Bacterial infections caused by cefazolin-sensitive microorganisms:

• respiratory tract infections;
• urinary and genital tract infections;
• biliary tract infections;
• infections of the skin, soft tissues, bones and joints, including osteomyelitis;
• bacterial endocarditis, sepsis;
• intraoperative prophylaxis of the development of infections (prophylactic administration of cefazolin may reduce the likelihood of infection in the postoperative period).

In vitro antibiotic sensitivity 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

Cefazolin

Composition

Powder for the preparation of a solution for intravenous and intramural administration.

Active substance: cefazolin sodium converted into cefazolin – 1.0 g.

How to take, the dosage

Cefazolin is intended for parenteral administration only – intramuscularly and intravenously (by stream or drop). Doses are set individually, taking into account the severity of the course and localization of the infection and the sensitivity of the pathogen.

Preparation of solutions and use

For intravenous administration 1 g of the drug is dissolved in 4 ml of water for injection.

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

For IV drops the drug is diluted in 50-100 ml of 5-10% dextrose solution, 0.9% sodium chloride solution, Ringer’s solution, 5% sodium bicarbonate solution. Infusion is carried out for 20-30 minutes (infusion rate – 60-80 drops per minute). During dilution vials should be shaken vigorously until complete dissolution.

Please use only freshly prepared and clear solutions. The possible yellowish coloration of the solution after dissolution of the powder is not an indication of any change in the properties of the product or of any difference in its therapeutic effectiveness.

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

Dosage instructions for adults

Mild course infections caused by susceptible gram-positive cocci 0.5-1 g After 8 hours
Pneumococcal pneumonia 0.5 g After 12 hours
Acute uncomplicated urinary tract infections 1 g After 12 hours
Moderate to severe 0.5-1 g After 6-8 hours
Severe, life-threatening infections: Endocarditis, septicemia 1-1.5 g After 6 hours

Application in children with normal renal function

In children 1 month old. and older, cefazolin is prescribed at a dose of 25-50 mg/kg body weight per day. Frequency of administration is 3-4 times a day. In case of severe infection the daily dose of cefazolin may be increased to 100 mg/kg of body weight. Frequency of administration – 3-4 times a day.

Application in adult patients with impaired renal function

In patients with impaired renal function the dosing regimen must be adjusted according to the creatinine clearance (CK) values:

• when the CK is 55 mL/min or greater or when the plasma creatinine concentration is 1.5 mg% or less, a full daily dose can be administered;
• when the CK is 54-35 mL/min or the plasma creatinine concentration is 3-1.6 mg%, a full daily dose can be administered, but injection intervals must be increased to 8 hours;
• in patients with a CKR of 34-11 ml/min or a plasma creatinine concentration of 4.5-3.1 mg%, 1/2 of the usual dose at 12-hour intervals;
• in patients with a CKR of 10 ml/min or less or a plasma creatinine concentration of 4.6 mg% or more, 1/2 of the usual dose every 18-24 hours.

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

Application in children with impaired renal function

The dosing regimen is adjusted according to CK values:

• for CK 70-40 ml/min/1.73 m² – 60% of the average daily dose after 12 hours;
• for CK 40-20 ml/min/1.73 m^2<
• For IQ 20-5 ml/min/1.73 m² – 25% of the average daily dose after 12 hours;
• For IQ 20-5 ml/min/1.73 m² – 10% of the average daily dose after 24 hours.

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

Perioperative prophylaxis

To prevent infections during surgical procedures, the dose of cefazolin depends on the type and duration of surgery.

• 1 g is given intravenously or intramuscularly 30 minutes to 1 hour before surgery (the dose is sufficient for minor surgical procedures of short duration);
• in the postoperative period, after the initial dose, administer 0.5 g to 1 g intravenously or intramuscularly at 6-8 hour intervals for 24 hours;

It is important to adhere to the above timescales so that sufficient concentrations of the antibiotic are already present in the patient’s serum and tissues at the time of the surgical incision.

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 administered together with other antibacterial drugs with bacteriostatic action (e.g., tetracyclines, sulfonamides, erythromycin, chloramphenicol), because in in vitro studies antagonism between these drugs was found.

. In concomitant use with cefazolin it is possible increase of nephrotoxic properties of other antibacterial drugs (for example, aminoglycosides, colistin, polymyxin B), iodine-containing contrast agents, high doses of methotrexate, some antiviral drugs (for example, acyclovir, foscarnet), pentamidine, cyclosporine, tacrolimus, platinum-containing drugs and diuretics (for example, 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.

The renal clearance of cefazolin and probenecid is decreased when co-administration, which leads to increased elimination time and increased plasma concentration of the drug.

In rare cases cephalosporins can cause clotting disorders.

If co-administration with oral anticoagulants is necessary, especially in high doses, coagulogram parameters should be monitored.

Some cephalosporin antibiotics, such as cefamandole, cefotetan and cefazolin, by suppressing gut microflora, can disrupt metabolism of vitamin K, which reduces its formation in the body, especially in patients with baseline deficiency.

Vitamin K preparations may need to be prescribed.

Concomitant use with drugs that reduce platelet aggregation (e.g., non-steroidal 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

Patients with a history of allergic reactions to penicillins, carbapenems may have hypersensitivity to cephalosporin antibiotics. If allergic reactions develop, the drug administration should be discontinued and appropriate desensitization therapy should be prescribed.

In case of renal failure the drug dose should be reduced and further treatment should be carried out under control of urea nitrogen and creatinine blood dynamics.

When treating with cefazolin it is possible to get positive direct and indirect Coombs tests as well as false positive urine sugar reaction.

When the drug is prescribed, gastrointestinal diseases, especially colitis, may worsen.

The solution is stable when thawed within 10 days when stored in a refrigerator (5 degrees C) or 48 hours at room temperature.

The safety of the product in premature infants and children of the first year of life has not been established.

Contraindications

• high sensitivity to cephazolin;
• An history of severe hypersensitivity reactions (e.g., anaphylactoid reactions) to cephalosporins or any other beta-lactam antibiotics (penicillins, monobactams, carbapenems);
• neonatal period up to 1 month, including premature infants.

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

With caution

Co-administration of other nephrotoxic drugs, non-serious hypersensitivity reactions to penicillins in the history.

Chronic renal failure, bowel disease (including history of colitis), children from 1 to 12 months of age.

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

seldom: leukopenia, granulocytopenia, neutropenia, thrombocytopenia, leukocytosis, granulocytosis, monocytosis, lymphocytosis, thrombocytosis, lymphocytopenia, basophilia, eosinophilia. As a rule, these adverse events are transient and reversible; very rarely: disorders of blood clotting and, as a consequence, increased bleeding, anemia, agranulocytosis, aplastic anemia, pancytopenia, hemolytic anemia.

Immune system disorders

infrequent: fever, arthralgia;

very rarely: anaphylactic shock (development of laryngeal edema with narrowing of the airway lumen, increased heart rate, shortness of breath, drop in blood pressure, tongue swelling, facial edema, anal and/or genital itching).

Metabolic and nutritional disorders

seldom: hyperglycemia or hypoglycemia.

Nervous system disorders

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

rarely: dizziness, malaise, general weakness, nightmares, vertigo, hyperactivity, nervousness or anxiety, insomnia or drowsiness, color vision disturbance, confusion, increased seizure activity of the brain.

Vascular disorders

seldom: “hot flashes”.

Respiratory system, chest and mediastinum disorders

Rare: 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 rarely: development of pseudomembranous colitis. This condition requires immediate initiation of treatment (see also section “Special indications”).

Liver and biliary tract disorders

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

Skin and subcutaneous tissue disorders

often: rash;

infrequently: 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 in combination with other nephrotoxic agents), nephropathy unspecified and other manifestations of nephrotoxicity.

Impact on the results of laboratory and instrumental studies

frequency 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 intramuscular injection, sometimes with the development of thickening;

infrequently: thrombophlebitis and phlebitis when administered intravenously.