Cefazolin - instructions for use, dose, side effects, contraindications

Cephalosporin semisynthetic antibiotic of the first generation for parenteral use. It acts bactericidal, blocking penicillin-binding proteins (eg, transpeptidase), disrupts the synthesis of the cell wall of microorganisms. Has a wide range of activities. The prevalence of acquired resistance may vary geographically, as well as change over time, local information should be taken into account, especially when treating 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: Neisseria meningitides, Neisserria 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 *; Streptococcus pneumoniae * (moderately sensitive to penicillins).

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

Microorganisms, possessing natural sustainability to cefazolin

Gram-positive aerobes: Enterococcus spp .; Staphylococcus aureus (stable to methicillin); Staphylococcus pneumoniae (stable 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.

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

* at in some regions, the frequency of resistance of microorganisms may exceed 50%;

** current data on the prevalence of resistance are not available, studies (over 5 years old) reported a frequency of resistance of microorganisms> 50%;

*** in community-based conditions, the prevalence of resistance does not exceed 10%.

Pharmacokinetics:

When taken orally cefazolin It is not absorbed, therefore the drug is used only parenterally.

After intramuscular (IM) administration cefazolin quickly absorbed from the injection site, compared with most other cephalosporins, the concentration of the drug in the blood plasma is higher and last longer.

After intra / m or intravenous (iv) administration 1.0 g of the drug, its concentration in the blood plasma changes as follows:

Concentrations (μg / ml) in blood plasma after intramuscular injection
Dose	30 min	1 h	2 hours	4 hours	6 hours	8 h	10 hours
1.0 g	60,1	63,8	54,3	29,3	13,2	7,1	<4,1

Concentrations (μg / ml) in blood plasma after intravenous administration
Dose	5 minutes	15 minutes	30 min	1 h	2 hours	4 hours
1.0 g	188,4	135,8	106,8	73,7	45,6	16,5

The association of the drug with plasma proteins is 70-90%. Cefazolin it penetrates into various organs and tissues, including lungs, liver, skin and soft tissues, joints, heart, peritoneum, middle ear, tonsils, gallbladder wall, appendix, and physiological body fluids. Very high concentrations of the drug are created in the kidneys - after the administration of 1.0 g of cefazolin, its concentration in the urine reaches 4000 μg / ml.In the absence of bile duct obstruction 90-120 minutes after drug administration cefazolin is found in the bile in a greater concentration than in the blood plasma. It should be borne in mind that in patients with impaired bile ductility the concentration of the drug in bile can be significantly lower than plasma concentration. The drug penetrates the placental barrier, is found in breast milk. Penetrates into the cerebrospinal fluid (CSF) in small amounts, against the background of inflammation of the mild cerebral membrane, the concentration of the drug in the CSF is 0-0.4 μg / ml. The drug passes through the capillary membranes in the bones and reaches bactericidal concentrations in both healthy and osteomyelitis-affected bones. The concentration of the drug in the joint fluid is comparable to the concentration in the blood plasma. In therapeutic concentrations found in ascites and pleural fluids, inflammatory exudate.

Cefazolin is not metabolized in the human body. Most of the injected drug is excreted in the urine due to glomerular filtration and tubular secretion in a microbiologically active form.During the first 6 hours from the administration of the urine output of 60-90% of the drug during the day - 70-95% of the administered dose. A small part of the drug is excreted from the body together with bile. Half-life in patients with impaired renal function (T_1/2) can be extended to 20-40 hours.

Indications:

Bacterial infections caused by microorganisms sensitive to cefazolin:

- respiratory tract infections;

- urinary and genital tract infections;

- bile duct infection;

- infections of the skin, soft tissues, bones and joints, including osteomyelitis;

- bacterial endocarditis, sepsis;

- intraoperative prophylaxis of infection development (preventive appointment of cefazolin may reduce the probability of infection in the postoperative period).

Sensitivity of antibiotics in vitro varies depending on the geographic region and over time, therefore, when choosing antibacterial therapy, local resistance information should be taken into account. If possible, the susceptibility of the pathogen to antibacterial drugs should be assessed. Therapy can be started empirically, until the results of a test for antibiotic sensitivity.

Contraindications:

- Hypersensitivity to cefazolin;

- the presence in the history of severe hypersensitivity reactions (for example, anaphylactoid reactions) to cephalosporins or any other beta-lactam antibiotics (penicillins, monobactams, carbapenems);

- the newborn period is up to 1 month, including premature infants.

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

Carefully:

Joint reception of other nephrotoxic drugs, not severe reactions of hypersensitivity to penicillins in the anamnesis.

Chronic kidney failure, intestinal diseases (including colitis in the anamnesis), children's age from 1 to 12 months.

Pregnancy and lactation:

Cefazolin penetrates the placenta. Preclinical studies of the drug on animals did not show the presence of direct or indirect reproductive toxicity. However, since there is insufficient information on the safety of the drug, the use of cefazolin during pregnancy is only permissible if the expected benefit to the mother exceeds the potential risk to the fetus.

Cefazolin is excreted in breast milk in extremely small quantities, when the drug is administered in therapeutic doses, exposure to the newborn is unlikely.If a breastfeeding newborn develops diarrhea or symptoms of candidiasis, the question of stopping breastfeeding or abolishing the drug should be resolved.

Dosing and Administration:

Cefazolin is intended only for parenteral administration - the drug should be administered iv in (jet or drip) or deep in / m.

Doses of the drug and the duration of the course of treatment are set individually, taking into account the severity of the course and localization of the infection, as well as the potential sensitivity of the pathogen.

The average daily intake for adults is 1-4 g; the frequency of administration is 3-4 times a day. The maximum daily dose is 6 g. The average duration of treatment is 7-10 days.

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

Application of the drug in adults

Type of infection	Single dose	Frequency of administration
Infections of mild severity caused by sensitive Gram-positive cocci	0.5-1.0 g	every 8 hours
Pneumococcal pneumonia	0.5 g	every 12 hours
Acute uncomplicated urinary tract infections	1.0 g	every 12 hours
Infections of moderate or severe severity	0.5-1.0 g	every 6-8 hours
Life-threatening infections (eg sepsis, bacterial endocarditis) *	1.0-1.5 g	every 6 hours

* In rare cases, doses up to 12 g per day are applied.

Prevention of intraoperative infections

For 30 min-1 h before an intravenous or intravenous operation, the initial dose of cefazolin should be 1.0 g.

For prolonged operations (2 hours and longer), 0.5 g-1.0 g of the drug is additionally added during the operation. The dose and time of administration depend on the type and duration of the operation.

Within 24 hours after the operation, 0.5 g-1.0 g of the drug iv or ip is injected at intervals of 6-8 hours.

If the possibility of developing infection poses a great danger to the patient (for example, after a heart surgery or a serious orthopedic operation, such as a complete joint replacement), it is recommended that the drug be continued for 3-5 days. It is important to observe the above dates so that sufficient concentrations of antibiotic are already present in the blood serum and tissues during the surgical procedure. In the case of an increased risk of anaerobic infection (eg,after surgery on the large intestine) is recommended an additional appointment of a drug that is active against anaerobes.

Correction of dose the of adult patients with impaired renal function

Creatinine clearance (ml / min x 1.73 m²)	Concentration of creatinine (mg / 100 ml)	Dose (% of initial)	Intervals between administrations
>55	<1,5	100%	correction is not required
35-54	1,6-3,0	100%	8h
11-34	3,1 -4,5	50%	12h
<10	>4,6	50%	18-24h

All recommended doses are administered after the initial dose corresponding to the indication and severity of the infection. In patients on hemodialysis, the dosing schedule depends on the dialysis regime used.

Elderly patients

Correction of the dose is not required.

Use in children from 1 month to 18 years of age

For treatment of most infections of mild and 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 may be increased to the maximum recommended dose of 100 mg / kg.

The safety of the drug in newborns is not established. Correction of dose the children with impaired renal function

Children who have a creatinine clearance (CC) of 70-40 ml / min / 1.73 m², 60% of the average daily dose of cefazolinum is administered after 12 hours.

Children whose QC is 39 - 20 ml / min / 1.73 m² 25 is entered% average daily dose of the drug after 12 hours.

With QC 19-5 ml / min / 1.73 m² 10% of the average daily dose of cefazolin is administered at intervals of 24 hours.

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

Preparation of the solution

For intramuscular administration, 1 g is dissolved in 4 ml of water for injection or a 0.5% solution of lidocaine. For intravenous fluid administration, a single dose of the drug is diluted in 10 ml of water for injection, then injected slowly, within 3-5 minutes. For intravenous drip, 50-100 ml of a 5% dextrose solution or 0.9% sodium chloride solution is diluted. During the dilution, vials should be vigorously shaken until completely dissolved.

Doses up to 1 g can be administered by slow intravenous injection for 3-5 minutes. Large doses of the drug should be administered by intravenous infusion for 20-30 minutes.

The maximum single dose for intramuscular injection is 1 g, the drug should be injected only into large muscles.

The solution containing lidocaine can not be administered intravenously.

To prepare the infusion solution, the following solvents can be used:

- 0,9% solution of sodium chloride;

- 5% dextrose solution or 5% dextrose solution with 0.9% sodium chloride solution;

Only freshly prepared and transparent solutions should be used. The possible yellowish color that appears after dissolving the powder is not an indication of any change in the properties of the drug or the difference in its therapeutic effectiveness.

Side effects:

In accordance with the classification of the World Health Organization (WHO), adverse reactions are presented according to the frequency of their development: very often (≥1 / 10); often (≥1 / 100, <1/10), infrequently (≥1 / 1000, <1/100), rarely (≥1 / 10000, <1/1000) and very rarely (<1/10000), the frequency is unknown - According to available data to establish the frequency of occurrence was not possible.

Infections and parasitic infestations

infrequently: Candidiasis of the oral cavity (with long-term use);

rarely: genital candidiasis, vaginitis.

Violations of the blood and lymphatic system

rarely: leukopenia, granulocytopenia, neutropenia, thrombocytopenia, leukocytosis, granulocytosis, monocytosis, lymphocytosis, thrombocytosis, lymphocytopenia, basophilia, eosinophilia.As a rule, these undesirable phenomena are of a short-term nature and are reversible;

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

Immune system disorders

infrequently: fever, arthralgia;

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

Disorders from the metabolism and nutrition

rarely: hyperglycemia or hypoglycemia.

Disturbances from the nervous system

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

rarely: dizziness, malaise, general weakness, nightmarish dreams, vertigo, hyperactivity, nervousness or anxiety, insomnia or drowsiness, violation of color perception, confusion, increased convulsive activity of the brain.

Vascular disorders

rarely: "tides".

Disturbances from the respiratory system, chest and mediastinal organs

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

Disorders from the gastrointestinal tract

often: loss of appetite, diarrhea, nausea, vomiting, abdominal pain. As a rule, moderate expression, these symptoms are often resolved spontaneously during or after completion of treatment;

rarely: development of pseudomembranous colitis. This condition requires immediate treatment (see also "Special instructions").

Disturbances from the liver and bile ducts

rarely: transient increase in the activity of "liver" transaminases: alanine aminotransferase (ALT), aspartate aminotransferase (ACT), alkaline phosphatase, gamma-glutamyltransferase, lactate dehydrogenase, increased bilirubin concentration in blood plasma, transient hepatitis, cholestatic jaundice.

Disturbances from the skin and subcutaneous tissues

often: rash;

infrequently: erythema, exudative (polymorphic) erythema, urticaria, skin itching, angioedema (Quincke's edema);

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

Disorders from the kidneys and urinary tract

rarely: interstitial nephritis, proteinuria, transient increase in urea concentration in blood plasma (usually in patients receiving therapy in combination with other nephrotoxic drugs), nephropathy, unspecified and other manifestations of nephrotoxicity.

Impact on the results of laboratory and instrumental studies

frequency unknown: a false positive Coombs reaction, hypercreatininaemia, an increase in prothrombin time, a false positive urine reaction to glucose.

General disorders and reactions at the site of administration

often: pain at the injection site after intramuscular injection, sometimes with the development of compaction;

infrequently: thrombophlebitis and phlebitis - with intravenous administration.

Overdose:

Symptoms: headache, vertigo, paresthesia, agitation, myoclonia, seizures.

Laboratory features: an increase in the concentration of creatinine and urea in the blood plasma, an increase in the activity of "liver" transaminases and bilirubin concentrations,a positive Coombs reaction, thrombocytopenia or thrombocytosis, eosinophilia, leukopenia, and an increase in prothrombin time.

Treatment: in the case of seizures cefazolin should be immediately abolished, the vital signs should be carefully monitored, symptomatic therapy should be carried out if necessary, in the case of seizures, the appointment of anticonvulsants may be required. In case of severe overdose and ineffectiveness of other methods of treatment, hemodialysis is possible. Peritoneal dialysis is ineffective.

Interaction:

Cefazolin is able to reduce the effectiveness of oral contraceptives. For this reason, additional contraceptive measures should be taken during treatment with the drug.

Cefazolin should not be administered in conjunction with other antibacterial drugs having a bacteriostatic effect (eg, tetracyclines, sulfonamides, erythromycin, chloramphenicol), since in studies in vitro antagonism between these drugs was detected.

When combined with cefazolinum, nephrotoxic properties of other antibacterial(eg, aminoglycosides, colistin, polymyxin B), iodine-containing contrast agents, high doses of methotrexate, some antiviral drugs (eg, acyclovir, foscarnet), pentamidine, cyclosporine, tacrolimus, platinum-containing drugs and diuretics (eg, furosemide). If necessary, their combined use with cefazolin should closely monitor the kidney function.

When used simultaneously with "loop" diuretics (for example, furosemide), blockade of tubular secretion of cefazolin occurs, which leads to an increase in its concentration in the blood plasma. For this reason, joint use of these drugs should be avoided.

With the co-administration of cefazolin and probenecid, the renal clearance of cefazolin decreases, which leads to an increase in the time taken to remove the drug and increase its plasma concentration.

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

Some cephalosporin antibiotics, for example cefamandol, cefotetan and cefazolin, suppressing the intestinal microflora, can disrupt the metabolism of vitamin K, which reduces its formation in the body, especially in patients with initial deficiency. It may be necessary to prescribe vitamin K.

When used simultaneously with drugs that reduce platelet aggregation (for example, non-steroidal anti-inflammatory drugs), the risk of bleeding increases.

Cefazolin can cause disulfiram-like reactions when used simultaneously with ethanol.

Cefazolin is pharmaceutically incompatible with the antibiotics of the aminoglycoside group (gentamycin, kanamycin, amikacin, etc.), tetracyclines (oxytetracycline, tetracycline and others), sodium colistimetate, polymyxin B, erythromycin (as a glucoheptonate salt), barbituric derivatives (amobarbital, pentobarbital), bleomycin, calcium salts (calcium glucoheptonate, calcium gluconate), cimetidine, ascorbic acid.

Special instructions:

Hypersensitivity reactions

Before starting the use of cefazoline, you should collect an allergic patient's anamnesis.Due to the possibility of developing a cross-hypersensitivity between cephalosporins and other beta-lactam antibiotics. On the background of cefazolin therapy, the development of severe, including fatal, allergic reactions was described. If a severe hypersensitivity reaction develops, cefazolin should be discontinued and appropriate symptomatic therapy should be prescribed. The drug is contraindicated in patients with severe reactions of hypersensitivity to cephalosporins or any other beta-lactam antibiotics in the anamnesis.

Especially careful observation of patients with a tendency to allergic reactions (allergic rhinitis, bronchial asthma) is necessary, as against the background of the presence of such conditions the risk of hypersensitivity reactions increases.

Diarrhea associated with the use of antibacterial drugs The development of severe and persistent diarrhea during treatment and in the first weeks after completion of therapy may be a manifestation of Clostridium difficile associated diarrhea - pseudomembranous colitis. Since this state is life-threatening, cefazolin should immediately be abolished and a specific antibiotic therapy (for example, vancomycin or metronidazole). Symptomatic maintenance therapy, including correction of water-electrolyte balance, nutritional deficiencies, is shown. The use of drugs that inhibit the intestinal peristalsis is contraindicated. In particularly severe cases, with resistance of the infection to antibiotic therapy, colectomy may be required.

Special attention should be paid to careful collection of the patient's anamnesis, since cases of development of pseudomembranous colitis have been described for two months from the time of antibiotic therapy.

Impaired renal function

Due to the cumulation of the drug in the body, in patients with reduced renal function, the dose of the drug should be selected in accordance with the severity of renal failure (see also section "Dosing and Administration"). Although the use of cefazolin rarely causes renal dysfunction and the development of renal insufficiency, it is recommended to evaluate the kidney function against the background of the drug, especially in patients in serious condition,when using high doses of the drug and / or other nephrotoxic drugs (eg, aminoglycosides, loop diuretics).

Development of bacterial resistance and superinfections

Long-term use of cefazolin can provoke the emergence of resistant strains of bacteria. Patients should be carefully monitored for possible development of superinfection and take appropriate measures in case of its development.

Reduced coagulation and bleeding

In rare cases, with the use of cefazolin, blood coagulability may be reduced. Risk factors include vitamin K deficiency, parenteral nutrition, nutritional deficiencies, renal and / or hepatic insufficiency, thrombocytopenia, anticoagulant therapy. In addition, diseases such as hemophilia, ulceration of the mucous membrane of the stomach and / or duodenum can lead to the development or increase of the severity of bleeding. Therefore, it is necessary to monitor the coagulogram indices in patients with a known presence of these diseases. If there is a decrease in blood clotting, vitamin K therapy should be prescribed (10 mg / week).

Use of the drug in children

Cefazolin should not be given to premature and newborn babies for 1 month of life, since to date, data showing safety of its use in this patient population are not provided.

The sodium content

1 g of cefazolin contains approximately 48 mg of sodium ions, which should be taken into account when prescribing the drug to patients with diet limiting intake of table salt.

Impact on laboratory performance

Against the background of the use of cefazolin, false positive reactions are possible to determine the concentration of glucose in the urine using a Benedict or Felling reagent, as well as false positive results of a direct and indirect Coombs test.

With prolonged use of the drug, control of the peripheral blood pattern is necessary.

Ethanol intake during treatment

Due to the possibility of development of disulfiram-like reactions against the background of the drug, during the treatment patients should refrain from drinking alcohol.

The drug should not be administered intrathecally.

Effect on the ability to drive transp. cf. and fur:

Effects of cefazolin on the ability to drive vehicles and work with mechanisms were not identified. However, since the development of side effects such as nausea, vomiting, dizziness and convulsions is possible against the background of the drug, caution should be exercised in performing these activities and refraining from them if these undesirable events develop.

Form release / dosage:

Powder for solution for intravenous and intramuscular injection, 1.0 g.

Packaging:

By 1.0 g of cefazolin in glass bottles, hermetically sealed with rubber stoppers, crimped with aluminum caps. 1 or 10 bottles together with the instructions for use are placed in a pack of cardboard.

For hospitals: 50 bottles together with an equal number of instructions for use are placed in a box of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-003947

Date of registration:08.11.2016

Expiration Date:08.11.2021

The owner of the registration certificate:BORISOVSKIY FACTORY OF MEDPREPARATES, OJSC BORISOVSKIY FACTORY OF MEDPREPARATES, OJSC Republic of Belarus

Manufacturer: & nbsp

BORISOVSKIY FACTORY OF MEDPREPARATES, OJSC Republic of Belarus

Representation: & nbspBORISOVSKIY FACTORY OF MEDPREPARATES, OJSCBORISOVSKIY FACTORY OF MEDPREPARATES, OJSC

Information update date: & nbsp10.12.2016

Illustrated instructions

Instructions

Cefazolin (Cefazolin)