Ceftazidime, 1 g

Pharmacotherapeutic group: Antibiotic, cephalosporin

ATX code: J01DD02

Pharmacological properties

Pharmacodynamics
Ceftazidime is a III generation cephalosporin antibiotic. It has a bactericidal effect by disrupting bacterial cell wall synthesis.
Pharmacodynamic Effects
The prevalence of acquired bacterial resistance to ceftazidime varies by region and over time, certain types of microorganisms may have very high resistance. It is preferable to have local data on the sensitivity and prevalence of microorganisms producing extended spectrum beta lactamase (ELBP), especially for therapy of severe infections.
In vitro activity of ceftazidime is shown below. Bacteria commonly sensitive to ceftazidime:
Gram-positive aerobes: Beta-hemolytic streptococci1, Staphylococcus aureus (strains sensitive to methicillin)1, Coagulazonegative staphylococci (strains sensitive to methicillin).
Gram-negative aerobes: Haemophilus influenzae, including ampicillin-resistant strains1, Haemophilus parainfluenzae, Neisseria gonorrhoeae, Neisseria meningitidis1, Pasteurella multocida, Proteus spp.1, Providencia spp., Salmonella spp., Shigella spp.
Bacteria for which acquired resistance to ceftazidime is likely: Gram-negative aerobes: Acinetobacter spp., Burkholderia cepacia, Citrobacter spp.1, Enterobacter spp.1, Escherichia coli1, Klebsiella spp. including K. pneumoniae1, Pseudomonas spp. including P. aeruginosa1, Serratia spp.1, Morganella morganii, Yersinia enterocolitica.
Gram-positive aerobes: Streptococcus pneumoniae1, Viridans group Streptococcus. Gram-positive anaerobes: Clostridium spp. not including C. difficile, Peptostreptococcus spp, Propionibacterium spp.
Gram-negative anaerobes: Fusobacterium spp.
Bacteria with natural resistance to ceftazidime:
Gram-positive aerobes: Enterococcus spp. including E. faecalis and E. faecium, Listeria spp. Gram-negative aerobes: Campylobacter spp.
Gram-positive anaerobes: Clostridium difficile. Gram-negative anaerobes: Bacteroides spp. including B. fragilis. Other: Chlamydia spp., Legionella spp., Mycoplasma spp.
1 – for these bacteria the clinical effectiveness of ceftazidime has been demonstrated in clinical trials.

Pharmacokinetics
Absorption
After intramuscular administration of ceftazidime at doses of 500 mg and 1 g, maximum plasma concentrations of the drug are quickly reached (18 mg/L and 37 mg/L, respectively). Five minutes after intravenous bolus administration of the drug in doses of 500 mg, 1 g or 2 g, its plasma concentrations are 46 mg/L, 87 mg/L and 170 mg/L, respectively.
Distribution
In plasma therapeutically effective concentrations of ceftazidime are maintained

8-12 hours after intravenous or intramuscular administration. The binding to blood plasma proteins is about 10%.
Concentrations of ceftazidime exceeding the minimum inhibitory concentrations for most common pathogens can be achieved in bone tissue, heart tissue, bile, sputum, synovial fluid, intraocular fluid, pleural and peritoneal fluids. Ceftazidime readily penetrates the placenta and is excreted with breast milk. In the absence of inflammatory process in meningeal membranes ceftazidime poorly penetrates through the blood-brain barrier, the drug concentration in cerebrospinal fluid (CSF) is low. In meningitis in CSF therapeutic concentrations of ceftazidime of 4-20 mg/l and higher are achieved.

Metabolism
Ceftazidime is not metabolized in the body.

Exhaustion
Parenteral administration achieves high plasma concentrations for a long time, which decrease with a half-life of about 2 hours. In neonates aged 0-28 days and children aged 28 days to 2 months the elimination period of ceftazidime may be 3-4 times longer than in adults.
Ceftazidime is excreted unchanged by the kidneys through glomerular filtration, with about 80-90% of the administered dose being excreted by the kidneys within 24 hours. Less than 1 % is excreted with bile, as a result of which a limited volume of the drug is excreted through the intestine.
Patients with impaired renal function
In patients with impaired renal function the excretion rate of ceftazidime is reduced, therefore the dose should be reduced (see sections “Dosage and administration” – “Patients with impaired renal function”, “Cautionary instructions”).

Indications

Ceftazidime is indicated for the treatment of monoinfections or mixed infections caused by microorganisms sensitive to ceftazidime, including

Active ingredient

Composition

Composition per vial:
Active ingredient:
Ceftazidime pentahydrate 1.165 g
in terms of ceftazidime 1.000 g
Excipient:
Sodium carbonate 0.1165 g

(Ceftazidime sodium is a mixture of ceftazidime pentahydrate and sodium carbonate 10:1)

How to take, the dosage

The dose of the drug is set individually depending on the severity of the disease, localization, type of the causative agent and its sensitivity to the drug, as well as the patient’s age and renal function.

The drug is given intravenously or deeply intramuscularly in the area of the upper outer quadrant of the greater gluteal muscle or the lateral surface of the thigh.

The ceftazidime solution may be injected directly into a vein or into a tube of an infusion system if the patient is receiving infusion therapy.

Adults and children with a body weight of 40 kg or more: 1-6 g/day in 2 or 3 infusions intravenously or intramuscularly.

The prolonged infusion regimen

. In febrile neutropenia due to bacterial infection, bronchopulmonary bacterial infection in cystic fibrosis, nosocomial pneumonia, bacterial meningitis, bacteremia, bone and joint infections, complicated skin and soft tissue infections, complicated intra-abdominal infections peritonitis associated with haemo- and peritoneal dialysis and with continuous ambulatory peritoneal dialysis ceftazidime is administered as a loading dose of 2 g followed by a prolonged infusion of the drug at doses of 4 to 6 g every 24 hours1.

1 No adverse effects were observed in adult patients with normal renal function when the drug was administered at a dose of 9 g daily.

Special patient groups

Children over 2 months of age with a body weight less than 40 kg.

The extended infusion regimen

In febrile neutropenia due to bacterial infection, bronchopulmonary bacterial infection in cystic fibrosis, nosocomial pneumonia, bacterial pneumonia, bacterial meningitis, bacteremia, bone and joint infections, complicated skin and soft tissue infections, complicated intra-abdominal infections, peritonitis associated with hemo- and peritoneal dialysis and with continuous ambulatory peritoneal dialysis ceftazidime is given as a loading dose of 60-100 mg/kg followed by a prolonged infusion of the drug at a dose of 100-200 mg/kg/day, maximum 6 g/day.

Infants 0 to 28 days and children 28 days to 2 months

25-60 mg/kg/day in 2 infusions. Extended infusion regimen

The safety and efficacy of ceftazidime in the extended infusion regimen in

newborns 0 to 28 days and children 28 days to 2 months have not been studied.

Elderly patients

Given the reduced clearance of ceftazidime in elderly patients, the recommended dose of ceftazidime should not exceed 3 g/day, especially in patients older than 80 years.

Patients with impaired renal function

Ceftazidime is excreted unchanged by the kidneys. Therefore, in patients with impaired renal function it is recommended to reduce the dose of ceftazidime.

The initial dose is 1 g. Maintenance doses are adjusted depending on creatinine clearance values.

Adults and children with a body weight of 40 kg or more

. Maintenance doses of ceftazidime for patients with impaired renal function

Creatinine clearance (ml/min)

Plasma creatinine concentration, μmol/L

/p>

(mg/dL)

Recommended single dose of ceftazidime (g)

/p>

Frequency of administration

> 50

<150 (< 1.7)

standard doses

50 to 31

150 to 200

(1.7 to 2.3)

1.0

every 12 hours

30 to 16

200 to 350

(2.3 to 4.0)

1.0

every 24 hours

15 to 6

350 to 500

(4.0 to 5.6)

0.5

every 24 hours

< 5

> 500

(> 5,6)

0.5

every 48 hours

Patients with severe infections should have the recommended single dose increased by 50% or the frequency of administration increased. Plasma ceftazidime concentrations should be monitored in these patients; ceftazidime concentrations should not exceed 40 mg/L.

In children, creatinine clearance is calculated according to fat-free body weight or body surface area.

Doses of ceftazidime for patients with impaired renal function – extended infusion regimen

Creatinine clearance (ml/min)

Plasma creatinine concentration, μmol/L

(mg/mL)

Frequency of drug administration

50 to 31

150 to 200

(1.7 to 2.3)

Load dose of 2 g followed by 1 to 3 g for 24 hours in an extended

infusion

30 to 16

200 to 350

(2.3 to 4.0)

Capacity dose of 2 g with

followed by 1 g

within 24 hours in

extended infusion mode

≤ 15

> 350

(> 4.0)

Not rated

Caution should be exercised in dose selection. Close clinical monitoring of the safety and effectiveness of the therapy is recommended.

Children with a body weight less than 40 kg

Maintenance doses of ceftazidime for patients with impaired renal function

Creatinine clearance (ml/min)**

Plasma creatinine concentration*, μmol/L

(mg/dL)

Recommended single dose of ceftazidime mg/kg body weight

p> Frequency of drug administration

50 to 31

150 to 200

(1.7 to 2.3)

25

every 12 hours

30 to 16

200 to 350

(2.3 to 4.0)

25

every 24 hours

15 to 6

350 to 500

(4.0 to 5.6)

12.5

every 24 hours

< 5

> 500

(> 5.6)

12.5

every 48 hours

* Plasma creatinine concentrations are guideline values that may not indicate the same degree of renal impairment for all patients.

** Calculation is based on body surface area or measurements.

In children with impaired renal function, creatinine clearance is calculated according to body surface area or fat-free body weight.

A close clinical monitoring of the safety and efficacy of the therapy is recommended.

Prolonged infusion regimen for patients with impaired renal function

The efficacy and safety of ceftazidime administered as an extended infusion in children with renal dysfunction weighing less than 40 kg have not been studied. Close monitoring of safety and efficacy of the therapy is recommended. If the prolonged infusion regimen is used in children with impaired renal function, creatinine clearance should be calculated according to body surface area or lean body mass.

Hemodialysis

During hemodialysis, the half-life is 3-5 hours.

After each hemodialysis session, administer maintenance doses of ceftazidime according to the table above.

Peritoneal dialysis

Ceftazidime can be used during peritoneal dialysis and continuous ambulatory peritoneal dialysis. In addition to intravenous administration, ceftazidime can be added to dialysis solution (usually at a dose of 125-250 mg per 2 liters of dialysis solution).

For patients with renal failure who are on continuous hemodialysis using an arterio-venous shunt or for patients on high-speed hemofiltration in an intensive care unit, the recommended dose is 1 g/day daily (in one or more injections).

For patients on low-rate hemofiltration, the same doses of the drug are recommended as for impaired renal function.

Patients on hemodialysis or hemofiltration using a venous venous shunt are recommended the doses shown in the table below.

Doses of ceftazidime in patients on hemofiltration with a venous venous shunt

The table belowtable>

Maintenance dose (mg) depending on ultrafiltration rate (ml/min)*

5

16.7

33.3

50

0

250

250

500

500

5

250

250

500

500

10

250

500

500

750

15

250

Interaction

Concomitant administration of high doses of ceftazidime and nephrotoxic drugs may have adverse effects on renal function (see section “Cautions”). Ceftazidime, like other antibiotics, may interfere with the intestinal microflora, which may lead to decreased estrogen resorption and reduced efficacy of combined oral hormonal contraceptives.

Ceftazidime is compatible with most IV solutions.

V however, ceftazidime is less stable in sodium bicarbonate solution, so it is not recommended for use as a solvent.

Pharmaceutically incompatible with aminoglycosides, vancomycin, chloramphenicol. Ceftazidime and aminoglycosides should not be mixed in the same infusion system or syringe.

Chloramphenicol acts in vitro as an antagonist of ceftazidime and other cephalosporins. The clinical significance of this phenomenon is not known, but possible antagonism of action should be considered when concomitantly administered.

When vancomycin is added to ceftazidime solution, precipitation has been noted, so it is recommended that the infusion system be flushed between injections of the two drugs.

Special Instructions

Before initiating treatment with ceftazidime, a detailed history of prior hypersensitivity reactions to ceftazidime, cephalosporins, penicillins or other drugs should be taken.

Particular attention should be given to patients with a previous non-serious allergic reaction to penicillins or other beta-lactam antibiotics.

If an allergic reaction to ceftazidime develops, the drug should be withdrawn immediately; in severe cases, epinephrine, hydrocortisone, antihistamines or other emergency measures may be required.

The concomitant use of high-dose cephalosporins with nephrotoxic drugs such as aminoglycosides or potent diuretics (e.g., furosemide) may have adverse effects on renal function.

Because ceftazidime is excreted by the kidneys, in patients with renal impairment its dose should be reduced according to the degree of renal impairment. Neurological abnormalities have been reported in patients with renal impairment when the dose has not been reduced (see sections “Dosage and administration” and “Side effects”).

Cases of pseudomembranous colitis have been described when using antibiotics, the severity of which may vary from mild to life-threatening. Therefore, it is important to consider the possibility of pseudomembranous colitis in patients with diarrhea during or after antibiotic use. If the diarrhea is prolonged or severe, or if the patient experiences abdominal cramps, treatment should be stopped immediately and the patient should be examined. Drugs that inhibit intestinal peristalsis are contraindicated.

Long-term use of broad-spectrum antibiotics, including ceftazidime, may lead to increased growth of insensitive microorganisms (mainly of the genera Candida and Enterococcus), which may require discontinuation of treatment or appropriate therapy. The patient’s condition should be constantly evaluated during treatment.

As with other broad-spectrum cephalosporins and penicillins, when using ceftazidime some initially sensitive strains of Enterobacter spp. and Serratia spp. may develop resistance, so periodic antibiotic sensitivity testing should be performed when treating infections caused by these microorganisms.

Ceftazidime does not affect the results of glucose determination in urine by enzymatic methods, but may cause a slight distortion of the results of tests based on copper reduction (Benedict, Fehling, Clinist).

Ceftazidime does not affect the quantitative determination of creatinine by the alkaline-PCR method.

Impact on driving and operating machinery

As the drug may cause dizziness, patients should be warned about precautions when driving or operating moving machinery.

Synopsis

Contraindications

Cautions

With caution should be used in patients with impaired renal function, history of ulcerative colitis, during infancy, when combined with loop diuretics and aminoglycosides.

Side effects

The undesirable reactions presented below are listed according to organ and organ system involvement and frequency of occurrence. The frequency of occurrence appears as follows: very common (≥ 1/10), frequent (≥ 1/100 to < 1/10), infrequent (

≥ 1/1000 to < 1/100), frequent(≥ 1/10000 to < 1/1000), very rare(< 1/10000, including individual cases). Frequency categories were formed based on clinical studies of the drug and post-registration surveillance.

Frequency of adverse reactions

Infectious and parasitic diseases

Infrequent: candidiasis (including vaginitis and oral candidiasis).

Blood and lymphatic system disorders

Often: eosinophilia, thrombocytosis. Infrequent: leukopenia, neutropenia and thrombocytopenia. Very rare: lymphocytosis, hemolytic anemia, agranulocytosis.

Disorders of the immune system

Very rare: anaphylactic reactions (including bronchospasm and/or decreased blood pressure).

Nervous system disorders

Infrequent: headache and dizziness. Very rare: paresthesia.

There have been reported cases of neurologic disorders such as tremors, myoclonias, seizures, encephalopathy, and coma in patients with impaired renal function when the dose of ceftazidime is not reduced sufficiently.

Vascular disorders

Often: phlebitis or thrombophlebitis when administered intravenously.

Gastrointestinal tract disorders

Often: diarrhea. Infrequent: nausea, vomiting, abdominal pain and colitis. Very rare: bad taste in the mouth.

Colitis may be caused by Clostridium difficile and may manifest as pseudomembranous colitis (see section “Special Precautions”).

Liver and biliary tract disorders

Often: transient elevation of one or more “hepatic” enzymes: alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gammaglutamyl transpeptidase (GGTP) and alkaline phosphatase (ALP). Very rare: jaundice.

Skin and subcutaneous tissue disorders

Often: patchy-papular rash or urticaria. Infrequent: itching. Very rare: angioedema, erythema multiforme, Stephen-Johnson syndrome and toxic epidermal necrolysis.

Renal and urinary tract disorders

very rarely: interstitial nephritis, acute renal failure.

General reactions and reactions at the site of administration

Often: pain and/or inflammation after intramuscular injection. Infrequent: fever.

Laboratory and instrumental findings

Often: positive direct Coombs reaction. Infrequent: transient increase in blood urea, urea nitrogen and/or serum creatinine concentrations.

Positive Coombs reaction is observed in about 5% of patients, and corresponding changes in laboratory blood values may be observed.

Overdose

Symptoms

Overdose may lead to neurological disorders with the development of ncephalopathy, seizures and coma.

Treatment

The plasma content of ceftazidime can be reduced by hemodialysis or peritoneal dialysis. Symptomatic therapy.

Pregnancy use

Pregnancy

There is no evidence of embryotoxic or teratogenic effects of ceftazidime, but ceftazidime should be used with caution in women during the first months of pregnancy. If it is necessary to use ceftazidime in pregnancy, the expected benefit to the mother should be weighed against the potential risk to the fetus.

Breastfeeding

Ceftazidime is excreted with the breast milk in small amounts; therefore, caution should be exercised when using the drug in lactating women. In case of adverse effects in breastfed children it is necessary to stop breastfeeding.

Similarities