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Drug Description

Presentation

Indications

Kefadim is indicated in the treatment of the following infections when due to susceptible micro- organisms:

Lower respiratory tract infections

Skin and soft tissue infections

Bone and joint infections

Urinary tract infections

Gynaecological infections

Intra-abdominal infections, including peritonitis

Septicaemia

Central nervous system infections, including meningitis. In meningitis, it is recommended that the results of a sensitivity test are known before treatment with ceftazidime as a single agent.

Kefadim may be used alone in cases of confirmed or suspected sepsis. It may also be used concomitantly with other antibiotics, such as aminoglycosides, in severe and life-threatening infections and in the immunocompromised patient.

Adult Dosage

Ceftazidime may be given intravenously or by deep intramuscular injection into a large muscle mass (such as the upper outer quadrant of the gluteus maximus, or lateral part of the thigh).

The guidelines for dosage of Kefadim are listed in Table 1.

Table 1: Recommended Dosage Schedule for Kefadim

*Although clinical improvement has been shown, complete eradication of infecting organisms cannot be expected in patients with chronic respiratory disease and cystic fibrosis.

**The higher dose should be reserved for immunocompromised children or children with cystic fibrosis or meningitis.

Adults and the elderly: The usual dosage range for ceftazidime is 500mg to 2g every eight to twelve hours. The dosage and route of administration should be determined by the susceptibility of the causative organisms, the severity of infection, and the condition and renal function of the patient.

In view of the reduced clearance of ceftazidime in acutely ill elderly patients, the daily dosage should not normally exceed 2g, especially in those over 80 years of age (Table 2).

Infants and children over 2 months of age: The dosage range is 50-150mg/kg/day IV, in three divided doses, with a maximum of 6g/day. The higher dose should be reserved for immunocompromised children, or children with cystic fibrosis or meningitis.

Neonates and children up to 2 months of age: The dosage range is 25 to 60mg/kg/day, given as two divided doses. In the neonate, the serum half-life of ceftazidime can be three to four times that in adults.

Dosage in impaired renal function: Ceftazidime is excreted by the kidneys, almost exclusively by glomerular filtration. Therefore, in patients with impaired renal function (GFR <50ml/min), it is recommended that the dose of ceftazidime should be reduced to compensate for its slower excretion. In patients with suspected renal insufficiency, an initial loading dose of 1g may be given. An estimate of GFR should be made to determine the appropriate maintenance dose. The recommended dosage is shown in Table 2.

Table 2: Recommended Maintenance Dosage of Kefadim in Patients with Renal Insufficiency

When only serum creatinine is available, the following formula (Cockcroft's equation) may be used to estimate creatinine clearance. The serum creatinine should represent a steady state of renal function:

Males:

Females:

0.85 x above value

In patients with severe infections who would normally receive 6g of Kefadim daily, were it not for renal insufficiency, the dose in Table 2 may be increased by 50% or the dosing frequency increased appropriately. Continued dosage should be determined by further monitoring of creatinine clearance, severity of the infection, and susceptibility of the causative organism. In such patients, it is recommended that ceftazidime serum levels should be monitored and trough levels should not exceed 40mg/litre.

In children, as for adults, the creatinine clearance should be adjusted for body surface area or lean body mass and the dosing frequency reduced in cases of renal insufficiency.

The serum half-life of ceftazidime during haemodialysis ranges from 3 to 5 hours.

In patients undergoing haemodialysis, a loading dose of 1g of Kefadim is recommended, followed by 1g after each haemodialysis period. Kefadim can also be used in patients undergoing intraperitoneal and continuous ambulatory peritoneal dialysis (CAPD). In such patients, a loading dose of 1g of Kefadim may be given, followed by 500mg every 24 hours. In addition to intravenous use, Kefadim can be incorporated in the dialysis fluid at a concentration of 250mg for 2 litres of dialysis fluid.

NOTE: Kefadim should generally be continued for 2 days after the signs and symptoms of infection have disappeared, however, in complicated infections, longer therapy may be required.

Intramuscular administration: Kefadim should be reconstituted with Water for Injections PhEur or 0.5% or 1% Lignocaine Hydrochloride Injection BP. Refer to Table 3

Table 3:Preparation of Solutions of Kefadim

*Note: Addition should be in 2 stages (see 'Instructions for reconstitution' below).

Intravenous administration: For direct intermittent intravenous administration, reconstitute Kefadim with Water for Injections PhEur (see Table 3). Slowly inject the solution directly into the vein over a period of 3 to 5 minutes or give through the tubing of a giving set. Ceftazidime is compatible with the most commonly used intravenous fluids.

For intravenous infusion, reconstitute the 2g infusion (100ml) vial with 100ml Water for Injections PhEur or one of the compatible intravenous fluids. Alternatively, reconstitute the 500mg, 1g or 2g vial and add an appropriate quantity of the resulting solution to an IV container with one of the compatible intravenous fluids.

Intermittent intravenous infusion with a Y-type giving set can be accomplished with compatible solutions. However, during infusion of a solution containing ceftazidime, it is desirable to discontinue the other solution.

When Kefadim is dissolved, carbon dioxide is released and a positive pressure develops. For ease of use, please follow the recommended techniques of reconstitution described below.

Instructions for reconstitution:

For 500mg im/IV, 1g im/IV and 2g IV vials

1. Inject the diluent and shake well to dissolve. The vials may contain a vacuum to assist injection of the diluent.

2. Carbon dioxide is released as the antibiotic dissolves, generating pressure within the vial. The solution will become clear within 1 to 2 minutes.

3. Invert the vial and completely depress the syringe plunger prior to insertion.

4. Insert the needle through the vial stopper. Be sure the needle remains within the solution and withdraw contents of the vial in the usual manner. Pressure in the vial may aid withdrawal.

5. The withdrawn solution may contain carbon dioxide bubbles, which should be expelled from the syringe before injection.

For 2g infusion vials

1. Inject 10ml of the diluent and shake to dissolve. The vials may contain a vacuum to assist injection of the diluent.

2. Carbon dioxide is released as the antibiotic dissolves, generating pressure within the vial. The solution will become clear within 1 to 2 minutes.

3. Insert a vent needle to release pressure before adding additional diluent to the vial. Add diluent and then remove the vent needle.

4. Additional pressure that may develop in the vial, especially after storage, should be relieved prior to administration to the patient.

NOTE: To preserve product sterility, it is important that a gas relief needle is not inserted through the vial closure before the product has dissolved.

Child Dosage

Contra Indications

Ceftazidime is contra-indicated in patients with known hypersensitivity to ceftazidime or cephalosporin antibiotics.

Special Precautions

Warnings

Before therapy with ceftazidime is instituted, careful inquiry should be made to determine whether the patient has had previous hypersensitivity reactions to ceftazidime, cephalosporins, penicillins, or other drugs. Ceftazidime should be given only with special caution to patients with type 1 or immediate hypersensitivity reactions to penicillin. If an allergic reaction to ceftazidime occurs, discontinue the drug. Serious acute hypersensitivity reactions may require epinephrine (adrenaline), hydrocortisone, antihistamine, or other emergency measures.

Pseudomembranous colitis has been reported with the use of ceftazidime, other cephalosporins and virtually all broad-spectrum antibiotics, therefore, it is important to consider its diagnosis in patients who develop diarrhoea in association with antibiotic use. Such colitis may range in severity from mild to life-threatening. Symptoms can appear during or after treatment.

Mild cases of pseudomembranous colitis usually respond to drug discontinuance alone. In moderate to severe cases, appropriate measures should be taken.

Precautions

Kefadim has not been shown to be nephrotoxic, however, because high and prolonged serum antibiotic concentrations can occur from usual doses in patients with transient or persistent reduction of urinary output because of renal insufficiency, the total daily dosage should be reduced when ceftazidime is administered to such patients to avoid the clinical consequences, eg, seizures due to elevated levels of antibiotics. Continued dosage should be determined by degree of renal impairment, severity of infection and susceptibility of causative organisms.

As with other antibiotics, prolonged use of Kefadim may result in the overgrowth of non-susceptible organisms. Repeated evaluation of the patient's condition is essential. If superinfection occurs during therapy, appropriate measures should be taken.

Kefadim should be used with caution in individuals with a history of gastro-intestinal disease, particularly colitis.

Ceftazidime does not interfere with enzyme-based tests for glycosuria. Slight interference with copper reduction methods (Benedict's, Fehling's, Clinitest) may be observed.

Interactions

Nephrotoxicity has been reported following concomitant administration of cephalosporins and aminoglycoside antibiotics or potent diuretics, such as furosemide (frusemide). Renal function should be carefully monitored, especially if higher dosages of the aminoglycosides are to be administered or if therapy is prolonged, because of the potential nephrotoxicity and ototoxicity of aminoglycoside antibiotics. Nephrotoxicity and ototoxicity were not noted when Kefadim was given alone in clinical trials.

Adverse Reactions

The most common side-effects were local reactions following intravenous injection and allergic and gastro-intestinal reactions.

Local effects: Phlebitis or thrombophlebitis, and inflammation at the site of injection.

Hypersensitivity: Pruritus, urticarial rash, fever and very rarely angioedema and anaphylaxis (bronchospasm and/or hypotension).

Skin and subcutaneous tissue disorders: As with other cephalosporins, there have been rare reports of toxic epidermal necrolysis reported in association with ceftazidime.

Gastro-intestinal: Diarrhoea, nausea, vomiting and abdominal pain, pseudomembranous colitis. Very rarely, oral thrush.

Central nervous system: Headache, dizziness, paraesthesias and bad taste. There have been reports of neurological sequelae, including tremor, myoclonica, convulsions and encephalopathy, in patients with renal impairment in whom the dose of ceftazidime has not been appropriately reduced.

Reproductive system disorder: Candidiasis and vaginitis.

Laboratory test changes (usually transient): Eosinophilia, positive Coombs' test without haemolysis, thrombocytosis and slight elevations in one or more hepatic enzymes: AST (SGOT), ALT (SGPT), LDH, GGT and alkaline phosphatase. Transient elevations of blood urea, blood urea nitrogen and/or serum creatinine have been observed occasionally. Transient leucopenia, neutropenia, agranulocytosis, thrombocytopenia and lymphocytosis have been seen very rarely.

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