SPECTRAZID (Ceftazidime For Injection IP)

Ceftazidime is a semi-synthetic, broad-spectrum bactericidal cephalosporin for parenteral administration.
Parenteral administration produces high and prolonged serum levels, and has a half-life of about 2 hours. About 10% of the drug is bound to the serum proteins.

After IM administration of 500mg and 1gm, peak levels of 18 and 37 mg/I respectively are achieved rapidly. After 5 minutes of IV bolus injection of 500mg or 1 g serum levels achieved are 46 and 87 mg/I respectively.

Therapeutically effective concentrations are still present in the serum 8-12 hours after either IV or IM administration.

Ceftazidime is not metabolized in the body and is excreted unchanged, in active form into the urine by glomerular filteration; approximately 80-90% of the dose is recovered in the urine within 24 hours. Elimination of Ceftazidime is decreased in patients with impaired renal function and the dose should be reduced. See section on renal impairment.

Less than 1% excreted via the bile, which limits the amount entering the bowel.

Concentrations in excess of the MIC for common pathogens can be achieved in tissues such as bone, heart, bile, sputum and fluids such as aqueous humor, synovial, pleural and peritoneal fluids.

Ceftazidime crosses the placenta readily, and is excreted in the breast milk. Penetration of the intact blood-brain barrier is poor resulting in low levels of ceftazidime in the CSF in the absence of inflammation. However, therapeutic levels of 4-20 mg/I or more are achieved in the CSF when the meninges are inflamed.

It is active against a wide range of Gram-positive and Gram negative bacteria including many betalactamase producing strains.

It is indicated for the treatment of single of multiple infections caused by susceptible organisms.

It may be used alone as first choice drug before the results of sensitivity tests are available.

Ceftazidime can be used in combination with an aminoglycoside or most other beta-lactam antibiotics may be used with antibiotic against anaerobes such as metronidazole when the presence of Bacteroides fragilis is suspected.

In vitro, ceftazidime and aminoglycosides in combination exert additive effect with evidence of synergy against some strains.

Ceftazidime is active in vitro against the following organisms:

Gram-positive aerobes:
Staphylococcus aureus ( methicillin-sensitive strains), Staphylococcus epidermidis (methicillin-sensitive strains), Micrococcus spp, Streptococcus pyogenes (Group A beta-haemolytic Streptococci), Streptococcus Group B (Strep agalactiae) Streptococcus pneumoniae,
Streptococcus mitis, Streptococcus Spp (excluding Strep faecalis)

Gram-negative aerobes:
E coli, Klebsiella spp. (including Klebsiella pneumoniae), Proteus mirabilis, Proteus vulgaris, Morganella morganii (formerly Proteus morganii), Proteus rettgeri, Pseudomonas spp (including Ps aeruginosa), Providencia spp, Enteroacter spp, Citrobacter spp, Serratia spp, Salmonella spp, Shigella spp, Yersinia enterocolitica, Pasteurella multocida, Acinetobacter spp, Neisseria gonorrhoeae, Neisseria meningitides, Haemophilus influenzae (including ampicillin resistant strains), Haemophilus parainfuluenzae (including ampicillin resistant strains).

Anaerobic strains:
Peptococcus spp., Peptostreptococcus spp., Streptococcus spp., Propionibacterium spp., Clostridium perfringens, and Fusobacterium spp., Bacteroides spp. (many strains of Bact. Tragilis resistant).
Ceftazidime is not active in vitro against methicillin-resistant Staphylococci, Streptococcus faecalis and many other Enterococci, Listeria monocytogenes, Campylobacter spp. or Clostridium difficile.

Composition:
Each vial contains:
Ceftazidime IP (sterile) as ceftazidime pentahydrate
Equivalent to ceftazidime 250 mg/1000 mg

Indications:
Severe infections:
Such as septicemia, bacteremia, peritonitis, meningitis, infections in immuno compromised patients, infected burns and infections in patients in intensive care unit e.g., Nosocomial infections.

Respiratory tract infections.

Ear, nose and throat infections.

Urinary tract infections, Skin and soft tissue infections. Gastrointestinal, biliary and abdominal infections, Bone and joint infections.

Infections associated with haemo-and peritoneal dialysis and with continuous ambulatory peritoneal dialysis (CAPD).

Prophylaxis: High risk and potentially contaminated surgery

Contra-Indications, Precautions and Warning:
Ceftazidime is contra-indicated in patients with known hypersensitivity to cephalosporin antibiotics.

Before beginning treatment establish whether the patients has a history of hypersensitivity reactions to ceftazidime, cephalosporins, penicillins, or other drugs. Special caution is necessary when giving ceftazidime to patients who have shown type 1 or immediate hypersensitivity reactions to penicillin. If an allergic reaction to ceftazidime occurs, discontinue the drug. Serious hypersensitivity reactions may require epinephrine (adrenaline), hydrocortisone, antihistamine or other emergency measures.

Concurrent treatment with high doses of cephalosporins and nephrotoxic drugs such as aminoglycosides or potent diuretics (e.g. frusemide) may adversely affect renal function. Clinical experience with ceftazidime has shown that this is not likely to be a problem at the recommended dose levels. There is no evidence that ceftazidime adversely affects renal function at normal therapeutic doses.

Ceftazidime is eliminated via the kidneys, therefore, the dosage should be reduced according to the degree of renal impairment. Neurological sequelae have occasionally been reported when the dose has not been reduced appropriately (See Dosage in impaired Renal Function).

Pregnancy and lactation:
There is no experimental evidence of embryopathic or teratogenci effects, but as with all drugs, ceftazidime should be administered with caution during the early months of pregnancy and early infancy.

Ceftazidime is excreted in human milk in small quantities and should be used with caution in nursing mothers.

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

Ceftazidime does not interfere in the alkaline picrate assay for creatinine.

With ceftazidime positive Commbs' test develops in about 5% of patients and may interfere with blood cross-matching.

As with the other broad spectrum antibiotics, prolonged use of ceftazidime may result in the overgrowth on non-susceptible organisms (g.g., Candida, Enterococci) which may require stopping of treatment of appropriate measures. Repeated evaluation of patient's condition is essential.

Chloramphenicol is antagonistic in vitro to ceftazidime and other cephalosporins. The clinical relevance of this finding is unknown,but if concurrent administration of ceftazidime with chloramphenicol is proposed, the possibility of antagonism should be considered.

Side Effects:
Ceftazidime is generally well tolerated. Some of the side effects are as follows:

Local:
Phlebitis or thrombophlebitis with IV administration; pain and/or inflammation after IM injection.

Hypersensitivity:
Maculopapular or urticarial rash, fever pruritus and very rarely angioedema and anaphylaxis (bronchospasm and / or hypotension) have been reported

Gastrointestinal:
Diarrhoea, nausea, vomiting, a bdominal pain, and very rarely oral thrush or colitis. As with other cephalosporins, colitis may be associated with Clostridium difficile and may present as pseudomembranous colitis.

Genito-urinary:
Candidiasis, vaginits.

Central Nervous System:
headache, dizziness, paraesthesia and bad taste. There have been reports of neurological sequelae including tremor, convulsions and encephalopathy in patients with renal impairment in whom the dose of ceftazidime has not been appropriately reduced.

Laboratory test changes:
Transient changes noted during ceftazidime therapy include; eosinophilia, positive Coombs test without haemolysis, thrombocytosis and slight elevatioins in one or more of the hepatic enzymes.
ALT (SGPT),AST (SGOT), LDH, GGT and alkaline phosphatase.
As with some other cephalosporins, transient elevations of blood urea, blood urea nitrogen and / or serum creatinine have been observed occasionally very rarely, leucopenia, neutropenia, agranulocytosis, thrombocytopenia and lymphocytosis have been reported.

Dosage:
Dosage varies with the severity, sensitivity, site and type of infection, pathogen and upon the age and status of renal function of the patient.

Adults:
1-6 g/day in 2 or 3 divided doses by IV or IM injection, Urinary tract and less severe infections- 500mg or 1 g every 12 hours.
Most infections - 1 g every 8 hours or 2 g every 12 hours. Very severe infections particularly in immunocompromised patients including those with neutropenia- 2g every 8 or 12 hours.

Fibrocystic adults with Pseudomonal lung infections - 100 to 150 mg/kg/day in 3 divided doses.

In adults with normal renal function upto 9 g/day has been used without ill-effects.

When used as a prophylactic agent in surgery 1 g should be given at the time of induction of anaesthesia. A second dose should be considered during surgery or post-operatively as required.

Dosage in children:
The usual dosage range for children aged over two months is 30 - 100 mg/kg/day in 2 or 3 divided doses.
Doses up to 150mg/kg/day (maximum 6g/day) in three divided doses may be given to infected immunocompromised or fibrocystic children or children with meningitis.

Neonates (0-2 months)
25-60 mg/kg/day in 2 divided doses.
In neonates the serum half-life of ceftazidime can be 3-4 times that in adults.

Use in elderly:
In view of the reduced clearance of ceftazidime.
In acutely ill elderly patients, the daily dosage should not normally exceed 3g, especially in those over 80 years of age.

Dosage in impaired renal function:
Ceftazidime is excreted unchanged through the kidneys, therefore, in patients with impaired renal function the dosage should be adjusted. An initial loading dose of 1 gm should be given. Maintenance dose should be based on GFR:


Recommended Unit dose of Ceftazidime in renal insufficiency:

Creatinine Clearance ml/min	Approximate Serum Creatinine mcmol/I (mg/dl)	Recommended unit dose of ceftazidime	Recommended unit dose of ceftazidime
	>50 <150	1.0 g	Normal Dosage
50–31	150–200 (1,7–2.3)	1.0 g	12 hours
50–31	150–200 (1,7–2.3)	1.0 g	12 hours
30–16	200–350 (2,3–4.0)	1.0 g	24 hours
15–6	350–500 (4.0–5.6)	0.5 g	24 hours
<5	>500 (>5.6)	0.5 g	48 hours

In patients with severe infections the unit dose should be increased by 50% of the dosing frequency. In such patients the ceftazidime serum levels should be monitored and trough levels should not exceed 40 mg/l.

In children the creatinine clearance should be adjusted for body surface area or lean body mass.

Haemodialysis:
The serum half-life during haemodialysis ranges from 3 to 5 hours. Following each haemodialysis period the maintenance dose of ceftazidime recommended in the above table should be repeated.

Dosage in peritoneal dialysis:
Ceftazidime may be used in peritoneal dialysis and continuous ambulatory peritoneal dialysis (CAPD). In addition to intravenous use, ceftazidime can be incorporated into the dialysis fluid (usually 125 to 350 mg for 2 litres of dialysis solution).

Administration:
Use intravenously or by deep intramuscular injectin. Recommended IM injection sites are the upper outer quadrant of the gluteus maximus or lateral part of the thigh.

Overdosage:
Overdose lead to neurological sequelae including encephalopathy, convulsions and coma. Haemodialysis or peritoneal dialysis can reduce serum levels of ceftazidime.

Constitution instructions:
All sizes of vials are supplied under reduced pressure. As the product dissolves, carbon dioxide is released and a positive pressure develops. Small bubbles of carbon dioxide in the constituted solution may be ignored.

Table: Preparation of Solution

Vial Size	Amount of Diluent to be added (ml)	Approximate Concentration (mg/ml)
250 mg intramuscular	1.0 ml	210
250 mg intravenous	2.5 ml	90
500 mg intramuscular	1.5 ml	260
500 mg intravenous	5 ml	90
1 g intramuscular	3 ml	260
1 g intravenous bolus	10 ml	90
1 g intravenous infusion	50 ml	20

Note: Addition should be in two stages (see text).

Ceftazidime solutions may be given directly into the vein or through the tubing of an infusion set if the patient is receiving parenteral fluids.

Ceftazidime is compatible with most commonly used intravenous fluids.

Preparation of solution of IM / IV bolus injection

1. Remove the plastic seal and insert the syringe needle through the vial plug and inject the
   recommended volume of diluent.
2. Withdraw the needle and shake the vial to make a clear solution.
   
3. Inver the vial, with the syringe piston fully depressed insert the needle into the solution.
   Withdraw the total volume of solution into the syringe ensuring that the needle remains in the solution.
   Small bubbles of carbon dioxide may be disregarded.

Preparation of solution of IV infusion:

1. Remove the plastic seal and insert the syringe needle through the vial plug and inject 10 ml. of diluent.
2. Withdraw the needle and shake the vial to make a clear solution.
3. Insert a sterile gas relief needle through the vial closure to relieve the internal pressure.
4. With the gas relief in place add the reminder of the diluent. Remove both the gas relief and syringe needles, shake the vial and set up for infusion use in the normal way.
   
   Note: To preserve product sterility, it is important that the gas relief needle is not inserted through the vial closure before the product has dissolved.

Compatibility

Ceftazidime is compatible with most commonly used intravenous fluids.

Ceftazidime is less stable in Sodium Bicarbonate Injection than in other intravenous fluids. Hence it is not recommended as a diluent.

Ceftazidime and aminoglycosides should not be mixed in the same infusion set or syringe.

Precipitation has been reported when vancomycin has been added to ceftazidime in solution. Therefore, it would be prudent to flush infusion sets and intravenous lines between administration of these two agents.

Solution colour may range from light yellow to amber depending on concentration, diluent and storage conditions used. Within the stated recommendations, product potency is not adversely affected by such colour variations.

Ceftazidime at concentrations between 1 mg/ml and 40 mg/ml is compatible with :

0.9% Sodium Chloride Injection

M/6 Sodium Lactate Injection

Compound Sodium Lactate Injection (Hartmann's Solution) 5% Dextrose Injection

0.225% Sodium Chloride and 5% Dextrose Injection

0.45% Sodium Chloride and 5% Dextrose Injection

0.9% Sodium Chloride and 5% Dextrose Injection

10% Dextrose Injection

Dextran 40 Injection 10% in 0.9% Sodium Chloride Injection

Dextran 40 Injection 10% in 5% Dextrose Injection

Dextran 70 Injection 6% in 0.9% Sodium Chloride Injection

Dextran 70 Injection 6% in 5% Dextrose injection

Ceftazidime at concentrations between 0.05 mg/ml and 0.25 mg/ml is compatible with intra-peritoneal Dialysis Fluid (Lactate).

Ceftazidime may be constituted for intramuscular use with 0.5% or 1% Lignocaine Hydrochloride Injection.

Both components retain satisfactory potency when ceftazidime at 4 mg/ml is admixed with:

Hydrocortisone (hydrocortisone sodium phosphate) 1 mg/ml in 0.9% sodium chloride injection or 5% Dextrose injection

Cefuroxime (Cefuroxime sodium)

3 mg/ml in 0.9% sodium chloride injection

Cloxacillin (CloxacillinSodium) 4 mg/ml in 0.9% sodium chloride injection

Heparin 10 IU / ml or 50 IU / ml in 0.9% sodium chloride injection

Potassium chloride 10 m Eq/I or 40 mEq/I in 0.9% sodium chloride injection.

Storage:
Vials of Ceftazidime for injection are supplied under reduced pressure. A positive pressure is produced on constitution due to the release of carbon dioxide. Vials of Spectrazid for injection should be stored at a temperature below 25°C. Occasional storage at temperatures not higher than 30°C for upto 2 months is detrimental to the product.

Protect unconstituted vials from light.

Reconstituted solution should be used within 5 hours of preparation if stored at a temperature below 25°C or within 48 hours if stored between 2°C and 8°C.

Presentation:
Spectrazid injection is available in pack size of 250 mg and 1000 mg with solvent