Keftam

Ceftazidime pentahydrate.

Each vial contains: Ceftazidime (as pentahydrate), USP 1 g.

Antibacterial.
Pharmacology: Pharmacodynamics: Mechanism of Action: Ceftazidime inhibits bacterial cell wall synthesis following attachment to penicillin binding proteins (PBPs). This results in the interruption of cell wall (peptidoglycan) biosynthesis, which leads to bacterial cell lysis and death.
PK/PD relationship: For cephalosporins, the most important pharmacokinetic-pharmacodynamic index correlating with in vivo efficacy has been shown to be the percentage of the dosing interval that the unbound concentration remains above the minimum inhibitory concentration (MIC) of ceftazidime for individual target species (i.e. %T>MIC).
Mechanism of Resistance: Bacterial resistance to ceftazidime may be due to one or more of the following mechanisms: Hydrolysis by beta-lactamases. Ceftazidime may be efficiently hydrolysed by extended spectrum beta-lactamases (ESBLs), including the SHV family of ESBLs, and AmpC enzymes that may be induced or stably derepressed in certain aerobic Gram-negative bacterial species.
Reduced affinity of penicillin-binding proteins for ceftazidime.
Outer membrane impermeability, which restricts access of ceftazidime to penicillin binding proteins in Gram-negative organisms.
Bacterial efflux pumps.
Pharmacokinetics: Absorption: After intramuscular administration of 500 mg and 1 g of ceftazidime, peak plasma levels of 18 and 37 mg/L, respectively, are achieved rapidly. Five minutes after intravenous bolus injection of 500 mg, 1 g or 2 g, plasma levels are 46, 87 and 170 mg/L, respectively. The kinetics of ceftazidime are linear within the single dose range of 0.5 to 2 g following intravenous or intramuscular dosing.
Distribution: The serum protein binding of ceftazidime is low at about 10%. Concentrations in excess of the MIC for common pathogens can be achieved in tissues such as bone, heart, bile, sputum, aqueous humour, 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, concentrations of 4 to 20 mg/L or more are achieved in the CSF when the meninges are inflamed.
Biotransformation: Ceftazidime is not metabolised.
Elimination: After parenteral administration plasma levels decrease with a half-life of about 2 h.
Ceftazidime is excreted unchanged into the urine by glomerular filtration; approximately 80 to 90% of the dose is recovered in the urine within 24 h. Less than 1% is excreted via the bile.
Special patient populations: Renal impairment: Elimination of ceftazidime is decreased in patients with impaired renal function and the dose should be reduced.
Hepatic impairment: The presence of mild to moderate hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime in individuals administered 2 g intravenously every 8 hours for 5 days, provided renal function was not impaired.
Elderly: The reduced clearance observed in elderly patients was primarily due to age-related decrease in renal clearance of ceftazidime. The mean elimination half-life ranged from 3.5 to 4 hours following single or 7 days repeat BID dosing of 2 g IV bolus injections in elderly patients 80 years or older.
Paediatric population: The half-life of ceftazidime is prolonged in preterm and term neonates by 4.5 to 7.5 hours after doses of 25 to 30 mg/kg. However, by the age of 2 months the half-life is within the range for adults.
Microbiology: Microbiological Susceptibility: The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of ceftazidime in at least some types of infections is questionable. (See Table 1.)

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Ceftazidime is indicated for the treatment of the infections listed as follows in adults and children including neonates (from birth).
Nosocomial pneumonia; Broncho-pulmonary infections in cystic fibrosis; Bacterial meningitis; Chronic suppurative otitis media; Malignant otitis externa; Complicated urinary tract infections; Complicated skin and soft tissue infections; Complicated intra-abdominal infections; Bone and joint infections; Peritonitis associated with dialysis in patients on CAPD.
Treatment of patients with bacteraemia that occurs in association with, or is suspected to be associated with any of the infections listed previously.
Ceftazidime may be used in the management of neutropenic patients with fever that is suspected to be due to a bacterial infection.
Ceftazidime may be used in the peri-operative prophylaxis of urinary tract infections for patients undergoing trans-urethral resection of the prostate (TURP).
The selection of ceftazidime should take into account its antibacterial spectrum, which is mainly restricted to aerobic Gram-negative bacteria.
Ceftazidime should be co-administered with other antibacterial agents whenever the possible range of causative bacteria would not fall within its spectrum of activity. Consideration should be given to official guidelines on the appropriate use of antibacterial agents.

Posology: see Tables 2 and 3.

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Paediatric population: The safety and efficacy of Ceftazidime administered as continuous infusion to neonates and infants ≤ 2 months has not been established.
Elderly: In view of age related reduced clearance of Ceftazidime in elderly patients, the daily dose should not normally exceed 3 g in those over 80 years of age.
Hepatic impairment: Available data do not indicate the need for dose adjustment in mild or moderate liver function impairment. There are no study data in patients with severe hepatic impairment. Close clinical monitoring for safety and efficacy is advised.
Renal impairment: Ceftazidime is excreted unchanged by the kidneys. Therefore, in patients with impaired renal function, the dosage should be reduced.
An initial loading dose of 1 g should be given. Maintenance doses should be based on creatinine clearance: see Table 4.

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In patients with severe infections the unit dose should be increased by 50% or the dosing frequency increased.
In children the creatinine clearance should be adjusted for body surface area or lean body mass. (See Table 5.)

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Close clinical monitoring for safety and efficacy is advised. (See Table 6.)

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Caution is advised in dose selection. Close clinical monitoring for safety and efficacy is advised.
Children < 40 kg: The safety and effectiveness of Ceftazidime administered as continuous infusion in renally impaired children < 40 kg has not been established. Close clinical monitoring for safety and efficacy is advised.
If continuous infusion is used in children with renal impairment, 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 h.
Following each haemodialysis period, the maintenance dose of ceftazidime recommended in the table as follows should be repeated.
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 250 mg for 2 litres of dialysis solution).
For patients in renal failure on continuous arterio-venous haemodialysis or high-flux haemofiltration in intensive therapy units: 1 g daily either as a single dose or in divided doses. For low-flux haemofiltration, follow the dose recommended under renal impairment.
For patients on veno-venous haemofiltration and veno-venous haemodialysis, follow the dosage recommendations in tables 7 & 8 as follows. (See Tables 7 and 8.)

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Method of administration: The dose depends on the severity, susceptibility, site and type of infection and on the age and renal function of the patient.
Ceftazidime should be administered by intravenous injection or infusion, or by deep intramuscular injection. Recommended intramuscular injection sites are the upper outer quadrant of the gluteus maximus or lateral part of the thigh. Ceftazidime solutions may be given directly into the vein or introduced into the tubing of a giving set if the patient is receiving parenteral fluids.
The standard recommended route of administration is by intravenous intermittent injection or intravenous continuous infusion. Intramuscular administration should only be considered when the intravenous route is not possible or less appropriate for the patient.
Directions for Reconstitution: For single use. Discard any unused contents.
Instructions for reconstitution: See table for addition volumes and solution concentrations, which may be useful when fractional doses are required.
Preparation of Solution: see Table 9.

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Solutions range from light yellow to amber depending on concentration, diluent and storage conditions used.

Overdose can lead to neurological sequelae including encephalopathy, convulsion and coma.
Symptoms of overdose can occur if the dose is not reduced appropriately in patients with renal impairment.
Serum levels of ceftazidime can be reduced by haemodialysis or peritoneal dialysis.

Hypersensitivity to the active substance, to any other cephalosporin or to any of the excipients listed.
History of severe hypersensitivity (e.g. anaphylactic reaction) to any other type of beta-lactam antibacterial agent (penicillins, monobactams and carbapenems).

Hypersensitivity: As with all beta-lactam antibacterial agents, serious and occasionally fatal hypersensitivity reactions have been reported. In case of severe hypersensitivity reactions, treatment with ceftazidime must be discontinued immediately and adequate emergency measures must be initiated.
Before beginning treatment, it should be established whether the patient has a history of severe hypersensitivity reactions to ceftazidime, to other cephalosporins or to any other type of beta-lactam agent. Caution should be used if ceftazidime is given to patients with a history of non-severe hypersensitivity to other beta-lactam agents.
Spectrum of activity: Ceftazidime has a limited spectrum of antibacterial activity. It is not suitable for use as a single agent for the treatment of some types of infections unless the pathogen is already documented and known to be susceptible or there is a very high suspicion that the most likely pathogen(s) would be suitable for treatment with ceftazidime. This particularly applies when considering the treatment of patients with bacteraemia and when treating bacterial meningitis, skin and soft tissue infections and bone and joint infections. In addition, ceftazidime is susceptible to hydrolysis by several of the extended spectrum beta lactamases (ESBLs). Therefore, information on the prevalence of ESBL producing organisms should be taken into account when selecting ceftazidime for treatment.
Pseudomembranous colitis: Antibacterial agent-associated colitis and pseudo-membranous colitis have been reported with nearly all anti-bacterial agents, including ceftazidime, and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea during or subsequent to the administration of ceftazidime. Discontinuation of therapy with ceftazidime and the administration of specific treatment for Clostridium difficile should be considered.
Medicinal products that inhibit peristalsis should not be given.
Renal function: Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (e.g. furosemide) may adversely affect renal function.
Ceftazidime is eliminated via the kidneys, therefore the dose should be reduced according to the degree of renal impairment. Patients with renal impairment should be closely monitored for both safety and efficacy. Neurological sequelae have occasionally been reported when the dose has not been reduced in patients with renal impairment.
Overgrowth of non-susceptible organisms: Prolonged use may result in the overgrowth of non-susceptible organisms (e.g. Enterococci, fungi) which may require interruption of treatment or other appropriate measures. Repeated evaluation of the patient's condition is essential.
Test and assay interactions: Ceftazidime does not interfere with enzyme-based tests for glycosuria, but slight interference (false-positive) may occur with copper reduction methods (Benedict's, Fehling's, Clinitest).
Ceftazidime does not interfere in the alkaline picrate assay for creatinine.
The development of a positive Coombs' test associated with the use of ceftazidime in about 5% of patients may interfere with the cross-matching of blood.
Sodium content: This medicinal product contains 52 mg sodium per 1 g vial, equivalent to 2.6% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Pregnancy: There are limited amounts of data from the use of ceftazidime in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.
Ceftazidime should be prescribed to pregnant woman only if the benefit outweighs the risk.
Lactation: Ceftazidime is excreted in human milk in small quantities but at therapeutic doses of ceftazidime no effects on the breast-fed infant are anticipated. Ceftazidime can be used during breast-feeding.

The most common adverse reactions are eosinophilia, thrombocytosis, phlebitis or thrombophlebitis with intravenous administration, diarrhoea, transient increases in hepatic enzymes, maculopapular or urticarial rash, pain and/or inflammation following intramuscular injection and positive Coomb's test.
Data from sponsored and un-sponsored clinical trials have been used to determine the frequency of common and uncommon undesirable effects. The frequencies assigned to all other undesirable effects were mainly determined using post-marketing data and refer to a reporting rate rather than a true frequency. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The following convention has been used for the classification of frequency: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000); Unknown (cannot be estimated from the available data). (See Table 10.)

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Interaction studies have only been conducted with probenecid and furosemide.
Concurrent use of high doses with nephrotoxic medicinal products may adversely affect renal function. Chloramphenicol is antagonistic in vitro with 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.

Store at temperatures not exceeding 30°C.

Cephalosporins

J01DD02 - ceftazidime ; Belongs to the class of third-generation cephalosporins. Used in the systemic treatment of infections.

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