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Tazicef (Ceftazidime Pentahydrate) - Description and Clinical Pharmacology

 
 



PRESCRIBING INFORMATION
TAZICEF®
brand of
ceftazidime for injection, USP

To reduce the development of drug-resistant bacteria and maintain the effectiveness of Tazicef (ceftazidime) and other antibacterial drugs, Tazicef (ceftazidime) should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.

DESCRIPTION

Ceftazidime is a semisynthetic, broad-spectrum, beta-lactam antibiotic for parenteral administration. It is the pentahydrate of pyridinium, 1-[[7-[[(2-amino-4-thiazolyl)[(1-carboxy-1-methyl-ethoxy) imino]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo (4.2.0.)oct-2-en-3-yl] methyl]-,hydroxide, inner salt, [6R-[6α,7β(Z)]]. It has the following structure:

The molecular formula is C22H32N6O12S2, representing a molecular weight of 636.6.

Tazicef (ceftazidime for injection, USP) is a sterile, dry, powdered mixture of ceftazidime pentahydrate and sodium carbonate. The sodium carbonate at a concentration of 118 mg/gram of ceftazidime activity has been admixed to facilitate dissolution. The total sodium content of the mixture is approximately 54 mg (2.3 mEq)/gram of ceftazidime activity. Solutions of Tazicef range in color from light yellow to amber, depending on the diluent and volume used. The pH of freshly reconstituted solutions usually ranges from 5.0 to 7.5.

Tazicef is available in a 6 gram Pharmacy Bulk Package. The contents of this Pharmacy Bulk Package are intended for use by a pharmacy admixture service for addition to suitable parenteral fluids in the preparation of admixtures for intravenous infusion. FURTHER DILUTION IS REQUIRED BEFORE USE.

CLINICAL PHARMACOLOGY

This drug product can be administered intramuscularly, intraperitoneally or by direct intravenous infusion. HOWEVER THE INTENT OF THIS PHARMACY BULK PACKAGE IS FOR THE PREPARATION OF SOLUTIONS FOR INTRAVENOUS INFUSION ONLY.

After IV administration of 500-mg and 1-gram doses of ceftazidime over 5 minutes to normal adult male volunteers, mean peak serum concentrations of 45 mcg/mL and 90 mcg/mL, respectively, were achieved. After IV infusion of 500-mg, 1-gram and 2-gram doses of ceftazidime over 20 to 30 minutes to normal adult male volunteers, mean peak serum concentrations of 42 mcg/mL, 69 mcg/mL and 170 mcg/mL, respectively, were achieved. The average serum concentrations following IV infusion of 500-mg, 1-gram and 2-gram doses to these volunteers over an 8-hour interval are given in Table 1.

Table 1

Ceftazidime

Serum Concentrations (mcg/mL)

IV Dosage

0.5 hr.

1 hr.

2 hr.

4 hr.

8 hr.

500 mg

42

25

12

6

2

1 gram

60

39

23

11

3

2 grams

129

75

42

13

5

The absorption and elimination of ceftazidime were directly proportional to the size of the dose. The half-life following IV administration was approximately 1.9 hours. Less than 10% of ceftazidime was protein bound. The degree of protein binding was independent of concentration. There was no evidence of accumulation of ceftazidime in the serum in individuals with normal renal function following multiple IV doses of 1 gram and 2 grams every 8 hours for 10 days.

Following IM administration of 500-mg and 1-gram doses of ceftazidime to normal adult volunteers, the mean peak serum concentrations were 17 mcg/mL and 39 mcg/mL, respectively, at approximately 1 hour. Serum concentrations remained above 4 mcg/mL for 6 and 8 hours after the IM administration of 500-mg and 1-gram doses, respectively. The half-life of ceftazidime in these volunteers was approximately 2 hours.

The presence of hepatic dysfunction had no effect on the pharmacokinetics of ceftazidime in individuals administered 2 grams intravenously every 8 hours for 5 days. Therefore, a dosage adjustment from the normal recommended dosage is not required for patients with hepatic dysfunction, provided renal function is not impaired.

Approximately 80% to 90% of an IM or IV dose of ceftazidime is excreted unchanged by the kidneys over a 24-hour period. After the IV administration of single 500-mg or 1-gram doses, approximately 50% of the dose appeared in the urine in the first 2 hours. An additional 20% was excreted between 2 and 4 hours after dosing, and approximately another 12% of the dose appeared in the urine between 4 and 8 hours later. The elimination of ceftazidime by the kidneys resulted in high therapeutic concentrations in the urine.

The mean renal clearance of ceftazidime was approximately 100 mL/min. The calculated plasma clearance of approximately 115 mL/min. indicated nearly complete elimination of ceftazidime by the renal route. Administration of probenecid before dosing had no effect on the elimination kinetics of ceftazidime. This suggested that ceftazidime is eliminated by glomerular filtration and is not actively secreted by renal tubular mechanisms.

Since ceftazidime is eliminated almost solely by the kidneys, its serum half-life is significantly prolonged in patients with impaired renal function. Consequently, dosage adjustments in such patients as described in the DOSAGE AND ADMINISTRATION section are suggested.

Therapeutic concentrations of ceftazidime are achieved in the following body tissues and fluids.

Table 2. Ceftazidime Concentrations in Body Tissues and Fluids

Tissue or

Fluid

Dose/

Route

No.

Patients

Time of

Sample

Post-Dose

Average

Tissue or

Fluid

Level

(mcg/mL or mcg/g)

Urine

500 mg IM

6

0 to 2 hours

2,100.0

2 grams IV

6

0 to 2 hours

12,000.0

Bile

2 grams IV

3

90 min.

36.4

Synovial fluid

2 grams IV

13

2 hours

25.6

Peritoneal fluid

2 grams IV

8

2 hours

48.6

Sputum

1 gram IV

8

1 hour

9.0

Cerebrospinal

fluid (inflamed

2 grams q8h IV

5

120 min.

9.8

meninges)

2 grams q8h IV

6

180 min.

9.4

Aqueous humor

2 grams IV

13

1 to 3 hours

11.0

Blister fluid

1 gram IV

7

2 to 3 hours

19.7

Lymphatic fluid

1 gram IV

7

2 to 3 hours

23.4

Bone

2 grams IV

8

0.67 hour

31.1

Heart muscle

2 grams IV

35

30 to 280 min.

12.7

Skin

2 grams IV

22

30 to 180 min.

6.6

Skeletal muscle

2 grams IV

35

30 to 280 min.

9.4

Myometrium

2 grams IV

31

1 to 2 hours

18.7

Microbiology: Ceftazidime is bactericidal in action, exerting its effect by inhibition of enzymes responsible for cell-wall synthesis. A wide range of gram-negative organisms is susceptible to ceftazidime in vitro , including strains resistant to gentamicin and other aminoglycosides. In addition, ceftazidime has been shown to be active against gram-positive organisms. It is highly stable to most clinically important beta-lactamases, plasmid or chromosomal, which are produced by both gram-negative and gram-positive organisms and, consequently, is active against many strains resistant to ampicillin and other cephalosporins.

Ceftazidime has been shown to be active against the following organisms both in vitro and in clinical infections (see INDICATIONS AND USAGE).

Aerobes, Gram-Negative: Citrobacter spp. (including Citrobacter freundii and Citrobacter diversus); Enterobacter spp. (including Enterobacter cloacae and Enterobacter aerogenes); Escherichia coli; Haemophilus influenzae, including ampicillin-resistant strains, Klebsiella spp. (including Klebsiella pneumoniae); Neisseria meningitidis; Proteus mirabilis; Proteus vulgaris; Pseudomonas spp. (including Pseudomonas aeruginosa);and Serratia spp.

Aerobes, Gram-Positive: Staphylococcus aureus, including penicillinase- and non-penicillinase-producing strains; Streptococcus agalactiae (group B streptococci); Streptococcus pneumoniae, and Streptococcus pyogenes (group A beta-hemolytic streptococci).

Anaerobes: Bacteroides spp. (NOTE: Many strains of Bacteroides fragilis are resistant).

Ceftazidime has been shown to be active in vitro against most strains of the following organisms; however, the clinical significance of these data is unknown: Acinetobacter spp., Clostridium spp. (not including Clostridium difficile); Haemophilus parainfluenzae; Morganella morganii (formerly Proteus morganii); Neisseria gonorrhoeae; Peptococcus spp.; Peptostreptococcus spp.; Providencia spp. (including Providencia rettgeri, formerly Proteus rettgeri); Salmonella spp.; Shigella spp.; Staphylococcus epidermidis; and Yersinia enterocolitica.

Ceftazidime and the aminoglycosides have been shown to be synergistic in vitro against Pseudomonas aeruginosa and the enterobacteriaceae. Ceftazidime and carbenicillin have also been shown to be synergistic in vitro against Pseudomonas aeruginosa.

Ceftazidime is not active in vitro against: methicillin-resistant staphylococci, Streptococcus faecalis and many other enterococci, Listeria monocytogenes, Campylobacter spp., or Clostridium difficile.

Susceptibility Tests: Diffusion Techniques: Quantitative methods that require measurement of zone diameters give an estimate of antibiotic susceptibility. One such procedure1-3 has been recommended for use with disks to test susceptibility to ceftazidime.

Reports from the laboratory giving results of the standard single-disk susceptibility test with a 30 mcg ceftazidime disk should be interpreted according to the following criteria:

Susceptible organisms produce zones of 18 mm or greater, indicating that the test organism is likely to respond to therapy.

Organisms that produce zones of 15 mm to 17 mm are expected to be susceptible if high dosage is used or if the infection is confined to tissues and fluids (e.g., urine) in which high antibiotic levels are attained.

Resistant organisms produce zones of 14 mm or less, indicating that other therapy should be selected.

Organisms should be tested with the ceftazidime disk, since ceftazidime has been shown by in vitro tests to be active against certain strains found resistant when other beta-lactam disks are used.

Standardized procedures require the use of laboratory control organisms. The 30 mcg ceftazidime disk should give zone diameters between 25 mm and 32 mm for Escherichia coli ATCC 25922. For Pseudomonas aeruginosa ATCC 27853, the zone diameters should be between 22 mm and 29 mm. For Staphylococcus aureus ATCC 25923, the zone diameters should be between 16 mm and 20 mm.

Dilution Techniques: In other susceptibility testing procedures, e.g., ICS agar dilution or the equivalent, a bacterial isolate may be considered susceptible if the minimum inhibitory concentration (MIC) value for ceftazidime is not more than 16 mcg/mL. Organisms are considered resistant to ceftazidime if the MIC is ≥64 mcg/mL. Organisms having an MIC value of <64 mcg/mL but >16 mcg/mL are expected to be susceptible if high dosage is used or if the infection is confined to tissues and fluids (e.g., urine) in which high antibiotic levels are attained.

As with standard diffusion methods, dilution procedures require the use of laboratory control organisms. Standard ceftazidime powder should give MIC values in the range of 4 mcg/mL to 16 mcg/mL for Staphylococcus aureus ATCC 25923. For Escherichia coli ATCC 25922, the MIC range should be between 0.125 mcg/mL and 0.5 mcg/mL. For Pseudomonas aeruginosa ATCC 27853, the MIC range should be between 0.5 mcg/mL and 2 mcg/mL.

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