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Ceptaz

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Ceptaz

CLINICAL PHARMACOLOGY

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

Table 1. Average Serum Concentrations of Ceftazidime

Ceftazidime Serum Concentrations (mcg/mL)
IV Dose 0.5 hr 1 hr 2 hr 4 hr 8 hr
500 mg 42 25 12 6 2
1 g 60 39 23 11 3
2 g 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 and 2 g every 8 hours for 10 days.

Following intramuscular (IM) administration of 500-mg and 1-g doses of ceftazidime to normal adult volunteers, the mean peak serum concentrations were 17 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-g 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 g 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-g 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.

Ceftazidime concentrations achieved in specific body tissues and fluids are depicted in Table 2.

Table 2. Ceftazidime Concentrations in Body Tissues and Fluids

Tissue or Fluid Dose/ Route No. of Patients Time of Sample Postdose Average Tissue or Fluid Level (mcg/mL or mcg/g)
Urine 500 mg IM 6 0-2 hr 2,100.0
  2 g IV 6 0-2 hr 12,000.0
Bile 2 g IV 3 90 min 36.4
Synovial fluid 2 g IV 13 2 hr 25.6
Peritoneal fluid 2 g IV 8 2 hr 48.6
Sputum 1 g IV 8 1 hr 9.0
Cerebrospinal fluid 2 g q8hr IV 5 120 min 9.8
(inflamed meninges) 2 g q8hr IV 6 180 min 9.4
Aqueous humor 2 g IV 13 1-3 hr 11.0
Blister fluid 1 g IV 7 2-3 hr 19.7
Lymphatic fluid 1 g IV 7 2-3 hr 23.4
Bone 2 g IV 8 0.67 hr 31.1
Heart muscle 2 g IV 35 30-280 min 12.7
Skin 2 g IV 22 30-180 min 6.6
Skeletal muscle 2 g IV 35 30-280 min 9.4
Myometrium 2 g IV 31 1-2 hr 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).

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 this activity 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 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 and 32 mm for Escherichia coli ATCC 25922. For Pseudomonas aeruginosa ATCC 27853, the zone diameters should be between 22 and 29 mm. For Staphylococcus aureus ATCC 25923, the zone diameters should be between 16 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 to 16 mcg/mL for Staphylococcus aureus ATCC 25923. For Escherichia coli ATCC 25922, the MIC range should be between 0.125 and 0.5 mcg/mL. For Pseudomonas aeruginosa ATCC 27853, the MIC range should be between 0.5 and 2 mcg/mL.

REFERENCES

1. Bauer AW, Kirby WMM, Sherris JC, Turck M. Antibiotic susceptibility testing by a standardized single disk method. Am J Clin Pathol. 1966;45:493-496.

2. National Committee for Clinical Laboratory Standards. Approved Standard: Performance Standards for Antimicrobial Disc Susceptibility Tests. (M2-A3). December 1984.

3. Certification procedure for antibiotic sensitivity discs (21 CFR 460.1). Federal Register. May 30, 1974;39:19182-19184.

Last reviewed on RxList: 7/21/2008
This monograph has been modified to include the generic and brand name in many instances.

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