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CLINICAL PHARMACOLOGY

After 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 IV Dose Serum Concentrations (mcg/mL)
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.

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. 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 2gq8hrIV 5 120 min 9.8
  (inflamed meninges) 2gq8hrIV 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

Mechanism of Action

Ceftazidime is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis. Ceftazidime has activity in the presence of some beta-lactamases, both penicillinases and cephalosporinases, of Gram-negative and Gram positive bacteria.

Mechanism of Resistance

Resistance to ceftazidime is primarily through hydrolysis by beta-lactamase, alteration of penicillin-binding proteins (PBPs), and decreased permeability.

Interaction with Other Antimicrobials

In an In vitro study, antagonistic effects have been observed with the combination of chloramphenicol and ceftazidime.

Ceftazidime has been shown to be active against most isolates of the following bacteria, both In vitro and in clinical infections as described in the INDICATIONS AND USAGE section:

Gram-negative Bacteria
  • Citrobacter species
  • Enterobacter species
  • Escherichia coli
  • Klebsiella species
  • Haemophilus influenzae
  • Neisseria meningitidis
  • Proteus mirabilis
  • Proteus vulgaris
  • Pseudomonas aeruginosa
  • Serratia species
Gram-positive Bacteria
  • Staphylococcus aureus
  • Streptococcus pneumoniae
  • Streptococcus pyogenes
  • Streptococcus agalactiae
Anaerobic Bacteria
  • Bacteroides species (Note: many isolates of Bacteroides species are resistant)

The following In vitro data are available, but their clinical significance is unknown. At least 90 percent of the following microorganisms exhibit an In vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ceftazidime. However, the efficacy of ceftazidime in treating clinical infections due to these microorganisms has not been established in adequate and well-controlled clinical trials.

Gram-negative Bacteria
  • Acinetobacter species
  • Citrobacter diversus
  • Citrobacter freundii
  • Providencia species (including Providencia rettgeri)
  • Salmonella species
  • Shigella species
  • Haemophilus parainfluenzae
  • Morganella morganii
  • Neisseria gonorrhoeae
  • Yersinia enterocolitica
Gram-positive Bacteria
  • Staphylococcus epidermidis
Anaerobic Bacteria
  • Clostridium species (Not including Clostridium difficile)
  • Peptostreptococcus species

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide the results of In vitro susceptibility test results for antimicrobial drug products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment.

Dilution Techniques

Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method1,2. The MIC values should be interpreted according to criteria provided in Table 3.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method.2,3 This procedure uses paper disks impregnated with 30 mcg ceftazidime to test the susceptibility of microorganisms to ceftazidime. The disk diffusion interpretive criteria are provided in Table 3.

Table 3: Susceptibility Test Interpretive Criteria for Ceftazidime

Pathogen Minimum Inhibitory Concentrations (mcg/ml) Disk Diffusion Zone Diameters (mm)
(S) Susceptible (I) Intermediate (R) Resistant (S) Susceptible (I) Intermediate (R) Resistant
Enterobacteriaceae§ ≤ 4 8 ≥ 16 ≥ 21 18-20 ≤ 17
Haemophilus influenzaea ≤ 2 - - ≥ 26 - -
Pseudomonas aeruginosa* ≤ 8 - ≥ 16 ≥ 18 - ≤ 17
§ Susceptibility interpretive criteria for Enterobacteriaceae are based on a dose of 1 gram q 8h. For isolates with intermediate susceptibility, use a dose of 2 grams every 8 hours in patients with normal renal function.
*For P. aeruginosa, susceptibility interpretive criteria are based on a dose of 2 grams IV every 8 hours in patients with normal renal function.
aThe current absence of data on resistant isolates precludes defining any category other than 'Susceptible'. If isolates yield MIC results other than susceptible, they should be submitted to a reference laboratory for additional testing. Susceptibility of staphylococci to ceftazidime may be deduced from testing only penicillin and either cefoxitin or oxacillin.

A report of “Susceptible” indicates that the antimicrobial drug is likely to inhibit growth of the microorganism if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of “Intermediate” indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the microorganism if the antimicrobial drug reaches the concentration usually achievable at the site of infection; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test1,2,3,4. Standard ceftazidime powder should provide the following range of MIC values noted in Table 4. For the diffusion technique using the 30 mcg disk, the criteria in Table 4 should be achieved.

Table 4 : Acceptable Quality Control Ranges for Ceftazidime

QC Strain Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion Zone diameters (mm)
Escherichia coli ATCC 25922 0.06 - 0.5 25 - 32
Staphylococcus aureus ATCC 25923 - 16 - 20
Staphylococcus aureus ATCC 29213 4 - 16 -
Haemophilus influenzae ATCC 49247 0.12 - 1 27 - 35
Neisseria gonorrhoeae ATCC 49226 0.03 - 0.12 35 - 43
Pseudomonas aeruginosa ATCC 27853 1-4 22-29

REFERENCES

1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.

2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fourth Informational Supplement, CLSI document M100-S24. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2014.

3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.

4. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria; Approved Standard - Eight Edition. CLSI document M11-A8. Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, PA 19087 USA, 2012

Last reviewed on RxList: 11/7/2014
This monograph has been modified to include the generic and brand name in many instances.

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