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Cefazolin (Cefazolin Sodium) - Description and Clinical Pharmacology

 
 



DESCRIPTION

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

Cefazolin for Injection is a semi-synthetic cephalosporin for parenteral administration. It is the sodium salt of 3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-7-[2-(1H-tetrazol-1-yl)acetamido]-5-thia-1-azabicyclo [4.2.0]oct-2-ene-2-carboxylic acid.

Structural Formula:


The sodium content is 24 mg (1.05 mEq) per 500 mg of cefazolin sodium and 48 mg (2.1 mEq) per 1 gram of cefazolin sodium. Cefazolin for Injection is a sterile, white to yellowish powder.

Cefazolin for Injection is supplied in vials equivalent to 500 mg of cefazolin or to 1 gram of cefazolin.

CLINICAL PHARMACOLOGY

After intramuscular administration of Cefazolin for Injection to normal volunteers, the mean serum concentrations were 37 mcg/mL at 1 hour and 3 mcg/mL at 8 hours following a 500-mg dose, and 64 mcg/mL at 1 hour and 7 mcg/mL at 8 hours following a 1-gram dose.

Studies have shown that following intravenous administration of Cefazolin for Injection to normal volunteers, mean serum concentrations peaked at approximately 185 mcg/mL and were approximately 4 mcg/mL at 8 hours for a 1-gram dose.

The serum half-life for cefazolin is approximately 1.8 hours following IV administration and approximately 2 hours following IM administration.

In a study (using normal volunteers) of constant intravenous infusion with dosages of 3.5 mg/kg for one hour (approximately 250 mg) and 1.5 mg/kg the next 2 hours (approximately 100 mg), cefazolin produced a steady serum level at the third hour of approximately 28 mcg/mL.

Studies in patients hospitalized with infections indicate that cefazolin produces mean peak serum levels approximately equivalent to those seen in normal volunteers.

Bile levels in patients without obstructive biliary disease can reach or exceed serum levels by up to five times; however, in patients with obstructive biliary disease, bile levels of cefazolin for injection are considerably lower than serum levels (less than 1 mcg/mL).

In synovial fluid, the level of Cefazolin for injection becomes comparable to that reached in serum at about 4 hours after drug administration.

Studies of cord blood show prompt transfer of cefazolin for injection across the placenta. Cefazolin for injection is present in very low concentrations in the milk of nursing mothers.

Cefazolin for injection is excreted unchanged in the urine. In the first 6 hours approximately 60% of the drug is excreted in the urine and this increases to 70% to 80% within 24 hours. Cefazolin achieves peak urine concentrations of approximately 2,400 mcg/mL and 4,000 mcg/mL, respectively following 500-mg and 1-gram intramuscular doses.

In patients undergoing peritoneal dialysis (2L/hr.), Cefazolin for Injection produced mean serum levels of approximately 10 and 30 mcg/mL after 24 hours’ instillation of a dialyzing solution containing 50 mg/L and 150 mg/L, respectively. Mean peak levels were 29 mcg/mL (range 13 to 44 mcg/mL) with 50 mg/L (3 patients), and 72 mcg/mL (range 26 to 142 mcg/mL) with 150 mg/L (6 patients). Intraperitoneal administration of Cefazolin for Injection is usually well tolerated.

Controlled studies on adult normal volunteers, receiving 1 gram 4 times a day for 10 days, monitoring CBC, SGOT, SGPT, bilirubin, alkaline phosphatase, BUN, creatinine, and urinalysis, indicated no clinically significant changes attributed to cefazolin for injection.
  

Microbiology
In vitro tests demonstrate that the bactericidal action of cephalosporins results from inhibition of cell wall synthesis. Cefazolin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the  INDICATIONS AND USAGE section:

Aerobic Gram-positive microorganisms:
Staphylococcus aureus (including pencillinase-producing strains)
Staphylococcus epidermidis

Streptococcus pneumoniae

Streptococcus pyogenes,and other strains of streptococci



Note: Methicillin-resistant staphylococci are uniformly resistant to cefazolin. Many Enterococcus strains are resistant to cefazolin.

Aerobic Gram-negative microorganisms:

Escherichia coli

Haemophilus influenzae

Klebsiella species

Proteus mirabilis

Note: Most strains of indole positive Proteus (Proteus vulgaris), Enterobacter cloacae, Morganella morganii, and Providencia rettgeri are resistant. Serratia cloacae. Morganelia morganii, and Providencia rettgeri are resistant. Serratia, Pseudomonas. Mirna and Herellea species are almost uniformly resistant to cefazolin.

Susceptibility Testing

Dilution Techniques:
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs probide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1 (broth) or equivalent with standardized inoculum concentrations and standardized concentrations of cefazolin powder.

The MIC values should be interpreted according to the following criteria:

For Enterobacteriaceae and Staphylococcus spp.

MIC (mcg/mL)
Interpretation
less than 8
Susceptible (S)
16
Intermediate (I)
greater than 32
Resistant (R)
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. 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 high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the the concentrations usually achievable; other therapy should be selected.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard cefazolin powder should provide the following MIC values:

Microorganism
MIC (mcg/mL)
S. aureus ATCC 29213
0.25 to 1
E. coli ATCC 25922
1 to 4
Diffusion Techniques
Quantitative methods that requir measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 requires the use of standardized inoculum concentrations.  This procedure uses paper disks impregnated with 30-mcg cefazolin to test the susceptibility of microorganisms to cefazolin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-mcg cefazolin disk should be interpreted according to the following criteria:

For Enterobacteriaceae using the 30-mcg cefazolin disk


Zone diameter (mm)
Interpretation
greater than 18
Susceptible (S)
15 to 17
Intermediate (I)
less than 14
Resistant (R)
  
For Staphylococus spp. using the 30 mcg cefazolin or the 30-mcg cephalothin disks
Zone diameter (mm)
Interpretation
greater than 18
Susceptible (S)
15 to 17
Intermediate (I)
less than 14
Resistant (R)
Interpretation should be as stated above for results using dilution techniques. Interpretation involves correclation of the diameter obtained in the disk test with the MIC for cefazolin.  As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that ate used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30-mcg cefazolin disk should provide the following zone diameters in this laboratory test quality control strain:
Microorganism
Zone diameter (mm)
S. aureus ATCC 25923
29 to 35
E. coli ATCC 25922
23 to 29

 

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