CEFAZOLIN

CEFAZOLIN- cefazolin sodium injection, powder, lyophilized, for solution
GlaxoSmithKline

To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefazolin and other antibacterial drugs, cefazolin 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 sterile, semi-synthetic cephalosporin for intravenous or intramuscular 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:

Image from Drug Label Content

Its molecular formula is C14 H13 N8 NaO4 S3 and the molecular weight is 476.50.

Each vial contains 48 mg of sodium/1 gram of cefazolin sodium.

Cefazolin for injection is supplied as a lyophilized form.

Each ADD-Vantage® vial of cefazolin for injection is equivalent to 1 gram cefazolin.

CLINICAL PHARMACOLOGY

Human Pharmacology

After intramuscular administration of cefazolin to normal volunteers, the mean serum concentrations were 37 mcg/mL at one hour and

3 mcg/mL at eight hours following a 500 mg dose, and 64 mcg/mL at one hour and

7 mcg/mL at eight hours following a 1 gram dose.

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

The serum half-life for cefazolin is approximately 1.8 hours following I.V. administration and approximately 2.0 hours following I.M. 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 two 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 are considerably lower than serum levels (< 1.0 mcg/mL).

In synovial fluid, the cefazolin level becomes comparable to that reached in serum at about four hours after drug administration.

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

Cefazolin is excreted unchanged in the urine. In the first six hours approximately 60% of the drug is excreted in the urine and this increases to 70%-80% within 24 hours. Cefazolin achieves peak urine concentrations of approximately 2400 mcg/mL and 4000 mcg/mL respectively following 500 mg and 1 gram intramuscular doses.

In patients undergoing peritoneal dialysis (2 L/hr.), cefazolin 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 13-44 mcg/mL) with 50 mg/L (three patients), and 72 mcg/mL (range 26-142 mcg/mL) with 150 mg/L (six patients). Intraperitoneal administration of cefazolin 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.

Microbiology

In vitro tests demonstrate that the bactericidal action of cephalosporins results from inhibition of cell wall synthesis. Cefazolin is active against the following organisms in vitro and in clinical infections:

Staphylococcus aureus (including penicillinase-producing strains)

Staphylococcus epidermidis

Methicillin-resistant staphylococci are uniformly resistant to cefazolin

Group A beta-hemolytic streptococci and other strains of streptococci (many strains of enterococci are resistant)

Streptococcus pneumoniae

Escherichia coli

Proteus mirabilis

Klebsiella species

Enterobacter aerogenes

Haemophilus influenzae

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

Disk Susceptibility Tests

Disk diffusion technique

— Quantitative methods that require measurement of zone diameters give the most precise estimates of antibiotic susceptibility. One such procedure1 has been recommended for use with disks to test susceptibility to cefazolin.

Reports from a laboratory using the standardized single-disk susceptibility test1 with a 30 mcg cefazolin disk should be interpreted according to the following criteria:

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

Organisms of intermediate susceptibility produce zones 15 to 17 mm, indicating that the tested organism would 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.

For gram-positive isolates, a zone of 18 mm is indicative of a cefazolin-susceptible organism when tested with either the cephalosporin-class disk (30 mcg cephalothin) or the cefazolin disk (30 mcg cefazolin).

Gram-negative organisms should be tested with the cefazolin disk (using the above criteria), since cefazolin has been shown by in vitro tests to have activity against certain strains of Enterobacteriaceae found resistant when tested with the cephalothin disk. Gram-negative organisms having zones of less than 18 mm around the cephalothin disk may be susceptible to cefazolin.

Standardized procedures require use of control organisms. The 30 mcg cefazolin disk should give zone diameter between 23 and 29 mm for E. coli ATCC 25922 and between 29 and 35 mm for S. aureus ATCC 25923.

The cefazolin disk should not be used for testing susceptibility to other cephalosporins.

Dilution techniques

— A bacterial isolate may be considered susceptible if the minimal inhibitory concentration (MIC) for cefazolin is not more than 16 mcg per mL. Organisms are considered resistant if the MIC is equal to or greater than 64 mcg per mL.

The range of MIC’s for the control strains are as follows:

S. aureus ATCC 25923, 0.25 − 1.0 mcg/mL

E. coli ATCC 25922, 1.0 − 4.0 mcg/mL

CEFAZOLIN Indications and Usage

Cefazolin is indicated in the treatment of the following serious infections due to susceptible organisms:

RESPIRATORY TRACT INFECTIONS due to Streptococcus pneumoniae , Klebsiella species, Haemophilus influenzae , Staphylococcus aureus (penicillin-sensitive and penicillin-resistant) and group A beta-hemolytic streptococci.

Injectable benzathine penicillin is considered to be the drug of choice in treatment and prevention of streptococcal infections, including the prophylaxis of rheumatic fever.

Cefazolin is effective in the eradication of streptococci from the nasopharynx; however, data establishing the efficacy of cefazolin in the subsequent prevention of rheumatic fever are not available at present.

URINARY TRACT INFECTIONS due to Escherichia coli , Proteus mirabilis , Klebsiella species and some strains of enterobacter and enterococci.

SKIN AND SKIN STRUCTURE INFECTIONS due to Staphylococcus aureus (penicillin-sensitive and penicillin-resistant), group A beta-hemolytic streptococci and other strains of streptococci.

BILIARY TRACT INFECTIONS due to Escherichia coli , various strains of streptococci, Proteus mirabilis , Klebsiella species and Staphylococcus aureus.

BONE AND JOINT INFECTIONS due to Staphylococcus aureus.

GENITAL INFECTIONS (i.e., prostatitis, epididymitis) due to Escherichia coli , Proteus mirabilis , Klebsiella species and some strains of enterococci.

SEPTICEMIA due to Streptococcus pneumoniae , Staphylococcus aureus (penicillin-sensitive and penicillin-resistant), Proteus mirabilis , Escherichia coli and Klebsiella species.

ENDOCARDITIS due to Staphylococcus aureus (penicillin-sensitive and penicillin-resistant) and group A beta-hemolytic streptococci.

Appropriate culture and susceptibility studies should be performed to determine susceptibility of the causative organism to cefazolin.

PERIOPERATIVE PROPHYLAXIS: The prophylactic administration of cefazolin preoperatively, intraoperatively and postoperatively may reduce the incidence of certain postoperative infections in patients undergoing surgical procedures which are classified as contaminated or potentially contaminated (e.g., vaginal hysterectomy, and cholecystectomy in high-risk patients such as those over 70 years of age, with acute cholecystitis, obstructive jaundice or common duct bile stones).

The perioperative use of cefazolin may also be effective in surgical patients in whom infection at the operative site would present a serious risk (e.g., during open-heart surgery and prosthetic arthroplasty).

The prophylactic administration of cefazolin should usually be discontinued within a 24-hour period after the surgical procedure. In surgery where the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty), the prophylactic administration of cefazolin may be continued for 3 to 5 days following the completion of surgery.

If there are signs of infection, specimens for cultures should be obtained for the identification of the causative organism so that appropriate therapy may be instituted.

(See DOSAGE AND ADMINISTRATION.)

To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefazolin, and other antibacterial drugs, cefazolin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

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