Microbiology

Mechanism of Action

Cefazolin is a bactericidal agent that acts by inhibition of bacterial cell wall synthesis.

Resistance

Predominant mechanisms of bacterial resistance to cephalosporins include the presence of extended-spectrum beta-lactamases and enzymatic hydrolysis.

Antimicrobial Activity

Cefazolin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE (1) section.

Gram-Positive Bacteria

Staphylococcus aureus

Staphylococcus epidermidis

Streptococcus agalactiae

Streptococcus pneumoniae

Streptococcus pyogenes

Methicillin-resistant staphylococci are uniformly resistant to cefazolin.

Gram-Negative Bacteria

Escherichia coli

Proteus mirabilis

Most isolates of indole positive Proteus (Proteus vulgaris), Enterobacter spp., Morganella morganii, Providencia rettgeri, Serratia spp., and Pseudomonas spp. are resistant to cefazolin.

Susceptibility Testing

For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

General

Prolonged use of cefazolin may result in the overgrowth of nonsusceptible organisms. Careful clinical observation of the patient is essential.

When cefazolin is administered to patients with low urinary output because of impaired renal function, lower daily dosage is required (see DOSAGE AND ADMINISTRATION).

As with other beta-lactam antibiotics, seizures may occur if inappropriately high doses are administered to patients with impaired renal function (see DOSAGE AND ADMINISTRATION).

Cefazolin as with all cephalosporins, should be prescribed with caution in individuals with a history of gastrointestinal disease, particularly colitis.

Cephalosporins may be associated with a fall in prothrombin activity. Those at risk include patients with renal or hepatic impairment or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy, and patients previously stabilized on anticoagulant therapy. Prothrombin time should be monitored in patients at risk and exogenous vitamin K administered as indicated.

Prescribing cefazolin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Drug Interactions

Probenecid may decrease renal tubular secretion of cephalosporins when used concurrently, resulting in increased and more prolonged cephalosporin blood levels.

Drug/Laboratory Test Interactions

A false positive reaction for glucose in the urine may occur with Benedict’s solution, Fehling’s solution or with CLINITEST® tablets, but not with enzyme-based tests such as CLINISTIX®.

Positive direct and indirect antiglobulin (Coombs) tests have occurred; these may also occur in neonates whose mothers received cephalosporins before delivery.

Information for Patients

Patients should be counseled that antibacterial drugs including cefazolin, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When cefazolin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may: (1) decrease the effectiveness of the immediate treatment, and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by cefazolin or other antibacterial drugs in the future.

Carcinogenesis/Mutagenesis

Mutagenicity studies and long-term studies in animals to determine the carcinogenic potential of cefazolin have not been performed.

Pregnancy

Labor and Delivery

When cefazolin has been administered prior to caesarean section, drug levels in cord blood have been approximately one quarter to one third of maternal drug levels. The drug appears to have no adverse effect on the fetus.

Nursing Mothers

Cefazolin is present in very low concentrations in the milk of nursing mothers. Caution should be exercised when cefazolin is administered to a nursing woman.

Pediatric Use

Safety and effectiveness for use in premature infants and neonates have not been established. See DOSAGE AND ADMINISTRATION for recommended dosage in pediatric patients older than 1 month.

Geriatric Use

Of the 920 subjects who received cefazolin in clinical studies, 313 (34%) were 65 years and over, while 138 (15%) were 75 years and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see PRECAUTIONS, General and DOSAGE AND ADMINISTRATION).

Usual Adult Dosage

Perioperative Prophylactic Use

To prevent postoperative infection in contaminated or potentially contaminated surgery, recommended doses are:

 

a. 1 gram intravenous administered 1/2 hour to 1 hour prior to the start of surgery.

 

b. For lengthy operative procedures (e.g., 2 hours or more), 500 mg to 1 gram intravenous during surgery (administration modified depending on the duration of the operative procedure).

 

c. 500 mg to 1 gram intravenous every 6 to 8 hours for 24 hours postoperatively.

It is important that (1) the preoperative dose be given just (1/2 to 1 hour) prior to the start of surgery so that adequate antibiotic levels are present in the serum and tissues at the time of initial surgical incision; and (2) cefazolin for injection be administered, if necessary, at appropriate intervals during surgery to provide sufficient levels of the antibiotic at the anticipated moments of greatest exposure to infective organisms.

In surgery where the occurrence of infection may be particularly devastating (e.g., open-heart surgery and prosthetic arthroplasty), the prophylactic administration of cefazolin for injection may be continued for 3 to 5 days following the completion of surgery.

Dosage Adjustment for Patients with Reduced Renal Function

Cefazolin for injection may be used in patients with reduced renal function with the following dosage adjustments: Patients with a creatinine clearance of 55 mL/min. or greater or a serum creatinine of 1.5 mg% or less can be given full doses. Patients with creatinine clearance rates of 35 to 54 mL/min. or serum creatinine of 1.6 to 3 mg% can also be given full doses but dosage should be restricted to at least 8 hour intervals. Patients with creatinine clearance rates of 11 to 34 mL/min. or serum creatinine of 3.1 to 4.5 mg% should be given 1/2 the usual dose every 12 hours. Patients with creatinine clearance rates of 10 mL/min. or less or serum creatinine of 4.6 mg% or greater should be given 1/2 the usual dose every 18 to 24 hours. All reduced dosage recommendations apply after an initial loading dose appropriate to the severity of the infection. Patients undergoing peritoneal dialysis: See CLINICAL PHARMACOLOGY.

Pediatric Dosage

In pediatric patients, a total daily dosage of 25 to 50 mg per kg (approximately 10 to 20 mg per pound) of body weight, divided into 3 or 4 equal doses, is effective for most mild to moderately severe infections. Total daily dosage may be increased to 100 mg per kg (45 mg per pound) of body weight for severe infections. Since safety for use in premature infants and in neonates has not been established, the use of cefazolin for injection in these patients is not recommended.

In pediatric patients with mild to moderate renal impairment (creatinine clearance of 70 to 40 mL/min.), 60 percent of the normal daily dose given in equally divided doses every 12 hours should be sufficient. In patients with moderate impairment (creatinine clearance of 40 to 20 mL/min.), 25 percent of the normal daily dose given in equally divided doses every 12 hours should be adequate. Pediatric patients with severe renal impairment (creatinine clearance of 20 to 5 mL/min.) may be given 10 percent of the normal daily dose every 24 hours. All dosage recommendations apply after an initial loading dose.

Preparation of Parenteral Solution

Parenteral drug products should be SHAKEN WELL when reconstituted, and inspected visually for particulate matter prior to administration. If particulate matter is evident in reconstituted fluids, the drug solutions should be discarded.

When reconstituted or diluted according to the instructions below, cefazolin is stable for 24 hours at room temperature. Reconstituted solutions may range in color from pale yellow to yellow without a change in potency.

ADD-Vantage® Vials

ADD-Vantage® Vials of cefazolin for injection are to be reconstituted only with 0.9% Sodium Chloride Injection or 5% Dextrose Injection in the 50 mL or 100 mL ADD-Vantage® Flexible Diluent Containers or with 0.45% Sodium Chloride Injection in the 50 mL ADD-Vantage® Flexible Diluent Container. Cefazolin for injection supplied in single dose ADD-Vantage® Vials should prepared as directed below.

INSTRUCTIONS FOR USE

To Open Diluent Container:

Peel overwrap at corner and remove solution container. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually.

To Assemble Vial and Flexible Diluent Container:

(Use Aseptic Technique)

1.

Remove the protective covers from the top of the vial and the vial port on the diluent container as follows:

a. To remove the breakaway vial cap, swing the pull ring over the top of the vial and pull down far enough to start the opening (see Figure 1), then pull straight up to remove the cap (see Figure 2).

NOTE: Once the breakaway cap has been removed, do not access vial with syringe.

b. To remove the vial port cover, grasp the tab on the pull ring, pull up to break the three tie strings, then pull back to remove the cover (see Figure 3).

2.

Screw the vial into the vial port until it will go no further. THE VIAL MUST BE SCREWED IN TIGHTLY TO ASSURE A SEAL. This occurs approximately 1/2 turn (180°) after the first audible click (see Figure 4). The clicking sound does not assure a seal; the vial must be turned as far as it will go.

NOTE: Once vial is seated, do not attempt to remove (see Figure 4).

3.

Recheck the vial to assure that it is tight by trying to turn it further in the direction of assembly.

4.

Label appropriately.

To Reconstitute the Drug:

1.

Squeeze the bottom of the diluent container gently to inflate the portion of the container surrounding the end of the drug vial.

2.

With the other hand, push the drug vial down into the container telescoping the walls of the container. Grasp the inner cap of the vial through the walls of the container (see Figure 5).

3.

Pull the inner cap from the drug vial (see Figure 6). Verify that the rubber stopper has been pulled out, allowing the drug and diluent to mix.

4.

Mix container contents thoroughly and use within the specified time.

Preparation for Administration:

(Use Aseptic Technique)

1.

Confirm the activation and admixture of vial contents.

2.

Check for leaks by squeezing container firmly. If leaks are found, discard unit as sterility may be impaired.

3.

Close flow control clamp of administration set.

4.

Remove cover from outlet port at bottom of container.

5.

Insert piercing pin of administration set into port with a twisting motion until the pin is firmly seated.

NOTE: See full directions on administration set carton.

6.

Lift the free end of the hanger loop on the bottom of the vial, breaking the two tie strings. Bend the loop outward to lock it in the upright position, then suspend container from hanger.

7.

Squeeze and release drip chamber to establish proper fluid level in chamber.

8.

Open flow control clamp and clear air from set. Close clamp.

9.

Attach set to venipuncture device. If device is not indwelling, prime and make venipuncture.

10.

Regulate rate of administration with flow control clamp.

WARNING: Do not use flexible container in series connections.

Compatibility and Stability

Ordinarily ADD-Vantage® Vials should be reconstituted only when it is certain that the patient is ready to receive the drug. However, Cefazolin for Injection in ADD-Vantage® vials is stable for 24 hours at room temperature when reconstituted as directed (see RECONSTITUTION, ADD-Vantage® Vials and INSTRUCTIONS FOR USE).

(DO NOT REFRIGERATE OR FREEZE CEFAZOLIN SODIUM IN ADD-VANTAGE® VIALS.)

Prior to administration parenteral drug products should be inspected visually for particulate matter and discoloration whenever solution and container permit.