Cefazolin - How It Works

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Cefazolin is an antibacterial drug [see Microbiology ].

12.2 Pharmacodynamics The pharmacokinetic/pharmacodynamic relationship for cefazolin has not been evaluated in patients.

12.3 Pharmacokinetics 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 8 hours for a 1 gram dose.

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

In a study of constant intravenous infusion with dosages of 3.5 mg/kg for 1 hour (approximately 250 mg) and 1.5 mg/kg the next 2 hours (approximately 100 mg) in healthy volunteers, cefazolin serum concentrations at the third hour were approximately 28 mcg/mL.

Plasma pharmacokinetic parameters of cefazolin in healthy volunteers (N=12) following a single 15-minute IV infusion of 2 grams of Cefazolin for Injection and Dextrose Injection are summarized in Table 7.

Table 7: Mean (Standard Deviation) Plasma Pharmacokinetic Parameters of Cefazolin in Healthy Volunteers Dosage of Cefazolin for Injection and Dextrose Injection N C max (mcg/mL) T max T max reported as median (range) (h) AUC 0-inf (mcg*h/mL) t 1/2 (h) CL (L/h) V z (L) Single 2 grams Dose as a 15-Minute IV Infusion 12 280.9 0.25 (0.25-0.33) 509.9 2.01 4.03 11.50 N= number of subjects observed; C max = maximum plasma concentration; T max = time to maximum plasma concentration; AUC 0-inf = area under the plasma concentration-time curve extrapolated to infinity; t 1/2 = apparent plasma terminal elimination half-life; CL = total clearance; V z = volume of distribution Model derived plasma pharmacokinetic parameters of cefazolin in adult patients weighing 120 kg or greater (N=12) following a single 30-minute IV infusion of 3 grams of Cefazolin for Injection and Dextrose Injection are summarized in Table 8.

Table 8: Mean (Standard Deviation) Model Derived Plasma Pharmacokinetic Parameters of Cefazolin in Adult Patients Weighing ≥ 120 kg Dosage of Cefazolin for Injection and Dextrose Injection N C max (mcg/mL) T max (h) AUC 0--inf (mcg*h/mL) t 1/2 (h) CL (L/h ) Vz (L) Single 3 grams Dose as a 30-Minute IV Infusion 12 197.7 0.5 598.6 2.36 5.52 17.51 * T max reported based on infusion duration N= number of subjects observed; C max = maximum plasma concentration; T max = time to maximum plasma concentration; AUC 0-inf = area under the plasma concentration-time curve extrapolated to infinity; t 1/2 = apparent plasma terminal elimination half-life; CL = total clearance; V z = volume of distribution Studies in patients hospitalized with infections indicate that cefazolin mean peak serum concentrations were approximately equivalent to those seen in healthy volunteers.

Bile concentrations in patients without obstructive biliary disease can reach or exceed serum concentrations by up to five times; however, in patients with obstructive biliary disease, bile concentrations of cefazolin are considerably lower than serum concentrations (less than 1.0 mcg/mL).

In synovial fluid, the cefazolin concentration becomes comparable to that reached in serum at about 4 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 6 hours, approximately 60% of the drug is excreted in the urine and this increases to 70% to 80% within 24 hours.

Specific Populations Pediatric Patients for Perioperative Prophylaxis A simulation based on pharmacokinetic data from healthy adults (n=24), pediatric patients aged 10 to 17 years (n=26: Study 1 [see Adverse Reactions ] ), and pediatric patients aged 10 to 12 years (n=12: Study 2 [see Adverse Reactions ] indicate that the administration of a 1 gram cefazolin dose for pediatric patients weighing less than 50 kg and a 2 gram cefazolin dose for those weighing 50 kg or greater will provide comparable exposures between pediatric patients aged 10 to 17 years and healthy adults receiving 2 grams Cefazolin for Injection and Dextrose Injection [see Dosage and Administration ( 2.2 and 2.3 ) and Use in Specific Populations ].

12.4 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 [see Indications and Usage ] .

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.