Description: Cefazolin is a parenteral first-generation cephalosporin with greater activity against gram-positive bacteria than most other cephalosporins. Similar to other first-generation cephalosporins, cefazolin is active against gram-positive aerobic cocci, but has limited activity against gram-negative bacteria. Cefazolin has a longer half-life than other first-generation cephalosporins and, since fewer daily doses are required, is less expensive to use. Advantages of cefazolin over other first-generation cephalosporins include higher blood levels after IM/IV administration, greater gram-positive coverage, and less frequent dosing. Cefazolin was approved by the FDA in 1973.

Mechanism of Action: Cefazolin, a beta-lactam antibiotic similar to penicillins, inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall. Penicillin-binding proteins are responsible for several steps in the synthesis of the cell wall and are found in quantities of several hundred to several thousand molecules per bacterial cell. Penicillin-binding proteins vary among different bacterial species. Thus, the intrinsic activity of cefazolin as well as other cephalosporins and penicillins against a particular organism depends on their ability to gain access to and bind with the necessary PBP. Like all beta-lactam antibiotics, cefazolin's ability to interfere with PBP-mediated cell wall synthesis ultimately leads to cell lysis. Lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins). The relationship between PBPs and autolysins is unclear, but it is possible that the beta-lactam antibiotic interferes with an autolysin inhibitor.

As a rule, first-generation cephalosporins are more active against gram-positive organisms than are the second- or third-generation cephalosporins, but they have relatively little activity against gram-negative species. Gram-positive coverage includes nonpencillinase- and pencillinase-producing Staphylococcus aureus (methicillin-resistant strains are resistant) and streptococci (except enterococci). Few cephalosporins possess better activity against susceptible strains of S. aureus than cefazolin. Gram-negative coverage is limited to E. coli, Klebsiella, and Proteus mirabilis. Cefazolin is much less active against H. influenzae than are cefuroxime or ceftriaxone. Anaerobic coverage includes penicillin-susceptible anaerobic organisms such as mouth anaerobes. In general, B. fragilis is not susceptible to cefazolin.

Pharmacokinetics: Cefazolin is administered parenterally. It is not well absorbed from the GI tract. Peak serum levels of cefazolin occur within 1—2 hours following an IM dose. Approximately 75—85% of circulating drug is protein-bound. It is distributed into most body tissues and fluids including gallbladder, liver, kidney, bone, myocardium, sputum, bile, and pericardial, pleural, and synovial fluids. It does not reach therapeutic levels within the CSF but does cross the placenta. Cefazolin distributes into breast milk in low concentrations. A milk to plasma ratio of 0.02 has been reported.[10244] Unlike cephalothin, cefazolin is not hepatically metabolized. Cefazolin is largely excreted unchanged into the urine via glomerular filtration and tubular secretion, although tubular secretion appears to be less important for renal clearance of cefazolin than for cephalothin. Approximately 60% of cefazolin is excreted within the first 6 hours, reaching 70—80% within the first 24 hours. Elimination half-life is 1—2 hours in patients with normal renal function. The elimination half-life increases as renal function declines; half-life may be prolonged to 12—50 hours in patients with end-stage renal disease. Cefazolin is removed by hemodialysis.

•Special populations: The serum half-life of cefazolin in neonates decreases from 4.5—5 hours in the first week of life to approximately 3 hours by 3—4 weeks of age.[10241]

10241. Saez-Llorens X, McCracken GH. Clinical pharmacology of antibacterial agents. In: Remington JS, Klein JO, Wilson CB, Baker CJ, eds. Infectious diseases of the fetus and newborn infant. 6th ed. Philadelphia: Elsevier Saunders; 2006:1223—66.

10244. Drugs in Pregnancy and Lactation. A Reference Guide to Fetal and Neonatal Risk. Briggs GG, Freeman RK, Yaffe SJ (eds.) 7th ed., Philadelphia. PA. Lippincott Williams and Wilkins. 2005; 245.

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