Cefazolin Other names: Cephazolin

Cefazolin is a bactericidal cephalosporin antibiotic of the first generation for parenteral administration.

Cephalosporins inhibit cell wall synthesis (in the growth stage) through blocking the penicillin-binding proteins (PBPs) like transpeptidases. The outcome is a bactericidal action.

PK/PD relationship

For cephalosporins, the most important pharmacokinetic-pharmacodynamic index correlating with in vivo efficacy has been shown to be the percentage of the dosing interval that the unbound concentration remains above the minimum inhibitory concentration (MIC) of cefazolin for individual target species (i.e. %T>MIC).

Mechanisms of resistance

Resistance to cefazolin can rest upon one of the following mechanisms:

• Inactivation by beta-lactamases: cefazolin has a high stability against penicillinases of gram-positive bacteria, but only a low stability against plasmid-coded beta-lactamases, e.g. extended-spectrum beta-lactamases or chromosomal-coded beta-lactamases of AmpC-type.
• Reduced affinity of the PBPs to cefazolin: the acquired resistance of pneumococci and other streptococci is caused by modifications of the PBPs due to mutations. The resistance of methicillin (oxacillin)-resistant Staphylococci is due to the formation of an additional PBP with a lower affinity to cefazolin.
• Insufficient penetration of cefazolin through the outer cell wall of gramnegative bacteria can lead to an insufficient inhibition of the PBPs.
• Cefazolin can be transported outside the cell through efflux pumps.

There is a partial or total cross-resistance of cefazolin with other
cephalosporins and penicillins.

Microbiological susceptibility

The following table shows clinically relevant pathogens classified as sensitive or resistant on the basis of in vitro and in vivo data. Cefazolin is effective against some species in vitro, but not clinically, thus these species are classified here as resistant.

The prevalence of acquired resistance may vary geographically and with time for selected species and local information is desirable, particularly when treating severe infections. If necessary, expert advice should be sought when the local prevalence of resistance is such that the efficacy of cefazolin is questionable. Especially in case of severe infections or failure of therapy, a microbiological diagnosis including identification of the microorganism and its susceptibility to cefazolin should be conducted.

Commonly susceptible species

Aerobe Gram-positive:

Staphylococcus aureus (methicillin-sensitive)

Species for which acquired resistance may be a problem

Aerobe Gram-positive:

Group A, B, C and G beta-haemolytic streptococci
Staphylococcus epidermidis (methicillin-sensitive)
Streptococcus pneumoniae

Aerobe Gram-negative:

Haemophilus influenzae

Inherently resistant organisms

Aerobe Gram-positive:

Staphylococcus aureus, methicillin-resistant

Aerobe Gram-negative:

Citrobacter spp.
Enterobacter spp.
Klebsiella pneumoniae
Morganella morganii
Proteus mirabilis
Proteus stuartii
Proteus vulgaris
Pseudomonas aeruginosa
Serratia spp.

Absorption

Cefazolin is administered parenterally. After administration of 500 mg intramuscular injection, maximum serum levels obtained after approximately an hour were 20-40 micrograms/ml. After administration of 1 g maximum serum levels of 37-63 micrograms/ml were obtained. In one continuous intravenous infusion of cefazolin study in healthy adults at doses of 3.5 mg/kg for one hour (approx 250 mg) followed by 1.5 mg/kg for the next two hours (approx 100 mg) a stable serum concentration of approx. 28 micrograms/ml was demonstrated in the third hour. The following table shows the meanserum concentration of cefazolin after intravenous injection of a single dose of 1 g.

Distribution

Cefazolin for 70%-86% bound to plasma proteins. The volume of distribution is approximately 11 l/1.73 m². When cefazolin is administered to patients without obstruction of the bile ducts the antibiotic levels 90-120 minutes after administration were generally higher than antibiotic levels in the serum. Conversely, where obstruction exists the concentrations of antibiotic in the bile were much lower than serum levels. After administration of therapeutic doses in patients with inflamed meninges, varying concentrations of cefazolin from 0 to 0.4 micrograms/ml were measured in cerebrospinal fluid. Cefazolin can easily pass through inflamed synovial membranes and the antibiotic concentration achieved in joints is similar to serum levels.

Biotransformation

Cefazolin is not metabolised.

Elimination

The serum half-life is about 1 hour 35 minutes. Cefazolin is excreted in a microbiologically active form in the urine. Approximately 56-89% of an intramuscular dose of 500 mg is excreted in the first six hours, 80% to almost 100% is excreted within 24 hours. After intramuscular administration of 500 mg and 1 g urine levels can reach 500-4000 μg/ml. Cefazolin is mainly removed from the serum by glomerular filtration, the renal clearance is 65 ml/min/1.73 m².

The acute toxicity of cefazolin is low. By intravenous application the LD₅₀ in rats is 2400-3700 mg/kg body weight. Studies of chronic toxicity in different animal species (rat, dog) revealed no evidence of toxic effects. However, in dogs, muscle injury by repeated intramuscular administration was observed. Studies on the renal toxicity in rabbits showed a low nephrotoxic potential of cefazolin. Mutagenicity or animal experimental studies on the tumorigenic potential of cefazolin are not available. Animal studies showed no evidence of teratogenic effects of cefazolin. Fertility studies and studies on peri- and postnatal toxicity showed no evidence of harmful effects of cefazolin.