ZEPILEN Powder for solution for injection/infusion Ref.[28167] Active ingredients: Cefazolin

Source: Υπουργείο Υγείας (CY) Revision Year: 2018 Publisher: Medochemie Ltd, 1–10 Constantinoupoleus Street 3011 Limassol, Cyprus

5.1. Pharmacodynamic properties

Pharmacotherapeutic group: Beta-lactam antibiotics, first-generation cephalosporins
ATC code: JO1DB04

Mechanism of action

Cefazolin is a semisynthetic cephalosporin antibiotic for parenteral use. The bactericidal effect of cefazolin is based on inhibition of bacterial cell wall synthesis.

Microbiology

Cefazolin in vitro effect is generally against the following pathogens:

Staphylococcus aureus (including penicillinase-producing strains)
Staphylococcus epidermidis (coagulase-negative staphylococci and others)
Beta-hemolytic group A streptococci and other streptococci strains
Streptococcus pneumoniae
Escherichia coli
Klebsiella
Proteus mirabilis
Haemophilus influenzae
Enterobacter aerogenes

Resistant organisms:

Resistant are methicillin-resistant staphylococci, many strains of enterococci, as well as most Enterobacter cloacae strains-and indole-positive Proteus strains (P. vulgaris, P. morganii, P. rettgeri) and Serratia, Pseudomonas, Acinetobacter calcoaceticus (formerly Mima and Herellea) and Anaerobes, C. difficile.

Resistance Mechanisms

Beta-lactam antibiotics contain a so-called beta-lactam ring that is essential for antimicrobial activity. If this ring is split open, the antibiotic loses its effectiveness. Different bacteria, however, possess enzymes (beta-lactamases) that break the ring open, making them resistant against this type of antibiotics. As with all cephalosporins and other beta-lactam antibiotics, the acquired resistance mechanisms vary per group of bacteria and include: changes in the targets (penicillin-binding proteins, PBPs) enzymatic degradation of the target by beta-lactamases and altered access to the target. There is cross resistance between cephalosporins and penicillins. Gram-negative microorganisms which contain inducible chromosomal beta-bound lactamases, such as Enterobacter spp, Serratia spp, Citrobacter spp and Providentia spp should be regarded as resistant to cefazolin, despite in vitro susceptibility.

Breakpoints

According to EUCAST, the following breakpoints have been determined for cefazolin: Non-species related: S ≤1 μg/ml, R >2 μg/ml. The prevalence of resistance can vary geographically and in time for the selected microorganisms and local information on resistance is desirable, particularly when treating severe infections. If necessary, expert advice should be sought, especially when the local prevalence of resistance is such that the use of the agent in at least some types of infections is questionable. The sensitivity of Staphylococcus is derived from the sensitivity to methicillin.

5.2. Pharmacokinetic properties

Serum concentrations (ug/ml) after i.m. injection:

Dose	After ½ h	After 1 h	After 2 h	After 4 h	After 6 h	After 8 h
250 mg	15,5	17	13	5,1	2,5
500 mg	36,2	36,8	37,9	15,5	6,3	3
1h*	60,1	63,8	54,3	29,3	13,2	7,1

^* Average of the two tests

Serum concentrations (ug/ml) after 1 g intravenous injection:

After 5 min.	After 15 min.	After 30 min.	After 1 h	After 2 h	After 4 h
188,4	135,8	106,8	73,7	45,6	16,5

For intravenous administration, the half-life is approximately 1.4 hours.
A one-hour intravenous infusion with 3.5 mg cefazolin/kg (about 250 mg) and then two-hour intravenous infusion of 1.5 mg cefazolin/kg (about 100 mg) resulted in a uniform serum levels of about 28 ug/ml during the 3-rd hour of administration.
In patients undergoing peritoneal dialysis (2 l/h), the mean serum concentrations after 24 hours of administration of a solution of 50 mg/l or 150 mg/l was 10 or 30 ug/ml.
For the 50 mg/l solution concentration, the mean peak plasma concentration was 29 ug/ml (3 patients) and for the 150 mg/l solution concentration, the mean peak plasma concentration was 72 ug/ml (6 patients).
The intraperitoneal administration of cefazolin is usually well tolerated.
Cefazolin is excreted unchanged in the urine, mainly by glomerular filtration and to a lesser extent by tubular secretion.
After intramuscular injection of 500 mg, 56% to 89% of cefazolin administered dose is eliminated by the kidneys within 6 hours, and 80 to nearly 100% is eliminated within 24 hours.
After intramuscular administration of 500 mg and 1 g cefazolin, urinary concentrations of more than 1000 or more than 4000 ug/ml are achieved.
In patients without biliary obstruction, concentrations high above the serum levels occurs in gallbladder tissues and also in the bile. However, if there is a biliary obstruction, the concentration of the antibiotic in the bile become significantly lower than in serum.
Cefazolin crosses the inflamed synovial membrane, and the concentration achieved in the joint space is comparable with the serum concentration.
Cefazolin crosses the placenta and is excreted in cord blood and amniotic fluid. It is found in very low concentrations in breast milk.
Cefazolin is dialysable (hemodialysis and peritoneal dialysis). The elimination following a 6-hour dialysis is 23%.

5.3. Preclinical safety data

No long-term studies in animals regarding mutagenicity or carcinogenic potential were performed. Reproduction studies in rats with doses of 500mg or 1g cefazolin/kg showed no effect on fertility or fetal development.

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