Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1.    Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, ATC code: J01DD01 

Cefotaxime is a broad-spectrum bactericidal cephalosporin antibiotic. Cefotaxime is exceptionally active in vitro against Gram-negative organisms sensitive or resistant to first or second-generation cephalosporins. It is similar to other cephalosporins in activity against Gram-positive bacteria.


Bacteriology:
The following organisms have shown in vitro sensitivity to cefotaxime.
Gram Positive
Staphylococci, including coagulase-positive, coagulase-negative and penicillinase producing strains.
Beta-haemolytic and other streptococci such as Streptococcus mitis (viridans) (many strains of enterococci, e.g. Streptococcus faecalis, are relatively resistant).
Streptococcus (Diplococcus) pneumonia.
Clostridium spp.


Gram Negative
Escherichia coli.
Haemophilius influenzae including ampicillin resistant strains.
Klebsiella spp.
Proteus spp. (both indole positive and indole negative).
Enterobacter spp.
Neisseria spp. (including B-lactamase producing strains of N. gonorrhoea).
Salmonella spp. (including Sal. Typhi).
Shigella spp.
Providencia spp.
Serratia spp.
Citrobacter spp.

Cefotaxime has frequently exhibited useful in vitro activity against Pseudomonas and Bacteroides species although some strains of Bacteroides fragilis are resistant.


There is in vitro evidence of synergy between cefotaxime and aminoglycoside antibiotics such as gentamicin against some species of Gram-Negative bacteria including some strains of Pseudomonas.
No in vitro antagonism has been noted. In severe infections cause by Pseudomonas spp. the addition of an aminoglycoside antibiotic may be indicated.

Pharmacokinetic Properties

5.2.    Pharmacokinetic properties

After a 1000 mg intravenous bolus, mean peak plasma concentrations of cefotaxime usually range between 81 and 102 μg/ml. Doses of 500 mg and 2000 mg produce plasma concentrations of 38 and 200 μg/ml, respectively. There is no accumulation following administration of 1000 mg intravenously or 500 mg intramuscularly for 10 or 14 days.


The apparent volume of distribution at steady-state of cefotaxime is 21.6 L/1.73 m2 after 1 g intravenous 30 minute infusion.


Concentrations of cefotaxime (usually determined by non-selective assay) have been studied in a wide range of human body tissues and fluids. Cerebrospinal fluid concentrations are low when the meninges are not inflamed, but are between 3 and 30 μg/ml in children with meningitis.


Cefotaxime usually passes the blood-brain barrier in levels above the MIC of common sensitive pathogens when the meninges are inflamed. Concentrations (0.2-5.4 μg/ml), inhibitory for most Gram-negative bacteria, are attained in purulent sputum, bronchial secretions and pleural fluid after doses of 1 or 2 g. Concentrations likely to be effective against most sensitive organisms are similarly attained in female reproductive organs, otitis media effusions, prostatic tissue, interstitial fluid, renal tissue, peritoneal fluid and gall bladder wall, after usual therapeutic doses. High concentrations of cefotaxime and desacetyl-cefotaxime are attained in bile.


Cefotaxime is partially metabolised prior to excretion. The principle metabolite is the microbiologically active product, desacetyl-cefotaxime. Most of a dose of cefotaxime is excreted in 

the urine about 60% as unchanged drug and a further 24% as desacetyl-cefotaxime. Plasma clearance is reported to be between 260 and 390 ml/minute and renal clearance 145 to 217 ml/minute.


After intravenous administration of cefotaxime to healthy adults, the elimination half-life of the parent compound is 0.9 to 1.14 hours and that of the desacetyl metabolite, about 1.3 hours.


In neonates the pharmacokinetics are influenced by gestational and chronological age, the half-life being prolonged in premature and low birth weight neonates of the same age.


In severe renal dysfunction the elimination half-life of cefotaxime itself is increased minimally to about 2.5 hours, whereas that of desacetyl-cefotaxime is increased to about 10 hours. Total urinary recovery of cefotaxime and its principal metabolite decreases with reduction in renal function.