Pharmacology: Pharmacodynamics: Antibacterial action: Cefotaxime is primarily bactericidal; it also may be bacteriostatic. Activity depends on the organism, tissue penetration, dosage, and rate of organism multiplication. It acts by adhering to bacterial penicillin-binding proteins, thereby inhibiting cell walls synthesis. Third-generation cephalosporins appear to be more active against some beta-lactamase-producing gram-negative organisms. Cefotaxime is active against some gram-positive organisms and many enteric gram-negative bacilli, including streptococci (Streptococcus pneumoniae and S. pyogenes), Staphylococcus aureus (penicillinase-and non-penicillinase-producing), Staphylococcus epidermidis, Escherichia coli, Klebsiella species, Haemophilus influenzae, Enterobacter species, Proteus species, Peptostreptococcus species, and some strains of Pseudomonas aeruginosa. Listeria and Acinetobacter are often resistant. The active metabolite of cefotaxime, desacetylcefotaxime may act synergistically with the parent drug against some bacterial strains.
Pharmacokinetics: Cefotaxime is administered by injection as the sodium salt. It is rapidly absorbed after intramuscular injection and mean peak plasma concentration of about 12 and 20 μg per mL have been reported 30 minutes after doses of 0.5 and 1 g of cefotaxime, respectively. Immediately after intravenous injection of 0.5, 1 or 2 g of cefotaxime, mean peak plasma concentration of 38, 102, and 215 μg per mL, respectively, have been achieved with concentrations ranging from about 1 to 3 μg per mL after 4 hours. The plasma half-life of cefotaxime is about 1 hour and that of that active metabolite desacetylcefotaxime is about 1.5 hours; half-lives are increased in neonates and in patients with severe renal impairment, especially those of the metabolite, and a reduction in dosage may be necessary. The effects of liver disease on clearance of cefotaxime and its metabolite have been variable, but in general dosage adjustment has not been considered necessary. About 40% of cefotaxime in the circulation is reported to be bound to plasma proteins. Cefotaxime and desacetylcefotaxime are widely distributed in body tissues and fluids; therapeutic concentrations are achieved in the CSF particularly when the meninges are inflamed. It crosses the placenta and low concentrations have been detected in breast milk.
Following partial metabolism in the liver to desacetylcefotaxime and inactive metabolites, elimination is mainly by the kidneys and about 40 to 60% of a dose has been recovered unchanged in the urine within 24 hours; a further 20% is excreted as the desacetyl metabolite. Relatively high concentrations of cefotaxime and desacetylcefotaxime are achieved in bile and about 20% of a dose has been recovered in the faeces.
Probenecid competes for renal tubular secretions with cefotaxime resulting in higher and prolonged plasma concentrations of cefotaxime and its desacetyl metabolite. Cefotaxime and its metabolite are removed by haemodialysis.