Pharmacology: Pharmacodynamics: The bactericidal action of cefoperazone results from the inhibition of bacterial cell wall synthesis. Cefoperazone is active in vitro against a wide variety of clinically significant organisms, and is resistant to degradation by many beta-lactamases. Susceptible organisms include: Gram-Positive Organisms: Staphylococcus aureus, penicillinase and non-penicillinase-producing strains; Staphylococcus epidermidis; Streptococcus pneumoniae (formerly Diplococcus pneumoniae); Streptococcus pyogenes (Group A beta-hemolytic streptococci); Streptococcus agalactiae (Group B beta-hemolytic streptococci); Streptococcus faecalis (enterococcus); Beta-hemolytic streptococci.
Gram-Negative Organisms: Escherichia coli; Klebsiella species; Enterobacter species; Citrobacter species; Haemophilus influenzae; Proteus mirabilis; Proteus vulgaris; Morganella morganii (formerly Proteus morganii); Providencia rettgeri (formerly Proteus rettgeri); Providencia species; Serratia species (including S. marcescens); Salmonella and Shigella species; Pseudomonas aeruginosa and some other Pseudomonas; Acinetobacter calcoaceticus; Neisseria gonorrhoeae; Neisseria meningitidis; Bordetella pertussis; Yersinia enterocolitica.
Anaerobic Organisms: Gram-positive and gram-negative cocci (including Peptococcus, Peptostreptococcus and Veillonella species).
Gram-positive bacilli (including Clostridium, Eubacterium and Lactobacillus species).
Gram-negative bacilli (including Fusobacterium species, many strains of Bacteroides fragilis and other species of Bacteroides).
Pharmacokinetics: High serum bile and urine levels of cefoperazone are attained after a single dose of the drug. Table 1 demonstrates the serum concentrations of cefoperazone in normal volunteers following either a single 15-minute constant rate intravenous infusion of 1, 2, 3, or 4 grams of the drug or a single intramuscular injection of 1 or 2 grams of the drug. Probenecid has no effect on serum concentrations of cefoperazone. (See Table 1.)
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The mean serum half-life of cefoperazone is approximately 2 hours, independent of the route of administration.
Cefoperazone reaches therapeutic levels in all body fluids and tissues tested. Among these are ascitic and cerebrospinal (in patients with inflamed meninges) fluids; urine; bile and gallbladder wall; sputum and lung; palatine tonsil and sinus mucous membrane; atrial appendage; kidney, ureter, prostate, and testis; uterus and Fallopian tube; bone; and umbilical cord blood and amniotic fluid.
Cefoperazone is excreted in both the bile and urine. Maximum bile concentrations are generally obtained between one and three hours following drug administration and exceed concurrent serum concentrations by up to 100 times. Reported biliary concentrations of cefoperazone range from 66 mcg/ml at 30 minutes to as high as 6000 mcg/ml at 3 hours after an intravenous bolus injection of 2 grams in patients without biliary tract obstruction.
After a variety of dosages and routes of administration, the urinary recovery of cefoperazone averages 20 to 30% over a 12-hour period in individuals with normal renal function. Urinary concentrations greater than 2200 mcg/ml have been obtained following a 15-minute infusion of a 2 gram dose. After an IM injection of 2 gram, peak urine concentrations of approximately 1000 mcg/ml have been obtained.
Repeated administration of cefoperazone has not resulted in accumulation of the drug in normal subjects.
Use in Hepatic Dysfunction: In patients with hepatic dysfunction, the serum half-life is prolonged and urinary excretion is increased. In patients with both renal and hepatic insufficiencies, cefoperazone may accumulate in the serum.
Use in Renal Dysfunction: Peak serum concentrations, AUCs, and serum half-lives are similar in normal subjects and in patients with renal insufficiency.
Toxicology: Preclinical safety data: Cefoperazone had adverse effects on the testes of prepubertal rats at all doses tested. Subcutaneous administration of 1000 mg per kg per day (approximately 16 times the average adult human dose) resulted in reduced testicular weight, arrested spermatogenesis, reduced germinal cell population and vacuolation of Sertoli cell cytoplasm. The severity of lesions was dose dependent in the 100 to 1000 mg/kg per day range; the low dose caused a minor decrease in spermatocytes. This effect has not been observed in adult rats. Histologically the lesions were reversible at all but the highest dosage levels. However, these studies did not evaluate subsequent development of reproductive function in the rats. The relationship of these findings to humans is unknown.