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Pharmacology: Pharmacodynamics: The antibacterial component of sulbactam/cefoperazone is cefoperazone, a third generation cephalosporin which acts against sensitive organisms during the state of active multiplication by inhibiting biosynthesis of cell wall mucopeptide. Sulbactam does not possess any useful antibacterial activity, except against Neisseriaceae spp and Acinetobacter spp. However, biochemical studies with cell-free bacterial systems have shown it to be an irreversible inhibitor of most important beta-lactamases (Richmond types II, III, IV, and V - plasmid or chromosomally mediated) produced by beta-lactam antibiotic-resistant organisms.
The potential for sulbactam preventing the destruction of penicillins and cephalosporins in resistant organisms is confirmed in whole organism studies using resistant strain in which sulbactam exhibits marked synergistic effects when given together with penicillins and cephalosporins. As sulbactam also binds with some penicillin binding proteins, sensitive strains are also often rendered more susceptible to the combination of sulbactam/cefoperazone than to cefoperazone alone.
Cefoperazone sodium is a broad-spectrum, bactericidal third generation cephalosporin antibiotic that acts by inhibition of cell wall synthesis.
The combination of sulbactam and cefoperazone is active against all organisms sensitive to cefoperazone but in addition demonstrates synergistic activity (up to fourfold reduction in minimum inhibitory concentration values with the combination versus those for each component) against a variety of organisms, most markedly the following: Haemophilus influenzae, Bacteroides species, Staphylococcus species, Acinetobacter calcoaceticus, Enterobacter aerogenes, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus.
Cefoperazone/sulbactam combination in-vitro is active against the following organisms: 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-haemolytic streptococci); Most other strains of beta-haemolytic streptococci; Many strains of Streptococcus faecalis (enterococcus).
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 species, Acinetobacter calcoaceticus, Neisseria gonorrhoeae, Neisseria meningitidis, Bordetella pertussis, Yersinia enterocolitica.
Anaerobic organisms: Gram-negative bacilli (including Bacteroides fragilis, other Bacteroides species, Fusobacterium species); Gram-positive and gram-negative cocci (including Peptococcus, Peptostreptococcus and Veillonella species); Gram-positive bacilli (including Clostridium, Eubacterium and Lactobacillus species).
Susceptibility borders, established for sulbactam / cefoperazone, are shown as follows: See Tables 1 and 2.
Click on icon to see table/diagram/image
Click on icon to see table/diagram/imageFor MIC determination may be used serial dilution of sulbactam / cefoperazone in ratio 1:1 through culture in either broth or agar. It is recommended to be used disk diffusion method of susceptibility testing, containing 30 mcg sulbactam and 75 mcg cefoperazone for a disk.
A laboratory result of "susceptible" indicates that the infecting organism is likely to respond to sulbactam / cefoperazone therapy and a laboratory result of "resistant" indicates that the infecting organism is not likely to respond to therapy. A "moderately susceptible" laboratory result suggests that the infecting organism will be susceptible to sulbactam / cefoperazone if a higher than usual dosage of the medicinal product is used or if the infection is confined to tissues and fluids in which high antibiotic levels are attained.
It is recommended the following control stains to be used for quality control of disks for antibacterial susceptibility - 30 mcg / 75 mcg sulbactam / cefoperazone. (See Table 3.)
Click on icon to see table/diagram/imagePharmacokinetics: Approximately 84% of the sulbactam dose and 25% of the cefoperazone dose administered with sulbactam/cefoperazone is excreted by the kidney. Most of the remaining dose of cefoperazone is excreted in the bile. After sulbactam/cefoperazone administration the mean half-life for sulbactam is about 1 hour while that for cefoperazone is 1.7 hours. Serum concentrations have been shown to be proportional to the dose administered. These values are consistent with previously published values for the agents when given alone.
Mean peak sulbactam and cefoperazone concentrations after the administration of 2 grams of sulbactam/cefoperazone (1 g sulbactam, 1 g of cefoperazone) intravenously over 5 minutes were 130.2 and 236.8 mcg/ml, respectively. This reflects the larger volume of distribution for sulbactam (Vd 18.0 - 21.61) compared to cefoperazone (Vd 10.2 - 11).
Following intramuscular administration of 1.5 g sulbactam/cefoperazone (0.5 g sulbactam, 1 g cefoperazone), the serum concentration peak of sulbactam and cefoperazone are reached within 15 minutes - 2 hours, after the administration. The mean peak concentrations of sulbactam and cefoperazone are 19.0 and 64.2 mcg/ml, respectively.
Both sulbactam and cefoperazone distribute well into a variety of tissues and fluids including bile, gall bladder, skin, appendix, fallopian tubes, ovary, uterus, and others.
There is no evidence of any pharmacokinetic drug interaction between sulbactam and cefoperazone when administered together in the form of sulbactam/cefoperazone. After multiple dosing no significant changes in the pharmacokinetics of either component of sulbactam/cefoperazone have been reported and no accumulation has been observed when administered every 8 to 12 hours.
Special populations: Administration in hepatic dysfunction: See Precautions.
Administration in renal dysfunction: In patients with different degrees of renal function administered sulbactam/cefoperazone, the total body clearance of sulbactam was highly correlated with estimated creatinine clearance. Patients who are functionally anephric showed a significantly longer half-life of sulbactam (mean 6.9 and 9.7 hours in separate studies). Haemodialysis significantly altered the half-life, total body clearance, and volume of distribution of sulbactam. No significant differences have been observed in the pharmacokinetics of cefoperazone in renal failure patients.
Administration in elderly: The pharmacokinetics of sulbactam/cefoperazone has been studied in elderly individuals with renal insufficiency and compromised hepatic function. Both sulbactam and cefoperazone exhibited longer half-life, lower clearance, and larger volumes of distribution when compared to data from normal volunteers. The pharmacokinetics of sulbactam correlated well with the degree of renal dysfunction while for cefoperazone there was a good correlation with the degree of hepatic dysfunction.
Administration in children: Studies conducted in paediatrics have shown no significant changes in the pharmacokinetics of the components of sulbactam/cefoperazone compared to adult values.
The mean half-life in children has ranged from 0.91 to 1.42 hours for sulbactam and from 1.44 to 1.88 hours for cefoperazone.
Toxicology: Preclinical Safety Data: Cefoperazone had adverse effects on the testes of prepubertal rats at all doses tested. Subcutaneous administration of 1,000 mg/kg per day (approximately 16 times the average adult human dose) resulted in reduced testicular weight, arrested spermatogenesis, and reduced germinal cell population and vacuolation of Sertoli cell cytoplasm. The severity of lesions was dose dependent in the 100 to 1,000 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.
When sulbactam/cefoperazone (1:1) was given subcutaneously to neonatal rats for 1 month reduced testicular weights and immature tubules were seen in groups given 300 + 300 mg/kg/day. Because there is a great individual variation in the degree of testicular maturation in rat pups and because immature testes were found in controls any relation to study drug is uncertain. No such findings were seen in infant dogs at doses over 10 times the average adult dose.
