Zifam CS1/CS2

Zifam CS1/CS2

cefoperazone + sulbactam

Manufacturer:

Zifam Pinnacle

Distributor:

Pyrex
Full Prescribing Info
Contents
Sulbactam sodium, cefoperazone sodium.
Description
Zifam CS1: Each 1-g vial contains the equivalent of sulbactam 500 mg and cefoperazone 500 mg.
Zifam CS2: Each 2-g vial contains the equivalent of sulbactam 1000 mg and cefoperazone 1000 mg.
Zifam is available as a dry powder for reconstitution in a 1:1 ratio in terms of free sulbactam and cefoperazone.
Sulbactam sodium is a derivative of the basic penicillin nucleus. Sulbactam sodium is sodium penicillinate sulfone and is an off-white crystalline powder which is highly soluble in water. The molecular weight is 255.22.
Cefoperazone sodium is a semisynthetic broad-spectrum cephalosporin antibiotic for parenteral use only. It contains 34 mg sodium (1.5 mEq)/g. Cefoperazone is a white crystalline powder which is freely soluble in water. The molecular weight is 667.65.
Action
Pharmacology: Pharmacokinetics: 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. The mean half-life for sulbactam is about 1 hr while that for cefoperazone is 1.7 hrs. 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 g of sulbactam/cefoperazone (1 g sulbactam, 1 g of cefoperazone) IV over 5 mins were 130.2 mcg/mL and 236.8 mcg/mL, respectively. This reflects the larger volume of distribution for sulbactam (Vd=18-27.6 L) compared to cefoperazone (Vd=10.2-11.3 L). After IM administration of 1.5 g sulbactam/cefoperazone (0.5 g sulbactam, 1 g cefoperazone), peak serum concentrations of sulbactam and cefoperazone are seen from 15 mins-2 hrs after administration. Mean peak serum concentration were 19 and 64.2 mcg/mL for sulbactam and cefoperazone, respectively.
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 8-12 hrs.
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 longer 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.
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 hrs in separate studies). Hemodialysis 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.
Studies conducted in pediatrics 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 0.91-1.42 hrs for sulbactam and from 1.44-1.88 hrs for cefoperazone.
Both sulbactam and cefoperazone distribute well into a variety of tissues and fluids including bile, gallbladder, 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.
Microbiology: In Vitro Susceptibility Data: Cefoperazone is a 3rd generation cephalosporin, which acts against sensitive organisms during the stage of active multiplication by inhibiting biosynthesis of cell wall mucopeptide. Sulbactam does not possess any useful antibacterial activity, except against Neisseria and Acinetobacter. However, biochemical studies with cell-free bacterial systems have shown it to be an irreversible inhibitor of the most important β-lactamases produced by β-lactam antibiotic-resistant organisms.
The potential for sulbactam preventing the destruction of penicillins and cephalosporins by resistant organisms was confirmed in whole-organism studies using resistant strains in which sulbactam exhibited marked synergy with penicillins and cephalosporins. As sulbactam also binds with some penicillin-binding proteins, sensitive strains are also often rendered more susceptible to sulbactam/cefoperazone than to cefoperazone alone.
The combination of sulbactam and cefoperazone is active against all organisms sensitive to cefoperazone. In addition, it demonstrates synergistic activity [up to 4-fold reduction in minimum inhibitory concentrations (MIC) for the combination versus those for each component] in a variety of organisms, most markedly the following: Haemophilus influenzae, Bacteroides sp, Staphylococcus sp, Acinetobacter calcoaceticus, Enterobacter aerogenes, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus.
Sulbactam/cefoperazone is active in vitro against a wide variety of clinically significant organisms: Gram-positive organisms: Staphylococcus aureus, penicillinase- and non-penicillinase-producing strains; Staphylococcus epidermidis; Streptococcus pneumoniae (formerly Diplococcus pneumoniae); Streptococcus pyogenes (group A β-hemolytic Streptococci); most other strains of β-hemolytic Streptococci; many strains of Streptococcus faecalis (Enterococcus).
Gram-negative organisms: Escherichia coli; Klebsiella sp; Enterobacter sp; Citrobacter sp; Haemophilus influenzae; Proteus mirabilis; Proteus vulgaris; Morganella morganii (formerly Proteus morganii); Providencia rettgeri (formerly Proteus rettgeri); Providencia sp; Serratia sp (including S. marcescens); Salmonella and Shigella spp; Pseudomonas aeruginosa and some other Pseudomonas sp; Acinetobacter calcoaceticus; Neisseria gonorrhoeae; Neisseria meningitides; Bordetella pertussis; Yersinia enterocolitica.
Anaerobic organisms: Gram-negative bacilli (including Bacteroides fragilis, other Bacteroides and Fusobacterium spp). Gram-positive bacilli (including Clostridium, Eubacterium and Lactobacillus spp). Gram-positive and gram-negative cocci (including Peptococcus, Peptostreptococcus and Veillonella spp).
Indications/Uses
Treatment of the following infections when caused by susceptible organisms: Respiratory tract infections (upper and lower); urinary tract infections (upper and lower); peritonitis, cholecystitis, cholangitis and other intra-abdominal infections; septicemia; meningitis; skin and soft tissue infections; bone and joint infections; pelvic inflammatory disease, endometriosis, gonorrhea and other infections of the genital tract.
Combination Therapy: Because of the broad spectrum of activity of Zifam CS1/CS2, most infections can be treated adequately with this antibiotic alone. However, sulbactam/cefoperazone may be used concomitantly with other antibiotics if such combinations are indicated. If an aminoglycoside is used (see Dosage & Administration), renal function should be monitored during the course of therapy.
Dosage/Direction for Use
Zifam CS1/CS2 is available in 1 g and 2 g strength vials.
The total dosage of 1 g has an equivalent dosage of 0.5 g of sulbactam and 0.5 g of cefoperazone. The total volume of reconstituted solution is 4 mL and the maximum final concentration is 125 mg/mL of sulbactam and 125 mg/mL of cefoperazone.
The total dosage of 2 g has an equivalent dosage of 1 g of sulbactam and 1 g of cefoperazone. The total volume of reconstituted solution is 8 mL and the maximum final concentration is 125 mg/mL of sulbactam and 125 mg/mL of cefoperazone.
Adults: Usual Dose: 2-4 g/day. Doses should be administered IV or IM every 12 hrs in equally divided doses. In severe or refractory infections, the daily dosage may be increased up to 8 g (ie, 4-g cefoperazone activity).
Patients receiving the 1:1 ratio may require additional cefoperazone administered separately. Doses should be administered every 12 hrs in equally divided doses. The recommended maximum daily dosage of sulbactam is 4 g.
Dosage regimen of sulbactam/cefoperazone should be adjusted in patients with marked decrease in renal function (creatinine clearance of <30 mL/min) to compensate for the reduced clearance of sulbactam. Patients with creatinine clearance between 15 and 30 mL/min should receive a maximum of 1 g of sulbactam administered every 12 hrs (maximum daily dosage of 2-g sulbactam), while patients with creatinine clearance of <15 mL/min should receive a maximum of 500 mg of sulbactam every 12 hrs (maximum daily dosage of 1-g sulbactam). In severe infections, it may be necessary to administer additional cefoperazone.
The pharmacokinetic profile of sulbactam is significantly altered by hemodialysis. The serum half-life of cefoperazone is reduced slightly during hemodialysis. Thus, dosing should be scheduled to follow a dialysis period.
Children: Usual Daily Dose: 40-80 mg/kg/day (ie, 20-40 mg/kg/day cefoperazone activity) in 2-4 equally divided doses. In serious or refractory infections, the dosage may be increased up to 160 mg/kg/day (ie, 80 mg/kg/day cefoperazone activity) in 2-4 equally divided doses. For neonates in the 1st week of life, the drug should be given every 12 hrs. The maximum daily dosage of sulbactam in pediatrics should not exceed 80 mg/kg/day. In cases where doses above 80 mg/kg/day cefoperazone activity are necessary, additional cefoperazone should be administered.
IV Administration: For intermittent infusion, each vial of sulbactam/cefoperazone should be reconstituted with the appropriate amount of 5% dextrose in water, 0.9% sodium chloride injection or sterile water for injection and then diluted to 20 ml with the same solution followed by administration over 15-60 mins.
For IV injection, each vial should be reconstituted as previously mentioned and administered over a minimum of 3 mins.
IM Administration: Sterile water for injection should be used for reconstitution. For a concentration of cefoperazone of ≥250 mg/mL, a 2-step dilution is required using sterile water for injection further diluted with 2% lidocaine to yield solutions containing up to 250 mg cefoperazone and sulbactam 125 mg/mL in approximately 0.5% lidocaine HCl solution.
Incompatibilities: Aminoglycosides: Solution of sulbactam/cefoperazone and aminoglycosides should not be directly mixed, since there is a physical incompatibility between them. If combination therapy with sulbactam/cefoperazone and an aminoglycoside is contemplated, this can be accomplished by sequential intermittent IV infusion provided that separate secondary IV tubing is used and that the primary IV tubing is adequately irrigated with an approved diluent between doses. It is also suggested that doses of sulbactam/cefoperazone be administered throughout the day at times as far removed from administration of the aminoglycoside as possible.
Lactated Ringer's Solution: Initial reconstitution with Lactated Ringer's solution should be avoided since this mixture has been shown to be incompatible. However, a 2-step dilution process involving initial reconstitution in water for injection will result in a compatible mixture when further diluted with Lactated Ringer's solution.
Lidocaine: Initial reconstitution with 2% lidocaine HCl solution should be avoided since these mixtures have been shown to be incompatible. However, a 2-step dilution process involving initial reconstitution in water for injection will result in a compatible mixture when further diluted with 2% lidocaine HCl solution.
Contraindications
Patients with known hypersensitivity to penicillins, sulbactam, cefoperazone or any of the cephalosporins.
Warnings
Seriously and occasionally, hypersensitivity (anaphylactic) reactions have been reported in patients receiving β-lactam therapy. These reactions are more apt to occur in individuals with history of hypersensitivity reactions to multiple allergens. If any allergic reaction occurs, the drug should be discontinued and the appropriate therapy instituted. Serious anaphylactic reactions require immediate emergency treatment with epinephrine, oxygen, IV steroids and airway management, including intubation, should be administered as indicated.
Special Precautions
General: Those precautions that pertain to sulbactam and cefoperazone will also pertain to the combination as follows.
Cefoperazone is extensively excreted in bile. The serum half-life of cefoperazone is usually prolonged and urinary excretion of the drug increased in patients with hepatic disease and/or biliary obstruction. Even with severe hepatic dysfunction, therapeutic concentrations of cefoperazone are obtained in bile and only a 2- to 4-fold increase in half-life is seen.
Dose modification may be necessary in cases of severe biliary obstruction, severe hepatic disease or in cases of renal dysfunction coexistent with either of those conditions.
In patients with hepatic dysfunction and concomitant renal impairment, cefoperazone serum concentration should be monitored and dosage adjusted as necessary. In these cases, dosage should not exceed 2 g/day of cefoperazone without close monitoring of serum concentrations. The serum half-life of cefoperazone is reduced slightly during hemodialysis. Thus, dosing should be scheduled to follow a dialysis period.
As with other antibiotics, vitamin K deficiency has occurred in a few patients treated with cefoperazone. The mechanism is most probably related to the suppression of gut flora which normally synthesize this vitamin. Those at risk include patients with poor diet, malabsorption states (eg, cystic fibrosis) and patients on prolonged IV alimentation regimens. Prothrombin time should be monitored in these patients and exogenous vitamin K administered as indicated.
As with other antibiotics, overgrowth of nonsusceptible organisms may occur during prolonged use of Zifam CS1/CS2. Patients should be observed carefully during treatment.
As with any potent systemic agent, it is advisable to check periodically for organ system dysfunction during extended therapy including renal, hepatic and hematopoietic systems. This is particularly important in neonates, especially when premature and other infants.
A reaction characterized by flushing, sweating, headache and tachycardia has been reported when alcohol was ingested during and as late as the 5th day after cefoperazone administration. A similar reaction has been reported within certain other cephalosporins and patients should be cautioned concerning ingestion of alcoholic beverages in conjunction with administration of sulbactam/cefoperazone. For patients requiring artificial feeding orally or parenterally, solutions containing ethanol should be avoided.
Drug-Laboratory Test Interactions: A false-positive reaction for glucose in the urine may occur with Benedict's or Fehling's solution.
Use in pregnancy & lactation: Reproduction studies have been performed in rats at doses up to 10 times the human dose and have revealed no evidence of impaired fertility and no teratological findings. Sulbactam and cefoperazone cross the placental barrier. There are; however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Zifam CS1/CS2 should be used during pregnancy only if clearly needed.
Only small quantities of sulbactam and cefoperazone are excreted in human milk. Although both drugs pass poorly into breast milk of nursing mothers, caution should be exercised when Zifam CS1/CS2 is administered to a nursing mother.
Use In Pregnancy & Lactation
Reproduction studies have been performed in rats at doses up to 10 times the human dose and have revealed no evidence of impaired fertility and no teratological findings. Sulbactam and cefoperazone cross the placental barrier. There are; however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Zifam CS1/CS2 should be used during pregnancy only if clearly needed.
Only small quantities of sulbactam and cefoperazone are excreted in human milk. Although both drugs pass poorly into breast milk of nursing mothers, caution should be exercised when Zifam CS1/CS2 is administered to a nursing mother.
Adverse Reactions
Zifam CS1/CS2 is generally well tolerated. The majority of adverse events is of mild or moderate severity and is tolerated with continued treatment. In pooled clinical trial data from comparative and noncomparative studies in approximately 2500 patients, the following was observed.
Gastrointestinal: As with other antibiotics, the most frequent side effects observed with sulbactam/cefoperazone have been gastrointestinal. Diarrhea/loose stools (3.9%) have been reported most frequently followed by nausea and vomiting (0.6%).
Dermatologic Reactions: As with all penicillins and cephalosporins, hypersensitivity manifested by maculopapular rash (0.6%) and urticaria (0.08%) has been reported. These reactions are more likely to occur in patients with a history of allergies, particularly to penicillin.
Hematology: Slight decreases in neutrophils (0.4%, 5/1131) have been reported. As with other β-lactam antibiotics, reversible neutropenia (0.5%, 9/1696) may occur with prolonged administration. Some individuals have developed a positive direct Coombs' test (5.5%, 15/269) during treatment. Decreased hemoglobin (0.9%, 13/1416) or hematocrit (0.9%, 13/1409) have been reported, which is consistent with published literature on cephalosporins. Transient eosinophilia (3.5%, 40/1130) and thrombocytopenia (0.8%, 11/1414) have occurred and hypoprothrombinemia (3.8%, 10/262) has been reported.
Miscellaneous: Headache (0.04%), fever (0.5%), injection pain (0.08%), chills (0.04%).
Laboratory Abnormalities: Transient elevations of liver function tests, SGOT (5.7%, 94/1638), SGPT (6.2%, 95/1529), alkaline phosphatase (2.4%, 37/1518) and bilirubin (1.2%, 12/1040) levels, have been noted.
Local Reactions: Sulbactam/cefoperazone is well tolerated following IM administration. Occasionally, transient pain may follow administration by this route. As with other cephalosporins and penicillins, when sulbactam/cefoperazone is administered by an IV catheter, some patients may develop phlebitis 0.1% at the infusion site.
Storage
Store at temperatures below 25°C.
MIMS Class
ATC Classification
J01DD62 - cefoperazone and beta-lactamase inhibitor ; Belongs to the class of third-generation cephalosporins. Used in the systemic treatment of infections.
Presentation/Packing
Inj (vial) 1 g x 1's. 2 g x 1's.
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