Release form, packaging and composition of the drug Cefoperazone + Sulbactam
Powder for the preparation of a solution for intravenous and intramuscular administration, white or white with a yellowish tint; the reconstituted solution is light yellow to yellow.
| 1 fl. | |
| cefoperazone sodium | 518 mg, |
| which corresponds to the content of cefoperazone | 500 mg |
| sulbactam sodium | 550 mg, |
| which corresponds to the content of sulbactam | 500 mg |
1 g - Glass bottles with a capacity of 10 ml (1) - cardboard packs. 1 g - Glass bottles with a capacity of 10 ml (5) - cardboard packs. 1 g - Glass bottles with a capacity of 10 ml (10) - cardboard packs. 1 g - Glass bottles with a capacity of 10 ml (1) complete with solvent - water for 5 ml ampoules - 1 amp. - cardboard packs. 1 g - Glass bottles with a capacity of 10 ml (5) complete with solvent - water for and in 5 ml ampoules - 5 amps. - cardboard packs. 1 g - Glass bottles with a capacity of 10 ml (10) complete with solvent - water for and in ampoules 5 ml - 10 amps. - cardboard packs.
pharmachologic effect
Combined drug, broad-spectrum antibiotic.
Cefoperazone is a third-generation cephalosporin antibiotic that is bactericidal and has a wide spectrum of action; highly active against aerobic and anaerobic gram-positive and gram-negative microorganisms (including Pseudomonas aeruginosa), resistant to beta-lactamases of gram-positive and gram-negative microorganisms.
Sulbactam is an irreversible inhibitor of beta-lactamases, which are secreted by microorganisms resistant to beta-lactam antibiotics; prevents the destruction of penicillins and cephalosporins under the influence of beta-lactamases of resistant microorganisms; binding to penicillin-binding proteins, it exhibits synergism when used simultaneously with penicillins and cephalosporins.
The combination of cefoperazone + sulbactam is active against all microorganisms sensitive to cefoperazone and exhibits synergism (reduces the MIC of the combination by up to 4 times compared to the values for each component separately) against microorganisms: Haemophilus influenzae, Bacteroides spp., Staphylococcus spp., Acinetobacter calcoaceticus, Enterobacter aerogenes, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus.
Active in vitro against gram-positive bacteria - Staphylococcus aureus (including strains that form and do not form penicillinase), Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes (beta-hemolytic strain of group A), Streptococcus agalactiae (beta-hemolytic strain of group B), most strains of beta-hemolytic Streptococcus spp., Enterococcus faecalis; gram-negative bacteria - Escherichia coli, Klebsiella spp., Enterobacter spp., Citrobacter spp., Haemophilus influenzae, Proteus mirabilis, Morganella morganii, Providencia rettgeri, Providencia spp., Serratia spp. (including Serratia marcescens), Salmonella spp., Shigella spp., Pseudomonas aeruginosa, Acinetobacter calcoaceticus, Neisseria gonorrhoeae, Neisseria meningitidis; Bordetella pertussis, Yersinia enterocolitica; anaerobic bacteria - Bacteroides fragilis, Fusobacterium spp., Peptococcus spp., Peptostreptococcus spp., Veillonella spp., Clostridium spp., Eubacter spp., Lactobacillus spp.
Pharmacodynamics and pharmacokinetics
The combination of sulbactam and cefoperazone affects bacteria sensitive to cefoperazone . It acts synergistically against Escherichia coli, Staphylococcus spp., Proteus mirabilis, Enterobacter aerogenes, Morganella morganii, Bacteroides spp., Enterobacter cloacae, Acinetobacter calcoaceticus, Klebsiella pneumoniae, Citrobacter freundii, Haemophilus influenzae, Citrobacter diversus.
Cefoperazone affects microorganisms by inhibiting the biosynthesis of bacterial cell wall mucopeptide
Sulbactam promotes the activity of cefoperazone against resistant microorganisms that produce beta-lactamases .
The degree of binding of cefoperazone plasma proteins is about 85%, sulbactam - 38%.
The half-life of cefoperazone is approximately 2 hours, sulbactam - 1 hour. Cefoperazone is excreted in the urine within 8 hours.
In case of liver dysfunction, serum and urinary elimination time are increased.
Pharmacokinetics
Cmax of sulbactam and cefoperazone after intravenous administration of the combination at a dose of 2 g (1 g of sulbactam and 1 g of cefoperazone) for 5 minutes averaged 130.2 μg/ml and 236.8 μg/ml, respectively. This reflects the higher Vd of sulbactam (18.0 to 27.6 L) compared to that of cefoperazone (10.2 to 11.3 L).
After intramuscular administration of 1.5 g of sulbactam/cefoperazone (500 mg of sulbactam, 1 g of cefoperazone), the Cmax of sulbactam and cefoperazone in serum was observed from 15 minutes to 2 hours after administration. Cmax in serum were 19.0 and 64.2 μg/ml of sulbactam and cefoperazone, respectively.
Both sulbactam and cefoperazone are well distributed in various tissues and body fluids, including bile, gallbladder, skin, appendix, fallopian tubes, ovaries, and uterus.
There is no data on the presence of any pharmacokinetic interaction between sulbactam and cefoperazone when administered as part of combination drugs.
With repeated use, no significant changes in the pharmacokinetic parameters of both components were noted. When the drug was administered every 8-12 hours, no accumulation was observed.
Approximately 84% of the sulbactam dose and 25% of the cefoperazone dose when administered in combination are excreted by the kidneys. The remaining part of cefoperazone is excreted mainly in bile. When the combination is administered, T1/2 of sulbactam averages about 1 hour, T1/2 of cefoperazone is 1.7 hours. Plasma concentration is proportional to the administered dose.
Cefoperazone is actively excreted in bile. T1/2 of cefoperazone is usually prolonged, and urinary excretion is increased in patients with liver disease and/or biliary tract obstruction. Even with severe liver dysfunction, a therapeutic concentration of cefoperazone is achieved in the bile, and T1/2 increases only 2-4 times.
In patients with varying degrees of renal impairment who received this combination, a high correlation was revealed between the total clearance of sulbactam from the body and the calculated QC. In patients with end-stage renal failure, a significant prolongation of T1/2 of sulbactam was detected (on average 6.9 hours and 9.7 hours in various studies). Hemodialysis caused significant changes in T1/2, total body clearance and Vd of sulbactam.
In elderly people with renal failure and impaired liver function, compared with healthy volunteers, an increase in T1/2 duration, a decrease in clearance and an increase in Vd of both sulbactam and cefoperazone were detected. The pharmacokinetics of sulbactam correlated with the degree of renal dysfunction, and the pharmacokinetics of cefoperazone correlated with the degree of liver dysfunction.
Studies in children did not reveal significant changes in the pharmacokinetic parameters of the components of the combination compared to adults. The average T1/2 of sulbactam in children ranged from 0.91 to 1.42 hours, cefoperazone - from 1.44 to 1.88 hours.
Cefoperazone + Sulbactam
Pharmacodynamics
The antibacterial component of cefoperazone/sulbactam is cefoperazone, a third-generation cephalosporin that acts on sensitive microorganisms during their active reproduction by inhibiting the biosynthesis of cell wall mucopeptide. Sulbactam does not have clinically significant antibacterial activity (except for Neisseriaceae and Acinetobacter). However, it has been noted that it is an irreversible inhibitor of most major beta-lactamases, which are produced by microorganisms resistant to beta-lactam antibiotics.
The ability of sulbactam to prevent the destruction of penicillins and cephalosporins by resistant microorganisms was confirmed in studies using resistant strains, in relation to which sulbactam had pronounced synergism with penicillins and cephalosporins. In addition, sulbactam interacts with some penicillin-binding proteins, so cefoperazone/sulbactam often has a more pronounced effect on susceptible strains than cefoperazone alone.
The combination of cefoperazone and sulbactam is active against all microorganisms sensitive to cefoperazone. In addition, it has synergism against various microorganisms, primarily: Haemophilus influenzae, Bacteroides spp., Staphylococcus spp., Acinetobacter calcoaceticus, Enterobacter aerogenes, Escherichia coli, Proteus mirabilis, Klebsiella pneumoniae, Morganella morganii, Citrobacter freundii, Enterobacter cloacae, Citrobacter diversus.
Cefoperazone/sulbactam is active in vitro against a wide range of clinically significant microorganisms.
Gram-positive microorganisms
Staphylococcus aureus (penicillinase and non-penicillinase producing), Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes (group A beta-hemolytic streptococcus), Streptococcus agalactiae (group B beta-hemolytic streptococcus), most other strains of beta-hemolytic streptococci, many strains of Streptococcus faecalis (enterococci).
Gram-negative microorganisms
Escherichia coli, Klebsiella spp., Enterobacter spp., Citrobacter spp., Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia rettgeri, Providencia spp., Serratia spp. (including Serratia marcescens), Salmonella spp. and Shigella spp., Pseudomonas aeruginosa and some other Pseudomonas spp., Acinetobacter calcoaceticus, Neisseria gonorrhoeae, Neisseria meningitidis, Bordetella pertussis, Yersinia enterocolitica.
Anaerobic microorganisms
Gram-negative rods (including Bacteroides fragilis, other Bacteroides spp. and Fusobacterium spp.).
Gram-positive and gram-negative cocci (including Peptococcus spp., Peptostreptococcus spp. and Veillonella spp.).
Gram-positive rods (including Clostridium spp., Eubacterium spp. and Lactobacillus spp.).
The following sensitivity levels have been established for cefoperazone/sulbactam. The minimum inhibitory concentration (MIC) in mcg/ml, expressed in the concentration of cefoperazone, for sensitive microorganisms ≤16, for organisms with intermediate sensitivity is in the range of 17-63, and for resistant ones - more than 64. The sensitivity zones when determined by the disk diffusion method are : for sensitive microorganisms ≥21 mm; with intermediate sensitivity - from 16 to 20 mm, and for resistant ≤15 mm.
To determine the MIC, the method of serial dilutions of cefoperazone/sulbactam in a 1:1 ratio in broth or agar media can be used.
To determine MIC by the disk diffusion method, it is recommended to use a disk containing 30 μg of sulbactam and 75 μg of cefoperazone.
The following quality control standards are recommended when using discs containing 30 mcg sulbactam and 75 mcg cefoperazone. For the control strain Acinetobacter spp. (ATCC 43498) zone diameter is 26-32; for Pseudomonas aeruginosa (ATCC 27853) - 22-28; for Escherichia coli (ATCC 25922) - 27-33; for Staphylococcus aureus (ATCC 25923) - 23-30.
Pharmacokinetics
Suction and distribution
The maximum concentration (Cmax) of cefoperazone and sulbactam in the blood serum after intravenous administration of cefoperazone + sulbactam at a dose of 2000 mg (1000 mg cefoperazone + 1000 mg sulbactam) is achieved within 5 minutes and averages 236.8 mcg/ml for cefoperazone and 130. 2 µg/ml for sulbactam. This reflects the higher volume of distribution of sulbactam (Vd=18-27.6 L) compared to that of cefoperazone (Vd=10.2-11.3 L).
Serum concentration is proportional to the administered dose.
After intramuscular administration of 1500 mg cefoperazone + sulbactam (1000 mg cefoperazone, 500 mg sulbactam), maximum serum concentrations of sulbactam and cefoperazone were observed from 15 minutes to 2 hours after administration. Maximum serum concentrations were 19.0 and 64.2 μg/ml for sulbactam and cefoperazone, respectively. Both sulbactam and cefoperazone are well distributed into various tissues and fluids, including bile, gallbladder, skin, appendix, fallopian tubes, ovaries, uterus, etc.
Metabolism and excretion
The half-life (T1/2) of sulbactam averages 1 hour, T1/2 of cefoperazone - 1.7 hours.
Approximately 84% of a dose of sulbactam and 25% of a dose of cefoperazone are excreted by the kidneys.
The remaining part of cefoperazone is excreted mainly with bile through the intestines.
With repeated use, no significant changes in the pharmacokinetic parameters of both components of the drug were observed. When the drug was administered every 8-12 hours, no accumulation was observed.
Cefoperazone does not displace bilirubin from binding to plasma proteins. There is no data on the presence of any pharmacokinetic interaction between cefoperazone and sulbactam when cefoperazone + sulbactam is administered.
Pharmacokinetics in special clinical situations
In case of liver dysfunction
Cefoperazone is actively excreted in bile. T1/2 of cefoperazone is usually prolonged, and renal excretion of the drug is increased in patients with liver disease and/or biliary tract obstruction. Even with severe liver dysfunction, a therapeutic concentration of cefoperazone is achieved in the bile, and T1/2 increases only 2-4 times.
If kidney function is impaired
In patients with varying degrees of renal impairment who received cefoperazone + sulbactam, a high correlation was found between the total body clearance of sulbactam and the estimated creatinine clearance. In patients with end-stage renal failure, a significant prolongation of T1/2 of sulbactam was detected (on average 6.9 and 9.7 hours in various studies). Hemodialysis caused significant changes in T1/2, total clearance and volume of distribution of sulbactam.
In older people
The pharmacokinetics of cefoperazone + sulbactam have been studied in elderly people with renal failure and impaired liver function. Compared with healthy volunteers, an increase in the duration of T1/2, a decrease in clearance and an increase in the volume of distribution of both sulbactam and cefoperazone were detected. The pharmacokinetics of sulbactam correlated with the degree of renal dysfunction, and the pharmacokinetics of cefoperazone correlated with the degree of liver dysfunction.
In children
Studies in children did not reveal significant changes in the pharmacokinetic parameters of the cefoperazone + sulbactam components compared to those in adults. The average half-life of sulbactam in children was 0.91-1.42 hours, cefoperazone - 1.44-1.8 hours.
Indications of the active substances of the drug Cefoperazone + Sulbactam
Treatment of infectious and inflammatory diseases caused by microorganisms sensitive to the combination of cefoperazone + sulbactam: pharyngitis, tonsillitis, sinusitis, bronchitis, pneumonia, bronchopneumonia, empyema, lung abscess, pyelonephritis, cystitis, prostatitis, endometritis, gonorrhea, vulvovaginitis; peritonitis, cholecystitis, cholangitis; acute otitis media, sinusitis, tonsillitis; furunculosis, abscess, pyoderma, lymphadenitis, lymphangitis; osteomyelitis, joint infections, sepsis, meningitis.
Prevention of infectious complications after abdominal, gynecological and orthopedic operations, in cardiovascular surgery
Indications for use
The drug Cefoperazone + Sulbactam is used for urinary tract infections, respiratory tract infections, intraperitoneal infections, skin infections, osteomyelitis , sepsis , soft tissue infections, joint infections, ENT infections, meningitis .
The medicine is also prescribed for the prevention of infectious complications after orthopedic , abdominal , gynecological and cardiovascular surgeries .
Dosage regimen
The method of administration and dosage regimen of a particular drug depend on its release form and other factors.
The optimal dosage regimen is determined by the doctor. The compliance of the dosage form of a particular drug with the indications for use and dosage regimen should be strictly observed. Enter intramuscularly or intravenously.
The ratio of the components of the combination is 1:1.
For adults, the daily dose of the combination is 2-4 g (cefoperazone 1-2 g + sulbactam 1-2 g). The daily dose should be divided into equal parts and administered every 12 hours.
For severe or refractory infections, the daily dose of the combination can be increased to 8 g (cefoperazone 4 g + sulbactam 4 g).
For children, the daily dose of the combination is 40-80 mg/kg/day (cefoperazone 20-40 mg/kg + sulbactam 20-40 mg/kg). The daily dose should be divided into equal parts and administered every 6-12 hours.
For serious or treatment-resistant infections, the daily dose of the combination can be increased to 160 mg/kg.
In newborns, during the first week of life, the combination should be administered every 12 hours. The maximum daily dose of sulbactam in children should not exceed 80 mg/kg/day.
In patients with severe renal impairment (creatinine clearance 15-30 ml/min), the maximum dose of sulbactam is 1 g every 12 hours (the maximum daily dose of sulbactam is 2 g), and in patients with creatinine clearance less than 15 ml/min, the maximum dose of sulbactam is 500 mg every 12 hours (maximum daily dose of sulbactam - 1 g). For severe infections, additional administration of cefoperazone may be required. Since during hemodialysis the pharmacokinetics of sulbactam changes significantly and the serum T1/2 of cefoperazone is slightly reduced, administration of this combination should be planned after dialysis.
If regular monitoring of serum concentrations of cefoperazone is not carried out, then the minimum daily dose should not exceed 2 g.
If it is necessary to administer more than 80 mg/kg/day, calculated by the activity of cefoperazone, an increase in the dose is achieved through additional administration of cefoperazone.
For intravenous bolus administration, the contents of the bottle are dissolved in an adequate volume of 5% dextrose solution, 0.9% sodium chloride solution, 5% dextrose solution in 0.225% sodium chloride solution, 5% dextrose solution in 0.9% sodium chloride solution or sterile water d/i , and injected over 3 minutes; for intravenous infusion, dissolve as stated above, dilute to 20-100 ml and administer over 15-60 minutes; for intramuscular administration, sterile water for dissolution is used.
Preparation of a solution using lidocaine: dilution is carried out in 2 stages - with sterile water, then with a 2% lidocaine solution to obtain a 0.5% lidocaine solution. The total volume of solvent is 6.7 ml.
Side effect
Allergic reactions: anaphylactic shock.
From the digestive system: diarrhea, nausea, vomiting, pseudomembranous colitis; transient increase in liver function indicators - AST, ALT, alkaline phosphatase, bilirubin in the blood serum.
Allergic reactions: maculopapular rash, itching, urticaria, Stevens-Johnson syndrome (the risk of developing these reactions is higher in patients with a history of allergic reactions).
From the hematopoietic system: decreased number of neutrophils, reversible neutropenia (with long-term treatment), decreased hemoglobin and hematocrit levels, transient eosinophilia, leukopenia, thrombocytopenia, hypoprothrombinemia; in some cases - a positive Coombs test. When using Benedict's or Fehling's solution, a false-positive reaction to glucose in the urine may occur.
From the urinary system: hematuria.
Local reactions: sometimes after an intramuscular injection there is transient pain and a burning sensation at the injection site. When administered intravenously using a catheter, phlebitis may develop at the infusion site.
Other: headache, fever, chills, vasculitis.
Interaction
It is advisable not to combine with alcohol and products containing ethanol, including within 5 days after the course of the drug. Otherwise, negative reactions such as facial redness, headache , sweating , and tachycardia .
When using the drug Cefoperazone + Sulbactam, an erroneously positive reaction to glucose in the urine is possible if or Fehling's solution .
special instructions
When using aminoglycosides concomitantly, it is necessary to monitor renal function.
In patients with liver disease and/or biliary obstruction, T1/2 of cefoperazone increases and renal excretion is increased. In severe liver dysfunction, the concentration of cefoperazone in bile is therapeutic, T1/2 increases by 2-4 times. Changing the dose and monitoring the concentration of cefoperazone in the blood serum is required for severe obstruction of the biliary tract, severe liver failure (maximum daily dose - 2 g).
Patients who adhere to an inadequate diet or have malabsorption of food (patients with cystic fibrosis; patients on parenteral nutrition for a long time) are at risk of developing vitamin K deficiency. In such patients, prothrombin time should be monitored; if necessary, vitamin K is prescribed. The mechanism for the development of vitamin K deficiency is the suppression of the intestinal microflora, which normally synthesizes this vitamin.
With long-term treatment, it is necessary to monitor indicators of kidney, liver and hematopoietic system function.
During the treatment period, false-positive results of determining glucose in urine may be observed when using Benedict's or Fehling's solutions, or a false-positive Coombs reaction.
Treatment of premature newborns, pregnant women, and lactation is carried out if the possible benefit outweighs the potential risk.
Drug interactions
Compatible with water, 5% dextrose solution, 0.9% sodium chloride solution, 5% dextrose solution in 0.225% sodium chloride solution, 5% dextrose solution in 0.9% sodium chloride solution.
Incompatible with Ringer's solution, 2% lidocaine hydrochloride solution (initial use of water d/i leads to the formation of a compatible mixture); aminoglycosides (if combination therapy is necessary, it is carried out by sequential fractional intravenous infusion of two drugs, using 2 separate systems for intravenous transfusion; in the interval between doses, the system should be flushed with a compatible solvent).
Consumption of ethanol (at the same time or within the next 5 days after the end of treatment) increases the risk of developing a disulfiram-like reaction (“hot flashes”, increased sweating, headache, tachycardia).
Terms of sale
The drug is available with a prescription.
