Cefoperazone + Sulbactam: instructions for use

pharmachologic effect

Cefoperazone + Sulbactam is a combination drug.

Cefoperazone is a broad-spectrum antibiotic It affects aerobic and anaerobic bacteria and is resistant to many beta-lactamases of microorganisms.

Sulbactam is an irreversible beta-lactamase . It prevents the destruction of penicillins and cephalosporins . Binds to penicillin-binding proteins exhibits synergism when combined with penicillins and cephalosporins .

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.

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 .

Side effects

Taking the drug Cefoperazone + Sulbactam can lead to the following adverse reactions:

urinary system: hematuria ;
CVS: vasculitis , arterial hypotension ;
circulatory system: decreased hemoglobin hematocrit level , positive direct Coombs test , thrombocytopenia , eosinophilia , hypoprothrombinemia , leukopenia ;
CNS: decreased albumin , bilirubin encephalopathy (in the case of treatment of newborns with jaundice );
Gastrointestinal tract: diarrhea , vomiting, nausea, pseudomembranous colitis ;
skin: Stevens-Johnson syndrome , urticaria , pruritus , maculopapular rash ;
changes in laboratory parameters: increased liver function tests ;
local reactions: pain at the injection site, phlebitis at the injection site during infusion through an intravenous catheter ;
other: anaphylactic reactions , headache , fever , muscle twitching.

Cefoperazone+Sulbactam

The development of hypersensitivity reactions, including those leading to death, has been reported during therapy with beta-lactam antibacterial drugs, including cephalosporins, including cefoperazone + [sulbactam]. The risk of hypersensitivity reactions, including those resulting in death, is higher in patients who have a history of hypersensitivity reactions to multiple allergens. If an allergic reaction occurs, it is necessary to discontinue the drug and prescribe adequate therapy.

In case of serious anaphylactic reactions (see section “Side Effects”), immediate administration of epinephrine and glucocorticosteroids is necessary, ensuring airway patency, including intubation.

Severe skin reactions, such as toxic epidermal necrolysis, Stevens-Johnson syndrome and exfoliative dermatitis, in some cases fatal (see Adverse Reactions section), have been observed in patients receiving cefoperazone+[sulbactam] therapy. If severe skin reactions occur, discontinue cefoperazone+[sulbactam] and initiate appropriate treatment.

Patients should be warned about the possibility of disulfiram-like effects when consuming alcoholic beverages during treatment with the drug. Dose changes may be required in cases of severe biliary obstruction, severe liver disease, and renal impairment combined with any of these conditions.

In patients with impaired liver function and concomitant impaired renal function, it is necessary to monitor the serum concentration of cefoperazone and adjust its dose if necessary. If the daily dose of cefoperazone does not exceed 2 g, there is no need to monitor its serum concentration.

Serious bleeding events, including death, have been observed in patients receiving cefoperazone+[sulbactam] therapy.

During treatment with cefoperazone, vitamin K deficiency developed, leading to coagulopathy. The reason is probably the suppression of normal intestinal microflora, which synthesizes this vitamin. The risk group includes patients receiving malnutrition, with malabsorption syndrome (for example, with cystic fibrosis) and who have been on intravenous artificial nutrition for a long time. In such cases, as well as in patients receiving anticoagulants, it is necessary to monitor the prothrombin time and, if indicated, prescribe vitamin K. It is necessary to stop taking cefoperazone + [sulbactam] if persistent bleeding occurs when there are no alternative causes for its manifestation. With long-term treatment with cefoperazone+[sulbactam], like other antibiotics, excessive growth of insensitive microorganisms may occur. Patients must be carefully monitored during treatment.

During long-term therapy, it is recommended to periodically monitor indicators of the function of internal organs, including the kidneys, liver and hematopoietic system. This is especially important for newborns, especially premature babies, and young children.

Cases of Clostridium difficile-associated diarrhea have been reported in association with the use of virtually all antibacterial agents, including cefoperazone+[sulbactam]. The severity of diarrhea can vary from mild to severe. Treatment with antibacterial drugs disrupts the normal intestinal microflora, which leads to excessive growth of Clostridium difficile. Clostridium difficile produces toxins A and B, which lead to Clostridium difficile-associated diarrhea. Excessive amounts of toxins produced by Clostridium difficile strains may cause increased mortality in patients, as such infections may be resistant to antimicrobial therapy and may require colonectomy. The use of drugs that inhibit intestinal motility is contraindicated.

The possibility of developing Clostridium difficile-associated diarrhea should be considered in all patients with diarrhea following the use of antibacterial drugs. Close medical observation for 2 months is necessary for patients who experience Clostridium difficile-associated diarrhea after administration of antibacterial drugs.

Use in newborns

Cefoperazone+[sulbactam] is effective in young children. The use of this drug has not been studied extensively in newborns, including premature infants. Thus, before initiating drug therapy in newborns, including premature infants, the degree of benefit to the patient and the risk of developing serious adverse reactions should be assessed.

Cefoperazone does not displace bilirubin from protein compounds in the blood plasma.

Instructions for use Cefoperazone + Sulbactam (Method and dosage)

The medicine is used intravenously or intramuscularly. For adults, daily dosages of 2-4 g are indicated. They are divided into several doses with an interval of 12 hours. If the infection is severe, the daily dosage can be increased to 8 g.

For chronic renal failure, it is necessary to take medications 2 times a day in the following dosages:

creatinine clearance 15–30 ml/min – up to 1 g is prescribed;
creatinine clearance up to 14 ml/min – 500 mg is prescribed.

Children are shown daily doses of 40-80 mg/kg. The daily dosage is divided into 2-4 doses. In case of severe infections, up to 160 mg/kg can be prescribed. If it is necessary to administer more than 80 mg/kg, the daily dose is increased by additional of cefoperazone

Instructions for use Cefoperazone + Sulbactam states that for intravenous administration the medicine is diluted in sterile water for injection, Dextrose 5% or sodium chloride 0.9%. The drug is administered within three minutes. In the case of intravenous infusion, the drug is diluted in 20-100 ml of solution and administered for 15-60 minutes.

When administered intramuscularly, the drug is diluted in sterile water for injection.

If Lidocaine , the drug is diluted in 2 stages: first, this is done with sterile water, and then with a 2% solution of Lidocaine until a 0.5% solution of Lidocaine . In this case, the total volume of the solvent is 6.7 ml.

Cefoperazone and Sulbactam Jodas 1 g + 1 g No. 1 bottle

Content

Pharmacodynamics Indications Contraindications Use with caution During pregnancy and lactation Method of administration and dosage Method of preparation Side effects Overdose Interaction Special instructions Effect on the ability to drive vehicles and machinery Storage conditions Shelf life

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 sodium is a derivative of the main core of penicillin. 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 sulbactam and cefoperazone is active against all microorganisms sensitive to cefoperazone. In addition, it has synergism against various microorganisms, primarily: Haemophilus influenzae, Bacteroides spp., Staphylococcus spp., Acinetobacter calcociceticus, 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-producing and non-penicillinase-producing), Staphylococcus epidermidis. Streptococcus pneumoniae, Streptococcus pyogenes (group A beta-hemolytic streptococcus), Streptococcus agalacliae (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. (including Klebsiella pneumonia). Enterobacter spp. (including Enterobacter aerogenes and Enterobacter cloacae). Citrobacter spp. (including Citrobacter freundii and Citrobacter diversus), Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris. Morganella morganii, Providencia rettgeri, Providencia spp., Serratia spp. (including Serratia marcescens), Salmonella 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 species and Fusobacterium spp.).
Gram-positive and gram-negative cocci (including Peptococcus, Peptostreptococcus 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 is less than or equal to 16, for organisms with intermediate sensitivity it is in the range of 17-63, and for resistant organisms it is more than 64. Sensitivity zones when determined by the disk diffusion method are: for sensitive microorganisms more than 21 mm; with intermediate sensitivity - from 16 to 20 mm, and for resistant - more than 15 mm.

To determine the MIC, the method of serial dilutions of sulbactam/cefoperazone 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.

Indications

Infectious and inflammatory diseases caused by microorganisms sensitive to cefoperazone + sulbactam:

Infections of the upper and lower respiratory tract;
Urinary tract infections;
Peritonitis, cholecystitis, cholangitis and other intra-abdominal infections;
Sepsis;
Meningitis;
Skin and soft tissue infections;
Bone and joint infections;
Gonorrhea;
Inflammatory diseases of the pelvic organs, endometritis and other genital tract infections.

Contraindications

Hypersensitivity to sulbactam, cefoperazone or other cephalosporins, penicillin and beta-lactam antibiotics.

Carefully

Severe renal and liver dysfunction;
Newborns, including premature babies.

Use during pregnancy and breastfeeding

Sulbactam and cefoperazone penetrate the placental barrier.

Adequate clinical studies have not been conducted for use in pregnant women. Cefoperazone + Sulbactam is excreted in breast milk. During pregnancy and lactation, the drug is used only if the expected benefit to the mother outweighs the potential risk to the fetus and child.

If it is necessary to prescribe the drug during lactation, breastfeeding should be stopped.

Directions for use and doses

Intravenously and intramuscularly.

Use in adults:

In adults, sulbactam/cefoperazone is recommended for use in the following daily doses:

Ratio 1:1.
Sulbactam / Cefoperazone: 2.0 - 4.0.
Sulbactam dose (g): 1.0 - 2.0.
Cefoperazone dose (g): 1.0 - 2.0.

The daily dose should be divided into equal parts and administered every 12 hours.

For severe or refractory infections, the daily dose of cefoperazone/sulbactam can be increased to 8 g with a ratio of the main components of 1:1 (i.e. 4 g of cefoperazone).

Patients receiving cefoperazone/sulbactam in a 1:1 ratio may require additional administration of cefoperazone. The dose should be divided into equal parts and administered every 12 hours.

The recommended maximum daily dose of sulbactam is 4 g.

Use for renal impairment:

In patients with a creatinine clearance of 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 a creatinine clearance of less than 15 ml/min, the maximum dose of sulbactam is 500 mg every 12 hours ( the maximum daily dose of sulbactam is 1 g). For severe infections, additional administration of cefoperazone may be required.

The pharmacokinetics of sulbactam changes significantly during hemodialysis. The half-life of cefoperazone from blood serum is slightly reduced during hemodialysis. Therefore, administration of the drug should be planned after dialysis.

Use for liver dysfunction:

A dose change in case of impaired liver function may be required only in cases of severe obstruction of the biliary tract and severe liver disease, as well as in patients with a combination of hepatic and renal failure. In these cases, it is recommended to monitor the serum concentration of cefoperazone and adjust its dose if necessary. If regular monitoring of the serum concentration of cefoperazone is not possible, then its daily dose should not exceed 2 g.

Use in children:

In children, sulbactam/cefoperazone is recommended for use in the following daily doses:

Ratio 1:1.
Sulbactam / Cefoperazone (mg/kg/day): 40-80.
Sulbactam dose (mg/kg/day): 20-40.
Cefoperazone dose (mg/kg/day): 20-40.

The dose should be divided into equal parts and administered every 6-12 hours.

For serious or refractory infections, these dosages can be increased to 160 mg/kg/day for a 1:1 ratio of the main components. The daily dose is divided into 2-4 equal parts.

Use in newborns:

In newborns, during the first week of life, the drug should be administered every 12 hours. The maximum daily dose of sulbactam in children should not exceed 80 mg/kg/day.

Cooking method

Preparation of the solution.

Total dose (g): 2.0.
Equivalent doses of sulbactam + cefoperazone: 1.0 + 1.0.
Solvent volume: 6.7.
Maximum final concentration (mg/ml): 125 + 125.

Intramuscular administration:

Preparation of a solution using lidocaine. To prepare a solution for intramuscular administration, you can use a 2% solution of lidocaine hydrochloride, but it cannot be used for initial dissolution, given their incompatibility. Compatibility can be achieved by a two-step solution preparation - initially, the powder (2 g of Cefoperazone/sulbactam) is dissolved in 4.7 ml of sterile water for injection. Then the resulting solution is diluted with a 2% solution of lidocaine hydrochloride, adding 2 ml of local anesthetic to the solution obtained during the initial dilution. The total volume of solvent is 6.7 ml. The final solution will contain cefoperazone/sulbactam in a ratio of 125 mg/125 mg in 1 ml of 0.5% lidocaine solution. Injected deeply intramuscularly into areas of the body with an affected muscle layer (for example, the upper outer quadrant of the buttock).

Intravenous administration:

To prepare a solution for intravenous infusion, dilute 2 g (1 g + 1 g) of cefoperazone and sulbactam in an initial volume of 6.7 ml of one of the following and infusion solutions: 5% dextrose solution in water, 5% dextrose solution in 0.225% sodium chloride solution, 5 % dextrose solution in saline, 0.9% sodium chloride solution or sterile water for injection, and then diluted to 20 ml with the same solvent.

Preparation of a solution using Ringer's lactate. Since Ringer's lactate is not suitable for initial dilution, the solution is prepared in two stages: first, water for injection is used (see table above), and then the resulting solution is diluted with Ringer's lactate solution to a sulbactam concentration of 5 mg/ml (2 ml of the initial solution is diluted in 50 ml of lactated Ringer's solution or 4 ml in 100 ml of lactated Ringer's solution).

The infusion is carried out over 15-60 minutes.

For intravenous injection, the contents of each vial should be dissolved in 6.7 ml of one of the diluents described above and administered over a minimum of 3 minutes.

Side effects

Blood and lymphatic system disorders: leukopenia, neutropenia, positive direct Coombs reaction, decreased hemoglobin, decreased hematocrit, thrombocytopenia, eosinophilia, hypoprothrombinemia.
Immune system disorders: anaphylactoid reaction (including shock), hypersensitivity reaction (including anaphylactic shock).
Nervous system disorders: headache.
Vascular disorders: vasculitis, arterial hypotension.
Gastrointestinal disorders: diarrhea, nausea, vomiting, pseudomembranous colitis.
Disorders of the liver and biliary tract: increased activity of alanine aminotransferase, aspartate aminotransferase, blood alkaline phosphatase, increased concentration of bilirubin in the blood, jaundice.
Skin and subcutaneous tissue disorders: pruritus, urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome, maculopapular rash.
Renal and urinary tract disorders: hematuria.
General disorders and disorders at the injection site: phlebitis at the infusion site, pain and burning at the injection site, fever, chills.

Overdose

Information on the acute toxicity of cefoperazone sodium and sulbactam sodium in humans is limited.

In case of overdose, you can expect undesirable effects recorded when using the drug.

It is necessary to take into account the fact that high concentrations of beta-lactam antibiotics in the cerebrospinal fluid can lead to neurological disorders, including seizures.

Treatment: symptomatic, hemodialysis is effective, especially in patients with impaired renal function.

Interaction

When consuming ethanol during treatment with cefoperazone and for up to 5 days after its administration, disulfiram-like effects may develop, characterized by hot flashes, sweating, headache and tachycardia. In patients who require artificial nutrition (orally or parenterally), the use of solutions containing ethanol should be avoided.

Compatible with water for injection, 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 solution (initial use of water for injection results in a compatible mixture).

special instructions

Given the wide spectrum of activity of the drug, adequate monotherapy can be carried out.

The risk of hypersensitivity reactions, including those resulting in death, is higher in patients who have a history of hypersensitivity reactions to multiple allergens. If an allergic reaction occurs, it is necessary to discontinue the drug and prescribe adequate therapy.

Serious anaphylactic reactions require immediate administration of epinephrine. Oxygen is prescribed, corticosteroids are administered intravenously, and the airway is maintained, including intubation. Patients should be warned about the possibility of disulfiram-like effects when consuming alcoholic beverages during treatment with sulbactam and cefoperazone.

Dose changes may be required in cases of severe biliary obstruction, severe liver disease, and renal dysfunction associated with any of these conditions.

In patients with impaired liver function and concomitant impaired renal function, it is necessary to monitor the serum concentration of cefoperazone and adjust its dose if necessary. If regular monitoring of the serum concentration of cefoperazone is not carried out in such cases, then its daily dose should not exceed 2 g.

When using Benedict's or Fehling's solution, a false positive reaction to glucose in the urine may occur.

When using aminoglycosides concomitantly, it is necessary to monitor renal function.

Long-term use of the drug may disrupt the normal intestinal microflora, which can lead to the growth of Clostridium Difficile and cause the development of pseudomembranous colitis. In this case, it is necessary to discontinue the drug and prescribe specific treatment. The use of drugs that inhibit intestinal motility is contraindicated.

With prolonged treatment, excessive growth of insensitive microorganisms may occur. Patients must be carefully monitored during treatment. During long-term therapy, it is recommended to periodically monitor indicators of the function of internal organs, including the kidneys, liver and hematopoietic system. This is especially important for newborns, especially premature babies, and small children. The effectiveness and safety of use in newborns and children under 1 year of age has not been sufficiently studied. Before prescribing the drug, the potential benefits and possible risks should be weighed. Cefoperazone does not displace bilirubin from protein compounds in the blood plasma.

Impact on the ability to drive vehicles and machinery

Based on clinical experience with the use of cefoperazone + sulbactam, its effect on the ability to drive vehicles and operate machinery is unlikely.

Storage conditions

Store at a temperature not exceeding 30°C.

Prepared solutions of the drug for intravenous and intramuscular administration are stable for 24 hours at room temperature.

Keep out of the reach of children.

Best before date

3 years. Do not use after expiration date.

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 .

INSTRUCTIONS

Compound

1 bottle contains:

Active Ingredient	Dosage
Cefoperazone sodium in terms of cefoperazone	1.034g 1.0 g
Sulbactam sodium in terms of sulbactam	1.094 g 1.0 g

of the active substance according to ND are 90-110%, i.e. The total content of cefoperazone and sulbactam in the preparation varies up to 2.2 g.

Medium: water for injection - 5.0 or 10.0 ml

Dosage form

Powder for preparing a solution for intravenous and intramuscular administration.

Description

Crystalline powder of white or white with a yellowish color.

Liquid: Colorless, transparent, odorless liquid.

Pharmacodynamics

The combination of sulbactam and cefoperazone is active against all microorganisms sensitive to cefoperazone. In addition, it has synergism against various microorganisms, primarily: Haemophilus influenzae, Bacleroiclesspp., Staphylococcus spp., Acinetobactercalcoaceticus, Enterobacteraerogenes, Escherichiacoli, Proteusmirabilis, Klebsiellapneumoniae, Morganellamorganii, Citrobacterfreundii, Enterobactercloacae. Citrobacter divers.

Cefoperazone/sulbactam is active in vitro against a wide range of clinically significant microorganisms.

Gram-positive microorganisms

Staphylococcusaureus (producing and not producing penicillinase), Staphylococcusepidermidis. Streptococcus pneumoniae. Streptococcus pyogenes (group A beta-hemolytic streptococcus), Streptococcus agalactiac (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. (including Klebsiella pneumonia). Enterobacter spp. (including Enterobacter aerogenes and Enterobacter cloacae). Citrobacter spp. (including Citrobacter freundii and Citrobacter diversus), Haemophilus influenzae. Proteus mirabilis. Proteus vulgaris, Morganella morganii, Providencia rettgeri, Providencia spp., Serratia spp. (including Serratia marcescens), Salmonella and Shigella spp., Pseudomonas aeruginosa and some others Pseudomonas spp., Acinetobacler calcoaceticus, Neisseria gonorrhoeae, Neisseria meningitidis, Bordetella pertussis. Yersinia enlerocolitica.

Anaerobic microorganisms

Gram-negative rods (including Bacteroides fragilis, other Bacteroides species and Fusobacterium spp.).

Gram-positive and gram-negative cocci (including Peptococcus, Peptostreptococcus and Veillonella spp.).

Gram-positive rods (including Clostridium spp., Eubacterium spp. and Lactobacillus spp.).

The following sensitivity levels have been established for cefoperazone/sulbactam. Minimum inhibitory concentration (MIC) in mkt/ml Expressed in the concentration of cefoperazone for sensitive microorganisms is less than or equal to 16, for organisms with intermediate sensitivity it is in the range of 17-63, and for resistant ones it is more than 64. The sensitivity zones when determined by the disc diffusion method are : for sensitive microorganisms more than 1 mm, with intermediate sensitivity - from 16 to 20 mm, and for resistant microorganisms - more than 15 mm.

To determine the MIC, the method of serial dilutions of sulbactam/cefoperazone 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 sulbakgam and 75 μg of cefoperazone.

The following quality control standards are recommended when using discs containing 30 mcg sulbakgam 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

The maximum concentrations of sulbactam and cefoperazone after intravenous administration of g cefoperazone/sulbactam (1 g sulbakgam, 1 g cefoperazone) for 5 minutes averaged 130.2 and 236.8 μg/ml, respectively. This reflects the higher volume of distribution of sulbactam (Vd = 18.0-27.6 L) compared to that of cefoperazone (Vd = 10.2-11.3 L).

After intramuscular administration of 1.5 g sulbactam/cefoperazone (0.5 g sulbakgam, 1 g cefoperazone), 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, gall bladder, skin, appendix, fallopian tubes, ovaries, uterus, etc. Sulbactam and cefoperazone penetrate the placental barrier. There is no data on the presence of any pharmacokinetic interaction between sulbactam and cefoperazone when cefoperazone/sulbactam is administered. With repeated use, no significant changes in the pharmacokinetics of both components of sulbactam/cefoperazone were observed. When the drug was administered every 8-12 hours, no accumulation was observed.

Approximately 84% of a dose of sulbactam and 25% of a dose of cefoperazone administered as a cefoperazone/sulbactam combination is excreted by the kidneys. Most of the remaining dose of cefoperazone is excreted in the bile. Cefoperazone does not displace bilirubin from binding to plasma proteins. The half-life of sulbactam averages about 1 hour, cefoperazone - 1.7 hours. Serum concentration is proportional to the administered dose.

In case of liver dysfunction

Cefoperazone is actively excreted in bile. The half-life 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 the half-life 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 the half-life of sulbactam was detected (on average 6.9 and 9.7 hours in various studies). Hemodialysis caused significant changes in the half-life, total clearance and volume of distribution of sulbactam.

Use in the elderly

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 half-life, 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.

Use in children

In studies in children, there were no significant changes in the pharmacokinetics of the components of cefoperazone/sulbactam compared to those in adults. The average half-life of sulbactam in children ranged from 0.91 to 1.42 hours, cefoperazone - from 1.44 to 1.88 hours.

Indications for use

Infectious and inflammatory diseases caused by microorganisms sensitive to cefoperazone + sulbactam:

- infections of the upper and lower respiratory tract,

- urinary tract infections,

- peritonitis, cholecystitis, cholangitis and other intra-abdominal infections,

- sepsis,

- meningitis,

- infections of the skin and soft tissues,

- infections of bones and joints,

- gonorrhea,

- inflammatory diseases of the pelvic organs, endometritis and other infections of the head tract.

Contraindications

Information on the acute toxicity of cefoperazone sodium and sulbactam sodium in humans is limited.

In case of overdose, undesirable effects can be expected when using the drug.

It is necessary to take into account the fact that high concentrations of beta-lactam antibiotics in the cerebrospinal fluid can lead to neurological disorders, including seizures.

Treatment: symptomatic, hemodialysis is effective, especially in patients with impaired renal function.

Use during pregnancy and breastfeeding

Sulbactam and cefoperazone penetrate the placental barrier.

Side effects

Cefoperazone and sulbactam are usually well tolerated. The following reactions were noted:

From the cardiovascular system: decreased blood pressure.

From the gastrointestinal tract: diarrhea, nausea, vomiting, pseudomembranous

colitis.

Allergic reactions: hypersensitivity, manifested in the form of maculopapular rash and urticaria, as well as itching, Stevens-Johnson syndrome, anaphylactic shock, skin hyperemia, angioedema, toxic epidermal necrolysis. The risk of reactions is higher in patients with a history of allergic reactions.

From the hematopoietic system: decrease in the number of neutrophils. With long-term treatment, reversible neutropenia, a decrease in hemoglobin and hematocrit may develop. Transient eosinophilia, thrombocytopenia, leukopenia, and hypoprothrombinemia are observed.

Laboratory indicators: transient increase in liver transaminases - aspartate aminotransferase (ACT), alanine aminotransferase (AJIT), alkaline phosphatase and bilirubin in the blood serum, hypercreatininemia, hematuria. Some patients had a positive Coombs test during treatment.

Local reactions: after intramuscular injection, transient pain and burning is observed at the injection site. When administered intravenously using a catheter, phlebitis may develop at the injection site.

Others: headache, fever, chills, vasculitis, jaundice.

Interaction

Solutions of cefoperazone/sulbactam and aminoglycosides should not be directly mixed, given the pharmaceutical incompatibility between them. If combination drug therapy is carried out, the two drugs are administered by sequential infusions using separate secondary catheters, and the primary catheter is sufficiently flushed with the solution between drug doses. Intervals between injections during the day they should be as large as possible. When consuming ethanol during treatment with cefoperazone and for up to 5 days after the administration, disulfiram-like effects may develop, characterized by (hot flashes, sweating, headache and tachycardia. In patients who need artificial nutrition (orally or parenterally), the use of solutions containing ethanol should be avoided.

Compatible with water for injection, 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 Rigger's solution, 2% lidocaine solution (initial use of water for injection results in a compatible mixture).

Directions for use and doses

Intravenously and intramuscularly.

Use in adults

In adults, sulbactam/cefoperazone is recommended for use in the following daily doses:

Ratio	Sulbactam/Cefoperazone	Sulbactam dose (g)	Cefoperazone dose (g)
1:1	2,0 — 4,0	1,0 -2,0	1,0 -2,0

The daily dose should be divided into equal parts and administered every 12 hours. For severe or refractory infections, the daily dose of cefoperazone/sulbactam can be increased to 8 g with a ratio of the main components of 1:1 (i.e. 4 g of cefoperazone).

Patients receiving cefoperazone/sulbactam in a 1:1 ratio. Additional administration of cefoperazone may be required. The dose should be divided into equal parts and administered every 12 hours.

The recommended maximum daily dose of sulbactam is 4 g. Use for impaired renal function

Use for liver dysfunction

Use in children

In children, sulbactam/cefoperazone is recommended for use in the following daily doses:

Ratio	Sulbactam/Cefoperazone (mg/kg/day)	Sulbactam dose (mg/kg/day)	Cefoperazone dose (mg/kg/day)
1:1	40 — 80	20-40	20-40

The dose should be divided into equal parts and administered every 6-12 hours. For serious or refractory infections, these dosages can be increased to 160 mg/kg/day for a 1:1 ratio of the main components. The daily dose is divided into 2-4 equal parts.

Use in newborns

In newborns, during the first week of life, the drug should be administered every 12 hours. The maximum daily dose of sulbactam in children should not exceed 80 mg/kg/day.

Method for preparing solutions for parenteral use.

Preparation of the solution

Total dose (g)	Equivalent doses of sulbactam + cefoperazone	Solvent volume	Maximum final concentration (mg/ml)
2,0	1,0+ 1,0	6,7	125 + 125

Intramuscular administration

Preparation of a solution using lidocaine. To prepare a solution for intramuscular administration, you can use a 2% solution of lidocaium hydrochloride, but it cannot be used for initial dissolution, given their incompatibility. Compatibility can be achieved by a two-step solution preparation - initially, the powder (2 g of Cefoperazone / sulbactam) is dissolved in 4.7 ml of sterile water for injection. Then the resulting solution is diluted with a 2% solution of lidocaium hydrochloride, adding 2 ml of local anesthetic to the solution obtained during the initial dilution. The total volume of solvent is 6.7 ml. The final solution will contain cefoperazone/sulbactam in a ratio of 125 mg/125 mg II ml of 0.5% lidocaine solution. Injected deeply intramuscularly into areas of the body with a pronounced muscle layer (for example, the upper outer quadrant of the buttock).

Intravenous administration

To prepare a solution for intravenous infusion, dilute 2 g (1g + 1g) of cefoperazone and sulbactam in an initial volume of 6.7 ml of one of the following infusion solutions: 5% dextrose solution in water, 5% dextrose solution in 0.225% sodium chloride solution, 5% dextrose solution in saline, 0.9% sodium chloride solution or sterile water for injection, and then diluted to 20 ml with the same solvent.

Preparation of a solution using Ringer's lactate. Since Ringer's lactate is not suitable for initial dilution, the solution is prepared in two stages: first, water for injection is used (see table above), and then the resulting solution is diluted with Ringer's lactate solution to a sulbakgam concentration of 5 mg/ml (2 ml of the initial solution is diluted in 50 ml of lactated Ringer's solution or 4 ml in 100 ml of lactated Ringer's solution).

The infusion is carried out over 15-60 minutes.

For intravenous injection, the contents of each vial should be dissolved in 6.7 ml of one of the diluents described above and administered over a minimum of 3 minutes.

Overdose

Information on the acute toxicity of cefoperazone sodium and sulbactam sodium in humans is limited.

In case of overdose, undesirable effects can be expected when using the drug.

It is necessary to take into account the fact that high concentrations of beta-lactam antibiotics in the cerebrospinal fluid can lead to neurological disorders, including seizures.

Treatment: symptomatic, hemodialysis is effective, especially in patients with impaired renal function.

special instructions

Given the wide spectrum of activity of the drug, adequate monotherapy can be carried out.

Patients should be warned about the possibility of disulfiram-like effects when consuming alcoholic beverages during treatment with sulbactam and cefoperazone.

Dose changes may be required in cases of severe biliary obstruction, severe liver disease, and renal dysfunction associated with any of these conditions.

In patients with impaired liver function and concomitant impaired renal function, it is necessary to monitor the serum concentration of cefoperazone and adjust its dose if necessary. If regular monitoring of the serum concentration of cefoperazone is not carried out in such cases, then its daily dose should not exceed 2 g.

When using Benedict's or Fehling's solution, a false positive reaction to glucose in the urine may occur.

When using aminoglycosides concomitantly, it is necessary to monitor renal function.

During treatment with cefoperazone, in rare cases, vitamin K deficiency developed. The reason for this is probably the suppression of the normal intestinal microflora, which synthesizes this vitamin. The risk group includes patients who receive poor nutrition, suffer from malabsorption (for example, with cystic fibrosis) and are on intravenous artificial nutrition for a long time. In such cases, as well as in patients receiving anticoagulants, it is necessary to monitor the prothrombin time and, if indicated, prescribe vitamin K. With long-term treatment, excessive growth of insensitive microorganisms may occur. Patients must be carefully monitored during treatment. During long-term therapy, it is recommended to periodically monitor indicators of the function of internal organs, including the kidneys, liver and hematopoietic system. This is especially important for newborns, especially premature babies, and small children. The effectiveness and safety of use in newborns and children under 1 year of age has not been sufficiently studied. Before prescribing the drug, the potential benefits and possible risks should be weighed.

Impact on the ability to drive vehicles and operate machinery

Based on clinical experience with the use of cefoperazone + sulbactam, its effect on the ability to drive vehicles and operate machinery is unlikely.

Release form

Powder for the preparation of a solution for intravenous and intramuscular administration 1.0 g + 1.0 g.

Conditions for dispensing from pharmacies

On prescription

Storage conditions

Store in a dry place, protected from light, at a temperature not exceeding 25 C. Prepared solutions of the drug for intravenous and intramuscular administration are stable for 24 hours at room temperature. Keep out of the reach of children.

Best before date

3 years. Do not use after expiration date.