Cefoperazone and Sulbactam Jodas - instructions for use, dose, side effects, contraindications

The acceptable values for the active substance content according to ND are 90-110%, t.e. the content of cefoperazone and sulbactam in the preparation totals up to 2.2 g.

Racmatopumee: water for injection - 5.0 or 10.0 ml

Description:

Crystalline powder white or white with yellowish color.

Removable: Colorless transparent liquid, odorless.

Pharmacotherapeutic group:Antibiotic - cephalosporin + beta-lactamase inhibitor

ATX: & nbsp

J.01.D.D.62 Cefoperazone in combination with other drugs

Pharmacodynamics:The antibacterial component of cefoperazone / sulbactam is cefoperazone Third-generation cephalosporin, which acts on sensitivemicroorganisms during their active reproduction by inhibiting the biosynthesis of the mucopeptide of the cell wall.

Sulbactam sodium is a derivative of the main nucleus of penicillin. Sulbactam does not have clinically significant antibacterial activity (except for Neisseriaceae and Acinetobacter). However,that it is an irreversible inhibitor of most of the major beta-lactamases that 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 for which sulbactam possessed a pronounced synergy with penicillins and cephalosporins. In addition, sulbactam interacts with some penicillin-binding proteins, so cefoperazone / sulbactam often has a more pronounced effect on sensitive strains than one cefoperazone.

The combination of sulbactam and cefoperazone is active against all microorganisms sensitive to cefoperazone. In addition, it has a synergistic effect on various microorganisms, primarily: Haemophilus influenzae, Bacleroicles 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 for a wide range of clinically relevant microorganisms.

Gram-positive microorganisms

Staphylococcus aureus (producing and not producing penicillinase), Staphylococcus epidermidis. Streptococcus pneumoniae. Streptococcus pyogenes (beta-hemolytic group streptococcus A), Streptococcus agalactiac (beta-hemolytic streptococcus group B), most other strains of beta-hemolytic streptococci, many strains Streptococcus faecalis (enterococci).

Gram-negative microorganisms

Escherichia coli. Klebsiella spp. (at Tom number of Klebsiella pneumonia). Enterobacter spp. ( at Tom number of 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, Bordetellapertussis. Yersinia enlerocolitica.

Anaerobese microorganisms

Gram-negative sticks (including Bacteroides fragilis, others Bacteroides species and Fusobacterium spp.).

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

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

The following sensitivity levels were established for cefoperazone / sulbactam. The minimum inhibitory concentration (MIC) in mct / ml Expressed in the concentration of cefoperazone for sensitive microorganisms is less than or equal to 16, for organisms with intermediate sensitivity is in the range of 17-63, and for resistant ones, more than 64. Sensitivity zones when determined by a disk diffusion method are : for sensitive microorganisms more than 1 mm; with an intermediate sensitivity of 16 to 20 mm, and for resistance - more than 15 mm.

For the determination of BMD, a serial dilution method of sulbactam / cefoperazone can be used in a ratio of 1: 1 in broth or agar media.

To determine the MPC by disc-diffusion method, it is recommended to use a disk containing 30 μg of sulbacam and 75 μg of cefoperazone.

The following quality control standards are recommended when using discs containing 30 μg of sulbacam and 75 μg of cefoperazone. For the control strain Acinetobacter spp. (ATCC 43498), the diameter of the zone 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 of cefoperazone / sulbactam (1 g of sulbacam, 1 g of cefoperazone) for 5 minutes averaged 130.2 and 236.8 μg / ml, respectively. This reflects a higher volume of distribution of sulbactam (Vd = 18.0-27.6 l) compared with that of cefoperazone (Vd = 10.2-11.3 l).

After intramuscular injection, 1.5 g of sulbactam / cefoperazone (0.5 g of sulbacam, 1 g of cefoperazone), the maximum concentrations of sulbactam and cefoperazone in serum They were observed in the period from 15 minutes to 2 hours after administration. The maximum serum concentrations were 19.0 and 64.2 μg / ml of sulbactam and cefoperazone, respectively. Both sulbactam and cefoperazone well distributed into various tissues and fluids, including bile, gall bladder, skin, appendix, fallopian tubes, ovaries, uterus, etc. Sulbactam and cefoperazone penetrate through the placental barrier. There is no data on the presence of any pharmacokinetic interaction between sulbactam and cefoperazone with the introduction of cefoperazone / sulbactam. With repeated use of significant changes in the pharmacokinetics of both components of sulbactam / cefoperazone was not noted. With the introduction of the drug every 8-12 hours cumulation was not observed.

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

When a violation of liver function

Cefoperazone is actively excreted with bile. The half-life of cefoperazone usually lengthens, and the excretion of the drug by the kidneys increases in patients with liver disease and / or biliary tract obstruction.Even with a serious violation of liver function in bile, the therapeutic concentration of cefoperazone is reached, and the half-life period increases only 2-4 times.

When impaired renal function

Patients with varying degrees of renal dysfunction who received cefoperazone / sulbactam showed a high correlation between total clearance of sulbactam from the body and estimated clearance of creatinine. In patients with terminal renal failure, a significant elongation of the half-life of sulbactam (an average of 6.9 and 9.7 hours in various studies) was found. Hemodialysis caused significant changes in the half-life, total clearance and volume of distribution of sulbactam.

Application in the elderly

The pharmacokinetics of cefoperazone / sulbactam has been studied in elderly people with renal insufficiency and impaired liver function. Compared with healthy volunteers, an increase in the half-life, a decrease in clearance, and an increase in the distribution of both sulbactam and cefoperazone have been found.

The pharmacokinetics of sulbactam correlated with the degree of impaired renal function, and the pharmacokinetics of cefoperazone - with a degree of impaired hepatic function.

Use in children

In studies in children, no significant changes in the pharmacokinetics of the components of cefoperazone / sulbactam were found in comparison with those in adults. The mean half-life of sulbactam in children was 0.91 to 1.42 h, of cefoperazone from 1.44 to 1.88 h.

Indications:

Infectious-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;

- infection of bones and joints;

- gonorrhea;

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

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

Carefully:Impaired renal and hepatic function; Newborns, including premature infants.

Pregnancy and lactation:

Sulbactam and cefoperazone penetrate through the placental barrier.

Adequate clinical studies of use in pregnant women have not been conducted. Cefoperazone + Sulbactam is excreted in breast milk. During pregnancy and lactation, the drug is used only if the expected benefit to the mother exceeds the potential risk to the fetus and the baby. If it is necessary to prescribe the drug during lactation, breastfeeding should be stopped.

Dosing and Administration:

Intravenous and intramuscular.

Application 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. In severe or refractory infections, the daily dose of cefoperazone / sulbactam can be increased to 8 g with a 1: 1 ratio of the major components (ie 4 g of cefoperazone).

Patients receiving cefoperazone / sulbactam in a ratio of 1: 1. 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. Application for renal dysfunction

In patients with creatinine clearance of 15-30 ml / min, the maximum dose of sulbactam is 1 g every 12 hours (maximum daily dose of sulbactam 2 g), and in patients with creatinine clearance less than 15 ml / min the maximum dose of sulbactam is 500 mg every 12 hours the maximum daily dose of sulbactam 1 g). In severe infections, additional administration of cefoperazone may be required.

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

Application for violations of liver function

Dose changes in case of liver dysfunction may be required only in cases of severe obstruction of the biliary tract and severe liver diseases, as well as in patients with a combination of hepatic and renal insufficiency. In these cases it is recommended to monitor the serum concentration of cefoperazone and correct its dose if necessary. If regular monitoring of serum concentration of cefoperazone is impossible,then its daily dose should not exceed 2 g.

PImplications 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 major components. The daily dose is divided into 2-4 equal parts.

Neonatal application

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

Method of preparing solutions for parenteral use .

Preparation of the solution

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

Intramuscular injection

Preparation of a solution using lidocaine. To prepare the solution for intramuscular injection, a 2% solution of lidocaine hydrochloride can be used, but it can not be used for initial dissolution, given their incompatibility.Compatibility can be achieved by two-stage solution preparation - initially a powder (2 g Cefoperazone / sulbactam) are 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 the solvent is 6.7 ml. The final solution will contain cefoperazone / sulbactam in a ratio of 125 mg / 125 mg I I ml of a 0.5% lidocaine solution. Enter deeply intramuscularly into areas of the body with a pronounced muscular layer (for example, the uppermost quadrant of the buttock).

Intravenous administration

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

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

Infusion is carried out for 15-60 minutes.

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

Side effects:

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

From the cardiovascular system: lowering of 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 allergic reactions in the anamnesis.

On the part of the hematopoiesis system: decrease in the number of neutrophils. With prolonged treatment, reversible neutropenia, a decrease in hemoglobin and hematocrit may develop.There is transient eosinophilia, thrombocytopenia, leukopenia, hypoprothrombinemia.

Laboratory indicators: transient increase in "hepatic" transaminases - aspartate aminotransferase (ACT), alanine aminotransferase (AJIT), alkaline phosphatase in bilirubin in the serum, hyperkreatinemia, hematuria. In some patients, a positive Coombs test was observed during treatment.

Local reactions: After intramuscular injection, transient pain and burning at the injection site are observed. When administered intravenously with a catheter, phlebitis may develop at the site of administration.

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

Overdose:

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

In case of overdose, it is possible to expect undesirable effects registered with the use of the drug.

It should be borne in mind that a high concentration of beta-lactam antibiotics in cerebrospinal fluid can lead to neurologic disorders, including convulsions.

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

Interaction:

Solutions cefoperazone / sulbactam and aminoglycosides should not be directly mixed using (pharmaceutical incompatibility between them. If performed combination therapy drug, the two drugs are administered by consecutive infusions using the separate secondary catheters and the primary catheter sufficiently washed well with solution between doses of drugs. Intervals between their administration during the day should be as large as possible.When using ethanol during treatment with cefoperazone and for up to 5 days after : the introduction of disulfiramoid-like effects, characterized by (hot flashes, sweating, headache and tachycardia), and patients who need artificial feeding (inside or parenteral), the use of solutions containing ethanol.

Compatible with water for injection, 5% dextrose, 0.9% sodium chloride solution, 5% dextrose in 0.225% sodium chloride solution, 5% dextrose in 0.9% sodium chloride solution. Incompatible with Rigger's solution, 2% with lidocaine solution (initial use of water for injection leads to the formation of a compatible mixture).

Special instructions:

Given the wide spectrum of drug activity, it is possible to conduct adequate monotherapy.

The risk of hypersensitivity reactions, including those leading to death, is higher in patients who have a history of hypersensitivity reactions to many allergens. In case of an allergic reaction, it is necessary to cancel the drug and prescribe adequate therapy.

Serious anaphylactic reactions require the urgent administration of epinephrine. Assign oxygen, intravenously injected glucocorticosteroids and provide airway patency, including intubation.

Patients should be warned about the possibility of manifestation disulfiramopodobnyh 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 renal dysfunction, monitoring the serum concentration of cefoperazone and correcting its dose should be necessary.If regular monitoring of serum concentration of cefoperazone in such cases is not carried out, then its daily dose should not exceed 2 g.

When using a solution of Benedict or Felling, a false positive reaction to glucose in the urine can be observed.

With the simultaneous use of aminoglycosides, kidney function should be monitored.

With prolonged use of the drug, a violation of normal intestinal microflora is possible, which can lead to the growth of Clostridium Difficile and cause the development of pseudomembranous colitis. In this case, it is necessary to cancel the drug, the purpose of a specific treatment. The use of drugs that inhibit intestinal peristalsis is contraindicated.

In the treatment of cefoperazonom in rare cases, a vitamin K deficiency developed. Its cause is probably suppression of normal intestinal microflora, which synthesizes this vitamin. The risk group can include patients receiving malnutrition, suffering from malabsorption (for example, in cystic fibrosis) and for a long time on intravenous artificial feeding. In such cases, as well as in patients receiving anticoagulants,it is necessary to monitor prothrombin time and in the presence of indications to prescribe vitamin K. With prolonged treatment, excessive growth of insensitive microorganisms can be observed. Patients should be carefully observed during treatment. With prolonged therapy, it is recommended to periodically monitor the performance of internal organs, including the kidneys, liver and hematopoiesis system. This is especially important for newborns, especially premature babies, and small children. Efficacy and safety of use in newborns and children under 1 year of age is insufficiently studied. Prior to the appointment of the drug should be related to the potential benefits and possible risks.

Effect on the ability to drive transp. cf. and fur:Based on the clinical experience of the use of cefoperazone + sulbactam, its effect on the ability to drive vehicles and control mechanisms is unlikely.

Form release / dosage:

Powder for solution for intravenous and intramuscular injection 1.0 g + 1.0 g.

Packaging:

According to 2.0 g of the drug (1.0 g of cefoperazone + 1.0 g of sulbactam) in a vial of colorless glass, sealed with a stopper of chlorobutyl rubber, crimped with an aluminum ring with a protective plastic cap.

Solvent: water for injection (RU No. LP-002377 dated February 18, 2014) to 5.0 or 10.0 ml in a vial of colorless neutral glass or from low-density polyethylene. 1 bottle with a drug and 1 ampoule of 10.0 ml or 2 ampoules of 5.0 ml with a solvent of aphids without a solvent, along with instructions for use in a cardboard pack.

For hospitals:

10, 25, 48 or 100 vials, together with an appropriate number of ampoules with a solvent (or without a solvent) and instructions for use in a cardboard box.

Storage conditions:Store in a dry, dark place at a temperature of no higher than 25 ° C. The prepared solutions of the preparation for intravenous and intramuscular administration are stable for 24 hours at room temperature. Keep out of the reach of children.

Shelf life:3 years. Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-000391/09

Date of registration:26.01.2009

The owner of the registration certificate:JODAS EKSPOIM, LLC JODAS EKSPOIM, LLC Russia

Manufacturer: & nbsp

JODAS EXPOIM, Pvt. Ltd. India

Representation: & nbspJodas Expoim, Open CompanyJodas Expoim, Open Company

Information update date: & nbsp31.10.2015

Illustrated instructions

Instructions

Cefoperazone and Sulbactam Jodas (Cefoperazone sodium & Sulbactame Jodas)