Sulzoncef^® (Powder) Instructions for Use

ATC Code

J01DD62 (Cefoperazone and beta-lactamase inhibitor)

Active Substances

Cefoperazone (Rec.INN registered by WHO)

Sulbactam (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Third generation cephalosporin with beta-lactamase inhibitor

Pharmacotherapeutic Group

Systemic antibacterial agents; other beta-lactam antibacterial agents; third-generation cephalosporins

Pharmacological Action

A combined drug, a broad-spectrum antibiotic.

Cefoperazone is a third-generation cephalosporin antibiotic that acts bactericidally and has a broad spectrum of action; it is highly active against aerobic and anaerobic gram-positive and gram-negative microorganisms (including Pseudomonas aeruginosa), and is resistant to beta-lactamases of gram-positive and gram-negative microorganisms.

Sulbactam is an irreversible inhibitor of beta-lactamases produced by microorganisms resistant to beta-lactam antibiotics; it prevents the destruction of penicillins and cephalosporins by the action of beta-lactamases from resistant microorganisms; by 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 producing and not producing penicillinase), Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes (beta-hemolytic strain group A), Streptococcus agalactiae (beta-hemolytic strain 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., Eubacterium spp., Lactobacillus spp.

Pharmacokinetics

The C_max of sulbactam and cefoperazone after IV administration of the combination at a dose of 2 g (1 g sulbactam and 1 g cefoperazone) over 5 min averaged 130.2 µg/ml and 236.8 µg/ml, respectively. This reflects a higher V_d of sulbactam (from 18.0 to 27.6 L) compared to that of cefoperazone (from 10.2 to 11.3 L).

After IM administration of 1.5 g sulbactam/cefoperazone (500 mg sulbactam, 1 g cefoperazone), the C_max of sulbactam and cefoperazone in serum were observed from 15 min to 2 h after administration. The C_max in serum were 19.0 and 64.2 µg/ml for 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, uterus.

There are no data on any pharmacokinetic interaction between sulbactam and cefoperazone when administered as part of combined drugs.

No significant changes in the pharmacokinetic parameters of either component were noted upon repeated use. No accumulation was observed when the drug was administered every 8-12 h.

Approximately 84% of the sulbactam dose and 25% of the cefoperazone dose are excreted by the kidneys when the combination is administered. The remaining portion of cefoperazone is excreted mainly in the bile. When the combination is administered, the T_1/2 of sulbactam averages about 1 h, and the T_1/2 of cefoperazone is 1.7 h. The plasma concentration is proportional to the administered dose.

Cefoperazone is actively excreted in the bile. The T_1/2 of cefoperazone is usually prolonged, and urinary excretion is increased in patients with liver disease and/or biliary obstruction. Even with severe liver dysfunction, a therapeutic concentration of cefoperazone is achieved in the bile, and the T_1/2 increases only 2-4 times.

In patients with varying degrees of renal impairment receiving this combination, 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 T_1/2 of sulbactam was detected (averaging 6.9 h and 9.7 h in various studies). Hemodialysis caused significant changes in the T_1/2, total body clearance, and V_d of sulbactam.

In elderly people with renal failure and liver dysfunction compared to healthy volunteers, an increase in the duration of T_1/2, a decrease in clearance, and an increase in V_d for both sulbactam and cefoperazone were detected. The pharmacokinetics of sulbactam correlated with the degree of renal impairment, and the pharmacokinetics of cefoperazone correlated with the degree of liver impairment.

In studies in children, no significant changes in the pharmacokinetic parameters of the combination components were found compared to adults. The average T_1/2 of sulbactam in children ranged from 0.91 to 1.42 h, and that of cefoperazone ranged from 1.44 to 1.88 h.

Indications

Treatment of infectious and inflammatory diseases caused by microorganisms sensitive to the cefoperazone+sulbactam combination: 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 surgeries, in cardiovascular surgery.

ICD codes

Dosage Regimen

Powder

Administered IM or IV.

The ratio of the combination components 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 h.

For severe or refractory infections, the daily dose of the combination may 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 h.

For serious or treatment-refractory infections, the daily dose of the combination may be increased to 160 mg/kg.

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

In patients with severe renal impairment ( CrCl 15-30 ml/min), the maximum dose of sulbactam is 1 g every 12 h (maximum daily dose of sulbactam – 2 g), and in patients with CrCl less than 15 ml/min, the maximum dose of sulbactam is 500 mg every 12 h (maximum daily dose of sulbactam – 1 g). In severe infections, additional administration of cefoperazone may be required. Since hemodialysis significantly alters the pharmacokinetics of sulbactam and slightly reduces the T_1/2 of cefoperazone from serum, the administration of this combination should be planned after dialysis.

If regular monitoring of serum cefoperazone concentration is not performed, the minimum daily dose should not exceed 2 g.

If it is necessary to administer more than 80 mg/kg/day, calculated based on cefoperazone activity, the dose increase is achieved by additional administration of cefoperazone.

For IV bolus administration, the vial contents are dissolved in an adequate volume of 5% dextrose solution, 0.9% sodium chloride solution, 5% dextrose in 0.225% sodium chloride solution, 5% dextrose in 0.9% sodium chloride solution, or sterile water for injection, and administered over 3 min; for IV infusion administration, dissolve as indicated above, dilute to 20-100 ml and administer over 15-60 min; for IM administration, use sterile water for injection for dissolution.

Preparation of solution using lidocaine: dilution is carried out in 2 stages – with sterile water, then with 2% lidocaine solution to obtain a 0.5% lidocaine solution. The total volume of solvent is 6.7 ml.

Adverse Reactions

Allergic reactions anaphylactic shock.

From the digestive system diarrhea, nausea, vomiting, pseudomembranous colitis; transient increase in liver function parameters – AST, ALT, ALP, serum bilirubin.

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 neutrophil count, reversible neutropenia (with prolonged treatment), decreased hemoglobin and hematocrit levels, transient eosinophilia, leukopenia, thrombocytopenia, hypoprothrombinemia; in some cases – positive Coombs test. When using Benedict’s or Fehling’s solution, a false-positive reaction for glucose in urine may be observed.

From the urinary system hematuria.

Local reactions sometimes after IM injection, transient pain, burning at the injection site is observed. With IV administration via catheter, phlebitis may develop at the infusion site.

Other headache, fever, chills, vasculitis.

Contraindications

Hypersensitivity to cefoperazone, sulbactam, penicillins, other cephalosporins.

With caution renal and/or hepatic insufficiency, colitis (including in history), premature newborns, pregnancy.

Use in Pregnancy and Lactation

Cefoperazone and sulbactam cross the placental barrier.

The use of this combination during pregnancy and lactation is possible only if the intended benefit to the mother outweighs the potential risk to the fetus or child.

Use in Hepatic Impairment

With caution hepatic insufficiency.

Dosage adjustment and monitoring of serum cefoperazone concentration is required in cases of severe biliary obstruction, severe hepatic insufficiency (maximum daily dose – 2 g).

If it is necessary to use the drug in patients with impaired liver function, the instructions should be carefully studied.

Use in Renal Impairment

With caution renal insufficiency.

If it is necessary to use the drug in patients with impaired renal function, the instructions should be carefully studied.

Pediatric Use

With caution premature newborns.

If it is necessary to use the drug in children, the instructions should be carefully studied.

Special Precautions

When used concomitantly with aminoglycosides, renal function should be monitored.

In patients with liver disease and/or biliary obstruction, the T_1/2 of cefoperazone increases, and renal excretion is increased. In severe liver dysfunction, the concentration of cefoperazone in bile is therapeutic, and the T_1/2 increases 2-4 times. Dosage adjustment and monitoring of serum cefoperazone concentration is required in cases of severe biliary obstruction, severe hepatic insufficiency (maximum daily dose – 2 g).

Patients with an inadequate diet or malabsorption (such as those with cystic fibrosis, or patients on long-term parenteral nutrition) are at risk of developing vitamin K deficiency. In such patients, prothrombin time should be monitored; if necessary, vitamin K should be prescribed. The mechanism for the development of vitamin K deficiency is the suppression of intestinal microflora, which normally synthesizes this vitamin.

During long-term therapy, indicators of kidney function, liver function, and hematopoietic system function should be monitored.

During treatment, false-positive results for urine glucose determination may be observed when using Benedict’s or Fehling’s solutions, as well as a false-positive Coombs’ test.

Treatment of premature newborns, pregnant women, and during lactation is carried out only if the potential benefit outweighs the possible risk.

Drug Interactions

It is compatible with water for injections, 5% dextrose solution, 0.9% sodium chloride solution, 5% dextrose in 0.225% sodium chloride solution, and 5% dextrose in 0.9% sodium chloride solution.

It is incompatible with Ringer’s solution and 2% lidocaine hydrochloride solution (initial use of water for injections results in a compatible mixture); with aminoglycosides (if combination therapy is necessary, it should be carried out by sequential fractional intravenous infusion of the two drugs using 2 separate IV transfusion systems; the system must be flushed with a compatible solvent between dose administrations).

Consumption of ethanol (concurrently or within 5 days after the end of treatment) increases the risk of developing a disulfiram-like reaction (“flushing,” increased sweating, headache, tachycardia).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.