Cefosulbine

Cefosulbin is a complex antibacterial drug with a wide range of therapeutic activity.

Indications Cefosulbine

It is used for therapy in cases of infections caused by bacteria that are sensitive to the drug:

• lesions in the respiratory tract (lower and upper parts);
• infections of the urethra (lower and upper areas);
• cholecystitis with peritonitis, and in addition cholangitis and other infections affecting the peritoneum;
• meningitis or septicemia;
• lesions of the subcutaneous layer and epidermis;
• infections of joints with bones;
• inflammations affecting the organs in the pelvic area, as well as endometritis and gonorrhea with other genital infections.

Release form

The drug is released in the form of a combined lyophilisate for the preparation of injection liquid in portions of 1 g (0.5 g cefoperazone and 0.5 g sulbactam) or 2 g (1 g cefoperazone and 1 g sulbactam) inside 1 vial.

Pharmacodynamics

The drug contains the components cefoperazone (third-generation cephalosporin), as well as sulbactam (a substance that irreversibly slows the activity of most of the main β-lactamases produced by microbes resistant to penicillin).

The antibacterial element of the drug is cefoperazone, which affects sensitive microbes at the stage of their active reproduction – suppressing the biosynthesis of mucopeptide in the area of bacterial cell walls.

Sulbactam has no real antibacterial effect, excluding the effect on acinetobacter and Neisseriaceae. However, biochemical tests involving cell-free microbial systems have determined the ability of sulbactam to irreversibly inhibit the activity of the most important β-lactamases produced by penicillin-resistant bacteria. The potential of the substance to prevent the destruction of cephalosporins with penicillins under the influence of resistant bacteria was confirmed by tests on strains of resistant microbes, within which sulbactam showed significant synergism with cephalosporins, as well as penicillins. Due to the fact that sulbactam is also synthesized with individual proteins that bind penicillin, bacteria with sensitivity are even more strongly affected by cefoperazone with sulbactam (in comparison with the effect of cefoperazone alone).

The combination of sulbactam with cefoperazone actively affects all bacteria sensitive to cefoperazone. At the same time, when using this combination, synergism of the effect of its elements is observed in relation to the following microbes: bacteroides, coli, influenza bacilli, Acinetobacter calcoaceticus, Klebsiella pneumoniae, and in addition to this, enterobacter cloacae, enterobacter aerogenes, citrobacter freundii, Morgan bacteria, proteus mirabilis and Citrobacter diversus.

Cefoperazone with sulbactam demonstrate in vitro activity against a relatively wide range of clinically important bacteria.

Gram-positive bacteria: Staphylococcus aureus (penicillinase-producing or non-penicillinase-producing strains), Staphylococcus epidermidis, Pneumococcus (mainly Diplococcus pneumoniae), Streptococcus pyogenes (β-hemolytic form of Streptococcus subtype A). In addition, the list includes Streptococcus agalactiae (β-hemolytic form of Streptococcus subtype B), most other types of β-hemolytic streptococci, and most strains of fecal streptococci (enterococci).

Gram-negative microbes: Klebsiella, Escherichia coli, Citrobacter, Proteus, Enterobacter, and Influenza bacilli. In addition, the list includes Proteus mirabilis, Providencia, Morgan's bacteria (mainly Morgan's Proteus), Providencia Röttger (often Röttger's Proteus), Salmonella with Serratia (including Serratia marcescens), and Shigella. Also included here are Pseudomonas aeruginosa and certain types of Pseudomonas, Meningococcus, Yersinia enterocolitica, Gonococcus, and Acinetobacter calcoaceticus with whooping cough bacilli.

Anaerobes: Gram-negative microorganisms (including Bacteroides fragilis and other types of Bacteroides, as well as Fusobacteria), as well as Gram-negative and -positive cocci (including Peptostreptococci with Peptococci and Veillonella), as well as Gram-positive bacilli (including Clostridia, Eubacteria and Lactobacilli).

The drug has the following effective dosage ranges (MIC, μg/ml for cefoperazone): presence of sensitivity – below 16, intermediate values – within 17-36, resistant – >64.

Pharmacokinetics

Approximately 84% of sulbactam and 25% of cefoperazone are excreted in the urine. The major part of cefoperazone is excreted in the bile. After administration of the drug, the mean half-life values for sulbactam are 60 minutes, and for cefoperazone - approximately 1.7 hours. Plasma parameters of the drug are proportional to the size of the portion used. These pharmacokinetic data were recorded when the components were used separately.

The average Cmax level of sulbactam and cefoperazone when using 2000 mg of the drug (1000 mg of both components) intravenously over 5 minutes is 130.2 and 236.8 mcg/ml, respectively. From this, we can conclude that sulbactam has a larger distribution volume (Vα is within 18.0-27.6 l) compared to similar values of cefoperazone (Vα is approximately 10.2-11.3 l). Both components of Cefosulbin are subject to intensive distribution inside fluids with tissues, including the gallbladder with bile, appendix, uterus with ovaries and fallopian tubes, epidermis, etc.

In children, the half-life of sulbactam is 0.91-1.42 hours, and that of cefoperazone is 1.44-1.88 hours. No data have been registered on the pharmacokinetic interaction of cefoperazone with sulbactam when they are used together in combination.

With repeated use, no noticeable changes in the pharmacokinetic parameters of the drug elements were detected, nor was any accumulation of them observed when used at 8-12 hour intervals.

A significant portion of cefoperazone is excreted with bile. The half-life of the substance in blood plasma and the degree of excretion with urine often increases in people with biliary obstruction and liver diseases. Even in severe forms of liver dysfunction, the level of the drug in bile reaches the medicinal concentration, while the half-life of the drug from blood plasma increases only twofold/fourfold.

Dosing and administration

The medication can be administered intramuscularly or intravenously.

For adults, an average of 2-4 g of the drug is required per day (at 12-hour intervals). If the infections are severe, the daily dose can be increased to 8 g with a 1:1 ratio of active ingredients (the cefoperazone level is 4 g). People using both components of the drug in a 1:1 ratio may need a separate additional use of cefoperazone. In this case, it should be administered in equal doses at 12-hour intervals. It is recommended to use no more than 4 g of sulbactam per day.

Use in patients with renal impairment.

The dosage regimen in the case of treatment of people with significant weakening of renal function (creatinine clearance level below 30 ml/minute) should be adjusted to compensate for the reduced clearance of sulbactam.

Individuals with CC values within 15-30 ml/minute require the maximum dose of sulbactam (1000 mg), which is administered at 12-hour intervals (no more than 2000 mg of sulbactam can be used per day).

For people with a CC level below 15 ml/minute, sulbactam is prescribed in a maximum dose of 0.5 g, administered at 12-hour intervals (a maximum of 1000 mg of the substance is used per day).

In the development of severe forms of the disease, there may be a need for additional use of cefoperazone.

The pharmacokinetics of sulbactam are significantly affected by hemodialysis sessions. The half-life of cefoperazone in plasma is slightly reduced after hemodialysis. Therefore, when performing dialysis, the dosage regimen should be adjusted.

Complex treatment.

Due to the fact that Cefosulbin has a wide range of antibacterial activity, many infections can be cured by monotherapy. But sometimes the drug can be combined with other antibiotics. When combining drugs with aminoglycosides, it is necessary to monitor renal and hepatic activity throughout the treatment cycle.

Use in people with liver dysfunction.

A change in dosage may be necessary in cases of severe obstructive jaundice, as well as in cases of severe liver pathologies or if renal dysfunction is observed against the background of this disease.

In people with liver problems and concomitant renal impairment, plasma levels of cefoperazone should be monitored and the dose adjusted accordingly if necessary. In the absence of close monitoring of plasma drug levels, the dose of cefoperazone should be a maximum of 2000 mg per day.

Use in children.

Children should be administered 40-80 mg/kg per day. The medication is administered at 6-12 hour intervals in evenly divided portions.

In severe stages of diseases, it is allowed to increase the dose to 160 mg/kg per day with the proportions of active components 1:1. The dosage should be applied, dividing into 2-4 equal portions.

For infants under 7 days of age, the drug is administered at 12-hour intervals. A maximum of 80 mg/kg of the substance can be administered per day.

Intravenous administration method.

For infusions through a dropper, the lyophilisate from the vials is diluted in the required amount of 5% glucose solution, 0.9% NaCl solution or sterile injection water. Then, using a similar solvent, the substance is diluted to 20 ml, and then administered through a dropper over 15-60 minutes.

Scheme for selecting the dosage regimen:

• the total dose of the medicine is 1 g (the dosage of 2 active elements is 500+500 mg) – the volume of the solvent used is 3.4 ml, and the maximum permissible final concentration is 125+125 mg/ml;
• the total dosage of the drug is 2 g (2 active components 1000+1000 mg) – the volume of the solvent used is 6.7 ml, and the maximum concentration level is 125+125 mg/ml.

The medication can be combined with injection water, 5% glucose liquid in 0.225% NaCl solution, and also with 5% glucose solution in isotonic NaCl liquid (the concentrations of the drug are within the range of 10-125 mg/ml of the drug).

The lactate form of Ringer's solution can be used for the preparation of infusion, but is prohibited for primary dissolution. For the injection portion, the lyophilisate is dissolved according to the above scheme, after which it is administered for at least 3 minutes. For direct injections, the maximum permissible single adult dose is 2000 mg, and for children - 50 mg / kg.

Intramuscular administration method.

Lidocaine hydrochloride may be used for dilution during application, but not for initial dissolution.

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Use Cefosulbine during pregnancy

The drug crosses the placenta. It is only allowed to be prescribed to pregnant women in situations where the probable benefit to the woman is more likely to outweigh the risk of complications for the fetus.

Contraindications

Contraindication: use in people with a history of allergy to penicillins, sulbactam or cephalosporins.

Side effects Cefosulbine

Cefosulbin is often tolerated without complications. Most of the negative symptoms are mild or moderate, so there is no need to stop using the drug. Among the side effects are:

Digestive disorders: vomiting, superinfection or hyperesthesia of the oral mucosa are often observed, as well as pseudomembranous colitis, diarrhea and nausea;

Lesions of the subcutaneous layer and epidermis: erythema, maculopapular rashes, TEN, urticaria, and also exfoliative dermatitis, Stevens-Johnson syndrome and itching. The described manifestations most often occur in people with a history of allergy (often to penicillins);

Lymphatic and blood disorders: there is information about a slight decrease in the level of neutrophils. Treatable neutropenia may also develop. In some patients, a positive direct Coombs test may occur. In addition, a decrease in hematocrit or hemoglobin values or the development of leukopenia and thrombocytopenia, as well as anemia and hypoprothrombinemia, can be expected;

Problems associated with the functioning of the central nervous system: cefoperazone can significantly reduce albumin reserves, and during therapy of newborns with jaundice, it increases the likelihood of bilirubin encephalopathy;

Disorders in the functioning of the cardiovascular system: vasculitis, decreased blood pressure, tachycardia or bradycardia, as well as cardiac arrest and cardiogenic shock;

Immune disorders: signs of intolerance and anaphylactoid symptoms (including shock);

Other symptoms: drug fever, chills, headaches, anxiety, changes and pain in the injection area, as well as muscle twitching;

Disorders of the urinary system and kidneys: hematuria;

Digestive problems: jaundice;

Respiratory system symptoms: sometimes bronchospasms occur in people with a history of asthma and chronic obstruction of the respiratory tract, as well as laryngospasms. Dyspnea and allergic rhinitis are occasionally observed;

Changes in laboratory test data: transient increase in liver function tests (ALT or AST), bilirubin or alkaline phosphatase levels, increased PT levels and false positive results when determining urine sugar levels (using non-enzymatic methods);

Local signs: the drug is usually tolerated without complications when injected; only occasionally does pain occur in the injection site. As with other penicillins and cephalosporins, after administration of the drug through an intravenous catheter, some patients may develop phlebitis in the infusion site.

Overdose

In case of overdose of the drug, potentiation of negative symptoms may occur. It is necessary to take into account that large portions of β-lactam antibiotics in the cerebrospinal fluid may lead to the appearance of neurological signs (e.g., seizures).

Because sulbactam and cefoperazone are excreted from the body through hemodialysis, this procedure may increase the elimination of the drug in poisoning in people with kidney disorders.

Interactions with other drugs

The use of drugs in one syringe together with aminoglycosides causes their mutual inactivation. If it is necessary to use these categories of antibacterial agents simultaneously, they must be administered into different areas with a 1-hour interval. Cefosulbin increases the likelihood of nephrotoxicity of furosemide and aminoglycosides.

Bacteriostatic substances (including sulfonamides and chloramphenicol with tetracyclines and erythromycin) weaken the therapeutic properties of the drug.

Probenecid reduces the tubular excretion of sulbactam. This results in increased plasma levels and half-life of the drug, increasing the risk of poisoning.

When used together with NSAIDs, the risk of bleeding increases.

In case of alcohol consumption during the treatment cycle, as well as for 5 days after the end of cefoperazone use, the following symptoms were recorded: hyperhidrosis, facial hyperemia, tachycardia and headaches. Similar manifestations were also noted when using other cephalosporins. Patients should be extremely careful when combining alcohol and drug administration.

If the patient is on artificial nutrition (parenteral or oral method), ethanol-containing solutions should not be used.

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Storage conditions

Cefosulbin should be kept in a place out of reach of small children. Temperature indicators – maximum 25°C.

Shelf life

Cefosulbin can be used within 24 months from the date of manufacture of the therapeutic agent.

Analogues

Analogues of the drug are the drugs Gepacef Combi, Cebanex with Cefopectam, as well as Sulcef and Cefoperazone + Sulbactam.