Cefoperazone, 1 g

Pharmacotherapeutic group

Cephalosporin antibiotic

ATX code: J01DD12

Pharmacokinetics

The binding to plasma proteins is 82-93%. Time of reaching maximum concentration after intramuscular administration – 1-2 hours, after intravenous – at the end of infusion, maximum concentration after intramuscular administration of 1 and 2 g is 65-75 and 97 mcg/ml respectively; after single intravenous administration of 1, 2, 3 and 4 g maximum concentration is 153, 252, 340, and 506 mcg/ml respectively. Maximum concentration in urine after intramuscular and intravenous administration of 2 g is 1 and more than 2.2 mg/ml, respectively. Reaches therapeutic concentrations in such tissues and body fluids as peritoneal, ascitic fluid and cerebrospinal fluid (in meningitis), urine, bile, gallbladder walls, lungs, sputum, palatine tonsils and sinus mucosa, atria, kidneys, ureters, prostate, testicles, uterus, fallopian tubes, bone, cord blood and amniotic fluid.

The volume of distribution is 0.14-2 l/kg. Period of semiejection – 1.6-2.4 hours, regardless of method of administration, 2.8-4.2 hours – in hemodialysis, 2.2 hours – in infants and children from 2 months to 11 years. It is excreted 70-80% in bile, 20-30% unchanged in the kidneys. Half-life of patients with impaired liver function and biliary obstruction is 3-7 hours; renal excretion is 90% or more. Even with severe liver damage, therapeutic concentrations are achieved in bile, and the elimination half-life is only 2-4 times longer. In patients with renal-hepatic insufficiency may cumulate.

Pharmacodynamics

The semisynthetic cephalosporin antibiotic of the III generation of a broad spectrum of antibacterial action. It has a bactericidal effect caused by inhibition of the synthesis of the bacterial cell wall.

It is active in vitro against a large number of clinically relevant microorganisms.

It is resistant to the action of many beta-lactamases.

The following microorganisms are sensitive to cefoperazone: Gram-positive – Staphylococcus aureus (penicillinase-producing and non-producing strains), Staphylococcus epidermidis, Streptococcus pneumoniae, Streptococcus pyogenes (beta-hemolytic Streptococcus group A), Streptococcus agalactiae (beta-hemolytic Streptococcus group B), Enterococcus (Streptococcus faecalis, S. faecium and S. durans); Gram-negative – Escherichia coli, Klebsiella species (including K. pneumoniae), Enterobacter spp, Citrobacter spp., Haemophilus influenzae, Proteus mirabilis, Proteus vulgaris, Morganella morganii, Providencia stuartii, Providencia rettgeri, Serratia marcescens, Pseudomonas aeruginosa, Pseudomonas spp, some strains of Acinetobacter calcoaceticus, Neisseria gonorrhoeae; anaerobic microorganisms: gram-positive cocci (including Peptococcus spp., Peptostreptococcus spp.), Clostridium spp., Bacteroides fragilis and other strains of Bacteroides spp. Cefoperazone is also active in vitro against a wide range of other pathogens; however, the clinical significance of this is unknown: Salmonella spp. and Shigella spp, Serratia liquefaciens, Neisseria meningitidis, Bordetella pertussis, Yersinia enterocolitica, Clostridium difficile, Fusobacterium spp, Eubacterium spp. and betalactamase-producing strains of Haemophilus influenzae and Neisseria gonorrhoeae‑.

Indications

– Infectious and inflammatory diseases caused by microorganisms sensitive to the drug:

> bacterial infections of the upper and lower respiratory tracts (including. bronchitis, pneumonia, pleural empyema and lung abscess);

> renal and urinary tract infections (including pyelonephritis and cystitis);

> abdominal infections (including peritonitis, cholecystitis, cholangitis);

> sepsis, meningitis;

> skin and soft tissue infections;

> bone and joint infections;

> pelvic inflammatory diseases (including endometritis, gonorrhoea, gonorrhoea, and cystic fibrosis).Endometritis, gonorrhea and other infections of the reproductive tract.)

; prevention of infectious complications after abdominal, gynecological and orthopedic operations and in cardiovascular surgery.

Active ingredient

Composition

The active ingredient:

Sodium cefoperazone converted into cefoperazone – 1.0 g.

How to take, the dosage

Cefoperazone is administered by IV (drip and stream) and IM.

Adults: average daily dose of cefoperazone 2-4 g, administered in equal portions every 12 hours. In severe infections the daily dose may be increased to 8 g, administered also in equal portions every 12 hours. No complications have been found with cefoperazone administered at a daily dose of 12 g or even 16 g, divided into equal doses every 8 h. Treatment can be initiated until the results of the microbial sensitivity study are available.

In uncomplicated gonococcal urethritis, a single 500 mg of the drug is recommended in an IV/m injection.

For prevention of postoperative complications, 1 g or 2 g v/v 30-90 minutes before surgery. The dose can be repeated, every 12 h, however, in most cases for no more than 24 h.

In surgeries with an increased risk of infection (e.g., colorectal surgery), or if the resulting infection is particularly dangerous (e.g., open heart surgery or joint replacement), prophylactic use may continue for 72 h after completion of surgery.

Patients with impaired renal function are prescribed the usual daily dose (2-4 g). In patients whose glomerular filtration rate is below 18 ml/min or whose serum creatinine level is above 3.5 mg/mL, the daily dose should not exceed 4 g.

In patients with severe hepatic impairment and marked bile duct obstruction, the daily dose of the drug should not exceed 2 g.

In patients with renal and hepatic insufficiency the cefoperazone concentration in blood should be monitored and the dose should be adjusted if necessary.

Performance in children

In children, the daily dose of cefoperazone is 50-200 mg/kg of body weight, administered in equal portions in two doses every 12 hours or more if necessary. The maximum daily dose is 12 g.

When administered by intravenous stream the maximum single dose for children is 50 mg/kg, the duration of administration is at least 3-5 minutes. Newborns (< 8 days) are administered 50-200 mg/kg body weight per day in equal portions every 12 hours. Daily doses up to 300 mg/kg have been used without complications in infants and children with severe infections, including bacterial meningitis.

Intravenous administration

The solvent to be used is 5% dextrose solution, isotonic sodium chloride solution (0.9%), sterile water for injection.

To prepare a solution for intravenous injection it is necessary to dissolve 1 g of cefoperazone in 10 ml of sterile water for injection or other compatible solution and administer it for at least 3-5 minutes. For IV/injection by injection, the maximum single dose of cefoperazone for adults is 2 g, for children – 50 mg/kg of body weight.

When preparing a solution for intravenous drop administration 1 g of cefoperazone is dissolved in 5 ml of sterile water for injection; the obtained solution is added to the infusion solution (Ringer’s lactate solution, 5% dextrose solution, sodium chloride isotonic solution) at a concentration of 20-100 mg/ml. The duration of injection depending on the volume of the solution may be from 10-30 minutes or more.

Intramuscular administration

Septic water for injection or isotonic sodium chloride solution can be used for preparation of solutions intended for intramuscular injection. To dilute 0.5 g of the drug, 2 ml of the solvent should be used, 1 g – 4 ml in order to obtain the final concentration of cefoperazone 250 mg/ml. In order to reduce pain during IV/m injections in cases when a solution with a concentration of 250 mg/ml or more is to be administered, it is recommended to use lidocaine solution for solution preparation (if the patient has no hypersensitivity reaction to lidocaine). This solution can be prepared using sterile water for injection combined with 2% lidocaine solution. The following two-step method of dilution is recommended: first add the required amount of sterile water for injection and shake until the cefoperazone powder is completely dissolved, then add the required amount of 2% lidocaine and mix.

I/m injection is made deep into a large muscle (large gluteal muscle or anterior thigh surface).

Interaction

Pharmaceutically incompatible with aminoglycosides (if combined therapy with cefoperazone and aminoglycoside is necessary, the drugs are administered as sequential fractional IV drug administration using 2 separate IV catheters).

Indirect anticoagulants, heparin, thrombolytics, antiaggregants, nonsteroidal anti-inflammatory drugs increase the risk of hypoprothrombinemia, bleeding.

Aminoglycosides and “loop” diuretics increase the risk of nephrotoxicity, especially in persons with renal insufficiency.

Drugs that reduce tubular secretion increase the blood concentration of the drug and slow its excretion.

It is not compatible with ethanol and disulfiram-like reactions may occur in the form of hyperemia, nausea, vomiting, headache, shortness of breath, tachycardia, decreased BP, abdominal cramps.

Special Instructions

Before prescribing cefoperazone, a detailed allergic history should be taken to identify the patient’s hypersensitivity to cephalosporins, penicillins and other medications.

If an allergic reaction occurs during treatment, cefoperazone should be discontinued and appropriate treatment initiated.

In some patients, treatment with cefoperazone may lead to vitamin K deficiency in the body, which is associated with suppression of intestinal flora that synthesize this vitamin. Patients with malabsorption syndrome (e.g., cystic fibrosis), as well as patients on an incomplete diet or who are on parenteral nutrition for a long time are most at risk. In these patients during treatment it is necessary to monitor prothrombin time and prescribe vitamin K if necessary.

In long-term therapy it is recommended that renal, hepatic and hematopoietic function be monitored periodically. This is especially important for newborns, including premature babies.

Clostridium difficile-associated diarrhea occurs with virtually all antibacterials, including cefoperazone, and appears in mild forms of diarrhea to severe colitis. with lethal outcome. Treatment with antibiotics leads to disruption of normal colon microflora, resulting in increased growth of Clostrifium difficile, producing toxins A and B, which lead to the development of Clostridium difficile-associated diarrhea. Hypertoxin-producing strains of Clostridium difficile lead to increased morbidity and mortality because they may be resistant to current antibiotic therapy. All cases of diarrhea in patients on antibiotic therapy should be considered suspicious for Clostridium difficile-associated diarrhea.

False positive urine glucose reactions are possible during treatment when testing with Benedict or Fehling solutions.

If it is necessary to use the drug in newborns, including premature infants, the expected positive effects of therapy and the possible risks associated with the treatment should be taken into account. In neonates with nuclear jaundice, cefoperazone does not displace bilirubin from plasma protein binding sites.

Influence on driving and operating ability

Take with caution.

Contraindications

Hypersensitivity to cefoperazone, other beta-lactam antibiotics.

With caution

Hepatic impairment, history of colitis, childhood under 1 year, biliary obstruction.

Side effects

Allergic reactions: urticaria, skin itching, maculopapular rash, fever, eosinophilia, erythema multiforme (including Stevens-Johnson syndrome), rarely – anaphylactic shock.

Gastro-intestinal tract: nausea, vomiting, diarrhea, pseudomembranous colitis.

Hematopoietic and hemostatic disorders: bleeding (vitamin K deficiency), anemia, reversible neutropenia (with long-term use).

Laboratory measures: hypoprothrombinemia, increased prothrombin time, increased activity of “hepatic” transaminases and alkaline phosphatase, hypercreatininemia, positive Coombs reaction.

Local reactions: when administered intravenously – phlebitis; when administered intravenously – pain at the injection site.

Overdose

Symptoms: neurological disorders; including seizures.

Treatment: symptomatic therapy. Hemodialysis is effective.