Piperacillin + Tazobactam (Lyophilisate, Powder) Instructions for Use

ATC Code

J01CR05 (Piperacillin and beta-lactamase inhibitor)

Active Substances

Piperacillin (Rec.INN registered by WHO)

Tazobactam (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Broad-spectrum penicillin antibiotic with a beta-lactamase inhibitor

Pharmacotherapeutic Group

Systemic antibacterial agents; beta-lactam antibacterial agents, penicillins; combinations of penicillins, including combinations with beta-lactamase inhibitors

Pharmacological Action

A combined medicinal product.

Piperacillin is a bactericidal semi-synthetic broad-spectrum antibiotic that suppresses the synthesis of the microbial cell wall.

Tazobactam is a beta-lactamase inhibitor (including plasmid and chromosomal), which are most often the cause of resistance to penicillins and cephalosporins (including third-generation cephalosporins). The presence of tazobactam significantly expands the spectrum of action of piperacillin.

Most strains of microorganisms resistant to piperacillin and producing beta-lactamases are susceptible.

It is active against gram-negative aerobic bacteria: Escherichia coli, Salmonella spp., Shigella spp., Citrobacter spp. (including Citrobacter freundii, Citrobacter diversus), Klebsiella spp. (including Klebsiella oxytoca, Klebsiella pneumoniae), Morganella morganii, Moraxella spp. (including Moraxella catarrhalis), Proteus spp. (including Proteus mirabilis, Proteus vulgaris), Pseudomonas aeruginosa (only piperacillin-susceptible strains) and other Pseudomonas spp. (including Burkholderia cepacia, Pseudomonas fluorescens), Neisseria spp. (including Neisseria meningitidis, Neisseria gonorrhoeae), Haemophilus spp. (including Haemophilus influenzae, Haemophilus parainfluenzae), Serratia spp. (including Serratia marcescens, Serratia liquefaciens), Pasteurella multocida, Yersinia spp., Campylobacter spp., Gardnerella vaginalis, Enterobacter spp. (including Enterobacter cloacae, Enterobacter aerogenes), Providencia spp, Stenotrophomonas maltophilia, Acinetobacter spp. (producing and non-producing chromosomal beta-lactamase); gram-negative anaerobic bacteria: Bacteroides spp. (Bacteroides fragilis, Bacteroides disiens, Bacteroides capillosus, Bacteroides melaninogenicus, Bacteroides oralis, Bacteroides distasonis, Bacteroides uniformis, Bacteroides ovatus, Bacteroides thetaiotaomicron, Bacteroides vulgatus, Bacteroides bivius, bacteroides asaccharolyticus), Fusobacterium nucleatum; gram-positive aerobic bacteria: Streptococcus spp. (including Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus bovis), Streptococcus group viridans (C and G), Enterococcus spp. (Enterococcus faecalis, Enterococcus faecium), Staphylococcus spp. (methicillin-susceptible Staphylococcus aureus strains, Staphylococcus epidermidis, Staphylococcus saprophyticus), Listeria monocytogenes, Nocardia spp.; gram-positive anaerobic bacteria: Clostridium spp. (including Clostridium perfringens, Clostridium difficile), Peptostreptococcus spp., Eubacterium spp.; Veillonella spp., Actinomyces spp.

Pharmacokinetics

The C_max of piperacillin after IV infusion of 2.25 or 4.5 g over 30 minutes is reached immediately after its completion and is 134 and 298 µg/ml, respectively; the corresponding average plasma concentrations are 15, 24 and 34 µg/ml (piperacillin plasma concentrations after its administration in combination with tazobactam are similar to those after administration of equivalent doses of piperacillin monodrug). The mean C_max values of tazobactam in plasma are 15 and 34 µg/ml, respectively.

The binding to plasma proteins of piperacillin and tazobactam is about 30% (the tazobactam metabolite practically does not bind to proteins). Piperacillin and Tazobactam penetrate well into tissues and body fluids, including the intestinal mucosa, gallbladder, lungs, bile, bone tissue and tissues of the female reproductive system (uterus, ovaries and fallopian tubes). Average tissue concentrations range from 50 to 100% of those in plasma. It practically does not penetrate the intact blood-brain barrier.

It is excreted in breast milk.

Piperacillin is metabolized to a weakly active desethyl metabolite, Tazobactam to an inactive metabolite.

They are excreted by the kidneys through glomerular filtration and tubular secretion: Piperacillin – 68% unchanged, Tazobactam – 80% unchanged and a small amount as a metabolite. Piperacillin, Tazobactam and desethylpiperacillin are also excreted in bile.

Tazobactam does not cause significant changes in the pharmacodynamics of piperacillin. Piperacillin appears to reduce the elimination rate of tazobactam.

The T_1/2 of piperacillin and tazobactam are 0.7-1.2 h.

Indications

Bacterial infections caused by susceptible microflora in adults and children over 12 years of age: infections of the lower respiratory tract (pneumonia, lung abscess, pleural empyema); abdominal infections (peritonitis, pelvioperitonitis, cholangitis, gallbladder empyema, appendicitis (including complicated by abscess or perforation)). infections of the genitourinary tract, including complicated ones (pyelonephritis, cystitis, prostatitis, epididymitis, gonorrhea, endometritis, vulvovaginitis, postpartum endometritis and adnexitis); infections of bones, joints, including osteomyelitis; infections of the skin and soft tissues (phlegmon, furunculosis, abscess, pyoderma, lymphadenitis, lymphangitis, infected trophic ulcers, infected wounds and burns); intra-abdominal infections (including in children over 2 years of age); bacterial infection in patients with neutropenia (including in children under 12 years of age); sepsis; meningitis; prevention of postoperative infection.

ICD codes

Dosage Regimen

Administer intravenously as a 30-minute infusion.

For adults and children over 12 years with normal renal function, the usual dosage for moderate infections is 2.25 g (2 g piperacillin/0.25 g tazobactam) every 6-8 hours.

For severe infections, including nosocomial pneumonia, use 4.5 g (4 g piperacillin/0.5 g tazobactam) every 6-8 hours.

For bacterial infection in patients with neutropenia, administer 4.5 g every 6 hours.

For surgical prophylaxis, administer a single 4.5 g dose pre-operatively.

Adjust dosage for renal impairment based on creatinine clearance (CrCl). For CrCl 20-40 mL/min, give 2.25 g every 6 hours; for CrCl <20 mL/min, give 2.25 g every 8 hours.

For patients on hemodialysis, administer a 2.25 g loading dose followed by 2.25 g after each dialysis session.

Reconstitute the powder with a compatible diluent such as 0.9% Sodium Chloride or Sterile Water for Injection.

Further dilute the reconstituted solution to a final volume of 50-150 mL.

Administer the final infusion solution immediately after preparation; stability times vary by diluent and storage conditions.

Do not mix with other drugs in the same IV solution; administer aminoglycosides separately.

Adverse Reactions

Allergic reactions urticaria, skin itching, rash, bullous dermatitis, multiforme erythema, Stevens-Johnson syndrome, toxic epidermal necrolysis, anaphylactic/anaphylactoid reactions (including anaphylactic shock).

From the digestive system diarrhea, nausea, vomiting, constipation, dyspepsia, jaundice, stomatitis, abdominal pain, pseudomembranous colitis, hepatitis.

From the hematopoietic organs leukopenia, neutropenia, thrombocytopenia, anemia, bleeding (including purpura, nosebleeds, increased time, bleeding), hemolytic anemia, agranulocytosis, false-positive direct Coombs test, pancytopenia, increased partial thromboplastin time, increased prothrombin time, thrombocytosis.

From the urinary system interstitial nephritis, renal failure.

From the nervous system headache, insomnia, convulsions.

From the cardiovascular system decreased blood pressure, flushing of the skin of the face.

Laboratory indicators hypoalbuminemia, hypoglycemia, hypoproteinemia, hypokalemia, eosinophilia, increased activity of “hepatic” transaminases (ALT, AST), hyperbilirubinemia, increased activity of alkaline phosphatase, GGT, increased concentration of creatinine and urea in blood serum.

Local reactions phlebitis, thrombophlebitis, hyperemia and induration at the injection site.

Others fungal superinfections, fever, arthralgia.

Contraindications

Hypersensitivity (including to penicillins, cephalosporins, other inhibitors of beta-lactam antibiotics); children’s age (up to 2 years).

With caution

Severe bleeding (including history), cystic fibrosis (increased risk of hyperthermia and skin rash), pseudomembranous colitis, children over 2 years of age, chronic renal failure (creatinine clearance less than 20 ml/min), patients on hemodialysis, with simultaneous use of high doses of anticoagulants, with hypokalemia, pregnancy, lactation period.

Use in Pregnancy and Lactation

With caution use during pregnancy and during lactation (breastfeeding).

Use in Renal Impairment

With caution in chronic renal failure. In chronic renal failure, the daily doses of piperacillin/tazobactam are adjusted depending on creatinine clearance.

Pediatric Use

Contraindication children under 2 years of age.

With caution: children over 2 years of age.

Special Precautions

During treatment, especially long-term, leukopenia and neutropenia may develop, so it is necessary to periodically monitor peripheral blood counts.

In some cases (most often in patients with renal failure), increased bleeding and concomitant changes in laboratory parameters of the blood coagulation system (blood clotting time, platelet aggregation and prothrombin time) may occur. If bleeding occurs, the administration of the drug should be discontinued and appropriate therapy should be prescribed.

Antibiotic-induced pseudomembranous colitis may present as severe, persistent diarrhea that is life-threatening. Pseudomembranous colitis can develop both during antibacterial therapy and after its completion. In such cases, the administration of the drug should be stopped immediately and appropriate therapy should be prescribed (for example, metronidazole, vancomycin orally). Drugs that inhibit intestinal peristalsis are contraindicated.

It is necessary to keep in mind the possibility of the appearance of resistant microorganisms that can cause superinfection, especially during a long course of treatment. This drug contains 2.79 mEq (64 mg) of sodium per gram of piperacillin, which may lead to a general increase in sodium intake. In patients with hypokalemia or taking drugs that promote potassium excretion, hypokalemia may develop during treatment (it is necessary to regularly check the electrolyte content in the blood serum).

In patients with chronic renal failure on hemodialysis, the dose of the drug and the frequency of administration must be adjusted depending on creatinine clearance.

During use, a false-positive urine glucose test result is possible when using the method based on the reduction of copper ions. Therefore, it is recommended to perform a test based on the enzymatic oxidation of glucose (glucose oxidase method).

Effect on ability to drive vehicles and mechanisms

Given the possibility of side effects from the nervous system during treatment with the drug, caution should be exercised when working with mechanisms and driving vehicles.

Drug Interactions

Concomitant use of the drug with probenecid increases the T_1/2 and reduces the renal clearance of both piperacillin and tazobactam, however, the C_max in plasma of both drugs remains unchanged.

Simultaneous use of the drug and vecuronium bromide may lead to a longer neuromuscular blockade caused by the latter (a similar effect may be observed when piperacillin is combined with other non-depolarizing muscle relaxants).

With simultaneous use of high doses of heparin, indirect anticoagulants or other drugs that affect the blood coagulation system, including platelet function, it is necessary to monitor the state of the blood coagulation system more often.

Piperacillin may delay the excretion of methotrexate (to avoid a toxic effect, it is necessary to monitor the concentration of methotrexate in the blood serum).

Pharmaceutical compatibility with other drugs

Do not mix in the same syringe or dropper with other drugs, including aminoglycosides. When used together with other antibiotics, the drugs should be administered separately; it is most preferable to separate the administration of piperacillin+Tazobactam and aminoglycosides in time.

Do not use together with solutions containing sodium bicarbonate and add to blood products or albumin hydrolysates.

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.