Zavicefta, 2000 mg+500 mg 10 pcs

A combination drug whose active ingredients are avibactam and ceftazidime.

The mechanism of action

Avibactam is an inhibitor of β-lactamases of non-beta-lactam structure. Avibactam forms a covalent bond with the enzyme that is not subject to hydrolysis. It inhibits β-lactamases of classes A and C and some β-lactamases of class D according to Ambler, including extended spectrum β-lactamases (ALRS), CRC and OXA-48 carbapenemases, as well as AmpC enzymes. Avibactam does not inhibit class B β-lactamases (metal-β-lactamases) and is unable to inhibit many class D β-lactamases. Avibactam has no clinically significant antibacterial activity in vitro. Avibactam does not induce blaAmrC transcription in Enterobacter cloacae, Citrobacter freundii or Pseudomonas aeruginosa in vitro at concentrations used to treat patients.

Ceftazidime is a broad-spectrum antibiotic of the cephalosporin class whose activity against many significant Gram-negative and Gram-positive pathogenic bacteria has been shown in vitro. Ceftazidime disrupts synthesis of bacterial cell wall peptidoglycan as a result of interaction with penicillin-binding proteins (PBP), which leads to destruction of cell wall and death of bacteria.

Resistance

The mechanism of resistance. The drug is not active against bacteria producing metallo-β-lactamases. Mechanisms of bacterial resistance that could potentially affect drug activity include mutant or acquired BPS, decreased outer membrane permeability to avibactam or ceftazidime, active excretion (efflux) of avibactam or ceftazidime, and β-lactamases that are resistant to inhibition by avibactam and capable of hydrolyzing ceftazidime.

Cross-resistance. The absence of cross-resistance between the drug and fluoroquinolones or aminoglycosides has been demonstrated in vitro using clinical isolates described at the molecular level. Some isolates resistant to ceftazidime (or other cephalosporins) or carbapenems are sensitive to the ceftazidime/avibactam combination. Cross-resistance with antibacterials from the beta-lactam group, including carbapenems, has been noted when the mechanism of resistance is the production of metallo-β-lactamases such as VIM-2.

In interaction with other antibacterial agents

In in vitro studies, neither synergism nor antagonism was noted with metronidazole, tobramycin, levofloxacin, vancomycin, linezolid, colistin and tigecycline when the drug was used together.

Sensitivity

The prevalence of acquired resistance of certain microbial species may vary in different regions and over time. Local information on resistance is desirable, especially when treating severe infections. Drug sensitivity for specific clinical isolates should be determined using standard methods. Interpretation of microbiological results should be done according to local guidelines.

Indications

Treatment of the following infections in adult patients: complicated intra-abdominal infections; complicated urinary tract infections, including pyelonephritis; hospital-acquired pneumonia, including pneumonia associated with mechanical ventilation;
infections caused by aerobic gram-negative microorganisms in patients with limited choice of antibiotic therapy.

Pharmacological effect

A combination drug whose active ingredients are avibactam and ceftazidime.

Mechanism of action

Avibactam is a non-beta-lactam β-lactamase inhibitor. Avibactam forms a covalent bond with the enzyme, which is not hydrolyzed. Inhibits class A and C β-lactamases and some Ambler class D β-lactamases, including extended spectrum β-lactamases (ESBLs), KPC and OXA-48 carbapenemases, as well as AmpC enzymes. Avibactam does not inhibit class B β-lactamases (metallo-β-lactamases) and is not able to inhibit many class D β-lactamases. Avibactam does not have clinically significant antibacterial activity in vitro. Avibactam does not induce blaAmpC transcription in Enterobacter cloacae, Citrobacter freundii or Pseudomonas aeruginosa in vitro at the concentrations used to treat patients.

Ceftazidime is a broad-spectrum antibiotic of the cephalosporin class, whose activity against many significant gram-negative and gram-positive pathogenic bacteria has been shown in vitro. Ceftazidime disrupts the synthesis of peptidoglycan in the bacterial cell wall as a result of interaction with penicillin-binding proteins (PBPs), which leads to destruction of the cell wall and death of bacteria.

Resistance

Mechanism of resistance. The drug is not active against bacteria that produce metallo-β-lactamases. Mechanisms of bacterial resistance that could potentially affect the activity of the drug include mutant or acquired PBPs, decreased outer membrane permeability to avibactam or ceftazidime, active efflux of avibactam or ceftazidime, and β-lactamases that are resistant to inhibition by avibactam and are capable of hydrolyzing ceftazidime.

Cross resistance. The absence of cross-resistance between the drug and fluoroquinolones or aminoglycosides has been demonstrated in vitro using molecularly characterized clinical isolates. Some isolates resistant to ceftazidime (or other cephalosporins) or carbapenems are susceptible to the ceftazidime/avibactam combination. Cross-resistance has been observed with antibacterial drugs from the beta-lactam group, including carbapenems, when the mechanism of resistance is the production of metallo-β-lactamases, such as VIM-2.

Interaction with other antibacterial drugs

In in vitro studies, when the drug was used together with metronidazole, tobramycin, levofloxacin, vancomycin, linezolid, colistin and tigecycline, no synergism or antagonism was observed.

Sensitivity

The prevalence of acquired resistance of certain types of microorganisms may vary between regions and over time. It is advisable to obtain local information on resistance, especially when treating severe infections. Drug susceptibility for specific clinical isolates should be determined using standard methods. Interpretation of microbiological test results should be carried out in accordance with local guidelines.

Active ingredient

Ceftazidime, [Avibactam]

Composition

Active substances:

avibactam sodium 543.5 mg, which corresponds to the content of avibactam 500 mg;

ceftazidime pentahydrate 2329.6 mg, which corresponds to the content of ceftazidime 2000 mg;

Excipients: anhydrous sodium carbonate – 233 mg.

Contraindications

Children and adolescents under 18 years of age (efficacy and safety have not been established); hypersensitivity to avibactam, ceftazidime or sodium carbonate (an excipient included in the drug); hypersensitivity to cephalosporins; severe immediate hypersensitivity reactions (for example, anaphylactic reaction) to any other antibacterial agent having a beta-lactam structure (for example, penicillins, monobactams or carbapenems).

Side Effects

Infections and infestations: often – candidiasis (including vulvovaginal candidiasis and oral candidiasis); uncommon – colitis associated with Clostridium difficile, pseudomembranous colitis.

From the hematopoietic system: very often – positive direct Coombs test; often – eosinophilia, thrombocytosis; uncommon – neutropenia, leukopenia, thrombocytopenia, lymphocytosis; unspecified frequency – agranulocytosis, hemolytic anemia.

From the immune system: unspecified frequency – anaphylactic reaction.

From the nervous system: often – headache, dizziness; infrequently – paresthesia.

From the digestive system: often – diarrhea, abdominal pain, nausea, vomiting, increased ALT activity, increased AST activity, increased alkaline phosphatase activity, increased GGT activity, increased LDH activity; infrequently – perversion of taste; unspecified frequency – jaundice.

From the skin and subcutaneous fat: often – maculopapulous rash, urticaria; infrequently – itching; unspecified frequency – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, angioedema, drug rash with eosinophilia and systemic symptoms.

From the urinary system: uncommon – increased creatinine concentration in the blood, increased urea concentration in the blood, acute renal failure; very rarely – tubulointerstitial nephritis.

Other: often – thrombosis at the infusion site, phlebitis at the infusion site, increased body temperature.

Interaction

Avibactam did not significantly inhibit cytochrome P450 isoenzymes. Avibactam and ceftazidime did not induce cytochrome P450 isoenzymes in vitro over a clinically relevant exposure range. Avibactam and ceftazidime do not inhibit major transporters in the kidneys and liver within the clinically relevant exposure range, and the potential for drug interactions through these mechanisms is considered low.

In vitro, avibactam is a substrate of the OAT1 and OAT3 transporters, which may contribute to its active uptake from the bloodstream and thus its excretion. Probenecid (a potent OAT inhibitor) inhibits this uptake by 56% to 70% in vitro and may therefore interfere with avibactam elimination when combined with avibactam. Clinical studies of the interaction of avibactam and probenecid have not been conducted, therefore it is not recommended to use avibactam in combination with probenecid.

Clinical data confirm the absence of interaction between ceftazidime and avibactam, as well as between ceftazidime-avibactam and metronidazole.

The use of cephalosporins in high doses in combination with nephrotoxic drugs such as aminoglycosides or powerful diuretics (for example, furosemide) can lead to impaired renal function.

Chloramphenicol is an antagonist of ceftazidime and other cephalosporins in vitro. The clinical significance of these data is unknown, but due to the potential for in vivo antagonism, coadministration of these drugs should be avoided.

Manufacturer

ACS Dobfar S.p.A., Italy