ZAVICEFTA

What it is

Zavicefta contains ceftazidime (as pentahydrate) and avibactam (as sodium). Each vial contains ceftazidime equivalent to 2000 mg and avibactam equivalent to 500 mg. Zavicefta is a powder for injection. Ceftazidime inhibits bacterial peptidoglycan cell wall synthesis following binding to penicillin binding proteins, which leads to bacterial cell lysis and death. Avibactam is a non β-lactam, β-lactamase inhibitor that acts by forming a covalent adduct with the enzyme. It inhibits both Ambler class A and class C β-lactamases and some class D enzymes, including extended-spectrum β-lactamases, KPC and OXA-48 carbapenemases, and AmpC enzymes.

Approved indications —

Complicated intra-abdominal infection (cIAI) in combination with metronidazole in adults. — Complicated urinary tract infection (cUTI) including pyelonephritis in adults. — Hospital-acquired pneumonia (HAP) including ventilator associated pneumonia (VAP) in adults. — Complicated intra-abdominal infection (cIAI) in combination with metronidazole in infants and paediatric patients (≥ 3 months to < 18 years). — Complicated urinary tract infection (cUTI) including pyelonephritis in infants and paediatric patients (≥ 3 months to < 18 years).

Dosing overview

The recommended adult dosage is one vial (2000 mg ceftazidime and 500 mg avibactam), repeated every 8 hours. Zavicefta is administered by intravenous infusion over 120 minutes. Treatment duration varies by indication: 5–14 days for complicated intra-abdominal infection, 5–10 days for complicated urinary tract infection (including pyelonephritis), and 7–14 days for hospital-acquired pneumonia (including ventilator-associated pneumonia). For cUTI including pyelonephritis, the total duration of treatment could be increased to 14 days for patients with bacteraemia. Dosage adjustment of Zavicefta is recommended in patients with moderate and severe renal impairment and end-stage renal disease, with dose adjustments for patients with estimated creatinine clearance ≤ 50 mL/min. No dosage adjustment is required in patients with hepatic impairment. No dosage adjustment is required in elderly patients.

Key safety warnings

Serious and occasionally fatal hypersensitivity reactions are possible. In case of hypersensitivity reactions, treatment with Zavicefta must be discontinued immediately and adequate emergency measures must be initiated. Before beginning treatment, it should be established whether the patient has a history of hypersensitivity reactions to ceftazidime, to other cephalosporins or to any other type of β-lactam antibacterial agent. Caution should be used if ceftazidime/avibactam is given to patients with a history of non-severe hypersensitivity to penicillins, monobactams or carbapenems. Clostridium difficile-associated diarrhoea has been reported with ceftazidime/avibactam and can range in severity from mild to life-threatening. This diagnosis should be considered in patients who present with diarrhoea during or subsequent to the administration of Zavicefta. Discontinuation of therapy with Zavicefta and the administration of specific treatment for Clostridium difficile should be considered. Concurrent treatment with high doses of cephalosporins and nephrotoxic medicinal products such as aminoglycosides or potent diuretics (for example, furosemide) may adversely affect renal function. Ceftazidime/avibactam use may cause development of a positive direct antiglobulin test (DAGT), which may interfere with the cross-matching of blood and/or may cause drug induced immune haemolytic anaemia. While DAGT seroconversion in patients receiving Zavicefta was very common in clinical studies, there was no evidence of haemolysis in patients who developed a positive DAGT on treatment. However, the possibility that haemolytic anaemia could occur in association with Zavicefta treatment cannot be ruled out. Severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis and drug reaction with eosinophilia and systemic symptoms, which can be life threatening or fatal, have been reported in patients taking beta-lactam antibiotics. When such a reaction is suspected, Zavicefta should be discontinued immediately and an alternative treatment should be considered. This medicinal product is subject to additional monitoring in Australia. This will allow quick identification of new safety information.

Contraindications

Zavicefta is contraindicated in patients with hypersensitivity to the active substances or to any of the excipients. Hypersensitivity to any cephalosporin antibacterial agent is a contraindication. Severe hypersensitivity (for example, anaphylactic reaction or severe skin reaction) to any other type of β-lactam antibacterial agent (for example, penicillins, monobactams or carbapenems) is a contraindication.

Regulatory history

Zavicefta 2000/500 was first listed on the ARTG on 22 February 2019. Zavicefta was approved by the TGA on 21 February 2019 for the treatment of complicated intra-abdominal infection, complicated urinary tract infection, and hospital-acquired pneumonia.