Ceftazidime Avibactam

Ceftazidime avibactam combines an antipseudomonal cephalosporin with a non-beta-lactam beta-lactamase inhibitor. It is a reserve agent for infection caused by ESBL, AmpC, KPC and OXA-48 producing Enterobacterales and for difficult-to-treat Pseudomonas aeruginosa.

Classification. Beta-lactam, third-generation cephalosporin plus diazabicyclooctane inhibitor. Doses are written as the combined weight: 2.5 g contains 2 g ceftazidime and 0.5 g avibactam.

Mechanism. Ceftazidime blocks penicillin-binding proteins; avibactam reversibly inactivates class A (including KPC), class C and some class D (OXA-48) enzymes.

Spectrum. Enterobacterales including ESBL, AmpC and KPC producers, Pseudomonas aeruginosa (including many multidrug-resistant strains). Not active against metallo-beta-lactamase producers (NDM, VIM, IMP), most Acinetobacter, Gram-positive cocci or anaerobes.

Pharmacokinetics. IV only. Half-life about 2 hours for both components. Protein binding under 10%. Over 80% excreted unchanged in urine.

Reserve agent; use only after specialist review. No loading dose. Maximum 7.5 g of the combination daily in adults.

Adults.

• Complicated intra-abdominal infection: 2.5 g IV over 2 hours every 8 hours, with metronidazole 500 mg every 8 hours, for 5 to 14 days.
• Complicated urinary tract infection including pyelonephritis: 2.5 g over 2 hours every 8 hours for 5 to 10 days (up to 14 days if bacteraemic).
• Hospital-acquired and ventilator-associated pneumonia: 2.5 g over 2 hours every 8 hours for 7 to 14 days.
• Bacteraemia and infection with limited options (aerobic Gram-negative bacilli): 2.5 g every 8 hours as directed by infectious diseases.
• Metallo-beta-lactamase producers (specialist use): 2.5 g every 8 hours given together with aztreonam 2 g every 8 hours.

Children. 3 months to under 6 months: 40 mg/kg ceftazidime (with 10 mg/kg avibactam) every 8 hours. 6 months to 17 years: 50 mg/kg ceftazidime (with 12.5 mg/kg avibactam) every 8 hours, maximum 2 g ceftazidime a dose.

Alternatives. Meropenem vaborbactam, imipenem cilastatin relebactam, cefiderocol, colistin-based regimens.

Contraindications. Hypersensitivity to ceftazidime, avibactam or any cephalosporin; severe hypersensitivity to other beta-lactams.

Adverse effects. Diarrhoea, nausea, vomiting, rash, positive direct Coombs test, raised liver enzymes. Serious: anaphylaxis, Clostridioides difficile infection, interstitial nephritis, neurotoxicity in renal failure (confusion, myoclonus, seizures).

Interactions. Probenecid inhibits renal transport of avibactam and is not advised with it. Nephrotoxic drugs may impair kidney function.

Common prescribing errors. Using it for metallo-beta-lactamase producers without aztreonam, omitting anaerobic cover in intra-abdominal infection, and failing to adjust the dose as kidney function changes in the first days.

Special groups.

• Pregnancy and breastfeeding: limited data; use only if the benefit outweighs unknown risk.
• Older adults: adjust by kidney function.
• Kidney impairment, by creatinine clearance: over 50 mL/min no change.
• 31 to 50 mL/min: 1.25 g every 8 hours.
• 16 to 30 mL/min: 0.94 g every 12 hours.
• 6 to 15 mL/min: 0.94 g every 24 hours.
• 5 mL/min or less: 0.94 g every 48 hours.
• Haemodialysis: give after the session.

Recheck creatinine clearance daily early in treatment because clinical cure fell in patients with moderate impairment. - Liver impairment: no adjustment. - Region: availability in East Africa is limited; stewardship control is needed to preserve activity.

Preparation. Reconstitute each 2.5 g vial with 10 mL water for injection, then dilute to 100 mL in 0.9% sodium chloride or 5% glucose and infuse over 2 hours.

Baseline and monitoring. - Baseline: allergy history, cultures with carbapenemase testing where available, creatinine, full blood count. - During treatment: daily creatinine early, then twice weekly; liver tests weekly. - No therapeutic drug monitoring.

Stop rules. Stop for anaphylaxis, severe diarrhoea, neurotoxicity or severe skin reaction.

Referral and escalation. Infectious diseases consultation is needed before and during use, and for any suspected metallo-beta-lactamase producer.