What is Ceftazidime-avibactam?

Ceftazidime-Avibactam: A Novel β-Lactam/β-Lactamase Inhibitor Combination

Ceftazidime-avibactam is a novel antimicrobial combination consisting of the third-generation cephalosporin ceftazidime and the non-β-lactam β-lactamase inhibitor avibactam, primarily used to treat serious multidrug-resistant Gram-negative bacterial infections. 1, 2, 3

Composition and Structure

• Components:

  • Ceftazidime: A semisynthetic third-generation cephalosporin (2 grams per dose)
  • Avibactam: A non-β-lactam β-lactamase inhibitor (0.5 grams per dose) 3

• Formulation: Available as a white to yellow sterile powder for intravenous administration, packaged in glass vials containing sodium carbonate 3

Mechanism of Action

• Ceftazidime component: Acts by binding to essential penicillin-binding proteins (PBPs) in bacterial cell walls, resulting in bacterial cell death 3

• Avibactam component: Inactivates specific β-lactamases that would otherwise degrade ceftazidime, thereby restoring ceftazidime's activity against resistant bacteria 3

• Spectrum of activity: Restores activity against bacteria producing:

  • Ambler class A β-lactamases (including ESBLs and KPC carbapenemases)
  • Class C (AmpC) β-lactamases
  • Some class D enzymes (e.g., OXA-48) 1, 2, 3

• Important limitation: Avibactam does not inhibit class B metallo-β-lactamase enzymes (MBLs) such as NDM, VIM, or IMP 1, 2, 3

Clinical Applications

• FDA-approved indications:

  • Complicated urinary tract infections (cUTI), including pyelonephritis
  • Complicated intra-abdominal infections (cIAI) in combination with metronidazole
  • Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) 3, 4

• European approval also includes:

  • Infections due to aerobic Gram-negative organisms in patients with limited treatment options 4

• Specific pathogens covered:

  • Enterobacteriaceae (including ESBL and KPC-producing strains)
  • Pseudomonas aeruginosa (including drug-resistant strains)
  • Specific coverage includes: Citrobacter freundii complex, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and others 3

Dosing and Administration

• Standard adult dose: 2.5 grams (2g ceftazidime + 0.5g avibactam) IV every 8 hours, infused over 2 hours 2, 3, 5

• Renal adjustment: Required for patients with creatinine clearance ≤50 mL/min 3, 5

• Special populations:

  • Elderly: Dosage adjustment based on renal function
  • Gender: No dose adjustment required despite slight pharmacokinetic differences 3

Clinical Efficacy

• Carbapenem-resistant infections: Significantly reduces mortality and treatment failure compared to other antimicrobial options, with 182 fewer deaths per 1000 patients (RR 0.55,95% CI 0.42-0.72) 2

• KPC-producing bacteria: Superior outcomes compared to colistin-based regimens, with a 64% probability of better outcomes (95% CI 57%-71%) 2

• Complicated infections: Non-inferior to carbapenems in pivotal phase III trials for cUTI, cIAI, and HAP/VAP 4

Resistance Concerns

• Emerging resistance mechanisms:

  • Mutations in KPC enzymes that disrupt avibactam binding
  • Reduced expression or loss of outer membrane proteins
  • Overexpression of efflux pumps 2, 6

• Resistance rates: 3.7-8.1% observed in treated patients 2

• Special consideration: For KPC-3 producing organisms, some experts recommend combination therapy with a carbapenem or colistin due to potential resistance development 2

Drug Interactions and Safety

• Drug interactions:

  • Avibactam is a substrate of OAT1 and OAT3 kidney transporters
  • Co-administration with probenecid (an OAT inhibitor) is not recommended
  • No clinically significant interactions with metronidazole 3

• Safety profile:

  • Generally well tolerated with a safety profile consistent with ceftazidime alone
  • No differences in frequency of adverse effects including liver and renal function compared to other antimicrobial regimens 1, 4

Clinical Pearls

• Susceptibility testing is essential before use to confirm activity against the specific pathogen
• For metallo-β-lactamase-producing infections (NDM, VIM, IMP), consider combination with aztreonam 2
• No cross-resistance with other classes of antimicrobials has been identified 3
• Combination therapy is not routinely recommended for CRE infections but may be considered in severely ill patients 1

Ceftazidime-avibactam represents a valuable treatment option for serious infections caused by multidrug-resistant Gram-negative pathogens, particularly those producing serine carbapenemases, while helping to preserve carbapenems and reduce the use of more toxic agents like colistin.