What is the treatment regimen for complicated infections caused by Gram-negative bacteria using Ceftazidime (Ceftazidime)-Avibactam?

Ceftazidime-Avibactam Treatment Regimen for Complicated Infections Caused by Gram-Negative Bacteria

Ceftazidime-avibactam is recommended at a dose of 2.5 grams (ceftazidime 2 grams and avibactam 0.5 grams) administered every 8 hours by intravenous infusion over 2 hours for the treatment of complicated infections caused by susceptible Gram-negative bacteria. 1

FDA-Approved Indications

• Complicated Intra-abdominal Infections (cIAI):

  • Must be used in combination with metronidazole 1
  • Treatment duration: 5-14 days 1
  • Active against: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, and Pseudomonas aeruginosa 1

• Complicated Urinary Tract Infections (cUTI), including Pyelonephritis:

  • Treatment duration: 7-14 days 1
  • Active against: Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae, Citrobacter freundii complex, Proteus mirabilis, and Pseudomonas aeruginosa 1

• Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP):

  • Treatment duration: 7-14 days 1
  • Active against: Klebsiella pneumoniae, Enterobacter cloacae, Escherichia coli, Serratia marcescens, Proteus mirabilis, Pseudomonas aeruginosa, and Haemophilus influenzae 1

Antimicrobial Spectrum and Resistance Considerations

• Effective against:

  • Extended-spectrum β-lactamase (ESBL)-producing Enterobacterales 2, 3
  • AmpC β-lactamase-producing organisms 3, 4
  • Klebsiella pneumoniae carbapenemase (KPC)-producing organisms 2
  • OXA-48-producing Carbapenem-Resistant Enterobacterales (CRE) 2
  • Multidrug-resistant Pseudomonas aeruginosa 4, 5

• Not effective against:

  • Metallo-β-lactamase (MBL)-producing organisms (e.g., NDM, VIM, IMP) 2
  • Acinetobacter species 4
  • Anaerobic bacteria (requires combination with metronidazole for anaerobic coverage) 1, 4

Dosing Recommendations

Adult Patients (≥18 years) with Normal Renal Function (CrCl >50 mL/min):

• 2.5 grams (ceftazidime 2 grams + avibactam 0.5 grams) every 8 hours 1
• Administered by intravenous infusion over 2 hours 1
• Dose adjustment required for renal impairment 1

Special Populations:

• For patients with CRE infections producing serine carbapenemases (KPC, OXA-48):

  • Standard dosing regimen of 2.5 grams every 8 hours 2
  • Has shown reduced mortality compared to other antimicrobial therapies 2

• For patients with metallo-β-lactamase-producing CRE:

  • Combination of ceftazidime-avibactam with aztreonam is recommended 2, 6
  • This combination has shown significantly lower 30-day mortality (19.2% vs 44%) compared to other treatment options 2

Clinical Efficacy Evidence

• Ceftazidime-avibactam has demonstrated non-inferiority to carbapenems in clinical trials for cUTI, cIAI, and HAP/VAP 7, 5

• For CRE infections, observational studies show ceftazidime-avibactam may be associated with:

  • 182 fewer deaths per 1000 patients treated (RR 0.55,95% CI 0.42-0.72) 2
  • 307 fewer treatment failures per 1000 patients (RR 0.49,95% CI 0.34-0.70) 2
  • 95 fewer acute renal injuries per 1000 patients (RR 0.37,95% CI 0.16-0.83) 2

• In HAP/VAP specifically, ceftazidime-avibactam has shown low-certainty evidence of non-inferiority to carbapenems for treatment of infections caused by resistant Enterobacterales 2, 8

Important Considerations and Caveats

• Resistance development: Resistance to ceftazidime-avibactam in KPC-producing organisms has been reported during treatment 2

• Carbapenemase testing: Determining the carbapenemase type and/or ceftazidime-avibactam susceptibility before initiation of treatment is recommended whenever possible 2

• Combination therapy:

  • For intra-abdominal infections, must be combined with metronidazole for anaerobic coverage 1, 4
  • For metallo-β-lactamase producers, combination with aztreonam is recommended 2, 6

• Penetration into infection sites: Penetration into epithelial lining fluid (ELF) is approximately 30% of plasma concentrations, which is sufficient for treatment of pneumonia with the recommended dosing 8

• Cost considerations: Despite higher cost compared to other antibiotics, ceftazidime-avibactam has been shown to be cost-effective for CRE bacteremia and pneumonia 2