Ceftazidime-Avibactam: Recommended Use and Dosage for Gram-Negative Bacterial Infections
Ceftazidime-avibactam is recommended for the treatment of infections caused by carbapenem-resistant Enterobacterales (CRE) producing serine carbapenemases (KPC and OXA-48), with a standard adult dosage of 2.5 g (2 g ceftazidime + 0.5 g avibactam) administered intravenously every 8 hours over 2 hours. 1, 2
Approved Indications and Dosing
Adult Patients
- For complicated urinary tract infections (cUTI) including pyelonephritis: 2.5 g IV every 8 hours for 7-14 days 1, 2
- For complicated intra-abdominal infections (cIAI): 2.5 g IV every 8 hours for 5-14 days, administered concurrently with metronidazole 500 mg IV every 6-8 hours 3, 2
- For hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP): 2.5 g IV every 8 hours for 7-14 days 3, 2
Pediatric Patients
- For patients 2 years to <18 years with normal renal function: 62.5 mg/kg (50 mg/kg ceftazidime + 12.5 mg/kg avibactam) to a maximum of 2.5 g IV every 8 hours 2
- For patients 6 months to <2 years: 62.5 mg/kg IV every 8 hours 2
- For patients 3 months to <6 months: 50 mg/kg IV every 8 hours 2
- For neonates >28 days to <3 months: 37.5 mg/kg IV every 8 hours 2
- For neonates ≤28 days with gestational age ≥31 weeks: 25 mg/kg IV every 8 hours 2
Renal Dosage Adjustments (Adults)
- CrCl 31-50 mL/min: 1.25 g IV every 8 hours 2
- CrCl 16-30 mL/min: 0.94 g IV every 12 hours 2
- CrCl 6-15 mL/min: 0.94 g IV every 24 hours 2
- CrCl ≤5 mL/min: 0.94 g IV every 48 hours 2
Specific Use in Resistant Infections
For Carbapenem-Resistant Enterobacterales (CRE)
- Ceftazidime-avibactam is effective against CRE producing serine carbapenemases (KPC and OXA-48) 1
- Compared to other antimicrobial therapies, ceftazidime-avibactam may reduce mortality (RR 0.55,95% CI 0.42-0.72) and treatment failures (RR 0.49,95% CI 0.34-0.70) in CRE infections 1
- For CRE urinary tract infections specifically, the recommended dosage is 2.5 g IV every 8 hours 1
For Metallo-β-lactamase-producing CRE
- Ceftazidime-avibactam combined with aztreonam is recommended for infections caused by metallo-β-lactamase-producing CRE 1
- This combination showed lower 30-day mortality (19.2% vs 44%, P=0.007) compared to other active antimicrobial agents 1
Clinical Efficacy and Safety
- Clinical trials have demonstrated that ceftazidime-avibactam is as effective as carbapenems in treating complicated urinary tract infections and complicated intra-abdominal infections 4, 5
- In the REPRISE trial, clinical cure rates were similar between ceftazidime-avibactam (91%) and best available therapy (91%, primarily carbapenems) in patients with ceftazidime-resistant Enterobacteriaceae and Pseudomonas aeruginosa infections 5
- Safety profile is similar to other cephalosporins, with gastrointestinal disorders being the most common adverse events (13% with ceftazidime-avibactam vs 18% with best available therapy) 5
Important Considerations and Caveats
- Determine the carbapenemase type and/or ceftazidime-avibactam susceptibility of CRE isolates before initiating treatment whenever possible 1
- Emergence of ceftazidime-avibactam resistance in carbapenemase-producing K. pneumoniae has been reported, particularly with prior administration of the drug 1, 3
- Risk factors for resistance development include mutations in the bla KPC-3 gene 1
- A "see-saw effect" phenomenon has been observed where variant KPC-3 enzymes may show reduced susceptibility to ceftazidime-avibactam but increased susceptibility to carbapenems 1
- For KPC-3 producing organisms, combination therapy of ceftazidime-avibactam with a carbapenem or colistin may be considered to prevent resistance development 1
- Pharmacodynamic studies indicate that ceftazidime-avibactam is bactericidal at concentrations achievable in human serum 4, 6