Ceftazidime-Avibactam: Uses and Dosing
Ceftazidime-avibactam is a β-lactam/β-lactamase inhibitor combination approved for treating serious infections caused by resistant gram-negative bacteria, with standard dosing of 2.5 g (ceftazidime 2 g + avibactam 0.5 g) IV every 8 hours over 2 hours. 1
Approved Indications and Spectrum of Activity
Ceftazidime-avibactam is indicated for the following infections in adults and pediatric patients ≥3 months of age:
- Complicated urinary tract infections (cUTI) including pyelonephritis 2, 3, 4
- Complicated intra-abdominal infections (cIAI) in combination with metronidazole 500 mg IV every 6-8 hours 4, 5
- Hospital-acquired pneumonia (HAP) including ventilator-associated pneumonia (VAP) 4, 5
- Infections due to carbapenem-resistant Enterobacterales (CRE) with limited treatment options 2, 3
The combination has excellent activity against Klebsiella pneumoniae carbapenemase (KPC)-producing organisms, OXA-48-producing Enterobacterales, extended-spectrum β-lactamase (ESBL)-producing pathogens, AmpC β-lactamases, and multidrug-resistant Pseudomonas aeruginosa 3, 5. Critically, ceftazidime-avibactam is NOT active against metallo-β-lactamase (MBL)-producing strains, which require aztreonam-based therapy 3, 5.
Standard Dosing Regimens
For Normal Renal Function (CrCL >50 mL/min)
- Standard dose: 2.5 g (ceftazidime 2 g + avibactam 0.5 g) IV every 8 hours administered as a 2-hour infusion 1, 6
- This dosing achieves pharmacodynamic targets (free ceftazidime >8 mg/L and avibactam >1 mg/L for ≥50% of dosing interval) in >94.9% of patients 7
For Renal Impairment (CrCL ≤50 mL/min)
- Dosage adjustment is required based on creatinine clearance, as CrCL is the key determinant of drug clearance variability 7, 6
- Modified dosing regimens must be used for patients with reduced renal function 6
Indication-Specific Treatment Duration
- Complicated UTI/pyelonephritis: 7-14 days 4
- Complicated intra-abdominal infections: 5-14 days (with metronidazole) 4
- Hospital-acquired/ventilator-associated pneumonia: 7-14 days 4
- CRE urinary tract infections: 7-14 days 2, 4
For urosepsis specifically, longer courses may be needed if prostatitis cannot be excluded in men 3.
Critical Resistance Considerations and Combination Therapy
A major pitfall is the emergence of ceftazidime-avibactam resistance in KPC-producing organisms, particularly with prior ceftazidime-avibactam exposure 3, 4. This occurs through mutations in the blaKPC-3 gene, creating a "see-saw effect" where meropenem MICs decrease to susceptible range while ceftazidime-avibactam MICs rise 2.
When treating KPC-3 producers:
- Consider combination therapy with ceftazidime-avibactam plus a carbapenem or colistin to prevent resistance development 2, 3
- Monitor for resistance emergence during therapy 3
For MBL-producing CRE (which are intrinsically resistant to ceftazidime-avibactam):
- Use aztreonam in combination with ceftazidime-avibactam 3
- The avibactam component protects aztreonam from degradation by other β-lactamases while aztreonam remains active against MBLs 3
Clinical Efficacy Data
High-quality phase III trials demonstrate:
- Clinical cure rates of 90.9-91.2% for ceftazidime-resistant organisms 8
- Microbiological response rates of 81.8% versus 63.5% for best available therapy 8
- Response rates ≥94.9% across patient subgroups including obesity, older age, and augmented renal clearance 7, 6
Practical Implementation Algorithm
- Confirm susceptibility or high suspicion for KPC/OXA-48-producing organisms (NOT MBL producers)
- Assess renal function and adjust dose if CrCL ≤50 mL/min
- Add metronidazole if treating intra-abdominal infection
- Consider combination therapy (add carbapenem or colistin) if treating KPC-3 producers or prior ceftazidime-avibactam exposure
- Add aztreonam if MBL-producing organism suspected or confirmed
- Ensure source control for urinary infections (relieve obstruction, drain abscesses, replace catheters) 3
- De-escalate to narrower spectrum antibiotics once susceptibilities confirm other options 3