Ceftazidime-Avibactam: Use and Dosing in Complicated Gram-Negative Infections
Ceftazidime-avibactam 2.5 g IV every 8 hours (infused over 2-3 hours) is the recommended dose for carbapenem-resistant Enterobacterales (CRE) infections including complicated urinary tract infections, bloodstream infections, and complicated intra-abdominal infections (with metronidazole), with mandatory dose adjustments based on creatinine clearance in patients with renal impairment. 1, 2
Primary Indications and Target Pathogens
Ceftazidime-avibactam is first-line therapy for infections caused by:
- KPC-producing CRE (superior outcomes compared to polymyxin-based regimens) 3
- OXA-48-producing CRE 3
- ESBL-producing Enterobacterales when other options are limited 3, 4
- Multidrug-resistant Pseudomonas aeruginosa with AmpC beta-lactamases 4, 5
Specific infection types with guideline support:
- Complicated urinary tract infections (cUTI) including pyelonephritis 1
- Bloodstream infections due to CRE 1
- Complicated intra-abdominal infections (cIAI) - must add metronidazole 500 mg IV every 8 hours for anaerobic coverage 1, 4
- Hospital-acquired/ventilator-associated pneumonia (HAP/VAP) with suspected MDR gram-negatives 4, 2
Standard Dosing Regimen
For patients with normal renal function (CrCl >50 mL/min):
- 2.5 grams IV every 8 hours (ceftazidime 2 g + avibactam 0.5 g) 1, 2
- Infusion time: 2-3 hours (prolonged infusion optimizes pharmacodynamics for high MIC pathogens) 1, 2
- Treatment duration: 2
- cUTI: 7-14 days
- Bloodstream infections: 7-14 days 3
- cIAI: 5-14 days
- HAP/VAP: 7-14 days
Renal Dose Adjustments (Critical for Safety)
Ceftazidime and avibactam are both renally cleared and hemodialyzable, requiring strict dose adjustments: 2, 6, 7
| CrCl (mL/min) | Dose | Frequency |
|---|---|---|
| 31-50 | 1.25 g (ceftazidime 1 g + avibactam 0.25 g) | Every 8 hours |
| 16-30 | 0.94 g (ceftazidime 0.75 g + avibactam 0.19 g) | Every 12 hours |
| 6-15 | 0.94 g (ceftazidime 0.75 g + avibactam 0.19 g) | Every 24 hours |
| ≤5 or hemodialysis | 0.94 g (ceftazidime 0.75 g + avibactam 0.19 g) | Every 48 hours* |
*For hemodialysis patients: Administer after hemodialysis on dialysis days (>50% removed during 4-hour session) 2, 7
Monitor creatinine clearance daily in patients with changing renal function and adjust doses accordingly - this is critical as rapidly improving renal function can lead to subtherapeutic exposures 2, 6
Critical Limitations and Contraindications
Do NOT use ceftazidime-avibactam for:
- Aspiration pneumonia (lacks anaerobic activity) 4
- Metallo-β-lactamase (MBL) producers (NDM, VIM, IMP) - requires combination with aztreonam 1, 3, 4
- Acinetobacter baumannii (intrinsic resistance via OXA-type carbapenemases) 4
- MRSA or gram-positive coverage (requires addition of vancomycin or linezolid) 4
- Routine ESBL infections when other options exist (reserve for extensively resistant bacteria) 3
For MBL-producing CRE: Combine ceftazidime-avibactam with aztreonam 1, 3
For intra-abdominal infections: Always add metronidazole due to lack of Bacteroides fragilis coverage 1, 4, 2
Combination vs. Monotherapy
Monotherapy is appropriate for CRE infections susceptible to ceftazidime-avibactam - combination therapy is not recommended when the organism is susceptible 3
Combination therapy is indicated for:
- MBL-producing CRE (add aztreonam) 1, 3
- Polymicrobial infections requiring anaerobic coverage (add metronidazole) 1
- Suspected MRSA co-infection in pneumonia (add vancomycin/linezolid) 4
Risk Factors Warranting Empirical Use
Use ceftazidime-avibactam empirically when patients have: 4
- Prior IV antibiotic use within 90 days
- Treatment in ICUs with >10-20% carbapenem-resistant gram-negative isolates
- Septic shock at pneumonia presentation
- ARDS preceding pneumonia
- ≥5 days hospitalization prior to infection onset
- Acute renal replacement therapy
Resistance Development and Monitoring
KPC variants with D179Y mutations confer ceftazidime-avibactam resistance, particularly with prior exposure 3
Renal replacement therapy is an independent predictor of resistance development (p=0.009), occurring in 3.7-8.1% of treated patients 4
Clinical success rate is 90.5% in real-world experience, with continuous renal replacement therapy being the only risk factor for treatment failure 5
Common Pitfalls to Avoid
- Failing to add metronidazole for intra-abdominal infections - ceftazidime-avibactam has no anaerobic activity 1, 4
- Not adjusting dose for renal impairment - leads to toxicity or subtherapeutic levels 2, 6
- Administering before hemodialysis - drug will be removed during dialysis 2, 7
- Using for aspiration pneumonia without anaerobic coverage - inappropriate pathogen coverage 4
- Not monitoring creatinine clearance daily in critically ill patients - rapidly changing renal function requires dose adjustment 2, 6