Ceftazidime-Avibactam Dosing Adjustments in Renal Impairment
For patients with impaired renal function, ceftazidime-avibactam dosing must be adjusted based on creatinine clearance (CrCl) to maintain therapeutic efficacy while preventing toxicity. 1
Standard Dosing
- The standard dose of ceftazidime-avibactam for patients with normal renal function (CrCl >50 mL/min) is 2.5 g (2 g ceftazidime + 0.5 g avibactam) administered intravenously every 8 hours by 2-hour infusion 1, 2
- This dosing regimen achieves probability of pharmacokinetic/pharmacodynamic target attainment of ≥94.9% across all patient subgroups with normal renal function 3
Renal Dosing Adjustments
- For moderate renal impairment (CrCl 31-50 mL/min): 1.25 g (1 g ceftazidime + 0.25 g avibactam) IV every 8 hours 1
- For severe renal impairment (CrCl 16-30 mL/min): 0.94 g (0.75 g ceftazidime + 0.19 g avibactam) IV every 12 hours 1
- For end-stage renal disease (CrCl 6-15 mL/min): 0.94 g (0.75 g ceftazidime + 0.19 g avibactam) IV every 24 hours 1
- For patients on hemodialysis: 0.94 g (0.75 g ceftazidime + 0.19 g avibactam) IV every 48 hours, with administration after hemodialysis on dialysis days 1, 4
Pharmacokinetic Considerations
- Both ceftazidime and avibactam are primarily eliminated by the kidneys, with approximately 80-90% of ceftazidime and 97% of avibactam excreted unchanged in the urine 1
- Renal clearance significantly impacts drug exposure, with avibactam AUC increasing 2.6-fold, 3.8-fold, and 7-fold in patients with mild, moderate, and severe renal impairment, respectively 1
- Avibactam is extensively removed by hemodialysis with an extraction coefficient of 0.77 and a mean hemodialysis clearance of 9.0 L/h 1
- Approximately 55% of the avibactam dose is removed during a 4-hour hemodialysis session 1
Special Considerations for Continuous Renal Replacement Therapy
- For patients on continuous venovenous hemodiafiltration (CVVHDF), a loading dose of 2 g ceftazidime followed by 3 g/day continuous infusion has been shown to maintain adequate serum concentrations 5
- When using ceftazidime-avibactam in patients on CVVHDF, dosing should be adjusted based on the specific CVVHDF parameters (blood flow, dialysate flow, and ultrafiltration rates) 5
Monitoring Recommendations
- Monitor renal function (CrCl in adults) at least daily in patients with fluctuating renal function and adjust dosage accordingly 1
- The FDA label emphasizes the importance of frequent monitoring because both ceftazidime and avibactam exposure are highly dependent on renal function 1
- Be vigilant for signs of neurotoxicity (seizures, encephalopathy, confusion) which can occur with excessive beta-lactam concentrations, particularly in patients with renal impairment 6
Hepatic Impairment
- No dosage adjustment is required for patients with hepatic impairment as neither ceftazidime nor avibactam undergo significant hepatic metabolism 1, 7
- Systemic clearance of avibactam is not expected to be significantly affected by hepatic impairment 1
Clinical Pearls and Pitfalls
- Dosing adjustments are critical to prevent accumulation and potential neurotoxicity in renal impairment 6
- The relative pro-convulsive activity of ceftazidime (17 compared to penicillin G = 100) is lower than some other beta-lactams but still requires careful monitoring in renal impairment 6
- For patients with rapidly improving renal function, the FDA-approved dosage adjustments include a 50% increase in total daily dose compared with original dosage adjustments to reduce the risk of subtherapeutic drug exposures 8
- In anuric end-stage renal disease patients on low-flux hemodialysis, 1 g of ceftazidime administered post-hemodialysis provides reliable pharmacodynamic efficacy over both 48- and 72-hour interdialytic intervals 4