What is the recommended dose of Zavicefta (ceftazidime and avibactam) for a patient with severe impaired renal function (CrCl 23 mL/min)?

Zavicefta (Ceftazidime-Avibactam) Dosing in Severe Renal Impairment (CrCl 23 mL/min)

For a patient with CrCl of 23 mL/min, the recommended dose of Zavicefta (ceftazidime-avibactam) is 0.94 grams (ceftazidime 0.75 grams and avibactam 0.19 grams) administered intravenously every 12 hours over 2 hours. 1

Rationale for Dosing Adjustment

Zavicefta requires dose adjustment in renal impairment because:

1. Pharmacokinetic considerations:

   • Ceftazidime is eliminated almost exclusively by the kidneys with minimal metabolism 2
   • Avibactam is also primarily excreted unchanged in the urine (97% recovery in urine) 1
   • Both components have significantly prolonged half-lives in renal impairment

2. Specific renal adjustment parameters:

   • A CrCl of 23 mL/min falls within the 16-30 mL/min range requiring specific dose adjustment
   • The FDA-approved dosing for this range is 0.94 grams every 12 hours 1
   • This represents a reduction from the standard dose of 2.5 grams every 8 hours in normal renal function

Administration Guidelines

• Administer the dose as a 2-hour intravenous infusion 1
• Monitor renal function (CrCl) at least daily and adjust dosage accordingly if renal function changes 1
• For patients on hemodialysis, administer the dose after the hemodialysis session on dialysis days 1

Monitoring Recommendations

1. Renal function:

   • Monitor CrCl daily due to the high dependence of drug clearance on renal function 1
   • Adjust dosing promptly if renal function changes

2. Clinical efficacy:

   • Monitor clinical response and microbiological data
   • The reduced dose is designed to achieve similar exposure to patients with normal renal function 3

3. Adverse effects:

   • Monitor for potential drug accumulation signs (neurological symptoms, seizures)
   • Be vigilant for superinfection or Clostridioides difficile-associated diarrhea

Special Considerations

• Both ceftazidime and avibactam are hemodialyzable, with avibactam having an extraction coefficient of 0.77 1
• Approximately 55% of avibactam is removed during a 4-hour hemodialysis session 1
• The ceftazidime-to-avibactam ratio may vary in patients with renal dysfunction compared to those with normal renal function 4

Pharmacokinetic Rationale

The recommended dose adjustment is based on pharmacokinetic studies showing:

• Avibactam clearance decreases significantly with declining renal function 5
• Severe renal impairment (CrCl 30 mL/min or less) results in 7-fold increase in avibactam systemic exposure 1
• Ceftazidime elimination half-life is significantly prolonged in renal impairment 2
• Population PK models confirm that the recommended dose adjustments provide comparable drug exposures in patients with renal impairment to those with normal renal function 1

The dosing recommendation maintains the 4:1 ratio of ceftazidime to avibactam present in the original formulation while accounting for the reduced clearance in renal impairment 5.