How to dose Zavicefta (ceftazidime-avibactam) in patients with impaired renal function indicated by elevated creatinine levels?

Zavicefta (Ceftazidime-Avibactam) Dosing in Renal Impairment

Dose adjustment based on creatinine clearance is mandatory for Zavicefta, as both ceftazidime and avibactam are primarily eliminated renally, and failure to adjust doses appropriately—particularly in patients with augmented renal clearance—significantly increases mortality risk.

Standard Dosing Algorithm

For Patients with CrCl >50 mL/min

• Standard dose: 2,000 mg ceftazidime + 500 mg avibactam (2.5 g total) IV every 8 hours as a 2-hour infusion 1, 2, 3
• This regimen achieves the joint pharmacodynamic targets: 50% free time above MIC for ceftazidime and 50% free time above 1 mg/L threshold for avibactam 2, 3

For Patients with CrCl 31-50 mL/min

• Reduced dose: 1,000 mg ceftazidime + 250 mg avibactam IV every 8 hours 1
• Administer after a loading dose of 2,000 mg + 500 mg 1

For Patients with CrCl 16-30 mL/min

• Reduced dose: 1,000 mg ceftazidime + 250 mg avibactam IV every 12 hours 1
• Loading dose of 2,000 mg + 500 mg recommended 1

For Patients with CrCl 6-15 mL/min

• Reduced dose: 750 mg ceftazidime + 187.5 mg avibactam IV every 24 hours 1
• Loading dose of 2,000 mg + 500 mg recommended 1

For Patients with CrCl <5 mL/min

• Reduced dose: 750 mg ceftazidime + 187.5 mg avibactam IV every 48 hours 1
• Loading dose of 2,000 mg + 500 mg recommended 1

Hemodialysis Patients

• Administer 2,000 mg + 500 mg loading dose, followed by 750 mg + 187.5 mg after each hemodialysis session 1
• Critical timing consideration: Give supplemental dose AFTER dialysis to facilitate directly observed therapy and prevent premature drug removal 4
• Both ceftazidime and avibactam are removed by hemodialysis 1, 2

Critical Safety Warnings

Augmented Renal Clearance (CrCl ≥130 mL/min)

• Patients with CrCl ≥130 mL/min face significantly higher risk of suboptimal drug exposure (below 4× MIC) for both ceftazidime and avibactam 5
• Free drug concentrations drop approximately 7.31% for ceftazidime and 9.23% for avibactam per 10-point increase in CrCl 5
• Consider therapeutic drug monitoring or higher doses in critically ill patients with augmented renal clearance 5

Dose Reduction and Mortality Risk

• Renal-adjusted dose reduction is independently associated with increased mortality (HR 4.47,95% CI 1.09-18.03, P=0.037) in KPC-producing Klebsiella pneumoniae bloodstream infections 6
• This mortality risk persists even when dose adjustments follow recommended guidelines, suggesting current renal dosing recommendations may provide inadequate exposure 6
• Median reduced dose in one study was only 1.9 g daily (versus 7.5 g standard), highlighting the substantial reduction required 6

Neurological Toxicity Risk

• High and prolonged serum ceftazidime concentrations in renal impairment can cause seizures, nonconvulsive status epilepticus, encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia 1
• This risk necessitates careful dose reduction but creates a therapeutic dilemma given the mortality risk of underdosing 1, 6

Calculating Creatinine Clearance

Use the CKD-EPI equation for most accurate estimation of renal function 6

Alternative Cockcroft-Gault formula when only serum creatinine available 1:

• Males: CrCl (mL/min) = [Weight (kg) × (140 - age)] / [72 × serum creatinine (mg/dL)]
• Females: 0.85 × male value
• Serum creatinine must represent steady-state renal function 1

Special Populations

Pediatric Patients

• Adjust creatinine clearance for body surface area or lean body mass 1
• Reduce dosing frequency in renal insufficiency 1

Peritoneal Dialysis

• Loading dose: 2,000 mg + 500 mg, followed by 750 mg + 187.5 mg every 24 hours 1
• Can incorporate into dialysis fluid at 250 mg per 2L 1

Hepatic Impairment

• No dose adjustment required for hepatic dysfunction alone 1

Common Pitfalls to Avoid

• Do not assume standard dosing is safe in patients with CrCl >50 mL/min—those with augmented renal clearance (≥130 mL/min) require higher vigilance and possibly therapeutic drug monitoring 5
• Do not overlook the mortality risk associated with dose reduction—consider more aggressive monitoring and combination therapy in severely ill patients requiring renal dose adjustment 6
• Do not give supplemental doses before hemodialysis—always administer after dialysis to prevent premature drug removal 4, 1
• Do not forget the loading dose in patients with renal impairment—this is critical for achieving rapid therapeutic concentrations 1
• Do not use serum creatinine alone without calculating CrCl—direct creatinine values do not accurately reflect drug clearance 1, 7