Dosing of Ceftazidime-Avibactam and Aztreonam in CRRT
For ceftazidime-avibactam in patients on CRRT, administer 2.5 g IV every 8 hours infused over 2 hours; for aztreonam in CRRT, specific dosing data is limited but the combination of aztreonam with ceftazidime-avibactam is recommended for metallo-β-lactamase-producing organisms.
Ceftazidime-Avibactam Dosing in CRRT
Standard CRRT Dosing Recommendation
The recommended dose is ceftazidime-avibactam 2.5 g (ceftazidime 2 g + avibactam 0.5 g) IV every 8 hours, infused over 2 hours 1.
This dosing regimen has been validated in critically ill patients undergoing continuous venovenous hemodiafiltration (CVVHDF) and achieves appropriate pharmacokinetic/pharmacodynamic targets 1.
The standard dose achieves free ceftazidime concentrations >4 times the MIC for 100% of the dosing interval and maintains avibactam concentrations >1 mg/L throughout the dosing interval 1.
Pharmacokinetic Considerations in CRRT
CRRT significantly removes both ceftazidime and avibactam, with sieving coefficients of approximately 0.81 and CRRT clearance accounting for 28.8-60% of total ceftazidime clearance and 14-33% of avibactam clearance 2, 3.
In critically ill patients on CVVHDF, ceftazidime elimination half-life is approximately 4-5 hours, with total clearance of 62 ml/min and CRRT clearance of approximately 33.6 ml/min 1, 3.
Do not use reduced dosing regimens intended for intermittent hemodialysis - CRRT provides continuous drug removal requiring higher doses than intermittent dialysis 4.
Alternative Dosing Strategy
Continuous infusion may be considered: A loading dose of 2 g ceftazidime followed by 3 g/day continuous infusion maintains steady-state concentrations of 33.5 mg/L, which exceeds 4 times the MIC for susceptible pathogens 3.
This approach may optimize time-dependent killing for β-lactams, though clinical outcome data comparing intermittent versus continuous infusion in CRRT are lacking 3.
Critical Monitoring Considerations
Therapeutic drug monitoring is strongly recommended to avoid both treatment failure and neurotoxicity, particularly given the variable CRRT clearance rates 5.
Ceftazidime-induced neurotoxicity is well-described in renal insufficiency and can occur even with appropriate dosing adjustments 5.
Monitor for neurological symptoms including confusion, myoclonus, seizures, and encephalopathy, which may indicate supratherapeutic concentrations 5.
Pediatric CRRT Dosing
In pediatric patients on CRRT, standard weight-based dosing (30-7.5 mg/kg every 8 hours) may be insufficient to achieve PK/PD targets 2.
Higher dosing or continuous infusion should be considered in critically ill children on CRRT, with therapeutic drug monitoring to guide therapy 2.
Aztreonam Dosing in CRRT
Limited Direct Evidence
- No specific aztreonam dosing recommendations for CRRT are provided in the available guidelines - the evidence focuses on aztreonam-ceftazidime-avibactam combination therapy rather than aztreonam monotherapy dosing 6.
Combination Therapy Indication
Aztreonam combined with ceftazidime-avibactam is recommended for severe CRE infections caused by metallo-β-lactamase-producing organisms that are resistant to ceftazidime-avibactam monotherapy 6.
This combination exploits the fact that avibactam protects aztreonam from AmpC and ESBL degradation while aztreonam remains stable against metallo-β-lactamases 6.
General Aztreonam Dosing Principles
Standard aztreonam dosing in normal renal function is 1-2 g IV every 8 hours; in CRRT, dosing should account for continuous drug removal similar to other β-lactams.
Given aztreonam's similar pharmacokinetic properties to other β-lactams (hydrophilic, low protein binding), expect significant CRRT clearance requiring dose adjustment upward from intermittent hemodialysis recommendations.
When using aztreonam-ceftazidime-avibactam combination, maintain the full 2.5 g every 8 hours dose of ceftazidime-avibactam as described above 6.
Clinical Application Algorithm
Step 1: Identify the Pathogen and Resistance Pattern
For CRE with KPC, OXA-48, or class A/C β-lactamases: Use ceftazidime-avibactam 2.5 g IV every 8 hours over 2 hours 6.
For CRE with metallo-β-lactamases (NDM, VIM, IMP): Use aztreonam plus ceftazidime-avibactam combination 6.
Step 2: Verify CRRT Parameters
Confirm blood flow rate, dialysate flow rate, and ultrafiltration rate - higher flow rates increase drug clearance 3.
Standard CVVHDF parameters (blood flow 150 ml/min, dialysate 1 L/hour, ultrafiltration 1.5 L/hour) support the 2.5 g every 8 hours dosing 3.
Step 3: Initiate Therapy
Start with 2.5 g ceftazidime-avibactam IV every 8 hours, infused over 2 hours 1.
Do not reduce the dose based on renal impairment calculations - CRRT is providing continuous clearance 1.
Step 4: Monitor and Adjust
Obtain therapeutic drug monitoring if available, targeting ceftazidime trough concentrations >4 times the MIC 1, 5.
Monitor daily for neurological symptoms suggesting ceftazidime toxicity 5.
If CRRT parameters change significantly, reassess dosing requirements 3.
Common Pitfalls to Avoid
Do not use the reduced doses recommended for CrCl 6-50 ml/min (1.25 g or 0.94 g doses) in patients on CRRT - these are for intermittent renal function, not continuous replacement 4.
Do not assume standard renal dosing charts apply to CRRT - continuous therapy removes drugs differently than intermittent hemodialysis 1, 3.
Do not overlook the need for combination therapy in metallo-β-lactamase producers - ceftazidime-avibactam monotherapy will fail against NDM, VIM, and IMP producers 6.
Do not use tigecycline as monotherapy for bloodstream infections even if susceptible in vitro, due to low serum concentrations and higher mortality 6.