What is the use and dosage of Ceftazidime (Ceftazidime) Avibactam (Avibactam) for treating infections in patients with normal or impaired renal function?

Ceftazidime-Avibactam: Use and Dosage

For carbapenem-resistant Enterobacterales (CRE) and difficult-to-treat Pseudomonas aeruginosa infections, administer ceftazidime-avibactam 2.5 g (2 g ceftazidime + 0.5 g avibactam) intravenously every 8 hours, infused over 2 hours, with dose adjustments required for creatinine clearance ≤50 mL/min. 1, 2

Standard Dosing for Normal Renal Function

• Adult dose: 2.5 g IV every 8 hours (2 g ceftazidime + 0.5 g avibactam), administered as a 2-hour infusion 1, 2
• Infusion duration: Must be given over 2 hours to achieve optimal pharmacodynamic targets 3, 4
• This dosing achieves >95% probability of target attainment (free ceftazidime >8 mg/L and avibactam >1 mg/L for ≥50% of dosing interval) 5, 4

Infection-Specific Treatment Durations

Complicated Urinary Tract Infections (cUTI)

• Duration: 7-14 days 2, 6
• Dosing: 2.5 g IV every 8 hours 1
• Clinical cure rates of 91% demonstrated in phase 3 trials 7

Complicated Intra-Abdominal Infections (cIAI)

• Duration: 5-14 days 6, 8
• Critical requirement: Must be given with metronidazole 500 mg IV every 6-8 hours for anaerobic coverage 6
• Dosing: 2.5 g IV every 8 hours 1

Bloodstream Infections (BSI) due to CRE

• Duration: 10-14 days 1
• Dosing: 2.5 g IV every 8 hours, infused over 3 hours for BSI specifically 1
• The longer 3-hour infusion for BSI optimizes time above MIC for serious infections 1

Hospital-Acquired/Ventilator-Associated Pneumonia

• Duration: 7-14 days 6
• Dosing: 2.5 g IV every 8 hours 1

Renal Dose Adjustments

Ceftazidime-avibactam requires mandatory dose reduction for impaired renal function, as both components are renally eliminated. 9, 3

Dosing by Creatinine Clearance:

• CrCl >50 mL/min: 2.5 g IV every 8 hours (standard dose) 1, 3
• CrCl 31-50 mL/min: 1.25 g IV every 8 hours 3
• CrCl 16-30 mL/min: 0.94 g IV every 12 hours 3
• CrCl 6-15 mL/min: 0.94 g IV every 24 hours 3
• CrCl <5 mL/min: 0.94 g IV every 48 hours 3

Hemodialysis Patients:

• Loading dose: 2.5 g IV once 9
• Maintenance: 0.94 g IV after each hemodialysis session 9
• Both ceftazidime and avibactam are removed by hemodialysis, necessitating post-dialysis dosing 3

Continuous Ambulatory Peritoneal Dialysis:

• Loading dose: 1 g IV once 9
• Maintenance: 0.5 g IV every 24 hours 9
• Can be incorporated into dialysis fluid at 250 mg per 2 L 9

Specific Pathogen Considerations

Carbapenem-Resistant Enterobacterales (CRE)

• Effective against: KPC and OXA-48 serine carbapenemases 2
• NOT effective against: Metallo-β-lactamases (MBL) as monotherapy 2
• For MBL-producing CRE, combine ceftazidime-avibactam with aztreonam (30-day mortality 19.2% vs 44% with other agents, P=0.007) 2

Difficult-to-Treat Pseudomonas aeruginosa (DTR-PA)

• Ceftazidime-avibactam is a recommended option for DTR-PA infections 1
• Dosing remains 2.5 g IV every 8 hours 1

Critical Resistance Considerations

Emergence of resistance during therapy is a documented concern, particularly with KPC-3 producing organisms. 1, 2

Risk Factors for Resistance Development:

• Prior ceftazidime-avibactam exposure 1, 2
• Mutations in bla KPC-3 gene causing "see-saw effect" (ceftazidime-avibactam MIC rises while meropenem MIC falls to susceptible range) 1

Resistance Prevention Strategy:

• For KPC-3 producing organisms, consider combination therapy with a carbapenem or colistin 1, 2
• Obtain carbapenemase typing and susceptibility testing before initiating therapy when possible 2
• The British Society for Antimicrobial Chemotherapy specifically recommends combination therapy for KPC-3 producers 1

Special Populations

Pediatric Patients (≥3 months)

• Approved for use in children ≥3 months of age 1
• Specific pediatric dosing should be weight-based and adjusted for renal function 9

Hepatic Impairment

• No dose adjustment required for hepatic dysfunction 9
• Both drugs are renally eliminated with minimal hepatic metabolism 3

Pharmacokinetic Optimization

• Protein binding: Ceftazidime <10%, avibactam 5.7-8.2% 3
• Volume of distribution: Ceftazidime 17 L, avibactam 22.2 L at steady state 3
• Renal clearance: Ceftazidime ~115 mL/min, avibactam 158 mL/min (includes active tubular secretion) 3
• Steady state: Achieved without accumulation after multiple doses every 8 hours 3, 5
• Prolonged infusion (2-3 hours) maximizes time above MIC for optimal β-lactam pharmacodynamics 1, 4

Common Pitfalls to Avoid

1. Never use as monotherapy for anaerobic coverage in cIAI - always add metronidazole 6
2. Do not use standard dosing in renal impairment - avibactam clearance decreases 2.6-fold in mild renal impairment and 3-fold in moderate impairment 3
3. Avoid for MBL-producing organisms without aztreonam - ceftazidime-avibactam has no activity against metallo-β-lactamases 2
4. Do not shorten infusion time below 2 hours - rapid infusion compromises pharmacodynamic target attainment 3, 4