What is the antimicrobial spectrum of ceftazidime‑avibactam, the recommended adult dosing regimen and treatment duration (including renal dose adjustment), and what alternative agents are available if the isolate is resistant?

Ceftazidime-Avibactam Coverage and Dosing

Ceftazidime-avibactam covers >99% of Enterobacteriaceae including ESBL and KPC/OXA-48 carbapenemase producers, and 95-99% of Pseudomonas aeruginosa, but has NO activity against metallo-β-lactamase (MBL) producers (NDM, VIM, IMP) or anaerobes, requiring combination with aztreonam for MBL infections. 1, 2, 3

Antimicrobial Spectrum

Organisms Covered

• Enterobacteriaceae: >99.9% susceptibility, including ESBL-producing strains and carbapenem-resistant Enterobacteriaceae (CRE) with KPC or OXA-48 carbapenemases 4, 5
• Pseudomonas aeruginosa: 95-99% susceptibility, including 94% of meropenem-resistant and 91.7% of piperacillin-tazobactam-resistant strains 4, 5
• Class A β-lactamases: ESBLs, KPC carbapenemases 3, 6
• Class C β-lactamases: AmpC enzymes 3, 6
• Some Class D β-lactamases: OXA-48 (but not all OXA variants) 2, 3

Critical Coverage Gaps

• NO activity against MBL producers (NDM, VIM, IMP) - requires combination with aztreonam 1, 2, 7
• NO activity against anaerobes - must add metronidazole for intra-abdominal infections or aspiration pneumonia 1, 7
• Limited/NO activity against: Acinetobacter species, Burkholderia species, Stenotrophomonas maltophilia 1, 2

Recommended Adult Dosing

Standard Dosing

• Ceftazidime 2g-avibactam 0.5g IV every 8 hours as a 2-hour infusion 6, 8
• Alternative: 2.5g IV every 8 hours for severe infections 9, 7
• Prolonged infusion: 3-hour infusion associated with improved 30-day survival 9

Renal Dose Adjustments

Appropriate renal adjustment is associated with improved 30-day survival and must be performed 9. Specific adjustments required based on creatinine clearance (consult package insert for exact dosing).

Treatment Duration

• Complicated UTI/pyelonephritis: 7-14 days 9
• Bloodstream infections: 10-14 days minimum 9
• Complicated intra-abdominal infections: 4-14 days (with metronidazole) 6, 8
• Hospital-acquired/ventilator-associated pneumonia: 7-14 days 6

Algorithm for Carbapenemase Type

If Carbapenemase Type Known:

• KPC or OXA-48 producer → Ceftazidime-avibactam monotherapy 2.5g IV q8h 1, 7
• MBL producer (NDM, VIM, IMP) → Ceftazidime-avibactam 2.5g IV q8h PLUS aztreonam (combination reduces 30-day mortality: HR 0.37,95% CI 0.13-0.74) 9, 7

If Carbapenemase Type Unknown and Critically Ill:

• Start empirically: Ceftazidime-avibactam 2.5g IV q8h PLUS aztreonam until susceptibilities return 7

Combination Therapy Considerations:

• Monotherapy vs combination: Five retrospective studies (824 patients) showed no mortality difference between ceftazidime-avibactam monotherapy vs combination for KPC/OXA-48 infections 9
• Exception for KPC-3 producers: Consider adding carbapenem or colistin to prevent resistance emergence due to "see-saw effect" (variant KPC-3 mutations cause ceftazidime-avibactam resistance while restoring meropenem susceptibility) 9, 2

Alternative Agents for Resistant Isolates

If Ceftazidime-Avibactam Resistant:

• Meropenem-vaborbactam 4g IV q8h - particularly if "see-saw effect" with restored carbapenem susceptibility 9, 2
• Imipenem-cilastatin-relebactam 1.25g IV q6h - active against 83.8% of CRE in surveillance studies 9
• Cefiderocol - active against MBL producers and some ceftazidime-avibactam-resistant strains 9
• Aztreonam plus ceftazidime-avibactam - for MBL producers 9, 7
• Plazomicin 15 mg/kg IV q12h - for complicated UTI due to CRE 9

For MBL Producers (Primary Resistance):

• Aztreonam plus ceftazidime-avibactam (first-line for MBL-producing CRE bloodstream infections) 9, 7
• Cefiderocol 9

Critical Pitfalls to Avoid

• Never use ceftazidime-avibactam alone for MBL producers - it will fail; always add aztreonam 1, 2, 7
• Never use for aspiration pneumonia without metronidazole - completely lacks anaerobic coverage 1, 7
• Do not assume all CRE are covered - obtain susceptibility testing and identify carbapenemase type 2
• Resistance emergence occurs in 3.7-8.1% of treated patients - prior ceftazidime-avibactam exposure increases risk 2, 3
• Reserve for documented resistant pathogens - not for empiric community-acquired infections to preserve activity 1

Advantages Over Alternatives

• Superior efficacy: Significantly higher microbiological eradication and clinical cure rates than comparators for KPC-producing Enterobacteriaceae 1, 7
• Lower mortality: Reduced 30-day mortality compared to colistin-based therapies 1
• Less nephrotoxicity: Significantly less nephrotoxic than colistin-based regimens 1
• Shorter colonization period: Evidence of shorter multidrug-resistant organism colonization compared to other agents 3