Ceftazidime-Avibactam for Complicated Infections
Ceftazidime-avibactam is indicated for complicated urinary tract infections (including pyelonephritis), complicated intra-abdominal infections (combined with metronidazole), and hospital-acquired/ventilator-associated pneumonia caused by resistant gram-negative organisms, particularly when carbapenem-resistant Enterobacteriaceae or multidrug-resistant Pseudomonas aeruginosa are suspected or documented. 1
FDA-Approved Indications and Dosing
Standard Adult Dosing
- 2.5 grams (ceftazidime 2 grams + avibactam 0.5 grams) intravenously every 8 hours over 2-hour infusion for patients with creatinine clearance >50 mL/min 1
- Treatment duration: 5-14 days for complicated intra-abdominal infections, 7-14 days for complicated urinary tract infections, and 7-14 days for hospital-acquired/ventilator-associated pneumonia 1
Pediatric Dosing
- 62.5 mg/kg (maximum 2.5 grams) every 8 hours over 2-hour infusion for patients aged 2 years to <18 years with eGFR >50 mL/min/1.73 m² 1
- Approved for patients ≥31 weeks gestational age 1
Antimicrobial Spectrum and Target Pathogens
Organisms Covered
- Extended-spectrum β-lactamase (ESBL)-producing Enterobacterales including E. coli, K. pneumoniae, Enterobacter cloacae, Proteus mirabilis 2, 1
- Klebsiella pneumoniae carbapenemase (KPC)-producing organisms (KPC-2 and KPC-3) 2, 3
- OXA-48 carbapenemase-producing Enterobacterales 2, 3
- Multidrug-resistant Pseudomonas aeruginosa including AmpC β-lactamase producers 1, 4
Critical Coverage Gaps
- NO activity against metallo-β-lactamase (MBL) producers (NDM, VIM, IMP) - requires combination with aztreonam 2, 5
- NO activity against Acinetobacter species due to intrinsic OXA-type carbapenemases not inhibited by avibactam 6, 5
- NO activity against anaerobic bacteria - must add metronidazole for intra-abdominal infections and aspiration pneumonia 6, 5, 1
- NO gram-positive coverage - requires addition of vancomycin or linezolid for MRSA coverage in pneumonia 5
Clinical Efficacy by Infection Type
Carbapenem-Resistant Enterobacterales (CRE) Infections
- For severe CRE infections producing serine carbapenemases (KPC, OXA-48), ceftazidime-avibactam or meropenem-vaborbactam are preferred first-line agents 2
- Ceftazidime-avibactam reduces mortality by approximately 182 deaths per 1000 patients treated compared to other therapies (RR 0.55,95% CI 0.42-0.72) 2, 3
- Treatment failures reduced by 307 per 1000 patients (RR 0.49,95% CI 0.34-0.70) 2, 3
- Clinical cure rates of 90.9% versus 91.2% for best available therapy, with superior microbiological response (81.8% vs 63.5%) 4, 7
Complicated Urinary Tract Infections
- Ceftazidime-avibactam 2.5 grams IV every 8 hours is recommended for complicated UTI caused by CRE 2
- Microbiological success rates of 70.4% comparable to imipenem-cilastatin (71.4%) 4
- Alternative options include meropenem-vaborbactam or imipenem-cilastatin-relebactam 2
Complicated Intra-Abdominal Infections
- Must be combined with metronidazole 0.5 grams IV every 8 hours for anaerobic coverage 1
- Clinical cure rates of 91.2% comparable to meropenem (93.4%) 4
- Non-inferiority demonstrated against carbapenems in patients with ESBL-producing Enterobacterales 2
Hospital-Acquired/Ventilator-Associated Pneumonia
- Use empirically when prior IV antibiotic use within 90 days, ICU with >10-20% carbapenem resistance, septic shock, ARDS, ≥5 days hospitalization, or acute renal replacement therapy 5
- Low-certainty evidence of non-inferiority to carbapenems for HAP/VAP caused by resistant Enterobacterales 2, 3
- Epithelial lining fluid penetration approximately 30% of plasma concentrations 8
Aspiration Pneumonia
- NOT appropriate for community-acquired aspiration pneumonia due to lack of anaerobic coverage 6
- Only consider for healthcare-associated aspiration pneumonia with suspected resistant gram-negatives, and must add metronidazole 6, 5
- Preferred alternatives: ampicillin-sulbactam, amoxicillin-clavulanate, or piperacillin-tazobactam for community-acquired cases 6
Special Situations and Combination Therapy
Metallo-β-Lactamase Producers
- Combine ceftazidime-avibactam with aztreonam for MBL-producing CRE 2
- This combination reduces 30-day mortality from 44% to 19.2% (HR 0.37,95% CI 0.13-0.74) 2
- Aztreonam is not hydrolyzed by metallo-β-lactamases, providing synergistic activity 2
Resistance Development During Treatment
- Resistance emerges in 3.7-8.1% of treated patients, particularly with KPC-producing organisms 2, 5
- Mechanisms include amino acid substitutions in the KPC omega loop, disrupting avibactam binding 2
- "See-saw effect" observed: ceftazidime-avibactam resistance develops with concurrent 4-fold reduction in meropenem MIC to susceptible range 2
- Consider combination with carbapenem or colistin for KPC-3 producers to prevent resistance emergence 2
Critical Implementation Considerations
When to Use Ceftazidime-Avibactam
- Determine carbapenemase type before treatment initiation whenever possible 2, 3
- Reserve for documented or highly suspected KPC or OXA-48 producers to preserve activity 5
- Use as carbapenem-sparing strategy in settings with high ESBL prevalence 2
When NOT to Use Ceftazidime-Avibactam
- Do not use for MBL producers without aztreonam combination 2
- Avoid for Acinetobacter infections (intrinsically resistant) 6, 5
- Do not use alone for polymicrobial infections requiring anaerobic coverage 6, 5
- Not appropriate for community-acquired aspiration pneumonia 6
Pharmacokinetic/Pharmacodynamic Optimization
PK/PD Targets
- Ceftazidime target: 50% free time above MIC 9
- Avibactam target: free time above 1 mg/L threshold concentration 9
- Joint target attainment >95% achieved against MICs ≤8 mg/L with standard dosing 9
- Dosing robust across subgroups including obesity, augmented renal clearance, and severe infection 9
Renal Dose Adjustments
- Modify dosing for creatinine clearance ≤50 mL/min per FDA label 1
- Both ceftazidime and avibactam are renally eliminated, requiring parallel dose reduction 9
Comparative Effectiveness
Versus Carbapenems
- Non-inferior to meropenem for complicated intra-abdominal infections (91.2% vs 93.4% cure) 4
- Non-inferior to imipenem for complicated urinary tract infections 4
- Low-certainty evidence of non-inferiority for HAP/VAP 2
Versus Other Novel Agents
- Meropenem-vaborbactam showed superior cure rates and lower mortality in TANGO-II trial for CRE infections 5
- Both ceftazidime-avibactam and meropenem-vaborbactam are conditional recommendations for severe CRE infections 2
- Imipenem-cilastatin-relebactam is alternative option with similar efficacy profile 2