What is Ceftazidime-avibactam sensitive to and how is it used?

Ceftazidime-Avibactam: Antimicrobial Spectrum and Clinical Applications

Ceftazidime-avibactam is active against Ambler class A carbapenemases (including KPC-2 and KPC-3) and certain class D carbapenemases (OXA-48), but is NOT active against metallo-β-lactamase (MBL) producers such as NDM, VIM, and IMP. 1

Spectrum of Activity

Organisms Covered by Ceftazidime-Avibactam

Enterobacteriaceae:

• Extended-spectrum β-lactamase (ESBL)-producing Enterobacterales 2, 3
• KPC-producing organisms (KPC-2 and KPC-3) 2, 3
• OXA-48-producing carbapenem-resistant Enterobacterales (CRE) 2
• Specific organisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Enterobacter cloacae, Klebsiella oxytoca, Citrobacter freundii complex, Serratia marcescens 4

Pseudomonas aeruginosa:

• Drug-resistant P. aeruginosa isolates, including many ceftazidime-resistant strains 1, 5

Other:

• Haemophilus influenzae 4

Critical Gaps in Coverage

Ceftazidime-avibactam has NO activity against:

• Metallo-β-lactamase (MBL) producers (NDM, VIM, IMP) 1, 2, 3
• Acinetobacter species (intrinsic resistance due to OXA-type carbapenemases not inhibited by avibactam) 3, 6
• Anaerobic bacteria 3, 6
• Gram-positive organisms including MRSA 3

FDA-Approved Indications and Dosing

Adult Patients (≥18 years, CrCl >50 mL/min)

Standard dose: 2.5 grams (ceftazidime 2g + avibactam 0.5g) IV every 8 hours over 2 hours 4

Approved indications:

• Complicated intra-abdominal infections (cIAI): MUST be combined with metronidazole 0.5g IV every 8 hours; duration 5-14 days 4
• Complicated urinary tract infections (cUTI) including pyelonephritis: Duration 7-14 days 4
• Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP): Duration 7-14 days 4

Pediatric Patients (≥31 weeks gestational age)

For patients 2 years to <18 years with eGFR >50 mL/min/1.73 m²:

• 62.5 mg/kg (max 2.5g) IV every 8 hours over 2 hours 4
• For cIAI, combine with metronidazole 10 mg/kg IV every 8 hours 4

Clinical Efficacy Evidence

Carbapenem-Resistant Enterobacterales (CRE)

For KPC and OXA-48 producers:

• Ceftazidime-avibactam demonstrated 64% probability of better outcomes versus colistin (95% CI 57%-71%) 1
• Low-certainty evidence shows advantage over polymyxins for CRE susceptible to ceftazidime-avibactam 1
• Associated with 182 fewer deaths per 1000 patients (RR 0.55,95% CI 0.42-0.72) and 307 fewer treatment failures per 1000 patients (RR 0.49,95% CI 0.34-0.70) 2

For MBL producers (NDM, VIM):

• Combination with aztreonam is required 1, 2
• Ceftazidime-avibactam plus aztreonam showed significantly lower 30-day mortality (19.2% vs 44%) compared to other treatment options in MBL-producing CRE bacteremia 1, 2
• This combination demonstrated independent association with lower mortality (HR 0.37,95% CI 0.13-0.74) 1

Hospital-Acquired/Ventilator-Associated Pneumonia

• Low-certainty evidence of non-inferiority to carbapenems for HAP/VAP caused by third-generation cephalosporin-resistant Enterobacterales 1, 2
• In subgroup analysis of 75 patients, ceftazidime-avibactam showed comparable outcomes to meropenem 1

Intra-Abdominal Infections

• Compared to meropenem in 106 patients with third-generation cephalosporin-resistant Enterobacterales: similar clinical and microbiological outcomes 1
• Phase II data: 91.2% clinical success with ceftazidime-avibactam plus metronidazole versus 93.4% with meropenem 7

Critical Clinical Considerations

When to Use Ceftazidime-Avibactam

Empirical use is appropriate when:

• Prior IV antibiotic use within 90 days 3
• ICU with >10-20% carbapenem-resistant gram-negative isolates 3
• Septic shock at pneumonia presentation 3
• ARDS preceding pneumonia 3
• ≥5 days hospitalization prior to infection onset 3
• Acute renal replacement therapy prior to infection 3

When NOT to Use Ceftazidime-Avibactam

Aspiration pneumonia:

• NOT appropriate as monotherapy due to lack of anaerobic coverage 3, 6
• If used in healthcare-associated aspiration pneumonia, MUST add metronidazole 3, 6
• Better alternatives: ampicillin-sulbactam, amoxicillin-clavulanate, or piperacillin-tazobactam for community-acquired aspiration 6

MBL-producing organisms:

• Requires combination with aztreonam 1, 2

MRSA or gram-positive coverage needed:

• Must add vancomycin or linezolid 3

Resistance Development

Resistance can emerge during treatment:

• Occurs in 3.7-8.1% of treated patients 1, 2
• Mechanisms include amino acid insertion, substitution, or deletion in KPC protein U loop 1
• Novel VEB-25 β-lactamase described in Greece causing resistance independent of prior exposure 1
• Renal replacement therapy is independent predictor of resistance development (p=0.009) 3
• Combination therapy does NOT prevent resistance development 1

Optimal Administration

• Prolonged infusion (3 hours) associated with improved 30-day survival 1
• Appropriate renal dose adjustment critical for outcomes 1
• Renal adjustment required for CrCl <50 mL/min 4

Comparative Efficacy

Versus meropenem-vaborbactam:

• Meropenem-vaborbactam showed superior cure rates (65.6% vs 33.3%, p=0.03) and lower 28-day mortality (15.6% vs 33.3%) compared to best available therapy in small RCT 1
• Meropenem-vaborbactam has moderate-certainty evidence for advantage over older antibiotics for susceptible CRE 1

Versus ceftolozane-tazobactam:

• High-certainty evidence for non-inferiority of ceftolozane-tazobactam versus meropenem in HAP/VAP caused by third-generation cephalosporin-resistant Enterobacterales 1

Key Pitfalls to Avoid

1. Never use as monotherapy for intra-abdominal infections - always combine with metronidazole for anaerobic coverage 4
2. Do not use for aspiration pneumonia without metronidazole 3, 6
3. Obtain carbapenemase typing before use when possible - ineffective against MBL producers 2, 3
4. Do not assume combination therapy prevents resistance - resistance develops at similar rates with monotherapy versus combination 1
5. Adjust for renal function - critical for efficacy and safety 1, 4