What is the recommended treatment for Klebsiella infections using Ceftazidime (Ceftazidime)-Avibactam (Avibactam)?

Ceftazidime-Avibactam for Klebsiella Infections

Ceftazidime-avibactam is strongly recommended as first-line therapy for Klebsiella pneumoniae infections producing KPC or OXA-48 carbapenemases, administered at 2.5 grams IV every 8 hours over 2 hours, with demonstrated mortality reduction of 182 fewer deaths per 1000 patients treated compared to alternative therapies. 1, 2

Carbapenemase-Specific Treatment Algorithm

For KPC-Producing Klebsiella pneumoniae

Use ceftazidime-avibactam monotherapy at 2.5 grams (ceftazidime 2 grams + avibactam 0.5 grams) IV every 8 hours, infused over 2 hours. 1, 3

• Nearly 100% of KPC-producing strains are susceptible to ceftazidime-avibactam 1
• This regimen reduces mortality (RR 0.55,95% CI 0.42-0.72) and treatment failures (RR 0.49,95% CI 0.34-0.70) compared to other antimicrobials 1, 2
• Combination therapy with other agents shows no significant mortality benefit over monotherapy in most cases 1

For OXA-48-Producing Klebsiella pneumoniae

Use ceftazidime-avibactam monotherapy at the same dosing regimen (2.5 grams IV every 8 hours over 2 hours). 1, 2

• OXA-48-producing strains demonstrate high susceptibility to ceftazidime-avibactam 1
• Evidence quality is lower than for KPC, but clinical outcomes support this recommendation 1

For Metallo-β-Lactamase (MBL)-Producing Klebsiella pneumoniae

Ceftazidime-avibactam is NOT effective as monotherapy. Instead, use ceftazidime-avibactam 2.5 grams IV every 8 hours PLUS aztreonam (standard dosing). 1, 2, 4

• Avibactam does not inhibit metallo-β-lactamases (NDM, VIM, IMP) 1, 2
• The combination regimen reduces 30-day mortality from 44% to 19.2% (P = 0.007) compared to other active antimicrobials 1, 4
• Aztreonam is not hydrolyzed by MBLs but requires avibactam protection against co-produced ESBLs and AmpC enzymes 4

Infection-Specific Dosing and Duration

Complicated Urinary Tract Infections (cUTI) Including Pyelonephritis

• Dose: 2.5 grams IV every 8 hours over 2 hours 3
• Duration: 7-14 days 3

Bloodstream Infections

• Dose: 2.5 grams IV every 8 hours over 2 hours 3, 5
• Duration: 7-14 days 6
• Consider prolonged infusion (≥3 hours) as this was associated with reduced mortality in observational data 5

Hospital-Acquired/Ventilator-Associated Pneumonia (HAP/VAP)

• Dose: 2.5 grams IV every 8 hours over 2 hours 3
• Duration: 7-14 days (typically 10-14 days) 6, 3
• For pneumonia specifically, consider meropenem-vaborbactam as an alternative due to superior lung penetration (63-65% ELF concentrations) 1

Complicated Intra-Abdominal Infections (cIAI)

• Dose: 2.5 grams IV every 8 hours over 2 hours 3
• Duration: 5-14 days 3
• MUST add metronidazole 500 mg IV every 8 hours for anaerobic coverage 3

Critical Implementation Considerations

Pre-Treatment Testing

Determine carbapenemase type before initiating therapy whenever possible through genotyping or phenotypic testing. 1, 4

• This prevents inappropriate use against MBL-producing strains where monotherapy will fail 1, 2
• If testing is unavailable, use local epidemiology to guide empiric selection 4, 3

Resistance Monitoring

Resistance to ceftazidime-avibactam can emerge during treatment, particularly with KPC-3 variants and specific mutations (D179Y in blaKPC-3 gene). 1, 2, 7

• KPC-3 variants demonstrate higher MICs than KPC-2 (P = 0.02) 7
• Resistance rates range from 0% to 12.8% in different regions 1
• If resistance develops, meropenem-vaborbactam may be effective 1

Dose Adjustments

Adjust dosing for renal impairment (CrCl ≤50 mL/min) per FDA labeling. 3

• Dose adjustment for renal function was paradoxically associated with increased mortality in one study, likely reflecting confounding by illness severity 5

Pediatric Dosing

For children ≥2 years with eGFR >50 mL/min/1.73 m²: 62.5 mg/kg (maximum 2.5 grams) IV every 8 hours over 2 hours. 3

Clinical Efficacy Data

The evidence supporting ceftazidime-avibactam demonstrates:

• 182 fewer deaths per 1000 patients (RR 0.55,95% CI 0.42-0.72) 1, 2
• 307 fewer treatment failures per 1000 patients (RR 0.49,95% CI 0.34-0.70) 1, 2
• 179 fewer pathogen eradication failures per 1000 patients (RR 0.37,95% CI 0.16-0.83) 1
• 95 fewer acute kidney injuries per 1000 patients (RR 0.55,95% CI 0.23-1.33) 1

Common Pitfalls to Avoid

1. Do not use ceftazidime-avibactam monotherapy for MBL-producing strains - it will fail. Always add aztreonam. 1, 2, 4

2. Do not assume combination therapy is always superior - for KPC/OXA-48 strains, monotherapy is equally effective and avoids unnecessary toxicity. 1

3. Do not forget metronidazole for intra-abdominal infections - ceftazidime-avibactam lacks anaerobic coverage. 3

4. Do not use standard 2-hour infusions exclusively - consider prolonged infusions (≥3 hours) for severe infections, particularly bloodstream infections, as this may improve survival. 5

5. Do not ignore site-specific considerations - for pneumonia, meropenem-vaborbactam may be preferable due to better lung penetration. 1