What is the role of Ceftazidime (Ceftazidime)-Avibactam in the treatment of meningitis?

Role of Ceftazidime-Avibactam in Meningitis Treatment

Ceftazidime-avibactam has limited established role in the treatment of bacterial meningitis and should be reserved for specific cases of multidrug-resistant Gram-negative meningitis, particularly those caused by carbapenem-resistant organisms producing KPC or OXA-48 carbapenemases. 1, 2

Standard Treatment for Bacterial Meningitis

• For empiric treatment of bacterial meningitis, the combination of vancomycin plus either ceftriaxone or cefotaxime remains the standard of care 1
• Traditional third-generation cephalosporins (ceftriaxone, cefotaxime) revolutionized meningitis treatment and are first-line agents for most common meningeal pathogens 1
• Of the older cephalosporins, only ceftazidime (without avibactam) achieves adequate CSF concentrations to treat Pseudomonas aeruginosa meningitis 3

Specific Role of Ceftazidime-Avibactam

Indications for Use

• Ceftazidime-avibactam should be considered for meningitis caused by:
  • Carbapenem-resistant Enterobacterales (CRE) producing KPC or OXA-48 carbapenemases 2
  • Multidrug-resistant Pseudomonas aeruginosa 4, 3
  • Acinetobacter species with limited treatment options 5

Evidence for CSF Penetration

• Standard ceftazidime (without avibactam) achieves CSF concentrations of 2-30 μg/mL in patients with meningitis 6
• In pediatric patients, mean CSF concentrations of 6.7 μg/mL have been documented, which exceeded the MBC for isolated pathogens by 16 to >100-fold 7
• Limited data exists specifically on avibactam penetration into CSF

Efficacy Considerations

• Ceftazidime-avibactam significantly reduces mortality in carbapenem-resistant infections compared to other antimicrobial options (RR 0.55,95% CI 0.42-0.72) 2
• Treatment failures are also reduced with ceftazidime-avibactam (RR 0.49,95% CI 0.34-0.70) 2
• For metallo-β-lactamase-producing organisms (NDM, VIM, IMP), ceftazidime-avibactam alone is ineffective and must be combined with aztreonam 1, 2

Treatment Recommendations for MDR Gram-Negative Meningitis

1. Confirm susceptibility testing and carbapenemase type before initiating ceftazidime-avibactam 1

2. Dosing for meningitis:

   • Standard adult dose: 2.5 grams (2g ceftazidime + 0.5g avibactam) IV every 8 hours, infused over 2 hours 2
   • Adjust for renal impairment
   • Consider higher doses or more frequent administration for meningitis to ensure adequate CSF levels

3. For specific pathogens:

   • KPC or OXA-48-producing organisms: Ceftazidime-avibactam as primary therapy 2
   • Metallo-β-lactamase producers: Ceftazidime-avibactam plus aztreonam 1, 2
   • Consider intraventricular/intrathecal administration of additional antibiotics in refractory cases 5

Limitations and Considerations

• Resistance to ceftazidime-avibactam can develop during treatment, particularly with KPC-3 producing organisms 2
• Limited clinical data exists specifically for meningitis treatment (most evidence comes from other infection types)
• For suspected acinetobacter meningitis, meropenem plus intraventricular aminoglycoside may be superior to cephalosporins 5
• Removal of infected neurosurgical hardware is critical for successful treatment when present 5

Monitoring

• Monitor CSF cultures to confirm sterilization
• Watch for emergence of resistance during therapy
• Monitor for adverse effects consistent with ceftazidime (seizures, hypersensitivity reactions)
• Consider therapeutic drug monitoring when available