Ceftazidime-Avibactam for Neurosurgical Meningitis
Ceftazidime-avibactam is effective for neurosurgical meningitis caused by carbapenem-resistant Enterobacterales (particularly KPC-producing organisms) and extensively drug-resistant Pseudomonas aeruginosa, with documented CSF penetration achieving therapeutic concentrations and successful clinical outcomes in case series. 1, 2, 3
Spectrum of Activity and Mechanism
Ceftazidime-avibactam restores antibacterial activity against Ambler class A (including KPC), class C (AmpC), and some class D enzymes (OXA-48), but does NOT inhibit class B metallo-β-lactamases (NDM, VIM, IMP). 4 This limitation is critical—if your neurosurgical meningitis is caused by an NDM-producing organism, ceftazidime-avibactam monotherapy will fail. 5, 6
Evidence for CNS Infections
Pharmacokinetic Data Supporting Use
CSF concentrations of ceftazidime range from 2-30 μg/mL following 2g IV doses, with higher concentrations achieved in inflamed meninges (mean 9.8 μg/mL at 120 minutes). 7, 8
Therapeutic drug monitoring in three patients with healthcare-associated ventriculitis and meningitis demonstrated CSF ceftazidime concentrations of 15.0-29.0 μg/mL and avibactam concentrations of 0.92-4.20 μg/mL using standard 2.5g IV q8h dosing. 3 Avibactam maintained concentrations ≥1 μg/mL throughout the dosing interval in 11 of 12 CSF samples. 3
In a pediatric case, CSF concentrations measured 3,5, and 7 hours post-dose were 15.6,7.1, and 3.5 μg/mL (ceftazidime) and 4.0,2.1, and 1.2 μg/mL (avibactam), achieving adequate concentrations throughout the drug interval. 1
Clinical Outcomes
All three patients with KPC-producing Enterobacterales or DTR Pseudomonas aeruginosa neurosurgical meningitis treated with ceftazidime-avibactam 2.5g IV q8h achieved both microbiologic and clinical cure. 3 The MICs were 0.25/4 μg/mL for KPC-Klebsiella and KPC-Enterobacter, and 4/4 μg/mL for DTR Pseudomonas. 3
A 4-year-old with post-neurosurgical meningitis and abscess caused by ESBL-producing E. coli was successfully treated with ceftazidime-avibactam, demonstrating efficacy in pediatric CNS infections. 1
Two cases of cervical osteomyelitis and one meningitis due to XDR Pseudomonas aeruginosa were successfully treated with ceftazidime-avibactam-based regimens following neurosurgical procedures. 2
Recommended Dosing Strategy
Use ceftazidime-avibactam 2.5g IV every 8 hours as standard or extended infusion for neurosurgical meningitis. 3 The FDA-approved indication includes CNS infections caused by susceptible organisms including Haemophilus influenzae and Neisseria meningitidis for ceftazidime. 7
Critical Decision Algorithm
Step 1: Identify the Carbapenemase Type
- If KPC, ESBL, AmpC, or OXA-48 producer → Use ceftazidime-avibactam monotherapy 2.5g IV q8h. 4, 3
- If metallo-β-lactamase producer (NDM, VIM, IMP) → Add aztreonam to ceftazidime-avibactam. 4, 5, 6 The combination demonstrates 19.2% vs 44% 30-day mortality compared to other regimens for MBL-producing CRE bloodstream infections. 4, 6
- If carbapenemase type unknown and patient critically ill → Start ceftazidime-avibactam plus aztreonam empirically until susceptibilities return. 9
Step 2: Monitor for Treatment Failure
- Obtain repeat CSF cultures if clinical deterioration occurs within 48-72 hours, as 3.8-10.4% of patients develop ceftazidime-avibactam resistance during treatment of KPC-producing organisms. 6
- One case developed resistance to ceftolozane-tazobactam during therapy, requiring switch to ceftazidime-avibactam plus aztreonam. 2
Step 3: Consider Combination Therapy Selectively
- Combination therapy with aminoglycosides, colistin, carbapenem, fosfomycin, or tigecycline shows no mortality benefit over monotherapy in general CRE infections, but may reduce mortality in severely ill patients. 4
- For XDR Pseudomonas aeruginosa neurosurgical infections, combinations with aztreonam, meropenem plus amikacin, or fosfomycin have been used successfully. 2
Common Pitfalls to Avoid
Do NOT use ceftazidime-avibactam alone for NDM-producing organisms—it will fail due to lack of MBL inhibition. 4, 5, 6 Always add aztreonam in this scenario. 4, 9
Do NOT assume adequate CSF penetration without considering meningeal inflammation—concentrations are higher with inflamed meninges. 7, 8
Do NOT use standard ceftazidime or cefepime empirically for suspected Acinetobacter meningitis—pharmacodynamic modeling shows these achieve targets in <10% of contemporary isolates. 10
Do NOT remove external ventricular drains or other neurosurgical hardware prematurely—hardware removal plus intraventricular antibiotics may be necessary for carbapenem-resistant Acinetobacter. 10
Safety Profile
No differences in frequency or profile of adverse effects including hepatic, renal, and coagulation parameters were observed between ceftazidime-avibactam and comparator groups in CRE bloodstream infection studies. 4 Ceftazidime is eliminated 80-90% unchanged by the kidneys, requiring dose adjustment in renal impairment. 7
Comparative Context
For carbapenem-resistant Enterobacterales bloodstream infections, ceftazidime-avibactam demonstrates significantly higher microbiological eradication and clinical cure rates compared to other antimicrobial regimens, with lower 30-day mortality in several studies. 4 While these data are primarily from bloodstream infections rather than CNS infections specifically, the documented CSF penetration and successful case reports support extrapolation to neurosurgical meningitis. 1, 2, 3