What is the recommended management for meningitis with carbapenem-resistant enterobacteriaceae (CRE) cultures?

Management of Meningitis with CRE Cultures

For CRE meningitis, use combination therapy with high-dose prolonged-infusion meropenem (even if resistant) plus intravenous amikacin, combined with intraventricular aminoglycoside administration, while ensuring removal of any infected neurosurgical hardware. 1, 2

Initial Assessment and Antibiotic Selection

First-Line Combination Therapy

• Administer high-dose meropenem via prolonged infusion (e.g., 2g IV every 8 hours infused over 3 hours) combined with intravenous amikacin, even when the CRE isolate shows high carbapenem resistance (MIC ≥16 mg/L). 1

• Add intraventricular (IVT) amikacin to achieve adequate CSF concentrations, as systemic aminoglycosides alone have poor CNS penetration. 1, 2

• This triple-drug approach (IV meropenem + IV amikacin + IVT amikacin) has demonstrated successful outcomes in extremely carbapenem-resistant cases where MIC to imipenem was ≥16 mg/L. 1

Alternative Newer Agents (If Available and Susceptible)

• Ceftazidime-avibactam 2.5g IV every 8 hours infused over 3 hours is recommended for CRE bloodstream infections when the isolate is susceptible in vitro. 3

• Meropenem-vaborbactam 4g IV every 8 hours or imipenem-cilastatin-relebactam 1.25g IV every 6 hours are alternatives for susceptible CRE. 3

• However, these newer beta-lactam/beta-lactamase inhibitor combinations have limited clinical data specifically for meningitis, and CSF penetration data remain sparse. 4, 5

Polymyxin-Based Regimens (When Other Options Fail)

• Polymyxin B-based combination therapy is recommended for severe CRE infections when newer agents are unavailable or the organism is resistant. 3

• Intravenous polymyxin alone is inadvisable for meningitis—must combine with intraventricular administration plus removal of infected hardware. 2

• Polymyxin B is FDA-approved for meningeal infections caused by susceptible organisms, including Pseudomonas aeruginosa, E. coli, Klebsiella pneumoniae, and Aerobacter aerogenes. 6

• For polymyxin dosing in normal renal function: loading dose of 300mg colistin methanesulfonate (CMS) (9 million units) infused over 0.5-1 hour, followed by maintenance dose of 300-360mg CMS (9-10.9 million units) divided in two doses. 3

Critical Management Principles

Combination Therapy is Essential

• Monotherapy should be avoided for CRE meningitis given the high mortality (>15% for resistant Gram-negative meningitis) and poor CNS penetration of most antibiotics. 2, 4

• Combination antimicrobial therapy should be based on susceptibility testing results. 3

• The selection of combination agents must account for synergistic effects confirmed by antimicrobial synergy testing when possible. 3

Therapeutic Drug Monitoring (TDM)

• TDM is strongly suggested for polymyxins, aminoglycosides, and carbapenems in CRE meningitis, as small differences in concentration can lead to therapeutic failure or life-threatening toxicity. 3

• TDM is particularly critical for CNS infections where achieving effective therapeutic concentrations is difficult due to the blood-brain barrier. 3

Source Control

• Remove all infected neurosurgical hardware (external ventricular drains, shunts, etc.) whenever feasible, as this is essential for treatment success. 2

• The case report demonstrating successful treatment required four surgeries including tumor excision and three external ventricular drainages over 100 days of hospitalization. 1

Infectious Disease Consultation

• Infectious disease consultation is highly recommended (strong recommendation) for all MDRO infections including CRE meningitis. 3

Agents to Avoid

Tigecycline

• Do not use tigecycline for CRE meningitis—it has poor CSF penetration and is not recommended for bloodstream infections or CNS infections. 3, 2

• Tigecycline monotherapy is associated with higher mortality compared to combination therapy for CRE bloodstream infections. 3

Cefiderocol Considerations

• While cefiderocol may be considered for severe CRE infections with metallo-β-lactamases, be aware of the paradoxical effect (no growth at lower dilutions but growth at higher dilutions) that can occur with broth microdilution testing. 7

• Resistance can develop during therapy through mutations in iron transport genes and penicillin-binding proteins. 7

Duration and Monitoring

• Treatment duration for CRE meningitis typically requires prolonged courses (e.g., 70 days of antibiotics in the successful case report). 1

• Monitor closely for nephrotoxicity and ototoxicity with aminoglycoside use, avoiding other nephrotoxic drugs in the combination regimen. 3

• Serial CSF cultures should guide therapy duration, with treatment continuing until CSF sterilization is documented. 1, 7

Common Pitfalls to Avoid

• Do not rely on empirical ceftazidime or cefepime for suspected Gram-negative meningitis in the neurosurgical setting—pharmacodynamic data show these achieve targets against fewer than 10% of contemporary resistant isolates. 2

• Do not use intravenous polymyxin as monotherapy for meningitis—combination with intraventricular administration is essential. 2

• Do not assume newer agents will penetrate the CNS adequately—even when systemically active, blood-brain barrier penetration remains a major obstacle. 4

• Be aware that obstructive hydrocephalus and brain abscess caused by CRE meningitis are important causes of death and require aggressive surgical management. 4