1. Overview of Empiric Antimicrobial Therapy

Early, broad-spectrum antimicrobial coverage initiated within 60 minutes of recognition is a cornerstone of managing bacterial meningitis and significantly reduces mortality. The primary goal is to target the most common pathogens based on patient-specific factors while awaiting definitive culture results.

Empiric Regimen Selection

• Adults (18–50 yrs) without comorbidities: Vancomycin + a third-generation cephalosporin (e.g., ceftriaxone).
• Adults >50 yrs or with immunocompromise: Vancomycin + a third-generation cephalosporin + ampicillin (to cover Listeria monocytogenes).
• Neonates/Infants (<1 month): Ampicillin + cefotaxime (covers Listeria, Group B Streptococcus, and gram-negative rods).
• Healthcare-associated/Post-neurosurgical: Vancomycin + an anti-pseudomonal β-lactam (e.g., meropenem or ceftazidime) to cover resistant gram-negative organisms.

2. Key Empiric Antimicrobial Agents

2.1 Vancomycin

A glycopeptide antibiotic that inhibits bacterial cell wall synthesis. It achieves therapeutic CSF concentrations primarily when the meninges are inflamed, making it essential for covering resistant gram-positive organisms.

• Indications: Empiric coverage for drug-resistant S. pneumoniae, methicillin-resistant S. aureus (MRSA), and coagulase-negative staphylococci in shunt or drain-related infections.
• Dosing: Initiate with a loading dose of 25–30 mg/kg (based on actual body weight), followed by maintenance doses of 15–20 mg/kg every 8–12 hours.
• Monitoring: Target serum trough concentrations of 15–20 µg/mL. Monitor serum creatinine every 48 hours to assess for nephrotoxicity.

2.2 Third-Generation Cephalosporins (Ceftriaxone/Cefotaxime)

Time-dependent β-lactam antibiotics with excellent activity against common community-acquired meningitis pathogens and reliable CSF penetration during inflammation.

• Indications: S. pneumoniae, N. meningitidis, H. influenzae, and susceptible Enterobacterales.
• Dosing (Adults): Ceftriaxone 2 g IV every 12 hours or Cefotaxime 2 g IV every 4–6 hours. Dosing in neonates is weight-based and cefotaxime is preferred.
• Contraindications: Ceftriaxone is contraindicated in neonates with hyperbilirubinemia and should not be co-administered with calcium-containing IV solutions due to risk of precipitation.

2.3 Acyclovir

A guanosine analogue that, once activated by viral thymidine kinase, inhibits viral DNA polymerase. It is the cornerstone of therapy for herpes simplex virus (HSV) and varicella-zoster virus (VZV) encephalitis.

• Indications: Should be started empirically in any patient with suspected viral encephalitis, particularly with temporal lobe involvement, without waiting for PCR results.
• Dosing: 10 mg/kg IV every 8 hours for 14–21 days. Dose must be adjusted for renal impairment.
• Warnings: Can cause crystalline nephropathy; ensure adequate patient hydration to minimize risk.

2.4 Intraventricular/Intrathecal Therapy

This route of administration delivers antibiotics directly into the CSF and is reserved for refractory or device-associated infections where systemic therapy provides inadequate penetration.

• Common Agents: Preservative-free vancomycin (5–20 mg daily) or aminoglycosides (e.g., gentamicin 4 mg/dose).
• Administration: Injected via an external ventricular drain (EVD) or Ommaya reservoir under strict sterile conditions.

3. Pharmacokinetic & Pharmacodynamic (PK/PD) Considerations

The critically ill state profoundly alters drug disposition. Optimizing dosing requires an understanding of these changes to ensure therapeutic targets are met in the CNS.

3.1 Blood-Brain Barrier (BBB) Permeation

Meningeal inflammation disrupts the tight junctions of the BBB, increasing paracellular drug entry. This is crucial for hydrophilic agents like β-lactams and vancomycin. As inflammation subsides during treatment, penetration decreases, reinforcing the need for aggressive initial dosing.

3.2 Dosing in Renal Replacement Therapy (RRT) and ECMO

Both continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO) significantly impact drug clearance.

• CRRT: Clearance of many antibiotics correlates with the effluent flow rate. Higher doses or shorter intervals are often needed. Therapeutic drug monitoring (TDM) is essential for agents like vancomycin.
• ECMO: The large surface area of the ECMO circuit can sequester lipophilic drugs, reducing available serum concentration. Higher loading doses may be necessary.

4. Monitoring and De-Escalation Strategies

Effective antimicrobial stewardship involves tailoring therapy based on definitive microbiology and monitoring for efficacy and toxicity, followed by narrowing the spectrum and defining a finite duration of treatment.

4.1 Microbiology-Guided De-escalation

Once a pathogen is identified and susceptibilities are known, therapy should be narrowed to the most effective, narrowest-spectrum agent. For example, if cultures grow penicillin-susceptible S. pneumoniae, therapy can be de-escalated from vancomycin and ceftriaxone to high-dose penicillin G or ampicillin.

4.2 Duration of Therapy

The duration of antibiotic therapy is pathogen-dependent and aims to balance eradication with minimizing toxicity and resistance pressure.

5. Pharmacoeconomics and Formulary Considerations

Choosing an antimicrobial involves balancing acquisition cost with the downstream costs of monitoring, managing adverse events, and overall resource utilization.

Cost and Monitoring Comparison: Vancomycin vs. Linezolid

Linezolid is an alternative for MRSA meningitis but has a different cost and safety profile compared to vancomycin.

6. Special Populations

6.1 Neonates and Pediatric Dosing

Physiology and common pathogens differ significantly in neonates, requiring distinct empiric regimens. Dosing is universally weight-based and changes rapidly with age.

• Neonatal Empiric Regimen: Ampicillin (e.g., 50 mg/kg IV q6h) + Cefotaxime (e.g., 50 mg/kg IV q6-8h).
• >1 Month to 18 Years: Regimens generally mirror adult choices but always require weight-based dosing calculations.

6.2 Elderly with Altered PK/PD

6.3 Immunocompromised Hosts