Treatment by Age Group

• Listeria risk factors: age >50, pregnancy, alcoholism, immunosuppression (steroids, transplant, HIV), iron overload
• Ceftriaxone does NOT cover Listeria — this is a commonly tested fact; ampicillin or TMP-SMX must be added
• Penicillin allergy: substitute meropenem for ceftriaxone; TMP-SMX can replace ampicillin for Listeria
• Duration of treatment: S. pneumoniae: 10–14 days; N. meningitidis: 7 days; H. influenzae: 7–10 days; Listeria: 21 days or more; gram-negative bacilli: 21 days
• Ceftriaxone is NOT used in neonates — displaces bilirubin from albumin → risk of kernicterus; use cefotaxime instead

Indications and Evidence

• Mechanism: reduces subarachnoid inflammation and cytokine release triggered by bacterial lysis after antibiotics
• Concern: dexamethasone may reduce vancomycin CSF penetration — some experts recommend higher vancomycin dosing or adding rifampin when dexamethasone is used
• TB meningitis: dexamethasone is ALSO indicated and has proven mortality benefit (Thwaites trial, NEJM 2004) — longer course (6–8 weeks taper)

Antibiotic CSF Penetration

• Meningeal inflammation increases penetration — disrupted BBB allows hydrophilic drugs to enter CSF; as infection resolves and meninges heal, penetration decreases
• Vancomycin trough goal in meningitis: 15–20 mcg/mL (higher than standard targets) to ensure adequate CSF levels
• Linezolid has excellent CSF penetration and is used for vancomycin-resistant organisms and some cases of resistant TB meningitis
• Fluoroquinolones (moxifloxacin) achieve good CSF levels and are used in multidrug-resistant TB meningitis regimens
• Chloramphenicol has excellent CSF penetration but is rarely used due to aplastic anemia risk; may be used in resource-limited settings

Key Antiviral Agents

• HSV encephalitis is a neurologic emergency — start acyclovir immediately on clinical suspicion; do NOT wait for CSF HSV PCR results
• Acyclovir resistance: thymidine kinase mutations; treat with foscarnet
• Neonatal HSV: acyclovir 20 mg/kg IV q8h × 21 days (higher dose, longer course)
• Prevent acyclovir crystalluria: ensure adequate hydration (IV NS) and avoid rapid infusion; check renal function regularly
• Duration matters: 14 days for HSV-2 meningitis (benign recurrent lymphocytic meningitis/Mollaret); 21 days for HSV encephalitis in neonates and immunocompromised

Antiretroviral Therapy and Neurologic Complications

• HAART (highly active antiretroviral therapy): cornerstone of treating HIV-associated CNS infections and HIV-associated neurocognitive disorders (HAND)
• CNS-penetrant antiretrovirals: zidovudine, nevirapine, efavirenz, dolutegravir have relatively good CSF penetration
• Immune reconstitution inflammatory syndrome (IRIS): paradoxical worsening after starting HAART due to recovering immune system mounting exaggerated response against opportunistic infections
• IRIS timing: typically 1–12 weeks after HAART initiation; risk factors include low baseline CD4, high viral load, early HAART initiation
• IRIS treatment: continue HAART; corticosteroids for severe cases; supportive care

Cryptococcal Meningitis Treatment Protocol

• Amphotericin B mechanism: binds ergosterol in fungal membrane → forms pores → cell lysis
• Amphotericin B toxicities: nephrotoxicity (monitor BUN/Cr, give NS pre-hydration), hypokalemia, hypomagnesemia, infusion reactions (fever, rigors — premedicate with acetaminophen/diphenhydramine), anemia
• Liposomal amphotericin B: less nephrotoxic than conventional; preferred when available
• Flucytosine: converted to 5-fluorouracil intracellularly; synergistic with amphotericin B; dose-adjust for renal impairment; monitor for myelosuppression
• Raised intracranial pressure in cryptococcal meningitis — serial therapeutic LPs or lumbar drain; goal: opening pressure <20 cm H2O or 50% reduction

Other CNS Antifungal Agents

TB Meningitis Treatment

Anti-TB Drug Side Effects and Pearls

• Dexamethasone in TB meningitis — Thwaites et al. (NEJM 2004) showed significant mortality reduction; one of the few CNS infections where steroids have proven mortality benefit
• INH peripheral neuropathy: due to competitive inhibition of pyridoxine (vitamin B6) metabolism → always co-prescribe pyridoxine 25–50 mg/day
• INH seizures: also related to B6 depletion (B6 is cofactor for GAD, which converts glutamate to GABA); treat INH-induced seizures with IV pyridoxine (gram-for-gram replacement)
• Rifampin turns body fluids orange — tears, urine, sweat; counsel patients (can stain contact lenses)
• Slow vs fast acetylators (INH): N-acetyltransferase polymorphism determines INH metabolism; slow acetylators have higher INH levels → increased risk of hepatotoxicity and neuropathy; fast acetylators may need higher doses
• Rifampin drug interactions are extensive: reduces efficacy of OCPs, warfarin, phenytoin, dexamethasone, protease inhibitors, and many others; always review medication list before starting RIPE
• Hydrocephalus in TB meningitis: common complication due to basilar exudates; may require VP shunt; does not change antibiotic regimen

Neurocysticercosis

• Albendazole mechanism: inhibits microtubule polymerization (binds beta-tubulin) → impairs glucose uptake by parasite
• Praziquantel mechanism: increases calcium permeability of parasite cell membrane → paralysis and death
• Critical principle: antiparasitic drugs cause cyst death → intense inflammatory response → cerebral edema, seizures; steroids must be given FIRST (typically 1–2 days before antiparasitics)
• Albendazole + dexamethasone actually increases albendazole levels (dexamethasone inhibits albendazole metabolism)
• Albendazole + praziquantel combination: dual therapy shown to be superior to albendazole alone for patients with >2 viable cysts (Garcia et al., Lancet Infectious Diseases 2014)
• AED management: seizures are the most common presentation; AEDs are indicated if seizures occur; can consider AED withdrawal after 1–2 years if seizure-free and cysts resolved

CNS Toxoplasmosis

• First-line: pyrimethamine + sulfadiazine + leucovorin (folinic acid) × 6 weeks
• Pyrimethamine: inhibits dihydrofolate reductase (DHFR) → folate antagonist; leucovorin prevents bone marrow toxicity
• Alternative: TMP-SMX (for sulfa-tolerant patients) or pyrimethamine + clindamycin (for sulfa-allergic)
• Prophylaxis: TMP-SMX when CD4 <100 (also provides PCP prophylaxis)
• Maintenance therapy: continue at lower dose until CD4 >200 for ≥6 months on HAART
• Imaging: multiple ring-enhancing lesions with surrounding edema, predilection for basal ganglia and gray-white junction; single lesion more suggestive of CNS lymphoma (order thallium SPECT or biopsy)
• Empiric trial: if imaging is consistent with toxoplasmosis in an HIV patient with CD4 <100, treat empirically; if no improvement in 10–14 days, perform brain biopsy to rule out lymphoma

Brain Abscess (Anaerobic Coverage)

• Metronidazole is the drug of choice for anaerobic coverage in brain abscess — excellent CSF/abscess penetration
• Mechanism: reduced by anaerobic organisms to toxic free radicals that damage DNA
• Side effects: disulfiram-like reaction with alcohol, metallic taste, peripheral neuropathy (with prolonged use), seizures (rare)
• Nocardia brain abscess: treat with TMP-SMX (first-line); often seen in immunocompromised patients; prolonged treatment required (6–12 months)

Treatment Approach

• No proven antiviral for JC virus — cidofovir, mirtazapine, mefloquine have been tried but none have demonstrated benefit in controlled trials
• PML-IRIS occurs in 15–20% of HIV patients starting HAART with PML; presents with new contrast enhancement and clinical worsening despite rising CD4 counts
• Natalizumab PML risk factors: JC virus antibody positive (especially index >1.5), treatment duration >24 months, prior immunosuppressant use
• Checkpoint inhibitors (pembrolizumab) are being investigated as potential PML treatment by enhancing T-cell response against JC virus
• JC virus PCR in CSF confirms diagnosis; sensitivity is ~75–80% (may be low in early disease or with immune reconstitution)
• MRI findings in PML: asymmetric, multifocal white matter lesions (subcortical U-fibers involved); no mass effect; no enhancement (unless IRIS is occurring)
• Prognosis: 1-year mortality ~50% in HIV-associated PML (improved with HAART); natalizumab-associated PML has better prognosis (~25% mortality) with early detection and drug removal

Empiric Antibiotic Therapy

Surgical Indications

• Surgical drainage/aspiration indicated if: abscess >2.5 cm diameter, significant mass effect, intraventricular rupture, or failure to respond to antibiotics after 1–2 weeks
• Stereotactic aspiration is preferred over excision for deep or eloquent-area abscesses
• Duration of antibiotics: typically 6–8 weeks IV; longer if abscess not drained surgically
• Serial imaging: follow with MRI every 1–2 weeks to monitor response; ring enhancement may persist for weeks after successful treatment
• Empiric coverage rationale: ceftriaxone covers streptococci and gram-negatives; metronidazole covers anaerobes (Bacteroides, Fusobacterium); vancomycin added when Staphylococcus (including MRSA) is suspected
• Nocardia vs Toxoplasma: both cause ring-enhancing lesions in immunocompromised patients; Nocardia is treated with TMP-SMX; Toxoplasma with pyrimethamine + sulfadiazine; biopsy if no response to empiric toxoplasma therapy in 10–14 days