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: meropenem is acceptable for non-severe PCN allergy (low cross-reactivity); for true anaphylaxis, use moxifloxacin + vancomycin (± aztreonam) + TMP-SMX (TMP-SMX for Listeria); 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)
• Rifampin–dexamethasone interaction: rifampin is a potent CYP3A4 inducer and reduces dexamethasone levels — consider higher dexamethasone dosing when concurrent rifampin is used (e.g., TB meningitis on RIPE)

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 (higher dose); 21 days for CNS or disseminated disease; 14 days for SEM (skin/eye/mouth) disease only
• 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 first-line; temporary CSF diversion (lumbar drain or EVD) preferred for refractory ICP; goal: opening pressure <20 cm H2O or 50% reduction. VP shunt only after CSF sterilization to avoid seeding the shunt with viable fungus
• Adjunctive dexamethasone is NOT recommended in cryptococcal meningitis — the CryptoDex trial (NEJM 2016) showed worsened outcomes (higher disability, more adverse events). Steroids may be considered specifically for cryptococcal IRIS

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. To distinguish toxoplasmosis from PCNSL, use CSF EBV PCR, FDG-PET, or MR perfusion (rCBV) — PCNSL shows EBV PCR positivity, FDG/rCBV uptake; toxoplasmosis does not
• 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), cerebellar dysfunction (bilateral dentate nucleus T2 hyperintensity on MRI — high-yield board finding), optic neuropathy, and encephalopathy (typically reversible after discontinuation)
• 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

• Treatment: Penicillin G IV 18–24 million units/day (3–4 MU IV q4h or continuous infusion) × 10–14 days
• Alternative (PCN-allergic): desensitization preferred; ceftriaxone 2 g IV/IM daily × 10–14 days is an alternative
• CSF diagnostics: CSF VDRL is specific but NOT sensitive (positive confirms, negative does not exclude); CSF FTA-Abs is sensitive but not specific (negative essentially rules out neurosyphilis); CSF pleocytosis and elevated protein support diagnosis
• HIV co-infection: more aggressive course, higher relapse rate; lower threshold for LP; follow CSF parameters closely after treatment
• Forms: meningovascular (stroke in young patient), general paresis (dementia, psychosis), tabes dorsalis (sensory ataxia, Argyll Robertson pupils, lancinating pains), gummatous
• Jarisch-Herxheimer reaction: fever, chills, myalgia within hours of first dose due to spirochete lysis; supportive care

• First-line (meningitis / cranial neuritis / radiculoneuritis): oral doxycycline 100–200 mg PO BID OR IV ceftriaxone 2 g daily OR IV cefotaxime OR IV penicillin G × 14–21 days — all considered equivalent for most adult neuroborreliosis per 2020 IDSA/AAN/ACR guidelines
• Parenchymal CNS involvement (brain/spinal cord): IV therapy preferred (ceftriaxone, cefotaxime, or penicillin G)
• Manifestations: lymphocytic meningitis, cranial neuritis (facial nerve palsy is most common — can be bilateral), painful radiculoneuritis (Bannwarth syndrome), rare encephalomyelitis
• Diagnosis: two-tiered serology (ELISA → Western blot); CSF antibody index (intrathecal antibody production) supports CNS involvement
• “Post-Lyme syndrome”: persistent symptoms after treatment; prolonged antibiotic therapy is NOT recommended (multiple RCTs show no benefit, real harm)

• Treatment: Doxycycline 100 mg PO/IV BID × 5–7 days (or at least 3 days after defervescence); start empirically on clinical suspicion — do NOT wait for serology
• Pediatric use: CDC reversed prior pediatric restriction in 2017 — doxycycline is now first-line in children of any age for suspected RMSF; benefit outweighs risk of dental staining with short courses
• Organism: Rickettsia rickettsii (obligate intracellular)
• Clinical: fever, headache, myalgia, petechial rash starting on wrists/ankles → centripetal spread (palms/soles involved); encephalitis, vasculitis, AMS, focal deficits
• Mortality: high if treatment delayed beyond day 5 of illness; do not wait for confirmatory testing

• Wound care: immediate thorough washing with soap and water × 15 min, then povidone-iodine
• Human rabies immune globulin (HRIG): 20 IU/kg; infiltrate the FULL dose around/into the wound if anatomically feasible; remainder IM at distant site (NEVER in same syringe or site as vaccine)
• Rabies vaccine: 4-dose IM schedule (deltoid) on days 0, 3, 7, 14 for immunocompetent (ACIP); 5-dose schedule (add day 28) for immunocompromised
• Previously vaccinated: 2 doses (days 0 and 3); do NOT give HRIG
• Established rabies encephalitis: nearly universally fatal once symptomatic; Milwaukee protocol largely abandoned

• Indications: household contacts, intimate kissing contacts, child-care contacts, healthcare workers with direct mucosal exposure (unprotected intubation/suction); ideally within 24 hours
• Options:
  • Rifampin 600 mg PO BID × 2 days (adults); 10 mg/kg q12h × 2 days (children)
  • Ciprofloxacin 500 mg PO × 1 dose (adults; not pregnant)
  • Ceftriaxone 250 mg IM × 1 dose (preferred in pregnancy; 125 mg in children <15 yr)
• Index case: also needs chemoprophylaxis (unless treated with ceftriaxone/cefotaxime, which eradicate carriage) before discharge

Cefepime / Imipenem Encephalopathy

• Cefepime neurotoxicity: encephalopathy, nonconvulsive status epilepticus (NCSE), myoclonus, asterixis — classically in patients with renal failure and inadequate dose adjustment
• Imipenem: lowers seizure threshold (highest seizure risk among carbapenems); avoid in patients with CNS disease/renal failure — meropenem preferred for CNS infections
• Management: recognize early, EEG to assess for NCSE, hold drug, dose-adjust for renal clearance, hemodialysis can accelerate clearance of cefepime

Linezolid

• Serotonin syndrome with SSRIs, SNRIs, MAOIs, tramadol, meperidine — linezolid is a weak nonselective MAO inhibitor; review medication list before starting
• Optic neuropathy and peripheral neuropathy with use >28 days (often irreversible)
• Lactic acidosis from mitochondrial toxicity (inhibits mitochondrial protein synthesis)
• Reversible myelosuppression (thrombocytopenia) with prolonged use

Fluoroquinolones

• Tendinopathy/tendon rupture (especially Achilles; higher risk with steroids, age >60, transplant)
• Peripheral neuropathy (can be permanent)
• CNS effects: encephalopathy, agitation, seizures, lowered seizure threshold
• Dysglycemia (both hypo- and hyperglycemia)
• QT prolongation → torsades
• Aortic dissection/aneurysm: FDA warning (2018) — avoid in patients at risk

• Common neurologic manifestations:
  • Anosmia/ageusia — early hallmark, often isolated
  • Encephalitis/encephalopathy — can be parainfectious, autoimmune, or post-viral
  • Stroke — large-vessel occlusion in younger patients; hypercoagulable state
  • Guillain-Barré syndrome (GBS) — post-infectious AIDP/AMAN
  • PRES (posterior reversible encephalopathy syndrome)
  • ADEM, transverse myelitis, cranial neuropathies
• Antiviral therapy:
  • Remdesivir — nucleotide analog; RNA polymerase inhibitor; IV; used in hospitalized patients
  • Nirmatrelvir-ritonavir (Paxlovid) — oral; major CYP3A4 drug interactions via ritonavir (review AEDs, statins, immunosuppressants); use within 5 days of symptom onset in outpatients at high risk
• Long COVID neurologic symptoms: brain fog, dysautonomia (POTS), persistent headache, fatigue, sleep disturbance — supportive management