Antimicrobials & CNS Infections
Antimicrobials & CNS Infections Pharmacology
What You'll Learn
- Empiric bacterial meningitis treatment varies by age — neonates: ampicillin + gentamicin and/or a 3rd-gen cephalosporin such as cefotaxime (AVOID ceftriaxone — bilirubin displacement); 1 mo–50 yr: ceftriaxone + vancomycin + dexamethasone; >50 yr/immunocompromised: add ampicillin for Listeria coverage
- Dexamethasone timing is critical — give BEFORE or WITH first antibiotic dose; reduces mortality in S. pneumoniae meningitis and hearing loss in H. influenzae; do NOT give if antibiotics already started
- CSF penetration determines drug choice — good: ceftriaxone, meropenem, metronidazole, linezolid, TMP-SMX, fluoroquinolones; poor: aminoglycosides, 1st-gen cephalosporins, clindamycin
- HSV encephalitis — acyclovir 10 mg/kg IV q8h × 14–21 days; do NOT wait for PCR results to start treatment; renal toxicity is the main adverse effect
- Cryptococcal meningitis — induction: liposomal amphotericin B + flucytosine × 2 weeks (preferred); consolidation: fluconazole × 8 weeks; discontinue maintenance fluconazole only after ≥1 year on antifungal therapy AND clinically stable AND CD4 ≥100 cells/μL AND suppressed HIV RNA on ART; adjunctive dexamethasone NOT recommended (CryptoDex 2016)
- TB meningitis — RIPE × 2 months then RI × 7–10 months; ADD dexamethasone (proven mortality benefit); isoniazid causes peripheral neuropathy (give B6) and hepatotoxicity; rifampin is a potent CYP inducer
- Neurocysticercosis — give steroids FIRST to prevent inflammation, then albendazole ± praziquantel; do NOT give antiparasitics without steroid cover
- PML has no specific antiviral — treatment is immune reconstitution (HAART for HIV, stop natalizumab/immunosuppression, consider PLEX); watch for IRIS
HighYield Pearls
- Empiric adult meningitis (1 mo–50 yr): vancomycin + ceftriaxone 2 g IV q12h + dexamethasone 0.15 mg/kg q6h × 4 d — give dex BEFORE/WITH first antibiotic dose; mortality benefit proven for S. pneumoniae (de Gans/van de Beek)
- Add ampicillin for Listeria if >50 yr, pregnant, immunocompromised, or neonate — cephalosporins do NOT cover Listeria; TMP-SMX is the PCN-allergy alternative
- Neonates: ampicillin + gentamicin and/or cefotaxime (3rd-gen ceph) — depending on age, severity, local resistance, and meningitis concern; AVOID ceftriaxone (bilirubin displacement → kernicterus); covers GBS, E. coli, Listeria; triple therapy is protocol-dependent, not a universal default
- HSV encephalitis: acyclovir 10 mg/kg IV q8h × 14–21 d — start EMPIRICALLY before PCR; hydrate to prevent crystal nephropathy; renal dose-adjust; VZV vasculitis/stroke after HZ ophthalmicus → IV acyclovir then valacyclovir PO
- TB meningitis: RIPE (rifampin + INH + pyrazinamide + ethambutol) ≥12 mo + dexamethasone 6–8 wk taper (Thwaites mortality benefit); ALWAYS co-administer pyridoxine (B6) 25–50 mg/d with INH to prevent neuropathy/seizures; ethambutol → optic neuropathy (renal dose-adjust)
- Cryptococcal meningitis (HIV): induction liposomal amphotericin B + flucytosine ≥2 wk → consolidation fluconazole 800 mg → maintenance fluconazole 200 mg — discontinue only after ≥1 year on antifungal therapy AND clinically stable AND CD4 ≥100 cells/μL AND suppressed HIV RNA on ART; serial LPs for opening pressure >25 cm H2O reduce mortality
- Toxoplasmosis: pyrimethamine + sulfadiazine + folinic acid (leucovorin) × 6 wk then maintenance; TMP-SMX prophylaxis if CD4 <100. Neurocysticercosis: steroids FIRST, then albendazole 15 mg/kg/d (± praziquantel) + AED; ophtho eval first — ocular cysts contraindicate antiparasitics; calcified inactive cysts need no antiparasitic
- Neurosyphilis: aqueous PCN G 18–24 MU/d IV × 14 d (desensitize if PCN-allergic). Neuroborreliosis (Lyme): for meningitis / cranial neuritis / radiculoneuritis → oral doxycycline OR IV ceftriaxone/cefotaxime/PCN G × 14–21 d (2020 IDSA/AAN/ACR); parenchymal CNS disease → IV. CMV encephalitis: ganciclovir + foscarnet. PML: reverse immunosuppression — no specific antiviral
- High-yield neurotoxicity: cefepime/imipenem → encephalopathy + NCSE (renal dose); metronidazole → cerebellar toxicity with reversible T2 dentate hyperintensity + peripheral neuropathy; linezolid → serotonin syndrome (avoid SSRI/MAOI/triptan) + optic neuropathy + lactic acidosis; fluoroquinolones → seizures + worsen myasthenia gravis + tendinopathy + QT
🔍 Quick ReferenceEmpiric / pathogen · Drug / mechanism · Neurotoxicity / pearls
Empiric / pathogen-specific
- Adult community-acquired meningitis → vancomycin + ceftriaxone + dexamethasone (add ampicillin if >50 / immunocompromised / pregnant)
- Neonatal meningitis → ampicillin + gentamicin and/or cefotaxime (3rd-gen ceph) — covers GBS / E. coli / Listeria; AVOID ceftriaxone (bilirubin displacement); triple therapy is protocol-dependent, not universal default
- HSV encephalitis / VZV vasculitis → IV acyclovir 10 mg/kg q8h × 14–21 d (VZV step-down to valacyclovir PO)
- TB meningitis → RIPE + dexamethasone + pyridoxine
- Cryptococcal meningitis (HIV) → liposomal amphotericin B + flucytosine → fluconazole + serial LP
- Toxoplasmosis → pyrimethamine + sulfadiazine + folinic acid; neurocysticercosis → albendazole + steroids + AED
- Neurosyphilis → aqueous PCN G 18–24 MU/d × 14 d; neuroborreliosis (meningitis / cranial neuritis / radiculoneuritis) → oral doxycycline OR IV ceftriaxone/cefotaxime/PCN G × 14–21 d (2020 IDSA/AAN/ACR); parenchymal CNS → IV
- CMV encephalitis → ganciclovir + foscarnet; PCP/Toxo prophylaxis → TMP-SMX if CD4 <100–200
Drug / mechanism
- Ceftriaxone → 3rd-gen cephalosporin, excellent CSF penetration — covers S. pneumo / N. meningitidis / H. flu but NOT Listeria/MRSA
- Vancomycin → covers penicillin-resistant pneumococcus + MRSA; CSF penetration reduced by concurrent dexamethasone
- Ampicillin / TMP-SMX → Listeria coverage (Listeria is intrinsically resistant to all cephalosporins)
- Acyclovir → thymidine kinase–activated guanosine analog; renal dose-adjust + hydrate
- Amphotericin B (liposomal) → binds ergosterol → pores; liposomal less nephrotoxic. Flucytosine → converted to 5-FU; monitor cytopenias
- Rifampin → potent CYP3A4 inducer (reduces dexamethasone, ART, AEDs); orange body fluids
- Albendazole / praziquantel → antihelminthic for neurocysticercosis; steroids first to blunt inflammatory response
- Linezolid → reversible MAO inhibitor → serotonin syndrome risk with SSRI / triptan / MAOI
Neurotoxicity / pearls
- Reversible T2 dentate / cerebellar hyperintensity + ataxia + neuropathy → metronidazole
- Cefepime / imipenem encephalopathy + NCSE → β-lactam neurotoxicity (renal dose-dependent; check EEG)
- Serotonin syndrome + optic / peripheral neuropathy + lactic acidosis → linezolid
- INH peripheral neuropathy + seizures → pyridoxine (B6) deficiency — co-administer B6 25–50 mg/d
- Worsens myasthenia gravis + tendinopathy + QT prolongation + seizures → fluoroquinolones
- Ototoxicity + vestibulotoxicity + nephrotoxicity + MG worsening → aminoglycosides
- Pseudotumor cerebri / benign intracranial hypertension → tetracyclines (doxycycline, minocycline)
- Optic neuropathy (red-green color vision loss) → ethambutol; kernicterus in neonates → ceftriaxone (use cefotaxime)
- SIADH / hyponatremia → β-lactams (and carbamazepine class effect); visual hallucinations → voriconazole / fluconazole
Empiric Bacterial Meningitis Treatment
Treatment by Age Group
| Age Group | Common Organisms | Empiric Regimen | Notes |
|---|---|---|---|
| Neonates (<1 month) | Group B Streptococcus (GBS), E. coli, Listeria monocytogenes | Ampicillin + gentamicin and/or cefotaxime (3rd-gen ceph) depending on age, severity, local resistance, meningitis concern | AVOID ceftriaxone (bilirubin displacement → kernicterus) — use cefotaxime instead; ampicillin covers Listeria + GBS; triple therapy can be used in some protocols but is NOT the universal default |
| 1 month – 50 years | S. pneumoniae, N. meningitidis, H. influenzae | Ceftriaxone + vancomycin + dexamethasone | Vancomycin added for penicillin-resistant pneumococcus; dex given before/with first antibiotic dose |
| >50 years or immunocompromised | S. pneumoniae, Listeria, N. meningitidis, gram-negative bacilli | Ceftriaxone + vancomycin + ampicillin + dexamethasone | Add ampicillin for Listeria coverage; Listeria is intrinsically resistant to cephalosporins |
- 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
Board Pearl
Listeria monocytogenes is intrinsically resistant to all cephalosporins. Any patient >50 years, pregnant, or immunocompromised with suspected meningitis MUST receive ampicillin in addition to ceftriaxone. TMP-SMX is the alternative for penicillin-allergic patients.
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