192.1 🎓 醫學生版

192.1.0.1 📌 一頁重點

• First-line (RIPE):
  • R Rifampin — bactericidal; inhibits RNA polymerase; hepatotoxic, orange secretions, CYP3A4 inducer
  • I Isoniazid (INH) — bactericidal; inhibits mycolic acid synthesis; hepatotoxic, peripheral neuropathy (give pyridoxine B6 25-50 mg/d), drug-induced lupus
  • P Pyrazinamide (PZA) — bactericidal in acid environment; hyperuricemia, hepatotoxic
  • E Ethambutol — bacteriostatic; inhibits arabinosyl transferase; optic neuritis (color vision, visual acuity)
• Second-line:
  • Fluoroquinolones (moxi, levo) — bactericidal
  • Aminoglycosides (amikacin, streptomycin) — bactericidal
  • Linezolid — protein synthesis, bone marrow suppression long-term
  • Bedaquiline (Sirturo, FDA 2012) — ATP synthase inhibitor, QTc, MDR-TB cornerstone
  • Delamanid, Pretomanid — nitroimidazole, MDR-TB
  • Cycloserine, Terizidone — D-Ala incorporation, neuropsych side effects
  • Para-aminosalicylic acid (PAS) — pre-1950s reused for MDR; GI
  • Clofazimine — for leprosy + MDR-TB adjunct; skin discoloration
• 新 Regimens (2024 WHO):
  • 4-month rifapentine-moxifloxacin for drug-sensitive non-cavitary smear-neg TB
  • BPaL (Bedaquiline + Pretomanid + Linezolid) 6-month for MDR + Pre-XDR / XDR TB
  • BPaLM = BPaL + Moxifloxacin for some MDR-TB
• Hepatotoxicity profile (1st-line): PZA > INH > Rifampin
  • Monitor LFT baseline + monthly; stop if AST/ALT > 5× ULN or > 3× + sx

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192.1.0.2 1️⃣ First-Line Drugs (RIPE)

192.1.0.2.1 Rifampin (RIF)

• Mechanism: inhibits DNA-dependent RNA polymerase (β subunit, rpoB)
• Bactericidal (both replicating + slow-dividing organisms)
• Penetration: excellent (CSF, biofilms, intracellular, macrophage)
• Toxicity:
  • Hepatotoxic (5-10%)
  • Orange-red discoloration of urine, sweat, tears, contact lenses
  • Flu-like syndrome (intermittent dosing)
  • Thrombocytopenia, hemolytic anemia
• Drug interactions (major):
  • CYP3A4 inducer — reduces levels of: warfarin, OCs, antiretrovirals (ART), DOACs, calcineurin inhibitors, steroids
  • Dose adjustments / alternative agents needed
• Resistance: rpoB mutation (rapid detection by GeneXpert MTB/RIF)

192.1.0.2.2 Isoniazid (INH)

• Mechanism: inhibits mycolic acid synthesis (InhA, KatG)
• Bactericidal (replicating organisms)
• Best for active TB + LTBI treatment
• Toxicity:
  • Hepatotoxic (10-20% mild ↑ ALT; severe 0.1-1%, more in older + ETOH + HBV/HCV)
  • Peripheral neuropathy — pyridoxine deficiency
  • Pyridoxine (vitamin B6) 25-50 mg/day prophylaxis
  • Drug-induced lupus (anti-histone Ab +)
  • Sideroblastic anemia (B6 def)
  • Optic neuritis (rare)
  • Seizure (overdose — give B6 IV emergent)
• Acetylator status: slow vs fast (NAT2 polymorphism); slow → higher toxicity, fast → less efficacy at standard dose
• Resistance: KatG, inhA mutations

192.1.0.2.3 Pyrazinamide (PZA)

• Mechanism: prodrug, converted to pyrazinoic acid by mycobacterial pyrazinamidase (pncA gene) — only active in acidic environment (macrophage phagosome)
• Bactericidal in acid environment
• Critical for first 2 months (intensive phase) for rapid kill
• Toxicity:
  • Hepatotoxic (highest of 1st-line)
  • Hyperuricemia (often asymptomatic; rarely gout) — monitor uric acid
  • GI, rash, photosensitivity
• Pregnancy: WHO recommends; US guidelines slightly cautious historically — now generally accepted

192.1.0.2.4 Ethambutol (EMB)

• Mechanism: inhibits arabinosyl transferase (cell wall arabinogalactan)
• Bacteriostatic
• Toxicity:
  • Optic neuritis — reduced visual acuity, color blindness (red-green), central scotoma
  • Dose-dependent + age-dependent
  • Monthly visual acuity + color vision check
  • Reversible if early; permanent if late
• Renal clearance — dose adjust CKD
• Children — caution under 5 (visual acuity testing hard)

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192.1.0.3 2️⃣ Second-Line Drugs

192.1.0.3.1 A. Fluoroquinolones (FQ)

• Moxifloxacin > Levofloxacin > Ofloxacin
• Bactericidal — inhibit DNA gyrase
• Cornerstone of MDR-TB regimens
• 2024 WHO 4-month regimen for drug-sensitive: rifapentine + moxifloxacin
• Toxicity: QTc prolongation, tendon rupture (especially elderly), CNS, dysglycemia
• Resistance: gyrA mutation (test before MDR regimens)

192.1.0.3.2 B. Aminoglycosides + Capreomycin

• Amikacin > Streptomycin > Capreomycin (cyclic peptide)
• Bactericidal
• IM/IV — no oral
• Toxicity: nephro + ototoxicity (irreversible)
• Reserved for severe / MDR

192.1.0.3.3 C. Bedaquiline (Sirturo)

• FDA 2012 — first new TB drug in 40 yr
• Inhibits mycobacterial ATP synthase
• 6-month course for MDR-TB
• Toxicity: QTc prolongation (monitor), hepatotoxic
• Drug interaction: CYP3A4 (avoid rifampin co-administration)
• BPaL regimen cornerstone

192.1.0.3.4 D. Delamanid + Pretomanid (Nitroimidazoles)

• Inhibit mycolic acid synthesis (different than INH)
• Pretomanid — FDA 2019 (part of BPaL)
• Delamanid — Japan / Europe
• Toxicity: QTc, hepatic, peripheral neuropathy

192.1.0.3.5 E. Linezolid

• Protein synthesis inhibitor (50S ribosome)
• BPaL component
• Toxicity: bone marrow suppression (long-term), peripheral neuropathy, optic neuropathy, lactic acidosis, serotonin syndrome (with SSRI)
• Reduced dose 600 mg qd (vs standard 600 bid) in long-term TB

192.1.0.3.6 F. Cycloserine + Terizidone

• D-Ala incorporation inhibition
• CNS toxicity prominent: psychosis, depression, suicidality, seizures
• Vitamin B6 supplementation
• Pre-Sertraline screening for depression

192.1.0.3.7 G. Para-Aminosalicylic Acid (PAS)

• Old drug repurposed for MDR
• GI side effects (nausea, vomiting, diarrhea)
• Hypothyroidism

192.1.0.3.8 H. Clofazimine

• Leprosy primary use
• MDR-TB adjunct
• Skin discoloration (red-brown) — reversible but prolonged
• GI

192.1.0.3.9 I. Rifapentine

• Long-acting rifamycin
• Once-weekly INH-rifapentine for LTBI (3HP regimen)
• 4-month regimen for active TB with moxifloxacin (2024)
• Same CYP3A4 induction concern

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192.1.0.4 3️⃣ 2024 WHO Updates

192.1.0.4.1 4-Month Regimen for Drug-Susceptible TB

• Non-cavitary, smear-negative, drug-susceptible pulmonary TB
• Rifapentine 1200 mg + Moxifloxacin 400 mg + INH + PZA daily × 8 wk → Rifapentine + Moxifloxacin + INH × 9 wk = 17 wk total (≈ 4 months)
• Equivalent outcome to standard 6-month RIPE
• Adherence improvement

192.1.0.4.2 BPaL / BPaLM for MDR + Pre-XDR / XDR

• BPaL = Bedaquiline + Pretomanid + Linezolid × 6 months
• Pre-2019: MDR-TB regimens were 18-24 months, toxic, ~ 50% cure
• BPaL trial (Nix-TB): 90% cure in XDR-TB cohort
• BPaLM = BPaL + Moxifloxacin for selected MDR-TB
• WHO 2024 first-line for MDR / Pre-XDR / XDR
• Game changer

192.1.0.4.3 LTBI Treatment Updates

• 3HP regimen: weekly INH + rifapentine × 12 doses (3 months)
• 4R regimen: rifampin 4 months
• 6H or 9H: INH 6 or 9 months (older, longer)
• Choice based on:
  • HIV status (drug interactions with ART → avoid rifamycin if not adjusted)
  • Pregnancy (3HP safer than INH alone)
  • Pediatric considerations

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192.1.0.5 4️⃣ Drug Monitoring + Toxicity

192.1.0.5.1 Baseline + Monthly

• CBC, LFT, BUN/Cr, uric acid
• Visual acuity + color vision (ethambutol)
• HIV test
• Pregnancy

192.1.0.5.2 Hepatotoxicity Management

• Stop drugs if:
  • AST/ALT > 5× ULN (asymptomatic)
  • AST/ALT > 3× ULN + symptomatic (jaundice, abdominal pain, N/V)
  • Bilirubin > 3× ULN
• Reintroduce sequentially after normalization
• Higher-risk drugs (PZA, INH, rifampin) reintroduced carefully

192.1.0.5.3 Optic Neuritis (Ethambutol)

• Monthly Snellen + Ishihara color plates
• Reduced acuity or red-green discrimination → stop EMB
• Early reversible; late permanent

192.1.0.5.4 Peripheral Neuropathy (INH, Linezolid)

• Pyridoxine prophylaxis for INH
• Sensory + motor — gabapentin / pregabalin if painful

192.1.0.5.5 CNS (Cycloserine)

• Pre-screen depression, alcoholism, seizure
• Pyridoxine
• Tx + monitor weekly first month
• Stop if severe sx

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192.1.0.6 5️⃣ DOT (Directly Observed Therapy)

• Standard for active TB in many settings
• Health worker / family member observes patient swallow each dose
• Daily or 3×/wk depending phase
• Reduces relapse + emergence of resistance
• Video DOT (vDOT) — modern alternative for self-administered with periodic check

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