150.1 🎓 醫孞生版

150.1.0.1 📌 䞀頁重點

  • 抗藥四倧機蜉:
    1. 酶降解 (β-lactamase, aminoglycoside-modifying enzymes)
    2. 改變 target (PBP for MRSA, ribosome methylation for macrolide, gyrase mutation for FQ)
    3. 枛少 entry / efflux pump (porin loss, AcrAB-TolC)
    4. 新代謝路埑 (VRE Van A: D-Ala-D-Lac)
  • WHO Priority Pathogens 2024: MDR Acinetobacter, MDR Pseudomonas, ESBL Enterobacteriaceae, CRE, MRSA, VRE, Drug-resistant TB, Salmonella, Shigella, N. gonorrhoeae, C. jejuni
  • Resistance spread: horizontal gene transfer (plasmid, transposon) — across genus/species; mobile genetic elements
  • 解套: stewardship + surveillance + new antibiotics + vaccines + diagnostics

150.1.0.2 1⃣ 䞻芁抗藥機蜉

150.1.0.2.1 A. 酶降解

β-Lactamases (β-lactam ring 氎解): - Penicillinase (S. aureus → MSSA → MRSA via mecA): natural - ESBL (Extended-Spectrum β-Lactamase): TEM, SHV, CTX-M (most common globally) - 氎解 3rd-gen ceph (ceftriaxone) but not carbapenem - Inhibited by clavulanic acid, tazobactam, sulbactam - AmpC β-lactamase: chromosomal in Enterobacter, Citrobacter; inducible - Carbapenemases: - KPC (Class A serine) — Klebsiella, US/Israel - NDM (Class B metallo) — India/South Asia - OXA-48 (Class D) — Turkey/Middle East - VIM, IMP (Class B metallo) — Asia, Europe - Inhibited variably: avibactam (KPC + OXA), vaborbactam (KPC), relebactam (KPC)

Aminoglycoside-modifying enzymes (acetyl, phospho, nucleotidyl transferases) — Gram + and Gram -

Chloramphenicol acetyltransferase (CAT)

150.1.0.2.2 B. Target Modification
  • MRSA (mecA): PBP2a (low β-lactam affinity)
  • VRE (vanA, vanB): D-Ala-D-Lac (not D-Ala-D-Ala) — vancomycin can’t bind
  • Macrolide (erm): 23S rRNA methylation
  • FQ (gyrA, parC): gyrase / topo IV mutations
  • Rifampin (rpoB): RNA polymerase mutation
  • Daptomycin: cardiolipin / membrane charge changes
  • Linezolid (cfr): 23S rRNA modification
150.1.0.2.3 C. Reduced Entry / Efflux
  • Porin loss (OmpF, OmpC in Enterobacteriaceae): reduced β-lactam, FQ entry
  • Efflux pumps: AcrAB-TolC (multidrug), MexAB-OprM (Pseudomonas), Tet efflux
150.1.0.2.4 D. Metabolic Bypass
  • Sulfonamide resistance: alternative folate pathway
  • VanA D-Ala-D-Lac (vs D-Ala-D-Ala): VRE example

150.1.0.3 2⃣ 䞻芁 MDR 病原 + Treatment

150.1.0.3.1 Gram + MDR
Organism Resistance Treatment
MRSA PBP2a (mecA) Vancomycin, Daptomycin, Linezolid, Ceftaroline, Tedizolid
VRE (E. faecium) vanA/B → D-Ala-D-Lac Linezolid, Daptomycin (high-dose), Tigecycline, Quinupristin-Dalfopristin (rare now)
VRSA (rare) vanA from Enterococcus Daptomycin, Linezolid, Ceftaroline + Daptomycin combination
PRSP (Pen-Resistant S. pneumo) PBP alterations Vancomycin + 3rd gen ceph; carbapenem for severe
150.1.0.3.2 Gram - MDR
Organism Resistance Treatment
ESBL Enterobacteriaceae CTX-M, TEM, SHV Carbapenem (preferred per MERINO); pip-tazo only if mild + susceptible
AmpC Chromosomal Cefepime, carbapenem (avoid ceftriaxone — selects for AmpC)
CRE (Carbapenem-Resistant Enterobacteriaceae) KPC, NDM, OXA-48, etc. Ceftazidime-avibactam (KPC/OXA-48), Meropenem-vaborbactam (KPC), Imipenem-relebactam (KPC), Cefiderocol (all), Plazomicin
MDR Pseudomonas β-lactamase, porin loss, efflux, gyrase Ceftolozane-tazobactam, Ceftazidime-avibactam, Imipenem-relebactam, Cefiderocol, ± aminoglycoside
MDR Acinetobacter OXA, NDM, AmpC Sulbactam-durlobactam (2023), Cefiderocol, Polymyxin B/Colistin, Tigecycline, combination therapy
Stenotrophomonas maltophilia Intrinsic倚重 TMP-SMX (first-line), Levofloxacin, Minocycline, Tigecycline, Cefiderocol
150.1.0.3.3 Mycobacterial MDR
  • MDR-TB: resistance to INH + RIF
  • XDR-TB: + FQ + injectable
  • Treatment: BPaL (bedaquiline + pretomanid + linezolid) 6-month regimen (FDA 2019) — TB Alliance / WHO 2024 first-line
150.1.0.3.4 N. gonorrhoeae XDR
  • Increasing ceftriaxone MIC creep
  • Ceftriaxone 500 mg IM doubled from 250 (2020 CDC)
  • Future drugs: zoliflodacin, gepotidacin (2025), solithromycin (failed FDA but in development)

150.1.0.4 3⃣ Resistance Spread

150.1.0.4.1 Horizontal Gene Transfer (3 ways)
  1. Conjugation: plasmid transfer via pilus (sex pilus) — most clinical relevance; ESBL, CRE, VRE plasmids
  2. Transduction: phage-mediated
  3. Transformation: uptake free DNA
150.1.0.4.2 Mobile Genetic Elements
  • Plasmids: extrachromosomal; carry resistance + virulence
  • Transposons: hop between DNA
  • Integrons: capture gene cassettes
  • Insertion sequences
150.1.0.4.3 Selection Pressure
  • Hospital + community antibiotic use
  • Animal husbandry (60-70% global antibiotic use!)
  • Aquaculture
  • Crops (less commonly)

150.1.0.5 4⃣ Stewardship Strategies

150.1.0.5.1 Core Elements (CDC, WHO)
  1. Leadership commitment
  2. Accountability (ID lead)
  3. Drug expertise (clinical pharmacist)
  4. Action:
    • Empirical → culture-directed within 48-72 hr
    • De-escalation when culture +
    • PCT-guided discontinuation
    • Shorter courses (CAP 5d, intra-abdominal 4d STOP-IT, etc.)
    • Oral switch when stable
    • Formulary restriction (restricted antibiotics require ID approval)
  5. Tracking + Reporting
  6. Education
150.1.0.5.2 Diagnostic Stewardship
  • Avoid unnecessary cultures
  • BioFire / MALDI-TOF → rapid pathogen ID → narrow earlier
  • PCT > 0.5 = bacterial
  • Avoid screening urine in asymptomatic
150.1.0.5.3 Infection Prevention
  • Hand hygiene
  • Contact precautions for CRE, VRE, MRSA
  • Environmental cleaning (sporicidal for C. diff)
  • Universal masking (post-COVID era)
  • Vaccination (HBV, flu, COVID, pneumococcal) — reduces antibiotic demand