2024 IDSA AmpC β-Lactamases治療策略

1. Characteristics of AmpC β-Lactamases

• Function: Assist with cell wall recycling.
• Activity: Hydrolyze β-lactam agents, rendering them ineffective.
• Mechanisms of Increased Production:
  1. Inducible chromosomal expression (e.g., exposure to antibiotics like ceftriaxone induces production).
  2. Stable chromosomal de-repression (mutations leading to constitutive overexpression).
  3. Plasmid-mediated ampC genes (e.g., blaCMY, blaDHA).

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2. Organisms at Risk for Clinically Significant AmpC Production

• Moderate Risk: 約20%在使用抗生素後產生AmpC⇒ 用Cefepime (E. cloacae MICs of 4-8 µg/mL要用高劑量2g q8h over 3hr)
  • Enterobacter cloacae complex.
  • Klebsiella aerogenes. 產氣腸桿菌
  • Citrobacter freundii.
• Lower Risk: <5% 產生AmpC
  • Serratia marcescens.
  • Morganella morganii.
  • Providencia spp.
• Key Considerations:
  • Avoid ceftriaxone, cefotaxime, or ceftazidime for moderate-risk organisms even if initially susceptible.
  • Use AST results for treatment guidance for lower-risk organisms.

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3. Antibiotic Selection

• AmpC Induction Spectrum:
  • Potent Inducers: Aminopenicillins, first-generation cephalosporins, cephamycins.
  • Weak Inducers: Ceftriaxone, cefotaxime, ceftazidime, aztreonam, piperacillin-tazobactam.
  • Resistant to AmpC Hydrolysis: Carbapenems, cefepime.

Key Agents and Roles

1. Cefepime:

   • Preferred for infections caused by E. cloacae, K. aerogenes, and C. freundii.
   • Stable against AmpC hydrolysis and low induction potential.
   • Limitations: Suboptimal against ESBL-producing strains.

2. Carbapenems:

   • Stable against AmpC hydrolysis.
   • Preferred for critically ill patients or when broader resistance is present.

3. Ceftriaxone and Third-Generation Cephalosporins:

   • Not recommended for invasive infections caused by moderate-risk organisms.
   • May be used for uncomplicated cystitis when susceptibility is demonstrated.

4. Piperacillin-Tazobactam:

   • Not recommended for invasive infections due to weak protection by tazobactam.
   • May be considered for mild infections or polymicrobial settings after clinical improvement.

5. Newer β-Lactam-β-Lactamase Inhibitors:

   • Ceftazidime-avibactam, meropenem-vaborbactam, imipenem-cilastatin-relebactam, and cefiderocol should be reserved for carbapenem-resistant organisms.
   • Ceftolozane-tazobactam not suggested for AmpC-E due to limited data and hydrolysis concerns.

6. Non-β-Lactam Antibiotics:

   • Preferred for uncomplicated cystitis:
     • Nitrofurantoin.
     • TMP-SMX.
   • Alternative for uncomplicated cystitis:
     • Ciprofloxacin, levofloxacin, or single-dose aminoglycosides.
   • Preferred for pyelonephritis or complicated UTI (cUTI):
     • TMP-SMX, ciprofloxacin, or levofloxacin.
     • Aminoglycosides as alternatives if resistance/toxicities limit options.
   • For non-urinary infections, transition to oral TMP-SMX or fluoroquinolones when clinically appropriate.

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4. Special Considerations

• Cefepime MICs of 4-8 µg/mL: Require high-dose (2 g every 8 hours) extended infusions.
• Emergence of Resistance:
  • Common with ceftriaxone in moderate-risk organisms (~20% of cases).
  • Monitor for treatment failure and consider alternatives if no clinical improvement.
• Polymicrobial Infections:
  • Ceftolozane-tazobactam can be considered in combination therapy for Pseudomonas aeruginosa and AmpC-E.

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This structured guidance emphasizes tailored antibiotic selection based on organism risk, resistance mechanisms, and infection severity to optimize treatment outcomes and minimize resistance development.