Multi-drug resistant gram-negatives

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MDR Gram-Negatives - The Usual Suspects

  • Key Pathogens (SPACE-E):

    • Serratia
    • Pseudomonas aeruginosa
    • Acinetobacter baumannii
    • Citrobacter
    • Enterobacter spp.
    • Escherichia coli (not traditionally SPACE, but a major MDR threat)
    • Klebsiella pneumoniae
  • Primary Resistance Mechanisms:

    • Enzymatic Degradation: Extended-spectrum β-lactamases (ESBLs) & Carbapenemases (KPC, NDM, OXA).
    • Efflux Pumps: Multi-drug efflux systems (e.g., MexAB-OprM in Pseudomonas).
    • Target Modification/Protection: e.g., Porin loss to block antibiotic entry.

⭐ Carbapenem-resistant Enterobacteriaceae (CRE) infections can have mortality rates approaching 50%. Resistance is often carried on mobile genetic elements (plasmids), facilitating rapid spread.

Resistance Mechanisms - Their Bag of Tricks

  • Enzymatic Degradation: Bacteria produce enzymes that destroy the antibiotic.
    • β-Lactamases: The most common mechanism against β-lactam antibiotics.
      • ESBLs (Extended-Spectrum β-Lactamases): Inactivate most penicillins & cephalosporins.
      • AmpC β-Lactamases: Chromosomally inducible or plasmid-mediated; resist cephamycins.
      • Carbapenemases: Degrade carbapenems, the last-resort antibiotics (e.g., KPC, NDM-1, OXA).
  • Target Site Modification: Altering the drug's binding site reduces its efficacy.
    • Examples: Changes in Penicillin-Binding Proteins (PBPs) → Methicillin resistance (MRSA).
  • Reduced Permeability & Active Efflux:
    • Porin Channel Loss: Decreased entry of antibiotics into the bacterial cell.
    • Efflux Pumps: Actively pump the antibiotic out of the cell (e.g., TetA for tetracycline).

High-Yield: Carbapenemase genes are often located on plasmids, facilitating rapid horizontal transfer between different bacterial species and leading to widespread resistance.

📌 Mnemonic: Remember the core mechanisms with "E.A.T."

  • Enzymatic degradation
  • Altered target site
  • Transport (reduced permeability/efflux)

Gram-negative bacterial resistance mechanisms

Treatment Strategies - The Big Guns

  • Core Principle: Use newer agents based on resistance mechanism, often requiring combination therapy.
  • Last-Resort Agents (High Toxicity):

    • Polymyxins (Colistin, Polymyxin B): High rates of nephrotoxicity and neurotoxicity. Used when other options are exhausted.
    • Tigecycline: Broad spectrum, but bacteriostatic. ⚠️ Increased mortality (black box warning); poor choice for bacteremia.
  • Other Key Agents:

    • Cefiderocol: Siderophore cephalosporin; active against many CRE, including MBLs.
    • Eravacycline, Omadacycline: Newer tetracyclines with activity against some resistant strains.

High-Yield: For severe CRE infections, especially those caused by metallo-β-lactamases (MBLs), combination therapy (e.g., ceftazidime-avibactam plus aztreonam) is often required as single agents may be ineffective.

High‑Yield Points - ⚡ Biggest Takeaways

  • MDR gram-negatives are a major threat in healthcare settings, causing high-mortality infections like HAP/VAP and sepsis.
  • Key pathogens: CRE (Carbapenem-resistant Enterobacteriaceae), MDR Pseudomonas, and Acinetobacter baumannii.
  • Primary resistance mechanism: beta-lactamase enzymes (e.g., ESBLs, KPCs) that destroy most beta-lactam antibiotics.
  • Resistance genes are typically on plasmids, allowing for rapid horizontal gene transfer between different bacterial species.
  • Treatment often requires last-resort drugs like colistin, tigecycline, or newer beta-lactamase inhibitor combinations.

Practice Questions: Multi-drug resistant gram-negatives

Test your understanding with these related questions

A 37-year-old woman with a history of anorectal abscesses complains of pain in the perianal region. Physical examination reveals mild swelling, tenderness, and erythema of the perianal skin. She is prescribed oral ampicillin and asked to return for follow-up. Two days later, the patient presents with a high-grade fever, syncope, and increased swelling. Which of the following would be the most common mechanism of resistance leading to the failure of antibiotic therapy in this patient?

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Flashcards: Multi-drug resistant gram-negatives

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_____ is a -lactamase producing bacteria resistant to penicillin.

TAP TO REVEAL ANSWER

_____ is a -lactamase producing bacteria resistant to penicillin.

Staph aureus

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