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Zorluk: ZorInfectious Disease Mechanisms

A 68-year-old man is hospitalized due to a 3-week history of low-grade fever, severe fatigue, and night sweats. His temperature is 38.2°C (100.8°F), blood pressure is 118/74 mm Hg, and pulse is 96/min. Physical examination reveals a new III/VI holosystolic murmur best heard at the cardiac apex and radiating to the axilla. Echocardiography demonstrates a 1.2-cm mobile vegetation on the anterior leaflet of the mitral valve.

Four sets of blood cultures obtained prior to antibiotic administration grow *Enterococcus faecalis*. The patient is initiated on intravenous ampicillin and gentamicin. On hospital day 5, his blood cultures remain positive, and susceptibility testing results are reported as follows:

AntimicrobialMinimum Inhibitory Concentration (MIC)Interpretation
Ampicillin1 mcg/mLSusceptible
Vancomycin2 mcg/mLSusceptible
Gentamicin> 500 mcg/mLHigh-level Resistance
Streptomycin128 mcg/mLSusceptible

Due to the lack of anticipated synergistic bactericidal activity, the infectious disease service recommends discontinuing gentamicin and switching to intravenous ceftriaxone to be used in combination with ampicillin.

Which of the following best describes the molecular mechanism responsible for this pathogen's resistance to the initial adjunctive antimicrobial agent?

  1. Covalent attachment of functional groups to the antimicrobial moleculeCevap
  2. B
    Substitution of a terminal amino acid in the peptidoglycan precursor
  3. C
    Post-transcriptional methylation of the ribosomal RNA binding site
  4. D
    Downregulation of outer membrane channel proteins
  5. E
    Expression of energy-dependent transmembrane transport proteins

Cevap

The correct answer is the covalent attachment of functional groups to the antimicrobial molecule, mediated by aminoglycoside-modifying enzymes.
The patient has Enterococcus faecalis infective endocarditis. Native valve enterococcal endocarditis is traditionally treated with a synergistic combination of a cell-wall active agent (e.g., ampicillin) and an aminoglycoside (e.g., gentamicin). Enterococci are intrinsically resistant to low levels of aminoglycosides due to poor drug penetration across their thick peptidoglycan cell wall. Cell-wall active agents facilitate aminoglycoside entry, allowing binding to the 30S ribosomal subunit and resulting in bactericidal activity. However, high-level aminoglycoside resistance (HLAR) abolishes this synergy. The most common mechanism for high-level gentamicin resistance in enterococci is the acquisition of plasmid-mediated aminoglycoside-modifying enzymes (AMEs). The bifunctional enzyme AAC(6')-Ie-APH(2'')-Ia catalyzes the covalent attachment of acetyl and phosphoryl groups to multiple sites on the gentamicin molecule. This modification structurally alters the drug, preventing it from binding to the 16S rRNA of the 30S ribosomal subunit.

Adım Adım Çözüm

1
Identify the infecting organism and its standard initial treatment.
The pathogen is Enterococcus faecalis causing endocarditis. Standard initial empiric therapy often utilizes a cell-wall active agent (ampicillin) plus an aminoglycoside (gentamicin) for synergistic bactericidal effect.
Establishing the baseline therapeutic requirement and identifying the adjunctive agent in question (gentamicin).
2
Analyze the susceptibility testing results provided in the vignette.
The isolate demonstrates a minimum inhibitory concentration (MIC) > 500 mcg/mL for gentamicin, indicating High-Level Aminoglycoside Resistance (HLAR).
To determine why the initial adjunctive therapy failed to provide synergy and clear the bacteremia.
3
Determine the molecular mechanism of this specific resistance.
HLAR to gentamicin in enterococci is primarily mediated by the acquisition of aminoglycoside-modifying enzymes (AMEs), which covalently attach acetyl, phosphoryl, or adenyl groups to the drug.
Connecting the phenotypic resistance pattern to its precise molecular and genotypic basis.

Anahtar Kavram

High-level aminoglycoside resistance (HLAR) in Enterococcus species is predominantly mediated by plasmid-encoded aminoglycoside-modifying enzymes (AMEs) that covalently alter the antimicrobial molecule, preventing ribosomal binding and abolishing drug synergy.
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Infectious Disease Mechanisms

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