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Difficulty: Very hardInfectious Disease Mechanisms

A 68-year-old man is admitted to the hospital with a 3-week history of low-grade fevers, chills, and generalized fatigue. He recently underwent a cystoscopy for benign prostatic hyperplasia. On physical examination, his temperature is 38.2°C (100.8°F), and a new holosystolic murmur is heard at the cardiac apex. Blood cultures grow gram-positive cocci in pairs and short chains that are catalase-negative and grow in 6.5% NaCl broth. Transesophageal echocardiography reveals a 1.2-cm vegetation on the mitral valve.

The patient is started on continuous-infusion ampicillin and once-daily gentamicin to achieve synergistic bactericidal activity. Two days later, antimicrobial susceptibility testing results are reported as follows:

Antimicrobial AgentMIC (mcg/mL)Interpretation
Ampicillin2Susceptible
Vancomycin1Susceptible
Gentamicin>500High-level resistance
Streptomycin64Susceptible to synergy

Given these results, gentamicin is discontinued, and ceftriaxone is added to the ampicillin regimen. Which of the following best describes the precise molecular mechanism responsible for the lack of ampicillin-gentamicin synergy in this patient's isolate?

  1. Enzymatic transfer of functional groups to the hydroxyl or amino moieties of the drugAnswer
  2. B
    Amino acid substitution in a ribosomal protein altering the 30S subunit binding site
  3. C
    Enzymatic reprogramming of peptidoglycan precursors terminating in D-lactate
  4. D
    Chromosomal mutation resulting in the overproduction of low-affinity transpeptidases
  5. E
    Downregulation of outer membrane porin channels preventing intracellular accumulation

Answer

The correct mechanism is the enzymatic transfer of functional groups to the hydroxyl or amino moieties of the drug.
The patient has infective endocarditis caused by Enterococcus species. Enterococci possess intrinsic low-level resistance to aminoglycosides due to poor drug penetration across the cell wall. Combining a cell-wall active agent (ampicillin) with an aminoglycoside (gentamicin) allows the aminoglycoside to enter the cell, resulting in bactericidal synergy. However, if the isolate acquires high-level gentamicin resistance (MIC > 500 mcg/mL), synergy is abolished. In enterococci, high-level gentamicin resistance is almost exclusively mediated by the acquisition of mobile genetic elements encoding aminoglycoside-modifying enzymes (AMEs), such as the bifunctional AAC(6')-Ie-APH(2'')-Ia enzyme. These enzymes covalently transfer acetyl, phosphoryl, or adenylyl groups to the amino or hydroxyl moieties of the aminoglycoside, preventing the drug from binding to its target on the 30S ribosomal subunit. Without synergy, an alternative dual beta-lactam bactericidal regimen (such as ampicillin plus ceftriaxone) must be used.

Step-by-Step Solution

1
Identify the causative pathogen from the clinical and microbiologic description.
The organism is Enterococcus faecalis.
Gram-positive cocci in chains that are catalase-negative and capable of growth in 6.5% NaCl broth are classic laboratory characteristics of enterococci.
2
Analyze the provided minimum inhibitory concentration (MIC) profile.
The isolate is susceptible to ampicillin and vancomycin but exhibits high-level resistance to gentamicin (MIC > 500 mcg/mL) while remaining susceptible to streptomycin synergy (MIC < 1000 mcg/mL).
Understanding the susceptibility profile is required to determine why the initial ampicillin-gentamicin synergy failed.
3
Deduce the molecular mechanism of high-level gentamicin resistance in enterococci.
High-level gentamicin resistance is almost exclusively caused by the acquisition of aminoglycoside-modifying enzymes (AMEs).
Unlike intrinsic low-level resistance (poor cell wall penetration) which is overcome by ampicillin, acquired high-level resistance abolishes synergy.
4
Differentiate gentamicin resistance from streptomycin resistance mechanisms.
Ribosomal target site mutations cause high-level streptomycin resistance, but do not affect gentamicin. Because this isolate is resistant only to gentamicin, AMEs (which covalently modify the drug) must be the responsible mechanism.
Distinguishing between specific aminoglycoside resistance mechanisms is necessary to rule out the distractor involving the 30S ribosomal subunit.

Key Concept

High-level gentamicin resistance in Enterococcus species is primarily mediated by acquired aminoglycoside-modifying enzymes that covalently alter the drug structure, thereby abolishing the bactericidal synergy normally achieved by combining a cell-wall active agent with an aminoglycoside.
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Topics

Infectious Disease Mechanisms

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