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Difficulty: HardInfectious Disease Mechanisms

A 68-year-old woman is evaluated in the intensive care unit for a new-onset fever and increased oxygen requirements. She was admitted 12 days ago for severe acute pancreatitis and was intubated on day 3 due to acute respiratory distress syndrome. Her temperature is 38.9°C (102°F), blood pressure is 105/65 mm Hg, and pulse is 112/min. Physical examination reveals coarse crackles at the right lung base. A chest radiograph shows a new right lower lobe infiltrate. Endotracheal aspirate cultures grow oxidase-positive, non-lactose fermenting Gram-negative bacilli. The isolate is initially reported as susceptible to cefepime, piperacillin-tazobactam, and imipenem. She is started on empiric intravenous imipenem-cilastatin. Five days later, her clinical condition deteriorates. Repeat respiratory cultures grow the same organism, but susceptibility testing now demonstrates resistance to imipenem; the isolate remains susceptible to cefepime and piperacillin-tazobactam. Which of the following is the most likely molecular mechanism underlying this pathogen's acquired resistance?

  1. Mutational loss of a specific outer membrane channel proteinAnswer
  2. B
    Chromosomal derepression of an inducible cephalosporinase
  3. C
    Horizontal acquisition of a plasmid-encoded metallo-beta-lactamase
  4. D
    Upregulation of a multidrug active efflux pump system
  5. E
    Inactivation of the antimicrobial agent by concurrent administration of cilastatin

Answer

Mutational loss of a specific outer membrane channel protein
The clinical vignette describes a patient with ventilator-associated pneumonia caused by Pseudomonas aeruginosa (an oxidase-positive, non-lactose fermenting Gram-negative bacillus). The pathogen initially responded to empiric imipenem-cilastatin but subsequently developed isolated resistance to imipenem while remaining susceptible to other antipseudomonal beta-lactams (cefepime and piperacillin-tazobactam). Imipenem requires a specific outer membrane channel protein, the OprD porin, to penetrate the Pseudomonas cell envelope. During treatment with imipenem, P. aeruginosa frequently undergoes mutational loss or downregulation of this OprD porin. Because cefepime and piperacillin-tazobactam utilize different porins and entry pathways, the selective loss of OprD confers isolated resistance to imipenem without affecting the organism's susceptibility to these other beta-lactam agents.

Step-by-Step Solution

1
Identify the infecting pathogen from the microbiologic description.
The organism is an oxidase-positive, non-lactose fermenting Gram-negative bacillus, which is characteristic of Pseudomonas aeruginosa.
Establishing the specific pathogen is required to understand its unique mechanisms of acquiring antimicrobial resistance.
2
Analyze the susceptibility profile change.
The organism developed isolated resistance to imipenem while remaining fully susceptible to cefepime and piperacillin-tazobactam.
Different resistance mechanisms create distinct phenotypic susceptibility patterns (antibiograms).
3
Correlate the acquired susceptibility pattern with the correct molecular mechanism.
Isolated imipenem resistance in Pseudomonas aeruginosa is almost exclusively caused by the mutational loss or downregulation of the OprD outer membrane porin.
Imipenem uniquely relies on the OprD porin to cross the outer membrane, whereas other beta-lactams utilize different entry pathways.

Key Concept

Molecular mechanisms of selective antimicrobial resistance in Pseudomonas aeruginosa
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Topics

Infectious Disease Mechanisms

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