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Difficulty: MediumInfectious Disease Mechanisms

A 67-year-old man is hospitalized in the intensive care unit for ventilator-associated pneumonia. Initial endotracheal aspirate cultures grow *Pseudomonas aeruginosa* that is susceptible to piperacillin-tazobactam, cefepime, ciprofloxacin, and imipenem. The patient is started on intravenous imipenem-cilastatin. He initially improves, but on day 11 of hospitalization, his respiratory status declines, and he requires an increase in ventilator support. His temperature is 38.9°C (102°F), blood pressure is 100/60 mm Hg, and pulse is 110/min. A repeat endotracheal aspirate culture again grows *Pseudomonas aeruginosa*. Susceptibility testing of the new isolate reveals resistance to imipenem, but continued susceptibility to cefepime, piperacillin-tazobactam, and ciprofloxacin. Which of the following is the most likely mechanism for the rapid emergence of antimicrobial resistance in this patient's infection?

  1. Decreased expression of an outer membrane channel proteinAnswer
  2. B
    Upregulation of a membrane-bound multidrug efflux pump
  3. C
    Derepression of a chromosomal AmpC beta-lactamase
  4. D
    Conformational alteration of a penicillin-binding protein
  5. E
    Acquisition of a plasmid encoding a metallo-beta-lactamase

Answer

Decreased expression of an outer membrane channel protein
The correct answer identifies that Pseudomonas aeruginosa can rapidly develop selective resistance to imipenem during therapy via the transcriptional downregulation or mutational loss of the outer membrane porin OprD. Because imipenem relies heavily on this specific channel to cross the outer membrane into the periplasmic space, loss of OprD confers imipenem resistance. However, this mechanism leaves the organism susceptible to other classes of antibiotics (such as fluoroquinolones) and other beta-lactams (like cefepime and piperacillin-tazobactam) that do not require OprD for entry.

Step-by-Step Solution

1
Analyze the susceptibility profile of the initial and repeat cultures.
The initial isolate was fully susceptible. The repeat isolate shows isolated resistance to imipenem, while remaining susceptible to other beta-lactams (cefepime, piperacillin-tazobactam) and fluoroquinolones (ciprofloxacin).
Identifying the specific pattern of acquired resistance is necessary to deduce the underlying molecular mechanism.
2
Correlate the isolated imipenem resistance with known mechanisms in Pseudomonas aeruginosa.
Imipenem specifically requires the OprD outer membrane porin to enter the periplasmic space of Pseudomonas aeruginosa.
Different antibiotics utilize different entry pathways or targets, leading to distinct resistance phenotypes when those pathways are altered.
3
Differentiate porin loss from other resistance mechanisms.
Loss of OprD explains the selective imipenem resistance, whereas efflux pumps or metallo-beta-lactamases would confer broader multi-drug resistance.
Ruling out broader mechanisms confirms that outer membrane channel modification is the most accurate explanation.

Key Concept

The primary mechanism for isolated imipenem resistance in Pseudomonas aeruginosa is the loss or decreased expression of the OprD outer membrane porin.
Estimated Time:1m 30s
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Topics

Infectious Disease Mechanisms

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