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Difficulty: MediumInfectious Disease Mechanisms

A 58-year-old man is hospitalized in the intensive care unit for the management of severe necrotizing pancreatitis. On hospital day 14, he develops new-onset fever, copious purulent endotracheal secretions, and worsening hypoxemia. He is intubated and requires mechanical ventilation. A Gram stain of the endotracheal aspirate reveals numerous polymorphonuclear leukocytes and Gram-negative bacilli. The culture grows a strictly aerobic, oxidase-positive organism. Susceptibility testing demonstrates that the isolate is highly susceptible to imipenem, cefepime, ciprofloxacin, and tobramycin. The patient is started on intravenous imipenem. After 10 days of therapy, his respiratory status declines again. A repeat endotracheal culture grows the same organism, but a new susceptibility panel reveals resistance to imipenem, while remaining susceptible to cefepime, ciprofloxacin, and tobramycin. Which of the following molecular mechanisms best explains the newly acquired antimicrobial resistance profile in this patient's isolate?

  1. Downregulation of an outer membrane porin channelAnswer
  2. B
    Acquisition of a plasmid encoding a metallo-beta-lactamase
  3. C
    Upregulation of active transmembrane drug efflux pumps
  4. D
    Structural alteration of target penicillin-binding proteins
  5. E
    Enzymatic modification of the antimicrobial via acetylation

Answer

Downregulation of an outer membrane porin channel
The patient's clinical presentation and microbiologic data (strictly aerobic, oxidase-positive, Gram-negative bacillus) indicate an infection with Pseudomonas aeruginosa. The isolate initially tested susceptible to imipenem but developed isolated resistance to this drug over the course of therapy. In P. aeruginosa, imipenem relies heavily on a specific outer membrane channel, the OprD porin, to enter the periplasmic space and reach its target penicillin-binding proteins. When Pseudomonas is exposed to carbapenems, it frequently undergoes mutations that downregulate or completely halt the expression of the OprD porin. Because other antibiotics (like cefepime, ciprofloxacin, and tobramycin) enter the cell via different pathways or channels, the loss of OprD creates an isolated resistance solely to carbapenems (especially imipenem).

Step-by-Step Solution

1
Identify the infecting organism based on microbiologic characteristics.
The organism is a strictly aerobic, oxidase-positive, non-fermenting Gram-negative bacillus causing a hospital-acquired infection, which is characteristic of Pseudomonas aeruginosa.
Identifying the pathogen is required to understand its specific characteristic mechanisms of antimicrobial resistance.
2
Analyze the change in the antimicrobial susceptibility profile.
The organism developed isolated resistance to imipenem (a carbapenem) while retaining susceptibility to cefepime (a 4th generation cephalosporin), ciprofloxacin (a fluoroquinolone), and tobramycin (an aminoglycoside).
Different resistance mutations yield distinct susceptibility profiles. Narrowing down which drugs are affected pinpoints the underlying molecular change.
3
Correlate the isolated imipenem resistance with Pseudomonas aeruginosa resistance mechanisms.
Isolated carbapenem resistance in P. aeruginosa developing during therapy is classically mediated by the loss or downregulation of the OprD outer membrane porin.
Imipenem uniquely relies on the OprD porin for entry into the periplasmic space of P. aeruginosa. Loss of this channel confers resistance to imipenem without affecting drugs that use other entry mechanisms.

Key Concept

The mutational loss or downregulation of the OprD outer membrane porin channel is a classic mechanism by which Pseudomonas aeruginosa develops isolated resistance to carbapenems (particularly imipenem) during therapy.
Estimated Time:1m 30s
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Topics

Infectious Disease Mechanisms

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