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Difficulty: HardInfectious Disease Mechanisms

A 54-year-old woman with acute myeloid leukemia develops a fever of 39.2∘C39.2^\circ\text{C} (102.6∘F102.6^\circ\text{F}) and profound neutropenia 1010 days after receiving induction chemotherapy. Blood cultures are drawn and subsequently grow an oxidase-positive, non-lactose fermenting Gram-negative bacillus. Initial antimicrobial susceptibility testing demonstrates that the isolate is susceptible to cefepime, imipenem, and amikacin. She is initiated on intravenous imipenem-cilastatin, and her fever resolves within 4848 hours. On day 1111 of antimicrobial therapy, she develops recurrent fevers, chills, and hypotension. Repeat blood cultures grow the same organism. However, the new isolate demonstrates high-level resistance to imipenem while remaining fully susceptible to both cefepime and amikacin. Which of the following is the most likely molecular mechanism responsible for this pathogen's new resistance profile?

  1. Decreased expression of an outer membrane channel proteinAnswer
  2. B
    Upregulation of a membrane-spanning active transport complex
  3. C
    Acquisition of a zinc-dependent hydrolytic enzyme
  4. D
    Structural modification of a transpeptidase target
  5. E
    Covalent modification of the antimicrobial via adenylation

Answer

Decreased expression of an outer membrane channel protein
The clinical vignette describes a patient with neutropenic fever caused by Pseudomonas aeruginosa (an oxidase-positive, non-lactose fermenting Gram-negative rod) that develops isolated resistance to imipenem during therapy. Imipenem and other carbapenems must pass through the outer membrane of Gram-negative bacteria to reach their target penicillin-binding proteins (PBPs) in the periplasmic space. In P. aeruginosa, imipenem relies almost exclusively on a specific outer membrane porin channel known as OprD for this entry. A well-recognized and classic mechanism by which P. aeruginosa develops rapid, isolated resistance to imipenem during clinical treatment is the mutational loss or decreased expression of this OprD porin. Because other beta-lactam antibiotics, such as cefepime, do not rely heavily on the OprD porin for cell entry, the organism remains fully susceptible to them.

Step-by-Step Solution

1
Identify the underlying pathogen from the microbiological data.
The organism is Pseudomonas aeruginosa (an oxidase-positive, non-lactose fermenting Gram-negative bacillus common in neutropenic patients).
Accurate identification is required to contextualize the organism's unique intrinsic and acquired resistance mechanisms.
2
Analyze the change in the antimicrobial susceptibility profile.
The initial isolate was susceptible to imipenem, cefepime, and amikacin. The subsequent isolate developed isolated resistance to imipenem but remained susceptible to cefepime and amikacin.
The differential susceptibility pattern (loss of carbapenem activity with retained anti-pseudomonal cephalosporin activity) points to a highly specific mechanism rather than broad-spectrum enzymatic degradation.
3
Correlate the susceptibility profile with known molecular mechanisms of resistance in P. aeruginosa.
Imipenem crosses the outer membrane of P. aeruginosa primarily via the OprD porin. Downregulation or mutational loss of this channel protein prevents imipenem entry, causing resistance, while sparing other beta-lactams that use different pathways.
This establishes decreased expression of an outer membrane channel protein as the precise cause of the observed clinical phenomenon.

Key Concept

In Pseudomonas aeruginosa, the emergence of isolated resistance to imipenem during active therapy is classically due to mutational loss or downregulation of the OprD outer membrane porin.
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Topics

Infectious Disease Mechanisms

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