A 68-year-old man is evaluated in the intensive care unit for a new onset of fever and inc… — USMLE Step 3

A 68-year-old man is evaluated in the intensive care unit for a new onset of fever and increased purulent respiratory secretions. He was admitted $14\text{ days}$ ago for a perforated diverticulum requiring emergency exploratory laparotomy and has been dependent on mechanical ventilation since the procedure. His temperature is $39.1^\circ\text{C}$ ( $102.4^\circ\text{F}$ ), blood pressure is $90/60\text{ mmHg}$ , pulse is $118\text{ beats/min}$ , and respirations are $24\text{/min}$ . Physical examination reveals coarse crackles at the right lung base. A chest radiograph demonstrates a new right lower lobe consolidation. Endotracheal aspirate cultures grow oxidase-positive, non-lactose fermenting, Gram-negative bacilli. The patient is started on intravenous imipenem-cilastatin therapy. Initial susceptibility testing shows the isolate is susceptible to imipenem, meropenem, cefepime, and amikacin. Five days later, the patient develops a recurrent fever and worsening oxygenation. Repeat sputum cultures grow the same organism. However, this time the isolate is reported as resistant to imipenem, while remaining completely susceptible to meropenem, cefepime, and amikacin. Which of the following best describes the molecular mechanism responsible for this pathogen's acquired resistance to the prescribed therapy?

A
Production of a plasmid-mediated zinc-dependent hydrolase
B
Genetic alteration of the active site in cell wall synthesizing enzymes
Downregulation of a specific outer membrane diffusion channelAnswer
D
Upregulation of a membrane-spanning active efflux pump complex
E
Covalent modification of the antimicrobial agent via acetylation

Answer

The mechanism responsible for the acquired isolated imipenem resistance is the downregulation or loss of a specific outer membrane diffusion channel, specifically the OprD porin.

The correct answer identifies the downregulation of a specific outer membrane diffusion channel. The clinical vignette describes a nosocomial ventilator-associated pneumonia caused by Pseudomonas aeruginosa (identified by being an oxidase-positive, non-lactose fermenting Gram-negative bacillus). During treatment with imipenem, the organism developed isolated resistance to this specific drug. Imipenem enters the periplasmic space of P. aeruginosa primarily through a specific outer membrane porin channel known as OprD. Downregulation or mutational loss of this OprD porin is a classic mechanism of rapidly acquired resistance to imipenem during active therapy. Because meropenem and cefepime utilize different or multiple entry pathways and are more heavily influenced by efflux pumps, an isolated loss of OprD typically leaves the organism susceptible to these other beta-lactam agents.

Step-by-Step Solution

Identify the causative organism based on the provided microbiological characteristics.

The organism is an oxidase-positive, non-lactose fermenting, Gram-negative bacillus, which is characteristic of Pseudomonas aeruginosa.

Accurate identification of the pathogen is required to understand its species-specific mechanisms of antibiotic resistance.

Analyze the change in the antimicrobial susceptibility profile during the course of treatment.

The organism developed isolated resistance to imipenem while maintaining full susceptibility to other anti-pseudomonal beta-lactams (meropenem, cefepime) and aminoglycosides (amikacin).

Different antimicrobial agents, even within the same class (like carbapenems), are affected by different resistance mechanisms.

Correlate the specific susceptibility pattern with the corresponding molecular resistance mechanism in P. aeruginosa.

Imipenem relies heavily on the specific outer membrane porin OprD to enter the periplasmic space. Downregulation or loss of OprD causes isolated imipenem resistance.

Meropenem and cefepime are less reliant on OprD for cellular entry, explaining why they remain susceptible despite the acquired resistance to imipenem.

Key Concept

Infection with Pseudomonas aeruginosa can result in the rapid development of isolated imipenem resistance during therapy due to the mutational loss or downregulation of the OprD outer membrane porin channel.

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