Examkin

Question

Difficulty: MediumInfectious Disease Mechanisms

A 58-year-old man is hospitalized for pyelonephritis and bacteremia. Initial blood cultures grow *Enterobacter cloacae*. Antibiotic susceptibility testing indicates that the isolate is susceptible to ceftriaxone, and therapy with this agent is initiated. The patient initially improves, but on day 5 of hospitalization, he develops recurrent fever, tachycardia, and a rising leukocyte count. Repeat blood cultures grow *Enterobacter cloacae* that is now resistant to ceftriaxone, ceftazidime, and piperacillin-tazobactam, but remains susceptible to meropenem and amikacin. Which of the following best describes the molecular mechanism responsible for the pathogen's new resistance profile?

  1. Derepression of a chromosomal gene encoding an enzyme that hydrolyzes the beta-lactam ringAnswer
  2. B
    Plasmid-mediated acquisition of an extended-spectrum beta-lactamase
  3. C
    Downregulation of outer membrane porin channel expression
  4. D
    Structural alteration of penicillin-binding proteins via horizontal gene transfer
  5. E
    Enzymatic modification of the antibiotic via an acetyltransferase

Answer

Derepression of a chromosomal gene encoding an enzyme that hydrolyzes the beta-lactam ring
The correct answer describes the derepression of the chromosomal AmpC beta-lactamase gene. Certain Gram-negative bacilli, often remembered by the mnemonic 'SPACE' or 'ESPM' (Enterobacter, Serratia, Pseudomonas, Morganella), harbor an inducible, chromosomal AmpC beta-lactamase gene. When these organisms are exposed to certain beta-lactam antibiotics like ceftriaxone, a mutant subpopulation that constitutively hyperproduces (derepresses) the AmpC enzyme is selected for. This results in clinical failure and widespread beta-lactam resistance, including resistance to third-generation cephalosporins and beta-lactamase inhibitors like piperacillin-tazobactam. Carbapenems, such as meropenem, are stable against AmpC hydrolysis and remain the treatment of choice for severe infections with these organisms.

Step-by-Step Solution

1
Analyze the clinical scenario and microbiology data
The patient has an Enterobacter cloacae infection that developed rapid resistance to 3rd-generation cephalosporins and beta-lactamase inhibitors while on ceftriaxone therapy, but retained susceptibility to carbapenems.
To identify the typical resistance pattern of the isolated organism.
2
Identify the primary resistance mechanism of the organism
Enterobacter cloacae has an inducible, chromosomally mediated AmpC beta-lactamase.
Matching the pathogen to its intrinsic genetic resistance capabilities.
3
Correlate the mechanism with the clinical presentation
Exposure to ceftriaxone selected for a derepressed mutant subpopulation that constitutively hyperproduces AmpC, explaining the new resistance to ceftriaxone and piperacillin-tazobactam.
To confirm that the resistance mechanism aligns with the drug susceptibilities provided.

Key Concept

Organisms with inducible chromosomal AmpC beta-lactamases (such as Enterobacter, Serratia, and Citrobacter) can rapidly develop resistance to third-generation cephalosporins during therapy due to derepression of the AmpC gene.
Rate this question

Topics

Infectious Disease Mechanisms

More questions from this topic