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Difficulty: MediumInfectious Disease Mechanisms

A 62-year-old man is hospitalized for the management of urosepsis. Blood and urine cultures obtained on admission grow *Enterobacter cloacae*. Initial susceptibility testing indicates the isolate is susceptible to ceftriaxone, cefepime, and meropenem. The patient is started on intravenous ceftriaxone, and his fever and leukocytosis improve over the next 72 hours. However, on day 5 of hospitalization, he develops recurrent fever, tachycardia, and altered mental status. Repeat blood cultures are drawn and again grow *Enterobacter cloacae*. Susceptibility testing of the new isolate reveals resistance to ceftriaxone, but it remains susceptible to cefepime and meropenem. Which of the following is the most likely molecular mechanism responsible for this patient's treatment failure?

  1. Chromosomal derepression of an inducible cephalosporinaseAnswer
  2. B
    Plasmid-mediated acquisition of an extended-spectrum beta-lactamase
  3. C
    Structural modification of a penicillin-binding protein
  4. D
    Target site mutation of DNA gyrase and topoisomerase IV
  5. E
    Post-transcriptional methylation of the 23S ribosomal RNA

Answer

Chromosomal derepression of an inducible cephalosporinase
The correct answer is chromosomal derepression of an inducible cephalosporinase. Certain Gram-negative bacilli, often remembered by the mnemonic SPICE or SPACE (Serratia, Pseudomonas/Providencia, Acinetobacter, Citrobacter, Enterobacter), possess an inducible chromosomal gene encoding AmpC beta-lactamase. When these organisms cause severe infections, initial susceptibility testing may show them to be sensitive to third-generation cephalosporins like ceftriaxone. However, exposure to these antibiotics exerts selective pressure, leading to the rapid emergence and overgrowth of mutant subpopulations that constitutively hyperproduce the AmpC enzyme (derepression). This results in clinical treatment failure. Importantly, AmpC beta-lactamases strongly hydrolyze third-generation cephalosporins but are weak hydrolyzers of cefepime (a fourth-generation cephalosporin) and carbapenems, which explains why the repeat isolate remained susceptible to cefepime and meropenem.

Step-by-Step Solution

1
Analyze the patient's clinical course and microbiological data.
The patient developed clinical failure on ceftriaxone therapy due to an initially susceptible Enterobacter cloacae isolate that became resistant to ceftriaxone but remained susceptible to cefepime.
Identifying the pattern of emerging resistance is necessary to deduce the underlying molecular mechanism.
2
Correlate the organism and resistance pattern with known mechanisms.
Enterobacter species are known to harbor chromosomal AmpC beta-lactamase genes. Treatment with third-generation cephalosporins (like ceftriaxone) selects for derepressed mutants that hyperproduce AmpC.
AmpC beta-lactamases hydrolyze penicillins and first- through third-generation cephalosporins, but cefepime (a fourth-generation cephalosporin) and carbapenems remain stable against them.

Key Concept

Emergence of AmpC beta-lactamase derepression in SPICE/SPACE organisms during therapy with third-generation cephalosporins.
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Topics

Infectious Disease Mechanisms

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