A 62-year-old woman is evaluated on the inpatient medical ward for sudden clinical deterio… — USMLE Step 3

A 62-year-old woman is evaluated on the inpatient medical ward for sudden clinical deterioration. She was admitted 4 days ago for a complicated urinary tract infection presenting with fever, right-sided flank pain, and dysuria. Initial urine cultures grew lactose-fermenting, indole-negative Gram-negative rods. Susceptibility testing demonstrated that the isolate was susceptible to ceftriaxone, cefepime, ciprofloxacin, and meropenem. She was started on intravenous ceftriaxone and initially showed clinical improvement, becoming afebrile by day 2. Today, she has developed recurrent chills and flank pain. Her temperature is $39.0^\circ\text{C}$ ( $102.2^\circ\text{F}$ ), blood pressure is $90/55\text{ mmHg}$ , and pulse is $112/\text{min}$ . Repeat blood and urine cultures are drawn and subsequently grow the same organism. Susceptibility testing of the new isolate reveals resistance to ceftriaxone, but retained susceptibility to cefepime, ciprofloxacin, and meropenem. Which of the following molecular mechanisms most likely explains this pathogen's acquired resistance to the current antimicrobial therapy?

Selection of a mutant strain with stably derepressed chromosomal beta-lactamase productionCevap
B
Acquisition of a plasmid encoding an extended-spectrum beta-lactamase enzyme
C
Downregulation of outer membrane porin channels restricting antibiotic entry
D
Expression of an altered penicillin-binding protein with decreased drug affinity
E
Upregulation of energy-dependent efflux pumps actively clearing the antibiotic

Cevap

Selection of a mutant strain with stably derepressed chromosomal beta-lactamase production

The patient is infected with a likely Enterobacter species (lactose-fermenting, indole-negative), which is a member of the SPICE/SPACE group of organisms (Serratia, Pseudomonas/Providencia, Acinetobacter/Morganella, Citrobacter, Enterobacter). These organisms characteristically possess an inducible, chromosomal ampC gene. When initially tested, the wild-type population produces low levels of the AmpC enzyme and appears susceptible to third-generation cephalosporins. However, treatment with a beta-lactam antibiotic such as ceftriaxone exerts a strong selective pressure. While the majority of the bacteria are eradicated, a small preexisting subpopulation with a mutation in the AmpC regulatory genes (typically ampD) survives. These mutants are 'stably derepressed,' meaning they continuously hyperproduce AmpC beta-lactamase regardless of inducer presence. This enzyme efficiently hydrolyzes ceftriaxone, leading to treatment failure. Importantly, AmpC beta-lactamases have low affinity for fourth-generation cephalosporins (cefepime) and carbapenems, which explains why the isolate remains susceptible to these agents.

Adım Adım Çözüm

Identify the likely pathogen based on microbiologic characteristics.

The organism is a lactose-fermenting, indole-negative Gram-negative rod, highly suggestive of Enterobacter cloacae or a closely related species (SPICE/SPACE organisms).

Recognizing the organism class is essential to anticipating its intrinsic resistance mechanisms.

Analyze the change in the susceptibility profile during treatment.

The pathogen initially appeared susceptible to ceftriaxone, but rapidly developed resistance to it while remaining susceptible to cefepime (a fourth-generation cephalosporin) and meropenem.

This specific pattern of resistance emerging during therapy with a third-generation cephalosporin is a classic hallmark of a specific molecular mechanism.

Determine the molecular mechanism underlying this susceptibility pattern.

Organisms with an inducible chromosomal ampC gene can undergo selection during beta-lactam therapy. The antibiotic kills the susceptible wild-type population, leaving behind a spontaneously mutated subpopulation that is 'stably derepressed' (hyperproducing AmpC beta-lactamase).

AmpC beta-lactamases readily hydrolyze first-, second-, and third-generation cephalosporins (like ceftriaxone) but have very low affinity for fourth-generation cephalosporins (like cefepime) and carbapenems.

Anahtar Kavram

Organisms with inducible chromosomal AmpC beta-lactamases (e.g., Enterobacter, Serratia, Citrobacter) can develop rapid clinical resistance to third-generation cephalosporins via the selection of stably derepressed mutant subpopulations that hyperproduce the enzyme. Cefepime and carbapenems typically remain effective.

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