A 68-year-old man is hospitalized for management of infective endocarditis involving a pro… — USMLE Step 3

A 68-year-old man is hospitalized for management of infective endocarditis involving a prosthetic aortic valve. Blood cultures drawn on admission grow methicillin-resistant *Staphylococcus aureus* (MRSA). He is started on intravenous vancomycin, and subsequent trough levels are maintained consistently between $15$ and $20 \mu\text{g/mL}$ . The patient's clinical status improves, and repeat blood cultures on day $4$ are sterile. However, on day $18$ of hospitalization, he develops a new fever of $38.9^\circ\text{C}$ ( $102.0^\circ\text{F}$ ) and worsening fatigue. Repeat blood cultures again grow MRSA. Susceptibility testing of the new bacterial isolate reveals a vancomycin minimum inhibitory concentration (MIC) of $4 \mu\text{g/mL}$ , compared to an initial MIC of $1 \mu\text{g/mL}$ . Which of the following best describes the molecular mechanism responsible for this pathogen's reduced susceptibility to the current therapy?

Synthesis of an abnormally thick peptidoglycan wall containing excessive target binding sitesAnswer
B
Plasmid-mediated substitution of the terminal peptide precursor to D-alanyl-D-lactate
C
Chromosomal expression of a novel transpeptidase with reduced affinity for the drug
D
Acquisition of a gene cluster encoding a transmembrane antibiotic efflux pump
E
Production of an extracellular modifying enzyme that cleaves the drug's cyclic peptide structure

Answer

Synthesis of an abnormally thick peptidoglycan wall containing excessive target binding sites

The correct answer identifies the mechanism for Vancomycin-Intermediate Staphylococcus aureus (VISA). VISA typically emerges in patients receiving prolonged vancomycin therapy (such as for endocarditis or osteomyelitis) and is characterized by a gradual increase in the minimum inhibitory concentration (MIC), known as 'MIC creep.' An MIC of

4

8 \mu\text{g/mL}

defines VISA. The underlying pathophysiology involves spontaneous point mutations that alter cell wall metabolism, leading to the synthesis of an exceptionally thick peptidoglycan layer. This hyper-thickened wall contains a vast excess of D-alanyl-D-alanine terminal residues. These residues act as 'decoys' or a sponge, binding vancomycin molecules in the outer layers of the cell wall. Consequently, the drug becomes physically trapped and cannot penetrate deeply enough to reach the critically located cell membrane precursors where it normally exerts its inhibitory effect on cross-linking.

Step-by-Step Solution

Analyze the clinical scenario and the change in microbiological data.

A patient with MRSA endocarditis initially responding to vancomycin develops recurrent bacteremia. The MRSA isolate's vancomycin MIC has increased from

1 \mu\text{g/mL}

4 \mu\text{g/mL}

Identifying the shift in the MIC is crucial for diagnosing the specific type of antimicrobial resistance that has emerged during therapy.

Interpret the new vancomycin MIC value.

An MIC of

4 \mu\text{g/mL}

for Staphylococcus aureus indicates Vancomycin-Intermediate S. aureus (VISA). (Susceptible is <=

2 \mu\text{g/mL}

, Intermediate is

4-8 \mu\text{g/mL}

, Resistant is >=

16 \mu\text{g/mL}

Differentiating between intermediate and high-level resistance dictates the specific molecular mechanism involved.

Determine the molecular mechanism underlying VISA.

VISA emerges through stepwise chromosomal mutations that result in a markedly thickened peptidoglycan cell wall.

This thick wall contains abundant D-alanyl-D-alanine residues that act as false targets, trapping vancomycin in the outer cell wall and preventing it from reaching the critically located targets at the cytoplasmic membrane.

Key Concept

Vancomycin-Intermediate Staphylococcus aureus (VISA) resistance mechanism

Estimated Time:1m 30s

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