A 48-year-old woman with a history of injection drug use is admitted to the hospital with … — USMLE Step 3

A 48-year-old woman with a history of injection drug use is admitted to the hospital with high fevers, chills, and pleuritic chest pain. Blood cultures drawn on admission grow methicillin-resistant *Staphylococcus aureus* (MRSA). A transesophageal echocardiogram reveals a $1.6 \text{ cm}$ mobile vegetation on the tricuspid valve. Intravenous vancomycin therapy is initiated. On hospital day 5, the patient's serum creatinine increases from a baseline of $0.7 \text{ mg/dL}$ to $2.2 \text{ mg/dL}$ . Due to concern for vancomycin-induced nephrotoxicity, her antimicrobial regimen is switched to intravenous daptomycin. The patient initially defervesces and improves, but $12$ days later, she develops recurrent fevers and bacteremia. Susceptibility testing of the new isolate demonstrates a daptomycin minimum inhibitory concentration (MIC) of $4.0 \text{ } \mu\text{g/mL}$ , indicating resistance. Which of the following best describes the molecular mechanism responsible for this pathogen's newly acquired resistance to the current antimicrobial therapy?

Increased incorporation of positively charged phospholipids into the bacterial cell membraneAnswer
B
Synthesis of a thickened peptidoglycan layer containing excess D-alanyl-D-alanine residues
C
Enzymatic modification of terminal peptidoglycan precursors to D-alanyl-D-lactate
D
Downregulation of outer membrane porin channels restricting antibiotic influx
E
Conformational change in the 50S ribosomal subunit via target site methylation

Answer

Increased incorporation of positively charged phospholipids into the bacterial cell membrane

The correct answer accurately describes the primary mechanism of daptomycin resistance in Staphylococcus aureus. Daptomycin is a cyclic lipopeptide antibiotic used for severe Gram-positive infections, including MRSA bacteremia and right-sided endocarditis. It works by inserting its lipid tail into the bacterial cell membrane in a calcium-dependent manner, leading to potassium efflux, membrane depolarization, and rapid bacterial death. When S. aureus is exposed to daptomycin over prolonged courses, it can develop non-susceptibility primarily through gain-of-function mutations in the mprF (multiple peptide resistance factor) gene. This mutation leads to an increased synthesis and translocation of lysyl-phosphatidylglycerol, a positively charged phospholipid, to the outer leaflet of the cell membrane. The resulting increase in the net positive charge of the membrane surface electrostatically repels the positively charged calcium-daptomycin complex, preventing it from binding to and disrupting the cell membrane.

Step-by-Step Solution

Evaluate the patient's clinical course and diagnosis.

The patient developed MRSA right-sided endocarditis. After vancomycin-induced nephrotoxicity, therapy was appropriately switched to daptomycin.

Establishing the correct clinical context confirms that the failure of therapy is related specifically to daptomycin.

Identify the normal mechanism of action of the failing antimicrobial.

Daptomycin is a cyclic lipopeptide that binds to Gram-positive bacterial cell membranes in a calcium-dependent manner, causing rapid membrane depolarization and cell death.

Understanding the drug's target is necessary to deduce how the bacteria might evade it.

Determine the pathogen-specific mechanism of acquired resistance to this agent.

Treatment-emergent daptomycin resistance in S. aureus most commonly occurs via mutations in the mprF gene. This increases the addition of positively charged lysyl-phosphatidylglycerol molecules to the outer leaflet of the cell membrane, which electrostatically repels the positively charged calcium-daptomycin complex.

This specific molecular mechanism explains the rising MIC and clinical failure observed in the vignette.

Key Concept

Mechanism of daptomycin resistance in Staphylococcus aureus

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