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Difficulty: HardInfectious Diseases

A 68-year-old man is admitted to the hospital due to a 3-week history of low-grade fevers, progressive fatigue, and dyspnea on exertion. He has a history of hypertension and osteoarthritis. His temperature is 38.2°C (100.8°F), blood pressure is 128/76 mm Hg, pulse is 92/min, and respirations are 16/min. Physical examination reveals a new grade 3/6 holosystolic murmur best heard at the cardiac apex and radiating to the axilla. Splinter hemorrhages are noted on the fingernails. Transesophageal echocardiography demonstrates a 1.2-cm mobile vegetation on the anterior leaflet of the mitral valve with moderate mitral regurgitation. Three sets of blood cultures are obtained, and the patient is started on empiric intravenous vancomycin and cefepime. Forty-eight hours later, all three blood cultures grow *Enterococcus faecalis*. Antimicrobial susceptibility testing results are as follows:

AntimicrobialInterpretation
AmpicillinSusceptible
PenicillinSusceptible
VancomycinSusceptible
GentamicinHigh-level resistance
StreptomycinSusceptible

Which of the following is the most appropriate definitive pharmacotherapy for this patient?

  1. Intravenous ampicillin and ceftriaxoneAnswer
  2. B
    Intravenous ampicillin and gentamicin
  3. C
    Intravenous vancomycin monotherapy
  4. D
    Intravenous daptomycin and linezolid
  5. E
    Intravenous ampicillin monotherapy

Answer

The most appropriate therapy is intravenous ampicillin and ceftriaxone.
The correct definitive therapy is intravenous ampicillin and ceftriaxone. The patient has infective endocarditis caused by *Enterococcus faecalis*. Enterococci are intrinsically tolerant to the bactericidal activity of cell-wall active agents (like ampicillin or vancomycin) when used alone. Therefore, successful treatment of enterococcal endocarditis requires a synergistic bactericidal regimen. The traditional synergistic combination is ampicillin plus an aminoglycoside (e.g., gentamicin). However, this patient's isolate demonstrates high-level aminoglycoside resistance (HLAR) to gentamicin, meaning gentamicin will not provide synergy. The combination of ampicillin and ceftriaxone provides synergistic bactericidal activity against *E. faecalis* through the dual saturation of essential penicillin-binding proteins (PBPs), specifically PBP4 and PBP2/3. This combination is highly effective, represents the standard of care for HLAR isolates, and avoids the nephrotoxicity associated with aminoglycosides.

Step-by-Step Solution

1
Identify the primary diagnosis based on clinical and diagnostic findings.
The patient has infective endocarditis caused by Enterococcus faecalis.
The clinical presentation (fever, new murmur, splinter hemorrhages), echocardiogram findings (mitral valve vegetation), and positive blood cultures fulfill the modified Duke criteria for definite infective endocarditis.
2
Evaluate the antimicrobial susceptibility profile of the isolate.
The isolate is susceptible to ampicillin but demonstrates high-level resistance to gentamicin.
Enterococci are intrinsically tolerant to beta-lactams and require a second agent for bactericidal synergy. The susceptibility profile dictates which second agent can be effectively used.
3
Select the optimal targeted, synergistic pharmacotherapy.
Intravenous ampicillin and ceftriaxone is the correct regimen.
Because high-level gentamicin resistance precludes traditional aminoglycoside synergy, dual beta-lactam therapy with ampicillin and ceftriaxone is indicated to achieve synergistic saturation of penicillin-binding proteins.

Key Concept

Treatment of Enterococcus faecalis infective endocarditis requires a synergistic bactericidal regimen, typically ampicillin plus ceftriaxone when the isolate exhibits high-level aminoglycoside resistance.
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Topics

Infectious Diseases

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