How to treat blood culture negative infective endocarditis (IE) with negative Methicillin-resistant Staphylococcus aureus (MRSA) results from blood and groin samples?

Treatment of Blood Culture-Negative Infective Endocarditis with Negative MRSA Results

For blood culture-negative infective endocarditis (BCNIE) with negative MRSA results from blood and groin samples, empiric therapy should include ampicillin (12 g/day IV in 4-6 doses) plus (flu)cloxacillin or oxacillin (12 g/day IV in 4-6 doses) with gentamicin (3 mg/kg/day IV or IM in 1 dose). 1

Initial Approach to BCNIE

BCNIE occurs in up to 31% of all IE cases and significantly impacts clinical outcomes due to delayed diagnosis and treatment 1. When managing BCNIE with negative MRSA results, follow this algorithm:

1. Rule out prior antibiotic administration:

   • Most common cause of BCNIE (reduces bacterial recovery by 35-40%) 1
   • If antibiotics were given before cultures, consider withdrawing antibiotics and repeating blood cultures if patient is stable 1

2. Consider fastidious organisms:

   • Investigate for atypical pathogens that are difficult to culture using specialized techniques 1, 2

3. Initiate empiric therapy based on clinical presentation:

   • For community-acquired native valve or late prosthetic valve (≥12 months post-surgery) endocarditis 1:

     • Ampicillin (12 g/day IV in 4-6 doses)
     • PLUS (Flu)cloxacillin or oxacillin (12 g/day IV in 4-6 doses)
     • PLUS Gentamicin (3 mg/kg/day IV or IM in 1 dose)

   • For penicillin-allergic patients:

     • Vancomycin (30-60 mg/kg/day IV in 2-3 doses)
     • PLUS Gentamicin (3 mg/kg/day IV or IM in 1 dose) 1

Additional Diagnostic Workup

While initiating empiric therapy, pursue additional diagnostic testing:

1. Specialized serological testing for common BCNIE pathogens 1, 2:

   • Coxiella burnetii (Q fever)
   • Bartonella species
   • Brucella species
   • Mycoplasma species
   • Legionella species

2. Advanced molecular techniques:

   • PCR of blood or excised valve tissue if surgery is performed 3, 4
   • Metagenomic analysis for detecting fastidious organisms like Abiotrophia defectiva 3

3. Histopathological examination of resected valvular tissue or embolic fragments (gold standard) 1

Treatment Duration and Monitoring

• Treat for 4-6 weeks for native valve endocarditis and at least 6 weeks for prosthetic valve endocarditis 2
• Monitor for:
  • Clinical response with daily assessment
  • Serial blood cultures until sterilization
  • Regular echocardiographic follow-up
  • Renal function
  • Drug levels (for gentamicin and vancomycin) 2

Special Considerations for Specific Pathogens

If diagnostic testing identifies a specific pathogen, adjust therapy accordingly 2:

Pathogen	Recommended Treatment	Duration
Brucella spp.	Doxycycline + cotrimoxazole + rifampin	≥3-6 months
C. burnetii (Q fever)	Doxycycline + hydroxychloroquine	>18 months
Bartonella spp.	Doxycycline + gentamicin	Doxycycline for 4 weeks, gentamicin for 2 weeks
Legionella spp.	Doxycycline + hydroxychloroquine	≥18 months
Mycoplasma spp.	Doxycycline + gentamicin	Variable
T. whipplei	Doxycycline + hydroxychloroquine	≥18 months

Surgical Evaluation

Consider surgical intervention for 2:

• Heart failure due to valvular dysfunction
• Uncontrolled infection despite appropriate antibiotics
• Large mobile vegetations (>10mm) with embolic risk
• Perivalvular abscess or fistula formation

Pitfalls and Caveats

1. Do not delay treatment while awaiting identification of the causative organism 1
2. Consult infectious disease specialists early, especially for BCNIE cases 1, 2
3. Monitor for treatment failure - persisting or relapsing bacteremia requires repeat blood cultures, MIC susceptibility testing, and evaluation for sequestered infection foci 5
4. Consider MRSA coverage in healthcare-associated native valve endocarditis, even with negative initial MRSA results, if local MRSA prevalence exceeds 5% 1
5. Beware of false-negative cultures due to prior antibiotic administration - mortality is lower in patients who received antibiotics before cultures (7% vs 22%) 6

By following this structured approach to BCNIE with negative MRSA results, you can optimize patient outcomes while awaiting definitive pathogen identification.