Infective Endocarditis Organism-Specific Therapy

Organism-specific regimens for infective endocarditis are provided below, including those for Staphylococcus aureus, Streptococcus, Enterococcus, HACEK organisms (Haemophilus parainfluenzae, Haemophilus aphrophilus, Haemophilus paraphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, and Kingella species), Q fever endocarditis, culture-negative endocarditis, and Brucella. ^{[1, 2, 3, 4]}

Staphylococcus aureus

Native valve endocarditis (NVE)

Methicillin-susceptible

• Nafcillin 12 g IV q24h in 4-6 divided doses for 6 weeks (optional: gentamicin 3 mg/kg IV or IM q24h in 2-3 divided doses for 3-5 days; however, the benefit of low-dose aminoglycoside is low and nephrotoxicity is a risk; gentamicin is not recommended for treatment of right-sided staphylococcal NVE)
• Cefazolin 6 g IV q24h in 3 divided doses for 6 weeks (optional: gentamicin 3 mg/kg IV or IM q24h in 2-3 divided doses for 3-5 days) for non-anaphylactoid penicillin allergy

Methicillin-resistant, penicillin-intolerant, or coagulase-negative staphylococci

• Vancomycin 30 mg/kg IV q24h in 2 divided doses for 6 weeks (rifampin 300-600 mg q12h may be added; gentamicin should not be added to vancomycin for native valve endocarditis treatment); vancomycin trough between 15 and 20 mcg/mL
• Daptomycin ≥8 mg/kg/dose for 6 weeks for normal renal function may be an alternative to vancomycin to treat left-sided MRSA endocarditis

Patients with unstable renal function

• Linezolid 600 mg IV q12h; note that linezolid is not yet recommended in guidelines, although there are anecdotal reports of successful treatment with linezolid in gram-positive endocarditis in patients with limited treatment options ^{[5, 6]}

Duration of therapy

• 2 weeks for uncomplicated right-side staphylococcal endocarditis in patients with a history of injection drug use
• 6 weeks for complicated right-side staphylococcal endocarditis

Prosthetic valve endocarditis (PVE)

Consideration should be given to early surgical intervention.

Methicillin-susceptible

• Nafcillin 12 g IV q24h in 6 divided doses for ≥ 6 weeks plus  gentamicin 3 mg/kg IV or IM q24h in 2-3 divided doses for 2 weeks plus  rifampin 900 mg IV or PO q24h in 3 divided doses for ≥ 6 weeks
• If the organism is gentamicin resistant, then other aminoglycosides may be used depending on susceptibility
• If the organism (especially coagulase-negative Staphylococcus) is resistant to all aminoglycosides, substitute a fluoroquinolone with other 2 drugs for the entire course of therapy
• If the organism is both aminoglycoside and fluoroquinolone resistant, then linezolid, ^[7] cefatrizine, or trimethoprim-sulfamethoxazole can be used for the first 2 weeks of treatment

Methicillin-resistant

• Vancomycin 30 mg/kg IV q24h in 2 divided doses for 6 weeks plus  rifampin 900 mg IV or PO q24h in 3 divided doses for ≥ 6 weeks plus gentamicin 3 mg/kg IV or IM q24h in 2-3 divided doses for 2 weeks
• In patients with fluctuating renal function, consider linezolid 600 mg q12h or ceftaroline 600 mg q12h; for both, clinical experience is very limited
• Patients failing therapy on vancomycin, if fever or symptoms persist, or for breakthrough bacteremia, vancomycin susceptibility testing should be done; vancomycin in such cases should be substituted for daptomycin >8 mg/kg/24 h, which has been approved for the treatment of S aureus BSI and right-sided infective endocarditis; higher doses of daptomycin 12 mg/kg/24 h have also been used ^{[8, 9]} ; patients who have received vancomycin have a higher rate of resistance to daptomycin
• Methicillin-resistant S aureus (MRSA) with vancomycin minimal inhibitory concentration (MIC) >1.0: Telavancin or daptomycin with nafcillin or ceftaroline has been used ^{[10, 11, 12]}

Streptococcus

Native valve endocarditis

Highly penicillin-susceptible viridans group streptococci and Streptococcus gallolyticus (bovis) (MIC ≤ 0.12)

• Aqueous penicillin G 12-18 million U IV q24h continuously or in 4-6 divided doses for 4 weeks or
• Ceftriaxone 2 g IV or IM q24h in 1 dose for 4 weeks if the isolate is ceftriaxone susceptible or
• Aqueous penicillin G 12-18 million U IV q24h continuously or in 4-6 divided doses for 2 weeks plus  gentamicin 3 mg/kg IV or IM q24h in 1 dose for 2 weeks or
• Ceftriaxone 2 g IV/IM q24h in 1 dose for 2 weeks plus gentamicin 3 mg/kg IV or IM q24h in 1 dose for 2 weeks
• If patient is penicillin or cephalosporin intolerant: Vancomycin 30 mg/kg IV q24h in 2 divided doses for 4 weeks

Relatively penicillin-resistant viridans group streptococci or S bovis (MIC > 0.12 and < 0.5)

• Aqueous penicillin G 24 million U IV q24h in 4-6 divided doses for 4 weeks plus  gentamicin 3 mg/kg IV q24h in 1 dose for 2 weeks or
• Ceftriaxone 2 g IV/IM q24h in 1 dose for 4 weeks plus gentamicin 3 mg/kg IV q24h in 1 dose for 2 weeks
• If patient is penicillin or cephalosporin intolerant: Vancomycin 30 mg/kg IV q24h in 2 divided doses for 4 weeks

Penicillin-resistant viridans group streptococci and S bovis (MIC ≥ 0.5)

• Ampicillin 12 g IV q24h in 6 divided doses for 4-6 weeks plus  gentamicin 3 mg/kg IV or IM q24h in 1 dose for 4-6 weeks or
• Aqueous penicillin G 18-30 million U IV q24h in 2 divided doses for 4-6 weeks plus gentamicin 3 mg/kg IV or IM q24h in 1 dose for 4-6 weeks
• If patient is penicillin or cephalosporin intolerant: Vancomycin 30 mg/kg IV q24h in 2 divided doses for 6 weeks plus gentamicin 3 mg/kg IV or IM q24h in 1 dose for 6 weeks
• Streptococcus pneumoniae can cause valve-damaging endocarditis. For penicillin-susceptible strains: Penicillin G 24 million units per day is used. Other penicillin-resistant strains may respond only to vancomycin. Other streptococcal species (eg, groups A, B, C, and G) may be relatively penicillin-resistant. They are treated by adding gentamicin to a penicillin or cephalosporin for the first 2 weeks of 4- to 6-week therapy.

Prosthetic valve endocarditis

Penicillin-susceptible viridans group streptococci or S bovis (MIC ≤ 0.12)

• Aqueous penicillin G 24 million U IV q24h continuously or in 4-6 divided doses for 6 weeks with or without  gentamicin 3 mg/kg IV or IM q24h in 1 dose for 2 weeks or
• Ceftriaxone 2 g IV or IM q24h in 1 dose for 6 weeks with or without gentamicin 3 mg/kg IV or IM q24h in 1 dose for 2 weeks
• If patient is penicillin or cephalosporin intolerant: Vancomycin 30 mg/kg IV q24h in 2 divided doses for 6 weeks

Penicillin relatively or fully resistant (MIC > 0.12)

• The American Heart Association recommends continuing aminoglycosides for the entire course of treatment (4-6 weeks)
• Aqueous penicillin G 24 million U IV q24h continuously or in 4-6 divided doses for 6 weeks plus  gentamicin 3 mg/kg IV or IM q24h in 1 dose for 6 weeks or
• Ceftriaxone 2 g IV or IM q24h in 1 dose for 6 weeks plus  gentamicin 3 mg/kg IV or IM q24h in 1 dose for 6 weeks or
• If patient is penicillin or cephalosporin intolerant: Vancomycin 30 mg/kg IV q24h in 2 divided doses for 6 weeks

Enterococcus

Native or prosthetic valve endocarditis

Penicillin, gentamicin, and vancomycin susceptible

• Ampicillin 12 g IV q24h in 6 divided doses for 4-6 weeks plus  gentamicin 3 mg/kg IV or IM q24h in 1 dose for 4-6 weeks or
• Aqueous penicillin G 18-30 million U IV q24h continuously or in 6 divided doses for 4-6 weeks plus gentamicin 3 mg/kg IV or IM q24h in 1 dose for 4-6 weeks
• If patient is penicillin intolerant: Vancomycin 30 mg/kg IV q24h in 2 divided doses for 6 weeks plus gentamicin 3 mg/kg IV or IM q24h in 1 dose for 6 weeks

Penicillin, streptomycin, and vancomycin susceptible; gentamicin resistant

• Ampicillin 12 g IV q24h in 6 divided doses for 4-6 weeks plus  streptomycin 15 mg/kg IV or IM q24h in 2 divided doses for 4-6 weeks or
• Aqueous penicillin G 18-30 million U IV q24h continuously or in 6 divided doses for 4-6 weeks plus streptomycin 15 mg/kg IV or IM q24h in 2 divided doses for 4-6 weeks
• If patient is penicillin intolerant: Vancomycin 30 mg/kg IV q24h in 2 divided doses for 6 weeks plus streptomycin 15 mg/kg IV or IM q24h in 2 divided doses for 6 weeks

Beta-lactamase producing; vancomycin and aminoglycoside susceptible

• Ampicillin-sulbactam 12 g IV q24h in 4 divided doses for 6 weeks plus gentamicin 3 mg/kg IV or IM q24h in 3 divided doses for 6 weeks
• If patient is penicillin intolerant: Vancomycin 30 mg/kg IV q24h in 2 divided doses for 6 weeks plus gentamicin 3 mg/kg IV or IM q24h in 1 dose for 6 weeks

Intrinsic penicillin resistance

• Vancomycin 30 mg/kg IV q24h in 2 divided doses for 6 weeks plus gentamicin 3 mg/kg IV or IM q24h in 1 dose for 6 weeks

Penicillin, gentamicin, and vancomycin resistant

• Infectious disease consultation recommended. Optimal therapy for VRE PVE has not been clearly defined. Daptomycin and linezolid susceptibility should be obtained.
• VRE: Enterococcus faecium or Enterococcus faecalis: Linezolid 1200 mg IV or PO q24h in 2 divided doses for ≥ 6 weeks or
• Daptomycin 10-12 mg/kg per dose for ≥6 weeks

HACEK organisms

Native or prosthetic valve endocarditis

• Ceftriaxone 2 g IV or IM q24h in 1 dose for 4 weeks for NVE, 6 weeks for PVE or
• Ampicillin-sulbactam 2 g IV q4h for 4 weeks for NVE, 6 weeks for PVE if isolate is susceptible
• If patient is penicillin or cephalosporin intolerant: Ciprofloxacin 1000 mg PO or 800 mg IV q24h in 2 divided doses for 4 weeks for NVE and 6 weeks for PVE

Corynebacteria (diphtheroids)

Native or prosthetic valve endocarditis

• Penicillin as for streptococci with gentamicin (for MIC < 4 mcg/mL)
• Vancomycin is bactericidal for diphtheroids; for penicillin-allergic or gentamicin-resistant patients, vancomycin can be used

Gram-negative bacilli

Native or prosthetic valve endocarditis

• Pseudomonas aeruginosa endocarditis, especially if prosthetic valves or left-sided requires consideration for surgical excision
• P aeruginosa endocarditis can be medically treated, especially native valve, with tobramycin 2.5 mg/kg IV q8h, (peak should be 15-20 mcg/mL and trough concentration should be 2 mcg/mL) plus piperacillin 4 g IV q4h or ceftazidime 2 g IV q8h for 4-6 weeks
• Alternatively, aztreonam, ciprofloxacin, or imipenem, each with gentamicin, tobramycin, or amikacin depending on susceptibilities

Fungi

Native valve endocarditis

• For Candida endocarditis, amphotericin B lipid formulation 0.8-1 mg/kg/d IV for at least 6 weeks plus  flucytosine (5-FC) 25 mg/kg/day divided in 4 doses for normal renal function plus surgery depending on clinical condition and other factors or
• Echinocandins: caspofungin 150 mg/day, micafungin 150 mg/day, or anidulafungin 200 mg/day

Prosthetic valve endocarditis

• Surgical excision of prosthetic valve, in addition to above
• Relapse is high in Candida endocarditis, even with surgical excision, and fluconazole 400-800 mg recommended for prolonged period after surgery or lifelong, if susceptible
• Fluconazole and echinocandins or fluconazole and amphotericin B have been used for Candida PVE without surgery in a few cases ^{[13, 14, 15]}

Culture-negative endocarditis

Native valve endocarditis

• Ampicillin: 12 g IV q24h in 4 divided doses for 4-6 weeks plus gentamicin 3 mg/kg IV or IM q24h in 3 divided doses for 4-6 weeks
• If patient is penicillin intolerant: Vancomycin 30 mg/kg IV q24h in 2 divided doses for 4-6 weeks plus  gentamicin 3 mg/kg IV or IM q24h in 3 divided doses for 4-6 weeks plus ciprofloxacin 1000 mg IV or IM q24h in 2 divided doses for 4-6 weeks

Prosthetic valve endocarditis (≤ 1y after implantation)

• Vancomycin 30 mg/kg IV q24h in 2 divided doses for 6 weeks plus  gentamicin 3 mg/kg IV or IM q24h in 3 divided doses for 2 weeks plus  cefepime 6 g IV q24h in 3 divided doses for 6 weeks plus rifampin 900 mg PO or IV q24h in 3 divided doses for 6 weeks

Prosthetic valve endocarditis (> 1y after implantation)

• Same regimen as for patients with culture-negative native valve endocarditis, with the addition of rifampin 900 mg PO or IV q24h in 3 divided doses for 6 weeks

Miscellaneous organism-specific treatment

Brucella  endocarditis

Brucella infective endocarditis is treated with an aminoglycoside, doxycycline, and rifampin for 6 weeks to 6 months in various regimens, as follows: ^{[16, 17]}

• Doxycycline 100 mg IV q12h with
• Streptomycin 1 g IM daily for 14-21 days or gentamicin 5 mg/kg IV daily for 7-10 days or
• Doxycycline with rifampin 600 or 900 mg orally once daily, both for 6 weeks

Q-fever endocarditis due to Coxiella burnetii

Q fever endocarditis requires at least 18 months of therapy with the following: ^{[18, 19]}

• Doxycycline 200 mg daily plus hydroxychloroquine 600 mg daily or
• Doxycycline plus ciprofloxacin (1500 mg/day) or ofloxacin (600 mg/day) or
• Doxycycline (200 mg/day) plus rifampin (900 mg/day)