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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editors-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]; Ahmed Zaghw, M.D. [3]

Overview

Blood cultures should be drawn prior to instituting antibiotics to identify the etiologic agent and to determine its antimicrobial susceptibility. Older antibiotics such as penicillin G, ampicillin, nafcillin, cefazolin, gentamycin, ceftriaxone, rifampin and vancomycin are the mainstays of therapy.

Timing of Initiation of Antibiotics

Antibiotic therapy for subacute or indolent disease can be delayed until results of blood cultures are known; in fulminant infection or valvular dysfunction requiring urgent surgical intervention, begin empirical antibiotic therapy promptly after blood cultures have been obtained.

Duration of Antibiotic Therapy

The duration for native valve endocarditis is often 4 weeks. For prosthetic valve endocarditis (including the presence of a valve ring), treatment should be continued for 6 to 8 weeks. For each infective agent, the preferred antimicrobial agent, dose, and duration is listed below.

Empirical Antibiotic Therapy

• Antibiotic therapy for subacute hemodynamically stable disease, and in those who have received antibiotics recently can be delayed waiting the results of blood cultures, as this delay allows an additional blood cultures without the confounding effect of empiric treatment, which is very important in determining the causing pathogens.

• On the other hand, the rapid progression of acute cases necessitate the start of empirical treatment antibiotic therapy once the blood cultures have been collected.

• Empirical therapy is needed for all likely pathogens, certain antibiotic agents, including aminoglycosides, is preferably avoided for its toxic effects.

• Clinical course of infection beside the epidemiological features should be considered upon selecting empirical treatment regimen.

• Consultation with an infectious disease specialist for the selection of one of the antibiotic regimens is recommended (see therapy for culture-negative endocarditis).

Treatment Based Upon Infectious Agent

Penicillin-Susceptible Strep Viridans and Other Nonenterococcal Streptococci

Penicillin G

• If Minimum inhibitory concentration [MIC] <0.2 µg/ml.
• Dose: 12–18 million units I.V. daily in divided doses q. 4 hour for 4 weeks.

Penicillin G + Gentamicin

• Dose: Penicillin G, 12–18 million units I.V. daily in divided doses q. 4 hour for 4 weeks plus gentamicin, 3 mg/kg I.M. or I.V. daily in divided doses q. 8 hour for 2 weeks (peak serum concentration should be ~ 3 µg/ml and trough concentrations < 1 µg/ml).

Ceftriaxone

• Dose: 2 g I.V. daily as a single dose for 2 weeks.

Vancomycin

• Vancomycin can be administered to patients with a history of penicillin hypersensitivity.
• Dose: 30 mg/kg I.V. daily in divided doses q. 12 hour for 4 weeks.

Native Valve Endocarditis Caused by Highly Penicillin-Susceptible Viridans Group Streptococci and Streptococcus bovis
Preferred Regimen
▸ penicillin G sodium 12–18 million U/24 h IV either continuously or in 4 or 6 equally divided doses x 4 weeks OR ▸ Ceftriaxone sodium 2 g/24 h IV/IM in 1 dose x 4 weeks
Pediatric dose
▸ penicillin G sodium 200 000 U/kg q24h IV in 4–6 equally divided doses
▸Ceftriaxone 100 mg/kg q24 h IV/IM in 1 dose
Alternative Regimen
▸ Penicillin G sodium 12–18 million U/24 h IV either continuously or in 6 equally divided doses x 2 weeks OR ▸Ceftriaxone sodium 2 g/24 h IV/IM in 1 dose x 2weeks
PLUS
▸Gentamicin sulfate 3 mg/kg per 24 h IV/IM in 1 dose X 2 weeks
Pediatric dose
▸ penicillin G sodium 200 000 U/kg q24h IV in 4–6 equally divided doses
▸ceftriaxone 100 mg/kg q24 h IV/IM in 1 dose
Alternative Regimen
▸ Vancomycin hydrochloride 15 mg/kg q12h IV x 4 weeks,doses not to exceed 2 g/24 h unless concentrations in serum are inappropriately low
Pediatric dose
▸Vancomycin hydrochloride 40 mg/kg per 24 h IV in 2–3 equally divided doses

===Endocarditis of Prosthetic Valves or Other Prosthetic Material Caused by Viridans Group Streptococci and Streptococcus bovis===

Penicillin-susceptible strain (minimum inhibitory concentration ≤0.12 g/mL) Preferred Regimen ▸ penicillin G sodium 24 million U/24 h IV either continuously or in 4–6 equally divided doses x 6 weeks OR ▸ Ceftriaxone 2 g/24 h IV/IM in 1 dose x 6 weeks WITH OR WITHOUT ▸ Gentamicin sulfate 3 mg/kg per 24 h IV/IM in 1 dose x 2 weeks Pediatric dose ▸ Penicillin G sodium 300 000 U/kg per 24 h IV in 4–6 equally divided doses ▸ Ceftriaxone 100 mg/kg IV/IM once daily ▸ Gentamicin 3 mg/kg per 24 h IV/IM, in 1 dose or 3 equally divided doses Alternative Regimen ▸ Vancomycin hydrochloride 30 mg/kg per 24 h IV in 2 equally divided doses x 6 weeks Pediatric dose ▸ 40 mg/kg per 24 h IV or in 2 or 3 equally divided doses

Penicillin relatively or fully resistant strain (minimum inhibitory concentration >0.12 >μg/mL)) Preferred Regimen ▸ penicillin G sodium 24 million U/24 h IV either continuously or in 4–6 equally divided doses x 6 weeks OR ▸ Ceftriaxone 2 g/24 h IV/IM in 1 dose x 6 weeks PLUS ▸ Gentamicin sulfate 3 mg/kg per 24 h IV/IM in 1 dose x 6 weeks Pediatric dose ▸ Penicillin G sodium 300 000 U/kg per 24 h IV in 4–6 equally divided doses Alternative Regimen ▸ Vancomycin hydrochloride 30 mg/kg per 24 h IV in 2 equally divided doses x 6 weeks Pediatric dose ▸ 40 mg/kg per 24 h IV or in 2 or 3 equally divided doses

Relatively Penicillin-Resistant Streptococci

Relatively Penicillin-Resistant Streptococci, MIC 0.2–0.5 µg/ml Preferred Regimen ▸ Adult:Aqueous crystalline penicillin G sodium 24 million U/24 h IV either continuously or in 4–6 equally divided doses X 4 Wks ▸ Pediatrics:Aqueous crystalline penicillin G sodium 300 000 U/24 h IV in 4–6 equally divided doses X 4 Wks OR ▸Adult:Ceftriaxone 2 g/24 h IV/IM in 1 dose ▸Pediatrics:Ceftriaxone 100 mg/kg per 24 h IV/IM in 1 dose AND ▸ Adult:Gentamicin 3 mg/kg I.M. or I.V. daily in divided doses q. 8 hr X 2 Wks ▸ Pediatrics: Gentamicin 3 mg/kg per 24 h IV/IM in 1 dose or 3 equally divided doses X 2 Wks Relatively Penicillin-Resistant Streptococci, MIC > 0.5 µg/ml, consider Enterococcal regimen Preferred Regimen ▸ Adult:Aqueous crystalline penicillin G sodium 24 million U/24 h IV either continuously or in 4–6 equally divided doses X 4 Wks AND ▸ Adult:Gentamicin 3 mg/kg I.M. or I.V. daily in divided doses q. 8 hr X 2 Wks Unable to tolerate Aqueous crystalline penicillin G sodium or Ceftriaxone Preferred Regimen ▸ Adult: Vancomycin 30 mg/kg per 24 h IV in 2 equally divided doses not to exceed 2 g/24 h, unless serum concentrations are inappropriately low ▸ Pediatrics: Vancomycin 40 mg/kg 24 h in 2 or 3 equally divided doses X 4 Wks

Enterococci

In general, treatment of enterococcal endocarditis requires combination therapy with two antibiotics:

Penicillin G + Gentamicin

• Dose is penicillin G, 20–30 million units I.V. daily in divided doses q. 4 hr for 4–6 weeks; gentamicin, 3 mg/kg I.M. or I.V. daily in divided doses q. 8 hour for 4–6 weeks (peak serum concentration should be ~ 3 µg/ml and trough concentrations < 1 µg/ml).

Ampicillin + Gentamicin

• Dose is ampicillin, 12 g I.V. daily in divided doses q. 4 hour for 4–6 weeks; gentamicin, dose as above.

Vancomycin + Gentamicin

• This regimen is for patients with history of penicillin hypersensitivity.
• Dose: Vancomycin, 30 mg/kg I.V. daily in divided doses q. 12 hour for 4–6 weeks; gentamicin, dose as above.

Staphylococci (Methicillin Susceptible) in the Absence of Prosthetic Material

Staphylococci (Methicillin Susceptible) in the Absence of Prosthetic Material Preferred Regimen ▸ Adult:Nafcillin or Oxacillin 12 g I.V. daily in divided doses q. 4 hour X 4–6 Wks ▸ Pediatrics:Nafcillin or oxacillin 200 mg/kg per 24 h IV in 4–6 equally divided doses X 4-6 Wks OR ( in non anaphylactoid Penicillin hypersensitivity) ▸ Adult:Cefazolin 12 g I.V. daily in divided doses q. 4 hour X 4–6 Wks ▸ Pediatrics:Cefazolin 100 mg/kg per 24 h IV in 3 equally divided doses X 4-6 Wks AND (optional) ▸ Adult:Gentamicin 3 mg/kg per 24 h IV/IM in 2 or 3 equally divided doses X 3-5 days ▸ Pediatrics: Gentamicin 3 mg/kg per 24 h IV/IM in 3 equally divided doses

Staphylococci (Methicillin Resistant) in the Absence of Prosthetic Material

Staphylococci (Methicillin-resistant) in the Absence of Prosthetic Material {in anaphylactoid Penicillin hypersensitivity} Preferred Regimen ▸ Adult: Vancomycin 30 mg/kg per 24 h IV in 2 equally divided doses X 6 Wks, Adjust vancomycin dosage to achieve 1-h serum concentration of 30–45 > g/mL and trough concentration of 10–15 >g/mL ▸ Pediatrics: Vancomycin 40 mg/kg per 24 h IV in 2 or 3 equally divided doses X 6 Wks

Staphylococci (Methicillin Susceptible) in the Presence of Prosthetic Material

Nafcillin or Oxacillin + Rifampin + Gentamicin

Oxacillin-susceptible strains ▸ Nafcillin or oxacillin 2 g q4h IV x ≥6 weeks PLUS ▸ Rifampin 300 mg q8h IV/PO x ≥6 weeks PLUS ▸ Gentamicin 3 mg/kg per 24 h IV/IM in 2 or 3 equally divided doses x 2 weeks Pediatric dose ▸Nafcillin or oxacillin 200 mg/kg per 24 h IV in 4–6 equally divided doses ▸Rifampin 20 mg/kg per 24 h IV/PO in 3 equally divided doses ▸Gentamicin 1 mg/kg q8h IV/IM

Staphylococci (Methicillin Resistant) in the Presence of Prosthetic Material

Oxacillin-resistant strains ▸ Vancomycin 15 mg/kg q12h x ≥6 weeks PLUS ▸ Rifampin 300 mg q8h IV/PO x ≥6 weeks PLUS ▸ Gentamicin 3 mg/kg per 24 h IV/IM in 2 or 3 equally divided doses x 2 weeks Pediatric dose ▸ vancomycin 40 mg/kg per 24 h IV in 2 or 3 equally divided doses ▸Rifampin 20 mg/kg per 24 h IV/PO in 3 equally divided doses ▸ Gentamicin 1 mg/kg q8h IV/IM

HACEK Organisms

HACEK organisms are more indolent and the infection is less complicated.

Ceftriaxone or another Third-Generation Cephalosporin

• Dose: 2 g I.V. daily as a single dose for 4 weeks.

Ciprofloxacin

• This is listed as an alternative, there is not a lot of data to support its regular use.

Culture Negative Endocarditis

Patients should be divided into 2 groups:

Patients who Received Antibiotic Therapy before the Blood Culture being Drawn

• Patients with acute clinical presentations with native valve infection: coverage of S. aureus should be followed as detailed in proven staphylococcal disease.

• Patients with subacute presentation: antibiotic coverage for S. aureus, viridians group streptococci, and enterococci should be considered.

• Antibiotics for HACEK group of organism also should be considered.

• Symptomatic patients with prosthetic valve and culture negative infection within 1 year of valve replacement should receive vancomycin to cover the oxacillin-resistant staphylococci.

• Symptomatic patients with prosthetic valve and culture negative infection within 2 months of valve replacement should also receive cefepime for gram negative bacilli coverage.

• Symptomatic patients with prosthetic valve more than 1 year, the most likely causing organisms are oxacillin-susceptible staphylococci, viridians group streptococci, and enterococci. Antibiotic coverage for those organisms should be continued for at least 6 weeks.

Patients with Culture-Negative Endocarditis and Suspected Infection with Uncommon Endocarditis Pathogens

• Examples of these pathogens include Bartonella species, Chlamydia species, Coxiella burnetii, Brucella species, Legionella species, Tropheryma whippleii, and non-Candida fungi.

• The most common pathogens that have been reported with culture-negative endocarditis are Bartonella species, Coxiella burnetii, and Brucella species.

• Antibiotic therapy for these pathogens should include aminoglycosides for at least 2 weeks.
• Therapeutic regimens for Bartonella endocarditis are mentioned below.

Native valve ▸ Ampicillin-Sulbactam 3 g q6h IV x 4–6 weeks PLUS ▸ Gentamicin sulfate 1 mg per kg q8h IV/IM x 4–6 weeks OR ▸ Vancomycin 15 mg per kg q12h IV x 4–6 weeks PLUS ▸ Gentamicin sulfate 1 mg per kg q8h IV/IM x 4–6 week PLUS Ciprofloxacin 500 mg q12h PO or 320 mg q12h IV x 4–6 weeks Native valve pediatric dose ▸Ampicillin-Sulbactam300 mg per kg per 24 h IV in 4–6 equally divided doses ▸Gentamicin 1 mg per kg q8h IV/IM ▸Vancomycin 32 mg per kg per 24 h in 2 or 3 equally divided doses ▸Ciprofloxacin 10-15 mg per kg q12h IV/PO

Prosthetic valve (early, ≤ 1y) ▸ Vancomycin 15 mg per kg q12h IV x 6 PLUS ▸ Gentamicin sulfate 1 mg per kg q8h IV/IM x 2weeks PLUS ▸Cefepime 2 g q8h IV x 6 weeks PLUS ▸ Rifampin 300 mg q8h PO/IV x 6 weeks Prosthetic valve pediatric dose ▸Vancomycin 32 mg per kg per 24 h IV in 2 or 3 equally divided doses ▸Gentamicin 1 mg per kg q8h IV/IM ▸Cefepime 50 mg q8h IV ▸Rifampin 20 mg per kg per 24 h PO/IV in 3 equally divided doses Prosthetic valve (late—greater than 1 y) (same regimens as for native valve endocarditis with addition of rifampin) ▸ Ampicillin-Sulbactam 3 g q6h IV x 4–6 weeks PLUS ▸ Gentamicin sulfate 1 mg per kg q8h IV/IM x 4–6 weeks PLUS ▸ Rifampin 300 mg q8h PO/IV x 6 weeks OR ▸ Vancomycin 15 mg per kg q12h IV x 4–6 weeks PLUS ▸ Gentamicin sulfate 1 mg per kg q8h IV/IM x 4–6 weeks PLUS ▸ Ciprofloxacin 500 mg q12h PO or 320 mg q12h IV x 4–6 weeks PLUS ▸ Rifampin 300 mg q8h PO/IV x 6 weeks

Suspected Bartonella, culture negative ▸ Ceftriaxone sodium 2 g per 24 h IV/IM in 1 dose x 6 weeks PLUS ▸ Gentamicin sulfate 1 mg per kg q8h IV/IM x 2 weeks WITH/WITHOUT ▸ Doxycycline 100 mg per kg q12h IV/PO x 6 weeks Documented Bartonella, culture positive ▸ Doxycycline 100 mg q12h IV or PO x 6 weeks PLUS ▸ Gentamicin sulfate 1 mg per kg q8h IV/IM x 2 weeks Documented Bartonella, culture positive pediatric dose ▸Ceftriaxone 100 mg per kg per 24 h IV/IM once daily ▸Gentamicin 1 mg per kg q8h IV/IM ▸Doxycycline 2–4 mg per kg per 24 h IV/PO in 2 equally divided doses ▸Rifampin 10 mg per kg q12h PO/IV