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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

Native Valve Endocarditis Caused by Highly Penicillin-Susceptible Viridans Group Streptococci and Streptococcus bovis

Native Valve Endocarditis Caused by Highly Penicillin-Susceptible Viridans Group Streptococci and Streptococcus bovis
Preferred Regimen ( 4 wks )
Adult dose
▸ Penicillin G sodium † 12–18 million U/24 h IV either continuously or in 4-6 equally divided doses x 4 Wks OR ▸ Ceftriaxone sodium 2 g/24 h IV/IM in 1 dose x 4 Wks
Pediatric dose ₳
▸ Penicillin G sodium 200 000 U/kg q24h IV either continuously or in 4-6 equally divided doses x 4 Wks OR ▸Ceftriaxone 100 mg/kg q24 h IV/IM in 1 dose x 4 Wks
Alternative Regimen ( 2 wks )
Adult dose
▸ Penicillin G sodium‡ 12–18 million U/24 h IV either continuously or in 6 equally divided doses x 2 Wks OR ▸ Ceftriaxone sodium 2 g/24 h IV/IM in 1 dose x 2 Wks
PLUS
▸ Gentamicin sulfate ฿ 3 mg/Kg per 24h 1 dose x 2 Wks\
Pediatric dose
▸ Penicillin G sodium 200 000 U/kg q24h IV in 4-6 equally divided doses x 2 Wks OR ▸Ceftriaxone 100 mg/kg q24 h IV/IM in 1 dose x 2 Wks
PLUS
▸ Gentamicin sulfate 3 mg/Kg per 24h 1 dose or 3 equally divided doses x 2 Wks
Alternative Regimen
Adult dose
▸ Vancomycin hydrochloride ¶ 15 mg/kg q12h IV x 4 Wks Doses should 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

Minimum inhibitory concentration ≤ 0.12 μg/mL.

† Preferred in most patients >65 y or patients with impairment of 8th cranial nerve function or renal function.

₳ Pediatric dose should not exceed that of a normal adult.

‡ 2-wk regimen not intended for patients with known cardiac or extracardiac abscess or for those with creatinine clearance of <20 mL/min, impaired 8th cranial nerve function, or Abiotrophia, Granulicatella, or Gemella spp infection; gentamicin dosage should be adjusted to achieve peak serum concentration of 3-4 μg/mL and trough serum concentration of >1 μg/mL when 3 divided doses are used; nomogram used for single daily dosing.

¶ Vancomycin therapy recommended only for patients unable to tolerate penicillin or ceftriaxone; vancomycin dosage should be adjusted to obtain peak (1 h after infusion completed) serum concentration of 30–45 μg/mL and a trough concentration range of 10–15 μg/mL

฿ Other potentially nephrotoxic drugs (eg, nonsteroidal antiinflammatory drugs) should be used with caution in patients receiving gentamicin therapy. Although it is preferred that gentamicin (3 mg/kg) be given as a single daily dose to adult patients with endocarditis due to viridans group streptococci, as a second option, gentamicin can be administered daily in 3 equally divided doses.

Prosthetic Valves Endocarditis or Other Prosthetic Material Caused by Viridans Group Streptococci and Streptococcus Bovis

Penicillin-susceptible strain (MIC ≤ 0.12 g/mL)

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

• Dosages recommended are for patients with normal renal function.

† Penicillin or ceftriaxone together with gentamicin has not demonstrated superior cure rates compared with monotherapy with penicillin or ceftriaxone for patients with highly susceptible strain; gentamicin therapy should not be administered to patients with creatinine clearance of <30 mL/min.

‡ Although it is preferred that gentamicin (3 mg/kg) be given as a single daily dose to adult patients with endocarditis due to viridans group streptococci, as a second option, gentamicin can be administered daily in 3 equally divided doses.

Penicillin relatively or fully resistant strain (MIC >0.12 >μg/mL)

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

Relatively Penicillin-Resistant Streptococci, MIC 0.2–0.5 µg/ml

Relatively Penicillin-Resistant Streptococci, MIC 0.2–0.5 µg/ml Preferred Regimen Adult dose ▸ Penicillin G potassium 24 million U/24 h IV either continuously or in 4–6 equally divided doses X 4 Wks OR ▸Ceftriaxone 2 g/24 h IV/IM in 1 dose AND ▸ Gentamicin 3 mg/kg I.M. or I.V. daily in divided doses q. 8 hr X 2 Wks Pediatric dose ▸ Penicillin G potassium 300 000 U/24 h IV in 4–6 equally divided doses X 4 Wks OR ▸ Ceftriaxone 100 mg/kg per 24 h IV/IM in 1 dose AND ▸ 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)

Relatively Penicillin-Resistant Streptococci, MIC > 0.5 µg/ml, consider Enterococcal regimen Preferred Regimen Adult dose ▸ Penicillin G potassium 24 million U/24 h IV either continuously or in 4–6 equally divided doses x 4 Wks PLUS ▸ Gentamicin 3 mg/kg I.M. or I.V. daily in divided doses q. 8 hr x 2 Wks Pediatric dose ▸ Penicillin G potassium 24 million U/24 h IV either continuously or in 4–6 equally divided doses x 4 Wks PLUS ▸ Gentamicin 3 mg/kg I.M. or I.V. daily in divided doses q. 8 hr x 2 Wks

Unable to tolerate Penicillin or Ceftriaxone

Unable to tolerate Aqueous crystalline penicillin G sodium or Ceftriaxone Preferred Regimen Adult dose ▸ 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 Pediatric dose ▸ 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:

Native Valve Endocarditis Caused by Highly Penicillin-Susceptible Viridans Group Streptococci and Streptococcus bovis

Native Valve Endocarditis Caused by Highly Penicillin-Susceptible Viridans Group Streptococci and Streptococcus bovis
Preferred Regimen
Adult dose
▸ penicillin G sodium 20–30 million units I.V. daily in 4-6 equally divided doses q. 4 hr X 4–6 Wks AND ▸Gentamicin sulfate 3 mg/kg per 24 h 3 equally divided doses IV/IM in 1 dose X 4-6 Wks
OR
▸ Ampicillin 12 g I.V. daily in divided doses q. 4 hour X 4–6 Wks AND ▸Gentamicin sulfate 3 mg/kg per 24 h 3 equally divided doses IV/IM in 1 dose X 4-6 Wks
OR (in penicillin hypersensitivity)
▸ Vancomycin 30 mg/kg I.V. daily in divided doses q. 12 hour X 4–6 Wks AND ▸Gentamicin sulfate 3 mg/kg per 24 h 3 equally divided doses IV/IM in 1 dose X 4-6 Wks|-
Pediatric dose
▸ penicillin G sodium 300 000 U/kg per 24 h IV in 4–6 equally divided doses X 4–6 Wks AND ▸Gentamicin sulfate 3 mg/kg per 24 h IV/IM in 3 equally divided doses X 4-6 Wks
OR
▸ Ampicillin 300 mg/kg per 24 h IV in 4–6 equally divided doses; X 4–6 Wks AND ▸Gentamicin sulfate 3 mg/kg per 24 h IV/IM in 3 equally divided doses X 4-6 Wks
OR (in penicillin hypersensitivity)
▸ Vancomycin 30 mg/kg I.V. daily in divided doses q. 12 hour X 4–6 Wks AND ▸Gentamicin sulfate 3 mg/kg per 24 h IV/IM in 3 equally divided doses X 4-6 Wks

Native Valve Endocarditis caused by Staphylococci in the Absence of Prosthetic Material

Staphylococci (Methicillin Susceptible) in the Absence of Prosthetic Material

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

Staphylococci (Methicillin-resistant) with Penicillin G Anaphylactoid Hypersensitivity in the Absence of Prosthetic Material

Staphylococci (Methicillin-resistant) in the Absence of Prosthetic Material (in anaphylactoid Penicillin hypersensitivity) Preferred Regimen Adult dose ▸ 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 dose ▸ Vancomycin 40 mg/kg per 24 h IV in 2 or 3 equally divided doses x 6 wks

Prosthetic Valves Endocarditis or Other Prosthetic Material Caused by Staphylococci

Oxacillin-susceptible strains in the Presence of Prosthetic Material

Oxacillin-susceptible strains Adult dose ▸ 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 PLUS ▸Rifampin 20 mg/kg per 24 h IV/PO in 3 equally divided doses

Oxacillin-resistant strains in the Presence of Prosthetic Material

Oxacillin-resistant strains Adult dose ▸ 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 wks Pediatric dose ▸ vancomycin 40 mg/kg per 24 h IV q12h x ≥6 wks PLUS ▸Rifampin 20 mg/kg per 24 h IV/PO q12h x ≥6 wks

HACEK Organisms

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

Therapy for Both Native and Prosthetic Valve Endocarditis Caused by HACEK Microorganisms Adult dose ▸ Ceftriaxone sodium 2 g/24 h IV/IM in 1 dose x 4 weeks OR ▸ Ampicillin- sulbactam 12 g/24 h IV in 4 equally divided doses x 4 weeks OR ▸ Ciprofloxacin 500 mg q12h PO or 400 mg q12h IV x 4 weeks Pediatric dose ▸ Ceftriaxone 100 mg/kg per 24 h IV/IM once daily OR ▸Ampicillin- sulbactam 300 mg/kg per 24 h IV divided into 4 or 6 equally divided doses OR ▸Ciprofloxacin 10-15 mg/kg q12h IV/PO

Culture Negative Endocarditis

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

• Patients should be divided into 2 groups:

Patients Who Received Antibiotic Therapy Before the Blood Culture

• 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 based on the epidemiological risk and high in index of suspicion.

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