infective%20endocarditis
INFECTIVE ENDOCARDITIS
Infective endocarditis is microbial infection of the endovascular structures of the heart.
It often presents in an occult fashion and early diagnosis depends on a high index of clinical suspicion especially in patients with congenital heart disease, prosthetic valves or previous infective endocarditis.
The established diagnosis of infective endocarditis is demonstrated by a positive blood culture and involvement of the endocardium detected during sepsis or systemic infection. It may also be established if there is involvement of the endocardium detected during sepsis or systemic infection but blood culture is negative.

Principles of Therapy

EMPIRIC PHARMACOLOGICAL THERAPY

General Therapeutic Principles

  • Counting days of duration of therapy should start on the 1st day on which BCs were negative in cases in which initial BCs were positive
  • At least 2 sets of BCs should be obtained every 24-48 hr until bloodstream infection is cleared
  • For patients w/ NVE who undergo valve resection w/ prosthetic valve replacement, the post-op treatment should be the one recommended for NVE, not for PVE
    • If the resected tissue is culture positive, then the entire course of therapy is recommended after valve resection
    • If the resected tissue is culture negative, then treatment should be given less the number of days of treatment administered for NVE before valve replacement
  • If combination antimicrobial therapy is used, then the agents should be administered close together to improve synergistic killing effect
  • Antibiotic prophylaxis has been limited to patients undergoing an invasive dental procedure in whom exists a history of IE, prosthetic valve, a heart transplant w/ abnormal heart valve function, or congenital heart disease w/ the following: Unrepaired cyanotic congenital heart disease, congenital heart defect completely repaired w/ prosthetic material or device for the 1st 6 mth post procedure, or repaired congenital heart disease w/ residual defects
    • Patients w/ prosthetic valves are at the highest risk of developing IE
    • Recommended regimens include the standard Amoxicillin, Ampicillin if unable to take PO meds, & Clindamycin (PO or IV), Clarithromycin, Cefazolin or Cefalexin if w/ penicillin allergy

Empiric Therapy

  • In uncomplicated cases, antibiotics may be postponed up to 48 hr until results of initial BCs are known
  • Empiric antibiotic treatment should be initiated immediately after 3 BCs have been taken in cases complicated by:
    • Sepsis, severe valvular dysfunction, conduction disturbances or embolic events
  • Empiric therapy should include use of agents that are effective against streptococci, staphylococci & enterococci
  • Subsequent changes in the antibiotic regimen should be based on the results of culture & sensitivity testing

PATHOGEN-SPECIFIC PHARMACOLOGICAL THERAPY

General Therapeutic Principles

  • Counting days of duration of therapy should start on the 1st day on which BCs become negative in cases in which initial BCs were positive
  • At least 2 sets of BCs should be obtained every 24-48 hr until blood stream infection is cleared
  • For patients w/ NVE who undergo valve resection w/ prosthetic valve replacement, the post-op treatment should be the one recommended for NVE, not for PVE
    • If the resected tissue is culture positive, then the entire course of therapy is recommended after valve resection
    • If the resected tissue is culture negative, then treatment should be given less the number of days of treatment administered for NVE before valve replacement
  • If combination antimicrobial therapy is used, then the agents should be administered close together to improve synergistic killing effect

The therapeutic goal is to produce bactericidal levels of drugs at the infected site for a max period of time


Pharmacotherapy

Streptococcal IE

Highly Penicillin-Susceptible Viridans Group Streptococci (MIC ≤0.12 mg/L)

  • Penicillin, Amoxicillin or Ceftriaxone
    • These agents when used alone x 4 wk obtain high bacteriologic cure rates
    • 4 wk of monotherapy has the advantage of avoiding the potential ototoxic or nephrotoxic effects of Gentamicin
    • Ceftriaxone has the advantage of once-daily dosing
  • (Penicillin, Amoxicillin or Ceftriaxone) plus Gentamicin or Netilmicin for the 1st 2 wk
    • When given in selected patients, gives similar cure rates to 4 wk of monotherapy
    • Once-daily dosing of Gentamicin may be used
  • Vancomycin
    • Reserved for patients who are unable to tolerate Penicillin or Ceftriaxone
  • Teicoplanin
    • Alternative drug that may be used once daily to treat streptococcal IE in penicillin-allergic patients
    • Inadequate doses can result in treatment failure
    • Steady-state serum is achieved only after 1 wk

Relatively Resistant Viridans Group Streptococci (MIC >0.12 to ≤0.5 mg/L)

  • (Penicillin or Amoxicillin) x 4 wk plus Gentamicin x 2 wk should be given
    • Once-daily dosing of Gentamicin may be used
  • Vancomycin
    • Reserved for patients who are unable to tolerate Penicillin or Amoxicillin

Highly Resistant Viridans Group Streptococci (MIC >0.5 mg/L)

  • Should be treated w/ regimens recommended for enterococcal endocarditis

Enterococcal IE

  • All enterococci causing IE should be tested for antimicrobial susceptibility to determine optimal therapy
    • In vitro susceptibility to Penicillin & Vancomycin along w/ high-level resistance to Gentamicin & Streptomycin should be tested
  • Successful treatment requires the synergistic action of Penicillin, Ampicillin or Vancomycin w/ either Gentamicin or Streptomycin
  • Multi-daily dosing should be used for the aminoglycosides

Ampicillin or Penicillin + Aminoglycoside

  • Treatment duration for 4-6 wk
  • For enterococcal strains susceptible to Penicillin:
    • Bactericidal activity of Ampicillin is 2x that of Penicillin against E faecalis
    • Penicillin may be preferred because higher serum conc of Penicillin will compensate for the difference & because it is important to avoid Ampicillin rash during long-term treatment

Enterococci w/ High-level Resistance to Gentamicin

  • These enterococci are usually resistant to all other aminoglycosides except Streptomycin
  • Combination therapy w/ Ampicillin & Ceftriaxone should also be considered

Glycopeptides (Vancomycin, Teicoplanin) + Aminoglycoside

  • Should be reserved for patients allergic to Penicillin or in Penicillin-resistant strains
  • Glycopeptides need to be combined w/ aminoglycosides since they are not usually bactericidal against enterococci

Vancomycin-Resistant Strains & Strains Resistant to Both Gentamicin & Streptomycin

  • Consultation w/ microbiologist/infectious disease specialist is recommended

Staphylococcal IE

  • Appropriate antibiotic therapy should be started promptly to improve overall prognosis
  • S aureus in non-IVDA usually involves the left-sided cardiac valves
  • Factor in determining antibiotic treatment is whether the organism is sensitive to Methicillin
  • Gentamicin in the following regimens should be administered in multiple daily dosing at 3 mg/kg/day

NVE - Penicillin Susceptible S aureus

  • <10% of IE strains of S aureus are susceptible to Penicillin
  • Penicillin may be used x 4 wk combined w/ Gentamicin for the 1st 3-5 days of therapy

NVE - MSSA

  • Antistaphylococcal Penicillin w/ or w/o Gentamicin
    • Antistaphylococcal Penicillin is the treatment of choice
    • Adding Gentamicin for the 1st 3-5 days may protect the infected valve from further damage & may decrease the duration of bacteremia which may result in faster defervescence
  • Antistaphylococcal Penicillin + Fusidic acid
    • This combination may be an option for Fusidic acid-sensitive strains
  • Cephalosporin (1st Generation) w/ or w/o Gentamicin
    • May be used for the treatment of MSSA endocarditis when patient has non-anaphylactoid Penicillin allergy
  • 4 wk of therapy w/ antistaphylococcal Penicillin or cephalosporin may be used for uncomplicated infection
    • Complicated IE eg abscess formation or septic metastatic complications should be treated x 6 wk
  • Vancomycin + Gentamicin
    • Reserved for patients allergic to beta-lactams; there are recent reports of suboptimal outcomes w/ Vancomycin therapy for serious S aureus infections
    • Vancomycin + Gentamicin x 3-5 days in MSSA is associated w/ faster clearing of bacteremia

NVE-MRSA

  • Vancomycin
    • Treatment of choice in MRSA
    • Treatment duration for 4-6 wk
    • Addition of Gentamicin or Rifampin to Vancomycin is not recommended for native valve IE
  • Linezolid or (Co-trimoxazole, Doxycycline or Minocycline w/ or w/o Rifampicin)
    • These agents may be an option in patients who are intolerant of Vancomycin or fail therapy
    • Data on clinical efficacy is limited compared to other agents

PVE-MSSA

  • (Antistaphylococcal penicillin + Rifampicin) x 6-8 wk, + Gentamicin for the 1st 2 wk of treatment
    • S aureus IE in PVE patients has a high mortality rate & surgery should be combined w/ antimicrobial therapy
    • Though in vitro & clinical studies are lacking, it is accepted that this 3-drug combination is used to treat MSSA in PVE
    • Cefazolin may be substituted for those w/ non-anaphylactoid-type Penicillin allergy
  • Vancomycin + Rifampicin + Gentamicin
    • Used for MRSA & coagulase-negative staphylococci
  • Quinolone
    • May be used in combination w/ Vancomycin & Rifampicin when the causative microorganism is resistant to all aminoglycosides

IVDA

Right-Sided Uncomplicated MSSA in IVDA

  • 2 wk antistaphylococcal penicillin + Gentamicin
    • Should be reserved for uncomplicated cases
  • 4 wk oral Ciprofloxacin + Rifampicin
    • Can be used in uncomplicated cases when compliance can be monitored
    • Though oral Ciprofloxacin & Rifampicin combination has been shown to be effective in IV drug users, currently, oral treatment for IE cannot be recommended

Left-Sided or Complicated MSSA in IVDA

  • Patient should be treated w/ standard 4-6 wk treatment if:
    • After >96 hr patient fails to show clinical or microbiological response to antibiotic therapy, CHF, vegetations >20 mm, acute resp failure, septic metastatic foci outside the lungs, extra-cardiac complications (eg renal failure) or IVDA w/ severe immunosuppression w/ or w/o AIDS

Organisms Other Than MSSA in IVDA

  • Treat as in non-addict

IE Caused by HACEK

  • HACEK group may not be identified in BCs for a wk or longer & empiric antibiotics may be necessary while awaiting culture results
  • Beta-lactamase-producing strains of HACEK are appearing w/ increased frequency
    • Difficult to perform antimicrobial susceptibility tests on HACEK organisms; therefore, these should now be considered Ampicillin resistant & Ampicillin should not be used for treatment
  • Ceftriaxone
    • Single-agent use is justified by its excellent pharmacokinetic profile
    • Effective against both β-lactamase-producing & non-β-lactamase-producing strains of the HACEK group
    • May be administered alone x 4 wk in NVE & x 6 wk in PVE
    • Alternative: Another 3rd or 4th generation cephalosporin
  • Ampicillin/Sulbactam
    • Limited published clinical data demonstrating efficacy
  • Quinolone
    • In vitro activity against the HACEK group but limited clinical use; therefore, consult w/ infectious disease specialist before using in patients intolerant to β-lactam therapy

Other Causes of IE

  • Treatment of these less common causes of IE is still not adequately defined
  • In patients w/ difficult-to-treat organisms (as below) & those w/ intracardiac device or foreign bodies, surgery combined w/ antibiotic therapy may be considered

Bartonella sp

  • Most cases of Bartonella sp IE have required antibiotic therapy & valve-replacement surgery for cure

Brucella sp

  • Few patients have been cured w/ antimicrobial agents alone; most require valve replacement in combination w/ antibiotics

Coxiella burnetii

  • Clinical response only persists as long as antimicrobial therapy continues; eradication is unlikely & reinfection of prosthetic material occurs after surgical replacement of infected valves

Pseudomonas aeruginosa

  • Most cases occur in IVDA & right-sided pseudomonal IE can usually be treated w/ antibiotic therapy w/ or w/o surgery
  • Valve replacement is usually considered mandatory in left-sided pseudomonal IE since medical therapy is rarely effective alone

Enterobacteriaceae sp

  • Susceptibility of these organisms can be unpredictable; therefore, treatment should be based on susceptibility testing
RECOMMENDED ANTIMICROBIAL THERAPY
Choice of therapy will depend on results of culture & sensitivity, patient's allergy profile, patient status & CV risk factors. If possible, reserve Teicoplanin & Vancomycin for patients w/ severe Penicillin allergy.
Pathogen NVE PVE
Viridans group streptococci,
Streptococcus bovis
Penicillin-susceptible
Ceftriaxone IV x 4 wk Ceftriaxone IV x 6 wk w/ or
w/o
Gentamicin x 2 wk
Penicillin or Amoxicillin IV x 4 wk
Penicillin IV or Ceftriaxone IV x 2 wk plus
Gentamicin IV x 2 wk
Penicillin IV x 6 wk w/ or w/o Gentamicin x 2 wk
Vancomycin IV x 4 wk Vancomycin IV x 4 wk
Viridans group streptococci,
Streptococcus bovis

Penicillin-relatively resistant
(Pen MIC >0.12 but ≤0.5 mg/L)
Ceftriaxone IV x 4 wk plus
Gentamicin x 2 wk
Ceftriaxone IV x 6 wk plus
Gentamicin x 6 wk
Penicillin or Amoxicillin IV x
4 wk plus
Gentamicin IV x 2 wk
Penicillin IV x 6 wk plus
Gentamicin IV x 6 wk
Vancomycin x 4 wk Vancomycin x 6 wk
Viridans group streptococci,
Streptococcus bovis
Penicillin resistant (Pen MIC >0.5 mg/L)
or Enterococci strains susceptible to Penicillin, Gentamicin
Ampicillin IV x 4-6 wk
Penicillin IV x 4-6 wk plus Gentamicin IV x 4 wk (6 wk in complicated cases)
Vancomycin IV x 6 wk plus Gentamicin IV x 6 wk
Enterococci strains susceptible to Penicillin, Streptomycin & Vancomycin but resistant to Gentamicin or Enterococci strains susceptible to Penicillin, Gentamicin Ampicillin IV x 4-6 wk plus Streptomycin IV x 4-6 wk
Penicillin IV x 4-6 wk plus Streptomycin IV x 4-6 wk
Vancomycin IV x 6 wk plus Streptomycin IV x 6 wk
Enterococci strains resistant to Penicillin & susceptible to aminoglycoside & Vancomycin Beta-lactamase - producing strain:
Ampicillin-sulbactam x 6 wk plus Gentamicin x 6 wk
Vancomycin x 6 wk plus Gentamicin x 6 wk
Intrinsic Penicillin resistance:
Vancomycin x 6 wk plus Gentamicin x 6 wk
Enterococci strains resistant to Penicillin, aminoglycoside & Vancomycin E faecium:
Linezolid IV/PO x ≥8 wk
Quinupristin-dalfopristin x ≥8 wk
E faecalis:
Imipenem x ≥8 wk plus Ampicillin IV x ≥8 wk
Ceftriaxone x ≥8 wk plus Ampicillin IV x ≥8 wk
Methicillin-susceptible S aureus (MSSA) Antistaphylococcal Penicillin IV x 4-6 wk w/ optional addition of Gentamicin IV x 3-5 days Antistaphylococcal penicillin IV x ≥6 wk
plus
Rifampicin IV x ≥6 wk
plus
Gentamicin IV x 2 wk
Antistaphylococcal Penicillin IV x 4-6 wk plus Fusidic acid PO x 4-6 wk
For Penicillin-allergic patients:
Cephalosporin (1st gen) IV x 6 wk w/ optional addition of
Gentamicin IV x 3-5 days
Vancomycin x 6 wk
Methicillin-resistant S aureus (MRSA) 1st-line agent:
Vancomycin x 4 wk
Vancomycin IV x ≥6 wk plus
Rifampicin IV x ≥6 wk plus
Gentamicin IV x 2 wk
Vancomycin treatment failure/intolerance may try the following:
Linezolid or
Co-trimoxazole, Doxycycline or
Minocycline w/ or w/o
Rifampicin
Right-sided MSSA in uncomplicated IE in IVDA Antistaphylococcal penicillin IV x
2 wk plus Gentamicin IV x 2 wk
-
Ciprofloxacin PO x 4 wk plus
Rifampicin PO x 4 wk
HACEK organisms Ceftriaxone x 4 wk Ceftriaxone x 6 wk
Ampicillin/sulbactam IV x 6 wk
Ciprofloxacin IV/PO x 6 wk
Ampicillin/sulbactam IV x 4 wk
Ciprofloxacin IV/PO x 4 wk
Culture-negative endocarditis caused by uncommon organisms including Bartonella sp Ampicillin/sulbactam IV x 4-6 wk plus Gentamicin IV x 4-6 wk Early, PVE (≤1 yr)
Vancomycin IV x 6 wk plus
Gentamicin IV x 2 wk plus
Cefepime x 6 wk plus
Rifampicin PO/IV x 6 wk plus
Late, PVE (>1 yr), Culture negative
Ceftriaxone IV x 6 wk plus
Gentamicin IV x 2 wk w/ or w/o
Doxycycline IV/PO x 6 wk
Late, PVE (>1 yr), Bartonella confirmed
Doxycycline IV/PO x 6 wk plus
Gentamicin IV x 2 wk
Vancomycin IV x 4-6 wk plus
Gentamicin IV x 4-6 wk plus
Ciprofloxacin IV/PO x 4-6 wk
Culture-negative endocarditis in patients who received antibiotics prior to blood culture Acute symptoms of NVE:
Treat as in NVE for MSSA
Subacute symptoms of NVE:
Treatment should cover MSSA, viridans streptococci, enterococci; HACEK may be considered
Ampicillin/sulbactam plus
Gentamicin x 4-6 wk
Early, PVE (≤1 yr)
Treat as in MRSA, Add Cefepime to cover aerobic Gram-negative bacilli
Late, PVE (>1 yr), Culture negative Treatment should cover MSSA, viridans streptococci & enterococci x 6 wk
Pseudomonas aeruginosa Treatment should be based on in vitro sensitivity studies
Antipseudomonal beta-lactam x 6 wk plus high-dose Tobramycin x 6 wk
Treatment should be based on in vitro sensitivity studies Antipseudomonal beta-lactam plus Tobramycin
Enterobacteriaceae sp
(E coli, Klebsiella sp, Enterobacter sp & Serratia sp)
Treatment should be based on in vitro sensitivity studies
Beta-lactam at high doses x 4-6 wk plus Gentamicin x 4-6 wk
Treatment should be based on in vitro sensitivity studies Beta-lactam at high doses plus Gentamicin
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