Bacteremia and Endocarditis

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Bacteremia and Endocarditis

• September 26th, 2005

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Blood Cultures

• 2 sets, gt15 minutes apart
• Now continuous monitoring
• No entry of bacteria for monitoring
• lysis-centrifugation system (Isolator) used for
  either routine bacteria, fungi, mycobacteria, or
  fastidious organisms such as Bartonella or
  Brucella
• Labor intensive
• More contamination

• Technique
• 70 alcohol, followed by tincture of iodine (1
  minute) or povidone iodine (2 minutes).
• septum of the culture bottle or tube need only be
  wiped with 70 alcohol
• transported to the laboratory promptly
• volume of blood cultured and the number of sets
  drawn are particularly important
• current recommendations for adults are to draw at
  least two separate blood cultures totaling 30 to
  40 ml of blood.
• Separate venipunctures should be performed to
  help interpret cultures that contain skin flora

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Classification of Bacteremia

• Community-acquired
• Nosocomial
• Healthcare-associated Bacteremia
• indwelling catheters
• HD
• receiving other outpatient therapy
• Wound care
• nursing home residents

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Friedman Ann Intern Med, Volume 137(10).November
19, 2002.791-797
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Martin N Engl J Med, Volume 348(16).April 17,
2003.1546-1554
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Infectious Endocarditis (IE)

• Traditional risk factor of RHD decreasing, newer
  factors increasing
• Emergence of enterococci and Staph, particularly
  MRSA and VRE, also VISA and VRSA
• Viridans Strep now emerging MDR strains
• Subtypes
• native value IE
• RHD
• MVP (10-100 fold increased risk if regurgitant)
• Degenerative/inherited valve disorders
• prosthetic valve IE
• Early (Staph epi, Staph aureus)
• Late (Strep, HACEK)
• IE in intravenous drug users
• Healthcare-associated IE
• nosocomial IE

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Microbiologic Etiology in 1779 Patients With
Definite Endocarditis From   Fowler JAMA,
Volume 293(24).June 22/29, 2005.30123021
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Trends in Age- and Sex-Adjusted Incidence Rates
of Infective Endocarditis Caused by
Staphylococcus aureus and Viridans Group
Streptococci From 1970 to 2000 in Olmsted County,
Minnesota From   Tleyjeh JAMA, Volume
293(24).June 22/29, 2005.30223028
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IDU-associated IE

• median age 30 and 40 yrs
• up to 40 of cases of IE in San Francisco
• tricuspid valve gt 50 of cases, aortic in 25,
  mitral in 20, mixed right- and left-sided IE
  unusual.
• injections of impure drugs and particulates might
  produce microtrauma to the tricuspid leaflets,
  facilitating microbial colonization
• 2040 of IDU with IE have pre-existing cardiac
  lesions
• Bacteria often originate from the skin
• streptococci and others also seen
• Pseudomonas aeruginosa and fungi may produce
  severe IE.
• mortality of IE higher in patients who have AIDS

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Nosocomial IE

• The incidence is increasing.
• Many patients have other debilitating underlying
• lt 50 had obvious cardiac predisposing factors
• In most circumstances a potential source of
  bacteremia could be identified, (lines,
  procedures)
• staphylococci and enterococci most common
• other organisms-Gram-negative bacteria and fungi.
  
• Right-sided IE is increasingly recognized in
  association with central venous lines, pulmonary
  artery catheters and pacemakers.
• procedures that produce transient bacteremia
  represent risk in hospitalized patients,
  especially when the circulating organism is S.
  aureus.
• mortality of nosocomial IE is greater than 50.

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Culture-negative IE

• HACEK
• Haemophilus spp.
• Actinobacillus actinomycetemcomitans
• Cardiobacterium hominis
• Eikenella corrodens
• Kingella kingae
• Nutritionally-deficient Strep spp.
• Fastidious GNR

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Culture-negative IE

• Coxiella burnetii (Q fever)
• Brucella
• Bartonella quintana
• Chlamydia
• Tropheryma whippelii

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Pathogenesis

• Basic lesion is endothelial damage
• IE pathogens possess surface ligands that mediate
  attachment to extracellular matrix proteins of
  the host (MSCRAMMs)
• direct invasion of endothelial cells may also
  occur
• Transient bacteremias occur during chewing,
  toothbrushing and other normal activities, and
  from more invasive procedures

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Microscopic appearance of a vegetation from a
patient suffering mitral valve infective
endocarditis due to Streptococcus sanguis. The
purple area represents clusters of streptococci
packed within a fibrin-platelet meshwork.
Professional phagocytes are essentially absent
from the lesion.
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IE Prophylaxis

• Goals
• identification of patients at risk
• determination of the procedures or circumstances
  that may result in bacteremias
• choice of an appropriate antimicrobial regimen
  and
• balancing of the known risks against the possible
  benefits of intervention.
• No controlled studies
• Regimens used in humans are based upon their
  proven efficacy in animal models of IE
• successful prophylaxis does not require
  bactericidal antibiotics
• Antiseptic mouth rinses applied immediately prior
  to dental procedures may reduce the incidence or
  magnitude of bacteremia
• Cover most probable pathogens circulating in the
  blood during a given procedure
• oropharyngeal manipulation-streptococci
• gastrointestinal or urogenital manipulations, it
  should be aimed at enterococci (plus results of a
  preprocedure urine culture)
• skin or other infected lesions-staphylococci
• If already on antibiotics, choose another class.

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Cardiac Conditions Associated With Endocarditis
Endocarditis prophylaxis recommended
   High-risk category
      Prosthetic cardiac valves, including bioprosthetic and homograft valves
      Previous bacterial endocarditis
      Complex cyanotic congenital heart disease (eg, single ventricle states, transposition of the great arteries, tetralogy of Fallot)
      Surgically constructed systemic pulmonary shunts or conduits
   Moderate-risk category
      Most other congenital cardiac malformations (other than above and below)
      Acquired valvar dysfunction (eg, rheumatic heart disease)
      Hypertrophic cardiomyopathy
      Mitral valve prolapse with valvar regurgitation and/or thickened leaflets1

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Endocarditis prophylaxis not recommended
   Negligible-risk category (no greater risk than the general population)
      Isolated secundum atrial septal defect
      Surgical repair of atrial septal defect, ventricular septal defect, or patent ductus arteriosus (without residua beyond 6 mo)
      Previous coronary artery bypass graft surgery
      Mitral valve prolapse without valvar regurgitation (risk only increased if prolapse and regurg)
      Physiologic, functional, or innocent heart murmurs1
      Previous Kawasaki disease without valvar dysfunction
      Previous rheumatic fever without valvar dysfunction
      Cardiac pacemakers (intravascular and epicardial) and implanted defibrillators
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AHA, 1997
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Diagnosis

• Duke criteria
• Classic exam/lab findings
• Osler nodes
• Splenomegaly
• Janeway lesions
• Microscopic hematuria
• Elevated ESR and CRP
• Septic pulmonary emboli (right)
• Classic findings may be absent
• Repeating TEE 7 to 10 days after an initial
  "negative" result may be advisable
• Posttreatment echocardiography is recommended

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Peripheral Stigmata of IE

• Osler nodesmall, raised, tender cutaneous
  lesion, usually on the pads of fingers or toes
  (vasculitic)
• Janeway lesionflat, painless small hemorrhages
  with a slightly nodular appearance that occur on
  the palms and soles (septic emboli)
• Splinter hemorrhages
• Petechiae
• Roth spotshemorrhage in the retina with a white
  center

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Definite infective endocarditis
    Pathological criteria
        Microorganisms demonstrated by culture or histological examination of a vegetation, a vegetation that has embolized, or an intracardiac abscess specimen
        Pathological lesions vegetation or intracardiac abscess confirmed by histological examination showing active endocarditis
    Clinical criteria
        2 major criteria or
        1 major criterion and 3 minor criteria or
        5 minor criteria
    Possible IE
        1 major criterion and 1 minor criterion or
        3 minor criteria
    Rejected
        Firm alternative diagnosis explaining evidence of IE or
        Resolution of IE syndrome with antibiotic therapy for lt4 days or
        No pathological evidence of IE at surgery or autopsy, with antibiotic therapy for lt4 days or
        Does not meet criteria for possible IE as above
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Major criteria
     Blood culture positive for IE
        Typical microorganisms consistent with IE from 2 separate blood cultures Viridans streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus or community-acquired enterococci in the absence of a primary focus or
        Microorganisms consistent with IE from persistently positive blood cultures defined as follows At least 2 positive cultures of blood samples drawn gt12 h apart or all of 3 or a majority of  4 separate cultures of blood (with first and last sample drawn at least 1 h apart)
        Single positive blood culture for Coxiella burnetii or antiphase 1 IgG antibody titer gt1800
    Evidence of endocardial involvement
        Echocardiogram positive for IE defined as follows oscillating intracardiac mass on valve or supporting structures, in the path of regurgitant jets, or on implanted material in the absence of an alternative anatomic explanation or abscess or new partial dehiscence of prosthetic valve new valvular regurgitation (worsening or changing or preexisting murmur not sufficient)
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Minor criteria
    Predisposition, predisposing heart condition, or IDU
    Fever, temperature gt38C
    Vascular phenomena, major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeways lesions
    Immunologic phenomena glomerulonephritis, Oslers nodes, Roths spots, and rheumatoid factor
    Microbiological evidence positive blood culture but does not meet a major criterion as noted above or serological evidence of active infection with organism consistent with IE
    Echocardiographic minor criteria eliminated
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Surgery

• Indication
• Severe CHF (reduced mortality with surgery)
• Persistent bacteremia
• Certain pathogens (fungal, GNR)
• Embolic events
• Large vegetation on mitral valve highest risk
• Valve abscess/dehiscence
• Timing
• 7-fold higher risk of recurrent IE if valve
  replaced during active infection

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Treatment

• If using synergistic agents give them together
• Day 1 is first day documented negative blood
  cultures
• postoperative treatment regimen should be one
  that is recommended for prosthetic valve
  treatment rather than one that is recommended for
  native valve treatment
• Start over if cultures positive

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Viridans Strep

• community-acquired native valve endocarditis in
  patients who are not intravenous drug users
  (IDUs).
• -hemolytic
• S sanguis, S oralis (mitis), S salivarius, S
  mutans, and Gemella morbillorum (formerly called
  S morbillorum).
• S anginosus group (S intermedius, anginosus, and
  constellatus) aka S milleri group
• tends to form abscesses and cause hematogenously
  disseminated infection (eg, myocardial and
  visceral abscesses, septic arthritis, vertebral
  osteomyelitis).
• S intermedius usually is sensitive to penicillin,
  but some strains may exhibit variable penicillin
  resistance.

• Abiotrophia defectiva and Granulicatella species
  (G elegans, G adiacens, G paraadiacens, and G
  balaenopterae formerly known as nutritionally
  variant streptococci),
• have nutritional deficiencies that hinder their
  growth
• Gemella (morbillorum, bergeriae, sanguinis, and
  hemolysans)
• share some physiological characteristics with
  nutritionally variant streptococci
• should be treated with more aggressive
  combination therapy
• S bovis expresses the group D antigen, but it can
  be distinguished from group D Enterococcus by
  appropriate biochemical tests.
• should undergo colonoscopy

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Treatment

• Native valve, highly susceptible viridans Strep
  or Strep bovis (MIC lt.12)
• Aq Pen G x 4 wks
• Rocephin x 4 wks
• Aq Pen G gent x 2 wks (synergy)
• Rocephin gent x 2 wks
• Vanc x 4 wks
• Viridans Group Streptococci and S bovis With
  Penicillin MIC gt0.12 to 0.5 µg/ml
• Aq pen or Rocephin x 4 wks gent 1st 2 wks
  (single daily dose)
• vancomycin

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Treatment

• A defectiva, Granulicatella species, and Gemella
  species and a microorganism with an MIC to
  penicillin gt0.5 µg/mL should be treated with a
  regimen that is recommended for enterococcal
  endocarditis
• prosthetic valves should receive 6 weeks of
  therapy with penicillin or ceftriaxone with or
  without gentamicin for the first 2 weeks
• S pneumoniae, S pyogenes, and Groups B, C, and G
  Streptococci
• highly penicillin-susceptible S pneumoniae should
  receive 4 weeks of antimicrobial therapy with
  penicillin, cefazolin, or ceftriaxone
• High-dose penicillin or a third-generation
  cephalosporin can be used in patients with
  penicillin-resistant infection and without
  meningitis
• If the isolate is resistant (MIC 2 µg/mL) to
  cefotaxime, then the addition of vancomycin and
  rifampin should be considered.
• Consider gentamicin for at least the first 2
  weeks of a 4- to 6-week course of antimicrobial
  therapy for group B, C, and G strep (relatively
  pen res)
• Aq pen G for Gp A

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Coagulase-negative Staph (CoNS)

• Usually associated with PVE
• Occasionally native valve, usually damaged
• More indolent than Staph aureus
• Staph lugdinensis more virulent

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Staph aureus endocarditis

• Nosocomial bacteremia previously thought to be
  lower risk for endocarditis
• health careassociated infection was the single
  most common form of S aureus IE
• health careassociated IE is distinguished by a
  relative infrequency of classic clinical stigmata
  of IE

• S aureus bacteremia associated with health care
  has increased among hospitalized patients and
  among those receiving outpatient medical therapy
• MRSA in both hospital and community increased
  dramatically
• implanted medical devices
• prosthetic heart valves
• grafts
• hemodialysis catheters
• pacemakers

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Endocarditis

• Factors associated with Staph aureus SBE
• Native valve
• Hemodialysis
• Invasive procedures
• Other chronic disease
• Multiple pulmonary emboli
• Intravascular device source
• Tricuspid
• Healthcare-associated
• IDU-associated
• Persistent bacteremia, emboli requiring surgery
• Complications including stroke, other emboli,
  death
• Factors associated with non-Staph aureus SBE
• Aortic valve
• Prosthetic valve
• Congenital heart disease
• Dental work
• Symptoms gt1 month

International Collaboration on Endocarditis-Prospe
ctive Cohort Study from June 2000 to December
2003.
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Figure. In-Hospital Mortality Rates Among
Patients With Health CareAssociated
Staphylococcus aureus Endocarditis. Includes both
nosocomial and nonnosocomial health
careassociated infections, community-acquired
injection drug useassociated S aureus
endocarditis, and community-acquired noninjection
drug useassociated S aureus endocarditis by
geographic region. From   Fowler JAMA, Volume
293(24).June 22/29, 2005.30123021
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Table 4. Clinical Characteristics and Outcomes
of 424 Prospectively Identified Patients With
Definite Endocarditis Due to Methicillin-Susceptib
le and Methicillin-Resistant Staphylococcus
aureus From   Fowler JAMA, Volume
293(24).June 22/29, 2005.30123021
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Treatment

• Staph aureus IDU (right)
• parenteral ß-lactam /- gent x 2 wks
  (uncomplicated)
• Oral also effective (Cipro rifampin x 4 wks)
• Vancomycin requires 4 wks
• Staph aureus non-IDU
• Beta lactam x 4-6wks, gent 1st few days if
  fulminant
• Faster clearance of bacteremia
• Not better mortality
• Vanc only if anaphylactoid history to PEN
• Clinda not recommended, high relapse rate
• Consider desensitizing or daptomycin.
• PVE add gentamicin for 2 wks, plus rifampin full
  6 wks

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Treatment

• MRSA
• Vancomycin (same gent caveats, plus possible
  increased ototox)
• Linezolid
• Synercid
• Daptomycin
• PVE add gentamicin for 2 wks, plus rifampin full
  6 wks
• CoNS
• Assume meth-resistant
• Vancomycin for 6 wks
• PVE add gentamicin for 2 wks, plus rifampin full
  6 wks

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Enterococci

• Group D
• test MICs to penicillin and vancomycin and for
  high-level resistance to gentamicin and
  streptomycin
• trough antibiotic concentration in serum must be
  maintained above the MIC.
• relatively resistant to penicillin, ampicillin,
  and vancomycin.
• requires the synergistic action of penicillin,
  ampicillin, or vancomycin in combination with
  either gentamicin or streptomycin.
• relatively impermeable to aminoglycosides.
• cell wallactive agents raise the permeability of
  the enterococcal cell so that a bactericidal
  effect can be achieved
• If resistant to high concentrations of an
  aminoglycoside (500 µg/mL of gentamicin or 1000
  µg/mL of streptomycin), then the combination of
  an aminoglycoside with the cell wallactive agent
  will not result in bactericidal activity, nor
  will it predictably produce a microbiological
  cure.
• lt3 months duration of symptoms 4 weeks gt3
  months duration of symptoms 6 weeks
• PVE 6 wks

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Enterococci

• Beta lactam resistant-vancomycin
• VRE
• vancomycin-resistant E faecalis and E
  gallinarum/casseliflavus usually are penicillin
  susceptible
• Linezolid
• Daptomycin
• Synercid (faecium only)

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HACEK

• fastidious Gram-negative bacilli (grow slowly )
• Haemophilus parainfluenzae, H aphrophilus, H
  paraphrophilus, H influenzae, Actinobacillus
  actinomycetemcomitans, Cardiobacterium hominis,
  Eikenella corrodens, Kingella kingae, and K
  denitrificans
• 5-10 of native valve community-acquired IE in
  non IDUs
• hold blood cultures for 2 wks in patients
  suspected of having IE.

• ß-lactamaseproducing strains increasing
• should be considered ampicillin resistant
• susceptible to ceftriaxone, ampicillin-sulbactam,
  and fluoroquinolones.
• limited published clinical data
• duration of therapy for native valve infection
  should be 4 weeks
• prosthetic valve 6 weeks
• bacteremia caused by HACEK is highly suggestive
  of endocarditis

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Other Gram-negatives

• IDU, prosthetic valve, and cirrhosis are risk
  factors
• Enterobacteriaceae
• Salmonella species have an affinity for abnormal
  cardiac valves
• Valvular perforation, atrial thrombi,
  myocarditis, and pericarditis are common
• Salmonellae also may produce endarteritis in
  aneurysms of major vessels. Other
  Enterobacteriaceae, including
• E coli and Serratia marcescens, may rarely cause
  endocarditis
• S marcescens endocarditis typically develops in
  IDUs.
• Left-sided disease, large vegetations, and
  involvement of normal valves
• mortality rates are 70.

• Cardiac surgery is a cornerstone of treatment
• Combinations of pens/cephs and aminoglycosides
  have been shown to be synergistic
• E. coli or Proteus mirabilis, a combination of
  either ampicillin or penicillin or a
  broad-spectrum ceph aminoglycoside, usually
  gent
• Endovascular Salmonella infections also may
  respond to third-generation cephalosporins.
• combination of a third-generation cephalosporin
  and an aminoglycoside (either gentamicin or
  amikacin) is recommended for Klebsiella
  endocarditis.

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Pseudomonas

• Nearly all IDUs
• Associated with tripelennamine and pentazocine
  ("Ts and blues")
• mean age 30 years
• affects normal valves
• Major embolic phenomena, inability to sterilize
  valves, neurol complications (53), ring and
  annular abscesses, splenic abscesses, bacteremic
  relapses, and rapidly progressive CHF are common.
  
• many authorities recommend early surgery for
  left-sided Pseudomonas endocarditis
• High-dose regimens of antipseudomonal penicillins
  combined with aminoglycosides are used minimum 6
  weeks
• Medical therapy works in P aeruginosa IE
  involving the right side of the heart in 50 to
  75

• partial tricuspid valvulectomy or "vegetectomy
  if failure
• quinolones (in combination with an
  aminoglycoside) appear promising, based on
  favorable results in animal models and humans,
  but development of stepwise resistance during
  therapy may limit the efficacy
• ceftazidime-tobramycin is preferred over
  aztreonam-tobramycin
• 7 cases of P aeruginosa endocarditis have been
  successfully treated with imipenem plus an
  aminoglycoside
• potential for the development of resistance
  exists with any of these regimens.

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Culture-negative IE

• Why?
• Antibiotics prior
• Cover your bases i.e. Staph, Strep, enterococcus
• Fastidious organism (Rocephin gent doxy)
• Bartonella
• Brucella
• Q fever
• Whipples
• Chlamydia
• Not infectious
• Marantic
• Autoimmune
• Neoplastic

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Fungal IE

• often a complication of medical and surgical
  advances
• usually have multiple predisposing conditions
  (cardiovascular devices, prosthetic cardiac
  valves and central venous catheters)
• mortality rates for fungal endocarditis are very
  high.
• survival rate for patients with mold-related
  endocarditis is lt20.
• Candida and Aspergillus species account for the
  large majority

• Historically, is an indication for surgical
  replacement of an infected valve.
• amphotericin B, a fungicidal agent, is the drug
  of choice
• antifungal therapy usually is given for 6 weeks.
  
• long-term (lifelong) suppressive therapy with an
  oral azole

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Predisposing Conditions in FE From   Pierrotti
Chest, Volume 122(1).July 2002.302-310
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Complications of FE From   Pierrotti Chest,
Volume 122(1).July 2002.302-310
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Complications of IE

• Cardiovascular
• CHF
• MI
• Mycotic aneurysms
• Embolic
• CVA
• Peripheral
• Organ
• Bowel
• Peripheral arteries
• spleen

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