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ELUSIVE BUG?!!
Gebre K Tseggay, MD
November 30, 2005
The Patient
• 73yo WF with h/o MV-repair, presented with a dry cough and
worsening shortness of breath which started as a “chest cold” 2
weeks earlier. She denied subjective fever or chills, but reported
several weeks h/o fatigue and significant limitation in her daily
activities. She denied ill contacts. A CXR suggested a RLL
infiltrate and levofloxacin was started in the ER. Although she
did not have fever in the ER, she had intermittent, mostly lowgrade fever after admission.
• TEE, done 4 days into Rx, showed two mitral valve annular
vegetations.
•
Endocarditis was presumed and ID consult called.
• PMH/PSH:
– Severe MR (s/p MV-annuloplasty about a year ago), and has
had significant weight loss since her mitral valve surgery.
– Left nephrectomy for atrophic kidney (4 decades ago),
– Clipping of brain aneurysm (2 decades ago),
– Hypertension, osteoporosis, & essential tremor.
• MEDS: Levaquin 500mg q24h, Lovenox, ASA,
dobutamine.
• FH: N/C.
• SH: No cig, alcohol, drugs. She lives alone, but her
daughter lives next door. Volunteers regularly at an
elementary school.
• EPIDEMIOLOGIC Hx: No ill contacts, no recent
travel, no arthropod or other animal bites/scratches.
Last dental visit a year earlier. She has a dog, and has
bird cages in yard (but no pet birds). Her daughter has
cats.
• ALLERGY: Penicillin, Sulfa
• EXAM: Cachectic elderly pt. Alert, well oriented.
• T 97.8F, P 74, 22, BP 152/78, RR 20/min, O2Sat 89% on RA
• HEENT: PEERLA, EOMI, without conjunctival/buccal
mucosa petechiae.
• Lungs: Few crackles over rt base.
• Heart: RR, without murmur.
• Abd: soft, NT, normoactive BS, no HSM
• Ext: no e/c/c.
• Skin: without rash, no obvious peripheral stigmata of SBE.
•
•
•
•
•
•
WBC 5.2, Hgb 13.5, Plt 199K, BUN 16. cr 0.8.
ESR 20, CRP 8.4 mg/dL
BC : negative (was drawn after a dose of Levaquin)
CXR: RLL atelectasis vs infiltrate
EKG: SR, LVH, non-specific ST-T changes
TEE: Reduced LV systolic function and moderate-sized, mobile
vegetations attached to the posterior mitral valve ring.
Questions
A culture-negative infective endocarditis?
Vs
Vegetations of a non-infectious etiology?
Proposed scheme for the pathogenesis of infective endocarditis
NON-INFECTIOUS CAUSES Of
ENDOCARDITIS
• Antiphospholipid syndrome: Primary or Secondary
(e.g. w SLE or malignancies)
• Neoplasia Associated: Atrial Myxoma, Marantic
endocarditis, Carcinoid
• AI associated: Rheumatic carditis, SLE, PAN, Behcet’s
disease
• Postvalvular surgery: Thrombus, stitch, or other
postsurgical changes
• Miscellaneous: eosinophilic heart disease, ruptured
mitral chordae, myxomatous degeneration
AHA Scientific STATEMENT on infective endocarditis. Circulation. June 14, 2005
©2005 UpToDate®
Vegetations (arrows) due to viridans streptococcal
endocarditis involving the mitral valve.
CAN YOU HAVE INFECTIVE ENDOCARDITIS
with Negative Blood Cultures?
• Yes, BCx may be negative in up to 2.5-30% of IE due
to:
– Administration of abx before blood cultures
– Inadequate microbiological techniques
– Infection with highly fastidious bacteria
– Infection with nonbacterial pathogens
Impact of Taking Antibiotics Before Blood Cultures Are
Obtained
• It’s the leading cause of BC-negative IE.
• Reduces the recovery rate of bacteria by 35-40%.
– The length of time the BCx will remain negative is determined by
the susceptibility of the organism and the duration of antibiotic
use before blood cultures are drawn.
– BC of pts who receive longer course of high dose, bactericidal
abx may remain negative for weeks.
– If the initial BCx were negative after only a few days of abx,
infective endocarditis pts may have a positive BCx after only
several days without antibiotics.
Tunkel AR, Kaye D. N Engl J Med. 1992; 20: 1215–1217
Back to Our Patient
• Antibiotic (levofloxacin) was discontinued on day 5
• How long can you safely hold antibiotics?
– “If the initial blood cultures are negative, a delay of 2 to 4 days
will allow additional blood cultures to be obtained without the
confounding effect of further antibiotic therapy and without
increased morbidity from IE.”
Circulation. 1998;98:2936-2948. AHA Scientific Statement
• Blood cultures were taken daily (and some held for 3
weeks).
• UNFORTUNATELY, ALL BLOOD CULTURES
REMAINED NEGATIVE!!
ARE THE CRITERIA FOR DIAGNOSIS OF
INFECTIVE ENDOCARDITIS APPLICABLE
EVEN IN PATIENTS WITH NEGATIVE
BLOOD CULTURES?
Definition of Infective Endocarditis
According to the Modified Duke Criteria
I. Definite IE
Pathological criteria
• Microorganisms demonstrated by culture or histological examination of a
vegetation, a vegetation that has embolized, or an intracardiac abscess
specimen; or
• 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
II. Possible IE
• 1 major criterion and 1 minor criterion; or
• 3 minor criteria
III. Rejected
- Firm alternative diagnosis explaining evidence of IE; or
- Resolution of IE syndrome with antibiotic therapy for <4 days; or
- No pathological evidence of IE at surgery or autopsy, with antibiotic therapy
for <4 days; or
- Does not meet criteria for possible IE as above
MAJOR CRITERIA
1. POSITIVE BLOOD CULTURE
• Typical microorganism for infective endocarditis from two separate blood cultures
-Viridans streptococci, Streptococcus bovis, HACEK group, Staphylococcus aureus, or
-Community-acquired enterococci in the absence of a primary focus, or
•
Persistently positive blood culture, defined as recovery of a microorganism consistent with
infective endocarditis from:
Blood cultures drawn >12 h apart; or
All of 3 or a majority of 4 or more separate blood cultures, with first and last drawn at least 1 h apart
• Single positive blood culture for Coxiella burnetii or phase I IgG antibody titer of >1:800
2. EVIDENCE OF ENDOCARDIAL INVOLVEMENT
• Positive echocardiogram
Oscillating intracardiac mass on valve or supporting structures or in the path of regurgitant jets or in
implanted material, in the absence of an alternative anatomic explanation, or
-
•
Abscess, or
New partial dehiscence of prosthetic valve, or
New valvular regurgitation (increase or change in preexisting murmur not sufficient)
MINOR CRITERIA
1. Predisposition: predisposing heart condition or injection drug use
2. Fever > 38.0°C (> 100.4°F)
3. Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial
hemorrhage, conjunctival hemorrhages, Janeway lesions
4. Immunologic phenomena: glomerulonephritis, Osler's nodes, Roth's spots, rheumatoid factor
5. Microbiologic evidence: positive blood culture but not meeting major criterion as noted previously or
serologic evidence of active infection with organism consistent with IE
BACK TO OUR PATIENT
(and The Modified Duke Criteria)
•
•
•
•
Has evidence of endocardial involvement = I major criterion
Has a predisposing condition = 1 minor criterion
Has fever = 1 minor criterion
1 major + 2 minor criteria= ‘Possible’ infective endocarditis
Definite IE
2 major criteria
1 major criterion and 3 minor criteria
5 minor criteria
Possible IE
1 major criterion and 1 minor criterion
3 minor criteria
Not a Duke’s Criteria, but……….
CULTURE-NEGATIVE
ENDOCARDITIS
JAMA. Vol. 293 No. 24, June 22/29, 2005
ETIOLOGY OF CULTURE-NEGATIVE INFECTIVE
ENDOCARDITIS
– Partially-treated bacteria.
– Fastidious bacteria.
– Non-bacterial pathogens (e.g., fungi)
Fastidious bacterial endocarditis:
–
–
–
–
–
–
–
–
–
HACEK (Haemophilus sp, Actinobacter, Cardiobacterium, Eikenella, Kingella)
Abiotrophia spp
Bartonella quintana, B. henslae
Q-fever
Brucellosis
Whipple’s…
Chlamydia …
Mycoplasma…
Other?
Relative frequency of bacteria as etiologic agents of IE
(Only infectious agents reported more than 50 times in the literature are listed)
•
Bacterium
•
•
•
•
•
•
•
•
•
No. of cases reported
Coxiella burnetii
Brucella spp.
Abiotrophia spp.
Actinobacillus actinomycetemcomitans
Haemophilus aphrophilus
Cardiobacterium hominis
Corynebacterium diphtheriae
Haemophilus parainfluenzae
Listeria monocytogenes
359
120
100
93
78
76
67
66
58
Clinical Microbiology Reviews, January 2001, p. 177-207, Vol. 14, No. 1
Blood Culture-Negative Endocarditis in a Reference
Center(1983-1991): Etiologic Diagnosis of 348 Cases
French National Reference Center for Rickettsial Diseases
• C. burnetii
• Bartonella sp
• Rare fastidious agents
167 (48%)
99 (28%)
5 (1%)
(e.g T. whipplei, Mycoplasma hominis, Abiotrophia elegans and Mycoplasma hominis)
Among those with IE but with unidentified etiology:
• Took abx before blood cultures
79%
• No etiology OR explanation found
1%
Houpikian P and Raoult D Medicine 2005;84:162
•
•
•
•
•
Epidemiological Clues in Etiological Diagnosis of Culture-Negative
Endocarditis
Poor dental health, dental
• Alcoholism
procedures
– Bartonella
– Strep viridans
– Aeromonas sp
– Nutrionally variant streptococci
– Listeria
– Abiotrophia defectiva
– S.pneumoniae
– Granulicatella sp
– B-hem strep
– Gemella sp
– HACEK
• AIDS
Homeless, body lice
– Salmonella
– Bartonella sp
– Strep pneumo
Dog-cat exposure
– Staph aureus
– Bartonella
– Pasteurella sp
• Injection Drug user
– Capnocytophaga sp
– S.aureus
Contact with contaminated milk
– Coag-neg staph
– Brucella
– B-hem strep
– Coxiella burnetii
– Fungi
– Erysipelothrix sp
– Aerobic GNR (including Ps.a)
Gastrointestinal lesions
– Streptococcus bovis
– Enterococcus
– Clostridium septicum
Culture-negative Endocarditis
Diagnosis
HISTORY
Contact with animals; for example contact with:
• a cat (including scratches or bites) or cat flea suggests Bartonella henselae
or Pasteurella spp.
• Cattle should suggest a role for C. burnetii or Brucella spp.
• Parrots, pheasants, and pigeons have been reported to play a role in
Chlamydia psittaci endocarditis
• Domestic animals such as swine, fish, and poultry is frequently reported in
the history of patients with Erysipelothrix endocarditis.
• The human body louse is involved in the transmission of Bartonella
quintana
Dental procedure may suggest HACEK group bacteria
Occupational exposure
• Farmers and veterinarians are exposed to both C. burnettii and
Erysipelothrix.
• Butchers, fishermen, and even in homemakers by contact with organic
matter in which the Erysipelothrix is commonly found
Culture-negative Endocarditis
Laboratory Diagnosis
•Blood cultures
- Hold for prolonged incubation (> 2-3wks)
- Other culture techniques (media supplements, lysis-centrifugation, etc..)
•Serology
•Antigen Testing
•Valve Culture
•Histopathology
•PCR
[specific, broad-based (16s rDNA)]
Abiotrophia spp. (formerly known as nutritionally deficient streptococci)
showing satellite growth with Staphylococcus aureus.
Unité des Rickettsies, Marseilles, France
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Immunohistochemical demonstration of Coxiella burnetii in a heart valve of a patient with
Q fever endocarditis. Magnification, ×600. Immumoalkaline phophatase staining was
used.
©2005 UpToDate®
Pathogen
Diagnostic procedure
Brucella spp.
Blood cultures
Serology
Culture, immunohistology and PCR of surgical material
Coxiella burnetii (agent of Q Serology: IgG phase 1 > 1/800
fever)
Bartonella spp.
Tissue culture, immunohistology and PCR of surgical
material
Blood cultures
Serology
Culture, immunohistology and PCR of surgical material
Chlamydia spp.
Serology §
Culture, immunohistology and PCR of surgical material
Mycoplasma spp.
Serology
Culture, immunohistology and PCR of surgical material.
Legionella spp.
Blood cultures
Serology
Culture, immunohistology and PCR of surgical material.
Tropheryma whippelii
(agent of Whipple's disease)
Histology and PCR of surgical material
Culture-negative Endocarditis
Treatment
– Selection of the antibiotics is very difficult
– May expose to unnecessary toxicity, e.g. using
aminoglycosides
– Usual treatment directed at the more common
bacterial pathogens, by considering:
• Epidemiologic features
• Clinical course
When Choosing Empiric Abx for CNBE
Classify pts into two Groups:
1. Those who received abx prior to collection of blood cultures:
Native valve:
• Acute presentation (Staph aureus>>)
• Subacute presentation (S.aureus, strep viridans, enterococci, HACEK)
Prosthetic valve:
• Within the year post-valve surgery (MRSA/MRSE>>)
• > I year after surgery: (OSSA, Strep viridans, enterococci)
2. Organisms that do not grow in routinely used blood culture systems:
• Bartonella, Chlamydia, Coxiella burnetti, Brucella, Legionella species,
Tropheryma whippleii, non-candida fungi.
• Bartonella(quintana>henslae)>>, Coxiella b, and Brucella may be the most
commonly identified causes of CNBE
(or both?)
Treatment of Some Agents of
Culture-negative Endocarditis
PATHOGEN
TREATMENT
DURATION
•
Brucella sp
Doxy + rifampin or trim/sulfa
>3 mos
•
Coxiella burnetti
Doxy + hydroxychloroquine or
Doxy+ quinolone
>18 mos
>6 mos
•
Bartonella sp
beta-lactams or doxy and aminoglycosides
•
Chlamydia
Doxy (newer quinolones?)
•
Mycoplasma
Doxy (quinolones?)
>3 mos
•
Legionella
macrolide + rifampin or newer quinolones
>6 mos
•
Whipple’s
>1yr
•
HACEK
Trim/sulfa
Beta lactam + aminoglycosides
ceftriaxone (or ampicillin+gent)
?
4-6 wks
Organisms to consider in empiric treatment of Prosthetic
Valve endocarditis
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®
Echocardiographic Features That Suggest Potential
Need for Surgical Intervention
Vegetation
•
Persistent vegetation after systemic embolization
•
Anterior mitral leaflet vegetation, particularly with size >10 mm*
•
>1 embolic events during first 2 wk of antimicrobial therapy*
•
Increase in vegetation size despite appropriate antimicrobial therapy*
Valvular dysfunction
• Acute aortic or mitral insufficiency with signs of ventricular failure
• Heart failure unresponsive to medical therapy
• Valve perforation or rupture
Perivalvular extension
• Valvular dehiscence, rupture, or fistula
• New heart block
• Large abscess or extension of abscess despite appropriate antimicrobial
therapy
.
*Surgery may be required because of risk of embolization.
Surgery may be required because of heart failure or failure of medical therapy.
Echocardiography should not be the primary modality used to detect or monitor heart block.
BACK TO OUR PATIENT
• ~6 weeks Rx: A f/up TEE showed same
mobile MV vegetations, with possible
abscess (?) between AV & MV.
• When some questions arose about
whether she really has an abscess a
labeled WBC-scan was done for
confirmation.
HOSPITAL COURSE (Cont’d)
• Surgery was strongly recommended, but, after
discussions between patient, family, CTS and Cardiology
surgery was deferred fearing she would not survive it.
• Transferred to KH where tube feeding was started to
improve nutritional status, and abx continued.
• She did better overall , her wt rose up to ~100 lbs (from
80’s). More discussions about surgery ensued, but
deferred once more after long discussions.
• Pt was transferred to a NH, where iv abx were cont’d
until 6/2005 (4 months of Rx), then discharged to home on po
doxycycline and rifampin.
• She was doing “OK” at home until 8/17/2005 (6 months of Rx)
HOSPITAL COURSE (Cont’d)
• Readmitted with a TIA and TEE showed a moderatesized mobile MV vegetation.
• Surgery was done next day.
– Findings: posterior leaflet vegetation and a small ring abscess.
Debridement of infected material of posterior
annulus,vegetectomy, and removal of the old ring was done
(valve replacement not done).
Valve tissue cultures, PCR, pathology remained non-diagnostic.
Some Lab studies done in our patient
• Blood culture:
– Routine BC
– BC for fungus (isolator
tube)
• Serology (repeated twice):
– Brucella,
– Bartonella,Coxiella,
– Chlamydia,
– Mycoplasma,
– Legionella,
– Fungal serology
•
ANTIGEN TESTING:
– Urine Pneumococcal antigen
– Urine Legionella Antigen
– Urine histoplasma antigen,
– Serum Cryptococcal antigen
•
•
NON-ID tests: ANA, RF, APA
PCR:
– T. whippeli, Bartonella, Qfever, Chlamydia,
Mycoplasma (on valve tissue)
•
HISTOPATHOLOGY with special
stains
All remained essentially negative
ELUSIVE BUG INDEED!!!
Clinical and Laboratory Features of Infective Endocarditis
Feature
Frequency,
%
Fever
80–90
Chills and sweats
40–75
Anorexia, weight loss, malaise
25–50
Myalgias, arthralgias
15–30
Back pain
7–15
Heart murmur
80–85
New/worsened regurgitant murmur
10–40
Arterial emboli
20–50
Splenomegaly
15–50
Clubbing
10–20
Neurologic manifestations
20–40
Peripheral manifestations (Osler's nodes, subungual hemorrhages, Janeway lesions, Roth's spots)
Petechiae
2–15
10–40
Laboratory manifestations
Anemia
70–90
Leukocytosis
20–30
Microscopic hematuria
30–50
Elevated ESR
Rheumatoid factor
>90
50
Circulating immune complexes
65–100
Decreased serum complement
5–40
BARTONELLA SPECIES
• are small, gram-negative bacilli that have recently been
shown to cause endocarditis.
• Currently, Bartonella quintana, the agent of trench
fever, and Bartonella henselae, the agent of cat-scratch
disease, are the major causes of Bartonella
endocarditis.
• Single cases of endocarditis caused by Bartonella
elizabethae and Bartonella vinsonii subspecies
berkhoffii have also been reported
Epidemiologic Findings in 16 Patients with Endocarditis
Caused by Bartonella quintana or Bartonella henselae
AIM. 15 October 1996 | Volume 125 Issue 8 | Pages 646-652
http://www.hosppract.com/issues/1998/12/celout.htmThe McGraw-Hill Companies.2001
©2005 UpToDate®
The optimum antibiotic treatment for Bartonella endocarditis is unknown
Q Fever
• zoonotic disease caused by Coxiella burnetii.
• Coxiella burnetii is a strict intracellular pathogen that
grows in the acidic phagolysosome of the host cell.
• Highly infectious. Resistant to desiccation.
• Contracted through exposure to infected ruminants
(especially parturient goats, sheep, and cattle), with
incubation time of 3-30 days.
-Ingestion of infected unpasteurized milk may also
transmit the disease
• Inhalation of aerosols of contaminated soil is the
major mode of transmission.
• Relatively common cause of IE in geographic areas
of the world in which cattle, sheep, and goat farming
are common.
• Distributed broadly throughout the United States too.
• Designated a possible bioterrorism agent
Q-Fever
Clinical Findings
•
•
Asymptomatic (up to 60% of infections).
Acute disease is characterized most frequently by:
(1) High fever and headache;
(2) Pneumonia or hepatitis in approximately 60% of acutely ill
persons;
(3) Infrequent acute manifestations: pericarditis, myocarditis, or
meningoencephalitis.
•
Chronic disease occurs in <1% of infected patients:
(1) Occurs predominantly in patients with underlying valvular heart
disease, vascular aneurysms, or vascular grafts;
(2) Manifests primarily as culture-negative endocarditis,
(3) Less commonly as vascular or osteoarticular infection
Q-fever Endocarditis
•Q-fever IE usually affects prosthetic or previously damaged aortic
or mitral valves.
•It has small vegetations often missed by echocardiography.
•.
Q-Fever
Laboratory Testing
(1) Demonstration of fourfold or greater changes in IgG or
IgM class-specific testing of paired acute- and
convalescent phase serum samples by
immunofluoresence antibody;
(2) Serology.
(1) High Phase II antibody titres indicates recent contact with
infection by C. burnetii, usually within last 6-8 months;
(2) high Phase I antibodies = chronic infection (e.g SBE)
(3) Detection of C. burnetii by polymerase chain reaction or
immunohistochemical staining.
(4) blood culture. (N.B.: Hazard to laboratory workers)
Q-FEVER
MANAGEMENT______
•
Acute disease: doxycycline 200 mg/day for 2-3 weeks.
•
Acute disease in patients with valvular heart disease: doxycycline 200 mg/day plus hydroxychloroquine 600
mg/day, for 1 year; dosage of hydroxychloroquine adjusted to maintain plasma level at 1 ± 0.2 µg/ml.
•
Chronic: doxycycline and hydroxychloroquine, dosage as above, for 1.5-3 years; cessation of therapy determined
by appropriate serologic profile.
•
The optimal regimen or duration of antimicrobial therapy for Q-fever IE is unknown.
– Doxycycline with trimethoprim/sulfamethoxazole, rifampin, or fluoroquinolones is the mainstay of therapy.
–
However, eradication of the organisms from vegetations with medical therapy is unlikely, and reinfection of
prosthetic material after surgical replacement of infected valves commonly occurs.
– Clinical response tends to persist as long as the drug regimen continues, but viable C burnetii can be
recovered from valve tissue even after years of antimicrobial therapy
The acidic conditions of the phagolysosome, where the organism resides , may inhibit antibiotic activity
Q-fever: Cures of IE after treatment with a combination of doxycycline and hydroxychloroquine (to alkalinize the
phagolysosome)
•
•
•
•
Prevention
Minimize or restrict exposures to livestock birthing areas.
•
Dispose of birth products properly (e.g., incinerate placenta and aborted fetuses).
•
Report all human cases to state health departments (Q fever is a nationally notifiable disease)
WHIPPLE’S SYNDROME
• Trophyrema whippeli
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BRUCELLA
• Brucellae are facultative
intracellular Gram-negative
bacilli.
• Infect humans after ingestion
of infected undercooked meat
or unpasteurized milk,
inhalation of infectious
aerosols, or direct contact with
infected tissues.
• Cause occupational disease of
veterinarians, abattoir workers,
livestock handlers, and
shepherds;
http://gsbs.utmb.edu/microbook/ch028.htm
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BRUCELLA ENDOCARDITIS
• It causes 4% of all IE cases in Spain.
• Previously damaged aortic or mitral valves develop bulky
vegetations,
– Followed commonly by valve destruction, perivalvular abscesses, and
CHF.
• Few patients with Brucella IE have been cured with antimicrobial
agents alone.
• Most require valve replacement in combination with antimicrobial
agents.
• The optimal regimen or duration of antimicrobial therapy for Brucella
endocarditis is unknown: doxycycline plus either streptomycin or
gentamicin or doxycycline plus trimethoprim/sulfamethoxazole
or rifampin have been recommended by some authorities for 8
weeks and up to 10 months after valve replacement.
NonBacterial Thrombotic Endocarditis (NBTE)
•Most cases of IE, although not all, begin with a damaged
endocardial surface.
•Damage to the endocardium may be caused by a number
of factors, ranging from rheumatic disease to senile
degeneration and calcification; indeed, any excessive
turbulence or high-pressure gradient may cause injury to
the nearby endocardium.
• Next, fibrin-platelet aggregates develop at the site of
damage to form sterile vegetations, also termed
nonbacterial thrombotic endocarditis (NBTE).
•NBTE may occur spontaneously in patients with systemic
illnesses (for instance, the marantic endocarditis of
malignancy or other wasting diseases or Libman-Sacks
endocarditis in systemic lupus erythematosus)
Etiology of Prosthetic Valve Endocarditis
Organism
Time of Onset after Valve Implantation and
Percentage of Cases
 2 months
Coagulase-negative
2–12 months
> 12 months
54
56
15
Staphylococcus aureus
8
9
13
Gram-negative bacilli
12
3
1
Streptococci
---
3
34
Enterococci
---
6
11
Corynebacteria
8
---
1
HACEK
---
3
14
Fungi
6
6
3
Miscellaneous
6
6
1
staphylococci
© 2004 WebMD Inc.
Chronology of important scientific and medical events in the history of infective endocarditis
Year
Scientist/physician,
Country
Major findings
1554
Jean François
Fernel, France
Earliest report of endocarditis in book Medicini
1669
Richard
Lower, England
Accurately described tricuspid valve endocarditis
1646
Lazarus Riverius,
France
Described unusual "outgrowths" from autopsy of patient with
endocarditis;
detected murmurs by placing hand on patient's chest
1708
Giovanni Maria
Lancisi, Italy
Described unusual structures in entrance of aorta
1715
Raymond
Vieussens, France
Described abnormality in aortic mitral valve
1749
Jean-Baptiste
Sénac, France
Described valvular lesions
1769
Giovanni Battistu
Morgagni, Italy
Linked infectious disease and endocarditis; observed
association with the spleen
1784
Eduard
Sandifort,
France
Accurately drew intracardiac abnormalities
1797
Matthew
Baillie,
England
Showed relationship between rheumatism and heart disease
1799
Xavier Bichat,
France
Described inflammatory process associated with endocarditis
1806
Jean Nicholas
Corvisart,
France
Described unusual structures in heart as "vegetations," syphilitic virus
as causative agent of endocarditis, and theory of antiviral treatment of
endocarditis
1809
Allan Burns,
England
Indicated vegetations were not "outgrowths" or "buds" but particles
adhering to heart wall
1815
Friedrich
Kreysig,
Germany
Elucidated inflammatory processes associated with endocarditis
1816
Théophile
Laënnec,
France
Invented cylindrical stethoscope to listen to heart murmurs; dismissed
link between venereal disease and endocarditis
1832
James Hope,
England
Confirmed Laënnec's observations
1835–
40
JeanBaptiste
Bouillaud,
France
Named endocardium and endocarditis; described symptoms; prescribed
herbal tea and bloodletting as treatment regimen; described link between
acute rheumatoid arthritis and endocarditis
1852
William
Senhouse
Kirkes,
England
Described consequences of embolization of vegetations throughout body.
Described cutaneous nodules (named "Osler's nodes" by Libman)
1858–
71
Rudolph
Virchow,
Germany
Examined fibrin vegetation associated with endocarditis by microscope;
coined term "embolism;" discussed role of bacteria, vibrios, and
micrococci in endocarditis
1861
JeanMartin
Charot,
France
Confirmed Virchow's theory on emboli
1861
Alfred
Vulpian,
Germany
Confirmed Virchow's theory on emboli
1862
Etienne
Described granulations or foreign elements in blood and valves, which
Lancereaux were motile and resistant to alkalis
, France
1868–70 Samuel
Wilks,
England
Described infected arterial blood as originating from heart; proposed
scarlet fever as cause of endocarditis
1869
Emmanuel
Winge,
Norway
Established "parasites" on skin transported to heart and attached to
endocardium; named "mycosis endocardii"
1872
Hjalmar
Heiberg,
Norway
Detected microorganisms in vegetations of endocarditis
1878
Edwin
Klebs,
Germany
All cases of endocarditis were infectious in origin
1878
Ottomar
Combined experimental physiology and infection to produce animal model
Rosenbach, of endocarditis in rabbit; noted valve had to be damaged before bacteria
Germany/P grafted onto valve
oland
1878
Karl
Koester,
Germany
Micrococci enter vessels that valves were fitted into; valves exposed to
abnormal mechanical attacks over long period created favorable niche for
bacterial colonization
1879
Joseph
Hamburg,
Germany
Virchow's student; employed early animal model of endocarditis
1879
Germain Sée,
France
Proposed etiology of endocarditis was based on infectious model
and treatment should focus on eliminating "parasitic infection"
1880
Jacques Doleris,
France
Working with Pasteur, proposed use of routine blood cultures
1881–86
Arnold Netter,
France
Believed endocarditis could appear during various infections;
noted translocation of respiratory pathogen from pulmonary
lesion to valve through blood
1883
Michel Peter, France Believed microorganisms were result, not cause, of endocarditis
1884
Joseph Grancher,
France
Named disease "infective endocarditis"
1886
Valimir
Wyssokowitsch and
Johannes Orth,
Germany
Demonstrated various bacteria introduced to bloodstream could
cause endocarditis on valve that had previous lesion
1885
Sir William Osler,
Canada
Synthesized work of others relating to endocarditis
1899
Hermann Lenhartz,
Austria
Described streptococcal, staphylococcal, pneumococcal, and
gonococcal endocarditis
1903
Hugo Schottmüller,
Germany
First described "endocarditis lenta"
1909
John Alexander Mullen, Canada
Credited by Osler as first to observe
cutaneous nodes (named "Osler's nodes"
by Libman) in patients with endocarditis
1909
Sir Thomas Horder, England
Analyzed 150 cases of endocarditis and
published diagnostic criteria relating to
signs and symptoms
1910
Emmanual Libman, USA
Described initial classification scheme to
include "subacute endocarditis," with
clinical signs/symptoms; absolute diagnosis
required blood cultures
1981
Von Reyn, USA
Described Beth Israel criteria based on
strict case definitions
1994
David Durack, USA
New criteria utilizing specific
echocardiographic findings
1995
American Heart Association, USA
Antibiotic treatment of adults with infective
endocarditis caused by streptococci,
enterococci, staphylococci, and HACEKa
microorganisms
1996
Pierre Fournier, France
Modified Duke criteria to allow serologic
diagnosis of Coxiella burnetii
•
Clinical Study of Culture-Negative Endocarditis. Medicine. 82(4):263-273, July 2003
infective endocarditis patients have CNE
•
Emerging Issues in Infective Endocarditis
Beverley C. Millar* and John E. Moore*
*Belfast City Hospital, Belfast, Northern Ireland, United Kingdom
Suggested citation for this article: Millar BC, Moore JE. Emerging issues in infective endocarditis. Emerg Infect Dis [serial on the Internet].
2004 Jun [date cited]. Available from: http://www.cdc.gov/ncidod/EID/vol10no6/03-0848.htm
About 20% in a Scandinavian population of
1997
American Heart
Association, USA
Guidelines for preventing bacterial endocarditis
1997
Lamas and Eykyn, UK
Suggested modifications to Duke criteria for clinical
diagnosis of native valve and prosthetic valve endocarditis:
analysis of 118 pathologically proven cases
1998
Working Party of the
British Society for
Antimicrobial
Chemotherapy, UK
Guidelines for antibiotic treatment of streptococcal,
enterococcal, and staphylococcal endocarditis
1998
Endocarditis Working
Group of the
International Society for
Chemotherapy, Europe
Antibiotic treatment of infective endocarditis due to viridans
streptococci, enterococci, and other streptococci;
recommendations for surgical treatment of endocarditis
2000
Jennifer Li, USA
Updated and modified Duke criteria
2002
Beverley C. Millar, UK
Modified Duke criteria to include a molecular diagnosis of
causal agents
2001–
2003
Didier Raoult, France
Described etiology of Bartonella spp., Tropheryma
whipplei, and Coxiella burnetii in endocarditis
HACEK, Haemophilus aphrophilus, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, Kingella kingae group, Bartonella
spp., and Coxiella burnetii.
MODIFIED DUKE CRITERIA
Definite endocarditis
Histologic and/or microbiologic evidence of infection at
surgery or autopsy
OR
2 major criteria
1 major criterion and 3 minor criteria
5 minor criteria
Possible endocarditis
1 major criterion and 1 minor criterion or
3 minor criteria
•
Blood Culture-Negative Endocarditis in a Reference Center: Etiologic Diagnosis
of 348 Cases [Houpikian P and Raoult D Medicine 2005;84:162]:
•
This is a report from the French National Reference Center for Rickettsial Diseases
for their experience with culture-negative endocarditis for the 18 year period of 1983
to 2001. Referring physicians were asked to complete a questionnaire and the
following were conducted: blood serology, blood cultures, and valve culture and PCR
if removed. Patients/specimens were obtained from a variety of sources in France
and other countries. The criteria used for endocarditis were the modified Duke
criteria. Of the 348 cases, there were 167 (48%) attributed to C. burnetii and 99
(28%) were attributed to Bartonella and 5 (1%) were attributed to rare fastidious
agents such as T. whipplei, Mycoplasma hominis, Abiotrophia elegans and
Mycoplasma hominis. The results for C. burnetii and Bartonella are summarized in
the following table which defines the source of specimens that implicated these two
agents.
C. burnetii
n = 167Bartonella
n = 99Serology16799Blood culture1710Valve culture4415Valve PCR4147
•
•
•
•
:
Circulation. 2005 Mar 22;111(11):1352-4.
Impact of a molecular approach to improve the microbiological diagnosis of infective heart valve endocarditis.
Breitkopf C, Hammel D, Scheld HH, Peters G, Becker K.
Institute of Medical Microbiology, University of Munster Hospital, Munster, Germany.
BACKGROUND: Even today, infective endocarditis (IE) remains a severe and potentially fatal
disease demanding sophisticated diagnostic strategies for detection of the causative
microorganisms. Despite the use of appropriate laboratory techniques, classic microbiological
diagnostics are characterized by a high rate of negative results. METHODS AND RESULTS:
Broad-range polymerase chain reaction (PCR) targeting bacterial and fungal rDNA followed by
direct sequencing was applied to excised heart valves (n=52) collected from 51 patients with
suspected infectious endocarditis and from 16 patients without any signs of IE during an 18-month
period. The sensitivity, specificity, and the positive and negative predictive values for the bacterial
broad-range PCR were 41.2%, 100.0%, 100.0%, and 34.8%, respectively, compared with 7.8%,
93.7%, 80.0%, and 24.2% for culture and 11.8%, 100.0%, 100.0%, and 26.2% for Gram staining.
Without exception, database analyses allowed identification up to the (sub)species level
comprising streptococcal (n=13), staphylococcal (n=4), enterococcal (n=2), and other signature
sequences such as Bartonella quintana and Nocardia paucivorans. Fungal ribosomal sequences
were not amplified. All valve tissues of the reference group were negative for both PCR and
conventional methods, except one sample that was contaminated by molds. CONCLUSIONS:
Culture-independent molecular methods substantially improve the diagnostic outcome of
microbiological examination of excised heart valves. Importantly, this was true not only for
fastidious, slow-growing, and/or nonculturable microorganisms but also for easy-to-culture
pathogens such as streptococci and staphylococci. Both patient management and empiric
antibiotic therapy of IE are likely to benefit from improved knowledge of the spectrum of pathogens
now causing IE.