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With these words William Osler began the rst of three seminal lectures
on endocarditis to the Royal College of Physicians of London in 1885. As
modern medicine moves into the twenty-rst century after decades of rapid
scientic advancement it is once again appropriate to take stock.
Over the past 30 years there have been substantial advances in our knowledge of infective endocarditis (IE). Examples include studies of the incidence
of IE [26], data on the magnitude of the association between certain risk
factors and IE [7,8], clinical criteria related to the diagnosis of IE [9,10], and
the introduction of echocardiography for both diagnosis [1113] and prognosis [1416].
Despite these and other advances, uncertainties remain about many
aspects of IE. For instance, recent evidence regarding the relationship
This study was supported by the following: Four Schools Physician Scientist Program
sponsored by the Lucille P. Markee Charitable Trust (CHC) and Joseph C. Greeneld Jr.
Scholars (CHC), and an investigator-initiated grant from Roche Laboratories Inc., Nutley, NJ.
Some data contained herein was partially presented at the 40th Interscience Conference on
Antimicrobial Agents and Chemotherapy on 18 September 2000.
* Corresponding author.
E-mail address: chris.cabell@duke.edu (C.H. Cabell).
0891-5520/02/$ - see front matter 2002, Elsevier Science (USA). All rights reserved.
PII: S 0 8 9 1 - 5 5 2 0 ( 0 1 ) 0 0 0 0 7 - 1
256
between dental and other risk factors and the subsequent development of IE
[7,8] may provoke a need to reexamine the policy of routine antibiotic prophylaxis for the prevention of IE [17]. In addition, although any of several
antibiotics may be used to treat the common causative agents of IE, few randomized trials have been conducted to dene optimal therapy [1820]. This
is also true when surgery is considered because the optimal role and timing
of surgery has not been denitively established. Finally, it is troubling that
mortality remains high, approaching 40% at one year [6,21,22], despite rapid
medical progress over the last 20 years.
In this article the authors take stock by summarizing current understanding of endocarditis in the areas of epidemiology and regional variation,
host factors, microorganisms, diagnosis, and therapy. In addition, the
authors discuss potential future directions for investigations by a newly
constituted multinational consortium, the International Collaboration on
Endocarditis (ICE). This collaboration aims to provide a mechanism to
advance the understanding of endocarditis in areas that are dicult to study
by traditional case reports and case series emanating from single centers.
The multinational nature of the collaboration should also provide a global
view of IE and opportunities for studies such as randomized trials of therapeutic treatment strategies.
Current standing
Epidemiology and regional variation
Recent studies have provided new insights into the epidemiology of IE
and have suggested variation in the rate of IE, the exploration of which may
be worthy of further study. For example, in 1991 Delahaye and colleagues
[3] reported that the crude incidence of IE in France in the early 1990s was
2.4 per 100,000 population, a value similar to that found in Denmark in the
1980s [6]. These incidence rates are lower than that found in the Philadelphia
area (11.6/100,000 population) [2] and Sweden (5.9/100,000 population) [5]
during similar time periods.
Dierences in the incidence of IE may be found when comparing series
reported from urban populations and rural populations. For instance, the
incidence of IE appears higher in an urban population and consistently lower in more rural groups [2,5], which may reect the impact of intravenous
drug users (IVDUs) and other socioeconomic factors on the rate of IE.
Other data suggest that the incidence of IE in the elderly is 4 to 6 times
greater than that of the general population [3,6]. These data suggest factors
that may be important in explaining the variation in incidence and identify
groups that may be at an increased risk for IE.
Variation is also suggested in the relative importance of dierent organisms in dierent series from dierent geographic areas. For instance, in
France, Streptococcus bovis IE appears to be more common (14%) [3] than
in Sweden (1%) [5]. Similarly, dierences can be found in populations
257
258
259
These studies may renew debate concerning the potential harm from
widespread antibiotic use for endocarditis prophylaxis, which may actually
be more dangerous on a population level than the possibleyet unprovenbenet. Collectively, these studies begin to create a critical mass of evidence that justies the re-examination of current practice.
Intensive medical care and other non-dental exposures
The changing face of endocarditis has been a common title for IE studies over the decades. As epidemiologic shifts occur in the overall population,
such as longevity of life and decreased prevalence of rheumatic heart disease, there have been parallel shifts in patients with IE. These shifts did not
go unnoticed by those involved in endocarditis care and research.
In 1978 Watanakunakorn [39] noted that the typical IE patient
described in textbooks was no longer representative of the majority of the
IE cases seen in medical centers. He hypothesized that medical progressnamely invasive medical proceduresplayed an important role in the
evolution of the spectrum of endocarditis. Specically, procedures such as
cardiopulmonary bypass, open heart surgery, hemodialysis, long-term intravenous cannulation, and intracardiac devices all contributedand would
continue to contributeto the changing spectrum of IE. Similar observations have been made by others [40,41]. Recent studies have conrmed relationships between particular procedures and pathogens associated with IE.
For example, hemodialysis appears to be a predictor of S. aureus IE [22].
Additionally, other studies have found an association between certain hospital-based procedures [35,42] and the subsequent development of IE.
Based on the aging of the population, the increasing reliance on intensive
and invasive medical care, and the decreasing prevalence of certain cardiac
risk factors, it seems reasonable to assume that an increasing proportion of
IE care in the future will be related to sequellae of previous medical exposures. This provides both a challenge and an opportunity for the medical
community. The challenge results from the recognition that medicallyrelated exposures may increase the risk of IE in certain vulnerable populations. The opportunity then exists to further characterize these relationships
such that medical care is impacted and devastating complications, such as
endocarditis, are targeted and prevented.
Microorganisms
we are only at the threshold of inquiries relating to the culture of these
organisms, to the macroscopic characteristics of their growth [27]
260
Although virtually any organism can cause IE, infective endocarditis was,
historically, a disease of patients with pre-existing valvular abnormalities
and community-associated bacteremia. Streptococcal species accounted for
60% to 80% of all cases, and most patients had rheumatic heart disease
[43,44].
For a variety of reasons, there has been a shift in the spectrum of microbiologic etiologies of IE [40]. Some of these reasons have been highlighted in
the previous discussion and include regional variation, changing prevalence
of predisposing cardiac conditions, the aging of the population, changes in
IVDU demographics, and increased exposures to intensive and invasive
medical care.
When studies are compared in aggregate over time, certain shifts in the
microbiologic spectrum are apparent (Table 1). For instance, viridans group
streptococci have decreased by approximately 35% over time while S. aureus
has increased by 50%. Additionally, streptococci other than viridans group
have increased. Finally, the no growth rate has dropped approximately
72% across these study periods with the development of better microbiologic
techniques and procedures.
Diagnosis
Few diseases present greater diculties in the way of diagnosis than malignant endocarditis, diculties which in many cases are practically insurmountable. It is no disparagement to the many skilled physicians who
have put their cases upon record to say that, in fully one-half the diagnosis
was made post mortem. [45]
The ability to diagnose IE has advanced rapidly over the last century.
Two important advancements were the creation of standardized clinical criteria for the diagnosis of IE and the development of imaging technology
such as echocardiography.
The diagnosis of IE has always hinged upon clinical suspicion derived
from association with appropriate signs and symptoms and, most importantly, the demonstration of continuous bacteremia. A major diagnostic
advance came in 1981 when von Reyn and colleagues [10] published an anal-
Table 1
Microorganisms in endocarditis by decades
Viridans
group
Other
strept
S. aureus
CNS
Gram-negative
Other
No
growth
43%
42.5%
29%
28%
12.5%
16%
19%
23%
14%
13%
24%
28%
4%
3%
9%
7%
5.5%
5%
4%
4%
3%
10%
7.5%
5%
18%
10%
7.5%
5%
261
Therapy
No treatment that has been tried cures Death is generally the result of
poisoning, the patient weakening progressively. Embolism of the brain or
heart occasionally kills. Recovery is almost unknown. [53]
Thus Sir Thomas Lewis commented on the near 100% mortality rate for
patients with IE in the early part of the twentieth century. Nearly half a century later, the introduction of penicillin, followed by intracardiac surgery,
provided eective treatment and increased survival rates.
Although the use of antibiotics and surgery has led to dramatic improvements in the overall outcomes of patients with endocarditis, there are few
data to help maximize the use of these choices to benet patients. For
instance, the timing of surgery in selected patients to prevent adverse outcomes yet limit surgical complications is poorly dened. In the absence of
denitive studies, particularly randomized trials, physicians must rely on
accepted guiding principles [54]. For antibiotic therapy, management
demands careful attention to antibiotic choice, susceptibility testing, dosing,
and duration of therapy. Whenever possible, the etiologic agent must be isolated in a pure culture with minimum inhibitory and bactericidal concentrations determined for the antibiotics used. Parenteral antibiotics are
recommended over oral agents because of the importance of sustained antibiotic activity. Additionally, long-term therapy is recommended because of
the relapse rate associated with shorter courses of therapy, but two-week
regimens have also shown to be eective.
Surgery has become an important component in the management of IE.
Generally accepted indications for surgical intervention include refractory
heart failure, more than one serious embolic event, uncontrolled infection,
signicant valve dysfunction, ineective antimicrobial therapy, mycotic
aneurysm, most cases of prosthetic valve IE, and invasive complications
(e.g., myocardial abscess) [54,55]; see also Chapter 11.
262
263
Country
Amsterdam
Ann Arbor
Barcelona
Beirut
Besancon
Birmingham
Birmingham
Buenos Aires
Christchurch
Durham
Goteborg
London
Marseille
Nancy
Napoli
Paris
Philadelphia
Netherlands
USA
Spain
Lebanon
France
United Kingdom
USA
Argentina
New Zealand
USA
Sweden
United Kingdom
France
France
Italy
France
USA
Santiago
Sao Paulo
Sydney
TelAviv
Victoria
Zagreb
Chile
Brazil
Australia
Israel
Australia
Croatia
X participating site.
Principal
investigator
Jan van der Meer
Suzanne Bradley
Jose Miro
Souha Kanj
Bruno Hoen
Thomas Elliott
William Dismukes
Liliana Clara
David Murdoch
G. Ralph Corey
Lars Olaison
Susannah Eykyn
Gilbert Habib
Christine Selton-Suty
Utili Riccardo
Catherine Leport
Elias Abrutyn
Brian Strom
Sandra Braun
Auristelo Ramos
Philip Jones
Ethan Rubinstein
Denis Spelman
Bruno Barsic
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
264
265
266
267
268
300 cases, the form was revised. In retrospect, revision probably could
have been accomplished earlier, perhaps after the rst 50 cases.
Throughout clinical research, the quality and strength of the evidence and
the generalizability of results are of concern to investigators. The authors
thoughts regarding a few issues relevant to the ICE eort follow. The
authors recognize the potential for referral bias; this study is not population-based and referrals are likely since the contributors at each site are well
known, locally and internationally, for expertise in the diagnosis and management of infective endocarditis. Referral bias is probably unavoidable
under these circumstances, so ndings from these studies must be interpreted
with this constraint in mind. Regarding the composition of the study sample,
the authors note that from the outset the importance of having each site collect consecutive cases has been stressed; however, eorts to validate eectiveness in this regard are dicult and have not been undertaken to date. Data
recording and entry, another potential issue, has been addressed by having
data coordinators at each site ll out case report forms under the supervision
of the principal investigator, and data sent to Duke are entered using double
data entry. Unfortunately, funding is not available for data monitors to verify chart abstraction by site visit because ICE is largely a volunteer eort.
Finally, the potential for clustering to aect results is recognized and will
be considered when data are analyzed. Because a single standardized case
report form is used for data collection of consecutive cases of infective endocarditis in all sites, the strength of the evidence generated from the cohort
study should be stronger than that derived from the merged database.
Logistical issues were also of concern. The authors were concerned about
the use of dierent computer systems and software at various study sites, but
major problems did not arise. The absence of problems may have been
related to our belief that Microsoft programs including Excel and
Access are in wide use, and these as well as other software programs have
the capacity to export information easily. Additionally, SAS, the foundation for the merged and cohort databases, imports data from many sources
with ease. In the end, the dominant mode of communication was by e-mail
using Adobe Acrobat and a PDF format for documents. E-mail was highly
ecient and largely problem free. Interpretation of eld names caused a
minor diculty because languages dier and truncated words for eld
names are sometimes used in databases and spreadsheets; creation of a dictionary of eld names solved the problem. To assure completeness and correctness, data sent to Duke were reviewed carefully before data entry to
identify errors and missing items needing completion. Variability in reading
and interpreting cardiac echocardiograms is well recognized, necessitating
development of a process to assure consistency and accuracy in the readings.
Therefore, in the prospective cohort study, copies of echocardiograms are
sent to a core ECHO laboratory to permit standardized readings using standard criteria as noted above. Lastly, the collection, preservation, and shipping of the etiologic organisms to the central laboratory at Duke could have
269
Conclusion
In the century and a quarter since William Osler delivered his famed Gulstonian lectures on endocarditis [27] continual advancements have been
made in understanding and treating this disease. Here the authors have
reviewed some key aspects of current knowledge in the areas of population
epidemiology, host factors, microorganisms, and diagnosis. The advent of
the ICE investigation provides the opportunity to further expand our understanding of IE by developing a very large, global database of IE patients
whose clinical, echocardiographic, and microbiologic ndings have been
characterized with standard methodology. Further, ICE may serve as a rich
source of material for investigators seeking to perform specic studies.
Finally, the ICE infrastructure creates the opportunity for performing randomized trials to test therapeutic strategies. Although many obstacles
remain to be overcome, ICE has created the opportunity for a quantum leap
in our knowledge of IE over the next 25 years.
Acknowledgment
This work could not have been possible without the tremendous eorts
put forth by the individual ICE investigators.
References
[1] Osler W. Gulstonian lectures on malignant endocarditis. Lecture I. Lancet 1885;1:4158.
[2] Berlin JA, Abrutyn E, Strom BL, et al. Incidence of infective endocarditis in the Delaware
Valley, 19881990. Am J Card 1995;76:9336.
[3] Delahaye F, Goulet V, Lacassin F, et al. Characteristics of infective endocarditis in France
1991: a one year survey. Eur Heart J 1995;16:394401.
[4] Grin MR, Wilson WR, Edwards WD, et al. Infective endocarditis. Olmstead County,
Minnesota, 19501981. JAMA 1985;254(9):1199202.
[5] Hogevik H, Olaison L, Andersson R, et al. Epidemioligic apects of infective endocarditis in
an urban population. Medicine (Baltimore) 1995;74(6):32439.
[6] Nissen H, Nielsen F, Frederiksen M, et al. Native valve infective endocarditis in the general
population: a 10-year survey of the clinical picture during the 1980s. Eur Heart J 1992;13:
8727.
[7] Strom BL, Abrutyn E, Berlin JA, Kinman JL, Feldman RS, Stolley PD, et al. Dental and
cardiac risk factors for infective endocarditis. A population-based, case-control study [see
comments]. Ann Intern Med 1998;129:7619.
[8] Strom BL, Abrutyn E, Berlin JA, et al. Risk factors for infective endocarditis: oral hygiene
and nondental exposures. Circ 2000;102:28428.
270
[9] Durack DT, Lukes AS, Bright DK. New criteria for diagnosis of infective endocarditis:
utilization of specic echocardiographic ndings. Am J Med 1994;96:2009.
[10] von Reyn CF, Levy BS, Arbeit RD, et al. Infective endocarditis: analysis based on strict
denitions. Ann Intern Med 1981;94:50518.
[11] Dillon JC, Feigenbaum H, Konecke LL, Davis RH, Chang S. Echocardiographic
manifestations of valvular vegetations. Am Heart J 1973;86:698704.
[12] Martin RP, Meltzer RS, Chia BL, et al. Clinical utility of two dimensional echocardiography in infective endocarditis. Am J Card 1980;46:37985.
[13] Stewart JA, Silimperi D, Harris P, et al. Echocardiographic documentation of vegetative
lesions in infective endocarditis. Circ 1980;61(2):37480.
[14] Cabell CH, Pond KK, Peterson GE, et al. The risk of stroke and death in patients with
aortic and mitral valve endocarditis. Am Heart J 2001;142:7580.
[15] Di Salvo G, Habib G, Pergola V, et al. Echocardiography predicts embolic events in
infective endocarditis. J Am Coll Card 2001;37:106976.
[16] Sanlippo AJ, Picard MH, Newell JB, et al. Echocardiographic assessment of patients with
infectious endocarditis. J Amer Coll Card 1991;18:11919.
[17] Durack DT. Antibiotics for prevention of endocarditis during dentistry: time to scale back?
Ann Intern Med 1998;129:82931.
[18] Heldman AW, Hartert TV, Ray SC, et al. Oral antibiotic treatment of right-sided
staphylococcal endocarditis in injection drug users: prospective randomized comparison
with parenteral therapy. Am J Med 1996;101:6876.
[19] Ribera E, Gomez-Jimenez J, Cortes E, et al. Eectiveness of cloxacillin with and without
gentamicin in short-term therapy for right-sided Staphylococcus aureus endocarditis. Ann
Intern Med 1996;125:96974.
[20] Sexton DJ, Tenenbaum MJ, Wilson WR, et al. Ceftriaxone once daily for four weeks
compared with ceftriaxone plus gentamicin once daily for two weeks for treatment of endocarditis due to penicillin-susceptible streptococci. Clin Infect Dis 1998;27:
14704.
[21] Benn M, Hagelskjaer LH, Tvede M. Infective endocarditis 1984 through 1993: a clinical
and microbiologic survey. J Intern Med 1997;242:1522.
[22] Cabell CH, Jollis JG, Peterson GE, et al. Changing patient characteristics and the eect on
mortality in endocarditis. Arch Intern Med 2002;162:904.
[23] Gouello JP, Asfar P, Brenet O, et al. Nosocomial endocarditis in the intensive care unit: an
analysis of 22 cases. Crit Care Med 2000;28:37782.
[24] Siddiq S, Missri J, Silverman DI. Endocarditis in an urban hospital in the 1990s. Arch
Intern Med 1996;156:24548.
[25] Sanabria TJ, Alpert JS, Goldberg R, Pape LA, Cheeseman SH. Increasing frequency of
staphylococcal infective endocarditis: experience at a university hospital, 1981 through 1988.
Arch Intern Med 1990;150:13059.
[26] Steckelberg JM, Melton LJ III, Ilstrup DM, Rouse MS, Wilson WR. Inuence of referral
bias on the apparent clinical spectrum of infective endocarditis. Am J Med 1990;88:5828.
[27] Osler W. Gulstonian lectures on malignant endocarditis. Lancet 1885;1:415508.
[28] Durack DT. Prevention of infective endocarditis. New Eng J Med 1995;332:3844.
[29] Steckelberg JM, Wilson WR. Risk factors for infective endocarditis. Infect Dis Clin N
Amer 1993;7:919.
[30] Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis. Recommendations by the American Heart Association. JAMA 1997;277:1794801.
[31] McKinsey DS, Ratts TE, Bisno AL. Underlying cardiac lesions in adults with infective
endocarditis. The changing spectrum. Am J Med 1987;82:6818.
[32] MacMahon SW, Roberts JK, KramerFox R, et al. Mitral valve prolapse and endocarditis. Am Heart J 1987;113:12918.
[33] Marks AR, Choon CY, Sanlippo AJ, et al. Identication of high-risk and low-risk
subgroups of patients with mitral valve prolapse. New Eng J Med 1989;320:10316.
271
[34] Nishimura RA, McGoon MD, Shub C, et al. Echocardiographically documented mitral
valve prolapse: long term follow-up of 237 patients. New Eng J Med 1985;313:13059.
[35] Kaye D, Abrutyn E. Prevention of bacterial endocarditis: 1991. Ann Intern Med 1991;114:
8034.
[36] van der Meer JT, van Wijk W, Thompson J, et al. Ecacy of antibiotic prophylaxis for
prevention of native-valve endocarditis. Lancet 1992;339:1359.
[37] Lacassin F, Hoen B, Leport C, et al. Procedures associated with infective endocarditis in
adults. Eur Heart J 1995;16:196874.
[38] van der Meer JT, Thompson J, Valkenburg HA, Michel MF. Epidemiology of bacterial
endocarditis in the Netherlands. II. Antecedent procedures and use of prophylaxis. Arch
Int Med 1992;152:186973.
[39] Watanakunakorn C. Infective endocarditis as a result of medical progress. Am J Med
1978;64:9179.
[40] Brandenburg RO, Giuliani ER, Wilson WR, Geraci JE. Infective endocarditis: a 25-year
overview of diagnosis and therapy. J Am Coll Card 1983;1:28091.
[41] Kaye D. Changing pattern of infective endocarditis. Am J Med 1985;78(Suppl 6B):15762.
[42] FernandezGuerrero ML, Verdejo C, Azofra J, de Gorgolas M. Hospital-acquired infectious endocarditis not associated with cardiac surgery: an emerging problem. Clin Infect
Dis 1995;20:1623.
[43] Rabinovich S, Evans J, Smith IM, January LE. A long-term view of bacterial endocarditis:
337 cases 19241963. Ann Intern Med 1965;63:18598.
[44] Weinstein L, Rubin RH. Infective endocarditis1973. Prog Cardvasc Dis 1973;16:23974.
[45] Osler W. Gulstonian lectures on malignant endocarditis. Lecture III, Lancet 1885;1:5058.
[46] Bayer AS, Ward JI, Ginzton LE, Shapiro SM. Evaluation of new clinical criteria for the
diagnosis of infective endocarditis. Am J Med 1994;96:2119.
[47] Cecchi E, Parrini I, Chinaglia A, et al. New diagnostic criteria for infective endocarditis.
A study of sensitivity and specicity. Eur Heart J 1997;18:114956.
[48] Hoen B, Selton-Suty C, Danchin N, et al. Evaluation of the Duke criteria versus the Beth
Isreal criteria for the diagnosis of infective endocarditis. Clin Infect Dis 1996;21(4):9059.
[49] Olaison L, Hogevik H. Comparison of the von Reyn and Duke criteria for the diagnosis of
infective endocarditis: a critical analysis of 161 episodes. Scand J Infect Dis 1996;28:399406.
[50] Fournier PE, Casalta JP, Habib G, Messana T, Raoult D. Modication of the diagnostic
criteria proposed by the Duke endocarditis service to permit improved diagnosis of Q fever
endocarditis. Am J Med 1996;100:62933.
[51] Lamas CC, Eykyn SJ. Suggested modications to the Duke criteria for the clinical diagnosis of native valve and prosthetic valve endocarditis. Clin Infect Dis 1997;25:7139.
[52] Li JS, Sexton DJ, Mick N, et al. Proposed modications to the Duke criteria for the diagnosis of infective endocarditis. Clin Infect Dis 2000;30:6338.
[53] Lewis T. Infective endocarditis. In: Diseases of the heart. New York: Macmillan Company;
1933. p. 18393.
[54] Bayer AS, Scheld WM. Infective endocarditis. In: Mandell GL, Bennett JE, Dolin R, editors.
Principles and practice of infectious diseases, 5th edition. Philadelphia: Churchill Livingston;
2000. p. 857902.
[55] Bayer AS, Bolger AF, Taubert KA, et al. Diagnosis and management of infective endocarditis and its complications. Circulation 1998;98:293648.
[56] Osler W. Gulstonian lectures on malignant endocarditis. Lecture II. Lancet 1885;1:45964.
[57] Bayer AS. Infective endocarditis. Clin Infect Dis 1993;17(3):31320.
[58] Fowler VG, Li J, Corey GR, et al. Role of echocardiography in evaluation of patients with
Staphylococcus aureus bacteremia. J Am Coll Card 1997;30:10728.
[59] Fowler VG, Sanders LL, Kong LK, et al. Infective endocarditis due to Staphylococcus
aureus: 59 prospectively identied cases with follow-up. Clin Infect Dis 1999;28:10614.
[60] Garvey GJ, Neu HC. Infective endocarditisan evolving disease. Medicine (Baltimore)
1978;57(2):10527.
272
[61] Tornos MP, Olona M, Permanyer-Miralda G, et al. Is the clinical spectrum and prognosis
of native valve infective endocarditis in non-addicts changing? Eur Heart J 1995;16:
168691.
[62] Netzer RO, Zollinger E, Seiler C, Cerny A. Infective endocarditis: clinical spectrum,
presentation and outcome. Heart 2000;84:2530.
[63] Dyson C, Barnes RA, Harrison GA. Infective endocarditis: an epidemiological review of
128 episodes. J Inf 1999;38:8793.