International Journal of Antimicrobial Agents 44 (2014) 290–294

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International Journal of Antimicrobial Agents

journal homepage: http://www.elsevier.com/locate/ijantimicag

Review

Fungal endocarditis: current challenges夽

Pierre Tattevin a,b,c,∗ , Matthieu Revest a,c , Agnès Lefort d ,
Christian Michelet a , Olivier Lortholary e
a
Infectious Diseases and ICU, Pontchaillou University Hospital, Rennes, France
b
INSERM U835, Faculté de Médecine, Université Rennes 1, IFR140, Rennes, France
c
Association pour l’Etude et la Prévention de l’Endocardite Infectieuse (AEPEI), Bichat-Claude Bernard Hôpital, Paris, France
d
Internal Medicine Department, Beaujon Hospital, Clichy, France
e
Infectious Diseases Unit, Necker Hospital, Paris, France

a r t i c l e i n f o a b s t r a c t

Article history: Whilst it used to affect mostly intravenous drug users and patients who underwent valvular surgery
Received 24 July 2014 with suboptimal infection control procedures, fungal endocarditis is now mostly observed in patients
Accepted 24 July 2014 with severe immunodeficiency (onco-haematology), in association with chronic central venous access
and broad-spectrum antibiotic use. The incidence of fungal endocarditis has probably decreased in most
Keywords: developed countries with access to harm-reduction policies (i.e. needle exchange programmes) and with
Endocarditis
improved infection control procedures during cardiac surgery. Use of specific blood culture bottles for
Candida sp.
diagnosis of fungal endocarditis has decreased due to optimisation of media and automated culture
Aspergillus sp.
Echinocandins
systems. Meanwhile, the advent of rapid techniques, including fungal antigen detection (galactomannan,
␤-1,3-d-Glucans mannan/anti-mannan antibodies and ␤-1,3-d-glucans) and PCR (e.g. universal fungal PCR targeting 18S
rRNA genes), shall improve sensitivity and reduce diagnostics delays, although limited data are available
on their use for the diagnosis of fungal endocarditis. New antifungal agents available since the early 2000s
may represent dramatic improvement for fungal endocarditis: (i) a new class, the echinocandins, has the
potential to improve the management of Candida endocarditis owing to its fungicidal effect on yeasts as
well as tolerability of increased dosages; and (ii) improved survival in patients with invasive aspergillosis
with voriconazole compared with amphotericin B, and this may apply to Aspergillus sp. endocarditis as
well, although its prognosis remains dismal. These achievements may allow selected patients to be cured
with prolonged medical treatment alone when surgery is considered too risky.
© 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

1. Introduction physicians who maintained expertise in this field has probably

Fungal endocarditis is a rare disease with a dismal progno-
sis related to the population affected (e.g. immunocompromised
patients), suboptimal diagnostic tools responsible for long diag-
nostic delays in most cases, and poorly defined activity of most
antifungal agents in endocarditis. The characteristics of patients
affected by fungal endocarditis have dramatically changed over
the last decades, with an overall decrease in the number of cases
managed each year in most institutions. Hence, the number of
夽 This paper was presented at the XIIth International Symposium on Modern
Concepts in Endocarditis and Cardiovascular Infections (ISCVID), 19–21 May 2013,
Dubrovnik, Croatia.
∗ Corresponding author. Present address: Service des Maladies Infectieuses et de
Réanimation Médicale, CHU Pontchaillou, 2 rue Henri Le Guilloux, 35033 Rennes
Cedex, France. Tel.: +33 2 9928 9564.
E-mail address: pierre.tattevin@chu-rennes.fr (P. Tattevin).
declined. We aimed to provide an update on the current challenges
in the management of fungal endocarditis based on a literature
review and on our own experience.
2. Epidemiology
2.1. Changing profile of fungal endocarditis
The characteristics of patients affected by infective endocardi-
tis have dramatically changed since the 1990s, as illustrated by
prospective cohort and population-based studies [1–7]. Charac-
teristics of the 270 cases reported during 1965–1995 are as
follows: male:female ratio, 2.2; mean age, 44.3 ± 14.3 years; and
main risk factors being previous valve surgery/prosthetic valve
endocarditis (54%), prolonged use of antibiotics (48%), rheumatic
heart disease (24%), surgery other than cardiac (23%), vascular
lines (18%), immunosuppressive treatment (17%), non-iatrogenic

http://dx.doi.org/10.1016/j.ijantimicag.2014.07.003
0924-8579/© 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.
 P. Tattevin et al. / International Journal of Antimicrobial Agents 44 (2014) 290–294 291

immunodeficiency (17%) and intravenous drug use (IVDU) (13%). Table 1

Epidemiology of fungal endocarditis for cases reported during the years 1995–2000.
A subsequent review of 152 cases reported between 1995 and
2000 found that prosthetic valves (45%), central venous catheters Characteristics Comments
(30%) and broad-spectrum antibiotic use (20%) were the main risk Host
factors, whilst intravenous drug users were much less affected Sex ratio Male:female ratio ca. 2
(4%). Two major observations emerged from these large litera- Age Mean, 44 + 14 years
ture reviews: (i) over time, dramatic changes have occurred in the Risk factors Main current risk Dramatic changes in risk
factors: factors from 1965 to 2014:
major risk factors for fungal endocarditis; once a disease affect-
• prosthetic valve, 45% • haematological malignancies,
ing mostly patients with recent valvular surgery, rheumatic heart • CVCs, 30% immunosuppressive drugs,
disease or IVDU, fungal endocarditis is currently more common in • broad-spectrum CVCs and broad-spectrum
immunocompromised patients, with long-term vascular lines, and antibiotic use, 20% antibiotics are emerging;
• malignancy, 9% • intravenous drug users rarely
who underwent complex non-cardiac surgery; and (ii) the progno-
• intravenous drug use, affected in countries with
sis gradually improved, with a mortality rate that decreased from 4% needle exchange programmes
86% during 1966–1971 to 56% during 1995–2000 [1,3–5]. Although Pathogens
these figures, mostly based on case reports, are subject to publica- Candida endocarditis, Candida albicans, 30–40%
tion bias, an improved outcome over the years would be expected 50–80% Non-albicans Candida
endocarditis:
owing to significant success achieved in the field of diagnosis as well
• Candida parapsilosis
as new antifungal agents. For example, diagnosis of fungal endo- • Candida glabrata
carditis was obtained before surgery in 43% of cases reported before • Candida tropicalis
1988 compared with 72% of cases reported during 1988–1995 Aspergillus Mostly Aspergillus fumigatus
endocarditis, 20–25% Others:
(P = 0.0001), which may be related to the advent of echocardiogra-
• Aspergillus terreus
phy (since 1975) as well as progress in automated blood culture sys- • Aspergillus niger
tems, with a sensitivity estimated at 54% during 1965–1995 [1] and • Aspergillus flavus
81% during 1995–2000 [5]. Likewise, development of lipid formula- CVC, central venous catheter.
tions of amphotericin B (AmB), new azoles with extended spectrum,
and echinocandins, over the last 20 years significantly enhanced the
therapeutic armamentarium against fungal endocarditis.
significant proportion of cases not diagnosed before valvular
surgery. For cases reported during 1965–1995, the mean duration
2.2. Characteristics of fungal endocarditis in the 21st century of symptoms before hospitalisation was 32 ± 39 days, and fungal
endocarditis was considered in the initial differential diagnosis in
In most contemporary studies, fungal endocarditis represents only 18% of patients [7].
<2% of all cases of endocarditis. This was the case in the Interna- Classically, fungal endocarditis is characterised by: (i) its
tional Collaboration on Endocarditis – Prospective Cohort Studies propensity to develop large (‘bulky’) vegetations, with an increased
(ICE-PCS) [8] and in nationwide studies from Italy [9], the USA [10] risk of dramatic embolic events (massive stroke, limb ischaemia);
and France [11]. However, higher proportions of fungal endocardi- (ii) a high frequency of ophthalmological complications, with
tis have been reported in various settings, including hospitals with specific fundoscopic findings; and (iii) typical cutaneous lesions
a high incidence of fungal endocarditis following cardiac surgery unique to particular fungal organisms (i.e. macronodules or macu-
owing to infection control issues, or in areas with a high preva- lopapules in candidaemia, black haemorrhagic lesions in Aspergillus
lence of IVDU and no access to harm-reduction policies such as endocarditis) [4]. However, when Baddley et al. compared 33
needle exchange programmes. consecutive cases of Candida endocarditis with 2716 cases of
The spectrum of fungal species causing endocarditis can be non-fungal endocarditis enrolled in the ICE-PCS database during
summarised as follow: (i) Candida endocarditis is the most com- 2000–2005 [8], the only significant differences were risk factors,
mon, representing 50–80% of all cases of fungal endocarditis; (ii) reasons for surgery and mortality (Table 2).
among these, although Candida albicans remains the most common
species (30–40% of all fungal endocarditis), non-albicans Candida
endocarditis is emerging, especially in patients previously exposed Table 2
to azoles. Candida parapsilosis, Candida glabrata and Candida trop- Comparison of Candida endocarditis and non-fungal endocarditis within the Inter-
national Collaboration on Endocarditis–Prospective Cohort Studies (ICE-PCS).
icalis are the main non-albicans Candida spp. causing endocarditis
[4]; and (iii) Aspergillus endocarditis represents 20–25% of all Candida Non-fungal P-value
fungal endocarditis and is due to Aspergillus fumigatus in two- endocarditis endocarditis
(n = 33) [n (%)] (n = 2716) [n (%)]
thirds of cases. Aspergillus terreus, Aspergillus niger and Aspergillus
flavus may rarely be encountered. Aspergillus endocarditis mostly Prosthetic valve 16 (48.5) 533 (19.6) 0.0005
Central venous 7 (21.2) 119 (4.4) <0.0001
occurs on prosthetic valves in patients recently operated and/or
catheter
in immunocompromised patients, especially with haematological Healthcare-associated 17 (51.5) 702 (25.8) 0.0009
malignancies [7,12,13]. These features are summarised in Table 1. endocarditis
Previous infective 7 (21.2) 213 (7.8) 0.005
endocarditis
3. Diagnosis Reasons for surgerya
Myocardial abscess 7/15 (46.7) 289/1302 (22.2) 0.026
3.1. Clinical diagnosis Embolic risk 6/15 (40.0) 257/1302 (19.7) 0.05
Persistent positive 5/15 (33.3) 129/1302 (9.9) 0.003
blood cultures
Fungal endocarditis shares many features with bacterial endo- Heart failure 2/15 (13.3) 554/1302 (42.5) 0.02
carditis, and modified Duke criteria are commonly used to classify In-hospital mortality 10 (30.3) 464 (17.1) 0.046
Candida endocarditis based on the same microbiological and Adapted from [8].
echocardiographic major criteria [8,9]. However, clinical diagnosis a
The denominator is the number of patients who underwent cardiac surgery for
of fungal endocarditis is more difficult, as documented by the endocarditis. Patients may have multiple reasons for surgery.
292 P. Tattevin et al. / International Journal of Antimicrobial Agents 44 (2014) 290–294

Table 3 to be a pan-fungal diagnostic method, as BDG is present in most

New diagnostic tests for fungal antigen detection in serum.
Characteristics
Mannan and Only for the diagnosis
anti-mannan of Candida bloodstream
antibodies infections [17]
␤-1,3-d-Glucan Pan-fungal diagnostic
method as
␤-1,3-d-glucan is
present in most
pathogenic fungal
species
Galactomannan Major constituent of
Aspergillus cell wall.
Cross-reactivity with
histoplasmosis,
blastomycosis,
cryptococcosis,
penicilliosis and with
concomitant antibiotics
(piperacillin/tazobactam,
amoxicillin/clavulanic
acid)
Diagnostic
performance
For candidaemia:
sensitivity, 80%;
specificity, 85%.
For Candida
endocarditis:
sensitivity, 83% [19]
For candidaemia, with
a cut-off value of
80 pg/mL: sensitivity,
>65%; specificity, >80%.
For Candida
endocarditis:
sensitivity, 100% [19]
Validated for the
diagnosis of invasive
aspergillosis in
neutropenic patients.
Not evaluated for the
diagnosis of Aspergillus
endocarditis
pathogenic fungal species. Its performance for the diagnosis of can-
didaemia has been evaluated in a meta-analysis [18]: with a cut-off
value of 80 pg/mL, sensitivity would be >65%, specificity >80% and
the negative predictive value >85%. In a prospective study of 18
patients with definite cases of Candida endocarditis, Lefort et al.
found that the sensitivity of BDG and mannan/anti-mannan anti-
body detection in serum were 100% and 83%, respectively, for the
diagnosis of Candida endocarditis [19].
For the diagnosis of Aspergillus endocarditis, potential diagnostic
tests include the detection of BDG and the detection of galactoman-
nan antigen in serum. Galactomannan is a major constituent of
the Aspergillus cell wall and has been validated for the diagnosis
of invasive aspergillosis in neutropenic patients. Caveats include
cross-reactivity with other fungal infections (histoplasmosis, blas-
tomycosis, cryptococcosis and penicilliosis) and with concomitant
antibiotics (piperacillin/tazobactam, amoxicillin/clavulanic acid),
and a suboptimal sensitivity for A. fumigatus [12]. Recent data sug-
gest that galactomannan may be of interest for the diagnosis of
Aspergillus endocarditis [13]. However, owing to the very low inci-
dence of Aspergillus endocarditis since galactomannan antigen and
BDG assays have been available, the diagnostic performance of
these tests for the diagnosis of Aspergillus endocarditis remains
poorly documented.

3.2. Blood cultures 4. Treatment

Blood cultures remain the main evidence for diagnosis of
Candida endocarditis. Most cases are diagnosed in the setting
of prolonged candidaemia, which is a standalone indication for
transoesophageal echocardiography and fundoscopic examination.
Diagnostic procedures for Candida diseases have been reviewed by
the European Society of Clinical Microbiology and Infectious Dis-
eases (ESCMID) in 2012 [14] and by the Infectious Diseases Society
of America (IDSA) in 2013 [15]. Briefly, these guidelines recommend
to inoculate 60 mL of blood obtained by venipuncture and divided
into six 10-mL aliquots among three aerobic and three anaerobic
bottles to be incubated for ≥5 days. Although the sensitivity of auto-
mated blood culture systems is lower for fungal than for bacterial
bloodstream infections, there is no evidence that use of specific
blood culture bottles for fungal detection increases the diagnostic
yield. Hence, guidelines for blood culture sampling in patients sus-
pected of infective endocarditis applies for fungal as for bacterial
endocarditis [16]. The sensitivity of blood culture for the diagno-
sis of C. albicans endocarditis has been estimated at 50–75% [14],
and somewhat lower for non-albicans Candida endocarditis. Unfor-
tunately, the yield of blood cultures is almost zero in Aspergillus
endocarditis, estimated at 4% (2/53) in a recent review [12]. Most
cases of Aspergillus endocarditis are diagnosed by tissue culture (e.g.
valves in patients who underwent valve replacement), galactoman-
nan antigen assay or post-mortem examination.
3.3. Innovative diagnostic tests (Table 3)
Given the shortcomings of blood cultures for the diagnosis of
fungal endocarditis, innovative biological diagnostic tests are being
developed and were recently reviewed [14]. The combined detec-
tion of mannan and anti-mannan antibodies in serum has been
developed for the diagnosis of Candida bloodstream infections [17],
and may also apply to Candida endocarditis. Its diagnostic perfor-
mance for the diagnosis of candidaemia has been estimated at ca.
80% for sensitivity and 85% for specificity, which translates into an
estimated accuracy of 50–70%.
The most promising test for the diagnosis of fungal endocardi-
tis may be ␤-1,3-d-glucan (BDG) detection in serum, considered
4.1. Antifungal agents
Most cases of fungal endocarditis reported in the literature have
been treated with amphotericin B deoxycholate (AmBD): 93% of
patients reported during 1965–1995 (of whom 22% also received
flucytosine) [7], and 78% of those reported during 1995–2000 (of
whom 28% also received flucytosine or azoles) [5]. AmB is a polyene,
fungicidal for most yeast and moulds potentially involved in fungal
endocarditis, but tolerability of conventional AmB (i.e. AmBD) is
poor, especially when a prolonged duration of treatment is manda-
tory for cure, as is the case for fungal endocarditis. Hence, owing
to its improved tolerability and the ability to administer higher
doses, lipid formulations of AmB are favoured over the deoxy-
cholate preparation in all guidelines recently published, based on
experimental studies and expert opinion rather than on clinical
studies [16,20–22]. In addition, lipid formulations of AmB may also
exert enhanced fungicidal activity on biofilms, which may be of
interest in patients with prosthetic valve fungal endocarditis, espe-
cially when surgery is not feasible. Of note, Candida lusitaniae is
naturally resistant to polyenes.
For the treatment of Candida endocarditis, the echinocandins
are promising alternatives to polyenes (i.e. AmB and derivatives)
for the following reasons: (i) they are rapidly fungicidal against
most Candida spp., including azole-resistant Candida spp.; (ii) they
remain active against Candida biofilms [23]; and (iii) their toler-
ability is much better than that of polyenes, allowing prolonged
treatment, at high doses, when necessary. Most recent reports illus-
trate the trend towards increased use of echinocandins (e.g. 77% of
patients with Candida endocarditis in the recent French observa-
tional prospective study [19]), either instead of, or in association
with, lipid formulations of AmB.
Azoles are only fungistatic in yeasts; hence, they cannot be
considered as primary treatment of Candida endocarditis. How-
ever, these compounds retain some potential indications for
the treatment of fungal endocarditis in at least three situations:
(i) as a primary choice for the medical treatment of Aspergillus
endocarditis, on the grounds that voriconazole is fungicidal against
Aspergillus spp. and has proven its superiority over AmB in invasive
 P. Tattevin et al. / International Journal of Antimicrobial Agents 44 (2014) 290–294 293

aspergillosis in a landmark randomised controlled trial [24]; (ii) Table 4

Treatment of fungal endocarditis according to recent guidelines (2009–2012).
in combination with an echinocandin (preferably) or a polyene
in difficult-to-treat fungal endocarditis; and (iii) as a long-term Antifungal agents Surgery
suppressive treatment to prevent late relapses of Candida endo- European • Amphotericin B or • Valve replacement
carditis. Indeed, relapses have been reported in as many as 30–40% guidelines on derivatives with or without for all patients
of patients who survive after the acute phase of fungal endocardi- infective azoles
tis and these relapses may occur as late as 9 years after patients endocarditis, • or caspofungin
2009 [16] a • Prolonged or lifelong
have been considered as ‘cured’ [25]. Hence, most experts would
fluconazole suppressive
recommend lifelong treatment with fluconazole in any situations treatment
when Candida endocarditis could not be adequately managed: this
US guidelines on • Liposomal amphotericin • Valve replacement
includes patients who were not treated with valvular replacement, Candida B or other lipid strongly recommended
patients who had positive valve cultures when valvular replace- infections, 2009 formulations with or • Lifelong fluconazole
ment was performed, patients with prolonged candidaemia, or [21] b without flucytosine suppressive treatment
patients with intracardiac devices that were not extracted. • or an echinocandin at in patients with
high doses (caspofungin prosthetic valve
Flucytosine demonstrates broad antifungal activity against most
50–150 mg/day, Candida endocarditis
Candida spp., with the exception of Candida krusei. It is some- micafungin who were not operated
times used at a dosage of 100 mg/kg/day in combination with a 100–150 mg/day or
lipid formulation of AmB or an echinocandin during initial treat- anidulafungin
100–200 mg/day)
ment of difficult-to-treat Candida endocarditis cases. Owing to bone
• Prolonged fluconazole
marrow toxicity, therapeutic drug monitoring is recommended in suppressive treatment
prolonged treatment, as well as dose adjustment in patients with (400–800 mg/day)
renal dysfunction [21].
European • Liposomal amphotericin • Surgical valve
guidelines on B with or without replacement within a
Candida flucytosine week if native valve
4.2. Cardiac surgery
infections, 2012 • or caspofungin 70 mg/day • Surgical valve
[20] b or 50 mg/day with or replacement within
Fungal endocarditis has long been considered as a ‘standalone’ without flucytosine days if prosthetic valve
indication for surgical valvular replacement for the following rea- • Prolonged, fluconazole
suppressive treatment
sons: (i) prognosis in patients who received only medical treatment
(400–800 mg/day)
has consistently been very poor, with mortality rates estimated
at 96% for Aspergillus endocarditis [12] and 50–70% for Candida British guidelines • First-line: an • Valve replacement
on infective echinocandin at high doses highly desirable if
endocarditis [5,19]; (ii) most antifungal agents have limited activity
endocarditis, (caspofungin 70 mg loading technically feasible for
within biofilm, vegetations and prosthetic devices; (iii) late relapses 2012 [22] a dose, then 50–100 mg/day, Candida endocarditis
are common in patients who did not undergo valve replacement; micafungin 200 mg/day or • Valve replacement
and (iv) large vegetations commonly encountered in fungal endo- anidulafungin, licensed mandatory for survival
carditis may lead to severe embolic events, even under optimised doses) in Aspergillus
• Second-line: liposomal endocarditis
antifungal treatment. amphotericin B or other
However, with the advent of new antifungal agents, includ- lipid formulations with or
ing the echinocandins, and better use of older antifungal agents, without flucytosine
a significant proportion of patients with native valve Candida • Prolonged, fluconazole
suppressive treatment
endocarditis may be controlled without cardiac surgery [26]. A
(400–800 mg/day)
recent meta-analysis of medical versus surgical therapy for Can-
a
dida endocarditis found a non-significant impact of surgical valve Guidelines apply both for Candida and Aspergillus endocarditis.
b
Guidelines apply only for Candida endocarditis.
replacement, with an odds ratio of 0.56 (95% confidence inter-
val 0.16–1.99) for death [27]. Another meta-analysis of 64 cases
of Candida endocarditis who did not undergo surgical valvular
replacement found that failure was more common in patients who
anidulafungin (licensed doses) as primary choices (preferably to
received only fluconazole compared with patients who received
AmB or derivatives) in the UK [22].
fluconazole combined with another antifungal agent (42% vs. 16%;
Regarding surgical indications, although case reports of Can-
P = 0.02) [28].
dida endocarditis controlled by medical treatment alone have
accumulated over recent years, fungal endocarditis is still con-
4.3. Current guidelines for the treatment of fungal endocarditis sidered as a standalone indication for valvular surgery by most
(Table 4) experts. Interestingly, guidelines differ in the way they express
these requirements: 2009 European guidelines for endocarditis
Although polyenes are proposed as the potential first choice for stated that ‘treatment of fungal endocarditis necessitates dual ther-
most cases of fungal endocarditis, a switch towards preferred use apy with antifungal agent and valve replacement [16]’; 2009 US
of echinocandins for Candida endocarditis has been observed in guidelines for Candida diseases stated that ‘valve replacement is
recent cohorts [8,19] as well as in updated guidelines [16,20–22]. strongly recommended. For those who are unable to undergo sur-
Accordingly, the recommended first-line treatment of Candida gical replacement of the valve, lifelong therapy with fluconazole,
endocarditis includes high doses of echinocandins as an alternative 400–800 mg/day is recommended [21]’; 2012 European guidelines
to lipid formulations of AmB for primary treatment of Candida for Candida diseases stated that ‘in patients with native valve Can-
endocarditis in the USA (caspofungin 50–150 mg/day, anidula- dida endocarditis, surgery within a week is recommended, and in
fungin 100–200 mg/day or micafungin 100–150 mg/day [21]), prosthetic valve Candida endocarditis, earlier surgery may even be
caspofungin ± flucytosine as an alternative to lipid formulations of beneficial [20]’; and lastly, 2012 guidelines for endocarditis in the
AmB ± flucytosine in Europe [20], and micafungin (200 mg/day), UK separated Aspergillus endocarditis where ‘surgical valve replace-
caspofungin (70 mg loading dose, then 50–100 mg/day) or ment is mandatory for survival’ and Candida endocarditis where
294 P. Tattevin et al. / International Journal of Antimicrobial Agents 44 (2014) 290–294
‘surgical valve replacement is highly desirable if technically feasible
[22]’.
5. Perspectives and challenges
Significant progress in the prevention, diagnosis and man-
agement of fungal endocarditis has been achieved over the last
decades. These include: (i) dramatic reduction in the propor-
tion of infective endocarditis due to fungus in most settings,
thanks to improvement in infection control procedures during
cardiac surgery as well as harm-reduction policies with access
to needle exchange programmes; (ii) development of antifun-
gal agents with rapid fungicidal activity against most Candida
spp. (echinocandins) or improved survival in patients with inva-
sive aspergillosis (voriconazole); and (iii) although less dramatic,
significant improvement in diagnostic tests (transoesophageal
echocardiography, automated blood culture systems).
Challenges for the future include: (i) expanded access to policies
that have proven effective in the reduction of fungal endocardi-
tis (e.g. needle exchange programmes in the USA and Eastern
Europe countries); (ii) development of innovative diagnostic tests
based on antigen or specific nucleic acid detection in serum (e.g.
universal fungal PCR targeting 18S rRNA genes, galactomannan,
mannan/anti-mannan antibodies and BDGs); (iii) identification of
clinical or biological criteria to select patients who may be cured
without surgical valvular replacement; and (iv) optimised treat-
ment of difficult-to-treat fungal endocarditis (e.g. C. parapsilosis
endocarditis with diminished susceptibility to echinocandins).
6. Conclusions
In conclusion, fungal endocarditis remains one of the most
severe infectious diseases, with mortality rates ranging from 96%
in Aspergillus endocarditis patients who could not undergo surgical
valvular replacement to 32% in patients with Candida endocarditis
treated with medical and surgical treatment. However, significant
progress has been achieved over the last decades, illustrated by
the dramatic decrease in the proportion of infective endocarditis
caused by fungus and the development of new antifungal agents
that increase the rate of success in patients who cannot undergo
surgical valve replacement.
Funding: No funding sources.
Competing interests: The authors have received support from
Astellas, Astra-Zeneca, Aventis, Bristol-Myers Squibb, Gilead Sci-
ences, Janssen-Cilag, MSD, Novartis and Pfizer for research
activities, consultancies, workshops or travel to meetings and
accommodation.
Ethical approval: Not required.
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