Medicine

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Clinical Case Report

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Fungal endocarditis with heart valve replacement
and atrial fibrillation posing a treatment challenge
A case report

∗

Xiaoxia Zhu, MDa, Shugang Cao, MDb, Mingwu Xia, MDb, Chandong Ding, MDa, , Rongfeng Wang, MDb
Abstract
Rationale: Fungal endocarditis (FE) is a rare disease, in which antifungal treatment is necessary. When FE is complicated with

prosthetic heart valve and/or atrial fibrillation, the coadministration of antifungal agents and warfarin is inevitable. We report a case of
rheumatic heart disease with atrial fibrillation who developed FE following prosthetic heart valve replacement. The international
normalized ratio (INR) increased significantly during the antifungal treatment with fluconazole. A discussion of the antifungal strategy in
FE patients with prosthetic heart valves and/or atrial fibrillation and the interaction between antifungal agents and warfarin was
performed.

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Patient concerns: A 54-year-old Chinese woman experienced intermittent fevers, aphemia, and weakness in her right
extremities. Her temperature was 38.7°C, and there was atrial fibrillation with heart rate 110 times/min. Neurological examination
revealed that she had drowsiness, Broca aphasia, right central facial paralysis, and hemiplegia (Medical Research Council scale,
upper limb grade 0, lower limb grade II).
Diagnoses: Multiple infarction on magnetic resonance imaging and the occlusion of left middle cerebral artery suggested the
occurrence of cerebral embolism. The presence of Candida parapsilosis in the results of 4 blood cultures and the existence of valve
vegetation in the reexamination of echocardiogram supported the diagnosis of FE.
Interventions: The patient was given antifungal therapy with fluconazol. The INR increased dramatically on the 9th day of
antifungal treatment, and subcutaneous bruising occurred at the intravenous infusion site. The antagonist of vitamin K1 was used and
warfarin was reduced to a smaller dosage. The antifungal agent was replaced with caspofungin.
Outcomes: Her speech improved significantly, and the muscle strength of her paralyzed side reached the Medical Research

Council scale of grade IV+. She continued to receive caspofungin for antifungal treatment with relatively stable INR and waited for
heart valve surgery.
Lessons: The choice of antifungal agents is often a big challenge for FE patients, especially when they need warfarin for
anticoagulation. It is better to administer a low dose of warfarin while carefully monitoring the INR or choose the antifungal drugs with
little or no effect on warfarin.
Abbreviations: FE = fungal endocarditis, INR = international normalized ratio, NIHSS = National Institutes of Health Stroke Scale.
Keywords: antifungal treatment, atrial fibrillation, cerebral embolism, fungal endocarditis, heart valve replacement, warfarin

Editor: Maya Saranathan.
XZ and SC contributed equally to this work.
The patient provided consent for the writing and publication of this case report.
Written informed consent was obtained from the patient for the publication of this case report and any accompanying images.
The authors have no conflicts of interest to disclose.
This study was supported by grants from the Major Research Development Program of Anhui Province in China (1804h08020233) and the Major Applied Medical
Research Foundation of the Health and Family Planning Commission of Hefei in China (hwk2017zd008).
The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
a
Department of Cardiology, The Second Affiliated Hospital of Anhui Medical University, b Department of Neurology, The Affiliated Hefei Hospital of Anhui Medical
University, Hefei, Anhui, P.R. China.
∗

Correspondence: Chandong Ding, Department of Cardiology, The Second Affiliated Hospital of Anhui Medical University, No. 888 Furong Road, Hefei, Anhui 230601,
P.R. China (e-mail: dcdsunshine@163.com).

Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.
This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
How to cite this article: Zhu X, Cao S, Xia M, Ding C, Wang R. Fungal endocarditis with heart valve replacement and atrial fibrillation posing a treatment challenge: a
case report. Medicine 2020;99:48(e22487).
Received: 17 February 2020 / Received in final form: 7 July 2020 / Accepted: 1 September 2020
http://dx.doi.org/10.1097/MD.0000000000022487

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Zhu et al. Medicine (2020) 99:48

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1. Introduction

range, 0–8.2 mg/L) but without other significant abnormal
findings. Electrocardiogram revealed atrial fibrillation with a
fast ventricular rate. Brain computerized topography showed no
cerebral hemorrhage.
After admission, she was given anticoagulation, blood pressure
stabilization, and anti-infective therapy with antibiotics and
symptomatic treatment. The next day, she became alert, and her
speech improved (NIHSS score: 10). Initial echocardiography
showed mitral valve and aortic valve replacement with mild
aortic regurgitation and left atrial enlargement. Magnetic
resonance imaging revealed multiple ischemic infarcts involving
the left frontal-temporal-parietal lobe, insula, hippocampus and
thalamus as well as the right parietal lobe (Fig. 1A–D), and MR
angiography indicated occlusion of the left middle cerebral artery
(Fig. 1E). The first blood culture revealed Candida parapsilosis on
the 5th day, but by this time, her temperature had returned to
normal. The results of 3 subsequent blood culture tests were
consistent with the first one, and the result of fungal D-glucan in
the fourth blood culture was 207 pg/mL (normal range, <70 pg/
mL). Echocardiogram reexamination suggested vegetation (1.41
cm ∗ 0.98 cm) in the anterior leaflet of the mitral valve (Fig. 1F).
She was finally diagnosed with FE leading to multiple cerebral
embolisms. The patient was then given antifungal therapy with
fluconazole based on the drug sensitivity test. On the third day of
antifungal treatment, the INR was 2.9 according to a portable
coagulation detector. However, on the ninth day of antifungal
treatment, subcutaneous bruising occurred at the intravenous
infusion site. The INR reached 10.21, so warfarin was stopped at
once. The INR decreased to 1.1 after using 10 mg vitamin K1.
The next day, warfarin was reduced to a smaller dosage (2 mg/d).
The replacement of the antifungal drug with caspofungin and
elective surgery were suggested. However, the patient was
transferred to a large hospital in Shanghai for surgical treatment.
At discharge, her speech had improved significantly, and the
muscle strength of her paralyzed side reached grade IV+ on the
Medical Research Council scale. Her final NIHSS score was 3.
She continued to receive caspofungin for antifungal treatment
while waiting for heart valve surgery. During antifungal therapy
with caspofungin, the retesting INR values fluctuated between
1.7 and 3.3 using the same dosage of warfarin (3 mg/d).

Fungal endocarditis (FE) is a rare form of infective endocarditis
with an extremely high mortality rate.[1] An implanted prosthetic
heart valve is a well-known risk factor for FE. Patients with
prosthetic heart valves usually need short-term or long-term
anticoagulation treatment using warfarin rather than new oral
anticoagulants.[2] When they are complicated with atrial
fibrillation, long-term anticoagulation is necessary. Azole
antifungal agents are often the first choice of empirical treatment
for FE. However, azole antifungal agents usually augment the
anticoagulant activity of warfarin, thereby increasing the risk of
bleeding.[3] It is challenging to determine whether to reduce
warfarin and measure the international normalized ratio (INR)
repeatedly or to replace the antifungal drugs with medications
with less or no influence on warfarin. We report a case of FE
manifested as cerebral embolism, in which the INR increased
dramatically during antifungal treatment with fluconazole. We
reversed the anticoagulant effects of warfarin with vitamin K1
and then reduced the dosage of warfarin. In the end, however, the
antifungal drug was replaced with caspofungin, which does not
interact with warfarin. Here, we intended to provide a concise
review of the clinical features of FE, the antifungal treatment
strategy for FE patients with prosthetic heart valve and/or atrial
fibrillation, and the interaction between antifungal agents and
warfarin.

2. Case presentation
A 54-year-old Chinese woman presented with intermittent fevers
for half a month and aphemia and weakness in her right
extremities approximately 10 hours after onset. In terms of
medical history, she had been diagnosed with rheumatic heart
disease complicated with mitral, tricuspid, and aortic insufficiency and atrial fibrillation for 1.5 years, and she underwent mitral
and aortic bioprosthetic valve replacement and tricuspid
valvuloplasty 16 months ago. She was given warfarin (3 mg/d)
for secondary prevention of cerebral and systemic embolism,
with an INR of 2.0 1 week before admission.
The physical examination findings were as follows: temperature (T): 38.7°C, pulse rate (P): 104 times/min, respiration (R): 20
times/min, and blood pressure: 78/56 mm Hg; there was atrial
fibrillation, with heart rate 110 times/min, but no abnormal
findings in the lungs and abdomen. Neurological examination
revealed that she had drowsiness, Broca aphasia, right central
facial paralysis, and hemiplegia (Medical Research Council scale,
upper limb grade 0, lower limb grade II), while she failed to
complete the sensory tests and coordinate movements. Her right
Babinski sign was positive. Her initial National Institutes of
Health Stroke Scale (NIHSS) score was 14.
The results of laboratory tests were as follows: coagulation
tests showed that the prothrombin time was 22.30 seconds
(normal range, 10.00–15.00 seconds), the activated partial
thromboplastin time was 53.50 seconds (normal range, 28.00–
45.00 seconds), and the INR was 1.98 (normal range, 0.7–1.6).
Routine blood examination showed that the red blood cell count
was 3.77 ∗ 10^12/L (normal range, 4.00–5.50 ∗ 10^12/L), the
white blood cell count was 6.72 ∗ 10^9/L (normal range, 4.00–
10.00 ∗ 10^9/L), the platelet count was 56.0 ∗ 10^9/L (normal
range, 100.0–300.00 ∗ 10^9/L), and the hemoglobin was 109.0 g/
L (normal range, 110.0–150.00 g/L). Biochemical tests demonstrated a high C-reactive protein level of 44.5 mg/L (normal

3. Discussion
FE, first reported by Wolfe et al[4] in 1951, is a rare but fatal entity
associated with high morbidity and mortality and is similar to
common bacterial endocarditis in clinical manifestations.[1]Candida albicans spp. and Aspergillus spp. are the most predominant
organisms causing FE. Non-albicans Candida spp. (eg, C
parapsilosis, Candida glabrata, and Candida tropicalis) and
other less frequent fungal species are much less common.[1]
Because most of the time, the blood culture is negative in over
50% of cases and it takes a long time for pathogenic fungi to
grow, the early diagnosis of FE is extremely challenging but very
crucial for antifungal treatment. The demonstrable valve
vegetation on echocardiography is very helpful for the diagnosis.
This patient was admitted for cerebral embolism, with
intermittent fever for half a month before admission. There
was a predisposing factor (namely, prosthetic valve replacement)
for infective endocarditis, but no evidence of infection in other
areas. Moreover, the body temperature returned to normal after
antibiotic treatment. Therefore, bacterial endocarditis should be
initially considered, although no thrombus was found in the first
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Figure 1. Cranial MRI. Axial diffusion-weighted imaging (DWI) showed high-signal lesions comprising the left frontal-temporal-parietal lobe, insula, hippocampus
and thalamus as well as the right parietal lobe (A–D), with low apparent diffusion coefficient signals in the corresponding regions (not shown), and MR angiography
(MRA) indicated the left middle cerebral artery occlusion (E, black arrows). Echocardiogram. Echocardiogram suggested the mural thrombus formation in the
anterior leaflet of the mitral valve (F, white arrows). MRI = magnetic resonance imaging.

activity of warfarin, such as caspofungin. Caspofungin plays an
antifungal role by inhibiting the synthesis of b(1,3)-D-glucan, a
basic component of the cell walls of many yeasts and molds. The
elimination of caspofungin follows a different pathway, mainly
through peptide hydrolysis and/or N-acetylation, that is not
involved in the elimination of warfarin.[6,7] The coadministration
of caspofungin and warfarin is relatively safe due to the lack of
interaction between these 2 compounds.[8] Moreover, caspofungin is generally well tolerated with fewer side effects than
amphotericin B.[8] Nevertheless, for FE patients, the effect of
antifungal therapy alone is poor, so surgical treatment is also
highly recommended. The combination of these 2 treatments can
improve the prognosis of FE patients.[1,9] Hence, the replacement
of antifungal drugs and elective surgery were finally suggested for
this patient.
In summary, the choice of antifungal agents is often a major
challenge for FE patients when they need warfarin for anticoagulation at the same time. It is better to administer a low
dosage of warfarin while carefully monitoring the INR or to
choose antifungal drugs with little or no effect on warfarin on the
basis of the antifungal drug sensitivity test.

echocardiography. However, unexpectedly, the results of 4 blood
cultures all indicated the presence of C parapsilosis and the
increase in fungal glucan, in support of FE. Subsequent
echocardiogram reexamination also confirmed the existence of
valve vegetation. The patient was finally diagnosed with FE
according to the modified Duke criteria for infective endocarditis.[5] The valve vegetations in FE patients are usually large, loose
in texture, and easy to fall off, which will significantly increase the
incidence of vascular embolism events, as in our case.
In addition, the longer course of FE, the difficulty of obtaining
timely diagnosis, and more severe valve damage frame FE as a
more serious condition than bacterial endocarditis and as having
a poor reaction to antifungal drugs. The patient was initially
treated with the antifungal agent fluconazole according to the
empirical treatment and drug sensitivity test. However, she
needed warfarin for anticoagulation due to the heart valve
replacement and atrial fibrillation. Unfortunately, the INR
increased gradually over the course of antifungal treatment,
and subcutaneous bruising occurred. The inhibition of hepatic
drug-metabolizing enzymes (mainly CYP2C9) is identified as the
mechanism of the interaction between warfarin and azoles such
as miconazole, fluconazole, voriconazole, and itraconazole,
among others.[3] However, such patients can only use warfarin
at present, but not new oral anticoagulants. Therefore, for such
patients, we could only reduce the dosage of warfarin or select
antifungal drugs with little or no effect on the anticoagulant

Author contributions
Conceptualization: Xiaoxia Zhu, Shugang Cao, Mingwu Xia,
Rongfeng Wang, Chandong Ding.
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[3] Yamamoto H, Habu Y, Yano I, et al. Comparison of the effects of azole
antifungal agents on the anticoagulant activity of warfarin. Biol Pharm
Bull 2014;37:1990–3.
[4] Wolfe EI, Henderson FW. Mycotic endocarditis;report of a case. J Am
Med Assoc 1951;147:1344–7.
[5] Li JS, Sexton DJ, Mick N, et al. Proposed modifications to the Duke
criteria for the diagnosis of infective endocarditis. Clin Infect Dis
2000;30:633–8.
[6] Balani SK, Xu X, Arison BH, et al. Metabolites of caspofungin acetate, a
potent antifungal agent, in human plasma and urine. Drug Metab Dispos
2000;28:1274–8.
[7] Stehle S, Kirchheiner J, Lazar A, et al. Pharmacogenetics of oral
anticoagulants: a basis for dose individualization. Clin Pharmacokinet
2008;47:565–94.
[8] Vedtofte T, Thisted CH, Friis-Hansen L. Warfarin treatment and
antifungal agent caspofungin for severe fungal infection in a patient
previously treated with radiotherapy for oropharyngeal cancer. Clin Case
Rep 2015;4:143–6.
[9] Thuny F, Grisoli D, Collart F, et al. Management of infective endocarditis:
challenges and perspectives. Lancet 2012;379:965–75.

Investigation: Xiaoxia Zhu, Shugang Cao, Rongfeng Wang.
Methodology: Xiaoxia Zhu, Shugang Cao, Rongfeng Wang.
Supervision: Rongfeng Wang, Mingwu Xia, Chandong Ding.
Validation: Rongfeng Wang, Chandong Ding.
Visualization: Xiaoxia Zhu.
Writing – original draft: Xiaoxia Zhu, Shugang Cao.
Writing – review & editing: Xiaoxia Zhu, Shugang Cao,
Rongfeng Wang, Chandong Ding.

References
[1] Pasha AK, Lee JZ, Low SW, et al. Fungal endocarditis: update on
diagnosis and management. Am J Med 2016;129:1037–43.
[2] Nishimura RA, Otto CM, Bonow RO, et al. 2017 AHA/ACC focused
update of the 2014 AHA/ACC guideline for the management of patients
with valvular heart disease: a report of the American College of
Cardiology/American Heart Association task force on clinical practice
guidelines. J Am Coll Cardiol 2017;70:252–89.

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