A case series of medically managed Candida Parapsilosis complex prosthetic valve endocarditis and literature review

Background: In recent years, Candida parapsilosis is recognized as a species complex and is composed of Candida parapsilosis sensu stricto, Candida orthopsilosis and Candida metapsilosis and Candida Parapsilosis complex prosthetic valve endocarditis (PVE) is rare and the survival rate is still low despite of optimal therapeutic strategies. Our paper is the rst to report cases as Candida Parapsilosis complex PVE. Case presentation: A series of 4 cases of Candida Parapsilosis complex PVE from our institution was reported. Three were infected by Candida parapsilosis sensu stricto and one was infected by Candida metapsilosis. The condition of two cases got better and the other died. Conclusions: More attention should be paid to Candida Parapsilosis complex PVE and early diagnosis and prompt antibiotic therapy may play a role in the treatment for Candida Parapsilosis complex PVE literature on Candida Parapsilosis complex PVE is limited. More information about Candida Parapsilosis complex PVE and its management is needed. Here we present a case series of Candida Parapsilosis complex PVE in patients with aortic valve replacement (AVR) or mitral valve replacement (MVR) from the First Aliated Hospital of Sun Yat-Sen University, providing more information about Candida Parapsilosis complex PVE and reference on the treatment of it. All patients received detailed counseling and informed written consent was obtained from each participant. stricto identied in the by desorption ionization-time of spectrometry (MALDI (Flucytosine inhibitory ug/mL, ug/mL, ug/mL, itraconazole ug/mL, MIC 1 ug/mL). to Candida parapsilosis stricto. In summary, our study raises signicant learning points about the medical management and combination antifungal therapy for Candida Parapsilosis complex PVE, providing reference for the treatment of Candida Parapsilosis complex PVE to other clinicians. These cases also emphasize the challenges when treating Candida Parapsilosis complex PVE. Early diagnosis and prompt antibiotic therapy may play a role in the treatment for Candida Parapsilosis complex PVE and more attention should be paid to the immunocompromised patients who underwent valve replacement.


Introduction
Prosthetic valve endocarditis(PVE) is a complication of cardiac valve replacement and it is related with a high mortality 1 . What's more, the incidence of PVE is increasing and it accounts for 20-30% of infective endocarditis episodes 2 . Generally, typical microorganisms causing PVE were mainly bacteria, especially Enterococci and Staphylococcus aureus 3 . Fungal endocarditis(FE) is a rare and fatal form of infectious endocarditis 4 . Candida and Aspergillus species are two of the most common etiologic fungi for FE. Among Candida endocarditis, Candida albicans is the main cause of FE and Candida parapsilosis is the most common non-albicans species responsible for FE 5 . In the last years, Candida parapsilosis is recognized as a species complex and is composed of Candida parapsilosis sensu stricto, Candida orthopsilosis and Candida metapsilosis, which are unique but related 6 . The Candida parapsilosis complex is opportunistic fungal pathogen responsible for many human nosocomial infections. Candida Parapsilosis complex PVE is rare and the survival rate is still low despite of optimal therapeutic strategies 7 . However, the literature on Candida Parapsilosis complex PVE is limited. More information about Candida Parapsilosis complex PVE and its management is needed. Here we present a case series of Candida Parapsilosis complex PVE in patients with aortic valve replacement (AVR) or mitral valve replacement (MVR) from the First A liated Hospital of Sun Yat-Sen University, providing more information about Candida Parapsilosis complex PVE and reference on the treatment of it. All patients received detailed counseling and informed written consent was obtained from each participant.

Case Description
Case report 1 The rst patient was a 55-year-old man who had a history of smoking for more than 10 years. The patient underwent mitral valve replacement in 2012. On 24th of December 2017, he was admitted into the First A liated Hospital of Sun Yat-Sen University because of aggravated shortness of breath for one month and edema of both lower extremities for 3 days. The initial blood count showed hemoglobin level of 100 g/L, WBC count of 5.28 × 10 9 cells/L (46.6% neutrophils, 36.2% lymphocytes), raised Erythrocyte sedimentation rate (ESR) (74 mm/h) and C-reactive protein (10.60 mg/L). The PCT, troponin T and Nterminal prohormone of brain natriuretic peptide (NT-proBNP) all increased (Table S1). Bed-side chest radiograph showed in ammation of both lungs and enlarged heart shadow in the supine position. Transthoracic echocardiography (TTE) showed two vegetations on prosthetic mitral valve, accelerated velocity of the prosthetic mitral valve and the effective ori ce area was 1.8 cm 2 (Fig. 1), which revealed infectious endocarditis after MVR. TTE also found moderate tricuspid regurgitation and mild pulmonary artery hypertension. The LVEF was approximately normal (56%) and diastolic function was reduced. The ECG indicated atrial utter (2-3: 1 conduction) with rapid ventricular rate. The (1,3) -β-D glucan was 93.99 pg / mL and Candida parapsilosis sensu stricto was identi ed in the blood culture by Matrix-assisted laser desorption ionization-time of ight mass spectrometry (MALDI TOF-MS®) (Flucytosine minimal inhibitory concentration (MIC) 4 ug/mL, amphotericin B MIC 0.5 ug/mL, voriconazole MIC 0.06 ug/mL, itraconazole MIC 0.125 ug/mL, uconazole MIC 1 ug/mL). Repeat blood cultures continued to grow Candida parapsilosis sensu stricto. The patient was initiated on vancomycin 1 g iv three times a day and voriconazole 200 mg iv twice a day after admission. Then, combination antifungal therapy with vancomycin 1 g iv three times a day and caspofungin iv 50 mg once a day was initiated on Dec 29. Because of high vancomycin blood concentration, the therapy changed to vancomycin 1 g iv twice a day and caspofungin 50 mg iv once a day on Dec 30 and lasted until discharging. Besides, Rocephin was administrated from Dec 30 of 2017 to Jan 3 of 2018 to ght lung infections. After a series of anti-infective treatment, the patient's condition improved. However, the blood cultures continued to grow Candida parapsilosis sensu stricto and the patient refused the surgical treatment despite of the indications of operation. The patient went back to local hospital and was recommended to continue the combination antifungal therapy according to the drug sensitivity.
Case report 2 The second patient was a 71-year-old man with a history of hypertension for 3 years and smoking for 30 years. He was admitted into the First A liated Hospital of Sun Yat-Sen University on April 26 of 2019 for repeated chest tightness and palpitations for more than 10 years, aggravating by 1 year. TTE showed that posterior mitral valve tendon cord was ruptured, which resulted posterior mitral valve prolapse and severe mitral valve regurgitation. At the same time, TEE found mild aortic valve stenosis and mild-moderate regurgitation, anterior tricuspid valve prolapse and medium regurgitation, severe pulmonary artery hypertension. The aorta root, the left atrium and left ventricle were signi cantly enlarged. The right atrium was slightly larger. And LVEF was about 70%.
On May 5, the patient underwent aortic valve and mitral valve bioprosthesis replacement, tricuspid valvuloplasty, aortic annuloplasty and temporary cardiac pacemaker implantation. The patient was given sulperazone 3 g iv three times a day from May 5 to May 17, imipenem cilastatin sodium iv 1 g once a day from May 20 to May 28 and sulperazone 3 g iv three times a day from May 28 to May 31. On May 24, the blood culture grew yeast-like fungus (Flucytosine minimal inhibitory concentration (MIC) 4 ug/mL, amphotericin B MIC 0.5 ug/mL, voriconazole MIC 0.06 ug/mL, itraconazole MIC 0.125 ug/mL, uconazole MIC 1 ug/mL) and the patient was administrated caspofungin (50 mg iv once day) to ght fungal infection. On June 13, the blood culture still grew yeast-like fungus and the patient continued to use caspofungin (50 mg iv once day). On June 24, the patient had a fever of 39.2℃ and the blood culture still grew yeast-  (Table 1 and Table S1). Transesophageal echocardiography (TEE) showed a dehiscence about 10mm × 0 mm and severe perivalvular leakage from the medial part of the prosthetic mitral valve. TEE also found a small strip uttering a lot from left atrium side of the medial prosthetic ring, suggesting infective endocarditis (Fig. 2). The patient was administrated voriconazole 200 mg iv twice a day from November 4 to 21, caspofungin 50 mg iv twice a day from November 21 to December 4 and amphotericin B 1 mg iv once a day from November 26 to December 4. Besides, the patient was administrated tazocin 4.5 g iv three times a day from Nov 4 to Nov 6, vancomycin 0.5 g iv once a day from Nov 17 to Nov 21 and tienam iv 1 g once a day from from Nov 21 to Dec 4. The patient's body temperature was relieved, uctuating around 37.5 ℃. Then the patient was discharged and recommended antifungal treatment in local hospital with imipenem and cilastatin sodium for injection 1000 mg three times a day, caspofungin 50 mg once a week and amphotericin B 30 mg once a week. University on November 22 of 2015 duo to repeated fever for more than 50 days and acute bloating for 12 days. The initial blood count showed WBC count of 2.95 × 10 9 cells/L (64.8% neutrophils, 22.7% lymphocytes). The PCT, troponin T, NT-proBNP and the (1,3) -β-D glucan all increased. (Table S1). TTE showed a hypoechoic vegetation was formed on prosthetic aortic valve and the size of the vegetation was about 17.8mm × 8.0 mm. Besides, enlarged left atrium and left ventricle, mild-moderate mitral valve regurgitation, moderate tricuspid regurgitation, moderate pulmonary artery hypertension was found. LVEF was about 74% and diastolic function of left ventricular was reduced (grade I) (Fig. 3). Abdominal examination showed gas accumulation in the intestine, indicating intestinal obstruction. The patient presented septic shock, poor heart function and arrhythmia, incomplete intestinal obstruction and water and electrolyte balance disorders. The blood culture grew Candida parapsilosis sensu stricto (Flucytosine minimal inhibitory concentration (MIC) 4 ug/mL, amphotericin B MIC 0.5 ug/mL, voriconazole MIC 0.06 ug/mL, itraconazole MIC 0.125 ug/mL, uconazole MIC 1 ug/mL). The patient was given combined anti-infection and anti-shock treatment. The patient was administrated uconazole 100 mg iv once a day from November 23 to November 27 and voriconazole 200 mg iv twice a day. Besides, the patient was also given sulperazone 3 g iv three times a day from  (Table 1 and Table S1). Then the patient was administrated uconazole 100 mg iv once a day from November 7 to 9 and caspofungin 50 mg iv once a day from November 9 to 10, as well as sulperazone 3 g iv three times a day for four days. On the fourth day of admission, the patient had a ventricular brillation suddenly. After a series of rescue measures, the patient's condition didn't improve and died.

Discussion
With the increasing infection rate of Candida, Candida endocarditis especially Candida parapsilosis complex endocarditis gains more and more attention because of its high mortality and morbidity 8,9 . In recent years, with the widespread application of life support systems, Candida parapsilosis complex has become the second most common pathogen of candidiasis. Candida Parapsilosis complex is the normal ora colonizing on gastrointestinal tract, skin and oropharynx. The general precipitating factors for Candida Parapsilosis complex contain the prosthetic valves (57.4%), IV drug use (IVDU; 20%), IV parenteral nutrition (6.9%), abdominal surgery (6.9%), immunosuppression (6.4%), using broad-spectrum antibiotics (5.6%) and previous valvular disease (4.8%) 10 . According to different clinical conditions, fungal endocarditis can be divided into three categories: natural valvular endocarditis, arti cial valvular endocarditis and cardiac assist devices related endocarditis. Prosthetic valve is an important risk factor for development of fungal endocarditis and Candida Parapsilosis complex PVE need more attention. No de nitive treatment is recommended for Candida Parapsilosis complex PVE and consensus on the best medical treatment and on its duration is limited. In recent years, the therapy tends to become combination antifungal therapy and the use of echinocandin is recommended 11,12 . In our case series, the combination antifungal therapy for them were mainly the combination of azoles and echinocandins and the combination antifungal therapies for them during period of hospitalization were shown in table 3. Moreover, the therapy obtained good outcomes in the patients who came to the hospital earlier, indicating early diagnosis and prompt antibiotic therapy were essential during the treatment of Candida Parapsilosis complex PVE. Through up-to-date review of all previous cases, 12 cases of Candida Parapsilosis complex prosthetic valve endocarditis had been reported (Table 2) [13][14][15][16][17][18][19][20][21][22][23] . Besides, two articles described outbreaks of Candida parapsilosis prosthetic valve endocarditis following cardiac surgery, including 8 dead cases and one alive case without detailed information 24,25 . Among the listed cases including our cases, 9 cases both chose antifungal drugs and valve replacement to treat Candida Parapsilosis complex prosthetic valve endocarditis while the treatment for it tended to combination antifungal therapy rather than surgery in the latest cases. It is worth trying combination antifungal therapy in the medically managed Candida Parapsilosis complex prosthetic valve endocarditis. One article had reported multidrug resistant Candida parapsilosis and surgical intervention for the management of it was necessary. What's more, another article reported Candida parapsilosis prosthetic valve endocarditis without typical echocardiograhy ndings, which should be paid attention to. Penghao Guo designed the work; Kang Liao have drafted the work and Peisong Chen substantively revised it; Yuting He was a major contributor in writing the manuscript; Rui Fan analyzed and interpreted the patient data; Zhongwen Wu was responsible for the acquisition of the data and Yili Chen was also responsible for the acquisition of the data. Yuli Huang was responsible for the imaging processing. All authors read and approved the nal manuscript