Candida parapsilosis Endocarditis: Report of Cases and Review of the Literature

Abstract

Introduction: Infective endocarditis (IE) due to Candida species is a rare disease representing about 1–2% of all IE cases and carries a high mortality rate. Given the rarity of the disease, there are no clear guidelines on the type and duration of antifungal therapy. Thus, long-term or even life-long antifungal treatment is commonly used. Case report: We report two patients with prosthetic valve C. parapsilosis IE and persistent candidemia that failed conservative treatment and ultimately developed heart failure. They underwent prosthetic valve replacement and prolonged antifungal treatment with favorable outcome. Discussion: Candida IE commonly occurs in the setting of underlying malignancy, chronic liver disease, previous endocarditis, previous antimicrobial exposure, previous abdominal surgery, intravenous drug use, presence of a central venous catheter, and previous cardiac surgery. Both present patients had undergone a cardiac surgery and had a prosthetic heart valve, while one patient had an underlying autoimmune disease that could be associated with higher risk of IE. In both patients transthoracic ultrasound failed to diagnose IE. In our patients, conservative treatment alone was not enough to control the infection, thus, both patients underwent valve replacement and were subsequently treated with antifungals for 6 weeks. Furthermore, both patients were put on long-term antifungal suppression treatment. Conclusions: Given the absence of controlled randomized trials, the treatment of Candida endocarditis mostly relies on experts’ opinion, and, thus, future studies focusing on the type and duration of antifungal treatment are required.

Introduction

Infective endocarditis (IE) by Candida species is an uncommon disease that accounts for about 1–2% of all cases of IE. This infection carries a mortality rate that can be as high as 43% [1,2,3,4]. Bothnative valve (NVE) and prosthetic valve endocarditis (PVE) due to Candida species are considered biofilm-related infections that follow after colonization of the heart valves by the fungus after an episode of candidemia, most likely originating in the gastrointestinal tract [5].

Given the rarity of this disease and the lack of definitive data on optimal treatment, management of Candida IE is debatable and mostly consists of chronic suppressive therapy with azoles [6]. Herein, we describe two cases of PVE due to Candida parapsilosis successfully treated with prosthetic valve replacement and long-term antifungal therapy with fluconazole.

Case reports

A 66 year old man with medical history of coronary artery disease and aortic valve replacement 16 months ago, arterial hypertension, dyslipidemia, and urothelial papillomas treated with BCG infusions 4 years ago, presented complaining of weakness and unintentional weight loss during the previous 3 months, as well as dyspnea during the last few days. The clinical examination was unremarkable. The laboratory examination revealed pancytopenia; hence, he was admitted to the Internal Medicine Department. During the first days of hospitalization he developed fever and 2 sets of blood cultures yielded Candida parapsilosis, while transthoracic ultrasound (TTE) of the heart revealed malfunction of the prosthetic valve. Additionally, an abdominal ultrasound revealed splenomegaly. A subsequent transesophageal ultrasound of the heart revealed vegetations and severe malfunction of the prosthetic valve due to paravalvular leak, as well as presence of pseudoaneurysm of the aortic valve along with aortic valve dehiscence. The patient did not have any other signs of IE, such as Janeway lesions, Roth spots or splinter hemorrhages. At that point in time, new blood cultures came back positive for C. parapsilosis. Immediately, treatment with intravenous liposomal amphotericin B at a dose of 5 mg/kg/d and intravenous micafungin at a dose of 150 mg/d was initiated. Blood cultures drawn on the 9th day of hospitalization were sterile, but the same day he developed acute pulmonary edema managed with nitrates, oxygen therapy and intravenous diuretics, and was transferred to a Cardiac Surgery Unit. Replacement of the prosthetic aortic valve was performed, and consequently, he was treated with a 6-week course of intravenous liposomal amphotericin B at the dose of 5 mg/kg/d. He was discharged on fluconazole at a dose of 400 mg once daily orally for the following 3 years and was followed up for the same duration, having an uneventful course.

A 59-year old man with medical history of systemic lupus erythematosus, cholecystectomy, choledocholithiasis treated with a stent at the common bile duct, epileptic seizures and a bioprosthetic aortic valve due to aortic stenosis that was replaced four years before presentation, was admitted to the Rheumatology Department because of fever due to consideration of systemic lupus erythematosus exacerbation. However, serial blood cultures grew Candida parapsilosis sensitive to all antifungals tested. Hence, the patient was transferred to the Internal Medicine Department. Clinical examination revealed the presence of a 3/6 systolic murmur, but was otherwise unremarkable. Laboratory examination was notable for hypochromic microcytic anemia and elevated erythrocyte sedimentation rate (ESR). A TTE revealed the presence of mild mitral stenosis and blood regurgitation, as well as aortic stenosis, with aortic valve area of 1.1 cm², and mild dilation of the ascending aorta. A transesophageal heart ultrasound revealed malfunction of the bioprosthetic aortic valve and, next to it, presence of an abscess of the aorta (Figure 1). The patient did not have any other signs of IE, such as Janeway lesions, Roth spots or splinter hemorrhages. He was treated with intravenous liposomal amphotericin B at a dose of 5 mg/kg/d once daily and flucytosine at a dose of 100 mg/kg/d divided in four doses orally, but due to persistent fungemia was transferred to Cardiac Surgery Unit. He had surgical replacement of the aortic valve one week later, and, consequently, was treated for 6 weeks with liposomal amphotericin B at a dose of 5 mg/kg/d in combination with micafungin 150 mg/day. The blood cultures drawn two days after surgery were sterile. He was discharged on oral fluconazole at a dose of 400 mg once daily for the next 2 years, and then at a dose of 200 mg once daily for the next 3 years, followed by a dose of 150 mg once weekly. Ever after surgery, he had an uneventful course for 6 years of follow-up.

Discussion

Candida IE is a rare disease that may occur after an initial episode of candidemia, most possibly via translocation from the gastrointestinal tract, that may pass clinically unnoticed [4]. The disease’s mortality can be as high as 43%, most times in association with an underlying disease, immunocompromised state, delayed diagnosis and failure of antifungal therapy, especially in cases where a surgery is not performed [4,7].

Even though C. albicans is the most common encountered species, non-albicans species have emerged as important causes of invasive fungal disease [8,9]. Among them, C. parapsilosis is of particular importance, since it is able to easily form biofilms on medical devices, such as on central venous catheters [10], while, on the other hand, it tends to grow rapidly in parenteral nutrition, thus placing patients to whom parenteral nutrition is administered, at increased risk for invasive candidiasis [9,11,12]. Even though infections by C. parapsilosis are generally associated with lower morbidity and mortality compared to infections by C. albicans, the particular antimicrobial susceptibility to antifungals of several clinical isolates of C. parapsilosis, with increased resistance to echinocandins and in some geographic regions, to azoles as well, may make treatment of these infections problematic [10,13,14,15]. Furthermore, horizontal transmission of C. parapsilosis has been described, in contrast to the colonization-dependent vertical transmission of C. albicans [16], making C. parapsilosis one of the most frequently isolated Candida species in critical care units [10]. The characteristics of Candida endocarditis (CE) have been recently reviewed [4]. The most common cause was C. albicans followed by C. parapsilosis, C. glabrata and C. tropicalis. CE commonly occurs in the setting of underlying malignancy, chronic liver disease, previous endocarditis, previous antimicrobial exposure, previous abdominal surgery, intravenous drug use, presence of a central venous catheter, and previous cardiac surgery [4]. Both present patients had undergone cardiac surgery in the past, and had a prosthetic heart valve. One patient had an underlying autoimmune disease that could be associated with higher risk of IE. Both patients had aortic valve PVE. Indeed, Candida PVE is more commonly left-sided and occurs most times at the aortic valve [4]. In both patients TTE failed to diagnose IE, being in line with the literature indicating that TTE could not diagnose CE, even in patients without prosthetic valve [4]. Interestingly, in a previous study comparing the characteristics of IE by C. parapsilosis with those by C. albicans, no significant differences were noted, with the exception of a slightly higher mortality in the group of patients with C. parapsilosis IE [17].

Table 1. Antifungal susceptibilities of isolated strains of C. parapsilosis.

MICs (μg/mL)	Patient 1	Patient 2
Fluconazole	2	≤1
Voriconazole	≤0.12	≤1
Caspofungin	1	NP
Micafungin	0.5	NP
Amphotericin B	0.5	1
Flucytosine	≤1	≤1

MICs—minimum inhibitory concentrations; NP—not performed.

Table 1. Antifungal susceptibilities of isolated strains of C. parapsilosis.

MICs (μg/mL)	Patient 1	Patient 2
Fluconazole	2	≤1
Voriconazole	≤0.12	≤1
Caspofungin	1	NP
Micafungin	0.5	NP
Amphotericin B	0.5	1
Flucytosine	≤1	≤1

MICs—minimum inhibitory concentrations; NP—not performed.

The source of candidemia could not be established in these two cases. Even though there are descriptions of cases of candidemia after heart valve replacement surgery associated with a later presentation with PVE, occurring even one year after surgery, the history of our patients was negative for a previous episode of candidemia [18,19]. Thus, it could be that an episode of candidemia did occur but was not clinically evident before the patients presented with PVE.

In terms of treatment, the first patient was treated with liposomal amphotericin B and flucytosine, while the second with a combination of high dose echinocandin and liposomal amphotericin B. As shown in a recent review, amphotericin B is commonly used either alone (20.4%) or in combination with another antifungal agent for CE treatment (27.7%). However, no differences in terms of survival were noted, independently of the antifungal used [4]. Use of amphotericin B in patients with Candida PVE has been shown in a recent study to be associated with increased survival [20], which was also the case with the patients presented herein. On the other hand, combination of antifungals was found to be superior to monotherapy in a model of simulated C. albicans endocardial vegetations, and more specifically, combinations including amphotericin B and micafungin [21]. In our patients, both treatments included amphotericin B, while in the second patient, micafungin was used in combination with amphotericin B. Conservative treatment alone was not enough to control the infection, in one case due to persistent candidemia and in the other due to development of heart failure. Thus, both patients underwent valve replacement and were subsequently treated with antifungals for 6 weeks. Furthermore, both patients were put on long-term antifungal suppression treatment. As shown in the literature, both valve replacement surgery and chronic therapy reduce the risk of death both in NVE and in PVE due to Candida species [4,22]. Hence, even though there is a lack of prospective trials in the field of CE treatment, the combination of valve replacement surgery and prolonged antifungal suppressive treatment should be used. This is supported by a recent study that showed reduced risk of relapse of CE in patients treated with maintenance antifungal therapy [20]. However, the duration of treatment, whether it should be indefinite or not, as well as the type of the appropriate antifungal agent are not yet clear, and should be addressed in future studies.

Conclusions

We have described two patients with prosthetic valve Candida endocarditis successfully treated. Both patients underwent prosthetic valve replacement and were put on long-term antifungal treatment.