INTRODUCTION — Candida endocarditis is one of the most serious manifestations of candidiasis, and Candida is the most common cause of fungal endocarditis, causing over half of all cases. In a 2001 review of 270 cases of fungal endocarditis in the world literature, the following distribution of organisms was noted [1]:
●Candida albicans – 24 percent
●Non-albicans species of Candida – 28 percent
●Aspergillus species – 24 percent
●Histoplasma capsulatum – 6 percent
●Other – 17 percent
Candida suppurative thrombophlebitis is an uncommon manifestation of Candida infection.
Candida endocarditis and suppurative thrombophlebitis will be reviewed here. An overview of Candida infections, Candida pericarditis, Aspergillus endocarditis, and fungal cardiac implantable device infections are discussed separately. (See "Overview of Candida infections" and "Candida infections of the abdomen and thorax", section on 'Pericarditis' and "Treatment and prevention of invasive aspergillosis", section on 'Role of surgery' and "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis".)
ENDOCARDITIS
Risk factors — Candida endocarditis results from candidemia.
Risk factors include [1-13]:
●Prosthetic heart valves or other valvular disease
●Injection drug use
●Indwelling central venous catheters
●Cancer chemotherapy
●Prior bacterial endocarditis
●Low birthweight in neonates
In the International Collaboration on Endocarditis (ICE) Prospective Cohort Study, 46 percent of 70 cases of Candida endocarditis between 2000 and 2010 were in patients with prosthetic heart valves [12]. Prosthetic valve infection can occur at the time of surgery or later during an episode of candidemia [4,6,14]. Contamination of an aortic valve allograft has been reported as the source for Candida prosthetic valve endocarditis [15]. Almost half of the patients in a large French and Spanish study encompassing the years 2001 to 2015 had a prior episode of endocarditis [16].
The magnitude of risk of endocarditis in patients with candidemia who have prosthetic heart valves was illustrated in a review of 44 patients on a cardiothoracic surgery service who developed nosocomial candidemia [17]. Seven patients were diagnosed with prosthetic valve endocarditis at the time of candidemia; among the remaining 37 patients, four (11 percent) developed endocarditis at a mean of 232 days (range 26 to 390 days) after candidemia. (See "Candidemia in adults: Epidemiology, microbiology, and pathogenesis".)
In a retrospective review including 1873 patients treated for candidemia from 2002 to 2015, 47 (0.05 percent) had Candida endocarditis [18]. C. albicans predominated (60 percent), followed by Candida parapsilosis (15 percent). In a multivariable analysis, the only risk factor for development of endocarditis in patients with candidemia was prior valvular heart disease. Factors associated with decreased risk for development of Candida endocarditis included parenteral nutrition, hematologic malignancy, and fungemia due to Candida glabrata.
Of the 70 cases in the ICE study described above, the most common species detected were C. albicans (44 percent), C. parapsilosis (27 percent), C. tropicalis (10 percent), and C. glabrata (6 percent) [12]. Similar proportions of patients had C. albicans (41 percent) and C. parapsilosis (35 percent) in a study from France and Spain [16]. People who inject drugs also most commonly have endocarditis due to C. albicans or C. parapsilosis, but those who use Iranian brown heroin and develop endocarditis almost always have C. albicans because the organism grows abundantly in the lemon juice that is used to cut the heroin [7,9]. In a retrospective review including 8 patients with a history of injection drug use treated for Candida endocarditis, there were 7 cases of C. parapsilosis infection and there was 1 case of C. glabrata infection; 75 percent were treated with surgery in addition to antifungal therapy and all survived [19].
Clinical features — The clinical manifestations of Candida endocarditis include symptoms and signs of cardiac involvement (dyspnea, edema, or other findings suggestive of congestive heart failure; chest pain; new or changing murmurs on physical examination); embolic phenomena, often involving major vessels supplying the brain, extremities, and the gastrointestinal tract; and systemic symptoms of fever, night sweats, malaise, and weight loss. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis".)
Arterial embolization is more common in fungal endocarditis than in bacterial endocarditis [20,21], likely a reflection of the larger size of the vegetations associated with fungal endocarditis. The most common sites are the cerebral circulation, extremities, and gastrointestinal tract. Classic signs of endocarditis, such as Osler nodes, Roth spots, and Janeway lesions are infrequently noted [1].
Patients with Candida endocarditis can develop other complications of candidemia, including endophthalmitis, vertebral osteomyelitis, and meningitis. Thus, all patients should be questioned about and examined for signs of other complications of candidemia. (See "Treatment of endogenous endophthalmitis and chorioretinitis due to Candida species" and "Clinical manifestations and diagnosis of candidemia and invasive candidiasis in adults".)
The diagnosis of Candida endocarditis is often delayed. In one review, fungal endocarditis was characterized by a long duration of symptoms before hospitalization (mean 32 days), extracardiac manifestations, and delayed or missed diagnosis [1]. With increasing use of cardiac echocardiography in the 20 years subsequent to that review, it is likely that the diagnosis is now made more quickly.
Diagnosis — The diagnostic criteria for Candida endocarditis are similar to those for bacterial endocarditis. Blood cultures usually show persistent candidemia, and echocardiography frequently reveals valvular vegetations that are often large. Although transthoracic echocardiography can show vegetations, transesophageal echocardiography is more sensitive and especially useful in patients with prosthetic valve Candida endocarditis [6,22]. (See "Clinical manifestations and evaluation of adults with suspected left-sided native valve endocarditis" and "Prosthetic valve endocarditis: Epidemiology, clinical manifestations, and diagnosis".)
Examination of vegetations or an embolus by histopathology shows yeast forms and by culture yields Candida species.
Treatment — The following section addresses the management of Candida endocarditis of native and prosthetic valves. Candida infection of cardiac implantable devices is discussed separately. (See "Infections involving cardiac implantable electronic devices: Epidemiology, microbiology, clinical manifestations, and diagnosis".)
Combined medical and surgical approach — Based upon case reports, case series, and clinical experience [1,6,12,23-36], a combined approach that utilizes both antifungal agents and valve replacement is recommended for treatment of native and prosthetic valve Candida endocarditis in the 2016 Infectious Diseases Society of America (IDSA) candidiasis guidelines and the 2015 American Heart Association infective endocarditis guidelines [11,14]. We agree with this approach, realizing that there are some studies that found no difference in mortality between patients receiving surgery and those treated medically [12,16].
There are conflicting data about the mortality rate associated with a combined medical and surgical approach compared with antifungal therapy alone. In a review of cases of fungal endocarditis that occurred between 1965 and 1995 Candida endocarditis mortality was 59 percent among those who received antifungal therapy alone and 42 percent among those who received combined surgical and antifungal therapy [1]. A subsequent meta-analysis of 72 of 163 patients who had Candida endocarditis between 1980 and 2002 also revealed that better outcomes were associated with a combined surgical and medical therapy approach, but the difference was not statistically significant (odds ratio 0.56, 95% CI 0.16-1.99) [36]. A subsequent series of 70 cases between 2000 and 2010 found that mortality was similar in patients who received combined medical-surgical therapy and those who received antifungal therapy alone (in hospital mortality: 38 versus 34 percent; 1 year mortality: 66 versus 62 percent) [12]. Among the 46 cases treated between 2001 and 2015 in the combined French-Spanish study, mortality was similar in those who had combined medical surgery therapy and those who were treated with antifungal agents only [16]. However, the authors pointed out that the most ill patients were deemed too frail to undergo valve replacement.
Surgical management of endocarditis is discussed in greater detail separately. (See "Surgery for left-sided native valve infective endocarditis" and "Surgery for prosthetic valve endocarditis".)
Initial antifungal therapy — For initial therapy of native or prosthetic valve endocarditis, we recommend either (table 1) [11]:
●A lipid formulation of amphotericin B (3 to 5 mg/kg intravenously [IV] daily) with or without flucytosine (25 mg/kg orally four times daily in patients with normal renal function)
or
●An echinocandin at an increased dose (caspofungin 150 mg IV daily, micafungin 150 mg IV daily, anidulafungin 200 mg IV daily)
The therapeutic regimen used most frequently is an echinocandin. For patients who receive amphotericin B, most are now treated with a lipid formulation of amphotericin B in order to reduce nephrotoxicity, and lipid formulations are preferred in the IDSA Candida guidelines. Amphotericin B deoxycholate (1 mg/kg IV daily) can be used as an alternative to a lipid formulation of amphotericin B if a lipid formulation is not available.
Flucytosine can be added to a lipid formulation of amphotericin B for synergistic activity, but caution must be used to avoid dose-related bone marrow toxicity. Serum flucytosine levels should be monitored routinely, especially if amphotericin B–associated nephrotoxicity occurs, to keep peak serum drug levels <75 mcg/mL. If flucytosine levels cannot be obtained in a timely fashion and if the patient has renal failure, then the risks of using this agent may outweigh the benefits. (See "Pharmacology of flucytosine (5-FC)".)
There are case reports and case series of successful treatment of Candida endocarditis with an echinocandin (eg, caspofungin), either alone or combined with amphotericin B, flucytosine, or fluconazole [12,33,34,37-46]. The efficacy of the echinocandins for Candida endocarditis has not been proven in clinical trials, but it seems reasonable that these agents, which are fungicidal against many species of Candida and have been proven efficacious for candidemia, could be used for endocarditis. Echinocandins are unique among the systemic antifungal agents in their activity against biofilm-embedded Candida species.(See "Pharmacology of echinocandins and other glucan synthesis inhibitors", section on 'Candida biofilms'.)
The ICE study of 70 patients found that mortality rates were similar between the group that received an echinocandin and the group that received amphotericin B [12]. However, the combined French-Spanish study found that mortality was lower in patients who were treated with amphotericin B in comparison with those who received treatment with an echinocandin [16].
The most appropriate dosing of the echinocandins for Candida endocarditis has not been studied, but higher doses than normally used for candidemia are recommended and appear to be safe [11,38,39]. Failure with development of resistance to caspofungin and other antifungal agents has also been documented [47].
Resection of the valve and any associated abscesses is essential for cure in most, but not all, patients. Following surgery, antifungal therapy should be continued for at least six weeks. After the patient's condition has stabilized and the blood cultures have remained negative, therapy can be changed to oral fluconazole (400 to 800 mg [6 to 12 mg/kg] daily) if the organism is susceptible to complete the course of therapy [11]. Alternative azoles for patients with a Candida isolate that is resistant to fluconazole are discussed below (see 'Chronic suppressive therapy' below). Because of the high rates of relapse, many clinicians will treat for longer than six weeks and follow clinical and laboratory parameters to decide on the total duration of therapy. A total course longer than six weeks is particularly important in patients with perivalvular abscesses and other complications [11].
For patients who cannot undergo surgical resection of the affected valve, initial treatment with either a lipid formulation of amphotericin B with or without flucytosine or monotherapy with a high dose of an echinocandin followed by lifelong suppression with an oral azole (fluconazole if the isolate is susceptible) is recommended in the 2016 IDSA guidelines [11]. Specific recommendations for chronic suppressive therapy are provided below. (See 'Chronic suppressive therapy' below.)
Fluconazole should not be used as monotherapy for initial therapy of Candida endocarditis [28,35]. In a review of 64 reported cases of Candida endocarditis that were treated with fluconazole alone or combined with another antifungal agent but without surgical intervention, 4 relapses and 11 failures (23 percent) occurred [35]. Failures were higher in the 19 patients who received only fluconazole (42 percent) than in the group of 45 patients who received fluconazole plus another antifungal agent, usually an amphotericin B formulation (16 percent).
Chronic suppressive therapy — As discussed above, all patients who cannot undergo surgical resection of the affected valve and patients with prosthetic valve endocarditis should receive lifelong suppression with oral fluconazole (400 to 800 mg [6 to 12 mg/kg] daily) if the Candida isolate is susceptible [4-6,11,42,48,49]. Some clinicians will use long-term suppressive antifungal therapy for months or even lifelong even when surgical resection has been performed because of the high relapse rate, especially in patients with complications of endocarditis, such as perivalvular abscesses.
In patients with endocarditis caused by a Candida species that is not susceptible to fluconazole, oral voriconazole (200 or 300 mg [3 to 4 mg/kg] twice daily) or delayed-release posaconazole (300 mg daily) should be used for chronic suppressive therapy if the organism is susceptible.
Neonates — A unique group in which antifungal therapy alone may be effective is that of neonates who have disseminated candidiasis with cardiac thrombi and vegetations [8,10]. The rate of success reported in a review of 30 neonates was 60 percent among the 20 patients treated with medical therapy alone, compared with 60 percent among the 10 patients treated with combined medical and surgical therapy [10].
In neonates with Candida endocarditis, we suggest amphotericin B deoxycholate (1 mg/kg IV daily) [11]. Flucytosine may be added, but toxicity is greater in neonates than in adults, and a strong recommendation cannot be made to use this agent for this population [50]. As with adults, after the patient has stabilized and the blood cultures are negative, the patient can be switched to fluconazole if the Candida isolate is susceptible.
Relapse — Relapses are common, even with surgical resection and treatment with amphotericin B [1,2,4,5,48]. For example, in one small case series, 4 of 10 patients had a late relapse (mean 25 months) despite a combined therapy approach [4]. Because of the risk of relapse, careful follow-up is essential, even after apparently successful therapy.
Mortality — In an international multicenter prospective cohort study that included 70 cases of Candida endocarditis between 2000 and 2010, in-hospital mortality was 36 percent and mortality at one year was 59 percent [12].
SUPPURATIVE THROMBOPHLEBITIS — Candida suppurative thrombophlebitis is an uncommon manifestation of invasive candidiasis. The approach to therapy includes antifungal therapy as well as removal of the intravenous catheter [11]. In addition, incision and drainage or resection of the vein should be performed, if feasible. However, when a central vein is involved, resection is not usually possible.
Most experience treating Candida thrombophlebitis has been with amphotericin B, but fluconazole and caspofungin have been reported to be effective [11,51-53]. Other agents used for the treatment of candidemia, such as the other echinocandins (anidulafungin, micafungin) and voriconazole are also likely to be effective [54]. As with the treatment approach to Candida endocarditis, higher-than-usual doses of the echinocandins should be used [11]. (See 'Initial antifungal therapy' above.)
For initial antifungal therapy of Candida thrombophlebitis, we recommend either (table 1):
●A lipid formulation of amphotericin B (3 to 5 mg/kg intravenously [IV] daily)
or
●Fluconazole (400 to 800 mg [6 to 12 mg/kg] IV or orally daily)
or
●An echinocandin at an increased dose (caspofungin 150 mg IV daily, micafungin 150 mg IV daily, anidulafungin 200 mg IV daily)
One of these regimens should be continued for at least two weeks after candidemia (if present) has cleared. Step-down therapy with fluconazole (at the same doses recommended above) can be used in those initially treated with amphotericin B or an echinocandin who have responded to the initial regimen, are clinically stable, and have a fluconazole-susceptible isolate. In patients who have responded clinically and whose cultures have cleared, antifungal therapy can be discontinued once resolution of the thrombus is documented.
Systemic anticoagulation or thrombolytic therapy has been used as adjunctive therapy in some cases, but there is inadequate evidence to recommend these modalities [11].
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Candidiasis" and "Society guideline links: Treatment and prevention of infective endocarditis".)
SUMMARY AND RECOMMENDATIONS
●Candida endocarditis is one of the most serious manifestations of candidiasis, and Candida is the most common cause of fungal endocarditis. (See 'Introduction' above.)
●Candida endocarditis results from candidemia. Risk factors include prosthetic heart valves or other valvular disease, injection drug use, indwelling central venous catheters, cancer chemotherapy, prior bacterial endocarditis, and, in neonates, low birthweight. (See 'Risk factors' above.)
●The clinical manifestations of Candida endocarditis include symptoms and signs of cardiac involvement (dyspnea, edema, or other findings suggestive of congestive heart failure; chest pain; new or changing murmurs on physical examination); embolic phenomena, often involving major vessels supplying the brain, extremities, and the gastrointestinal tract; and systemic symptoms of fever, night sweats, malaise, and weight loss. (See 'Clinical features' above.)
●The diagnostic criteria for Candida endocarditis are similar to those for bacterial endocarditis. Blood cultures usually show persistent candidemia, and echocardiography frequently reveals valvular vegetations that are often large. (See 'Diagnosis' above.)
●In patients with native or prosthetic valve Candida endocarditis, we suggest a combined approach that utilizes both antifungal agents and valve replacement rather than antifungal therapy alone (Grade 2C). (See 'Combined medical and surgical approach' above.)
●For initial antifungal therapy of Candida endocarditis, we recommend either a lipid formulation of amphotericin B at a dose of 3 to 5 mg/kg intravenous (IV) daily with or without flucytosine (25 mg/kg orally four times daily in patients with normal renal function) or an echinocandin at an increased dose (caspofungin 150 mg IV daily, micafungin 150 mg IV daily, anidulafungin 200 mg IV daily) (table 1) (Grade 1C). Amphotericin B deoxycholate (1 mg/kg IV daily) can be used as an alternative to a lipid formulation of amphotericin B if a lipid formulation is not available. (See 'Initial antifungal therapy' above.)
●For patients with Candida endocarditis who are infected with susceptible Candida spp and who are clinically stable and have cleared Candida from the bloodstream following initial antifungal therapy and valve surgery, we suggest stepdown therapy with an oral azole (Grade 2C). If the Candida isolate is susceptible to fluconazole, it should be given at a dose of 400 to 800 mg [6 to 12 mg/kg] daily. If the Candida isolate is not susceptible to fluconazole, oral voriconazole (200 or 300 mg [3 to 4 mg/kg] twice daily) or delayed-release posaconazole (300 mg daily) should be used. Treatment should be continued for at least six weeks following surgery. However, due to the high rates of relapse, especially in those who have a complication, such as a perivalvular abscess, many clinicians prefer to extend treatment longer than six weeks and follow clinical and laboratory parameters to decide on the total duration of therapy. (See 'Initial antifungal therapy' above.)
●For patients with Candida endocarditis who cannot undergo surgical resection of the affected valve and patients with prosthetic valve endocarditis, initial antifungal therapy (with either a lipid formulation of amphotericin B with or without flucytosine or a high dose of an echinocandin) should be followed by lifelong suppression with an oral azole (Grade 2C). If the Candida isolate is susceptible to fluconazole, it should be given at a dose of 400 to 800 mg (6 to 12 mg/kg) daily. If the Candida isolate is not susceptible to fluconazole, oral voriconazole (200 or 300 mg [3 to 4 mg/kg] twice daily) or delayed-release posaconazole (300 mg daily) should be used. (See 'Chronic suppressive therapy' above.)
●For neonates with Candida endocarditis in the absence of another indication for surgery, we suggest antifungal therapy without valve replacement (Grade 2C). Amphotericin B deoxycholate (1 mg/kg IV daily) is the drug of choice in neonates. (See 'Neonates' above.)
●For initial antifungal therapy of Candida thrombophlebitis, we recommend either a lipid formulation of amphotericin B (3 to 5 mg/kg IV daily) or fluconazole (400 to 800 mg [6 to 12 mg/kg] IV or orally daily) or an echinocandin at a high dose (caspofungin 150 mg IV daily, micafungin 150 mg IV daily, anidulafungin 200 mg IV daily) (table 1) (Grade 1C). Recommendations for step-down therapy and duration of therapy are discussed above. We also recommend removal of the IV catheter (Grade 1C). In addition, incision and drainage or resection of the vein should be performed, if feasible. (See 'Suppurative thrombophlebitis' above.)
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