Fungal Endocarditis

Fungal endocarditis is infection of the endocardium or a heart valve by yeasts or moulds. It accounts for about 1 to 10% of infective endocarditis.

Candida causes about half of cases (Candida albicans, C. parapsilosis, C. glabrata, C. tropicalis). Aspergillus accounts for about a quarter. The rest are Histoplasma, Cryptococcus, Fusarium, Scedosporium and Mucorales.

Risk factors are prosthetic valves (30 to 50% of cases), injection drug use, central venous catheters, parenteral nutrition, prolonged broad spectrum antibiotics, prolonged intensive care, cardiac surgery, neutropenia, immunosuppression, diabetes and HIV infection.

Mortality is about 50 to 80%, higher with Aspergillus. Treatment needs an antifungal drug and early surgery in most patients.

Pathophysiology. Fungaemia seeds damaged or prosthetic valves. Large friable vegetations form, which fragment and embolise to large arteries (limbs, brain, spleen) more often than in bacterial endocarditis. Hyphal invasion of the valve ring causes abscess and prosthesis dehiscence.

• Fever (may be absent), malaise, weight loss and night sweats over weeks.
• Large arterial emboli to the limbs, brain, spleen and kidneys, and strokes.
• A new or changing murmur, heart failure from valve destruction, and conduction block from a root abscess.
• Candida: endophthalmitis (floaters, blurred vision), skin lesions and osteomyelitis.
• Cryptococcus: meningitis and a high burden in HIV infection. Histoplasma: fever, hepatosplenomegaly, pancytopenia and travel or residence in an endemic region (including parts of Africa).

Red flags.

• Large arterial embolism or stroke
• Vegetation over 10 mm, or a prosthetic valve
• Persistent fungaemia (positive cultures over 5 to 7 days of treatment)
• Heart failure or new conduction block
• Neutropenia or profound immunosuppression
• Visual symptoms

• Blood cultures. Three sets before antifungal therapy. Candida usually grows in 2 to 4 days (sensitivity about 80 to 90%). Aspergillus almost never grows, and Histoplasma needs lysis centrifugation.
• Echocardiography. Transthoracic then transoesophageal. Large, mobile, bulky vegetations, often with obstruction or abscess.
• Fungal markers. Serum beta-D-glucan (positive in Candida, Aspergillus and Pneumocystis, negative in Cryptococcus and Mucorales). Aspergillus galactomannan and PCR. Cryptococcal antigen in serum. Histoplasma antigen in urine and serum.
• Tissue. Culture and histology of excised valve and emboli, with Grocott methenamine silver or periodic acid-Schiff stain and species identification with antifungal susceptibility testing.
• Eye examination. Dilated fundoscopy in every patient with candidaemia.
• Imaging. CT or MRI of the brain, chest and abdomen for emboli and abscess. PET-CT for prosthetic valve and device infection.
• Immune status. Full blood count with neutrophils, HIV test and CD4 count, glucose.

Differential diagnosis.

• Bacterial and culture negative endocarditis (Coxiella, Bartonella, Brucella)
• Nonbacterial thrombotic and Libman-Sacks endocarditis
• Atrial myxoma and valvular thrombus
• Prosthetic valve thrombosis
• Mycobacterial infection of the valve
• Systemic vasculitis and cardiac tumours
• Disseminated candidiasis without endocarditis

Combined antifungal therapy and surgery. Start therapy at once and plan early valve surgery. Remove infected catheters and devices.

Candida.

• Liposomal amphotericin B 3 to 5 mg/kg intravenously once daily (maximum 5 mg/kg daily), with or without flucytosine 25 mg/kg orally every 6 hours (maximum 100 mg/kg daily). Adjust flucytosine for renal function: 25 mg/kg every 12 hours at creatinine clearance 20 to 40 mL/min, every 24 hours at 10 to 20 mL/min, with levels (trough 25 to 50 mg/L, peak under 100 mg/L) and weekly full blood count. Monitor creatinine, potassium and magnesium for amphotericin, with saline loading before doses.
• An echinocandin in high dose is an alternative: caspofungin 70 mg intravenously as a loading dose, then 150 mg once daily (35 mg after the load in moderate liver impairment on the 50 mg dose), or micafungin 100 to 150 mg once daily, or anidulafungin 200 mg loading, then 100 mg once daily.
• Step down after clearance of blood cultures, stable haemodynamics and susceptible isolates: fluconazole 400 to 800 mg (6 to 12 mg/kg) orally or intravenously once daily. Halve the dose at creatinine clearance 50 mL/min or less. Interacts with warfarin, statins and QT-prolonging drugs. Avoid in pregnancy. Not suitable for C. glabrata or C. krusei without susceptibility.
• Lifelong suppression with fluconazole 400 mg daily when the valve cannot be replaced.

Aspergillus and other moulds.

• Voriconazole 6 mg/kg intravenously every 12 hours for two doses, then 4 mg/kg every 12 hours. Oral 200 mg every 12 hours for 40 kg or over (up to 300 mg every 12 hours) and 100 mg every 12 hours under 40 kg (up to 150 mg). Aim for a trough of 1 to 5.5 mg/L. In mild to moderate cirrhosis give the usual loading dose then halve the maintenance. Avoid in severe liver disease unless the benefit outweighs the risk. At creatinine clearance under 50 mL/min prefer the oral route, because the intravenous vehicle accumulates. Contraindicated with rifampicin, rifabutin, carbamazepine and ritonavir at high dose. Monitor liver enzymes, QTc and vision.
• Isavuconazole: isavuconazonium sulphate 372 mg (200 mg isavuconazole) intravenously or orally every 8 hours for 6 doses, then 372 mg once daily. Contraindicated in familial short QT syndrome.
• Mucorales: liposomal amphotericin B 5 to 10 mg/kg intravenously once daily.
• Histoplasma: liposomal amphotericin B 3 mg/kg intravenously once daily for 4 to 6 weeks, then itraconazole 200 mg orally three times daily for 3 days, then 200 mg twice daily for at least 12 months. Check itraconazole levels.
• Cryptococcus: liposomal amphotericin B 3 to 4 mg/kg intravenously once daily with flucytosine 25 mg/kg orally every 6 hours for at least 4 to 6 weeks, then fluconazole 400 to 800 mg once daily.

Duration. At least 6 weeks after valve surgery, and often 6 to 12 months for mould infection. Lifelong oral suppression when the infected valve or prosthesis remains.

Surgery. Indicated in nearly all patients: heart failure, abscess, vegetation over 10 mm, recurrent embolism, persistent fungaemia, prosthetic valve involvement and mould infection. Remove all infected tissue and replace the valve. Operative mortality is about 20 to 30%.

HIV infection. Start or continue antiretroviral therapy, with checks for interactions with azoles, and manage immune reconstitution inflammatory syndrome.

Special groups.

• Pregnancy: azoles are teratogenic, so use liposomal amphotericin B or an echinocandin.
• Anticoagulation: avoid in the absence of another strong indication, because of the risk of haemorrhage from cerebral mycotic aneurysm.

Monitoring. Blood cultures daily until negative. Creatinine, potassium, magnesium and full blood count twice weekly on amphotericin, and liver enzymes weekly on azoles. Drug levels for voriconazole, itraconazole and flucytosine. Echocardiography weekly during treatment and at the end, and at 3, 6 and 12 months. Follow up for at least 12 months for relapse.

Referral and escalation. Refer to infectious diseases and a cardiac surgical centre. Emergency for heart failure, large arterial embolism, persistent fungaemia or a prosthetic valve.