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Endocarditis, Fungal: Treatment & Medication
Updated: Feb 2, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
- In fungal endocarditis (FE), aggressive antifungal therapy is always necessary but may not prove sufficient to completely alleviate the problem. Removal of the infected nidus is often central to management.
- Provide inotropic support as required.
- Remove the central venous catheter (CVC) when appropriate.
- Decrease immune suppression as much as possible.
- Provide supportive measures.
Surgical Care
- Although a small number of patients have survived with medical therapy alone, most survivors have required both medical and surgical treatment. Operative intervention is almost always required.
- Specific indications include ongoing infection (not fully responsive to medical therapy), embolic phenomena, and cardiac decompensation.
- Delaying operation when specific indications are present is not advantageous.
- Thrombus removal, valve replacement, and abscess resection are the most frequent procedures.
- The occasional neonate with a line-associated candidal infection may not require operative intervention.
Consultations
- Consultation with infectious diseases specialists, cardiologists, and cardiothoracic surgeons is often required.
- Neonatology or critical care consultation should accompany admission to the ICU.
Diet
- As tolerated by the patient's condition and as needed for operative intervention
Activity
- As tolerated by the patient's condition and as needed for operative intervention
Medication
Antifungal antibiotics, frequently used in combination, are the mainstay of treatment of fungal endocarditis (FE). In almost all reported cases of survival, surgical management was necessary to supplement antifungal medical therapy. Studies suggest that fluconazole prophylaxis may help to prevent invasive fungal infections, including endocarditis, in the newborn population.3
Antifungal agents
The mechanism of action may involve increasing the permeability of the cell membrane, which, in turn, causes intracellular components to leak, alteration of RNA and DNA metabolism, or an intracellular accumulation of peroxide that is toxic to the fungal cell.
Amphotericin B (Fungizone, AmBisome, Abelcet)
DOC for severe fungal infections. Fungicidal or fungistatic (depending on the organisms); best-studied drug, despite its toxicities. Although few data are available, use of one of lipid formulations (ie, lipid complex, liposome) at comparable doses is recommended.
Adult
Conventional: 0.5-1 mg/kg/d IV q24h
Lipid complex or liposome: 3-5 mg/kg/d IV qd
Relatively high doses of lipid formulations are recommended
Pediatric
Administer as in adults
Antineoplastic agents may enhance the potential of amphotericin B for renal toxicity, bronchospasm, and hypotension; corticosteroids, digitalis, and thiazides may potentiate hypokalemia; risk of renal toxicity is increased with cyclosporine
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
Monitor renal, hepatic, electrolyte, and hematologic status closely; hypercalciuria, hypokalemia, hypomagnesemia, renal tubular acidosis, renal failure, acute hepatic failure, hypotension, and phlebitis may occur; common infusion-related reactions include fever, chills, headache, hypotension, nausea, and vomiting (patient may be given acetaminophen and diphenhydramine 30 min before and 4 h after infusion); meperidine useful for chills; hydrocortisone (1 mg/kg amphotericin B [maximum 25 mg]) added to infusion, may help prevent immediate adverse reactions; salt loading with 10-15 mL/kg of NS infused before each dose may minimize the risk of nephrotoxicity
All these adjunctive measures should be considered only as patient's condition tolerates; adjust dose in renal failure
Flucytosine (Ancobon)
Adjunct to amphotericin B that seems to have a synergistic therapeutic effect in severe fungal infections. Converted to fluorouracil after penetrating fungal cells. Inhibits RNA and protein synthesis. Active against candidal and cryptococcal infections and generally used in combination with amphotericin B.
Adult
100-150 mg/kg/d PO divided q6h
Pediatric
Administer as in adults
Amphotericin B may increase toxicity of flucytosine; cytosine may inactivate flucytosine
Documented hypersensitivity; preexisting thrombocytopenia, GI bleeding, or bone marrow suppression.
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Monitor CBC count and BUN, serum creatinine, alkaline phosphatase, and transaminase levels; common adverse effects include nausea, vomiting, diarrhea, rash, CNS disturbance, anemia, leukopenia, and thrombocytopenia; therapeutic levels are 25-100 mg/L; recommended serum sample at steady state (obtain peak level 2-4 h after PO dose following 4 d of continuous dosing); peak levels of 40-60 mg/L have been recommended for systemic candidiasis; prolonged levels above 100 mg/L can increase risk of bone marrow suppression; GI bleeding in neonates has been reported with serum levels in the 50-60 mg/L range; adjust dose in renal failure
Fluconazole (Diflucan)
Although it has fewer toxicities than the preceding drugs, insufficient data and concerns about efficacy keep fluconazole a second-line drug for this infection.
Adult
600-800 mg/d PO/IV
CrCl 21-50 mL/min: Decrease dose 50%
CrCL <20 mL/min: Decrease dose 75%
Pediatric
10-12 mg/kg PO/IV qd
CrCl 21-50 mL/min: Decrease dose 50%
CrCL <20 mL/min: Decrease dose 75%
Inhibits CYP450 2C9/10 and CYP450 3A3/4 (weak inhibitor); may increase effects or levels of cyclosporine, phenytoin, theophylline, warfarin, PO hypoglycemics, and AZT; rifampin increases fluconazole metabolism
Cisapride is a CYP450 3A3/4 substrate, fluconazole may decrease elimination and increase risk of arrhythmias
Documented hypersensitivity; concomitant administration with cisapride, terfenadine (recalled from US market), or astemizole (recalled from US market)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Adjust dose for renal insufficiency; closely monitor if rashes develop and discontinue drug if lesions progress; may cause clinical hepatitis, cholestasis, and fulminant hepatic failure (including death) when taken with underlying medical conditions (eg, AIDS, malignancy) or while taking multiple concomitant medications; not recommended for women who are breastfeeding
Caspofungin (Cancidas)
Used to treat refractory invasive aspergillosis and poorly responsive or nonresponsive yeast infections. First of a new class of antifungal drugs (glucan-synthesis inhibitors). Inhibits synthesis of 1,3-beta-D-glucan, an essential component of fungal cell wall.
Adult
70 mg IV infused over 1 h on day 1; 50 mg IV qd thereafter
Pediatric
70 mg/m2 IV infused over 1 h on day 1; 50 mg/m2 qd thereafter
Coadministration with cyclosporine may increase risk of hepatotoxicity; carbamazepine, nelfinavir, efavirenz, or dexamethasone may decrease levels of caspofungin; caspofungin may decrease levels of tacrolimus
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in moderate hepatic dysfunction (decrease dose); may exacerbate pre-existing renal dysfunction or myelosuppression
Voriconazole (Vfend)
Used for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or Scedosporium apiospermum infections. A triazole antifungal agent that inhibits fungal cytochrome P450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis. Posaconazole may become available as a similar, but potentially safer, alternative.
Adult
Loading dose: 6 mg/kg IV q12h infused over 2 h for 2 doses
Maintenance: 4 mg/kg IV q12h infused over 2 h; switch to 200 mg PO q12h when able to tolerate; may increase to 300 mg PO q12h if inadequate response
<40 kg: Average maintenance dose is 100 mg PO q12h (may increase to 150 mg PO q12h)
Pediatric
<12 years:
Not established; limited data suggests:
11 mg/kg IV q12h infused over 2 h for 2 doses
Maintenance: 6 mg/kg IV q12h infused over 2 h
>12 years: Administer as in adults
CYP450 2C19 (highest affinity), 2C9, and 3A4 (minor) substrate and inhibitor; CYP450 inducers (eg, rifampin, phenytoin) have shown to decrease steady state peak plasma levels by up to 93%; may increase serum levels of drugs metabolized by CYP450 2C19 or 2C9, some of which are contraindicated (eg, sirolimus, pimozide, quinidine, cisapride, ergot alkaloids), others may need more frequent monitoring (eg, cyclosporine, tacrolimus, warfarin, HMG CoA inhibitors, benzodiazepines, calcium channel blockers)
Documented hypersensitivity; CrCl <50 mL/min (decreased excretion of IV vehicle) if administering IV; coadministration with rifampin, rifabutin, carbamazepine, barbiturates, sirolimus, pimozide, quinidine, cisapride, ergot alkaloids
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Decrease maintenance dose in hepatic dysfunction; common adverse effects include visual disturbances, fever, rash, vomiting, nausea, diarrhea, headache, sepsis, peripheral edema, abdominal pain, rash (eg, Stevens-Johnson syndrome, phototoxicity), and respiratory disorder; rare cases of severe hepatotoxicity reported; administer PO dosage form 1 h ac or pc
Micafungin (Mycamine)
Member of new class of antifungal agents, echinocandins, which inhibit cell wall synthesis. Inhibits synthesis of 1,3-beta-D-glucan, an essential fungal cell wall component not present in mammalian cells.
Indications include (1) prophylaxis of Candida infections in patients undergoing hematopoietic stem cell transplantation and (2) treatment of esophageal candidiasis.
Adult
Candidiasis prophylaxis: 50 mg IV qd infused over 1 h
Esophageal candidiasis: 150 mg IV qd infused over 1 h
Pediatric
Not established; limited data suggests:
Neonates:
<1 kg: 12-16 mg/kg IV qd
>1 kg: 8 mg/kg IV qd
1-7 years: 4 mg/kg IV qd
>8 years: Administer as in adults
Increases sirolimus and nifedipine AUC approximately 20%
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Common adverse effects may include headache, nausea, vomiting, and abdominal pain; other adverse effects include skin rash, delirium, phlebitis, shock, leukopenia, and hyperbilirubinemia; rare cases of elevated hepatic enzyme, BUN, and creatine levels have been reported; transient acute intravascular hemolysis and hemoglobinuria may occur; do not mix or infuse in same IV line with other medications because precipitate forms with other commonly used medications (flush existing IV line with 0.9% NaCl before and after infusion); protect from light following dilution
Anidulafungin (Eraxis)
Antifungal agent of the echinocandin class. Inhibits synthesis of 1,3-beta-D-glucan, an essential component of fungal cell walls. Indicated to treat esophageal candidiasis, candidemia, and other forms of candidal infections (eg, intraabdominal abscesses, peritonitis).
Adult
Esophageal candidiasis: 100 mg IV on day 1, decrease dose on day 2 and thereafter to 50 mg/d IV
Candidemia and other Candida infections: 200 mg IV on day 1, decrease dose on day 2 and thereafter to 100 mg/d IV
Do not exceed infusion rate of 1.1 mg/min
Pediatric
Not established
None reported
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Common adverse effects include hypokalemia, diarrhea, elevated hepatic enzyme levels, and headache; rare reports of serious hepatotoxicity; infusion related reactions (eg, rash, urticaria, flushing, pruritus, dyspnea, hypotension) may occur, particularly with rapid infusion; following reconstitution, dilute further with D5W or NS before administration
Posaconazole (Noxafil)
Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption. Available as PO susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.
Adult
200 mg (5 mL) PO tid with food or liquid nutritional supplement to enhance absorption
Pediatric
<13 years: Not established
>13 years: Administer as in adults
Metabolized via UDP glucuronidation; P-gp efflux substrate; CYP3A4 inhibitor
UDP-G inducers (eg, rifabutin, phenytoin) and drugs that increase gastric pH (eg, cimetidine) decrease serum levels (avoid concomitant use unless benefit outweighs risk); inhibits CYP3A4 and may elevate serum levels of cyclosporine, tacrolimus, sirolimus, rifabutin, midazolam, phenytoin, calcium channel blockers (eg, nifedipine, bepridil), HMG-CoA reductase inhibitors (eg, lovastatin, pravastatin), ergot alkaloids, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine, or vinca alkaloids (eg, vincristine, vinblastine)
Documented hypersensitivity; coadministration with ergot alkaloids; coadministration with CYP3A4 substrates likely to result in serious toxicities (eg, terfenadine, astemizole, cisapride, pimozide, halofantrine, quinidine)
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Common adverse effects include nausea, vomiting, diarrhea, rash, hypokalemia, thrombocytopenia, and elevated liver enzyme levels; closely monitor patients with severe diarrhea or vomiting for breakthrough fungal infections; rare adverse events include arrhythmias caused by QTc prolongation, bilirubinemia, or liver function impairment; caution with preexisting cardiac risk factors (eg, history of arrhythmia, hypokalemia, hypomagnesemia); food improves absorption and provides optimal serum concentration; shake well before use; administer with measuring spoon provided in package; avoid if breastfeeding
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| Differential Diagnoses & Workup: Endocarditis, Fungal |
 Treatment & Medication: Endocarditis, Fungal |
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Further Reading
Keywords
fungal endocarditis, FE, arthritis, Aspergillus, bacterial endocarditis, Blastomyces dermatitidis, Candida, candidal endocarditis, candidal infection, cardiac infection, central hyperalimentation, CHA, Coccidioides immitis, Cryptococcus neoformans, disseminated candidal infection, fever, fungal infection, Fusarium, heart murmur, Histoplasma capsulatum, infectious endocarditis, Janeway lesions, Mucor, neonatal sepsis, Osler nodes, overwhelming infection, petechiae, Pseudallescheria boydii, Roth spots, splenomegaly, splinter hemorrhages, superior vena cava syndrome, Torulopsis galbrata, Trichosporon beigelii, weight loss
