TABLE 1.
Antifungal agents for the treatment of systemic fungal infections in children
| Agent | Routes of administration/relative costs* | Dosage/day | Most common indications for use† | Adverse events/cautionary notes |
Body fluid concentrations‡ |
|
|---|---|---|---|---|---|---|
| CSF/serum/comments | Other sites | |||||
| Amphotericin B deoxycholate | IV: $ (for 1 mg/kg/day) | 0.25 mg/kg to 0.5 mg/kg initially, increased to 0.5 mg/kg to 1.5 mg/kg§ Dosage for aspergillosis: 1.5 mg/kg |
Invasive fungal infections caused by susceptible organisms as shown in Table 2 Empirical therapy of presumed fungal infections in febrile neutropenic patients |
Infusion-related toxicity Nephrotoxicity, including hypokalemia Medication errors have occurred due to confusion between the lipid-based products and conventional amphotericin B. The dose of conventional amphotericin B should not exceed 1.5 mg/kg/day |
3% | Newborn serum/maternal serum = 50% Aqueous humor/serum = 25% |
| Liposomal amphotericin B (AmBisome) | IV: $$$ (for 3 mg/kg/day) | 3 mg/kg to 5 mg/kg Dosage for aspergillosis: AmBisome 5 mg/kg to 10 mg/kg; likely up to 10 mg/kg |
Invasive fungal infections, refractory or intolerance to conventional amphotericin B | Fewer infusion-related reactions and nephrotoxicity than amphotericin B deoxycholate | Higher levels may be achievable in brain tissue due to potential for greater per kg dosing | Concentrates in reticulo-endothelial system |
| Amphotericin B lipid complex (Abelcet) | IV: $$$$ (for 5 mg/kg/day) | 5 mg/kg Dosage for aspergillosis: Abelcet 5 mg/kg to 10 mg/kg; likely up to 7.5 mg/kg |
Invasive fungal infections; refractory or with intolerance to conventional amphotericin B | Less nephrotoxicity than amphotericin B deoxycholate | Higher levels may be achievable in brain tissue due to potential for greater per kg dosing | Concentrates in reticulo-endothelial system |
| Fluconazole | PO; IV PO: $ (for 5 mg/kg/day) IV: $ (for 5 mg/kg/day) |
PO: 6 mg/kg once, then 3 mg/kg/day for oropharyngeal or esophageal candidiasis; 6 mg/kg/day to 12 mg/kg/day for invasive fungal infections; 6 mg/kg/day for suppressive therapy in HIV-infected children with cryptococcal meningitis IV: 3 mg/kg to 6 mg/kg, single dose; up to 12 mg/kg per day for serious infections |
Candida infections (eg, intra-abdominal abscess, peritonitis, pleural space infection, candidemia, esophageal candidiasis, oropharyngeal candidiasis, Candida urinary tract infections, endophthalmitis) Cryptococcal infections Antifungal prophylaxis in HSCT patients and neonates |
Rare, serious hepatotoxicity possible Cytochrome P450 isoenzyme drug interactions |
50% to 94% | Newborn serum/maternal serum = 85% |
| Itraconazole | PO; IV PO: $ (for 5 mg/kg/day) IV: (Not marketed) |
IV, PO: 5 mg/kg/day to 10 mg/kg/day divided into 2 doses | Invasive and noninvasive aspergillosis, oropharyngeal and esophageal candidiasis Blastomycosis Chronic pulmonary histoplamosis Antifungal prophylaxis in HSCT and lung transplant patients |
Elevated liver enzymes Gastrointestinal intolerance: abdominal pain, vomiting, diarrhea Cytochrome P450 isoenzyme drug interactions |
<10% | Tissue and bronchial secretions levels higher than plasma Ocular levels low |
| Voriconazole | PO; IV PO: $$ (for 100 mg PO bid) IV: $$$ (for 8 mg/kg/day) |
PO: 8 mg/kg every 12 h for one day, then 7 mg/kg every 12 h IV: 6 mg/kg to 8 mg/kg every 12 h for one day, then 7 mg/kg every 12 h |
Invasive aspergillosis Esophageal candidiasis Refractory infections due to Scedosporium, Angiospermum and Fusarium species |
Main side effects are liver function abnormalities, skin rash, visual disturbances, CYP450 isoenzyme drug interactions | 42% to 67% | Excellent tissue penetration; levels exceed trough plasma levels several fold |
| Posaconazole | PO: $$$$ | 200 mg 4 times daily (age ≥13 years) | Aspergillosis, fusariosis and zygomycosis in patients intolerant/refractory to other agents | Gastrointestinal symptoms, headache, elevated liver enzymes, cytochrome P450 3A4 enzyme drug interactions | CSF penetration low, but activity demonstrated against CNS infections | Tissue penetration excellent |
| Ravuconazole | PO; IV Cost to be determined |
Not established | Under evaluation | Limited data | Low levels in CSF in animal model; brain tissue levels higher than in CSF | Concentration in liver greatest, followed by lungs, then kidneys, then brain |
| Caspofungin | IV: $$$ (for 50 mg/m2/day) | 70 mg/m2 loading, then 50 mg/m2 once daily |
Candida infections (eg, intra-abdominal abscess, peritonitis, pleural space infection, candidemia, esophageal candidiasis) Invasive aspergillosis in patients refractory/intolerant to other therapy Empirical therapy in febrile neutropenic patients |
Liver function abnormalities, fever, headache, rash, gastrointestinal symptoms, anemia | Low levels in CSF | In murine model, tissue levels higher than serum levels in liver and kidney; lower in heart and brain; similar in lung and spleen |
| Micafungin | IV: $$$$ | 4 mg/kg to 12 mg/kg once daily (higher doses for children <8 years of age) | Similar to caspofungin prophylaxis of Candida infections in HSCT patients | Liver function abnormalities, nausea, vomiting | Low to undetectable | Low levels in aqueous humor |
| Anidulafungin | IV Cost to be determined |
0.75 mg/kg to 1.5 mg/kg | Being evaluated for esophageal candidiasis | Phlebitis/thrombophlebitis, fever, headache, nausea, vomiting, rash | CSF levels not therapeutic | – |
| Flucytosine | PO (no longer marketed in Canada) | 50 mg/kg to 150 mg/kg in 4 doses | Combination therapy with amphotericin B for Candida and cryptococcal infections | Gastrointestinal intolerance and bone marrow suppression | 60% to 100% | Penetrates well into aqueous humor, joints, bronchial secretions, peritoneal fluid, brain, bile, bone |
*
These costs are for illustrative purposes to show relative costs and are based on the treatment of a 20 kg child for five days at The Hospital for Sick Children, Toronto, Ontario (modified from the 2009/2010 Drug Handbook and Formulary, The Hospital for Sick Children). Costs may vary across provinces. Doses may also vary depending on the nature of the illness. The costs reflect drug costs only;
†
This is not meant to be an all inclusive list; it includes licensed indications plus key scenarios in which the drugs have been identified as acceptable therapy;
‡
Data are lacking regarding tissue levels for several antifungal agents. Available data are summarized in different formats based on how they were generated;
§
A prospective surveillance study suggested little or no benefit when a titrated dosing regimen is used (39). $ <$200; $$ $200 to $500, $$$ $500 to $750; $$$$ $750 to $1200; bid Twice a day; CNS Central nervous system; CSF Cerebrospinal fluid; HSCT Hematopoietic stem cell transplant; IV Intravenous; PO Oral