Amphotericin B is the drug of choice for many disseminated, potentially life-threatening fungal infections. Amphotericin B is a fungicidal agent that is effective against a broad array of fungal species. Amphotericin B, especially the deoxycholate formulation, can cause adverse reactions, particularly renal toxicity, that limit its use in certain patients. Lipid-associated formulations of amphotericin B, especially liposomal amphotericin B, limit renal toxicity but also can cause adverse effects.

Amphotericin B deoxycholate is the preferred formulation for Treatment of neonates and young infants, because it is able to penetrate into the central nervous system, urinary tract, and eye, which often are involved in Candida species infections; lipid-associated formulations do not penetrate well into these body sites. Amphotericin B deoxycholate is given intravenously in a single daily dose of 0.5 to 1.5 mg/kg (maximum, 1.5 mg/kg/day). Amphotericin B is administered in 5% dextrose in water at a concentration of 0.1 mg/mL and delivered through a central or peripheral venous catheter (see Table 4.5). Infusion times of 1 to 2 hours have been shown to be well tolerated in adults and older children and theoretically increase the blood-to-tissue gradient, thereby improving drug delivery. After completing 1 week of daily therapy, adequate serum concentrations of the drug usually can be maintained by administering double the daily dose (maximum, 1.5 mg/kg) on alternate days. The duration of therapy depends on the type and extent of the specific fungal infection.

Amphotericin B deoxycholate is eliminated by a renal mechanism for approximately 2 weeks after therapy is discontinued. No adjustment in dose is required for neonates or for children with impaired renal function, because serum concentrations are not significantly increased in these patients. If renal toxicity occurs, alternate-day dosing is preferred to a decrease in daily dose. Neither hemodialysis nor peritoneal dialysis significantly decreases serum concentrations of the drug.

Infusion-related reactions to amphotericin B deoxycholate include fever, chills, and sometimes nausea, vomiting, headache, generalized malaise, hypotension, and arrhythmias. Onset usually is within 1 to 3 hours after starting the infusion; duration typically is less than an hour. Hypotension and arrhythmias are idiosyncratic reactions that are unlikely to occur if not observed after the initial dose but also can occur in association with very rapid infusion. Multiple regimens have been used to prevent infusion-related reactions, but few have been studied in controlled clinical trials. PreTreatment with acetaminophen, alone or combined with diphenhydramine, may alleviate febrile reactions; these reactions appear to be less common in children than in adults. Hydrocortisone (25-50 mg in adults and older children) also can be added to the infusion to decrease febrile and other systemic reactions. Tolerance to febrile reactions develops with time, allowing tapering and eventual discontinuation of the hydrocortisone and often diphenhydramine and antipyretic agents.

Meperidine and ibuprofen have been effective in preventing or treating fever and chills in some patients who are refractory to the conventional premedication regimen. Toxicity from amphotericin B deoxycholate can include nephrotoxicity, hepatotoxicity, thrombophlebitis, anemia, or neurotoxicity. Nephrotoxicity is caused by decreased renal blood flow and can be prevented or ameliorated by hydration, saline solution loading (0.9% saline solution over 30 minutes) before infusion of amphotericin B, and avoiding diuretic drugs. Hypokalemia is common and can be exacerbated by sodium loading. Renal tubular acidosis can occur but usually is mild. Permanent nephrotoxicity is related to cumulative dose. Nephrotoxicity can be enhanced by concomitant administration of amphotericin B and aminoglycosides, cyclosporine, tacrolimus, cisplatin, nitrogen mustard compounds, and acetazolamide. Anemia is secondary to inhibition of erythropoietin production. Neurotoxicity occurs rarely and can manifest as confusion, delirium, obtundation, psychotic behavior, seizures, blurred vision, or hearing loss.

Lipid-associated formulations of amphotericin B have a role in some children who are intolerant of or refractory to amphotericin B deoxycholate or can be considered in children who have renal insufficiency or at risk of significant renal toxicity from concomitant medications (see Table 4.5). In adults, none of the lipid-associated formulations have been demonstrated to be more efficacious than has conventional amphotericin B deoxycholate. Amphotericin B lipid formulations approved by the US Food and Drug Administration (FDA) for Treatment of invasive fungal infections in children and adults who are refractory to or intolerant of amphotericin B deoxycholate therapy are amphotericin B lipid complex (ABLC, Abelcet), and liposomal amphotericin B (L-AmB, AmBisome). Compared with amphotericin B deoxycholate, acute infusion-related reactions occur with both formulations but are less frequent with AmBisome. Nephrotoxicity is less common with lipid-associated products than with amphotericin B deoxycholate. Liver toxicity, which generally is not associated with amphotericin B deoxycholate, has been reported with the lipid formulations.

Pyrimidines

Among pyrimidine antifungal agents, only flucytosine (5-fluorocytosine) is approved by the FDA for use in children. Flucytosine has a limited spectrum of activity against fungi and potential for toxicity (see Table 4.5), and when flucytosine is used as a single agent, resistance often emerges. Flucytosine is used in combination with amphotericin B for cryptococcal meningitis and some life-threatening Candida infections, such as meningitis. It is critical to monitor serum concentrations of flucytosine to avoid bone marrow toxicity.

Azoles

Five oral azoles are available in the United States and include ketoconazole, fluconazole, itraconazole, voriconazole, and posaconazole. All have relatively broad activity against common fungi but differ in their activity, bioavailability, adverse effects, and potential for drug interactions (see Table 4.5). Limited data are available regarding the safety and efficacy of azoles in pediatric patients, and trials comparing these agents to amphotericin B have been limited. Azoles are easy to administer and have little toxicity, but their use can be limited by the frequency of their interactions with coadministered drugs. These drug interactions can result in decreased serum concentrations of the azole (ie, poor therapeutic activity) or unexpected toxicity from the coadministered drug (ie, increased serum concentrations of the coadministered drug). When considering use of azoles, the patient's concurrent medications should be reviewed to avoid potential adverse clinical outcomes. Another potential limitation of azoles is emergence of resistant fungi, especially Candida species resistant to fluconazole. Candida krusei are intrinsically resistant to fluconazole and strains of Candida glabrata are showing increasing resistance to fluconazole and voriconazole. Itraconazole is approved by the FDA for Treatment of blastomycosis, histoplasmosis (nonmeningeal), and aspergillosis in patients who are intolerant to amphotericin B and for empiric therapy of febrile neutropenic patients with suspected fungal infection. Itraconazole does not cross the blood-brain barrier and should not be used for infections of the central nervous system. Voriconazole has been approved by the FDA for primary Treatment of invasive Aspergillus species, for esophageal candidiasis, and for refractory infection with Scedosporium apiospermum (the asexual form of Pseudallescheria boydii ) and Fusarium species. Limited data are available regarding use of voriconazole in children. Posaconazole is approved for use in adults for prophylaxis against fungal infections and as salvage therapy for invasive aspergillosis. Ketoconazole seldom is used, because other azoles have fewer adverse effects and generally are preferred.

Echinocandins

Caspofungin, micafungin, and anidulafungin are the only echinocandins approved by the FDA. Caspofungin is approved for Treatment of esophageal candidiasis, invasive candidiasis, and aspergillosis in adults who are refractory to or intolerant of other antifungal drugs. Clinical trials assessing safety or efficacy in pediatric patients are being conducted. Table 4.6 provides recommendations for Treatment of serious fungal infections with amphotericin B, flucytosine, azoles, echinocandins, and other antifungal agents. Micafungin is approved by the FDA for intravenous Treatment of esophageal candidiasis and prophylaxis of invasive Candida infections in patients undergoing hematopoietic stem cell transplantation. Anidulafungin is approved by the FDA for intravenous Treatment of candidemia, Candida infections, and esophageal candidiasis.