Echinocandins in children.

The echinocandins (ECs), caspofungin (CA), micafungin (MI), anidulafungin (AD), and aminocandin (AM) are the newest class of parenterally administered antifungal agents. This review will discuss their general properties, current indications, and available pediatric data. ECs are semisynthetic cyclic lipopeptides which inhibit cell wall biosynthesis through noncompetitive inhibition of the (133)-D-glucan synthase complex. This target is unique to fungi, thus contributing to favorable toxicity profile of ECs. The spectrum of activity is related to the content of (133)-D glucan in cell walls; Candida and Aspergillus contain substantial amounts, leading to excellent activity against these fungi. In Candida spp. decreased synthesis of (133)-D glucan, composing up to 60% of the cell wall and responsible for cell wall integrity, leads to fungicidal instability of the cell. ECs exhibit concentration-dependent killing of Candida related to AUC/MIC or Cmax/MIC. The interpretive breakpoint for EC susceptible Candida spp. is 2.0 g/ mL, which also is achieved for triazoleresistant Candida albicans, Candida Krusei, and Candida glabrata. Concern exists about higher MICs for Candida parapsilosis (50– 100 fold more than those of C. albicans). A naturally occurring proline-to-alanine amino acid change in Fks1p in C. parapsilosis accounts for this reduced susceptibility. Although clinical failures in treatment of C. parapsilosis with ECs have been reported, organisms with MICs 2.0 g/mL are usually responsive. The finding that ECs exert activity against Candida biofilms may have important therapeutic implications for the treatment of foreign body/catheter infections. ECs have a unique form of activity against Aspergillus spp. , causing destruction of the hyphal tips and branch points of growing cells, thus decreasing invasion. The potency of ECs may be further augmented by immunomodulatory activity resulting from release or unmasking of cell wall glucans leading to dectin-1 dependent, proinflammatory enhancement of macrophage and neutrophil killing activity. In vitro, high concentrations of ECs can lead to attenuated activity against Candida and Aspergillus. A compensatory cell wall stress response upregulates cell wall chitin biosynthesis permitting paradoxical growth despite decreased glucan. In vivo, increased biomarkers and fungal burden may be observed, although the clinical relevance of paradoxical growth is not well understood. ECs are not active as single agents against zygomycetes (Mucorales), Fusarium spp. , or Scedosporium spp. (due to diminished (133)-D-glucan synthase activity) or against Trichosporon spp. and Cryptococcus neoformans (due to predominantly (136)-D glucan linkages). ECs have high MICs against the yeast phase of dimorphic fungi, and are not recommended for treatment of endemic fungi. ECs are highly protein bound, distribute well into most tissues, but achieve low cerebrospinal fluid and urine concentrations. Long half lives allow for once daily dosing. They are well tolerated; the most notable toxicity is transaminase elevation and gastrointestinal symptoms, rarely necessitating discontinuation. Severe liver toxicity has been infrequently reported in patients with other contributing factors. Infusion-related hypersensitivity reactions are rare. Dose adjustment is not necessary for renal dysfunction, but may be warranted in patients with severe hepatic dysfunction for CA and MI, which are hepatically transported and metabolized. Table 1 outlines current recommendations and licensure status for CA, MI, and AD. There do not appear to be clinically significant differences among the current ECs in spectrum, efficacy, or toxicity. Further details on the therapeutic and prophylactic roles of ECs, in the context of other antifungal agents, are discussed in Practice Guidelines of the Infectious Diseases Society of America, aspergillosis and candidiasis (available at: http://www.idsociety.org/). CASPOFUNGIN The recommended dose for children aged 3 months to 17 years is 50 mg/m/d (maximum, 70 mg), following a loading dose of 70 mg/m/d in comparison to that of adults at 50 mg/d. Clearance is lower in neonates and adults, and increased during childhood. These differences may be determined by the differential rate of distribution from plasma into hepatic tissue. Data based on 18 infants 3 months of age suggest a dose of 25 mg/m/d providing comparable plasma exposure to that in children and adults. The first pediatric double-blind, randomized controlled trial of empiric antifungal therapy (EAFT) compared liposomal amphotericin B with CA. Although not powered to test specific hypotheses (n 82), this study found comparable tolerability, safety, and efficacy between the 2 groups, and similar to that observed in adults. Although nephrotoxicity was similar in both groups (8.0% vs. 5.6%), 11.5% of patients receiving amphotericin B discontinued due to adverse events, compared with 3.6% receiving CA. A prospective multicenter trial for primary or salvage treatment of Candida and Aspergillus infections in 48 children, documented complete or partial response in 81% and 50% of patients, respectively, suggesting similar safety and efficacy as observed in adults. CA was used successfully in treatment of candidemia, renal candidiasis, and endocardial infection in 9 premature and 1 term infant. A Food and Drug Administration postmarketing adverse event report states “CA is generally well tolerated by patients of all ages” and did not “identify adverse events that would suggest the safety profile differs significantly between adults and pediatrics. ” Drug interactions may include rifampin, efavirenz, nevirapine, phenytoin, dexamethasone, carbamazepine, in which simultaneous use may lower CA levels. Coadministration with cyclosporine may increase CA levels and hepatobiliary events, whereas tacrolimus levels may be decreased with concomitant use.