Provided by Antifungal Therapy in Children Lead contributors: Valerio Cecinati MD, PhD Chiara Guastadisegno, MD Department of Biomedicine in Childhood University of Bari Bari, Italy A. Introduction Progress in the pharmacological development of antifungal agents has enabled the extension of therapeutic indications to many childhood mycoses, particularly invasive fungal infections (IFI) in children with primary or secondary immunodeficiences.1Thanks to the wider spectrum of action, and the expansion of available information about these drugs and their mechanisms of action as well as their pharmacokinetic and toxicity profiles, antifungal agents are now used to treat both common and uncommon invasive infections in immunocompromised children.1 We performed a systematic review of the literature to compile a guide to information on pediatric antifungal treatments. According to their side targets, the principal antifungal drugs are classified as either antifungal agents acting on plasmatic membranes (azoles, polyenes), antifungal agents acting on synthesis of nucleic acids (5-flucytosine), or antifungal agents acting on fungal cell walls (echinocandins). A. References 1Walsh TJ, Viviani MA, Arathoon E, et al. New targets and delivery systems for antifungal therapy. Med Mycol. 2000;38 Suppl 1:335-47. B. Azoles Azole antifungal agents are heterocyclic synthetic compounds and are subdivided into 2 groups: imidazoles and triazoles. The imidazoles are an older group consisting of miconazole, ketoconazole, and clotrimazole. The triazoles include fluconazole and itraconazole; the second generation of triazoles includes voriconazole, ravuconazole, and posaconazole. Isavuconazole, albaconazole, and E-1224, a prodrug of ravuconazole, are the 3 main azole antifungal agents currently under development.1 The azoles inhibit the fungal cytochrome 450-dependent lanosterol 14α-demethylase, which catalyzes a late step in ergosterol biosynthesis. The drugs block demethylation of the C-14 of lanosterol, leading to the accumulation of methylated sterols in the fungal cell membrane and depletion of ergosterol. This results in abnormalities in fungal cell membrane permeability, membrane bound enzyme activity, and deregulation of chitin synthesis.2-4 Azoles differ in their affinity for the 14α-demethylase enzyme and this difference is largely responsible for their varying antifungal potency and spectrum of activity.2 Cross- inhibition of several human CYP-dependent enzymes (3A4, 2C9, and 2C19) is responsible for most of the clinical side effects and drug interaction profiles that have been described with this class. Itraconazole and posaconazole act primarily as inhibitors of 3A4 and 2C9 but with little effect on 2C19. Voriconazole acts as both an inhibitor and a substrate on all 3 isoenzymes, providing ample opportunites for drug–drug interactions because of the frequently shared metabolic pathway. Caution should be used when these agents are concurrently administered with most HMG-CoA reductase inhibitors, benzodiazepines, phenytoin, carbamazepine, cyclosporine, tacrolimus, sirolimus, methylprednisolone, buspirone, alfentanil; the dihydropyridine calcium channel blockers verapamil and diltiazem; the sulfonylureas, rifampin, rifabutin, vincristine, busulfan, docetaxel; and the protease inhibitors ritonavir, indinavir, and saquinavir. The triazoles have also been associated with QTc prolongation and coadministration with other agents known to have similar effects (cisapride, terfenadine, astemizole, mizolastine, dofetilide, quinidine, and pimozide among others) should be avoided.5 Page 2 of 27 The triazoles are additionally embryotoxic and teratogenic, and are secreted into breast milk; therefore administration should be avoided when women are pregnant or lactating.5 Three resistance mechanisms have been described in Candida infections; reduced azole accumulation through active efflux, alteration, over-expression of the target lanosterol 14α-demethylase, and mutation in the ergosterol pathway, which allows for the accumulation of less toxic sterols in the presence of azoles.6 Intrinsic non-albicans Candida resistance is commonly associated with the increased use of fluconazole prophylaxis.6 The new triazole antifungals (voriconazole, posaconazole, and ravuconazole) show good activity against fluconazole- and itraconazole-resistant Candida species and moulds.5 B. References 1Pasqualotto AC, Thiele KO, Goldani LZ. Novel triazole antifungal drugs: focus on isavuconazole, ravuconazole, and albaconazole. Curr Opin Investig Drugs. 2010;11:165-74. 2 Walsh TJ, Viviani MA, Arathoon E, et al. New targets and delivery system for antifungal therapy. Med mycol. 2000;38:335-47. 3 De Beule K, Van Gestel J. Pharmacology of itraconazole.Drugs. 2001;61:27-37. 4 Kaya Z, Gursel T, Kocak U, et al.. Invasive fungal infections in pediatric leukemia patients receiving fluconazole prophylaxis. Pediatr Blood Cancer. 2009 ;52:470-5. 5 Thompson GR 3rd, Cadena J, Patterson TF., Overview of antifungal agents. Clin Chest Med. 2009;30:203-15. 6 Zaoutis TE, Benjamin DK, Steinbach WJ., Antifungal treatment in pediatric patients. Drug Resist Updat. 2005;8:235-45. C. The Triazoles C.1 Fluconazole Fluconazole is fungistatic, and its activity is concentration independent. It is available in oral or intravenous forms. The bioavailability of the oral form is approximately 90%. Drug concentrations in the cerebrospinal fluid (CSF) and vitreous humor are around 80% of those found in blood.1 Fluconazole continues to be one of the most frequently prescribed triazoles because of its excellent bioavailability, tolerability, and side-effect profile. More than 80% of the ingested drug is found in the circulation and 60% to 70% is excreted unchanged in the urine, so it is particularly indicated for treatment of fungal urinary infections. Fluconazole is relatively lipophobic and exhibits limited binding to plasma proteins. As a result of these characteristics, it passes into tissue and fluids very rapidly. Oral absorption remains Page 3 of 27 unchanged in patients receiving acid suppressive therapies such as proton pump inhibitors orH2-blockers.2 C. 2.1 Indications for Fluconazole Fluconazole is active against Candida species. with the exception of C. krusei and C. glabrata. There is no appreciable activity against aspergillus, fusarium, pseudoallescheria, or zygomycetes.3 Fluconazole remains the drug of choice in oropharyngeal candidiasis (not C. krusei, C. glabrata), superficial mycoses as in genital candidiasis and tinea capitis. Tinea capitis always requires systemic treatment because topical antifungal agents do not penetrate the hair follicle.4 Fluconazole can be used alone or as part of a combined antifungal treatment against invasive and disseminated candidiasis,5-6 cryptococcosis and cryptococcal meningitis,7 or histoplasmosis. It has been demonstrated that fluconazole prophylaxis for IFI is safe and effective for reducing Candida infections in neutropenic pediatric patients and in those undergoing chemotherapy.8,9 Recent guidelines from the Infectious Diseases Society of America recommend consideration of fluconazole or an echinocandin for empiric therapy in immunocompromised children at high risk of Candida infection. Echinocandin use in patients with moderate-to-severe disease, recent azole exposure, or a high risk of C. glabrata or C. krusei infection is preferred. Fluconazole or an echinocandin is also preferred as the initial therapy for non-neutropenic candidemia, depending on the disease severity and characteristics. The guidelines recommend treatment with an echinocandin or lipid formulation of AMB for most patients with neutropenic candidemia, although fluconazole has been identified as an alternative for less critically ill patients without recent azole exposure.10 C.2.2 Fluconazole Dosages, Side Effects, and Interactions Fluconazole is available as an oral suspension, in tablet form (50, 100, 150, and 200 mg), and as an intravenous formulation (in 200 or 400 mg doses).11 Several reports demonstrated that fluconazole clearance is more rapid in children than in adults.12 The mean plasma half-life was approximately 20 hours in children and30 hours in adults. Page 4 of 27 Therefore, to achieve comparable drug exposure, the daily fluconazole dosage needs to be approximately doubled for children over 3 months to 16 years of age to 6–12 mg/kg/day with respect to the suggested dosage in adults (3–6 mg/kg/day).12 Fluconazole could be administered to children with renal failureif the daily dosages were adapted to the serum creatinine level.13 Generally, fluconazole is well-tolerated by pediatric patients, even if prolonged treatment is necessary. Anorexia, vomiting, diarrhea, and elevated transaminases are the most reported side effects. Skin rash, alopecia, and headache are other side effects that are rarely described. Although fluconazole has substantially limited drug interactions than other triazole compounds, caution remains necessary because of increased serum levels of phenytoin, glipizide, glyburide, warfarin, rifabutin, and cyclosporine. Fluconazole levels are reduced in the presence of rifampin.14 C.3 Itraconazole Itraconazole is a highly protein-bound fungicide with less than 1% available free drug and with a relatively high volume of distribution.15 Hydroxy-itraconazole is the major metabolite with the same antifungal activity as itraconazole. The absorption of oral itraconazole depends on an acidic environment for maximal absorption, and the concomitant administration of H2-receptor