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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 agents has enabled the extension of therapeutic indications to many childhood mycoses, particularly invasive fungal (IFI) in children with primary or secondary immunodeficiences.1 Thanks 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 (, polyenes), antifungal agents acting on synthesis of nucleic acids (5-), or antifungal agents acting on fungal cell walls ().

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: and . The imidazoles are an older group consisting of , , and . The triazoles include and ; the second generation of triazoles includes , , and . Isavuconazole, albaconazole, and E-1224, a prodrug of ravuconazole, are the 3 main antifungal agents currently under development.1 The azoles inhibit the fungal cytochrome 450-dependent lanosterol 14α-demethylase, which catalyzes a late step in 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 26 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 (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 26 unchanged in patients receiving acid suppressive therapies such as proton pump inhibitors orH2-blockers.2

C.1.1 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 for empiric therapy in immunocompromised children at high risk of Candida . 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.1.2 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 26 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.2 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 antagonists, proton pump inhibitors, or antacids causes erratic and unpredictable drug absorption. Thus, it has been recommended that itraconazole capsules must be taken with food or a cola beverage, but the oral suspension is better absorbed on an empty stomach. Elimination of itraconazole is primarily hepatic with no need for dosage adjustment in patients who have renal function impairment.16

C.2.1 Indications for Itraconazole

Itraconazole was licensed in USA for salvage therapy of invasive aspergillosis and for allergic bronchopulmonary aspergillosis.14,16, 17 In a recent randomized trial that compared fluconazole and itraconazole for the treatment of candidemia in a pediatric intensive care Unit, itraconazole showed similar clinical and mycological cure rates of fluconazole.18 Itraconazole is also indicated in other invasive mycosis such as cryptococcal meningitis, histoplasmosis, non-meningeal coccidioidomycosis, and infections caused by Blastomycosis,

Page 5 of 26 Sporothrix schenckii, P. brasiliensis, and B dermatitidis.19,20 Thus, the development of new and more effective antifungal agents has relegated itraconazole to second-line therapy for the treatment of invasive mycoses. So, itraconazole is currently more appealing as a prophylactic drug rather than a therapeutic agent and may be superior to fluconazole for this purpose even in adult patients.21 Itraconazole remains the drug of choice for prophylaxis in children affected by HIV with a history of histoplasmosis before immune reconstitution with an antiretroviral drug.22

C.2.2 Itraconazole Dosages and Interactions

The approved dosage of itraconazole in pediatric patients is 2.5 mg/kg for 2 doses with respect to a single dose that is more appropriate for an adult patient.24 Itraconazole is a potent inhibitor of the CYP3A4 enzyme with specific drug interactions. Prior or concurrent use of cyclophosphamide, rifampin, phenytoin, carbamazepine, and phenobarbital should be avoided.23

C.2.3 Side Effects of Itraconazole

Generally, itraconazole is well tolerated. The most frequently reported side effects in pediatric patients are nausea, vomiting, and serum liver enzyme elevations.24

C. References

1Wildfeuer A, Laufen H, Schmalreck AF, et al. Fluconazole: comparison of pharmacokinetics, therapy and in vitro susceptibility.Mycoses. 1997;7-8:259-65. 2Brammer KW, Coates PE., Pharmacokinetics of fluconazole in pediatric patients. Eur J Clin Microbiol Infect Dis.1994;13:325-329. 3Charlier C, Hart E, Lefort A, et al. Fluconazole for the management of invasive candidiasis: where do we stand after 15 years? J Antimicrob Chemother. 2006;57:384-410. 4Kakourou T, Uksal U. Guidelines for the management of tinea capitis in children. Pediatr Dermatol. 2010;27:226-8. 5Castagnola E, Buratti S. Clinical aspects of invasive candidiasis in paediatric patients., Drugs. 2009;1:45-50. 6Kaya Z, Gursel T, Kocak U, et al. Invasive fungal infections in pediatric leukemia patients receiving fluconazole prophylaxis. Pediatr Blood Cancer. 2009 ;52:470-5. 7Perfect JR, Dismukes WE, Dromer F, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis. 2010;50:291-322. 8Walsh TJ, Hiemenz JW, Anaissie E. Recent progress and current problems in treatment of invasive fungal infections in neutropenic patients. Infect Dis Clin North Am. Jun 1996; 10(2):365-400. 9Groll AH, Just-Nuebling G, Kurz M, et al. Fluconazole versus in the prevention of candida infections in children and adolescents undergoing remission induction or consolidation chemotherapy for cancer. J Antimicrob Chemother. 1997 Dec;40(6):855-62.

Page 6 of 26 10Zaoutis T, Candidemia in children. Curr Med Res Opin. 2010;26:1761-8. 11Thompson GR 3rd, Cadena J, Patterson TF., Overview of antifungal agents. Clin Chest Med. 2009;30:203-15. 12Steinbach WJ, Benjamin DK. New antifungal agents under development in children and neonates. Curr Opin Infect Dis. 2005;18:484-9. 13Charlier C, Hart E, Lefort A, et al. Fluconazole for the management of invasive candidiasis: where do we stand after 15 years? J Antimicrob Chemother. 2006;57:384-410. 14Thompson GR 3rd, Cadena J, Patterson TF. Overview of antifungal agents. Clin Chest Med. 2009;30:203-15. 15Walsh TJ, Hiemenz JW, Anaissie E. Recent progress and current problems in treatment of invasive fungal infections in neutropenic patients. Infect Dis Clin North Am. Jun 1996;10(2):365-400. 16Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:327-–60. 17 Vicencio AG, Chupp GL, Tsirilakis K, et al. CHIT1 mutations: genetic risk factor for severe Asthma with fungal sensitization? Pediatrics. 2010;126:982-5. 18Mondal RK, Singhi SC, Chakrabarti A M J. Randomized comparison between fluconazole and itraconazole for the treatment of candidemia in a pediatric invasive care unit: a preliminary study. Pediatr Crit. Care Med. 2004; 5:561-565. 19Homans JD, Spencer L. Itraconazole treatment of nonmeningeal coccidioidomycosis in children: two case reports and review of the literature. Pediatr Infect Dis J. 2010;2965-7. 20Shukla S, Singh S, Jain M, et al. Paediatric cutaneous blastomycosis: a rare case diagnosed on FNAC. Diagn Cytopathol. 2009;37:119-21. 21Morgenstern GR, Prentice AG, Prentice HG, et al. A randomized controlled trial of itraconazole versus fluconazole for the prevention of fungal infections in patients with haematological malignancies.Br J Haematol. 1999;105:901-11. 22Zaoutis TE, Benjamin DK, Steinbach WJ., Antifungal treatment in pediatric patients. Drug Resist Updat. 2005;8:235-45. 23Marr KA, Leisenring W, Crippa F, et al. Cyclophosfamide metabolism is affected by azole antifungals. Blood. 2004;103:1557-1559. 24Steinbach WJ. Antifungal agents in children. Pediatr Clin North Am. 2005;52:895-915.

D. The Second Generation of Triazoles

D.1 Voriconazole

Voriconazole, a synthetic second-generation, broad-spectrum triazole derivative of fluconazole, inhibits the cytochrome P450 (CYP)-dependent enzyme 14α-sterol demethylase thereby, disrupting the cell membrane and halting fungal growth.1 It combines the broad spectrum of antifungal activity of itraconazole with increased bioavailability of fluconazole.2 Voriconazole is available as both an intravenous and oral formulation. The bioavailability of oral voriconazole is 96% and it is distributed through the lungs, kidneys, liver, spleen, eyes, as well as the central nervous system. Metabolism occurs via hepatic CYP isoenzymes, so drug interactions are common.3 It is metabolized by hepatic cytochrome P450 isoenzymes CYP2C19, CYP2C9, and CYP3A4. Individuals who are poor metabolizers of voriconazole due to polymorphisms in the CYP2C19 gene may have a significant overexposure to the drug.4 Page 7 of 26 The safety of voriconazole use in severe liver disease remains uncertain. In patients who have liver dysfunction, standard loading doses should be given, but the maintenance dose could be reduced by 50% of the standard dosage. No dosage adjustment is required if an oral drug is given to patients who have renal insufficiency, however, the drug should be administered orally rather than intravenously if possible as IV administration carries the potential side effect of cyclodextrin vehicle accumulation.4

D.1.2 Indications for Voriconazole

Voriconazole has a broad spectrum of antifungal activity in Candida species, including C. krusei and C. glabrata, which are resistant to fluconazole. It shows promising fungistatic and even fungicidal activity against Aspergillus species, including A. terreus that is inherently resistant to (AMB). Also, in primary cutaneous aspergillosis in immunocompetent children, voriconazole is a treatment option.5 It is active against Cryptococcus neoformans, Scedosporium species, many Fusarium species, and other mold fungi, including those that cause endemic mycosis.6 Zygomycetes are resistant to voriconazole.7 Voriconazole use is indicated in candidemia in non-neutropenic patients, invasive candidiasis (including fluconazole resistant species), invasive Aspergillosis, Scedosporium apiospermum, Scedosporium prolificans, and Fusarium species infections.8 In the USA, pediatric use of voriconazole is not approved. In Europe, IV and oral voriconazole is approved in pediatric patients aged from 2 to 11 years on the basis of compassionate use data.9 In immunocompromised children with fungal infections (mostly due to aspergillosis), voriconazole treatment had been shown to have a complete or partial response in 45% of patients.10 These observations were confirmed in a large clinical study of voriconazole in a pediatric population. In the study, an open-label compassionate use evaluation was conducted in 58 children with proven or probable fungal infection who had refractory or intolerance of conventional antifungal therapy. A complete or partial response was observed in 43% of children with aspergillosis, 50% with candidemia, and 63% with scedosporiosis.11 There are several case reports of successful use of voriconazole, in the treatment of children with invasive aspergillosis, scedosporiasis, or trichosporonosis. In some of these reports, however, voriconazole was administered with other antifungal agents.12,13 In

Page 8 of 26 addition, voriconazole has been used for antifungal prophylaxis in children with chronic granulomatous disease.14

D.1.3 Voriconazole Dosage

Voriconazole metabolism is nonlinear in adults. In contrast, it has demonstrated a linear pharmacokinesis in children.4 Pediatric patients are known to hypermetabolize voriconazole, and for this reason require higher doses than adults to attain similar serum concentrations over time.2,15 Voriconazole is available in IV and oral formulations. The suggested IV dosage in pediatric patients (children 2–12 years old) is 6 mg/kg/day administered every 12 hours on day 1, then, 4 mg/kg every 12 h from day 2. Suggested oral dosages in children of more than 40 kg are 400 mg for every 12 hours on day 1, and then, 200–300 mg for every 12 hours. For children who weigh than 40 kg, the suggested dosage is 200 mg every 12 hours on day 1, and then, 100–150 mg every 12 hours from day 2.16 It has been demonstrated that children <3 years of age require higher daily doses with greater variation as compared to the doses used to treat older children, resulting in complicated optimal dose adjustments. Therefore, plasma concentration monitoring and individual dose adjustments are recommended for optimal and less toxic voriconazole treatments, especially for <3-year-old children.17 The monitoring of plasma levels of voriconazole in children could be considered an important tool so the marked pharmacokinetic variability, particularly after enteral dosing, justifies the measurement of serum concentrations in the pediatric population.18Several reports from the US centers showed high infection rates of zygomycosis infections in patients being treated with voriconazole, which suggest that its intensive use may be a risk of factor for development of this relatively uncommon mold infection.19

D.1.4 Voriconazole Interactions

Voriconazole has a number of important interactions with other that are either substrates for, or inducers of the CYP enzyme system involved in its metabolism. Their concurrent use may be contraindicated or dosing/plasma levels may need to be adjusted, depending on the drug being used.9 A few examples of drugs that lower

Page 9 of 26 voriconazole concentrations are rifampicin, phenobarbital, carbamazepine, efavirenz, and ritonavir, while voriconazole increases serum concentrations of sirolimus, tacrolimus, cyclosporine, efavirenz, and terfenadine. When voriconazole is started in patients already receiving cyclosporine, the dose of cyclosporine needs to be halved and its serum levels need to be monitored.16

D.1.5 Side Effects of Voriconazole

The adverse reactions that occurred in greater than 5% of pediatric patients were transaminase or bilirubin elevation, skin rash, abnormal vision (photophobia or blurred visions), and photosensitivity reactions.2,20

D.2 Posaconazole

Posaconazole is a second-generation triazole closely related to itraconazole. Posaconazole absorption is increased when it is administered with food. This drug has a wide tissue distribution including the central nervous system. It is eliminated largely unchanged and only a minority of the dose is metabolized.21

D.2.1 Indications for Posaconazole

The spectrum of activity of posaconazole is similar to that of voriconazole but also includes Zygomycetes. Posaconazole demonstrates potent in vitro activity against Candida species, whether they are susceptible or resistant to fluconazole, Aspergillus species, C. neoformans, Coccidioides species, Histoplasma species, Trichosporum species, Fusarium oxysporum, and S. apiospermum. In vivo, the efficacy of posaconazole has been repeatedly demonstrated against Candida and Aspergillus (including A. terreus and A. fumigatus infections) especially in children with AMB or itraconazole resistance and intolerance, zygomycosis, cryptococcosis (including C. neoformans and C. immitis infections), coccidioidomycosis, histoplasmosis, phaeohyphomycosis, and trichosporonosis species.21-23 In a recent report, it was demonstrated that posaconazole could be active against Rhizopus microsporus infection when combined with other antifungal drugs in immunocompromised children.24 Recently, some reports demonstrated that posaconazole is

Page 10 of 26 active against mucormycosis in diabetic and immunocompromised children.25,26 Surveillance of clinical Aspergillus isolates indicates that so far resistance to posaconazole is extremely rare.27

Use of posaconazole is indicated to treat the following:

 Fusarium species infections in patients with AMB resistance or intolerance.  Chromoblastomycosis and mycetoma in patients with itraconazole resistance or intolerance.  Coccidioidomycosis in patients with AMB or itraconazole or fluconazole resistance or intolerance.  Oropharyngeal candidiasis in immunocompromised hosts and as a first choice therapy in serious infections.  IFI prophylaxis.28

Posaconazole was approved by the FDA in 2006 for antifungal prophylaxis (against Aspergillus and Candida infections) in patients with acute myeloid leukemia, myelodysplastic syndrome, graft versus host disease or for patients who have undergone hematopoietic stem cell transplant (HSCT). A long neutropenic period can be expected in these patients due to chemotherapy. 9,29 There is no clinical evidence that combining therapies with other antifungal drugs is beneficial.

D.2.2 Posaconazole Dosage

Data on the safety and effectiveness of posaconazole in children are very rare. Clinical experiences with posaconazole in children are limited to compassionate release data, and dosing continues to be experimental in children with different ages. In a recent open label study (2 of 7 patients with chronic granulomatous disease were under 18 years), 6 patients had a complete response after posaconazole treatment for IFI.30 In other research, posaconazole plasma levels were compared between juvenile (aged 8–17 years) and adult (aged 18–64 years) patients participating in an open-label phase III study for patients intolerant or refractory to other standard antifungal therapies. Posaconazole at a dosage of

Page 11 of 26 800 mg/day was given as salvage therapy for proven or probable IFI refractory to standard antifungal therapy. Posaconazole concentrations in plasma were similar for juvenile and adult patients suggesting that clinical outcomes are expected to be similar in both adult and juvenile groups with refractory IFI.31 No recommendations from the European Medicines Agency (EMEA) are available for patients less than18years of age. The Food and Drug Administration (FDA) recommended a dosage of 200 mg, 3 times a day for prophylaxis in patients less than 13 years of age.28,32 No pediatric dosage schedules yet been established yet.4,35,36. In a recent multicenter study, posaconazole was administered at a dosage of 21 mg/kg with a complete or partial response of IFI in more than 50% of pediatric patients.33

D.2.3 Posaconazole Interactions

As an inhibitor of the hepatic CYP3A4 isoenzyme system, posaconazole can cause elevation in the serum levels of several other medications with the potential for increased toxicity. Posaconazole increases the levels of tacrolimus, cyclosporine, vincristine, and midazolam. The manufacturer recommends that the dose of co-administered cyclosporine must be reduced by one quarter when posaconazole is co-prescribed. Co-administration of phenytoin, rifabutin, or cimetidine is not recommended because each will probably reduce serum concentrations of posaconazole, impairing its antifungal efficacy. However, neither antacids nor proton pump inhibitors appear to reduce its bioavailability.34

D.2.4 Side Effects of Posaconazole

Posaconazole is usually well-tolerated and is infrequently discontinued because of adverse events. The most frequent side effects of posaconazole therapy are gastrointestinal with transaminase elevation and hyperbilirubinemia occurring in 3% of patients.4 Three cardiac events were reported among those possibly related to posaconazole treatment in adulthood, including decreased ejection fraction, QTc prolongation, and torsades de pointes. For most patients, posaconazole is well-tolerated and even long-term therapy (>6 months) is frequently without toxicity.4

Page 12 of 26 D.3 Ravuconazole, Isavuconazole, Albaconazole

Ravuconazole, isavuconazole, and albaconazole are second-generation extended- spectrum triazoles that have demonstrated promise in the treatment of fungal infections. Data on these drugs in the pediatric group age are not available. They have been used in adult patients, are well-tolerated and drug interactions are uncommon. These new triazoles have demonstrated potent in-vitro activity against Candida and Aspergillus species that appears to be more effective than fluconazole. Conversely, these newer triazoles showed poor or limited activity against emerging fungal species of Fusarium, Scedosporium, and Zygomycetes.16

D. References

1Scott LJ, Simpson D, Voriconazole : a review of its use in the management of invasive fungal infections. Drugs 2007;67:269-98. 2Zaoutis TE, Benjamin DK, Steinbach WJ. Antifungal treatment in pediatric patients. Drug Resist Updat. 2005;8:235-45. 3Pia S, Pannaraj MD, Thomas J,et al. Advances in Antifungal Therapy. Pediatr Infect Dis J. 2005;24:921-2. 4Thompson GR 3rd, Cadena J, Patterson TF. Overview of antifungal agents. Clin Chest Med. 2009;30:203-15. 5Craiglow B, Hinds G, Antaya R, Girardi M. Primary cutaneous aspergillosis in an immunocompetent patient: successful treatment with oral voriconazole. Pediatr Dermatol. 2009;26493-5. 6Antachopoulos C, Walsh TJ. New agents for invasive mycoses in children. Curr Opin Pediatr. 2005;17:78-87. 7Almirante B, Rodriguez D. Antifungal agents in neonates:. Issues and recommendations. Paediatr Drugs. 2007; 9: 311-321. 8Troke P, Aguirrebengoa K, Arteaga C, et al. Treatment of scedosporiosis with voriconazole: clinical experience with 107 patients. Antimicrob Agents Chemother. 2008;52:1743-50. 9Das S, Shivaprakash MR, Chakrabarti A., New antifungal agents in pediatric practice. Indian Pediatrics. 2009;46:225-31. 10Jeu L, Cheng JW, Pharmacology and therapeutics of ezetimibe (SCH 58235), a cholesterol-absorption inhibitor. Clin Ther. 2003;25:2352-87. 11Walsh TJ, Lutsar I, Driscoll T, et al. Voriconazole in the treatment of aspergillosis, scedosporiosis and other invasive fungal infections in children. Pediatr Infect Dis J. 2002;21:240-8.12Shouldice E, Fernandez C, McCully B, et al. Voriconazole treatment of presumptive disseminated Aspergillus infection in a child with acute leukemia. J Pediatr Hematol Oncol. 2003;25:732-4. 13Bethell D, Hall G, Goodman TR, et al. Resolution of orbitocerebral aspergillosis during combination treatment with voriconazole and amphotericin plus adjunctive cytokine therapy. J Pediatr Hematol Oncol. 2004;26:304-7. 14Frisch S, Askari SK, Beaty SR, Burkemper CN. X-linked chronic granulomatous disease with voriconazole- induced photosensitivity/ photoaging reaction. J Drugs Dermatol. May 2010; 9(5):562-4. 15Walsh TJ, Karlsson MD, Driscoll T, et al. Pharmacokinetics and safety of intravenous voriconazole in children after single or multiple dose administration. Antimicrob Agent Chemother. 2004;48:2166-2172. 16Rogers TR, Frost S. Newer antifungal agents for invasive fungal infections in patients with haematological malignancy. Br J Haematol. 2009 Mar;144(5):629-41. 17Shima H, Miharu M, Osumi T, et al. Differences in voriconazole through plasma concentrations per oral dosages between children younger and older than 3 years of age. Pediatr Blood Cancer. 2010;54:1050-2. 18Neely M, Rushing T, Kovacs A, et al. Voriconazole pharmacokinetics and pharmacodynamics in children. Clin Infect Dis. 2010;50:27-36.

Page 13 of 26 19Trifilio SM, Bennett CL, Yarnold PR, et al. Breakthrough zygomycosis after voriconazole administration among patients with haematologic malignancies who have receive hematopoietic stem-cell transplants or intensive chemotherapy . Bone Marrow Transplant.2007;39:425-429. 20-Amigues I, Cohen N, Chung D, et al. Hepatic safety of voriconazole after allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant.2010 ;16:46-52. 21Sabatelli F, Patel R, Mann PA, et al. In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts. Antimicrob Agents Chemother.2006;50:2009-2015. 22Antachopoulos C, Walsh TJ. New agents for invasive mycoses in children. Curr Opin Pediatr. 2005;17:78-87. 23Andes D.Clinical utility of antifungal pharmacokinetics and pharmacodynamics. Curr Opin Infect Dis.2004;17:533-40. 24Ting JY, Chan SY, Lung DC, et al. Intra-abdominal Rhizopus microsporus infection successfully treated by combined aggressive surgical, antifungal, and iron chelating therapy. J Pediatr Hematol Oncol.2010;32:238- 40. 25Tarani L, Costantino F, Notheis G, et al. Long-term posaconazole treatment and follow-up of rhino-orbital- cerebral mucormycosis in a diabetic girl. Pediatr Diabetes. 2009;10:289-93. 26Lüer S, Berger S, Diepold M, et al. Treatment of intestinal and hepatic mucormycosis in an immunocompromised child. Pediatr Blood Cancer. 2009;52:872-4. 27Pfaller MA, Messer SA, Boyken L, et al. In vitro survey of triazole cross resistance among more than 700 clinical isolates of Aspergillus species.; J Clin Microbiol.2008;46:2568-–2572. 28European Medicines Agency.. Noxafil Scientific Discussion. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_- _Scientific_Discussion/human/000610/WC500037781.pdf. Accessed 03/31/2011 29 Frampton JE, Scott L.J. Posaconazole: a review of its use in the prophylaxis of invasive fungal infections. Drugs. 2008;68:993-–1016. 30 Segal BH, Barnhart LA, Anderson VL, et al. Posaconazole as salvage therapy in patients with chronic granulomatous disease and invasive filamentous fungal infection. Clin Infect Dis. Jun 2005;40:1684-8. 31Krishna G, Sansone-Parsons A, Martinho M, et al. Posaconazole plasma concentrations in juvenile patients with invasive fungal infection. Antimicrob Agent Chemother. 2007; 51:812-818. 32 Rogers TR, Frost S. Newer antifungal agents for invasive fungal infections in patients with haematological malignancy.Br J Haematol 2008;144:629-641. 33 Lehrnbecher T, Attarbaschi A, Duerken M, et al. Posaconazole salvage treatment in paediatric patients: a multicentre survey. Eur J Clin Microbiol Infect Dis. 2010;29:1043-5. 34 Antachopoulos C, Walsh TJ. New agents for invasive mycoses in children. Curr Opin Pediatr. 2005;17:78-87.

E. Echinocandins

There are 3 echinocandins approved by FDA and EMEA, , , .1 Caspofungin was the only echinocandin approved in July 2008, for pediatric use, and for use in children of 3 months of age and above.2 The echinocandins have a unique mechanism of action, inhibiting beta-(1,3)-D-glucan synthase, an enzyme that is necessary for the synthesis of an essential component of the cell wall of several fungi. The echinocandins display fungistatic activity against Aspergillus species and fungicidal activity against most Candida species., including strains that are fluconazole-resistant. The echinocandins have been shown to be efficacious for the treatment of esophageal Page 14 of 26 candidiasis, candidemia, and invasive candidiasis.3 Because of their distinct antifungal target in the cell wall, there should not be cross-resistance with the azoles or polyenes.1 No evidence of antagonism was reported for the combination of caspofungin with AMB for treatment of C. albicans or A. fumigatus infections in animal models.4 However, there was no additive effect with the combination in invasive pulmonary aspergillosis caused by A. fumigatus. Surveillance data collected from a large number of centers worldwide over the last years has not revealed any evidence of emerging resistance to echinocandins.5 However, there have been occasional reports of treatment failure associated with acquired resistance in Candida species. Interrogation of resistant isolates has shown that this is usually the result of acquired mutations in the target Fks1 gene leading to cross-resistance to all 3 licensed echinocandins.6 An unusual paradoxical resistance has also been reported in some isolates of Candida species following their in vitro exposure to high concentrations of caspofungin; one explanation for this appears to be that a compensatory repair mechanism involving up-regulation of chitin synthesis allows the fungal cells to persist.7

E.1 Caspofungin

Caspofungin acetate is a semi-synthetic lipopeptide synthesized from a fermentation product of Glarea lozoyensis. Caspofungin is only available as an IV formulation, due to limited oral bioavailability, and because it is metabolized by the liver and not mediated by CYP enzymes. It is the first echinocandin to be approved for the treatment of fungal infections in pediatric patients.8 Its antifungal properties result from inhibition of the synthesis of the glucose homopolymer beta-(1,3)-D-glucan, which is not present in mammalian cells, but is an essential component of fungi.4 Caspofungin is fungicidal in vitro against Candida species and is fungistatic against Aspergillus species, but has little or no fungicidal or fungistatic activity against Cryptococcus neoformans, Zygomycetes, Fusarium species, or Trichosporon beigelii.8 Caspofungin pharmacokinetics in pediatric patients have been investigated in 2 studies. One study was conducted in older infants and toddlers (aged 3–24 months) with fever and neutropenia,9 and the other was conducted in neutropenic children (aged 2–11 years) and adolescents (aged 12–17 years).10 These studies demonstrated that a daily 1-mg/kg caspofungin dose results in suboptimal levels in Page 15 of 26 pediatric patients. In addition, a dose of 50 mg/day (70 mg/day maximum) in children and adolescents provides comparable exposure to that obtained in adults receiving a standard 50-mg daily regimen.10 The biggest assets of caspofungin are its excellent tolerability/safety profile and minimal drug interactions.11 There was no evidence of antagonism with the combination of caspofungin plus AMB for C. albicans or A. fumigatus infections in animal models.12 No antagonism between the drugs has been observed for C. albicans or A. fumigatus in infected animals.4 Combination therapy with caspofungin and posaconazole had a synergistic effect in vivo against Aspergillus species.13

E.1.1 Indications for Caspofungin Use

In pediatric patients (3 months to 17 years of age), caspofungin is indicated for the empiric therapy of fungal infections in febrile neutropenic patients. In a recent paper, it has been demonstrated that caspofungin with respect to AMB is comparable in tolerability, safety, and efficacy as empiric antifungal therapy for persistently febrile neutropenic pediatric patients.14 Caspofungin use is also indicated in invasive candidiasis and the following Candida infections: intra-abdominal abscesses, esophageal candidosis, peritonitis, and pleural space infections. Refractory invasive aspergillosis is intolerant to other antifungal drugs.1,3,8,15,16 So, caspofungin seems to provide an effective, well-tolerated alternative for the treatment of Candida and Aspergillus species infections in pediatric patients.17

E.1.2 Caspofungin Dosages

Caspofungin should be administered as an IV infusion for over 1 hour.8,18 In pediatric patients from 12 months to 17 years old caspofungin dosing is base on body surface (Mosteller formula). For all indications, a single loading dose of 70 mg/m2 (effective dose must not exceed 70 mg/day) has to be administrated on the first day of treatment, followed by 50 mg/m2/day (effective dose must not exceed 70 mg/day). If a daily dose of 50 mg/m2 is tolerated well but there is no significant clinical improvement, the daily dose may be increased to 70 mg/m2 (effective dose must not exceed 70 mg/day).8 Duration of therapy is based on clinical response and is similar to specific indications in the treatment

Page 16 of 26 of adults. Empirical antifungal therapy should be continued until resolution of neutropenia (neutrophil cells ≥500). Patients with fungal infections should be treated at least for 14 days and the treatment has to be continued for at least 7 days after the resolution of neutropenia and its symptoms. Treatment for invasive aspergillosis should continue for a period dependent on the underlying disease severity, immunosuppression recovery, and clinical response of patient.8 Caspofungin use is not currently recommended in USA for use in patients less than 3 months of age and in neonates, and efficacy data are not available for this patient population.18

E.1.3 Caspofungin Interactions Caspofungin does not inhibit any cytochrome P450 (CYP) enzyme, is not an inducer of CYP3A4 metabolism of other drugs, and is a poor substrate for CYP enzymes.18 Caspofungin pharmacokinetics is not altered by concomitant treatment with itraconazole, AMB, mycophenolate, nelfinavir, and tacrolimus and it does not alter the pharmacokinetics of itraconazole, AMB , or the active metabolite of mycophenolate. However, plasma concentrations of tacrolimus are reduced by about 20% when the drug is administered with caspofungin, but tacrolimus does not alter the pharmacokinetics of caspofungin. Cyclosporine increases concentration of caspofungin by about 35%, but plasma concentrations of cyclosporine are not altered by the co-administration of caspofungin.8,18

E.1.4 Side Effects of Caspofungin The main side effects associated with caspofungin are fever, hypokalemia, nausea, and vomiting. Caspofungin is well-tolerated in the pediatric population.10,19 The most commonly reported clinical adverse experiences across all pediatric population in caspofungin studies were pyrexia (29.2%), diarrhea (14.0%), rash (11.7%), chills (11.1%), and hypotension (11.1%). Pyrexia was the most common clinically adverse experience reported at each of the caspofungin dose levels.8,10 To analyze the caspofungin safety experience in 5 clinical registration studies in 171 pediatric patients, 1 week to 17 years of age, caspofungin was administered for 1 to 87 (mean 12.1) days, and the most common drug- related adverse events were fever, increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, and rash.17 Few events were serious or required treatment

Page 17 of 26 discontinuation such as pyrexia, hypotension, and hypoxia. They were higher in the pediatric patients treated with caspofungin when compared to adult patients.8,11

E.2 Micafungin

Micafungin is a lipopeptide semi-synthetic derivative of Coleophoma empetri. IV micafungin is an echinocandin indicated in Japan and the European Union (EU) for the treatment of pediatric patients (including neonates) with invasive candidiasis and as prophylaxis against Candida infection in pediatric patients undergoing allogenic HSCT hematopoietic stem cell transplantation.2 In the EU, micafungin is also indicated in pediatric patients, who were expected to be neutropenic for ≥10 days. In Japan, children may also receive micafungin for the treatment of, or as prophylaxis against invasive Aspergillus infection.2 Micafungin is not currently approved for use in pediatric patients in the US. Micafungin has very good antifungal activity against a wide range of Candida species in vitro.,3,20 It has a favorable pharmacokinetic profile allowing for once-daily administration, has few drug-drug interactions, and reports of resistance are rare.3,20 It has linear pharmacokinetics, rapid distribution into tissue, and a half-life of 10–17 hours. Population pharmacokinetic modeling has been performed in children and indicated that increased renal clearance in younger children necessitated an increased dosing schedule.21 Micafungin is metabolized to several non-active compounds. In mild or moderate hepatic impairment, the pharmacokinetics of the drug appear to be unchanged, and no dosing adjustment is needed during therapy. Its use is not recommended in cases of severe hepatic impairment, as no data is available. No dose adjustment is needed in patients with renal impairment.22

E.2.1 Indications for Micafungin Use

Micafungin is the only echinocandin evaluated for use in children for the treatment of invasive candidiasis, and for prophylaxis of Candida infections in patients undergoing allogenic HSCT.1) In a recent paper it was demonstrated that micafungin was as effective as fluconazole and may be an alternative agent for antifungal prophylaxis in neutropenic patients.23 In addition, the largest pediatric micafungin trial was a randomized, double-blind, Page 18 of 26 multicenter trial in 98 children with invasive candidiasis or candidemia. Patients received micafungin or liposomal AMB for at least 14 days with ability to dose escalate for persistent infection after 5 days of therapy. The authors concluded that micafungin was as safe and effective as liposomal AMB in pediatric invasive candidiasis.24 Micafungin was also evaluated in a prospective, open label multicenter trial of adults and children as either monotherapy or combination therapy for primary or refractory invasive aspergillosis. The authors concluded that micafungin alone or in combination was effective and safe for primary and salvage therapy of invasive aspergillosis.25

E.2.2 Micafungin Dosage

Dosage is calculated according to the body weight and age. The recommended dosages are 1–3 mg/kg/day for weight less than 40 kg, and 50–150 mg/day for weight more than 40 kg.1 In a randomized double-blind trial of micafungin (2 mg/kg/day) vs. liposomal AMB (3 mg/kg/day) in 98 children aged <16 years, both the drugs achieved similar success rates for treating candidemia and invasive candidiasis.26A similar phase I study of a pediatric population (ages 2–12 years) febrile neutropenia study found that doses up to 4 mg/kg/day were well tolerated without any side effects.1,27 In general, the terminal half-life of micafungin does not change appreciably in pediatric versus adult patients, and the volume distribution is only slightly higher in children.28

E.2.3 Side Effects of Micafungin

The most common adverse events include fever, abdominal pain, nausea, diarrhea, headache, injection-site inflammation, and leukopenia.1,29 Increase in hepatic enzymes, hypokalemia, and neutropenia have been reported to occur during micafungin therapy, although, these may reflect concurrent events in the treated patient populations; hemolytic anemia is reported as a rare side-effect.1

E.2.4 Micafungin Interactions

Interactions with cyclosporine are not reported. Exposure to sirolimus is increased by about 20% when co-administered with micafungin. It is recommended to discontinue Page 19 of 26 micafungin therapy in the presence of significant and persistent elevation of ALT/AST. Under therapeutic indications, it is added that the decision to use micafungin should take into account a potential risk for development of liver tumors and it should therefore, only be used if other antifungals are not appropriate.1 The most common adverse events include fever, abdominal pain, nausea, diarrhea, headache, injection-site inflammation, and leukopenia.1,29 Increase in hepatic enzymes, hypokalemia, and neutropenia have been reported to occur during micafungin therapy, although, these may reflect concurrent events in the treated patient populations; hemolytic anemia is reported as a rare side-effect.1

E.3 Anidulafungin

Anidulafungin is a semi-synthetic lipopeptide derivative of Aspergillus nidulans with a spectrum of activity similar to caspofungin. It has a good activity in vitro against the most commonly pathogenic Candida species, with the exception of C. parapsilosis and C. guilliermondii, and has shown to be an effective therapy for invasive candidiasis in animal models. It is also fungistatic against Aspergillus species. in vitro and an effective treatment in experimental animal models of invasive Aspergillosis. Its use is not approved in children.1

E.3.1 Indications for Anidulafungin

It is approved for use in the treatment of invasive candidiasis in adult non-neutropenic patients. A phase I/II dose escalation study of anidulafungin involving 5 centers enrolled children aged 2–17-years-old with persistent neutropenia who were at risk of invasive infections, and showed that the drug was well tolerated in pediatric patients and can be dosed based on the body weight. Pediatric patients receiving 0.75 or 1.5 mg/kg/day have pharmacokinetic properties similar to adults receiving 50–100 mg/kg/day.30,31 The results of a multicenter, ascending-dosage study of anidulafungin trial in neutropenic pediatric patients have recently been published. Patients were divided into 2 age cohorts (2–11 years and 12–17 years) and were enrolled into sequential groups to receive 0.75 or 1.5 mg/kg/day. The drug was well tolerated in pediatric patients with only mild to moderate adverse effects. It was found that the drug can be dosed based on body weight, and pediatric patients receiving 0.75 mg/kg/day or 1.5 mg/kg/day were found to Page 20 of 26 have pharmacokinetics similar to adult patients receiving 50 or 100 mg/day respectively.30 This observation is in contrast to caspofungin, which requires a dosage adjustment based on a calculation of body surface area rather than a weight-adjusted scale.1,30

E. References

1Rogers TR, Frost S. Newer antifungal agents for invasive fungal infections in patients with haematological malignancy.; Br JHaematol.2008;144:629-641. 2VandenBussche HL, Van Loo DA. A clinical review of echinocandins in pediatric patients. Ann Pharmacother. 2010;44:166-77. 3Sucher AJ, Chahine EB, Balcer HE. Echinocandins: the newest class of antifungals. Ann Pharmacother. 2009;43:1647-57. 4Merck and Company. Cancidas (caspofungin acetate) for injection, for Intravenous Use. Prescribing Information.http://www.merck.com/product/usa/pi_circulars/c/cancidas/cancidas_pi.pdf. Updated June 10, 2010. Accessed March 31, 2011. 5 Pfaller MA, Boyken L, Hollis RJ, et al. In vitro susceptibility of invasive isolates of Candida spp. to anidulafungin, caspofungin, and micafungin: six years of global surveillance. J Clin Microbiol. 2008;46:150-–156. 6 Thompson GR 3rd, Cadena J, Patterson TF., Overview of antifungal agents. Clin Chest Med. 2009;30:203-15. 7 Stevens DA, Ichinomiya M, Koshi Y, Horiuchi H. Escape of Candida from caspofungin inhibition at concentrations above the MIC (paradoxical effect) accomplished by increased cell wall chitin; evidence for beta- 1,6-glucan synthesis inhibition by caspofungin. Antimicrob Agents Chemother.2006,50:3160-–3161. 8 Garnock-Jones KP, Keam SJ. Caspofungin in pediatric patients with fungal infections. Paediatr Drugs. 2009;11:259-69. 9 Neelby M, Jafri HS, Seibel N, et al. Pharmacokinetics and safety of caspofungin in older infants and toddlers. Antimicrob Agents Chemother. 2009 ;53: 1450-6. 10Walsh TJ, Adamson PC, Seibel NL, et al. Pharmacokinetics safety, and tolerability caspofungin in children and adolescents. Antimicrob Agents Chemother. 2005;49:4536-–4545. 11Parakh A, Dubey AP, Samanta D. Caspofungin. . Indian Pediatr. 2008 ;45:905-10. 12van Vianen W, de Marie S, ten Kate MT, et al. Caspofungin: antifungal activity in vitro, pharmacokinetics and effects on fungal load and animal survival in neutropenic rats with invasive pulmonary aspergillosis. J Antimicrob Chemother. 2006;57:732-40. 13 Keating GM. Posaconazole. Drugs. 2005;65:1553-67. 14 Maertens JA, Madero L, Reilly AF, et al. A randomized, double-blind, multicenter study of caspofungin versus liposomal amphotericin B for empiric antifungal therapy in pediatric patients with persistent fever and neutropenia. Pediatr Infect Dis J. 2010;29:415-20. 15 Maertens J, Raad I, Petrikkos G, et al. Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy. Clin Infect Dis. 2004;39:1563-1571. 16 Cornely OA, Lasso M, Betts R, et al. Caspofungin for the treatment of less common forms of invasive candidiasis. J Antimicrob Chemother. 2007;60:363-–369. 17 Zaoutis TE, Jafri HS, Huang LM, et al. A prospective, multicenter study of caspofungin for the treatment of documented Candida or Aspergillus infections in pediatric patients., Pediatrics. 2009;123:877-84. 18 Merck and Company. Cancidas (caspofungin acetate) for injection, for Intravenous Use. Prescribing Information.http://www.merck.com/product/usa/pi_circulars/c/cancidas/cancidas_pi.pdf. Updated June 10, 2010. Accessed March 31, 2011. 19 Groll AH, Attarbaschi A, Schuster FR, et al. Treatment with caspofungin in immunocompromised paediatric patients: a multicentre survey. J Antimicrob Chemother. 2006;57:527-–535. 20 Carter NJ, Keating GM. Micafungin: a review of its use in the prophylaxis and treatment of invasive Candida infections in pediatric patients. Paediatr Drugs. 2009;11:271-91. 21 Ikeda F, Tanaka S, Ohki H, et al. Role of micafungin in the antifungal armamentarium. Curr Med Chem. 2007;14(11):1263-75.

Page 21 of 26 22 Hope WW, Seibel NL., Schwarz CL., et al. Population pharmacokinetics of micafungin in pediatric patients and implications for antifungal dosing. Antimicrob Agents Chemother. 2007 Oct;51(10):3714-9. 23 van Burik JA, Ratanatharathorn V, Stepan DE, et al. Micafungin versus fluconazole for prophylaxis against invasive fungal infections during neutropenia in patients undergoing hematopoietic stem cell transplantation. Clin Infect Dis. 2004;39:1407-16. 24 Queiroz-Telles F, Berezin E, Leverger G, et al. Micafungin versus liposomal amphotericin B for pediatric patients with invasive candidiasis: substudy of a randomized double-blind trial. Pediatr Infect Dis J. 2008;27:820-6. 25 Denning DW, Marr KA, Lau WM, et al. Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis. J Infect. 2006;53:337-49. 26 Querioz-Telles F, Berezin E, Leverger G, et al. Micafungin versus liposomal amphotericin B for pediatric patients with invasive candidiasis: substudy of a randomized double-blind trial. Pediatr Infect Dis J. 2008 Sep;27(9):820-6. 27 Chandrasekar PH, Sobel JD. Micafungin: a new echinocandin. Clin Infect Dis. 2006;42:1171-8. 28 Kontoyiannis DP, Ratanatharathorn V, Young JA, et al. Micafungin alone or in combination with other systemic antifungal therapies in hematopoietic stem cell transplant recipients with invasive aspergillosis. Transpl Infect Dis. 2009;11:89-93. 29 Antachopoulos C, Walsh TJ. New agents for invasive mycoses in children. Curr Opin Pediatr. 2005;17:78-87. 30 Benjamin DK Jr, Driscoll T, Seibel NL, et al. Safety and pharmacokinetics of intravenous anidulafungin in children with neutropenia at high risk for invasive fungal infections. Antimicrob Agents Chemother. 2006;50:632-8. 31Pannaraj PS , Walsh TJ, Baker CJ. , Advances in antifungal therapy. Pediatr Infect Dis. 2005;24:921-2.

F. Polyenes: Amphotericin B

The oldest antifungal class is the polyenes, including macrolides, AMB, and nystatin. Nystatin is only used topically. AMB binds to ergosterol, the major sterol found in cytoplasmic membranes, causing changes in cell permeability that lead to cell lysis and death.1,2 There is also evidence that AMB acts as a proinflammatory agent, and further serves to stimulate innate host immunity. This process involves the interaction of AMB with toll-like receptor 2 (TLR-2), and the CD14 receptor, as well as the stimulation of the release of cytokines, chemokines, and other immunologic mediators. It has been suggested that AMB may interact with host humoral immunity after the observation of synergistic activity of AMB and antibodies directed at heat shock protein 90 (hsp90), although further confirmatory data are needed.2,3 AMB is the gold standard for the therapy of many invasive fungal infections. Resistance to AMB remains uncommon during treatment; and it is generally attributed to reductions in ergosterol biosynthesis of alternative sterols with a reduced affinity for AMB. Resistance to AMB is common in S. apiospermum, S. prolificans, A. terreus, Thricospon species, and Candida lusitaniae.2 AMB is primarily administered intravenously or through inhalation. The peak serum level to mean inhibitory concentration (MIC) ratio is the best Page 22 of 26 pharmacologic predictor of outcomes with polyene therapy. Drug levels are infrequently measured and are typically available only in the research setting.4 Three lipid-associated formulations are actually available: AMB lipid complex (ABLC, Abelced), AMB colloidal dispersion (ABCD, Amphocil, Amphotec), and liposomal AMB (L-AMB, AmBisome). All are currently available formulations are highly protein bound (>95%, primarily to albumin). AMB exhibits poor CSF levels; however, this agent is the treatment of choice for cryptococcal meningitis.5A 56-center prospective study evaluated the safety and efficacy of L-AMB administered to 260 adults, 242 children (<15 years old), and 43 infants (<2 months old). In general, infants and children tolerated the largest doses of L-AMB administrated for the longest time (median 18 days).4

F.1 Indications for Amphotericin B

The indications for AMB use in pediatric patients are:2,6  Disseminated candidemia (not C. lusitaniae)  Invasive aspergillosis  Cryptococcal infections and meningitis (AMB + flucytosine is the gold standard)  Blastomycoses  Coccidioidomycoses  Histoplasmosis (lipid formulation has greater efficacy)  Zygomycetes (not Scedosporium, Fusarium, Trichosporum)  Endemic mycoses

F.1.1 Amphotericin B Dosing

The preferred pediatric dosages for AMB are:  AMB deoxycholate: 1–1.5mg/kg/day.  AMB lipid complex: 5 mg/kg/day.  AMB colloidal dispersion: 5 mg/kg/day.  Liposomal AMB: 5 mg/kg/day.

Page 23 of 26 Children generally tolerated higher doses than adults, probably due to the more rapid clearance of the drug in children.7

F.1.2 Side Effects of Amphotericin B

Nephrotoxicity associated with AMB is less severe in infants than in adults, and it is due to the capacity of AMB of binding cholesterol in human cell membranes. This toxicity is believed secondary to vascular smooth muscle dysfunction with resultant vasoconstriction and ischemia.2 The use of the lipid formulation of AMB is better tolerated than the conventional AMB, and offers the advantage of an increased daily dose of parent drug, better delivery to primary reticuloendothelium, and reduced toxicity. Resistance to AMB remains uncommon during treatment of most IFI and the mechanisms include a decrease in the ergosterol content of the cell membrane or a change in membrane sterols, leading to a decrease in the binding affinity to AMB.7 During administration of AMB, the most common adverse reactions are sudden fever. The less frequent reactions related to infusion are dyspnea, wheezing, tachycardia, rash, hypertension, and back pain. Nausea, vomiting, diarrhea, and abdominal pain are common. An increase in urea and creatinine levels, hypokalemia, hypomagnesemia, hypocalcemia, hyperglycemia, hyperbilirubinemia, and alteration in alkaline phosphates are the other reported side effects.2,8

F.1.3 Amphotericin B Interactions

Nephrotoxicity may occur with liposomal AMB treatment. Routine laboratory assessment of serum electrolytes and markers of renal, hepatic, and hematopoietic function is recommended particularly in patients also receiving other nephrotoxic drugs (cyclosporine, aminoglycosides, or ).6,9 Hypokalemia associated with liposomal and other formulations of AMB may be potentiated by concomitant use of corticosteroids, corticotropin, and loop or thiazide diuretics. The concomitant use of other antifungal drugs such as 5-flucytosine (5-FC) may increase AMB toxicity by potentially increasing the cellular uptake of 5-FC and/or impairing renal excretion. 7,9

Page 24 of 26 F.2 5-Flucytosine

Flucytosine is deaminated to 5-fluorouracil (5-FU) by fungal cytosine deaminase. 5-FC is further converted to 5-fluorodeoxyuridylic acid, which interferes with DNA synthesis. Mammalian cells lack cytosine deaminase allowing for a selective inhibition of fungal organisms.2 5-FC activity has been observed against most fungal pathogens, including Candida, Cryptococcus, Cladosporium, and Phialophora; and Saccharomyces species, Aspergillus species, Zygomycetes, Dermatophytes, and the endemic mycoses are all resistant to 5-FC. Additionally, resistance commonly develops when 5-FC is used as monotherapy even in susceptible organisms and it should not be used as such except during the treatment of chromoblastomycoses or during the treatment of localized Candida infections when alternative agents are unavailable or contraindicated.2 5-FC is thought to enhance the antifungal activity of AMB, especially in anatomical sites where AMB penetration is poor such as the heart valves and vitreous body. 5-FC is always used in association with other antifungal drugs because resistance to monotherapy with 5-FC develops quickly.7 It is well adsorbed after oral administration and is distributed widely, attaining therapeutic concentrations in most body sites such as the CSF, vitreous and peritoneal fluids, and into inflamed joints, because it is small and highly water soluble and not bound by serum proteins to a great extent.7 Its toxicity appears to be due to the conversion to 5-FU. 5-FC may exacerbate myelosuppression in patients with neutropenia, and serum concentrations more than 100 μg/mL are associated with bone marrow aplasia.7

F.2.1 Indications for 5-flucytosine

5-FC is primarily used only in the treatment of Cryptococcus (combined with AMB),2,10 and chromoblastomycosis.2 AMB and 5-FC are also suggested for use in patients with candidal meningitis.11

F.2.2 Dosing for 5-flucytosine

Preferred pediatric dosing of 5-FC is 150 mg/kg/day divided q6h.7

Page 25 of 26 F.2.3 Side Effects of 5-flucytosine

Side effects of therapy include rash, diarrhea, hepatic transaminase elevation, and bone marrow suppression. The marrow suppressive effects are more common if drug levels in the blood exceed 100 to 125 mg/mL. In cases of prolonged therapy (>7 days), or with alterations in renal function, serum drug monitoring is recommended. Other lesser side effects such as abdominal pain or diarrhea are frequently indirect markers of elevated flucytosine levels and therapy is typically stopped in these circumstances.2

F. References

1Steinbach WJ., Antifungal agents in children., Pediatr Clin North Am. 2005;52:895-915. 2Thompson GR 3rd, Cadena J, Patterson TF. Overview of antifungal agents. Clin Chest Med. 2009;30:203-15. 3Ben-Ami R, Lewis RE, Kontoyiannis DP. Immunocompromised hosts: immunopharmacology of modern antifungals. Clin Infect Dis. 2008;47:226-–35. 4Andes D. In vivo pharmacodynamics of antifungal drugs in treatment of candidiasis. Antimicrob Agents Chemother .2003;43:S38:161-89. 5Saag MS, Graybill RJ, Larsen RA, Practice guidelines for the management of cryptococcical disease, Infectious Disease Society of America. Clin Infec Dis.2000;30:710-8. 6 Gilead Sciences Limited. AmBisome (Liposomal Amphotericin). http://www.medicines.ie/medicine/5306/SPC/AmBisome+%28Liposomal+Amphotericin%29/ Updated 09/11/2010. Accessed 03/31/2011. 7Zaoutis TE, Benjamin DK, Steinbach WJ. Antifungal treatment in pediatric patients. Drug Resist Updat. 2005;8:235-45. 8Doods A, Es LR, Lewis JS, et al. Pharmacology of systemic antifungal agents., Clin Infec Dis. 2004;47:1179-86. 9 Moen MD, Lyseng-Williamson KA, Scott LJ. Liposomal amphotericin B : a review of its use as empirical therapy in febrile neutropenia and in the treatment of invasive fungal infections. Drugs. 2009;69:361-92. 10Kaya Z, Gursel T, Kocak U, et al. Invasive fungal infections in pediatric leukemia patients receiving fluconazole prophylaxis. Pediatr Blood Cancer. 2009 ;52:470-5. 11Pappas PG, Rex JH Sobel JD, et al. Guidelines for treatment of candidiasis. Clin Infect Dis.2004;38:,161-189.

Additional Resources

1Steinbach WJ. Invasive aspergillosis in pediatric patients. Curr Med Res Opin. 2010;26:1779-87. 2Rogers TR, Johnson EM, Munro C. Echinocandin antifungal drug resistance. J Invasive Fungal Infect. 2007;1:99-105..

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