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CONCISE REVIEWS OF PEDIATRIC INFECTIOUS DISEASES

Antifungal Azoles: Old and New

Christopher C. Blyth, MB BS, FRACP, FRCPA

Key Words: azoles, fungal infection, neonates,

children, antifungal therapy

(Pediatr Infect Dis J 2011;30: 506507)

Management of fungal infections is com-plex with increasing choice of antifun-gals. Mortality and morbidity are significantdespite treatment. Azoles are commonlyused compounds which inhibit fungal lanos-terol 14 demethylase, thereby depleting er-gosterol in the fungal cell membrane with theaccumulation of lanosterol precursors. Imi-

dazoles (miconazole, ketoconazole, clotrim-azole) are used in topical preparations. Tria-zoles are used for prophylaxis, empirical anddirected systemic antifungal therapy, andwill be the focus of this review. There areimportant differences in structure, spectrumof activity, pharmacokinetics, drug interac-tions, and clinical indications.

FLUCONAZOLE

Fluconazole has activity against mostCandida spp. (except Candida krusei andsome Candida glabrata isolates), Cryptococ-cus spp., and many dimorphic fungi. Intra-

venous (IV) and oral formulations are avail-

able. The drug is well absorbed in children,has limited binding to plasma proteins, andpenetrates into cerebrospinal fluid.1,2 Flu-conazole is cleared mainly unchanged inurine; clearance occurs more rapidly in chil-dren than adults. The recommended dose forneonates and children with invasive fungalinfection (IFI) is 12 mg/kg/d.1,3,4 Therapeu-tic concentrations may be achieved morerapidly with a loading dose.5

Efficacy data from 213 infants andchildren with IFI unresponsive or intolerantto therapy are published: responses were ob-

served in 97% of infants (clinical/mycologi-cal response) and 73% (clinical) to 83% ofchildren (mycological response).6,7 Patho-gens with decreased fluconazole susceptibil-ity were infrequent in both the trials. Ascompared with placebo, fluconazole prophy-laxis reduces the incidence of invasive can-didiasis (IC) in preterm infants (birth weight1500 g).8 Candida infections are reducedin liver and hematopoietic stem cell trans-plant (HSCT) recipients receiving flucona-zole prophylaxis.4,9

Fluconazole is well tolerated in chil-dren. Fluconazole-related adverse events oc-

curred in only 6% of 213 infants/children:3% discontinued therapy.6,7 Gastrointestinalintolerance and elevated transaminases weremost frequent.

Fluconazole is recommended for non-neutropenic patients with candidemia or IC,for maintenance/eradication therapy in cryp-tococcal meningitis, and for mucocutaneouscandidiasis requiring systemic therapy.4,10

Alternatives such as amphotericin B or echi-nocandins may be preferred, especially inchildren with severe illness, neonates, chil-dren with neutropenia, prior azole use, or at

risk for C. krusei or C. glabrata infection.4

Prophylaxis should be considered in nurser-ies with a high incidence of IC.4,8

ITRACONAZOLE

Itraconazole is the first triazole withactivity against filamentous fungi includingAspergillus spp. Capsules, oral solution, andIV formulations are available. Oral absorp-tion is erratic: achlorhydria reduces andacidic beverages enhance capsule absorp-tion.2 The oral solution is better absorbed on

an empty stomach. The drug is highly pro-tein bound, extensively distributed into tis-sues and metabolized by the liver.2,11 Druginteractions are frequent: itraconazole is apotent inhibitor of cytochrome CYP3A4 en-zymes. More frequent dosing is required inchildren compared with adults (2.55 mg/kgtwice daily).2 No neonatal data for itracona-zole exist. Therapeutic drug monitoring mayassist in determining optimal dosing.

Prophylaxis with itraconazole solutionis more effective than fluconazole in adultswith hematological malignancy but may be

limited by intolerance.

9,12

In 103 neutro-penic children receiving itraconazole oral so-lution, 35% were noncompliant, intolerant,or developed adverse events on therapy.Nausea, vomiting, and diarrhea were mostfrequent.12

Itraconazole is recommended in mild-to-moderate infection or after amphotericinB therapy for severe/disseminated infectionwith dimorphic fungi including histoplasmo-sis, blastomycosis, and sporotrichosis.1315

Itraconazole is also recommended for aller-gic bronchopulmonary aspergillosis.16

From the School of Paediatrics and Child Health,University of Western Australia, Subiaco, Austra-lia; Department of Paediatric and AdolescentMedicine, Princess Margaret Hospital, Subiaco,Australia; and Department of Microbiology, Path-West Laboratory Medicine WA, Princess Marga-ret Hospital, Subiaco, Australia.

Dr Blyth has been on the antifungal advisory boards ofPfizer Australia and Schering-Plough Australia..

Copyright 2011 by Lippincott Williams & WilkinsISSN: 0891-3668/11/3006-0506DOI: 10.1097/INF.0b013e31821b958c

CONTENTS

Antifungal Azoles: Old and NewEchinocandins in Children

EDITORIAL BOARD

Co-Editors: Margaret C. Fisher, MD, and Gary D. Overturf, MD

Editor for this Issue: Theoklis Zaoutis, MDBoard MembersMichael Cappello, MD

Ellen G. Chadwick, MD

Janet A. Englund, MD

Leonard R. Krilov, MD

Charles T. Leach, MD

Kathleen McGann, MD

Jennifer Read, MD

Jeffrey R. Starke, MD

Geoffrey A. Weinberg, MD

Leonard Weiner, MD

Charles R. Woods, MD

The Concise Reviews of Pediatric Infectious Diseases (CRPIDS) topics, authors, and contents are chosen and approved indepen-dently by the Editorial Board of CRPIDS.

The Pediatric Infectious Disease Journal Volume 30, Number 6, June 2011506 | www.pidj.com

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VORICONAZOLE

Voriconazole is an extended-spec-trum, second-generation azole, structurallysimilar to fluconazole with activity againstmost fluconazole-resistant yeasts, Aspergil-lus spp., Penicillium spp., Scedosporium

spp., and Fusarium spp. It has no usefulactivity against zygomycetes. IV and oralpreparations are available. The bioavailabil-ity of voriconazole is 90% in adults, yetreduced in children.17 Absorption is reducedif taken with food. The drug has extensivedistribution into tissues, including the centralnervous system, and hepatically metabolizedby CYP2C19, CYP2C9, and CYP3A4. Sig-nificant interpatient variability is observed.15

This may be due to the factors includingvariable metabolism due to genetic polymor-phism or elimination capacity, and/or druginteractions. Recent data suggest that 7

mg/kg of IV and 200 mg of oral voriconazoletwice daily are required in children (212years) to approximate adult levels.15,17 Ther-apeutic drug monitoring may assist in opti-mizing dosing in children.

Voriconazole was administered (6mg/kg load then 4 mg/kg twice daily) to 69children with IFI, intolerant, or refractory toother therapies. Complete or partial re-sponses were observed in 45% (aspergillosis;43%: scedosporosis; 63%).18 Improved sur-vival has been demonstrated in adolescentsand adults receiving voriconazole comparedwith amphotericin B deoxycholate.16

The most frequent adverse events withvoriconazole are hepatotoxicity, visual distur-bances, rash, and gastrointestinal intoler-ance.15,18 Voriconazole-related adverse eventsoccurred in 23 of 69 children (33%) yet only 3discontinued therapy.18

Voriconazole is the drug of choice forinvasive aspergillosis (IA).16

POSACONAZOLE

Posaconazole is an extended-spec-trum, second-generation azole, structurallysimilar to itraconazole. In addition to thespectrum of voriconazole, posaconazole has

activity against zygomycetes. The drug isavailable in oral solution: an IV preparationis undergoing phase I trials. Optimum bio-availability is achieved with at least twicedaily dosing with food or nutritional supple-ments.11 Posaconazole is highly proteinbound and has large volume of distribution.It is not significantly metabolized, but mostlyexcreted unchanged in the feces.11 The druginhibits cytochrome CYP3A4 and as such,drug interactions are observed. Limited pe-diatric pharmacokinetic data are available:trials are presently underway. Eleven chil-dren (1017 years) receiving 800 mg/d had

similar plasma levels to adults receiving thesame dose.11

Pediatric safety and efficacy data are lim-ited. Complete or partial responses were observedin 9 of 15 children receiving posaconazole sal-vage therapy for proven/probable IFI, including 4of 7 with zygomycosis.19 The median dose was21 mg/kg (95% CI 1725). This response rate

was comparable to adults receiving therapy foraspergillosis and zygomycosis.19 The drug waswell tolerated; no children discontinued therapywith adverse events.

Posaconazole was compared with flu-conazole or itraconazole in neutropenic adoles-cents and adults with acute myeloid leukemia(AML) or myelodysplastic syndrome. IFI wasless frequent in those receiving posaconazole.20

Posaconazole and fluconazole were administeredto adolescents and adults with graft-versus-hostdisease. IA- and IFI-related mortality was less inthose receiving posaconazole.21

Although prophylaxis with posacona-

zole is recommended in neutropenic patientswith AML/myelodysplastic syndrome andHSCT recipients with graft-versus-host dis-ease at high risk of IA, no pediatric dosingrecommendations exist.16

NEW TRIAZOLES

Three new extended-spectrum triazolesare in advanced stages of development: isavu-conazole, ravuconazole, and albaconazole.22

Isavuconazonium, the water soluble prodrug ofisavuconazole, is available in oral or IV prep-arations. Unlike itraconazole and voriconazole,this drug does not require cyclodextrin to in-

crease solubility. Absorption is minimally af-fected by food intake. Isavuconazole has a longelimination half life, large volume of distribu-tion, and high protein binding. Less frequentdrug interactions and comparable safety profileto licensed azoles are observed.22 Isavuconazolehas activity against Candida spp., Cryptococcusspp., Aspergillus spp., Paecilomyces spp., anddermatophytes including many resistant species.Variable activity against zygomycetes and noactivity against Fusarium spp. and Scedospo-rium prolificans are observed.22 Phase III stud-ies using isavuconazole prophylaxis in adultswith AML and treatment in adults with IC and

aspergillosis are being performed.Ravuconazole and its prodrug E-1224

are structurally similar to isavuconazole.22

Ravuconazole has a half life comparable tothat of isavuconazole. Its absorption is in-creased with a high fat meal. In addition tothe antifungal spectrum observed with isavu-conazole, activity against Histoplasma cap-sulatum has been demonstrated.22 Phase IIstudies using ravuconazole prophylaxis inadults undergoing HSCT are underway.

Albaconazole is a new potent triazoleavailable as an oral preparation. The drug hasexcellent bioavailability and is widely dis-

tributed throughout body fluids.22 It has ac-tivity against Candida spp., Cryptococcus

spp., Malassezia spp., dermatophytes, Asper-gillus spp., and Paecilomyces spp. Phase IIstudies have been conducted in adults withvulvovaginitis and onychomyoses.

Further research is required to deter-mine the optimal role of the new triazoles.

Further studies in infants and children arerequired for these and some licensed agentsto determine pediatric pharmacokinetics, op-timal dosing, and safety.

REFERENCES

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2. Steinbach WJ. Antifungal agents in children. Pe-diatr Clin North Am. 2005;52:895915.

3. Wade KC, et al. Fluconazole dosing. in younginfants. Pediatr Infect Dis J. 2009;28:717723.

4. Pappas PG, et al. Clinical practice guidelinesof candidiasis. Clin Infect Dis. 2009;48:503535.

5. Piper L, et al. Fluconazole loading dose. . . ininfants. Pediatr Infect Dis J. 2011;30:375378.

6. Fasano C, et al. Fluconazole treatment of neo-nates and infants. Eur J Clin Microbiol Infect Dis.1994;13:351354.

7. FasanoC, et al. Fluconazole treatment of children.EurJ Clin Microbiol Infect Dis. 1994;13:344347.

8. Clerihew L, et al. Prophylactic systemic antifun-gal agents to prevent mortality and morbidityin very low birth weight infants. Cochrane Da-tabase Syst Rev 2007:CD003850.

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10. Perfect JR, et al. Clinical practice guidelinesfor cryptococcal disease. Clin Infect Dis. 2010;

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12. Foot AB, et al. Itraconazole oral solution asantifungal prophylaxis. Bone Marrow Trans-plant. 1999;24:10891093.

13. Wheat LJ, et al. Clinical practice guidelines forthe management of patients with histoplasmosis.Clin Infect Dis. 2007;45:807825.

14. Chapman SW, et al. Clinical practice guidelinesfor the management of blastomycosis. Clin InfectDis. 2008;46:18011812.

15. Michael C, et al. Voriconazole pharmacokineticsand safety in immunocompromised children. An-timicrob Agents Chemother. 2010;54:32253232.

16. Walsh TJ, et al. Treatment of aspergillosis. ClinInfect Dis. 2008;46:327360.

17. Karlsson MO, et al. Population pharmacokinetic anal-ysis of voriconazole data from pediatric studies.Antimicrob Agents Chemother. 2009;53:935944.

18. Walsh TJ, et al. Voriconazole in the treatment ofaspergillosis in children. Pediatr Infect Dis J.2002;21:240 248.

19. Lehrnbecher T, et al. Posaconazole salvage treat-ment in paediatric patients. Eur J Clin MicrobiolInfect Dis. 2010;29:10431045.

20. Cornely OA, et al. Posaconazole vs. fluconazoleor itraconazole prophylaxis. N Engl J Med. 2007;356:348359.

21. Ullmann AJ, et al. Posaconazole or fluconazole forprophylaxis. N Engl J Med. 2007;356:335347.

22. Pasqualotto AC, et al. Novel triazole antifungaldrugs. Curr Opin Investig Drugs. 2010;11:165174.

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