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Pharmacokinetics and Pharmacodynamics of Antifungal Agents in Neonates and Children

  • Pediatric Fungal Infections (D Corzo Leon, Section Editor)
  • Published:
Current Fungal Infection Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

This review summarizes current knowledge on pharmacokinetics (PK) and pharmacodynamics (PD) of various formulations of amphotericin B, triazoles (fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole), and echinocandins (caspofungin, micafungin, anidulafungin) in the pediatric population.

Recent Findings

The PD indices associated with in vivo outcome have been defined for all antifungal agents. PK parameters have been studied across all range of ages; however, data often originate from small patient series, particularly regarding neonates and young infants. Dose-exposure simulations in population PK studies provide the probability of PD target attainment using various dosage regimens. Therapeutic drug monitoring (TDM) has been recognized as a valuable tool to individualize dosing for azoles due to significant inter-patient variability.

Summary

Our understanding of PK/PD of antifungal agents in pediatric patients has significantly advanced over the last years allowing age-specific dosing recommendations. Yet, however, several PK questions regarding specific patient groups remain to be addressed.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Pana ZD, Roilides E, Warris A, Groll AH, Zaoutis T. Epidemiology of invasive fungal disease in children. J Pediatric Infect Dis Soc. 2017;6(suppl_1):S3–S11.

    PubMed  PubMed Central  Google Scholar 

  2. Robbins N, Wright GD, Cowen LE. Antifungal drugs: the current armamentarium and development of new agents. Microbiol Spectr. 2016;4(5). https://doi.org/10.1128/microbiolspec.FUNK-0002-2016.

  3. Lepak A, Andes D. Antifungal pharmacokinetics and pharmacodynamics. Cold Spring Harb Perspect Med. 2015;5:a019653.

    PubMed Central  Google Scholar 

  4. Hong Y, Shaw PJ, Nath CE, Yadav SP, Stephen KR, Earl JW, et al. Population pharmacokinetics of liposomal amphotericin B in pediatric patients with malignant diseases. Antimicrob Agents Chemother. 2006;50(3):935–42.

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Baley JE, Meyers C, Kliegman RM, Jacobs MR, Blumer JL. Pharmacokinetics, outcome of treatment, and toxic effects of amphotericin B and 5-fluorocytosine in neonates. J Pediatr. 1990;116(5):791–7.

    CAS  PubMed  Google Scholar 

  6. • Silver C, Rostas S. Comprehensive drug utilization review in neonates: liposomal amphotericin B. J Pharm Pharmacol. 2018;70(3):328–34. A comprehensive review and comparison of pharmacological properties, safety, and efficacy of deoxycholate and liposomal amphotericin B formulations in neonates.

    CAS  PubMed  Google Scholar 

  7. Benson JM, Nahata MC. Pharmacokinetics of amphotericin B in children. Antimicrob Agents Chemother. 1989;33(11):1989–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Groll AH, Giri N, Petraitis V, Petraitiene R, Candelario M, Bacher JS, et al. Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system. J Infect Dis. 2000;182(1):274–82.

    CAS  PubMed  Google Scholar 

  9. Walsh TJ, Whitcomb P, Piscitelli S, Figg WD, Hill S, Chanock SJ, et al. Safety, tolerance, and pharmacokinetics of amphotericin B lipid complex in children with hepatosplenic candidiasis. Antimicrob Agents Chemother. 1997;41(9):1944–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Wurthwein G, Groll AH, Hempel G, Adler-Shohet FC, Lieberman JM, Walsh TJ. Population pharmacokinetics of amphotericin B lipid complex in neonates. Antimicrob Agents Chemother. 2005;49(12):5092–8.

    PubMed  PubMed Central  Google Scholar 

  11. Amantea MA, Bowden RA, Forrest A, Working PK, Newman MS, Mamelok RD. Population pharmacokinetics and renal function-sparing effects of amphotericin B colloidal dispersion in patients receiving bone marrow transplants. Antimicrob Agents Chemother. 1995;39(9):2042–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. • Groll AH, Rijnders BJA, Walsh TJ, Adler-Moore J, Lewis RE, Bruggemann RJM. Clinical pharmacokinetics, pharmacodynamics, safety and efficacy of liposomal amphotericin B. Clin Infect Dis. 2019;68(Supplement_4):S260–S74. An excellent review of the pharmacokinetics, safety, and efficacy of liposomal amphotericin B across all range of ages and in different patient groups.

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Hong Y, Shaw PJ, Tattam BN, Nath CE, Earl JW, Stephen KR, et al. Plasma protein distribution and its impact on pharmacokinetics of liposomal amphotericin B in paediatric patients with malignant diseases. Eur J Clin Pharmacol. 2007;63(2):165–72.

    CAS  PubMed  Google Scholar 

  14. Seibel NL, Shad AT, Bekersky I, Groll AH, Gonzalez C, Wood LV, et al. Safety, tolerability, and pharmacokinetics of liposomal amphotericin B in immunocompromised pediatric patients. Antimicrob Agents Chemother. 2017;61(2):e01477–16.

  15. Lestner JM, Groll AH, Aljayyoussi G, Seibel NL, Shad A, Gonzalez C, et al. Population pharmacokinetics of liposomal amphotericin B in immunocompromised children. Antimicrob Agents Chemother. 2016;60(12):7340–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Vogelsinger H, Weiler S, Djanani A, Kountchev J, Bellmann-Weiler R, Wiedermann CJ, et al. Amphotericin B tissue distribution in autopsy material after treatment with liposomal amphotericin B and amphotericin B colloidal dispersion. J Antimicrob Chemother. 2006;57(6):1153–60.

    CAS  PubMed  Google Scholar 

  17. Strenger V, Meinitzer A, Donnerer J, Hofer N, Dornbusch HJ, Wanz U, et al. Amphotericin B transfer to CSF following intravenous administration of liposomal amphotericin B. J Antimicrob Chemother. 2014;69(9):2522–6.

    CAS  PubMed  Google Scholar 

  18. Howard SJ, Lestner JM, Sharp A, Gregson L, Goodwin J, Slater J, et al. Pharmacokinetics and pharmacodynamics of posaconazole for invasive pulmonary aspergillosis: clinical implications for antifungal therapy. J Infect Dis. 2011;203(9):1324–32.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Lepak AJ, Marchillo K, Vanhecker J, Andes DR. Isavuconazole (BAL4815) pharmacodynamic target determination in an in vivo murine model of invasive pulmonary aspergillosis against wild-type and cyp51 mutant isolates of Aspergillus fumigatus. Antimicrob Agents Chemother. 2013;57(12):6284–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Sudan A, Livermore J, Howard SJ, Al-Nakeeb Z, Sharp A, Goodwin J, et al. Pharmacokinetics and pharmacodynamics of fluconazole for cryptococcal meningoencephalitis: implications for antifungal therapy and in vitro susceptibility breakpoints. Antimicrob Agents Chemother. 2013;57(6):2793–800.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Andes D, van Ogtrop M. Characterization and quantitation of the pharmacodynamics of fluconazole in a neutropenic murine disseminated candidiasis infection model. Antimicrob Agents Chemother. 1999;43(9):2116–20.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Andes D, Marchillo K, Stamstad T, Conklin R. In vivo pharmacokinetics and pharmacodynamics of a new triazole, voriconazole, in a murine candidiasis model. Antimicrob Agents Chemother. 2003;47(10):3165–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Bellmann R, Smuszkiewicz P. Pharmacokinetics of antifungal drugs: practical implications for optimized treatment of patients. Infection. 2017;45(6):737–79.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Wade KC, Wu D, Kaufman DA, Ward RM, Benjamin DK Jr, Sullivan JE, et al. Population pharmacokinetics of fluconazole in young infants. Antimicrob Agents Chemother. 2008;52(11):4043–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Piper L, Smith PB, Hornik CP, Cheifetz IM, Barrett JS, Moorthy G, et al. Fluconazole loading dose pharmacokinetics and safety in infants. Pediatr Infect Dis J. 2011;30(5):375–8.

    PubMed  PubMed Central  Google Scholar 

  26. •• Leroux S, Jacqz-Aigrain E, Elie V, Legrand F, Barin-Le Guellec C, Aurich B, et al. Pharmacokinetics and safety of fluconazole and micafungin in neonates with systemic candidiasis: a randomized, open-label clinical trial. Br J Clin Pharmacol. 2018;84(9):1989–99. A randomized clinical trial comparing fluconazole and micafungin in neonates with invasive candidiasis.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Gerhart JG, Watt KM, Edginton A, Wade KC, Salerno SN, Benjamin DK Jr, et al. Physiologically-based pharmacokinetic modeling of fluconazole using plasma and cerebrospinal fluid samples from preterm and term infants. CPT Pharmacometrics Syst Pharmacol. 2019;8(7):500–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Momper JD, Capparelli EV, Wade KC, Kantak A, Dhanireddy R, Cummings JJ, et al. Population pharmacokinetics of fluconazole in premature infants with birth weights less than 750 grams. Antimicrob Agents Chemother. 2016;60(9):5539–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Watt KM, Benjamin DK Jr, Cheifetz IM, Moorthy G, Wade KC, Smith PB, et al. Pharmacokinetics and safety of fluconazole in young infants supported with extracorporeal membrane oxygenation. Pediatr Infect Dis J. 2012;31(10):1042–7.

    PubMed  PubMed Central  Google Scholar 

  30. Watt KM, Gonzalez D, Benjamin DK Jr, Brouwer KL, Wade KC, Capparelli E, et al. Fluconazole population pharmacokinetics and dosing for prevention and treatment of invasive Candidiasis in children supported with extracorporeal membrane oxygenation. Antimicrob Agents Chemother. 2015;59(7):3935–43.

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Stott KE, Hope WW. Therapeutic drug monitoring for invasive mould infections and disease: pharmacokinetic and pharmacodynamic considerations. J Antimicrob Chemother. 2017;72(suppl_1):i12–i8.

    CAS  PubMed  Google Scholar 

  32. van der Elst KC, Pereboom M, van den Heuvel ER, Kosterink JG, Scholvinck EH, Alffenaar JW. Insufficient fluconazole exposure in pediatric cancer patients and the need for therapeutic drug monitoring in critically ill children. Clin Infect Dis. 2014;59(11):1527–33.

    PubMed  Google Scholar 

  33. Caputo R. Itraconazole (Sporanox) in superficial and systemic fungal infections. Expert Rev Anti-Infect Ther. 2003;1(4):531–42.

    CAS  PubMed  Google Scholar 

  34. de Repentigny L, Ratelle J, Leclerc JM, Cornu G, Sokal EM, Jacqmin P, et al. Repeated-dose pharmacokinetics of an oral solution of itraconazole in infants and children. Antimicrob Agents Chemother. 1998;42(2):404–8.

    PubMed  PubMed Central  Google Scholar 

  35. Schmitt C, Perel Y, Harousseau JL, Lemerle S, Chwetzoff E, le Moing JP, et al. Pharmacokinetics of itraconazole oral solution in neutropenic children during long-term prophylaxis. Antimicrob Agents Chemother. 2001;45(5):1561–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Kim H, Shin D, Kang HJ, Yu KS, Lee JW, Kim SJ, et al. Successful empirical antifungal therapy of intravenous itraconazole with pharmacokinetic evidence in pediatric cancer patients undergoing hematopoietic stem cell transplantation. Clin Drug Investig. 2015;35(7):437–46.

    CAS  PubMed  Google Scholar 

  37. Leong YH, Boast A, Cranswick N, Curtis N, Gwee A. Itraconazole dosing and drug monitoring at a tertiary children’s hospital. Pediatr Infect Dis J. 2019;38(1):60–4.

    PubMed  Google Scholar 

  38. Zane NR, Thakker DR. A physiologically based pharmacokinetic model for voriconazole disposition predicts intestinal first-pass metabolism in children. Clin Pharmacokinet. 2014;53(12):1171–82.

    CAS  PubMed  Google Scholar 

  39. Walsh TJ, Driscoll T, Milligan PA, Wood ND, Schlamm H, Groll AH, et al. Pharmacokinetics, safety, and tolerability of voriconazole in immunocompromised children. Antimicrob Agents Chemother. 2010;54(10):4116–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Kobayashi R, Sano H, Kishimoto K, Suzuki D, Yasuda K, Kobayashi K. Voriconazole concentrations in cerebrospinal fluid during prophylactic use in children with acute myelogenous leukemia. Pediatr Infect Dis J. 2016;35(3):297–8.

    PubMed  Google Scholar 

  41. Sandherr M, Maschmeyer G. Pharmacology and metabolism of voriconazole and Posaconazole in the treatment of invasive aspergillosis: review of the literature. Eur J Med Res. 2011;16(4):139–44.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Yanni SB, Annaert PP, Augustijns P, Ibrahim JG, Benjamin DK Jr, Thakker DR. In vitro hepatic metabolism explains higher clearance of voriconazole in children versus adults: role of CYP2C19 and flavin-containing monooxygenase 3. Drug Metab Dispos. 2010;38(1):25–31.

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Xu G, Zhu L, Ge T, Liao S, Li N, Qi F. Pharmacokinetic/pharmacodynamic analysis of voriconazole against Candida spp. and Aspergillus spp. in children, adolescents and adults by Monte Carlo simulation. Int J Antimicrob Agents. 2016;47(6):439–45.

    CAS  PubMed  Google Scholar 

  44. Zembles TN, Thompson NE, Havens PL, Kaufman BA, Huppler AR. An optimized voriconazole dosing strategy to achieve therapeutic serum concentrations in children younger than 2 years old. Pharmacotherapy. 2016;36(10):1102–8.

    CAS  PubMed  Google Scholar 

  45. Karlsson MO, Lutsar I, Milligan PA. Population pharmacokinetic analysis of voriconazole plasma concentration data from pediatric studies. Antimicrob Agents Chemother. 2009;53(3):935–44.

    CAS  PubMed  Google Scholar 

  46. Teusink A, Vinks A, Zhang K, Davies S, Fukuda T, Lane A, et al. Genotype-directed dosing leads to optimized voriconazole levels in pediatric patients receiving hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2016;22(3):482–6.

    CAS  PubMed  Google Scholar 

  47. Hsu AJ, Dabb A, Arav-Boger R. Autoinduction of voriconazole metabolism in a child with invasive pulmonary aspergillosis. Pharmacotherapy. 2015;35(4):e20–6.

    CAS  PubMed  Google Scholar 

  48. Boast A, Curtis N, Cranswick N, Gwee A. Voriconazole dosing and therapeutic drug monitoring in children: experience from a paediatric tertiary care centre. J Antimicrob Chemother. 2016;71(7):2031–6.

    CAS  PubMed  Google Scholar 

  49. Allegra S, Fatiguso G, De Francia S, Favata F, Pirro E, Carcieri C, et al. Therapeutic drug monitoring of voriconazole for treatment and prophylaxis of invasive fungal infection in children. Br J Clin Pharmacol. 2018;84(1):197–203.

    CAS  PubMed  Google Scholar 

  50. Hu L, Dai TT, Zou L, Li TM, Ding XS, Yin T. Therapeutic drug monitoring of voriconazole in children from a tertiary care center in China. Antimicrob Agents Chemother. 2018;62(12):e00955–18.

  51. Moore JN, Healy JR, Kraft WK. Pharmacologic and clinical evaluation of posaconazole. Expert Rev Clin Pharmacol. 2015;8(3):321–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. •• Ullmann AJ, Aguado JM, Arikan-Akdagli S, Denning DW, Groll AH, Lagrou K, et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018;24(Suppl 1):e1–e38. Most recent guidelines by ESCMID-ECMM-ERS for the diagnosis and management ofAspergillusinfections.

    PubMed  Google Scholar 

  53. Vanstraelen K, Colita A, Bica AM, Mols R, Augustijns P, Peersman N, et al. Pharmacokinetics of posaconazole oral suspension in children dosed according to body surface area. Pediatr Infect Dis J. 2016;35(2):183–8.

    PubMed  Google Scholar 

  54. Krishna G, Sansone-Parsons A, Martinho M, Kantesaria B, Pedicone L. Posaconazole plasma concentrations in juvenile patients with invasive fungal infection. Antimicrob Agents Chemother. 2007;51(3):812–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Gubbins PO, Krishna G, Sansone-Parsons A, Penzak SR, Dong L, Martinho M, et al. Pharmacokinetics and safety of oral posaconazole in neutropenic stem cell transplant recipients. Antimicrob Agents Chemother. 2006;50(6):1993–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Krishna G, Moton A, Ma L, Medlock MM, McLeod J. Pharmacokinetics and absorption of posaconazole oral suspension under various gastric conditions in healthy volunteers. Antimicrob Agents Chemother. 2009;53(3):958–66.

    CAS  PubMed  Google Scholar 

  57. •• Arrieta AC, Sung L, Bradley JS, Zwaan CM, Gates D, Waskin H, et al. A non-randomized trial to assess the safety, tolerability, and pharmacokinetics of posaconazole oral suspension in immunocompromised children with neutropenia. PLoS One. 2019;14(3):e0212837. A prospective study of safety and pharmacokinetics of oral posaconazole suspension in children with neutropenia, stratified by different age and dosage groups.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. •• Boonsathorn S, Cheng I, Kloprogge F, Alonso C, Lee C, Doncheva B, et al. Clinical pharmacokinetics and dose recommendations for posaconazole in infants and children. Clin Pharmacokinet. 2019;58(1):53–61. This is the largest population pharmacokinetic study of oral posaconazole preparations in children, elucidating factors related with reduced bioavailability and suggesting age-specific dosages likely to achieve appropriate drug exposure.

    CAS  PubMed  Google Scholar 

  59. Doring M, Cabanillas Stanchi KM, Queudeville M, Feucht J, Blaeschke F, Schlegel P, et al. Efficacy, safety and feasibility of antifungal prophylaxis with posaconazole tablet in paediatric patients after haematopoietic stem cell transplantation. J Cancer Res Clin Oncol. 2017;143(7):1281–92.

    PubMed  Google Scholar 

  60. Jancel T, Shaw PA, Hallahan CW, Kim T, Freeman AF, Holland SM, et al. Therapeutic drug monitoring of posaconazole oral suspension in paediatric patients younger than 13 years of age: a retrospective analysis and literature review. J Clin Pharm Ther. 2017;42(1):75–9.

    CAS  PubMed  Google Scholar 

  61. Vicenzi EB, Cesaro S. Posaconazole in immunocompromised pediatric patients. Expert Rev Anti-Infect Ther. 2018;16(7):543–53.

    CAS  PubMed  Google Scholar 

  62. Doring M, Cabanillas Stanchi KM, Klinker H, Eikemeier M, Feucht J, Blaeschke F, et al. Posaconazole plasma concentrations in pediatric patients receiving antifungal prophylaxis during neutropenia. Med Mycol. 2017;55(4):375–84.

    PubMed  Google Scholar 

  63. Strommen A, Hurst AL, Curtis D, Abzug MJ. Use of intravenous posaconazole in hematopoietic stem cell transplant patients. J Pediatr Hematol Oncol. 2018;40(4):e203–e6.

    CAS  PubMed  Google Scholar 

  64. Rouzaud C, Jullien V, Herbrecht A, Palmier B, Lapusan S, Morgand M, et al. Isavuconazole diffusion in infected human brain. Antimicrob Agents Chemother. 2019:63(10):e02474–18.

  65. • Decembrino N, Perruccio K, Zecca M, Colombini A, Calore E, Muggeo P, et al. A case series and literature review of isavuconazole use in pediatric patients with hemato-oncologic diseases and hematopoietic stem cell transplantation. Antimicrob Agents Chemother. 2020;64(3):e01783–19. A recently published paper on the use of isavuconazole in pediatric hematology/oncology patients providing pharmacokinetic and safety data.

  66. Arrieta A, Frangoul H, Steinbach W, Muller W, Sue P, Yin D, et al. An open-label, phase I, multi-centre study to evaluate the pharmacokinetic, safety and tolerability profile of intravenous isavuconazonium sulfate in paediatric patients. Amsterdam: ECCMID; 2019.

    Google Scholar 

  67. Smith RP, Baltch A, Bopp LH, Ritz WJ, Michelsen PP. Post-antifungal effects and time-kill studies of anidulafungin, caspofungin, and micafungin against Candida glabrata and Candida parapsilosis. Diagn Microbiol Infect Dis. 2011;71(2):131–8.

    CAS  PubMed  Google Scholar 

  68. Odds FC, Motyl M, Andrade R, Bille J, Canton E, Cuenca-Estrella M, et al. Interlaboratory comparison of results of susceptibility testing with caspofungin against Candida and Aspergillus species. J Clin Microbiol. 2004;42(8):3475–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Andes D, Diekema DJ, Pfaller MA, Bohrmuller J, Marchillo K, Lepak A. In vivo comparison of the pharmacodynamic targets for echinocandin drugs against Candida species. Antimicrob Agents Chemother. 2010;54(6):2497–506.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Wiederhold NP, Kontoyiannis DP, Chi J, Prince RA, Tam VH, Lewis RE. Pharmacodynamics of caspofungin in a murine model of invasive pulmonary aspergillosis: evidence of concentration-dependent activity. J Infect Dis. 2004;190(8):1464–71.

    CAS  PubMed  Google Scholar 

  71. Kofla G, Ruhnke M. Pharmacology and metabolism of anidulafungin, caspofungin and micafungin in the treatment of invasive candidosis: review of the literature. Eur J Med Res. 2011;16(4):159–66.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Walsh TJ, Adamson PC, Seibel NL, Flynn PM, Neely MN, Schwartz C, et al. Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. Antimicrob Agents Chemother. 2005;49(11):4536–45.

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Neely M, Jafri HS, Seibel N, Knapp K, Adamson PC, Bradshaw SK, et al. Pharmacokinetics and safety of caspofungin in older infants and toddlers. Antimicrob Agents Chemother. 2009;53(4):1450–6.

    CAS  PubMed  Google Scholar 

  74. Li CC, Sun P, Dong Y, Bi S, Desai R, Dockendorf MF, et al. Population pharmacokinetics and pharmacodynamics of caspofungin in pediatric patients. Antimicrob Agents Chemother. 2011;55(5):2098–105.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Mori M, Imaizumi M, Ishiwada N, Kaneko T, Goto H, Kato K, et al. Pharmacokinetics, efficacy, and safety of caspofungin in Japanese pediatric patients with invasive candidiasis and invasive aspergillosis. J Infect Chemother. 2015;21(6):421–6.

    CAS  PubMed  Google Scholar 

  76. Yang XM, Leroux S, Storme T, Zhang DL, de Beaumais TA, Shi HY, et al. Body surface area-based dosing regimen of caspofungin in children: a population pharmacokinetics confirmatory study. Antimicrob Agents Chemother. 2019;63(7):e00248–19.

  77. Saez-Llorens X, Macias M, Maiya P, Pineros J, Jafri HS, Chatterjee A, et al. Pharmacokinetics and safety of caspofungin in neonates and infants less than 3 months of age. Antimicrob Agents Chemother. 2009;53(3):869–75.

    CAS  PubMed  Google Scholar 

  78. Seibel NL, Schwartz C, Arrieta A, Flynn P, Shad A, Albano E, et al. Safety, tolerability, and pharmacokinetics of Micafungin (FK463) in febrile neutropenic pediatric patients. Antimicrob Agents Chemother. 2005;49(8):3317–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Albano E, Azie N, Roy M, Townsend R, Arrieta A. Pharmacokinetic and safety profiles of repeated-dose prophylactic micafungin in children and adolescents undergoing hematopoietic stem cell transplantation. J Pediatr Hematol Oncol. 2015;37(1):e45–50.

    CAS  PubMed  Google Scholar 

  80. Hope WW, Seibel NL, Schwartz CL, Arrieta A, Flynn P, Shad A, et al. Population pharmacokinetics of micafungin in pediatric patients and implications for antifungal dosing. Antimicrob Agents Chemother. 2007;51(10):3714–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Hope WW, Kaibara A, Roy M, Arrieta A, Azie N, Kovanda LL, et al. Population pharmacokinetics of micafungin and its metabolites M1 and M5 in children and adolescents. Antimicrob Agents Chemother. 2015;59(2):905–13.

    PubMed  PubMed Central  Google Scholar 

  82. Hope WW, Mickiene D, Petraitis V, Petraitiene R, Kelaher AM, Hughes JE, et al. The pharmacokinetics and pharmacodynamics of micafungin in experimental hematogenous Candida meningoencephalitis: implications for echinocandin therapy in neonates. J Infect Dis. 2008;197(1):163–71.

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Hope WW, Smith PB, Arrieta A, Buell DN, Roy M, Kaibara A, et al. Population pharmacokinetics of micafungin in neonates and young infants. Antimicrob Agents Chemother. 2010;54(6):2633–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Benjamin DK Jr, Kaufman DA, Hope WW, Smith PB, Arrieta A, Manzoni P, et al. A phase 3 study of micafungin versus amphotericin B deoxycholate in infants with invasive candidiasis. Pediatr Infect Dis J. 2018;37(10):992–8.

    PubMed  PubMed Central  Google Scholar 

  85. Auriti C, Falcone M, Ronchetti MP, Goffredo BM, Cairoli S, Crisafulli R, et al. High-dose micafungin for preterm neonates and infants with invasive and central nervous system candidiasis. Antimicrob Agents Chemother. 2016;60(12):7333–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Autmizguine J, Hornik CP, Benjamin DK Jr, Brouwer KL, Hupp SR, Cohen-Wolkowiez M, et al. Pharmacokinetics and safety of micafungin in infants supported with extracorporeal membrane oxygenation. Pediatr Infect Dis J. 2016;35(11):1204–10.

    PubMed  PubMed Central  Google Scholar 

  87. Pfaller MA. Anidulafungin: an echinocandin antifungal. Expert Opin Investig Drugs. 2004;13(9):1183–97.

    CAS  PubMed  Google Scholar 

  88. Benjamin DK Jr, Driscoll T, Seibel NL, Gonzalez CE, Roden MM, Kilaru R, et al. Safety and pharmacokinetics of intravenous anidulafungin in children with neutropenia at high risk for invasive fungal infections. Antimicrob Agents Chemother. 2006;50(2):632–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Cohen-Wolkowiez M, Benjamin DK Jr, Piper L, Cheifetz IM, Moran C, Liu P, et al. Safety and pharmacokinetics of multiple-dose anidulafungin in infants and neonates. Clin Pharmacol Ther. 2011;89(5):702–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  90. Roilides E, Carlesse F, Tawadrous M, Leister-Tebbe H, Conte U, Raber S, et al. Safety, efficacy and pharmacokinetics of anidulafungin in patients 1 month to <2 years of age with invasive candidiasis, including candidemia. Pediatr Infect Dis J. 2020;39(4):305–9.

    PubMed  PubMed Central  Google Scholar 

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  1. 3rd Department of Pediatrics, Faculty of Medicine, Aristotle University School of Health Sciences, Hippokration General Hospital, Konstantinoupoleos 49, GR-546 42, Thessaloniki, Greece

    Charalampos Antachopoulos & Emmanuel Roilides

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Emmanuel Roilides has received research grants from Astellas, Gilead, Merck, Pfizer Inc., and Sanofi; he is a scientific advisor and member of speaker bureaus for Astellas, Gilead, Merck, GlaxoSmithKline, Pfizer Inc., and VIANEX.

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Antachopoulos, C., Roilides, E. Pharmacokinetics and Pharmacodynamics of Antifungal Agents in Neonates and Children. Curr Fungal Infect Rep 14, 317–328 (2020). https://doi.org/10.1007/s12281-020-00402-6

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  • DOI: https://doi.org/10.1007/s12281-020-00402-6

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