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Pharmacokinetics and Pharmacodynamics of Antifungals in Children: Clinical Implications

Drugs volume 74, pages 891–909 (2014)Cite this article

Abstract

Invasive fungal disease (IFD) remains life threatening in premature infants and immunocompromised children despite the recent development of new antifungal agents. Optimal dosing of antifungals is one of the few factors clinicians can control to improve outcomes of IFD. However, dosing in children cannot be extrapolated from adult data because IFD pathophysiology, immune response, and drug disposition differ from adults. We critically examined the literature on pharmacokinetics (PK) and pharmacodynamics (PD) of antifungal agents and highlight recent developments in treating pediatric IFD. To match adult exposure in pediatric patients, dosing adjustment is necessary for almost all antifungals. In young infants, the maturation of renal and metabolic functions occurs rapidly and can significantly influence drug exposure. Fluconazole clearance doubles from birth to 28 days of life and, beyond the neonatal period, agents such as fluconazole, voriconazole, and micafungin require higher dosing than in adults because of faster clearance in children. As a result, dosing recommendations are specific to bracketed ranges of age. PD principles of antifungals mostly rely on in vitro and in vivo models but very few PD studies specifically address IFD in children. The exposure-response relationship may differ in younger children compared with adults, especially in infants with invasive candidiasis who are at higher risk of disseminated disease and meningoencephalitis, and by extension severe neurodevelopmental impairment. Micafungin is the only antifungal agent for which a specific target of exposure was proposed based on a neonatal hematogenous Candida meningoencephalitis animal model. In this review, we found that pediatric data on drug disposition of newer triazoles and echinocandins are lacking, dosing of older antifungals such as fluconazole and amphotericin B products still need optimization in young infants, and that target PK/PD indices need to be clinically validated for almost all antifungals in children. A better understanding of age-specific PK and PD of new antifungals in infants and children will help improve clinical outcomes of IFD by informing dosing and identifying future research areas.

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References

  1. Kao AS, Brandt ME, Pruitt WR, et al. The epidemiology of candidemia in two United States cities: results of a population-based active surveillance. Clin Infect Dis. 1999;29(5):1164–70.

    CAS  PubMed  Google Scholar 

  2. Benjamin DK Jr, Stoll BJ, Gantz MG, et al. Neonatal candidiasis: epidemiology, risk factors, and clinical judgment. Pediatrics. 2010;126(4):e865–73.

    PubMed Central  PubMed  Google Scholar 

  3. Burgos A, Zaoutis TE, Dvorak CC, et al. Pediatric invasive aspergillosis: a multicenter retrospective analysis of 139 contemporary cases. Pediatrics. 2008;121(5):e1286–94.

    PubMed  Google Scholar 

  4. Benjamin DK Jr, Stoll BJ, Fanaroff AA, et al. Neonatal candidiasis among extremely low birth weight infants: risk factors, mortality rates, and neurodevelopmental outcomes at 18 to 22 months. Pediatrics. 2006;117(1):84–92.

    PubMed  Google Scholar 

  5. Fernandez M, Moylett EH, Noyola DE, Baker CJ. Candidal meningitis in neonates: a 10-year review. Clin Infect Dis. 2000;31(2):458–63.

    CAS  PubMed  Google Scholar 

  6. Friedman S, Richardson SE, Jacobs SE, O’Brien K. Systemic Candida infection in extremely low birth weight infants: short term morbidity and long term neurodevelopmental outcome. Pediatr Infect Dis J. 2000;19(6):499–504.

    CAS  PubMed  Google Scholar 

  7. Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;48(5):503–35.

    CAS  PubMed  Google Scholar 

  8. Brajtburg J, Powderly WG, Kobayashi GS, Medoff G. Amphotericin B: current understanding of mechanisms of action. Antimicrob Agents Chemother. 1990;34(2):183–8.

  9. Sokol-Anderson M, Sligh JE Jr, Elberg S, Brajtburg J, Kobayashi GS, Medoff G. Role of cell defense against oxidative damage in the resistance of Candida albicans to the killing effect of amphotericin B. Antimicrob Agents Chemother. 1988;32(5):702–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Klepser ME, Wolfe EJ, Jones RN, Nightingale CH, Pfaller MA. Antifungal pharmacodynamic characteristics of fluconazole and amphotericin B tested against Candida albicans. Antimicrob Agents Chemother. 1997;41(6):1392–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Pfaller MA, Messer SA, Hollis RJ. Strain delineation and antifungal susceptibilities of epidemiologically related and unrelated isolates of Candida lusitaniae. Diagn Microbiol Infect Dis. 1994;20(3):127–33.

    CAS  PubMed  Google Scholar 

  12. Sabatelli 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(6):2009–15.

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Sutton DA, Sanche SE, Revankar SG, Fothergill AW, Rinaldi MG. In vitro amphotericin B resistance in clinical isolates of Aspergillus terreus, with a head-to-head comparison to voriconazole. J Clin Microbiol. 1999;37(7):2343–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Walsh TJ, Melcher GP, Rinaldi MG, et al. Trichosporon beigelii, an emerging pathogen resistant to amphotericin B. J Clin Microbiol. 1990;28(7):1616–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Ernst EJ, Klepser ME, Pfaller MA. Postantifungal effects of echinocandin, azole, and polyene antifungal agents against Candida albicans and Cryptococcus neoformans. Antimicrob Agents Chemother. 2000;44(4):1108–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Andes D, Stamsted T, Conklin R. Pharmacodynamics of amphotericin B in a neutropenic-mouse disseminated-candidiasis model. Antimicrob Agents Chemother. 2001;45(3):922–6. doi:10.1128/aac.45.3.922-926.2001.

  17. Wiederhold NP, Tam VH, Chi J, Prince RA, Kontoyiannis DP, Lewis RE. Pharmacodynamic activity of amphotericin B deoxycholate is associated with peak plasma concentrations in a neutropenic murine model of invasive pulmonary aspergillosis. Antimicrob Agents Chemother. 2006;50(2):469–73. doi:10.1128/aac.50.2.469-473.2006.

  18. Lass-Florl C, Kofler G, Kropshofer G, et al. In-vitro testing of susceptibility to amphotericin B is a reliable predictor of clinical outcome in invasive aspergillosis. J Antimicrob Chemother. 1998;42(4):497–502.

    CAS  PubMed  Google Scholar 

  19. Park BJ, Arthington-Skaggs BA, Hajjeh RA, et al. Evaluation of amphotericin B interpretive breakpoints for Candida bloodstream isolates by correlation with therapeutic outcome. Antimicrob Agents Chemother. 2006;50(4):1287–92.

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Kravetz HM, Andriole VT, Huber MA, Utz JP. Oral administration of solubilized amphotericin B. N Engl J Med. 1961;27(265):183–4.

    Google Scholar 

  21. Christiansen KJ, Bernard EM, Gold JW, Armstrong D. Distribution and activity of amphotericin B in humans. J Infect Dis. 1985;152(5):1037–43.

    CAS  PubMed  Google Scholar 

  22. Luna B, Drew RH, Perfect JR. Agents for treatment of invasive fungal infections. Otolaryngol Clin North Am. 2000;33(2):277–99.

    CAS  PubMed  Google Scholar 

  23. 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 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Koren G, Lau A, Klein J, et al. Pharmacokinetics and adverse effects of amphotericin B in infants and children. J Pediatr. 1988;113(3):559–63.

    CAS  PubMed  Google Scholar 

  26. Nath CE, McLachlan AJ, Shaw PJ, Gunning R, Earl JW. Population pharmacokinetics of amphotericin B in children with malignant diseases. Br J Clin Pharmacol. 2001;52(6):671–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Starke JR, Mason EO Jr, Kramer WG, Kaplan SL. Pharmacokinetics of amphotericin B in infants and children. J Infect Dis. 1987;155(4):766–74.

    CAS  PubMed  Google Scholar 

  28. Wingard JR, Kubilis P, Lee L, et al. Clinical significance of nephrotoxicity in patients treated with amphotericin B for suspected or proven aspergillosis. Clin Infect Dis. 1999;29(6):1402–7.

    CAS  PubMed  Google Scholar 

  29. Holler B, Omar SA, Farid MD, Patterson MJ. Effects of fluid and electrolyte management on amphotericin B-induced nephrotoxicity among extremely low birth weight infants. Pediatrics. 2004;113(6):e608–16.

    PubMed  Google Scholar 

  30. Le J, Adler-Shohet FC, Nguyen C, Lieberman JM. Nephrotoxicity associated with amphotericin B deoxycholate in neonates. Pediatr Infect Dis J. 2009;28(12):1061–3.

    PubMed  Google Scholar 

  31. Linder N, Klinger G, Shalit I, et al. Treatment of candidaemia in premature infants: comparison of three amphotericin B preparations. J Antimicrob Chemother. 2003;52(4):663–7.

    CAS  PubMed  Google Scholar 

  32. Goodwin SD, Cleary JD, Walawander CA, Taylor JW, Grasela TH Jr. Pretreatment regimens for adverse events related to infusion of amphotericin B. Clin Infect Dis. 1995;20(4):755–61.

    CAS  PubMed  Google Scholar 

  33. Andes D, Safdar N, Marchillo K, Conklin R. Pharmacokinetic-pharmacodynamic comparison of amphotericin B (AMB) and two lipid-associated AMB preparations, liposomal AMB and AMB lipid complex, in murine candidiasis models. Antimicrob Agents Chemother. 2006;50(2):674–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Ralph ED, Khazindar AM, Barber KR, Grant CW. Comparative in vitro effects of liposomal amphotericin B, amphotericin B-deoxycholate, and free amphotericin B against fungal strains determined by using MIC and minimal lethal concentration susceptibility studies and time-kill curves. Antimicrob Agents Chemother. 1991;35(1):188–91.

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Subira M, Martino R, Gomez L, Marti JM, Estany C, Sierra J. Low-dose amphotericin B lipid complex vs. conventional amphotericin B for empirical antifungal therapy of neutropenic fever in patients with hematologic malignancies: a randomized, controlled trial. Eur J Haematol. 2004;72(5):342–7.

    CAS  PubMed  Google Scholar 

  36. Fleming RV, Kantarjian HM, Husni R, et al. Comparison of amphotericin B lipid complex (ABLC) vs. ambisome in the treatment of suspected or documented fungal infections in patients with leukemia. Leuk Lymphoma. 2001;40(5–6):511–20.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Walsh TJ, Whitcomb P, Piscitelli S, 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 Central  PubMed  Google Scholar 

  39. Adedoyin A, Bernardo JF, Swenson CE, Bolsack LE, Horwith G, DeWit S, et al. Pharmacokinetic profile of ABELCET (amphotericin B lipid complex injection): combined experience from phase I and phase II studies. Antimicrob Agents Chemother. 1997;41(10):2201–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  40. 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. doi:10.1128/aac.49.12.5092-5098.2005.

    PubMed Central  PubMed  Google Scholar 

  41. Groll AH MD, Petraitis V, Petraitiene R, Roussillion K, Hemmings M, Lyman LA, Walsh TJ, editor. Disposition and efficacy of amphotericin B formulations in a kidney target model of invasive candidiasis. In: 41st Interscience Conference on Antimicrobial Agents Chemotherapy; 2001; Chicago, IL.

  42. Groll AH, Giri N, Petraitis V, 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 

  43. Ascher SB, Smith PB, Watt K, et al. Antifungal therapy and outcomes in infants with invasive Candida infections. Pediatr Infect Dis J. 2012;31(5):439–43.

    PubMed Central  PubMed  Google Scholar 

  44. Bowden R, Chandrasekar P, White MH, et al. A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin B for treatment of invasive aspergillosis in immunocompromised patients. Clin Infect Dis. 2002;35(4):359–66.

    CAS  PubMed  Google Scholar 

  45. Cetin H, Yalaz M, Akisu M, Hilmioglu S, Metin D, Kultursay N. The efficacy of two different lipid-based amphotericin B in neonatal Candida septicemia. Pediatr Int. 2005;47(6):676–80.

    CAS  PubMed  Google Scholar 

  46. Juster-Reicher A, Flidel-Rimon O, Amitay M, Even-Tov S, Shinwell E, Leibovitz E. High-dose liposomal amphotericin B in the therapy of systemic candidiasis in neonates. Eur J Clin Microbiol Infect Dis. 2003;22(10):603–7.

    CAS  PubMed  Google Scholar 

  47. Juster-Reicher A, Leibovitz E, Linder N, et al. Liposomal amphotericin B (AmBisome) in the treatment of neonatal candidiasis in very low birth weight infants. Infection. 2000;28(4):223–6.

  48. Scarcella A, Pasquariello MB, Giugliano B, Vendemmia M, de Lucia A. Liposomal amphotericin B treatment for neonatal fungal infections. Pediatr Infect Dis J. 1998;17(2):146–8.

    CAS  PubMed  Google Scholar 

  49. Walsh TJ, Seibel NL, Arndt C, et al. Amphotericin B lipid complex in pediatric patients with invasive fungal infections. Pediatr Infect Dis J. 1999;18(8):702–8.

    CAS  PubMed  Google Scholar 

  50. Wiley JM, Seibel NL, Walsh TJ. Efficacy and safety of amphotericin B lipid complex in 548 children and adolescents with invasive fungal infections. Pediatr Infect Dis J. 2005;24(2):167–74.

    PubMed  Google Scholar 

  51. Pfizer. Diflucan [package insert]. New York, 2013.

  52. Carrillo AJ, Guarro J. In vitro activities of four novel triazoles against Scedosporium spp. Antimicrob Agents Chemother. 2001;45(7):2151–3.

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Lewis RE, Lund BC, Klepser ME, Ernst EJ, Pfaller MA. Assessment of antifungal activities of fluconazole and amphotericin B administered alone and in combination against Candida albicans by using a dynamic in vitro mycotic infection model. Antimicrob Agents Chemother. 1998;42(6):1382–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Louie A, Drusano GL, Banerjee P, et al. Pharmacodynamics of fluconazole in a murine model of systemic candidiasis. Antimicrob Agents Chemother. 1998;42(5):1105–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  55. 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 Central  PubMed  Google Scholar 

  56. Rex JH, Pfaller MA, Galgiani JN, et al. Development of interpretive breakpoints for antifungal susceptibility testing: conceptual framework and analysis of in vitro-in vivo correlation data for fluconazole, itraconazole, and Candida infections: Subcommittee on Antifungal Susceptibility Testing of the National Committee for Clinical Laboratory Standards. Clin Infect Dis. 1997;24(2):235–47.

    CAS  PubMed  Google Scholar 

  57. Baddley JW, Patel MS, Bhavnani SM, Moser SA, Andes DR. Association of fluconazole pharmacodynamics with mortality in patients with candidemia. 20080826 DCOM 20081023 (1098-6596 (Electronic)).

  58. Seay RE, Larson TA, Toscano JP, Bostrom BC, O’Leary MC, Uden DL. Pharmacokinetics of fluconazole in immune-compromised children with leukemia or other hematologic diseases. Pharmacotherapy. 1995;15(1):52–8.

  59. Brammer KW, Farrow PR, Faulkner JK. Pharmacokinetics and tissue penetration of fluconazole in humans. Rev Infect Dis. 1990;12 Suppl 3:S318–26.

  60. Tucker RM, Williams PL, Arathoon EG, et al. Pharmacokinetics of fluconazole in cerebrospinal fluid and serum in human coccidioidal meningitis. Antimicrob Agents Chemother. 1988;32(3):369–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Gross AS, McLachlan AJ, Minns I, Beal JB, Tett SE. Simultaneous administration of a cocktail of markers to measure renal drug elimination pathways: absence of a pharmacokinetic interaction between fluconazole and sinistrin, p-aminohippuric acid and pindolol. Br J Clin Pharmacol. 2001;51(6):547–55.

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Soczo G, Kardos G, McNicholas PM, et al. Correlation of posaconazole minimum fungicidal concentration and time kill test against nine Candida species. J Antimicrob Chemother. 2007;60(5):1004–9.

    CAS  PubMed  Google Scholar 

  63. Wade KC, Wu D, Kaufman DA, et al. Population pharmacokinetics of fluconazole in young infants. Antimicrob Agents Chemother. 2008;52(11):4043–9.

    CAS  PubMed Central  PubMed  Google Scholar 

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

    PubMed Central  PubMed  Google Scholar 

  65. Brammer KW, Coates PE. Pharmacokinetics of fluconazole in pediatric patients. Eur J Clin Microbiol Infect Dis. 1994;13(4):325–9.

    CAS  PubMed  Google Scholar 

  66. Osowski CL, Dix SP, Lin LS, Mullins RE, Geller RB, Wingard JR. Evaluation of the drug interaction between intravenous high-dose fluconazole and cyclosporine or tacrolimus in bone marrow transplant patients. Transplantation. 1996;61(8):1268–72.

    CAS  PubMed  Google Scholar 

  67. Novelli V, Holzel H. Safety and tolerability of fluconazole in children. Antimicrob Agents Chemother. 1999;43(8):1955–60.

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Driessen M, Ellis JB, Cooper PA, et al. Fluconazole vs. amphotericin B for the treatment of neonatal fungal septicemia: a prospective randomized trial. Pediatr Infect Dis J. 1996;15(12):1107–12.

    CAS  PubMed  Google Scholar 

  69. Manzoni P, Stolfi I, Pugni L, et al. A multicenter, randomized trial of prophylactic fluconazole in preterm neonates. N Engl J Med. 2007;356(24):2483–95.

    CAS  PubMed  Google Scholar 

  70. Fung-Tomc JC, White TC, Minassian B, Huczko E, Bonner DP. In vitro antifungal activity of BMS-207147 and itraconazole against yeast strains that are non-susceptible to fluconazole. Diagn Microbiol Infect Dis. 1999;35(2):163–7.

    CAS  PubMed  Google Scholar 

  71. Manavathu EK, Cutright JL, Chandrasekar PH. Organism-dependent fungicidal activities of azoles. Antimicrob Agents Chemother. 1998;42(11):3018–21.

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Burgess DS, Hastings RW, Summers KK, Hardin TC, Rinaldi MG. Pharmacodynamics of fluconazole, itraconazole, and amphotericin B against Candida albicans. Diagn Microbiol Infect Dis. 2000;36(1):13–8.

    CAS  PubMed  Google Scholar 

  73. Groll AH, Wood L, Roden M, et al. Safety, pharmacokinetics, and pharmacodynamics of cyclodextrin itraconazole in pediatric patients with oropharyngeal candidiasis. Antimicrob Agents Chemother. 2002;46(8):2554–63.

    CAS  PubMed Central  PubMed  Google Scholar 

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

    PubMed Central  PubMed  Google Scholar 

  75. Prentice AG, Warnock DW, Johnson SA, Taylor PC, Oliver DA. Multiple dose pharmacokinetics of an oral solution of itraconazole in patients receiving chemotherapy for acute myeloid leukaemia. J Antimicrob Chemother. 1995;36(4):657–63.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Hardin TC, Graybill JR, Fetchick R, Woestenborghs R, Rinaldi MG, Kuhn JG. Pharmacokinetics of itraconazole following oral administration to normal volunteers. Antimicrob Agents Chemother. 1988;32(9):1310–3.

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Foot AB, Veys PA, Gibson BE. Itraconazole oral solution as antifungal prophylaxis in children undergoing stem cell transplantation or intensive chemotherapy for haematological disorders. Bone Marrow Transplant. 1999;24(10):1089–93.

    CAS  PubMed  Google Scholar 

  79. Lestner JM, Roberts SA, Moore CB, Howard SJ, Denning DW, Hope WW. Toxicodynamics of itraconazole: implications for therapeutic drug monitoring. Clin Infect Dis. 2009;49(6):928–30.

    CAS  PubMed  Google Scholar 

  80. Bermudez M, Fuster JL, Llinares E, Galera A, Gonzalez C. Itraconazole-related increased vincristine neurotoxicity: case report and review of literature. J Pediatr Hematol Oncol. 2005;27(7):389–92.

    PubMed  Google Scholar 

  81. Pharmaceuticals J. SPORANOX (itraconazole) [package insert]. 2012.

  82. van Schie RM, Bruggemann RJ, Hoogerbrugge PM, te Loo DM. Effect of azole antifungal therapy on vincristine toxicity in childhood acute lymphoblastic leukaemia. J Antimicrob Chemother. 2011;66(8):1853–6. doi:10.1093/jac/dkr223.

  83. Abdel-Rahman SM, Jacobs RF, Massarella J, et al. Single-dose pharmacokinetics of intravenous itraconazole and hydroxypropyl-beta-cyclodextrin in infants, children, and adolescents. Antimicrob Agents Chemother. 2007;51(8):2668–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Espinel-Ingroff A, Johnson E, Hockey H, Troke P. Activities of voriconazole, itraconazole and amphotericin B in vitro against 590 moulds from 323 patients in the voriconazole phase III clinical studies. J Antimicrob Chemother. 2008;61(3):616–20.

    CAS  PubMed  Google Scholar 

  85. Johnson EM, Szekely A, Warnock DW. In-vitro activity of voriconazole, itraconazole and amphotericin B against filamentous fungi. J Antimicrob Chemother. 1998;42(6):741–5.

    CAS  PubMed  Google Scholar 

  86. Klepser ME, Malone D, Lewis RE, Ernst EJ, Pfaller MA. Evaluation of voriconazole pharmacodynamics using time-kill methodology. Antimicrob Agents Chemother. 2000;44(7):1917–20.

    CAS  PubMed Central  PubMed  Google Scholar 

  87. 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.

  88. Neely M, Rushing T, Kovacs A, Jelliffe R, Hoffman J. Voriconazole pharmacokinetics and pharmacodynamics in children. Clin Infect Dis. 2010;50(1):27–36.

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Troke PF, Hockey HP, Hope WW. Observational study of the clinical efficacy of voriconazole and its relationship to plasma concentrations in patients. Antimicrob Agents Chemother. 2011;55(10):4782–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Lutsar I, Roffey S, Troke P. Voriconazole concentrations in the cerebrospinal fluid and brain tissue of guinea pigs and immunocompromised patients. Clin Infect Dis. 2003;37(5):728–32.

    PubMed  Google Scholar 

  91. Weiler S, Fiegl D, MacFarland R, et al. Human tissue distribution of voriconazole. Antimicrob Agents Chemother. 2011;55(2):925–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  92. 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 Central  PubMed  Google Scholar 

  93. Narita A, Muramatsu H, Sakaguchi H, et al. Correlation of CYP2C19 phenotype with voriconazole plasma concentration in children. J Pediatr Hematol Oncol. 2013;35(5):e219–23.

    CAS  PubMed  Google Scholar 

  94. Walsh TJ, Karlsson MO, Driscoll T, et al. Pharmacokinetics and safety of intravenous voriconazole in children after single- or multiple-dose administration. Antimicrob Agents Chemother. 2004;48(6):2166–72.

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Friberg LE, Ravva P, Karlsson MO, Liu P. Integrated population pharmacokinetic analysis of voriconazole in children, adolescents, and adults. Antimicrob Agents Chemother. 2012;56(6):3032–42.

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Walsh 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(3):240–8.

    PubMed  Google Scholar 

  98. Bernhard S, Kernland Lang K, Ammann RA, et al. Voriconazole-induced phototoxicity in children. Pediatr Infect Dis J. 2012;31(7):769–71.

  99. Suzuki Y, Tokimatsu I, Sato Y, et al. Association of sustained high plasma trough concentration of voriconazole with the incidence of hepatotoxicity. Clin Chim Acta. 2013;6(424C):119–22.

    Google Scholar 

  100. Pascual A, Calandra T, Bolay S, Buclin T, Bille J, Marchetti O. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis. 2008;46(2):201–11.

    CAS  PubMed  Google Scholar 

  101. Pieper S, Kolve H, Gumbinger HG, Goletz G, Wurthwein G, Groll AH. Monitoring of voriconazole plasma concentrations in immunocompromised paediatric patients. J Antimicrob Chemother. 2012;67(11):2717–24.

    CAS  PubMed  Google Scholar 

  102. EMA. Vfend: EPAR, product information. 2013.

  103. Roerig. VFEND (voriconazole) [package insert]. 2013.

  104. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347(6):408–15.

    CAS  PubMed  Google Scholar 

  105. Park WB, Kim NH, Kim KH, et al. The effect of therapeutic drug monitoring on safety and efficacy of voriconazole in invasive fungal infections: a randomized controlled trial. Clin Infect Dis. 2012;55(8):1080–7.

    CAS  PubMed  Google Scholar 

  106. Espinel-Ingroff A. Comparison of in vitro activities of the new triazole SCH56592 and the echinocandins MK-0991 (L-743,872) and LY303366 against opportunistic filamentous and dimorphic fungi and yeasts. J Clin Microbiol. 1998;36(10):2950–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Petraitiene R, Petraitis V, Groll AH, et al. Antifungal activity and pharmacokinetics of posaconazole (SCH 56592) in treatment and prevention of experimental invasive pulmonary aspergillosis: correlation with galactomannan antigenemia. Antimicrob Agents Chemother. 2001;45(3):857–69.

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Courtney R, Pai S, Laughlin M, Lim J, Batra V. Pharmacokinetics, safety, and tolerability of oral posaconazole administered in single and multiple doses in healthy adults. Antimicrob Agents Chemother. 2003;47(9):2788–95.

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Courtney R, Sansone A, Smith W, et al. Posaconazole pharmacokinetics, safety, and tolerability in subjects with varying degrees of chronic renal disease. J Clin Pharmacol. 2005;45(2):185–92.

    CAS  PubMed  Google Scholar 

  110. Doring M, Muller C, Johann PD, et al. Analysis of posaconazole as oral antifungal prophylaxis in pediatric patients under 12 years of age following allogeneic stem cell transplantation. BMC Infect Dis. 2012;12:263.

    PubMed Central  PubMed  Google Scholar 

  111. 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 Central  PubMed  Google Scholar 

  112. Segal BH, Barnhart LA, Anderson VL, Walsh TJ, Malech HL, Holland SM. Posaconazole as salvage therapy in patients with chronic granulomatous disease and invasive filamentous fungal infection. Clin Infect Dis. 2005;40(11):1684–8.

    CAS  PubMed  Google Scholar 

  113. Welzen ME, Bruggemann RJ, Van Den Berg JM, et al. A twice daily posaconazole dosing algorithm for children with chronic granulomatous disease. Pediatr Infect Dis J. 2011;30(9):794–7.

    PubMed  Google Scholar 

  114. Jang SH, Colangelo PM, Gobburu JV. Exposure-response of posaconazole used for prophylaxis against invasive fungal infections: evaluating the need to adjust doses based on drug concentrations in plasma. Clin Pharmacol Ther. 2010;88(1):115–9.

    CAS  PubMed  Google Scholar 

  115. Ullmann AJ, Lipton JH, Vesole DH, et al. Posaconazole or fluconazole for prophylaxis in severe graft-versus-host disease. N Engl J Med. 2007;356(4):335–47.

    CAS  PubMed  Google Scholar 

  116. EMA. Noxafil: EPAR, product information. 2012.

  117. Merck. NOXAFIL (posaconazole) [package insert]. 2012.

  118. Andes D, Marchillo K, Stamstad T, Conklin R. In vivo pharmacodynamics of a new triazole, ravuconazole, in a murine candidiasis model. Antimicrob Agents Chemother. 2003;47(4):1193–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Roberts J, Schock K, Marino S, Andriole VT. Efficacies of two new antifungal agents, the triazole ravuconazole and the echinocandin LY-303366, in an experimental model of invasive aspergillosis. Antimicrob Agents Chemother. 2000;44(12):3381–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Ramos G, Cuenca-Estrella M, Monzon A, Rodriguez-Tudela JL. In-vitro comparative activity of UR-9825, itraconazole and fluconazole against clinical isolates of Candida spp. J Antimicrob Chemother. 1999;44(2):283–6.

    CAS  PubMed  Google Scholar 

  121. Miller JL, Schell WA, Wills EA, et al. In vitro and in vivo efficacies of the new triazole albaconazole against Cryptococcus neoformans. Antimicrob Agents Chemother. 2004;48(2):384–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Capilla J, Ortoneda M, Pastor FJ, Guarro J. In vitro antifungal activities of the new triazole UR-9825 against clinically important filamentous fungi. Antimicrob Agents Chemother. 2001;45(9):2635–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Cuenca-Estrella M, Gomez-Lopez A, Mellado E, Garcia-Effron G, Monzon A, Rodriguez-Tudela JL. In vitro activity of ravuconazole against 923 clinical isolates of nondermatophyte filamentous fungi. Antimicrob Agents Chemother. 2005;49(12):5136–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Lepak AJ, Marchillo K, Vanhecker J, Diekema D, Andes DR. Isavuconazole pharmacodynamic target determination for Candida species in an in vivo murine disseminated candidiasis model. Antimicrob Agents Chemother. 2013.

  125. Gupta AK, Leonardi C, Stoltz RR, Pierce PF, Conetta B. A phase I/II randomized, double-blind, placebo-controlled, dose-ranging study evaluating the efficacy, safety and pharmacokinetics of ravuconazole in the treatment of onychomycosis. J Eur Acad Dermatol Venereol. 2005;19(4):437–43.

    CAS  PubMed  Google Scholar 

  126. Schmitt-Hoffmann A, Roos B, Heep M, et al. Single-ascending-dose pharmacokinetics and safety of the novel broad-spectrum antifungal triazole BAL4815 after intravenous infusions (50, 100, and 200 milligrams) and oral administrations (100, 200, and 400 milligrams) of its prodrug, BAL8557, in healthy volunteers. Antimicrob Agents Chemother. 2006;50(1):279–85.

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Benjamin DK Jr, Smith PB, Arrieta A, et al. Safety and pharmacokinetics of repeat-dose micafungin in young infants. Clin Pharmacol Ther. 2010;87(1):93–9. doi:10.1038/clpt.2009.200.

    PubMed Central  PubMed  Google Scholar 

  128. van Rossem K, Lowe JA. A phase 1, randomized, open-label crossover study to evaluate the safety and pharmacokinetics of 400 mg albaconazole administered to healthy participants as a tablet formulation versus a capsule formulation. Clin Pharmacol. 2013;5:23–31.

    PubMed Central  PubMed  Google Scholar 

  129. Hatano K, Morishita Y, Nakai T, Ikeda F. Antifungal mechanism of FK463 against Candida albicans and Aspergillus fumigatus. J Antibiot (Tokyo). 2002;55(2):219–22.

    CAS  Google Scholar 

  130. Tawara S, Ikeda F, Maki K, et al. In vitro activities of a new lipopeptide antifungal agent, FK463, against a variety of clinically important fungi. Antimicrob Agents Chemother. 2000;44(1):57–62.

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Ikeda F, Wakai Y, Matsumoto S, et al. Efficacy of FK463, a new lipopeptide antifungal agent, in mouse models of disseminated candidiasis and aspergillosis. Antimicrob Agents Chemother. 2000;44(3):614–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Petraitis V, Petraitiene R, Groll AH, et al. Comparative antifungal activities and plasma pharmacokinetics of micafungin (FK463) against disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits. Antimicrob Agents Chemother. 2002;46(6):1857–69.

  133. Andes D, Ambrose PG, Hammel JP, Van Wart SA, Iyer V, Reynolds DK, et al. Use of pharmacokinetic-pharmacodynamic analyses to optimize therapy with the systemic antifungal micafungin for invasive candidiasis or candidemia. Antimicrob Agents Chemother. 2011;55(5):2113-21. doi:10.1128/aac.01430-10.

  134. Hope WW, Mickiene D, Petraitis V, 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 Central  PubMed  Google Scholar 

  135. Okugawa S, Ota Y, Tatsuno K, Tsukada K, Kishino S, Koike K. A case of invasive central nervous system aspergillosis treated with micafungin with monitoring of micafungin concentrations in the cerebrospinal fluid. Scand J Infect Dis. 2007;39(4):344–6.

    CAS  PubMed  Google Scholar 

  136. Astellas. Mycamine (micafungin) [package insert]. 2011. Accessed 2011. http://www.astellas.us/docs/mycamine.pdf.

  137. Astellas Pharma I. Mycamine [package insert]. Tokyo, Japan. 2013.

  138. Tabata K, Katashima M, Kawamura A, Tanigawara Y, Sunagawa K. Linear pharmacokinetics of micafungin and its active metabolites in Japanese pediatric patients with fungal infections. Biol Pharm Bull. 2006;29(8):1706–11.

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Seibel NL, Schwartz C, Arrieta A, et al. Safety, tolerability, and pharmacokinetics of micafungin (FK463) in febrile neutropenic pediatric patients. Antimicrob Agents Chemother. 2005;49(8):3317–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  141. 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. 54(6):2633–7. doi:10.1128/aac.01679-09.

  142. Smith PB, Walsh TJ, Hope W, et al. Pharmacokinetics of an elevated dosage of micafungin in premature neonates. Pediatr Infect Dis J. 2009;28(5):412–5.

    PubMed Central  PubMed  Google Scholar 

  143. Heresi GP, Gerstmann DR, Reed MD, van den Anker JN, Blumer JL, Kovanda L, et al. The pharmacokinetics and safety of micafungin, a novel echinocandin, in premature infants. Pediatr Infect Dis J. 2006;25(12):1110-5. doi:10.1097/01.inf.0000245103.07614.e1.

  144. Arrieta AC, Maddison P, Groll AH. Safety of micafungin in pediatric clinical trials. Pediatr Infect Dis J. 2011;30(6):e97–102.

    PubMed  Google Scholar 

  145. 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(9):820–6.

    PubMed  Google Scholar 

  146. EMA. Mycamine: EPAR, product information. 2013.

  147. Ernst EJ, Klepser ME, Ernst ME, Messer SA, Pfaller MA. In vitro pharmacodynamic properties of MK-0991 determined by time-kill methods. Diagn Microbiol Infect Dis. 1999;33(2):75–80.

    CAS  PubMed  Google Scholar 

  148. Bowman JC, Hicks PS, Kurtz MB, et al. The antifungal echinocandin caspofungin acetate kills growing cells of Aspergillus fumigatus in vitro. Antimicrob Agents Chemother. 2002;46(9):3001–12.

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  150. 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. doi:10.1128/aac.01027-08.

    CAS  PubMed Central  PubMed  Google Scholar 

  151. 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. doi:10.1128/aac.49.11.4536-4545.2005.

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Balani SK, Xu X, Arison BH, et al. Metabolites of caspofungin acetate, a potent antifungal agent, in human plasma and urine. Drug Metab Dispos. 2000;28(11):1274–8.

    CAS  PubMed  Google Scholar 

  153. Sobel JD, Bradshaw SK, Lipka CJ, Kartsonis NA. Caspofungin in the treatment of symptomatic candiduria. Clin Infect Dis. 2007;44(5):e46–9.

    CAS  PubMed  Google Scholar 

  154. Saez-Llorens X, Macias M, Maiya P, 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 Central  PubMed  Google Scholar 

  155. Cornely OA, Vehreschild JJ, Vehreschild MJ, et al. Phase II dose escalation study of caspofungin for invasive aspergillosis. Antimicrob Agents Chemother. 2011;55(12):5798–803.

    CAS  PubMed Central  PubMed  Google Scholar 

  156. 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(3):877–84.

    PubMed  Google Scholar 

  157. Franklin JA, McCormick J, Flynn PM. Retrospective study of the safety of caspofungin in immunocompromised pediatric patients. Pediatr Infect Dis J. 2003;22(8):747–9.

    PubMed  Google Scholar 

  158. Natarajan G, Lulic-Botica M, Rongkavilit C, Pappas A, Bedard M. Experience with caspofungin in the treatment of persistent fungemia in neonates. J Perinatol. 2005;25(12):770–7.

    CAS  PubMed  Google Scholar 

  159. Odio CM, Araya R, Pinto LE, et al. Caspofungin therapy of neonates with invasive candidiasis. Pediatr Infect Dis J. 2004;23(12):1093–7.

    PubMed  Google Scholar 

  160. Zhanel GG, Karlowsky JA, Harding GA, et al. In vitro activity of a new semisynthetic echinocandin, LY-303366, against systemic isolates of Candida species, Cryptococcus neoformans, Blastomyces dermatitidis, and Aspergillus species. Antimicrob Agents Chemother. 1997;41(4):863–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  161. Petraitiene R, Petraitis V, Groll AH, et al. Antifungal activity of LY303366, a novel echinocandin B, in experimental disseminated candidiasis in rabbits. Antimicrob Agents Chemother. 1999;43(9):2148–55.

    CAS  PubMed Central  PubMed  Google Scholar 

  162. Pfaller MA, Boyken L, Hollis RJ, Messer SA, Tendolkar S, Diekema DJ. In vitro activities of anidulafungin against more than 2,500 clinical isolates of Candida spp., including 315 isolates resistant to fluconazole. J Clin Microbiol. 2005;43(11):5425–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  163. Andes D, Diekema DJ, Pfaller MA, et al. In vivo pharmacodynamic characterization of anidulafungin in a neutropenic murine candidiasis model. Antimicrob Agents Chemother. 2008;52(2):539–50.

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Damle B, Stogniew M, Dowell J. Pharmacokinetics and tissue distribution of anidulafungin in rats. Antimicrob Agents Chemother. 2008;52(7):2673–6.

  165. 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(2):632–8.

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  167. EMA. ECALTA (anidulafungin): EPAR, product information. 2013.

  168. Roerig. ERAXIS (anidulafungin) [package insert]. 2012.

  169. Warn PA, Sharp A, Morrissey G, Denning DW. Activity of aminocandin (IP960; HMR3270) compared with amphotericin B, itraconazole, caspofungin and micafungin in neutropenic murine models of disseminated infection caused by itraconazole-susceptible and -resistant strains of Aspergillus fumigatus. Int J Antimicrob Agents. 2010;35(2):146–51.

    CAS  PubMed  Google Scholar 

  170. Andes D, Marchillo K, Lowther J, Bryskier A, Stamstad T, Conklin R. In vivo pharmacodynamics of HMR 3270, a glucan synthase inhibitor, in a murine candidiasis model. Antimicrob Agents Chemother. 2003;47(4):1187–92.

    CAS  PubMed Central  PubMed  Google Scholar 

  171. Najvar LK, Bocanegra R, Wiederhold NP, et al. Therapeutic and prophylactic efficacy of aminocandin (IP960) against disseminated candidiasis in mice. Clin Microbiol Infect. 2008;14(6):595–600.

    CAS  PubMed  Google Scholar 

  172. Sandage B, Cooper G, Najarian N, Lowther J, editor. Pharmacokinetics and fungicidal activity of aminocandin (HMR3270), a novel echinocandin in healthy volunteers. In: 15th European Congress of Clinical Microbiology and Infectious Diseases; 2005 April 2–5, 2005; Copenhagen, Denmark.

  173. Morikawa H, Tomishima M, Kayakiri N, et al. Synthesis and antifungal activity of ASP9726, a novel echinocandin with potent Aspergillus hyphal growth inhibition. Bioorg Med Chem Lett. 2014;24(4):1172–5.

    CAS  PubMed  Google Scholar 

  174. Polak A, Scholer HJ. Mode of action of 5-fluorocytosine and mechanisms of resistance. Chemotherapy. 1975;21(3–4):113–30.

    CAS  PubMed  Google Scholar 

  175. Pfaller MA, Messer SA, Coffman S. In vitro susceptibilities of clinical yeast isolates to a new echinocandin derivative, LY303366, and other antifungal agents. Antimicrob Agents Chemother. 1997;41(4):763–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  176. Johnson E, Espinel-Ingroff A, Szekely A, Hockey H, Troke P. Activity of voriconazole, itraconazole, fluconazole and amphotericin B in vitro against 1763 yeasts from 472 patients in the voriconazole phase III clinical studies. Int J Antimicrob Agents. 2008;32(6):511–4.

    CAS  PubMed  Google Scholar 

  177. Lewis RE, Klepser ME, Pfaller MA. In vitro pharmacodynamic characteristics of flucytosine determined by time-kill methods. Diagn Microbiol Infect Dis. 2000;36(2):101–5.

    CAS  PubMed  Google Scholar 

  178. Anaissie EJ, Karyotakis NC, Hachem R, Dignani MC, Rex JH, Paetznick V. Correlation between in vitro and in vivo activity of antifungal agents against Candida species. J Infect Dis. 1994;170(2):384–9.

    CAS  PubMed  Google Scholar 

  179. Scalarone GM, Mikami Y, Kurita N, Yazawa K, Miyaji M. The postantifungal effect of 5-fluorocytosine on Candida albicans. J Antimicrob Chemother. 1992;29(2):129–36.

    CAS  PubMed  Google Scholar 

  180. van der Horst CM, Saag MS, Cloud GA, et al. Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome: National Institute of Allergy and Infectious Diseases Mycoses Study Group and AIDS Clinical Trials Group. N Engl J Med. 1997;337(1):15–21.

    PubMed  Google Scholar 

  181. Brouwer AE, van Kan HJ, Johnson E, et al. Oral versus intravenous flucytosine in patients with human immunodeficiency virus-associated cryptococcal meningitis. Antimicrob Agents Chemother. 2007;51(3):1038–42.

    CAS  PubMed Central  PubMed  Google Scholar 

  182. Schonebeck J, Polak A, Fernex M, Scholer HJ. Pharmacokinetic studies on the oral antimycotic agent 5-fluorocytosine in individuals with normal and impaired kidney function. Chemotherapy. 1973;18(6):321–36.

    CAS  PubMed  Google Scholar 

  183. Soltani M, Tobin CM, Bowker KE, Sunderland J, MacGowan AP, Lovering AM. Evidence of excessive concentrations of 5-flucytosine in children aged below 12 years: a 12-year review of serum concentrations from a UK clinical assay reference laboratory. Int J Antimicrob Agents. 2006;28(6):574–7.

    CAS  PubMed  Google Scholar 

  184. Francis P, Walsh TJ. Evolving role of flucytosine in immunocompromised patients: new insights into safety, pharmacokinetics, and antifungal therapy. Clin Infect Dis. 1992;15(6):1003–18.

    CAS  PubMed  Google Scholar 

  185. Stamm AM, Diasio RB, Dismukes WE, et al. Toxicity of amphotericin B plus flucytosine in 194 patients with cryptococcal meningitis. Am J Med. 1987;83(2):236–42.

    CAS  PubMed  Google Scholar 

  186. Andes D, Pascual A, Marchetti O. Antifungal therapeutic drug monitoring: established and emerging indications. Antimicrob Agents Chemother. 2009;53(1):24–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  187. Mitsuyama J, Nomura N, Hashimoto K, et al. In vitro and in vivo antifungal activities of T-2307, a novel arylamidine. Antimicrob Agents Chemother. 2008;52(4):1318–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  188. Matsumoto YKK, Kato S, Iwami M, editor. A novel antifungal agent discovered from Streptomyces sp. in sea sand. ICAAC; 2013 September 10–13, 2013, Denver, Colorado.

  189. Atkinson AJ Jr, Bennett JE. Amphotericin B pharmacokinetics in humans. Antimicrob Agents Chemother. 1978;13(2):271–6.

    PubMed Central  PubMed  Google Scholar 

  190. Pharmaceuticals X-G. Amphotericin b [package insert]. 2009.

  191. Mehta P, Vinks A, Filipovich A, et al. High-dose weekly AmBisome antifungal prophylaxis in pediatric patients undergoing hematopoietic stem cell transplantation: a pharmacokinetic study. Biol Blood Marrow Transplant. 2006;12(2):235–40.

    CAS  PubMed  Google Scholar 

  192. Walsh TJ, Goodman JL, Pappas P, et al. Safety, tolerance, and pharmacokinetics of high-dose liposomal amphotericin B (AmBisome) in patients infected with Aspergillus species and other filamentous fungi: maximum tolerated dose study. Antimicrob Agents Chemother. 2001;45(12):3487–96.

    CAS  PubMed Central  PubMed  Google Scholar 

  193. Koks CH, Meenhorst PL, Hillebrand MJ, Bult A, Beijnen JH. Pharmacokinetics of fluconazole in saliva and plasma after administration of an oral suspension and capsules. Antimicrob Agents Chemother. 1996;40(8):1935–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  194. Driscoll TA, Frangoul H, Nemecek ER, et al. Comparison of pharmacokinetics and safety of voriconazole intravenous-to-oral switch in immunocompromised adolescents and healthy adults. Antimicrob Agents Chemother. 2011;55(12):5780–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  195. Driscoll TA, Yu LC, Frangoul H, et al. Comparison of pharmacokinetics and safety of voriconazole intravenous-to-oral switch in immunocompromised children and healthy adults. Antimicrob Agents Chemother. 2011;55(12):5770–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  196. Michael C, Bierbach U, Frenzel K, et al. Voriconazole pharmacokinetics and safety in immunocompromised children compared to adult patients. Antimicrob Agents Chemother. 2010;54(8):3225–32.

    CAS  PubMed Central  PubMed  Google Scholar 

  197. Stone JA, Holland SD, Wickersham PJ, et al. Single- and multiple-dose pharmacokinetics of caspofungin in healthy men. Antimicrob Agents Chemother. 2002;46(3):739–45.

    CAS  PubMed Central  PubMed  Google Scholar 

  198. Dowell JA, Knebel W, Ludden T, Stogniew M, Krause D, Henkel T. Population pharmacokinetic analysis of anidulafungin, an echinocandin antifungal. J Clin Pharmacol. 2004;44(6):590–8. doi:10.1177/0091270004265644.

  199. Weitkamp JH, Poets CF, Sievers R, et al. Candida infection in very low birth-weight infants: outcome and nephrotoxicity of treatment with liposomal amphotericin B (AmBisome). Infection. 1998;26(1):11–5.

  200. Benjamin DK Jr, Deville JG, Azie N, et al. Safety and pharmacokinetic profiles of repeated-dose micafungin in children and adolescents treated for invasive candidiasis. Pediatr Infect Dis J. 2013;32(11):e419–25.

    PubMed  Google Scholar 

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Acknowledgments

Julie Autmizguine receives support from the Training Award, Fonds Irma-Levasseur, Pediatric Department, Sainte-Justine University Hospital Center, Montreal, QC, Canada.

Jeffrey T. Guptill receives support from the American Academy of Neurology Foundation, Myasthenia Gravis Foundation of America (Clinician-Scientist Development Award) and from industry for drug development consulting (http://www.dcri.duke.edu/research/coi.jsp).

Michael Cohen-Wolkowiez receives support for research from the National Institutes of Health (NIH) (1K23HD064814), the National Center for Advancing Translational Sciences of the NIH (UL1TR001117), the Food and Drug Administration (1U01FD004858-01), the Biomedical Advanced Research and Development Authority (BARDA) (HHSO100201300009C), the nonprofit organization Thrasher Research Fund (http://www.thrasherresearch.org), and from industry for drug development in adults and children (http://www.dcri.duke.edu/research/coi.jsp).

Daniel K. Benjamin Jr. receives support from the US Government for his work in pediatric and neonatal clinical pharmacology (1R01HD057956-05, 1K24HD058735-05, UL1TR001117, and NICHD contract HHSN275201000003I) and the nonprofit organization Thrasher Research Fund for his work in neonatal candidiasis (http://www.thrasherresearch.org); he also receives research support from industry for neonatal and pediatric drug development (http://www.dcri.duke.edu/research/coi.jsp).

Edmund V. Capparelli receives research support from the US Government (U54 HD071600-01) and consulting fees from Trius, Cerexa Pharmaceuticals, Abbott, Cempra, and Theravance.

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Affiliations

  1. Duke Clinical Research Institute, 2400 Pratt St, PO Box 17969, Durham, NC, 27705, USA

    Julie Autmizguine, Jeffrey T. Guptill, Michael Cohen-Wolkowiez & Daniel K. Benjamin Jr

  2. Department of Pediatric Pharmacology, University of California, 9500 Gilman Drive, La Jolla, CA, 92093-0831, USA

    Edmund V. Capparelli

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  1. Julie Autmizguine
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Autmizguine, J., Guptill, J.T., Cohen-Wolkowiez, M. et al. Pharmacokinetics and Pharmacodynamics of Antifungals in Children: Clinical Implications. Drugs 74, 891–909 (2014). https://doi.org/10.1007/s40265-014-0227-3

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Keywords

  • Minimum Inhibitory Concentration
  • Fluconazole
  • Itraconazole
  • Voriconazole
  • Invasive Aspergillosis