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Antifungal Dosing Strategies for Critically Ill Patients

  • Pharmacology and Pharmacodynamics of Antifungal Agents (N Beyda, Section Editor)
  • Published:
Current Fungal Infection Reports Aims and scope Submit manuscript

Abstract

Purpose of review

This article provides updates on antifungals, dosing strategies for safe and effective therapy in the critically ill, including special populations, and the understanding of resistance over the last 5 years.

Recent findings

Reports of adverse effects with echinocandins have risen while antifungal resistance to this class has increased, especially in Candida glabrata. New formulations of posaconazole and isuvaconazole have been developed. Alternative dosing strategies including combination therapy are being evaluated for difficult to treat fungal infections. Other highlights include additional data on dosing patients with severe organ dysfunction, including those on continuous renal replacement therapy, and new breakpoints for individual Candida species being established for the echinocandins and triazole classes.

Summary

Increasing resistance in Candida spp. has made susceptibility testing a standard of care for critically ill patients. New formulations of the triazole antifungals have made prevention and treatment of mold infections more of a reality. There are many implications that must be considered when treating critically ill patients due to alterations in pharmacokinetics and pharmacodynamics in order to ensure adequate treatment. This article exposes the need for further clinical research in treating invasive infections in this patient population.

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References

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

  1. Ruping MJ, Vehreschild JJ, Cornely OA. Patients at high risk of invasive fungal infections: when and how to treat. Drugs. 2008;68:1941–62.

    Article  PubMed  Google Scholar 

  2. Calandra T, Roberts JA, Antonelli M, Bassetti M, Vincent JL. Diagnosis and management of invasive candidiasis in the ICU: an updated approach to an old enemy. Crit Care. 2016;20:125. doi:10.1186/s13054-016-1313-6.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Varghese JM, Roberts JA, Lipman J. Antimicrobial pharmacokinetic and pharmacodynamic issues in the critically ill with severe sepsis and septic shock. Crit Care Clin. 2011;27:19–34.

    Article  CAS  PubMed  Google Scholar 

  4. Chen SC, Slavin MA, Sorrell TC. Echinocandin antifungal drugs in fungal infections: a comparison. Drugs. 2011;71:11–41.

    Article  PubMed  Google Scholar 

  5. Fothergill AW, Sutton DA, McCarthy DI, Wiederhold NP. Impact of new antifungal breakpoints on antifungal resistance in Candida species. J Clin Microbiol. 2014;52:994–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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;54:2497–506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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;190:1464–71.

    Article  CAS  PubMed  Google Scholar 

  8. •• Pappas PG, Kauffman CA, Andes DR, Clancy CJ, Marr KA, Ostrosky-Zeichner L, et al. Executive summary: clinical practice guideline for the management of candidiasis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;62:409–17. This is the latest version of practice guidelines for treatment of candidiasis issued by the Infectious Diseases Society of America.

  9. Martial LC, Bruggemann RJ, Schouten JA, van Leeuwen HJ, van Zanten AR, de Lange DW, et al. Dose reduction of caspofungin in intensive care unit patients with child Pugh B will result in suboptimal exposure. Clin Pharmacokinet. 2016;55:723–33.

    Article  CAS  PubMed  Google Scholar 

  10. Cancidas [Prescribing Information]. Whitehouse Station: Merck & Co., Inc; 2016.

  11. Betts RF, Nucci M, Talwar D, Gareca M, Queiroz-Telles F, Bedimo RJ, et al. A Multicenter, double-blind trial of a high-dose caspofungin treatment regimen versus a standard caspofungin treatment regimen for adult patients with invasive candidiasis. Clin Infect Dis. 2009;48:1676–84.

    Article  CAS  PubMed  Google Scholar 

  12. van der Elst KC, Veringa A, Zijlstra JG, Beishuizen A, Klont R, Brummelhuis-Visser P, Uges DR, Touw DJ, Kosterink JG, van der Werf TS, Alffenaar JC. Low caspofungin exposure in patients in the Intensive Care Unit. Antimicrob Agents Chemother. 2016. doi:10.1128/AAC.01582-16.

  13. Jullien V, Azoulay E, Schwebel C, Le Saux T, Charles PE, Cornet M, et al. Population pharmacokinetics of micafungin in ICU patients with sepsis and mechanical ventilation. J Antimicrob Chemother. 2017;72(1):181–189.

  14. Stover KR, King ST, Cleary JD. Cardiac toxicity of the echinocandins: chance or cause and effect association? J Clin Pharm Ther. 2014;39:1–3.

    Article  CAS  PubMed  Google Scholar 

  15. • Cleary JD, Stover KR. Antifungal-associated drug-induced cardiac disease. Clin Infect Dis. 2015;61 Suppl 6:S662–8. Good review of antifungal-induced cardiac toxicities, especially for echinocandins.

  16. Lichtenstern C, Wolff M, Arens C, Klie F, Majeed RW, Henrich M, et al. Cardiac effects of echinocandin preparations - three case reports. J Clin Pharm Ther. 2013;38:429–31.

    Article  CAS  PubMed  Google Scholar 

  17. Stover KR, Cleary JD. Cardiac response to centrally administered echinocandin antifungals. J Pharm Pharmacol. 2015;67:1279–83.

    Article  CAS  PubMed  Google Scholar 

  18. Shah PJ, Sundareshan V, Miller B, Bergman SJ. Micafungin and a case of polymorphic ventricular tachycardia. J Clin Pharm Ther. 2016;41:362–4.

    Article  CAS  PubMed  Google Scholar 

  19. Lahmer T, Schnappauf C, Messer M, Rasch S, Fekecs L, Beitz A, et al. Influence of echinocandin administration on hemodynamic parameters in medical intensive care unit patients: a single center prospective study. Infection. 2015;43:723–7.

    Article  CAS  PubMed  Google Scholar 

  20. Liu P, Ruhnke M, Meersseman W, Paiva JA, Kantecki M, Damle B. Pharmacokinetics of anidulafungin in critically ill patients with candidemia/invasive candidiasis. Antimicrob Agents Chemother. 2013;57:1672–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gonzalez de Molina F, Martinez-Alberici Mde L, Ferrer R. Treatment with echinocandins during continuous renal replacement therapy. Crit Care. 2014;18:218.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Aguilar G, Azanza JR, Carbonell JA, Ferrando C, Badenes R, Parra MA, et al. Anidulafungin dosing in critically ill patients with continuous venovenous haemodiafiltration. J Antimicrob Chemother. 2014;69:1620–3.

    Article  CAS  PubMed  Google Scholar 

  23. Weiler S, Seger C, Pfisterer H, Stienecke E, Stippler F, Welte R, et al. Pharmacokinetics of caspofungin in critically ill patients on continuous renal replacement therapy. Antimicrob Agents Chemother. 2013;57:4053–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ruiz S, Papy E, Da Silva D, Nataf P, Massias L, Wolff M, et al. Potential voriconazole and caspofungin sequestration during extracorporeal membrane oxygenation. Intensive Care Med. 2009;35:183–4.

    Article  PubMed  Google Scholar 

  25. Spriet I, Annaert P, Meersseman P, Hermans G, Meersseman W, Verbesselt R, et al. Pharmacokinetics of caspofungin and voriconazole in critically ill patients during extracorporeal membrane oxygenation. J Antimicrob Chemother. 2009;63:767–70.

    Article  CAS  PubMed  Google Scholar 

  26. Aguilar G, Ferriols R, Carbonell JA, Ezquer C, Alonso JM, Villena A, et al. Pharmacokinetics of anidulafungin during venovenous extracorporeal membrane oxygenation. Crit Care. 2016;20:325.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Shekar K, Roberts JA, Mcdonald CI, Ghassabian S, Anstey C, Wallis SC, et al. Protein-bound drugs are prone to sequestration in the extracorporeal membrane oxygenation circuit: results from an ex vivo study. Crit Care. 2015;19(1):164. doi:10.1186/s13054-015-0891-z.

  28. Muilwijk EW, Lempers VJ, Burger DM, Warris A, Pickkers P, Aarnoutse RE, et al. Impact of special patient populations on the pharmacokinetics of echinocandins. Expert Rev Anti-Infect Ther. 2015;13:799–815.

    Article  CAS  PubMed  Google Scholar 

  29. Hall 2nd RG, Swancutt MA, Meek C, Leff R, Gumbo T. Weight drives caspofungin pharmacokinetic variability in overweight and obese people: fractal power signatures beyond two-thirds or three-fourths. Antimicrob Agents Chemother. 2013;57:2259–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Hall RG, Swancutt MA, Gumbo T. Fractal geometry and the pharmacometrics of micafungin in overweight, obese, and extremely obese people. Antimicrob Agents Chemother. 2011;55:5107–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Pasipanodya JP, Hall 2nd RG, Gumbo T. In silico-derived bedside formula for individualized micafungin dosing for obese patients in the age of deterministic chaos. Clin Pharmacol Ther. 2015;97:292–7.

    Article  CAS  PubMed  Google Scholar 

  32. Zomp A, Bookstaver PB, Ahmed Y, Turner JE, King C. Micafungin therapy in a critically ill, morbidly obese patient. J Antimicrob Chemother. 2011;66:2678–80.

    Article  CAS  PubMed  Google Scholar 

  33. Ryan DM, Lupinacci RJ, Kartsonis NA. Efficacy and safety of caspofungin in obese patients. Med Mycol. 2011;49:748–54.

    PubMed  Google Scholar 

  34. •• Andes DR, Safdar N, Baddley JW, Playford G, Reboli AC, Rex JH, et al. Impact of treatment strategy on outcomes in patients with candidemia and other forms of invasive candidiasis: a patient-level quantitative review of randomized trials. Clin Infect Dis. 2012;54:1110–22. Meta-analysis of antifungal studies show improved treatment outcomes for invasive candidiasis when echinocandins used.

  35. Timsit JF, Azoulay E, Schwebel C, Charles PE, Cornet M, Souweine B, et al. Empirical micafungin treatment and survival without invasive fungal infection in adults with ICU-acquired sepsis, Candida colonization, and multiple organ failure: the EMPIRICUS randomized clinical trial. JAMA. 2016;316:1555–64.

    Article  CAS  PubMed  Google Scholar 

  36. Gabardi S, Martin S, Sura M, Mohammed A, Golan Y. Micafungin treatment and eradication of candiduria among hospitalized patients. Int Urol Nephrol. 2016;48:1881–5.

    Article  CAS  PubMed  Google Scholar 

  37. Grau S, Luque S, Echeverria-Esnal D, Sorli L, Campillo N, Montero M, et al. Urinary micafungin levels are sufficient to treat urinary tract infections caused by Candida spp. Int J Antimicrob Agents. 2016;48:212–4.

    Article  CAS  PubMed  Google Scholar 

  38. Vallabhaneni S, Cleveland AA, Farley MM, Harrison LH, Schaffner W, Beldavs ZG, et al. Epidemiology and risk factors for echinocandin nonsusceptible Candida glabrata bloodstream infections: data from a large multisite population-based candidemia surveillance program, 2008-2014. Open Forum Infect Dis. 2015;2:ofv163.

    Article  PubMed  PubMed Central  Google Scholar 

  39. • Beyda ND, John J, Kilic A, Alam MJ, Lasco TM, Garey KW. FKS mutant Candida glabrata: risk factors and outcomes in patients with candidemia. Clin Infect Dis. 2014;59:819–25. Risk factor for FKS mutation leading to echinocandin resistance is prior echinocandin use.

  40. Alexander BD, Johnson MD, Pfeiffer CD, Jimenez-Ortigosa C, Catania J, Booker R, et al. Increasing echinocandin resistance in Candida glabrata: clinical failure correlates with presence of FKS mutations and elevated minimum inhibitory concentrations. Clin Infect Dis. 2013;56:1724–32.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Chiotos K, Vendetti N, Zaoutis TE, Baddley J, Ostrosky-Zeichner L, Pappas P, et al. Comparative effectiveness of echinocandins versus fluconazole therapy for the treatment of adult candidaemia due to Candida parapsilosis: a retrospective observational cohort study of the Mycoses Study Group (MSG-12). J Antimicrob Chemother. 2016;71:3536–9.

    Article  CAS  PubMed  Google Scholar 

  42. Fernandez-Ruiz M, Aguado JM, Almirante B, Lora-Pablos D, Padilla B, Puig-Asensio M, et al. Initial use of echinocandins does not negatively influence outcome in Candida parapsilosis bloodstream infection: a propensity score analysis. Clin Infect Dis. 2014;58:1413–21.

    Article  CAS  PubMed  Google Scholar 

  43. Bergman SJ, Tyagi I, Ronald K. Antifungal dosing in critically ill patients. Curr Fungal Infect Rep. 2010;4:78–86.

    Article  Google Scholar 

  44. Pennisi M, Antonelli M. Clinical aspects of invasive candidiasis in critically ill patients. Drugs. 2009;69 Suppl 1:21–8.

    Article  PubMed  Google Scholar 

  45. Galgiani JN, Ampel NM, Blair JE, Catanzaro A, Geertsma F, Hoover SE, et al. 2016 Infectious Diseases Society of America (IDSA) clinical practice guideline for the treatment of coccidioidomycosis. Clin Infect Dis. 2016;63:e112–46.

    Article  PubMed  Google Scholar 

  46. Perfect JR, Dismukes WE, Dromer F, Goldman DL, Graybill JR, Hamill RJ, et al. Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of America. Clin Infect Dis. 2010;50:291–322.

    Article  PubMed  Google Scholar 

  47. Pappas PG, Chetchotisakd P, Larsen RA, Manosuthi W, Morris MI, Anekthananon T, et al. A phase II randomized trial of amphotericin B alone or combined with fluconazole in the treatment of HIV-associated cryptococcal meningitis. Clin Infect Dis. 2009;48:1775–83.

    Article  CAS  PubMed  Google Scholar 

  48. Bergman SJ, Speil C, Short M, Koirala J. Pharmacokinetic and pharmacodynamic aspects of antibiotic use in high-risk populations. Infect Dis Clin N Am. 2007;21:821-46, x.

  49. Lipp HP. Antifungal agents--clinical pharmacokinetics and drug interactions. Mycoses. 2008;51 Suppl 1:7–18.

    Article  CAS  PubMed  Google Scholar 

  50. Thompson GR, 3rd, Cadena J, Patterson TF. Overview of antifungal agents. Clin Chest Med. 2009;30:203-15, v.

  51. Rex JH SD. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. Elsevier Health Sciences; 2014.

  52. Trotman RL, Williamson JC, Shoemaker DM, Salzer WL. Antibiotic dosing in critically ill adult patients receiving continuous renal replacement therapy. Clin Infect Dis. 2005;41:1159–66.

    Article  CAS  PubMed  Google Scholar 

  53. Heintz BH, Matzke GR, Dager WE. Antimicrobial dosing concepts and recommendations for critically ill adult patients receiving continuous renal replacement therapy or intermittent hemodialysis. Pharmacotherapy. 2009;29:562–77.

    Article  CAS  PubMed  Google Scholar 

  54. Nivoix Y, Leveque D, Herbrecht R, Koffel JC, Beretz L, Ubeaud-Sequier G. The enzymatic basis of drug-drug interactions with systemic triazole antifungals. Clin Pharmacokinet. 2008;47:779–92.

    Article  CAS  PubMed  Google Scholar 

  55. Bruggemann RJ, Alffenaar JW, Blijlevens NM, Billaud EM, Kosterink JG, Verweij PE, et al. Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents. Clin Infect Dis. 2009;48:1441–58.

    Article  PubMed  Google Scholar 

  56. • Patterson TF, Thompson 3rd GR, Denning DW, Fishman JA, Hadley S, Herbrecht R, et al. Practice guidelines for the diagnosis and management of Aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63:e1–60. Recent update of practice guidelines and summary of literature for the treatment of aspergillosis.

  57. Pascual A, Csajka C, Buclin T, Bolay S, Bille J, Calandra T, et al. Challenging recommended oral and intravenous voriconazole doses for improved efficacy and safety: population pharmacokinetics-based analysis of adult patients with invasive fungal infections. Clin Infect Dis. 2012;55:381–90.

    Article  CAS  PubMed  Google Scholar 

  58. Luke DR, Tomaszewski K, Damle B, Schlamm HT. Review of the basic and clinical pharmacology of sulfobutylether-beta-cyclodextrin (SBECD). J Pharm Sci. 2010;99:3291–301.

    Article  CAS  PubMed  Google Scholar 

  59. Neofytos D, Lombardi LR, Shields RK, Ostrander D, Warren L, Nguyen MH, et al. Administration of voriconazole in patients with renal dysfunction. Clin Infect Dis. 2012;54:913–21.

    Article  CAS  PubMed  Google Scholar 

  60. • Ashbee HR, Barnes RA, Johnson EM, Richardson MD, Gorton R, Hope WW. Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British society for medical mycology. J Antimicrob Chemother. 2014;69:1162–76. Review of target serum concentrations for efficacy and toxicity when monitoring antifungal agents.

  61. Smith J, Andes D. Therapeutic drug monitoring of antifungals: pharmacokinetic and pharmacodynamic considerations. Ther Drug Monit. 2008;30:167–72.

    Article  CAS  PubMed  Google Scholar 

  62. Percival KM, Bergman SJ. Update on posaconazole pharmacokinetics: comparison of old and new formulations. Curr Fungal Infect Rep. 2014;8:139–45.

    Article  Google Scholar 

  63. Gross BN, Ihorst G, Jung M, Wasch R, Engelhardt M. Posaconazole therapeutic drug monitoring in the real-life setting: a single-center experience and review of the literature. Pharmacotherapy. 2013;33:1117–25.

    Article  CAS  PubMed  Google Scholar 

  64. Krishna G, Ma L, Martinho M, Preston RA, O’Mara E. A new solid oral tablet formulation of posaconazole: a randomized clinical trial to investigate rising single- and multiple-dose pharmacokinetics and safety in healthy volunteers. J Antimicrob Chemother. 2012;67:2725–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Noxafil [Prescribing Information]. Whitehouse Station: Merck & Co., Inc; 2016.

  66. Maertens J, Cornely OA, Ullmann AJ, Heinz WJ, Krishna G, Patino H, et al. Phase 1B study of the pharmacokinetics and safety of posaconazole intravenous solution in patients at risk for invasive fungal disease. Antimicrob Agents Chemother. 2014;58:3610–7.

    Article  PubMed  PubMed Central  Google Scholar 

  67. Miceli MH, Perissinotti AJ, Kauffman CA, Couriel DR. Serum posaconazole levels among haematological cancer patients taking extended release tablets is affected by body weight and diarrhoea: single centre retrospective analysis. Mycoses. 2015;58:432–6.

    Article  CAS  PubMed  Google Scholar 

  68. Cresemba [Prescribing Information]. Northbrook: Astellas, Inc.; 2016.

  69. Miceli MH, Kauffman CA. Isavuconazole: a new broad-spectrum triazole antifungal agent. Clin Infect Dis. 2015;61:1558–65.

    Article  CAS  PubMed  Google Scholar 

  70. • Marty FM, Ostrosky-Zeichner L, Cornely OA, Mullane KM, Perfect JR, Thompson 3rd GR, et al. Isavuconazole treatment for mucormycosis: a single-arm open-label trial and case-control analysis. Lancet Infect Dis. 2016;16:828–37. Treatment results leading to orphan drug indication for isavuconazole against mucormycosis.

  71. • Maertens JA, Raad II, Marr KA, Patterson TF, Kontoyiannis DP, Cornely OA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387:760–9. Clinical trial results showing equal efficacy of isavuconazole and fewer adverse effects than voriconazole for invasive asgergillosis.

  72. Lewis 2nd JS, Graybill JR, Fungicidal versus fungistatic: what’s in a word? Expert Opin Pharmacother. 2008;9:927–35.

    Article  CAS  PubMed  Google Scholar 

  73. 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;50:674–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lewis RE, Wiederhold NP. The solubility ceiling: a rationale for continuous infusion amphotericin B therapy? Clin Infect Dis. 2003;37:871–2.

    Article  PubMed  Google Scholar 

  75. Lewis RE. Pharmacodynamic implications for use of antifungal agents. Curr Opin Pharmacol. 2007;7:491–7.

    Article  CAS  PubMed  Google Scholar 

  76. Kuiper L, Ruijgrok EJ. A review on the clinical use of inhaled amphotericin B. J Aerosol Med Pulm Drug Deliv. 2009;22:213–27.

    Article  CAS  PubMed  Google Scholar 

  77. Alvarez-Lerma F, Mariscal F, Quintana E, Rialp G, Diaz-Reganon J, Perez MJ, et al. Use of liposomal amphotericin B in critically ill patients: a retrospective, multicenter, clinical study. J Chemother. 2009;21:330–7.

    Article  CAS  PubMed  Google Scholar 

  78. Dismukes WE. Antifungal therapy: lessons learned over the past 27 years. Clin Infect Dis. 2006;42:1289–96.

    Article  CAS  PubMed  Google Scholar 

  79. Petrikkos GL. Lipid formulations of amphotericin B as first-line treatment of zygomycosis. Clin Microbiol Infect. 2009;15 Suppl 5:87–92.

    Article  CAS  PubMed  Google Scholar 

  80. Pasqualotto AC. Amphotericin B: the higher the dose, the higher the toxicity. Clin Infect Dis. 2008;47:1110. author reply 1110-1.

    Article  PubMed  Google Scholar 

  81. Patel TS, Eschenauer GA, Stuckey LJ, Carver PL. Antifungal prophylaxis in lung transplant recipients. Transplantation. 2016;100:1815–26.

    Article  CAS  PubMed  Google Scholar 

  82. Chuealee R, Aramwit P, Noipha K, Srichana T. Bioactivity and toxicity studies of amphotericin B incorporated in liquid crystals. Eur J Pharm Sci. 2011;43:308–17.

    Article  CAS  PubMed  Google Scholar 

  83. Burgess BL, He Y, Baker MM, Luo B, Carroll SF, Forte TM, et al. NanoDisk containing super aggregated amphotericin B: a high therapeutic index antifungal formulation with enhanced potency. Int J Nanomedicine. 2013;8:4733–43.

    PubMed  PubMed Central  Google Scholar 

  84. Jain V, Gupta A, Pawar VK, Asthana S, Jaiswal AK, Dube A, et al. Chitosan-assisted immunotherapy for intervention of experimental leishmaniasis via amphotericin B-loaded solid lipid nanoparticles. Appl Biochem Biotechnol. 2014;174:1309–30.

    Article  CAS  PubMed  Google Scholar 

  85. Gola J, Strzalka-Mrozik B, Kruszniewska-Rajs C, Janiszewski A, Skowronek B, Gagos M, et al. A new form of amphotericin B - the complex with copper (II) ions - downregulates sTNFR1 shedding and changes the activity of genes involved in TNF-induced pathways: AmB-Cu2+ downregulates sTNFR1 shedding and changes the activity of genes involved in TNF-induced pathways. Pharmacol Rep. 2016;69:22–8.

    Article  PubMed  Google Scholar 

  86. Hamill RJ, Sobel JD, El-Sadr W, Johnson PC, Graybill JR, Javaly K, et al. Comparison of 2 doses of liposomal amphotericin B and conventional amphotericin B deoxycholate for treatment of AIDS-associated acute cryptococcal meningitis: a randomized, double-blind clinical trial of efficacy and safety. Clin Infect Dis. 2010;51:225–32.

    Article  CAS  PubMed  Google Scholar 

  87. Cornely OA, Maertens J, Bresnik M, Ebrahimi R, Ullmann AJ, Bouza E, et al. Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis. 2007;44:1289–97.

    Article  CAS  PubMed  Google Scholar 

  88. •• Cornely OA, Arikan-Akdagli S, Dannaoui E, Groll AH, Lagrou K, Chakrabarti A, et al. ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013. Clin Microbiol Infect. 2014;20 Suppl 3:5–26. Although no practice guidelines exist from IDSA for treatment of mucormycosis, this European version exhibits the best compilation of literature available.

  89. • Lanternier F, Poiree S, Elie C, Garcia-Hermoso D, Bakouboula P, Sitbon K, et al. Prospective pilot study of high-dose (10 mg/kg/day) liposomal amphotericin B (L-AMB) for the initial treatment of mucormycosis. J Antimicrob Chemother. 2015;70:3116–23. The AmbiZygo trial evaluated 10 mg/kg doses of liposomal amphotericin B over 4 weeks for mucormycosis and showed substantially more nephrotoxicity toxicity without greater efficacy.

  90. Spellberg B, Ibrahim A, Roilides E, Lewis RE, Lortholary O, Petrikkos G, et al. Combination therapy for mucormycosis: why, what, and how? Clin Infect Dis. 2012;54 Suppl 1:S73–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Reed C, Bryant R, Ibrahim AS, Edwards Jr J, Filler SG, Goldberg R, et al. Combination polyene-caspofungin treatment of rhino-orbital-cerebral mucormycosis. Clin Infect Dis. 2008;47:364–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Merry M, Boulware DR. Cryptococcal meningitis treatment strategies affected by the explosive cost of flucytosine in the United States: a cost-effectiveness analysis. Clin Infect Dis. 2016;62:1564–8.

    Article  PubMed  Google Scholar 

  93. Brouwer AE, Rajanuwong A, Chierakul W, Griffin GE, Larsen RA, White NJ, et al. Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet. 2004;363:1764–7.

    Article  CAS  PubMed  Google Scholar 

  94. Kunka ME, Cady EA, Woo HC, Thompson Bastin ML. Flucytosine pharmacokinetics in a critically Ill patient receiving continuous renal replacement therapy. Case Rep Crit Care. 2015;2015:927496.

    PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy, HSHS St. John’s Hospital, Springfield, IL, USA

    Tyson E. Dietrich

  2. Department of Pharmaceutical and Nutrition Care, Nebraska Medicine, Omaha, NE, USA

    Carolyn J. Pfeifer, Kelsey E. Aker & Scott J. Bergman

  3. College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA

    Scott J. Bergman

  4. 981090 Nebraska Medical Center, Omaha, NE, 68198-1090, USA

    Scott J. Bergman

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  1. Tyson E. Dietrich
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Tyson E. Dietrich, Carolyn J. Pfeifer, Kelsey E. Aker, and Scott J. Bergman declare that they have no conflict of interest.

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This article is part of the Topical Collection on Pharmacology and Pharmacodynamics of Antifungal Agents

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Dietrich, T.E., Pfeifer, C.J., Aker, K.E. et al. Antifungal Dosing Strategies for Critically Ill Patients. Curr Fungal Infect Rep 11, 5–15 (2017). https://doi.org/10.1007/s12281-017-0270-0

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