Skip to main content

Advertisement

SpringerLink
Log in

Antifungal Dosing in Critically Ill Patients

  • Published:
Current Fungal Infection Reports Aims and scope Submit manuscript

Abstract

This article reviews appropriate dosing for antifungals and emphasizes factors specific to the critically ill patient, along with drug pharmacokinetics and pharmacodynamics. The rationale for doses of the echinocandins (caspofungin, micafungin, anidulafungin), triazoles (fluconazole, voriconazole, itraconazole, posaconazole), amphotericin B (including lipid formulations), and flucytosine are discussed.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

  1. Morrell M, Fraser VJ, Kollef MH: Delaying the empiric treatment of Candida bloodstream infection until positive blood culture results are obtained: a potential risk factor for hospital mortality. Antimicrob Agents Chemother 2005, 49:3640–3645.

    Article  CAS  PubMed  Google Scholar 

  2. Patel GP, Simon D, Scheetz M, et al.: The effect of time to antifungal therapy on mortality in candidemia associated septic shock. Am J Ther 2009, 16:508–511.

    Article  PubMed  Google Scholar 

  3. Pea F, Viale P, Furlanut M: Antimicrobial therapy in critically ill patients: a review of pathophysiological conditions responsible for altered disposition and pharmacokinetic variability. Clin Pharmacokinet 2005, 44:1009–1034.

    Article  CAS  PubMed  Google Scholar 

  4. •• Walsh TJ, Anaissie EJ, Denning DW, et al.: Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 2008, 46:327–360. This article summarizes the evidence supporting the treatment of aspergillosis.

  5. Lewis JS 2nd, Graybill JR: Fungicidal versus fungistatic: what’s in a word? Expert Opin Pharmacother 2008, 9:927–935.

    Article  CAS  PubMed  Google Scholar 

  6. Wiederhold NP, Kontoyiannis DP, Chi J, et al.: Pharmacodynamics of caspofungin in a murine model of invasive pulmonary aspergillosis: evidence of concentration-dependent activity. J Infect Dis 2004, 190:1464–1471.

    Article  CAS  PubMed  Google Scholar 

  7. Wagner C, Graninger W, Presterl E, Joukhadar C: The echinocandins: comparison of their pharmacokinetics, pharmacodynamics, and clinical applications. Pharmacology 2006, 78:161–177.

    Article  CAS  PubMed  Google Scholar 

  8. Mazzei T, Novelli A: Pharmacological properties of antifungal drugs with a focus on anidulafungin. Drugs 2009, 69(Suppl 1):79–90.

    Article  CAS  PubMed  Google Scholar 

  9. Constantin JM, Roszyk L, Guerin R, et al.: [Tolerance of caspofungin in intensive care unit: a prospective study] [in French]. Ann Fr Anesth Reanim 2008, 27(10):819–824.

    PubMed  Google Scholar 

  10. Dowell JA, Knebel W, Ludden T, et al.: Population pharmacokinetic analysis of anidulafungin, an echinocandin antifungal. J Clin Pharmacol 2004, 44:590–598.

    Article  CAS  PubMed  Google Scholar 

  11. Gumbo T: Impact of pharmacodynamics and pharmacokinetics on echinocandin dosing strategies. Curr Opin Infect Dis 2007, 20:587–591.

    Article  CAS  PubMed  Google Scholar 

  12. • Betts RF, Nucci M, Talwar D, 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, 48:1676–1684. This is the first clinical study to compare two different doses of caspofungin. The group receiving 150 mg per day did not have better outcomes than the standard-dose group.

  13. Gafter-Gvili A, Vidal L, Goldberg E, et al.: Treatment of invasive candidal infections: systematic review and meta-analysis. Mayo Clin Proc 2008, 83:1011–1021.

    Article  PubMed  Google Scholar 

  14. Dupont BF, Lortholary O, Ostrosky-Zeichner L, et al.: Treatment of candidemia and invasive candidiasis in the intensive care unit: post hoc analysis of a randomized, controlled trial comparing micafungin and liposomal amphotericin B. Crit Care 2009, 13:R159.

    Article  PubMed  Google Scholar 

  15. Mills EJ, Perri D, Cooper C, et al.: Antifungal treatment for invasive Candida infections: a mixed treatment comparison meta-analysis. Ann Clin Microbiol Antimicrob 2009, 8:23.

    Article  PubMed  Google Scholar 

  16. Mora-Duarte J, Betts R, Rotstein C, et al.: Comparison of caspofungin and amphotericin B for invasive candidiasis. N Engl J Med 2002, 347:2020–2029.

    Article  CAS  PubMed  Google Scholar 

  17. •• Reboli AC, Rotstein C, Pappas PG, et al.: Anidulafungin versus fluconazole for invasive candidiasis. N Engl J Med 2007, 356:2472–2482. This is the first study to show a difference in outcomes for an echinocandin. Although the difference did not remain statistically significant 6 weeks after the end of therapy, fewer patients died while receiving anidulafungin.

  18. •• Pappas PG, Rotstein CM, Betts RF, et al.: Micafungin versus caspofungin for treatment of candidemia and other forms of invasive candidiasis. Clin Infect Dis 2007, 45:883–893. This is the first clinical trial to demonstrate that there is no difference between micafungin (100 or 150 mg/d) and caspofungin.

  19. Pfaller MA, Boyken L, Hollis RJ, et al.: In vitro susceptibility of invasive isolates of Candida spp. to anidulafungin, caspofungin, and micafungin: six years of global surveillance. J Clin Microbiol 2008, 46:150–156.

    Article  CAS  PubMed  Google Scholar 

  20. Perlin DS: Resistance to echinocandin-class antifungal drugs. Drug Resist Updat 2007, 10:121–130.

    Article  CAS  PubMed  Google Scholar 

  21. •• 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, 48:503–535. This is a summary of the evidence supporting treatments for candidiasis.

  22. Mohr J, Johnson M, Cooper T, et al.: Current options in antifungal pharmacotherapy. Pharmacotherapy 2008, 28:614–645.

    Article  CAS  PubMed  Google Scholar 

  23. Thompson GR 3rd, Cadena J, Patterson TF: Overview of antifungal agents. Clin Chest Med 2009, 30:203–215.

    Article  PubMed  Google Scholar 

  24. Lewis RE: Pharmacodynamic implications for use of antifungal agents. Curr Opin Pharmacol 2007, 7:491–497.

    Article  CAS  PubMed  Google Scholar 

  25. Pennisi M, Antonelli M: Clinical aspects of invasive candidiasis in critically ill patients. Drugs 2009, 69(Suppl 1):21–28.

    Article  PubMed  Google Scholar 

  26. Connor H, Bergman S: Candida susceptibility to fluconazole [abstract 1–131]. Presented at American Society of Health-System Pharmacists Midyear Clinical Meeting. Las Vegas, NV; December 5–10, 2009.

  27. Galgiani JN, Ampel NM, Blair JE, et al.: Coccidioidomycosis. Clin Infect Dis 2005, 41:1217–1223.

    Article  PubMed  Google Scholar 

  28. • Perfect JR, Dismukes WE, Dromer F, et al.: Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the Infectious Diseases Society of America. Clin Infect Dis 2010, 50(3):291–322. This article summarizes the evidence supporting treatments for cryptococcal disease.

  29. Pappas PG, Chetchotisakd P, Larsen RA, 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, 48:1775–1783.

    Article  CAS  PubMed  Google Scholar 

  30. Longley N, Muzoora C, Taseera K, et al.: Dose-response effect of high-dose fluconazole for HIV-associated cryptococcal meningitis in southwestern Uganda. Clin Infect Dis 2008, 47:1556–1561.

    Article  CAS  PubMed  Google Scholar 

  31. Silling G: Fluconazole: optimized antifungal therapy based on pharmacokinetics. Mycoses 2002, 45(Suppl 3):39–41.

    CAS  PubMed  Google Scholar 

  32. Bergman SJ, Speil C, Short M, Koirala J: Pharmacokinetic and pharmacodynamic aspects of antibiotic use in high-risk populations. Infect Dis Clin North Am 2007, 21:821–846.

    Article  PubMed  Google Scholar 

  33. •• Baddley JW, Patel M, Bhavnani SM, et al.: Association of fluconazole pharmacodynamics with mortality in patients with candidemia. Antimicrob Agents Chemother 2008, 52:3022–3028. This study led to the establishment of an AUC/MIC ≥25 as the pharmacodynamic parameter most associated with efficacy.

  34. Garey KW, Pai MP, Suda KJ, et al.: Inadequacy of fluconazole dosing in patients with candidemia based on Infectious Diseases Society of America (IDSA) guidelines. Pharmacoepidemiol Drug Saf 2007, 16:919–927.

    Article  CAS  PubMed  Google Scholar 

  35. Lipp HP: Antifungal agents—clinical pharmacokinetics and drug interactions. Mycoses 2008, 51(Suppl 1):7–18.

    Article  CAS  PubMed  Google Scholar 

  36. • 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, 29:562–577. This good review article gives dosing recommendations for renal replacement therapy in critically ill adults.

  37. • Bruggemann RJ, Alffenaar JW, Blijlevens et al.: Clinical relevance of the pharmacokinetic interactions of azole antifungal drugs with other coadministered agents. Clin Infect Dis 2009, 48:1441–1458. This is another good review article, which discusses managing dosing for triazoles, along with their many drug-drug interactions.

  38. Nivoix Y, Leveque D, Herbrecht R, et al.: The enzymatic basis of drug-drug interactions with systemic triazole antifungals. Clin Pharmacokinet 2008, 47:779–792.

    Article  CAS  PubMed  Google Scholar 

  39. • Smith J, Andes D: Therapeutic drug monitoring of antifungals: pharmacokinetic and pharmacodynamic considerations. Ther Drug Monit 2008, 30:167–172. This article reviews when it may be necessary to conduct therapeutic drug monitoring for antifungals and why, and it discusses what concentrations to expect in patients in order to achieve efficacy and prevent toxicity.

  40. 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, 50:674–684.

    Article  CAS  PubMed  Google Scholar 

  41. Lewis RE, Wiederhold NP: The solubility ceiling: a rationale for continuous infusion amphotericin B therapy? Clin Infect Dis 2003, 37:871–872.

    Article  PubMed  Google Scholar 

  42. Dismukes WE: Antifungal therapy: lessons learned over the past 27 years. Clin Infect Dis 2006, 42:1289–1296.

    Article  CAS  PubMed  Google Scholar 

  43. Alvarez-Lerma F, Mariscal F, Quintana E, et al.: Use of liposomal amphotericin B in critically ill patients: a retrospective, multicenter, clinical study. J Chemother 2009, 21:330–337.

    CAS  PubMed  Google Scholar 

  44. Bicanic T, Wood R, Meintjes G, et al.: High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: a randomized trial. Clin Infect Dis 2008, 47(1):123–130.

    Article  CAS  PubMed  Google Scholar 

  45. • Petrikkos GL: Lipid formulations of amphotericin B as first-line treatment of zygomycosis. Clin Microbiol Infect 2009, 15(Suppl 5):87–92. This is the largest study to date of patients with zygomycosis treated with the lipid formulations of amphotericin B.

  46. Pasqualotto AC: Amphotericin B: the higher the dose, the higher the toxicity [comment]. Clin Infect Dis 2008, 47:1110; author reply 1110–1111.

  47. Moen MD, Lyseng-Williamson KA, Scott LJ: Liposomal amphotericin B: a review of its use as empirical therapy in febrile neutropenia and in the treatment of invasive fungal infections. Drugs 2009, 69:361–392.

    Article  CAS  PubMed  Google Scholar 

  48. Hamill RJ, Sobel J, El-Sadr W, et al.: Randomized double-blind trial of AmBisome (liposomal amphotericin B) and amphothericin B in acute cryptococcal meningitis in AIDS patients [abstract 1161]. Presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy (organized by the American Society of Microbiology). San Francisco, CA; 1999.

  49. •• Cornely OA, Maertens J, Bresnik M, 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, 44:1289–1297. A regimen with 10 mg/kg loading doses over 2 weeks showed substantially more toxicity than 3 mg/kg, without greater efficacy.

  50. Brouwer AE, Rajanuwong A, Chierakul W, et al.: Combination antifungal therapies for HIV-associated cryptococcal meningitis: a randomised trial. Lancet 2004, 363:1764–1767.

    Article  CAS  PubMed  Google Scholar 

  51. Milefchik E, Leal MA, Haubrich R, et al.: Fluconazole alone or combined with flucytosine for the treatment of AIDS-associated cryptococcal meningitis. Med Mycol 2008, 46:393–395.

    Article  CAS  PubMed  Google Scholar 

Download references

Disclosure

No potential conflicts of interest relevant to this article were reported.

Author information

Authors and Affiliations

  1. Division of Infectious Diseases, Southern Illinois University School of Medicine, 701 North 1st Street, Box 19636, Springfield, IL, 62794, USA

    Scott J. Bergman, Isha Tyagi & Katie Ronald

Authors
  1. Scott J. Bergman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Isha Tyagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katie Ronald
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Scott J. Bergman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bergman, S.J., Tyagi, I. & Ronald, K. Antifungal Dosing in Critically Ill Patients. Curr Fungal Infect Rep 4, 78–86 (2010). https://doi.org/10.1007/s12281-010-0012-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12281-010-0012-z

Keywords

Search

Navigation