Current Fungal Infection Reports

, Volume 4, Issue 2, pp 70–77 | Cite as

Using Antifungal Pharmacodynamics to Improve Patient Outcomes



In vitro and in vivo studies of available and investigational antifungals have broadened our understanding of the pharmacodynamics of these agents as well as the pharmacokinetic/pharmacodynamic characteristics that are associated with efficacy. These data are increasingly being used as surrogate means to answer questions about dosing and administration of antimicrobial agents in order to improve outcomes in patients with invasive fungal infections, as these questions are difficult to answer in clinical trials. The objective of this article is to review the pharmacodynamic activity of widely used classes of antifungal agents, including the azoles, amphotericin B, and the echinocandins, discuss the pharmacokinetic/pharmacodynamic parameters associated with efficacy of these agents in preclinical studies, and describe how this information is being translated into the clinical arena to optimize patient outcomes.


Pharmacodynamics Pharmacokinetics Triazoles Amphotericin B Echinocandins 



Dr. Wiederhold has received research support from Schering-Plough, Pfizer, Merck, Basilea, and CyDex.


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

  1. 1.
    Wisplinghoff H, Bischoff T, Tallent SM, et al.: Nosocomial bloodstream infections in US hospitals: analysis of 24,179 cases from a prospective nationwide surveillance study. Clin Infect Dis 2004, 39:309–317.CrossRefPubMedGoogle Scholar
  2. 2.
    Park BJ, Wannemuehler KA, Marston BJ, et al.: Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 2009, 23:525–530.CrossRefPubMedGoogle Scholar
  3. 3.
    Marr KA, Carter RA, Crippa F, et al.: Epidemiology and outcome of mould infections in hematopoietic stem cell transplant recipients. Clin Infect Dis 2002, 34:909–917.CrossRefPubMedGoogle Scholar
  4. 4.
    Garnacho-Montero J, Amaya-Villar R, Ortiz-Leyba C, et al.: Isolation of Aspergillus spp. from the respiratory tract in critically ill patients: risk factors, clinical presentation and outcome. Crit Care 2005, 9:R191–R199.CrossRefPubMedGoogle Scholar
  5. 5.
    Beauvais A, Bruneau JM, Mol PC, et al.: Glucan synthase complex of Aspergillus fumigatus. J Bacteriol 2001, 183:2273–2279.CrossRefPubMedGoogle Scholar
  6. 6.
    Ambrose PG, Bhavnani SM, Rubino CM, et al.: Pharmacokinetics-pharmacodynamics of antimicrobial therapy: it’s not just for mice anymore. Clin Infect Dis 2007, 44:79–86.CrossRefPubMedGoogle Scholar
  7. 7.
    Klepser ME, Wolfe EJ, Jones RN, et al.: Antifungal pharmacodynamic characteristics of fluconazole and amphotericin B tested against Candida albicans. Antimicrob Agents Chemother 1997, 41:1392–1395.PubMedGoogle Scholar
  8. 8.
    Lewis RE, Lund BC, Klepser ME, et al.: 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, 42:1382–1386.PubMedGoogle Scholar
  9. 9.
    Klepser ME, Malone D, Lewis RE, et al.: Evaluation of voriconazole pharmacodynamics using time-kill methodology. Antimicrob Agents Chemother 2000, 44:1917–1920.CrossRefPubMedGoogle Scholar
  10. 10.
    Lewis RE, Wiederhold NP, Klepser ME: In vitro pharmacodynamics of amphotericin B, itraconazole, and voriconazole against Aspergillus, Fusarium, and Scedosporium spp. Antimicrob Agents Chemother 2005, 49:945–951.CrossRefPubMedGoogle Scholar
  11. 11.
    Louie A, Drusano GL, Banerjee P, et al.: Pharmacodynamics of fluconazole in a murine model of systemic candidiasis. Antimicrob Agents Chemother 1998, 42:1105–1109.PubMedGoogle Scholar
  12. 12.
    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, 43:2116–2120.PubMedGoogle Scholar
  13. 13.
    Andes D, Marchillo K, Conklin R, et al.: Pharmacodynamics of a new triazole, posaconazole, in a murine model of disseminated candidiasis. Antimicrob Agents Chemother 2004, 48:137–142.CrossRefPubMedGoogle Scholar
  14. 14.
    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, 47:3165–3169.CrossRefPubMedGoogle Scholar
  15. 15.
    • Warn PA, Sharp A, Parmar A, et al.: Pharmacokinetics and pharmacodynamics of a novel triazole, isavuconazole: mathematical modeling, importance of tissue concentrations, and impact of immune status on antifungal effect. Antimicrob Agents Chemother 2009, 53:3453–3461. This is the first in vivo study to describe the PK/PD parameters of the investigational triazole isavuconazole.Google Scholar
  16. 16.
    Schmitt-Hoffmann A, Roos B, Maares J, et al.: Multiple-dose pharmacokinetics and safety of the new antifungal triazole BAL4815 after intravenous infusion and oral administration of its prodrug, BAL8557, in healthy volunteers. Antimicrob Agents Chemother 2006, 50:286–293.CrossRefPubMedGoogle Scholar
  17. 17.
    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, 24:235–247.PubMedGoogle Scholar
  18. 18.
    Lee SC, Fung CP, Huang JS, et al.: Clinical correlates of antifungal macrodilution susceptibility test results for non-AIDS patients with severe Candida infections treated with fluconazole. Antimicrob Agents Chemother 2000, 44:2715–2718.CrossRefPubMedGoogle Scholar
  19. 19.
    • Pai MP, Turpin RS, Garey KW: Association of fluconazole area under the concentration-time curve/MIC and dose/MIC ratios with mortality in nonneutropenic patients with candidemia. Antimicrob Agents Chemother 2007, 51:35–39. This clinical study described increased mortality at hospital discharge in patients with candidemia with low AUC/MIC ratios of fluconazole.Google Scholar
  20. 20.
    • 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 prospective observational study evaluated the impact of fluconazole MICs and pharmacodynamics, as well as patient characteristics, on all-cause mortality in hospitalized patients with candidemia.Google Scholar
  21. 21.
    Andes D, Forrest A, Lepak A, Nett J, et al.: Impact of antimicrobial dosing regimen on evolution of drug resistance in vivo: fluconazole and Candida albicans. Antimicrob Agents Chemother 2006, 50:2374–2383.CrossRefPubMedGoogle Scholar
  22. 22.
    •• Rodriguez-Tudela JL, Almirante B, Rodriguez-Pardo D, et al.: Correlation of the MIC and dose/MIC ratio of fluconazole to the therapeutic response of patients with mucosal candidiasis and candidemia. Antimicrob Agents Chemother 2007, 51:3599–3604. This analysis of patients with oropharyngeal candidiasis or candidemia correlated treatment response with the fluconazole dose/MIC ratio.Google Scholar
  23. 23.
    Clancy CJ, Yu VL, Morris AJ, et al.: Fluconazole MIC and the fluconazole dose/MIC ratio correlate with therapeutic response among patients with candidemia. Antimicrob Agents Chemother 2005, 49:3171–3177.CrossRefPubMedGoogle Scholar
  24. 24.
    Bekersky I, Fielding RM, Dressler DE, et al.: Plasma protein binding of amphotericin B and pharmacokinetics of bound versus unbound amphotericin B after administration of intravenous liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate. Antimicrob Agents Chemother 2002, 46:834–840.CrossRefPubMedGoogle Scholar
  25. 25.
    Lewis RE, Wiederhold NP, Prince RA, Kontoyiannis DP: In vitro pharmacodynamics of rapid versus continuous infusion of amphotericin B deoxycholate against Candida species in the presence of human serum albumin. J Antimicrob Chemother 2006, 57:288–293.CrossRefPubMedGoogle Scholar
  26. 26.
    Andes D, Stamsted T, Conklin R: Pharmacodynamics of amphotericin B in a neutropenic-mouse disseminated-candidiasis model. Antimicrob Agents Chemother 2001, 45:922–926.CrossRefPubMedGoogle Scholar
  27. 27.
    Wiederhold NP, Tam VH, Chi J, et al.: 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, 50:469–473.CrossRefPubMedGoogle Scholar
  28. 28.
    Petraitis V, Petraitiene R, Lin P, et al.: Efficacy and safety of generic amphotericin B in experimental pulmonary aspergillosis. Antimicrob Agents Chemother 2005, 49:1642–1645.CrossRefPubMedGoogle Scholar
  29. 29.
    Olson JA, Adler-Moore JP, Schwartz J, et al.: Comparative efficacies, toxicities, and tissue concentrations of amphotericin B lipid formulations in a murine pulmonary aspergillosis model. Antimicrob Agents Chemother 2006, 50:2122–2131.CrossRefPubMedGoogle Scholar
  30. 30.
    • Lewis RE, Liao G, Hou J, et al.: Comparative analysis of amphotericin B lipid complex and liposomal amphotericin B kinetics of lung accumulation and fungal clearance in a murine model of acute invasive pulmonary aspergillosis. Antimicrob Agents Chemother 2007, 51:1253–1258. This animal model of invasive aspergillosis demonstrated differences in the rate of fungal clearance secondary to differences in pulmonary drug levels between ABLC and LAMB.Google Scholar
  31. 31.
    Lewis RE, Albert ND, Liao G, et al.: Comparative pharmacodynamics of amphotericin B lipid complex and liposomal amphotericin B in a murine model of pulmonary mucormycosis. Antimicrob Agents Chemother 2010, 54(3):1298–1304.CrossRefPubMedGoogle Scholar
  32. 32.
    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, 337:15–21.CrossRefPubMedGoogle Scholar
  33. 33.
    de Lalla F, Pellizzer G, Vaglia A, et al.: Amphotericin B as primary therapy for cryptococcosis in patients with AIDS: reliability of relatively high doses administered over a relatively short period. Clin Infect Dis 1995, 20:263–266.PubMedGoogle Scholar
  34. 34.
    Larsen RA, Leal MA, Chan LS: Fluconazole compared with amphotericin B plus flucytosine for cryptococcal meningitis in AIDS. A randomized trial. Ann Intern Med 1990, 113:183–187.PubMedGoogle Scholar
  35. 35.
    de Gans J, Portegies P, Tiessens G, et al.: Itraconazole compared with amphotericin B plus flucytosine in AIDS patients with cryptococcal meningitis. AIDS 1992, 6:185–190.PubMedCrossRefGoogle Scholar
  36. 36.
    Saag MS, Powderly WG, Cloud GA, et al.: Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group. N Engl J Med 1992, 326:83–89.PubMedGoogle Scholar
  37. 37.
    •• 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. This randomized trial demonstrated increased toxicity without improved efficacy with high-dose LAMB in patients with proven or probable invasive fungal infection.Google Scholar
  38. 38.
    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, 45:3487–3496.CrossRefPubMedGoogle Scholar
  39. 39.
    Kurtz MB, Heath IB, Marrinan J, et al.: Morphological effects of lipopeptides against Aspergillus fumigatus correlate with activities against (1,3)-beta-D-glucan synthase. Antimicrob Agents Chemother 1994, 38:1480–1489.PubMedGoogle Scholar
  40. 40.
    Wiederhold NP, Lewis RE: The echinocandin antifungals: an overview of the pharmacology, spectrum and clinical efficacy. Expert Opin Investig Drugs 2003, 12:1313–1333.CrossRefPubMedGoogle Scholar
  41. 41.
    Roling EE, Klepser ME, Wasson A, et al.: Antifungal activities of fluconazole, caspofungin (MK0991), and anidulafungin (LY 303366) alone and in combination against Candida spp. and Crytococcus neoformans via time-kill methods. Diagn Microbiol Infect Dis 2002, 43:13–17.CrossRefPubMedGoogle Scholar
  42. 42.
    Clancy CJ, Huang H, Cheng S, et al.: Characterizing the effects of caspofungin on Candida albicans, Candida parapsilosis, and Candida glabrata isolates by simultaneous time-kill and postantifungal-effect experiments. Antimicrob Agents Chemother 2006, 50:2569–2572.CrossRefPubMedGoogle Scholar
  43. 43.
    Wiederhold NP, Najvar LK, Bocanegra R, et al.: In vivo efficacy of anidulafungin and caspofungin against Candida glabrata and association with in vitro potency in the presence of sera. Antimicrob Agents Chemother 2007, 51:1616–1620.CrossRefPubMedGoogle Scholar
  44. 44.
    Paderu P, Garcia-Effron G, Balashov S, et al.: Serum differentially alters the antifungal properties of echinocandin drugs. Antimicrob Agents Chemother 2007, 51:2253–2226.CrossRefPubMedGoogle Scholar
  45. 45.
    Andes D, Diekema DJ, Pfaller MA, et al.: In vivo pharmacodynamic characterization of anidulafungin in a neutropenic murine candidiasis model. Antimicrob Agents Chemother 2008, 52:539–550.CrossRefPubMedGoogle Scholar
  46. 46.
    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, 46:3001–3012.CrossRefPubMedGoogle Scholar
  47. 47.
    Arikan S, Lozano-Chiu M, Paetznick V, Rex JH: In vitro susceptibility testing methods for caspofungin against Aspergillus and Fusarium isolates. Antimicrob Agents Chemother 2001, 45:327–330.CrossRefPubMedGoogle Scholar
  48. 48.
    Louie A, Deziel M, Liu W, et al.: Pharmacodynamics of caspofungin in a murine model of systemic candidiasis: importance of persistence of caspofungin in tissues to understanding drug activity. Antimicrob Agents Chemother 2005, 49:5058–5068.CrossRefPubMedGoogle Scholar
  49. 49.
    Andes DR, Diekema DJ, Pfaller MA, et al.: In vivo pharmacodynamic target investigation for micafungin against Candida albicans and C. glabrata in a neutropenic murine candidiasis model. Antimicrob Agents Chemother 2008, 52:3497–3503.CrossRefPubMedGoogle Scholar
  50. 50.
    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.CrossRefPubMedGoogle Scholar
  51. 51.
    • Gumbo T, Drusano GL, Liu W, et al.: Once-weekly micafungin therapy is as effective as daily therapy for disseminated candidiasis in mice with persistent neutropenia. Antimicrob Agents Chemother 2007, 51:968–974. This in vivo study demonstrated the potential utility of extended-interval dosing of micafungin for invasive candidiasis.Google Scholar
  52. 52.
    • Najvar LK, Bocanegra R, Wiederhold NP, et al.: Therapeutic and prophylactic efficacy of aminocandin (IP960) against disseminated candidiasis in mice. Clin Microbiol Infect 2008, 14:595–600. This in vivo study demonstrated reductions in fungal burden and improvements in survival with single-dose administration of the investigational agent aminocandin against disseminated candidiasis caused by C. albicans.Google Scholar
  53. 53.
    Sirohi B, Powles RL, Chopra R, et al.: A study to determine the safety profile and maximum tolerated dose of micafungin (FK463) in patients undergoing haematopoietic stem cell transplantation. Bone Marrow Transplant 2006, 38:47–51.CrossRefPubMedGoogle Scholar
  54. 54.
    Buell D, Kovanda L, Drake T, Fisco C: Alternative day dosing of micafungin in the treatment of esophageal candidiasis [abstract M-719]. Presented at the 45th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC; December 16–19, 2005.Google Scholar
  55. 55.
    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.CrossRefPubMedGoogle Scholar
  56. 56.
    Wiederhold NP: Attenuation of echinocandin activity at elevated concentrations: a review of the paradoxical effect. Curr Opin Infect Dis 2007, 20:574–578.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.University of Texas Health Science Center at San AntonioSan AntonioUSA

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