Skip to main content

Advertisement

Log in

Antifungal Agents: In Vitro Susceptibility Testing, Pharmacodynamics, and Prospects for Combination Therapy

  • Review
  • Published:
European Journal of Clinical Microbiology and Infectious Diseases Aims and scope Submit manuscript

Abstract

As invasive fungal infections in immunocompromised patients become increasingly important, the field of antifungal chemotherapy continues to evolve rapidly. New agents have entered the clinical arena, providing physicians with a variety of choices for treatment of most infections. Standardized methods for testing the in vitro susceptibility of fungi have become available, and concentration-effect relationships are increasingly explored. Finally, the availability of an entirely new class of antifungal agents is opening new opportunities for combination therapy of infections that are notoriously difficult to treat and carry a dismal prognosis. However, the ongoing progress in these key areas has also made antifungal chemotherapy considerably more complex and susceptible to misconceptions. Continuing efforts in the laboratory and well designed collaborative clinical trials are needed more than ever to turn opportunities into lasting benefit for patients at risk for or suffering from life-threatening invasive mycoses.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Groll AH, Walsh TJ (2001) Uncommon opportunistic fungi: new nosocomial threats. Clin Microbiol Infect 7 (Suppl 2):8–24

    Article  CAS  Google Scholar 

  2. Schneider E, Hajjeh RA, Spiegel RA, Jibson RW, Harp EL, Marshall GA, Gunn RA, McNeil MM, Pinner RW, Baron RC, Burger RC, Hutwagner LC, Crump C, Kaufman L, Reef SE, Feldman GM, Pappagianis D, Werner SB (1997) A coccidioidomycosis outbreak following the Northridge, Calif., earthquake. JAMA 277:904–908

    Article  CAS  PubMed  Google Scholar 

  3. Centers for Disease Control (2001) Update: outbreak of acute febrile respiratory illness among college students – Acapulco, Mexico, March 2001. Morb Mortal Wkly Rep 50:359–360

    Google Scholar 

  4. Groll, AH, Piscitelli SC, Walsh TJ (1998) Clinical pharmacology of systemic antifungal agents: a comprehensive review of agents in clinical use, current investigational compounds, and putative targets for antifungal drug development. Adv Pharmacol 44:343–500

    CAS  PubMed  Google Scholar 

  5. Berenguer J, Buck M, Witebsky F, Stock F, Pizzo PA, Walsh TJ (1993) Lysis-centrifugation blood cultures in the detection of tissue-proven invasive candidiasis. Disseminated versus single-organ infection. Diagn Microbiol Infect Dis 17:103–109

    Article  CAS  PubMed  Google Scholar 

  6. Hebart H, Loffler J, Meisner C et al (2000) Early detection of Aspergillus infection after allogeneic stem cell transplantation by polymerase chain reaction screening. J Infect Dis 181:1713–1719

    CAS  PubMed  Google Scholar 

  7. Maertens J, Verhaegen J, Lagrou K et al (2001) Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: a prospective validation. Blood 97:1604–1610

    CAS  PubMed  Google Scholar 

  8. Caillot D, Casasnovas O, Bernard A et al (1997) Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomography scan and surgery. J Clin Oncol 15:139–147

    CAS  PubMed  Google Scholar 

  9. Caillot D, Couaillier JF, Bernard A, Casasnovas O, Denning DW, Mannone L, Lopez J, Couillault G, Piard F, Vagner O, Guy H (2001) Increasing volume and changing characteristics of invasive pulmonary aspergillosis on sequential thoracic computed tomography scans in patients with neutropenia. J Clin Oncol 19:253–259

    CAS  PubMed  Google Scholar 

  10. Walsh TJ, Roden M, Roilides E, Groll AH (2000) Concepts in design of comparative clinical trials of antifungal therapy in neutropenic patients. Int J Antimicrob Agents 16:151–156

    Article  CAS  PubMed  Google Scholar 

  11. Rex JR, Walsh TJ, Nettleman M et al (2001) Need for alternative trial designs and evaluation strategies for therapeutic studies of invasive mycoses. Clin Infect Dis 35:95–106

    Article  Google Scholar 

  12. Ascioglu S, Rex JH, de Pauw B, Bennett JE, Bille J, Crokaert F et al (2002) Defining opportunistic invasive fungal infections in immunocompromised patients with cancer and hematopoietic stem cell transplants: an international consensus. Clin Infect Dis 34:7–14

    CAS  PubMed  Google Scholar 

  13. Rex JH, Pfaller MA, Galgiani JN, Bartlett MS, Espinel-Ingroff A, Ghannoum MA, Lancaster M, Odds FC, Rinaldi MG, Walsh TJ, Barry AL (1997) 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. Clin Infect Dis 24:235–247

    CAS  PubMed  Google Scholar 

  14. Groll AH, Piscitelli SC, Walsh TJ (2001) Antifungal pharmacodynamics: concentration-effect relationships in vitro and in vivo. Pharmacotherapy 21 (Suppl):133–148

    Google Scholar 

  15. Andes D (2003) In vivo pharmacodynamics of antifungal drugs in treatment of candidiasis. Antimicrob Agents Chemother 47:1179–1186

    Article  CAS  PubMed  Google Scholar 

  16. Woods GL (1995) In vitro testing of antimicrobial agents. Infect Dis Clin North Am 9:463–481

    CAS  PubMed  Google Scholar 

  17. National Committee for Clinical Laboratory Standards (1997) Reference method for broth dilution antifungal susceptibility testing of yeasts. Approved standard M27-A. NCCLS, Wayne, PA

  18. Cuenca-Estrella M, Lee-Yang W, Ciblak MA, Arthington-Skaggs BA, Mellado E, Warnock DW, Rodriguez-Tudela JL (2002) Comparative evaluation of NCCLS M27-A and EUCAST broth microdilution procedures for antifungal susceptibility testing of Candida species. Antimicrob Agents Chemother 46:3644–3647

    Article  CAS  PubMed  Google Scholar 

  19. National Committee for Clinical Laboratory Standards (2000) Reference method for broth dilution antifungal susceptibility testing of conidium-forming filamentous fungi. Approved standard M38-A. NCCLS, Wayne, PA

  20. Rex JH, Pfaller MA (2002) Has antifungal susceptibility testing come of age? Clin Infect Dis 35:982–989

    Article  CAS  PubMed  Google Scholar 

  21. Perea S, Patterson TF (2002). Antifungal resistance in pathogenic fungi. Clin Infect Dis 35:1073–1080

    Article  PubMed  Google Scholar 

  22. Vanden Bossche H, Dromer F, Improvisi I, Lozano-Chiu M, Rex JH, Sanglard D (1998) Antifungal drug resistance in pathogenic fungi. Med Mycol 36 (Suppl 1):119–128

    Article  Google Scholar 

  23. Lopez-Ribot JL, McAtee RK, Lee LN, Kirkpatrick WR, White TC, Sanglard D, Patterson TF (1998) Distinct patterns of gene expression associated with development of fluconazole resistance in serial Candida albicans isolates from human immunodeficiency virus-infected patients with oropharyngeal candidiasis. Antimicrob Agents Chemother 42:2932–2937

    CAS  PubMed  Google Scholar 

  24. White TC, Marr KA, Bowden RA (1998) Clinical, cellular, and molecular factors that contribute to antifungal drug resistance. Clin Microbiol Rev 11:382–402

    CAS  PubMed  Google Scholar 

  25. Dannaoui E, Borel E, Monier MF, Piens MA, Picot S, Persat F (2001) Acquired itraconazole resistance in Aspergillus fumigatus. J Antimicrob Chemother 47:333–340

    Article  CAS  PubMed  Google Scholar 

  26. Hof H (2001) Critical annotations to the use of azole antifungals for plant protection. Antimicrob Agents Chemother 45:2987–2990

    Article  CAS  PubMed  Google Scholar 

  27. Vanden Bossche H, Engelen M, Rochette F. (2003) Antifungal agents of use in animal health – chemical, biochemical and pharmacological aspects. J Vet Pharmacol Ther 26:5–29

    Article  PubMed  Google Scholar 

  28. Morschhauser J (2002) The genetic basis of fluconazole resistance development in Candida albicans. Biochim Biophys Acta 1587:240–248

    PubMed  Google Scholar 

  29. Sanglard D, Odds FC (2002) Resistance of Candida species to antifungal agents: molecular mechanisms and clinical consequences. Lancet Infect Dis 2:73–85

    Article  CAS  PubMed  Google Scholar 

  30. Kontoyiannis DP, Lewis RE (2002) Antifungal drug resistance of pathogenic fungi. Lancet 359:1135–1144

    Article  CAS  PubMed  Google Scholar 

  31. Kurtz MB, Abruzzo G, Flattery A, Bartizal K, Marrinan JA, Li W, Milligan J, Nollstadt K, Douglas CM (1996) Characterization of echinocandin-resistant mutants of Candida albicans: genetic, biochemical, and virulence studies. Infect Immun 64:3244–3251

    CAS  PubMed  Google Scholar 

  32. Craig WA (1998) Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 26:1–10

    CAS  PubMed  Google Scholar 

  33. Janknegt R, de Marie S, Bakker-Woudenberg IA, Crommelin DJ (1992) Liposomal and lipid formulations of amphotericin B. Clinical pharmacokinetics. Clin Pharmacokinet 23:279–291

    PubMed  Google Scholar 

  34. Hiemenz JW, Walsh TJ (1996) Lipid formulations of amphotericin B: recent progress and future directions. Clin Infect Dis 22 (Suppl 2):133–144

    PubMed  Google Scholar 

  35. Wong-Beringer A, Jacobs RA, Guglielmo BJ (1998) Lipid formulations of amphotericin B: clinical efficacy and toxicities. Clin Infect Dis 27:603–618

    CAS  PubMed  Google Scholar 

  36. Chiou C, Groll AH, Walsh TJ (2000) New drugs and novel targets for treatment of invasive fungal infections in patients with cancer. Oncologist 5:120–135

    Article  CAS  PubMed  Google Scholar 

  37. Brajtburg J, Powderly WG, Kobayashi GS, Medoff G (1999) Amphotericin B: current understanding of mechanisms of action. Antimicrob Agents Chemother 34:183–188

    Google Scholar 

  38. Bekersky I, Fielding RM, Dressler DE, Lee JW, Buell DN, Walsh TJ (2002) 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 46:834–840

    Article  CAS  PubMed  Google Scholar 

  39. Bekersky I, Fielding RM, Dressler DE, Lee JW, Buell DN, Walsh TJ (2002) Pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate in humans. Antimicrob Agents Chemother 46:828–833

    Article  CAS  PubMed  Google Scholar 

  40. Bekersky I, Fielding RM, Dressler DE, Kline S, Buell DN, Walsh TJ (2001) Pharmacokinetics, excretion, and mass balance of 14C after administration of 14C-cholesterol-labeled AmBisome to healthy volunteers. J Clin Pharmacol 41:963–971

    Article  CAS  PubMed  Google Scholar 

  41. Klepser ME, Wolfe EJ, Jones RN, et al (1997) Antifungal pharmacodynamic characteristics of fluconazole and amphotericin B tested against Candida albicans. Antimicrob Agents Chemother 41:1392–1395

    CAS  PubMed  Google Scholar 

  42. Klepser ME, Wolfe EJ, Pfaller MA (1998) Antifungal pharmacodynamic characteristics of fluconazole and amphotericin B against Cryptococcus neoformans. J Antimicrob Chemother 41:397–401

    Article  CAS  PubMed  Google Scholar 

  43. Walsh TJ (1989) Trichosporonosis. Infect Dis Clin North Amer 3:43–52

    CAS  Google Scholar 

  44. Walsh TJ, Melcher G, Rinaldi M, Lecciones J, McGough D, Lee J, Callender D, Rubin M, Pizzo PA (1990) Trichosporon beigelii: an emerging pathogen resistant to amphotericin B. J Clin Microbiol 28:1616–1622

    Google Scholar 

  45. Walsh TJ, Lee JW, Melcher GP, Navarro E, Bacher J, Callender D, Reed KD, Wu T, Lopez-Berestein G, Pizzo PA (1992) Experimental disseminated trichosporonosis in persistently granulocytopenic rabbits: implications for pathogenesis, diagnosis, and treatment of an emerging opportunistic infection. J Infect Dis 166:121–133

    CAS  PubMed  Google Scholar 

  46. Turnidge JD, Gudmundsson S, Vogelman B, Craig WA (1994) The postantibiotic effect of antifungal agents against common pathogenic yeasts. J Antimicrob Chemother 34:83–92

    CAS  PubMed  Google Scholar 

  47. Ernst E, Klepser ME, Pfaller MA (2000) Postantifungal effects of echinocandin, azole, and polyene antifungal agents Candida albicans and Cryptococcus neoformans. Antimicrob Agents Chemother 44:1108–1111

    Article  CAS  PubMed  Google Scholar 

  48. Andes D, Stamsted T, Conklin R (2001) Pharmacodynamics of amphotericin B in a neutropenic-mouse disseminated-candidiasis model. Antimicrob Agents Chemother 45:922–926

    Article  CAS  PubMed  Google Scholar 

  49. Hoffman HL, Lewis RE, Ernst EJ, et al (2000) In vivo pharmacodynamics of liposomal amphotericin B against Candida albicans in a neutropenic murine lung infection model. Pharmacotherapy 20:357–358

    Google Scholar 

  50. Groll AH, Giri N, Petraitis V, et al\ (2000) Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system. J Infect Dis 182:274–282

    Article  CAS  PubMed  Google Scholar 

  51. Walsh TJ, Goodman JL, Pappas P, Bekersky I, Buell DN, Roden M, Barrett J, Anaissie EJ (2001) 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 45:3487–3496

    Article  CAS  PubMed  Google Scholar 

  52. Walsh TJ, Jackson AJ, Lee JW, Amantea M, Sein T, Bacher J, Zech L (2000) Dose-dependent pharmacokinetics of amphotericin B lipid complex in rabbits. Antimicrob Agents Chemother 44:2068–2076

    Article  CAS  PubMed  Google Scholar 

  53. Walsh TJ, Whitcomb T, Piscitelli S, Figg WD, Hill S, Chanock SJ, Jarosinski P, Pizzo PA (1997) Safety, tolerance, and pharmacokinetics of amphotericin B lipid complex in children with hepatosplenic candidiasis. Antimicrob Agents Chemother 41:1944–1948

    CAS  PubMed  Google Scholar 

  54. Polak A, Scholer HJ (1975) Mode of action of 5-fluorocytosine and mechanisms of resistance. Chemotherapy 21:113–130

    CAS  PubMed  Google Scholar 

  55. Pfaller MA, Messer SA, Coffman S (1997) In vitro susceptibilities of clinical yeast isolates to a new echinocandin derivative, LY303366, and other antifungal agents. Antimicrob Agents Chemother 41:763–766

    CAS  PubMed  Google Scholar 

  56. Hoban DJ, Zhanel GG, Karlowsky JA (1999) In vitro susceptibilities of Candida and Cryptococcus neoformans isolates from blood cultures of neutropenic patients. Antimicrob Agents Chemother 43:1463–1464

    CAS  PubMed  Google Scholar 

  57. Vermes A, Guchelaar HJ, Dankert J (2000) Flucytosine: a review of its pharmacology, clinical indications, pharmacokinetics, toxicity and drug interactions. J Antimicrob Chemother 46:171–179

    CAS  PubMed  Google Scholar 

  58. Brandt ME, Pfaller MA, Hajjeh RA, Hamill RJ, Pappas PG, Reingold AL, Rimland D, Warnock DW (2001) Cryptococcal Disease Active Surveillance Group. Trends in antifungal drug susceptibility of Cryptococcus neoformans isolates in the United States: 1992 to 1994 and 1996 to 1998. Antimicrob Agents Chemother 45:3065–3069

    Article  CAS  PubMed  Google Scholar 

  59. Francis P, Walsh TJ (1992) Evolving role of flucytosine in immunocompromised patients: new insights into safety, pharmacokinetics, and antifungal therapy. Clin Infect Dis 15:1003–1018

    CAS  PubMed  Google Scholar 

  60. van der Auwera P, Ceuppens AM, Heymans C, Meunier F (1986) In vitro evaluation of various antifungal agents alone and in combination by using an automatic turbidimetric system combined with viable count determinations. Antimicrob Agents Chemother 29:997–1004

    PubMed  Google Scholar 

  61. Lewis RE, Klepser ME, Pfaller MA (2000) In vitro pharmacodynamic characteristics of flucytosine determined by time-kill methods. Diagn Microbiol Infect Dis 36:101–105

    Article  CAS  PubMed  Google Scholar 

  62. Scalarone GM, Mikami Y, Kurita N, Yazawa K, Miyaji M (1992) The postantifungal effect of 5-fluorocytosine on Candida albicans. J Antimicrob Chemother 29:129–136

    CAS  PubMed  Google Scholar 

  63. Andes D, van Ogtrop M (2000) In vivo characterization of the pharmacodynamics of flucytosine in a neutropenic murine disseminated candidiasis model. Antimicrob Agents Chemother 44:938–942

    Article  CAS  PubMed  Google Scholar 

  64. Grant SM, Clissold SP (1990) Fluconazole. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in superficial and systemic mycoses. Drugs 39:877–916

    CAS  PubMed  Google Scholar 

  65. Grant SM, Clissold SP (1989) Itraconazole. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in superficial and systemic mycoses. Drugs 37:310–344

    CAS  PubMed  Google Scholar 

  66. Groll AH, Gea-Banacloche JC, Glasmacher A, Just-Nuebling G, Maschmeyer G, Walsh TJ (2003) Clinical pharmacology of antifungal compounds. Infect Dis Clin North Am 17:159–191

    PubMed  Google Scholar 

  67. Anaissie EJ, Kontoyiannis DP, Huls C, Vartivarian SE, Karl C, Prince RA, Bosso J, Bodey GP (1995) Safety, plasma concentrations, and efficacy of high-dose fluconazole in invasive mold infections. J Infect Dis 172:599–602

    CAS  PubMed  Google Scholar 

  68. Hoffman HL, Ernst EJ, Klepser ME (2000) Novel triazole antifungal agents. Expert Opin Investig Drugs 9:593–605

    CAS  PubMed  Google Scholar 

  69. Sohnle PG, Hahn BL, Erdmann MD (1996) Effect of fluconazole on viability of Candida albicans over extended periods of time. Antimicrob Agents Chemother 40:2622–2625

    CAS  PubMed  Google Scholar 

  70. Walsh TJ, Aoki S, Mechinaud F, Bacher J, Lee J, Rubin M, Pizzo PA (1990) Effects of preventive, early, and late antifungal chemotherapy with fluconazole in different granulocytopenic models of experimental disseminated candidiasis. J Infect Dis 161:755–760

    CAS  PubMed  Google Scholar 

  71. Anaissie EJ, Darouiche RO, Abi-Said D et al (1996) Management of invasive Candida infections: results of a prospective, randomized, multicenter study of fluconazole versus amphotericin B and review of the literature. Clin Infect Dis 23:964–972

    CAS  PubMed  Google Scholar 

  72. Anaissie EJ, Vartivarian SE, Abi-Said D et al (1996) Fluconazole versus amphotericin B in the treatment of hematogenous candidiasis: a matched cohort study. Am J Med 101:170–176

    CAS  PubMed  Google Scholar 

  73. Minguez F, Chiu ML, Lima JE, Nique R, Prieto J (1994) Activity of fluconazole: postantifungal effect, effects of low concentrations and of pretreatment on the susceptibility of Candida albicans to leucocytes. J Antimicrob Chemother 34:93–100

    CAS  Google Scholar 

  74. Lewis RE, Lund BC, Klepser ME, Ernst EJ, Pfaller MA (1998) 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 42:1382–1386

    CAS  PubMed  Google Scholar 

  75. Louie A, Drusano GL, Banerjee P, Liu QF, Liu W, Kaw P, Shayegani M, Taber H, Miller MH (1998) Pharmacodynamics of fluconazole in a murine model of systemic candidiasis. Antimicrob Agents Chemother 42:1105–1109

    CAS  PubMed  Google Scholar 

  76. Andes D, van Ogtrop M (1999) Characterization and quantitation of the pharmacodynamics of fluconazole in a neutropenic murine disseminated candidiasis infection model. Antimicrob Agents Chemother 43:2116–2120

    CAS  PubMed  Google Scholar 

  77. Manavathu EK, Cutright JL, Chandrasekar PH (1998) Organism-dependent fungicidal activities of azoles. Antimicrob Agents Chemother 42:3018–3021

    CAS  PubMed  Google Scholar 

  78. Johnson EM, Szekely A, Warnock DW (1998) In vitro activity of voriconazole, itraconazole and amphotericin B against filamentous fungi. J Antimicrob Chemother 42:741–745

    Article  CAS  PubMed  Google Scholar 

  79. Fung-Tomc JC, White TC, Minassian B, Huczko E, Bonner DP (1999) In vitro antifungal activity of BMS-207147 and itraconazole against yeast strains that are non-susceptible to fluconazole. Diagn Microbiol Infect Dis 35:163–167

    Article  CAS  PubMed  Google Scholar 

  80. Burgess DS, Hastings RW (2000) A comparison of dynamic characteristics of fluconazole, itraconazole, and amphotericin B against Cryptococcus neoformans using time-kill methodology. Diagn Microbiol Infect Dis 38:87–93

    Article  CAS  PubMed  Google Scholar 

  81. Burgess DS, Hastings RW, Summers KK, Hardin TC, Rinaldi MG (2000) Pharmacodynamics of fluconazole, itraconazole, and amphotericin B against Candida albicans. Diagn Microbiol Infect Dis 36:13–18

    Article  CAS  PubMed  Google Scholar 

  82. Zhanel GG, Saunders DG, Hoban DJ, Karlowsky JA (1999) Amphotericin B, azole, and 5-flucytosine pharmacodynamic parameters in the presence of human serum. In: Program and abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington DC, p 23

  83. Denning DW, Radford SA, Oakley KL, Hall L, Johnson EM, Warnock DW (1997) Correlation between in vitro susceptibility testing to itraconazole and in vivo outcome of Aspergillus fumigatus infection. J Antimicrob Chemother 40:401–414

    Article  CAS  PubMed  Google Scholar 

  84. Berenguer J, Ali NM, Allende MC, Lee J, Garrett K, Battaglia S, Piscitelli SC, Rinaldi MG, Pizzo PA, Walsh TJ (1994) Itraconazole for experimental pulmonary aspergillosis: comparison with amphotericin B, interaction with cyclosporine A, and correlation between therapeutic response and itraconazole concentrations in plasma. Antimicrob Agents Chemother 38:1303–1308

    CAS  PubMed  Google Scholar 

  85. Groll AH, Mickiene D, Petraitiene R, Petraitis V, Roussillion K, Hemmings M, Raskas S, Walsh TJ (2001) Dose escalation pharmacodynamic study of intravenous itraconazole in a neutropenic animal model of invasive pulmonary aspergillosis. In: Program and abstracts of the 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington DC, p 389

  86. Boogaerts MA, Verhoef GE, Zachee P, Demuynck H, Verbist L, De Beule K (1989) Antifungal prophylaxis with itraconazole in prolonged neutropenia: correlation with plasma levels. Mycoses 32 (Suppl 1):103–108

    PubMed  Google Scholar 

  87. De Beule K (1996) Itraconazole: pharmacology, clinical experience and future development. Int J Antimicrobial Agents 6:175–181

    Article  Google Scholar 

  88. Glasmacher A, Hahn C, Molitor E, Sauerbruch T, Marklein G, Schmidt-Wolf IGH (2000) Definition of itraconazole target concentration for antifungal prophylaxis. In: Programs and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington DC, p 363

  89. Groll AH, Mickiene D, McEvoy M, Dad L, Townley E, Piscitelli S, Wood L, Walsh TJ (2002) Safety, pharmacokinetics and pharmacodynamics of cyclodextrin itraconazole in pediatric patients with oropharyngeal candidiasis. Antimicrob Agents Chemother 46:2554–2563

    Article  CAS  PubMed  Google Scholar 

  90. Clancy CJ, Nguyen MH (1998) In vitro efficacy and fungicidal activity of voriconazole against Aspergillus and Fusarium species. Eur J Clin Microbiol Infect Dis 17:573–575

    Article  CAS  PubMed  Google Scholar 

  91. Klepser ME, Malone D, Lewis RE, Ernst EJ, Pfaller MA (2000) Evaluation of voriconazole pharmacodynamics using time-kill methodology. Antimicrob Agents Chemother 44:1917–1920

    Article  CAS  PubMed  Google Scholar 

  92. Garcia MT, Llorente MT, Lima JE, Minguez F, Del Moral F, Prieto J (1999) Activity of voriconazole: post-antifungal effect, effects of low concentrations and of pretreatment on the susceptibility of Candida albicans to leucocytes. Scand J Infect Dis 31:501–504

    Article  CAS  PubMed  Google Scholar 

  93. Andes D, Marchillo K, Stamstad T, Conklin R (2003) In vivo pharmacokinetics and pharmacodynamics of a new triazole, voriconazole, in a murine candidiasis model. Antimicrob Agents Chemother 47:3165–3169

    Article  CAS  PubMed  Google Scholar 

  94. Pfaller MA, Messer SA, Hollis RJ, Jones RN, Doern GV, Brandt ME, Hajjeh RA (1998) In vitro susceptibilities of Candida bloodstream isolates to the new triazole antifungal agents BMS-207147, Sch 56592, and voriconazole. Antimicrob Agents Chemother 42:3242–3244

    CAS  PubMed  Google Scholar 

  95. Pfaller MA, Messer SA, Hollis RJ, Jones RN, and the SENTRY Participants Group (2002) Antifungal activities of posaconazole, ravuconazole, and voriconazole compared to those of itraconazole and amphotericin B against 239 clinical isolates of Aspergillus species and other filamentous fungi: report from SENTRY Antimicrobial Surveillance Program, 2000. Antimicrob Agents Chemother 46:1032–1037

    CAS  Google Scholar 

  96. Krieter P, Flannery B, Musick T, Courtney R, Patrick J, Laughlin M (2002) Pharmacokinetics and excretion of 14c posaconazole following oral administration in healthy male subjects. In: Program and abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington DC, p 20

  97. Wexler D, Laughlin M, Lim J, Courtney R, Batra V (2002) Effect of posaconazole on drug metabolizing enzymes. In: Program and abstracts of the 42nd Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington DC, p 30

  98. Olsen SJ, Mummaneni V, Rolan P, Norton J, Grasela DM (2000) Ravuconazole: single ascending oral dose study in healthy subjects. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington DC, p 22

  99. Grasela DM, Olsen SJ, Rolan P, Mummaneni V, Birkhofer MJ, Christopher L, Norton J, Grasela DM, Hadjilambris OH, Marino MR (2000) Ravuconazole: multiple ascending oral dose study in healthy subjects. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington DC, p 22

  100. Fung-Tomc JC, Huczko E, Minassian B, Bonner DP (1998) In vitro activity of a new oral triazole, BMS-207147 (ER-30346). Antimicrob Agents Chemother 42:313–318

    CAS  PubMed  Google Scholar 

  101. Espinel-Ingroff A (1998) 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 36:2950–2956

    CAS  PubMed  Google Scholar 

  102. Groll AH, Mickiene D, Petraitiene R, Petraitis V, Sein T, Piscitelli SC, Walsh TJ. (2000) Pharmacokinetics and pharmacodynamics of posaconazole (SCH 56592) in a neutropenic animal model of invasive pulmonary aspergillosis. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington DC, p 385

  103. Andes D, Marchillo K, Stamstad T, Conklin R (2003) In vivo pharmacodynamics of a new triazole, ravuconazole, in a murine candidiasis model. Antimicrob Agents Chemother 47:1193–1199

    Article  CAS  PubMed  Google Scholar 

  104. Hector RF (1993) Compounds active against cell walls of medically important fungi. Clin Microbiol Rev 6:1–21

    CAS  PubMed  Google Scholar 

  105. Debono M, Gordee RS (1994) Antibiotics that inhibit fungal cell wall development. Ann Rev Microbiol 48:471–497

    Article  CAS  Google Scholar 

  106. Denning DW (2002) Echinocandins: a new class of antifungal agents. J Antimicrob Chemother 49:889–891

    Article  CAS  PubMed  Google Scholar 

  107. Georgopapadakou NH (2001) Update on antifungals targeted to the cell wall: focus on beta-1,3-glucan synthase inhibitors. Expert Opin Investig Drugs 10:269–280

    CAS  PubMed  Google Scholar 

  108. Tang J, Parr TR, Turner W, Debono M, Lagrandeur L, Burkhard F, Rodriguez M, Zweifel M, Nissen J, Clingerman K (1993) LY-303366: a non-competitive inhibitor of (1,3)-b-D glucan synthases from Candida albicans and Aspergillus fumigatus. In: Program and abstracts of the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington DC, Abstract no. 367

  109. Maki K, Morishita Y, Iguchi Y, Watabe E, Otomo K, Teratani M, Watanabe Y, Ikeda F, Tawara S, Goto T, Tomishima M (1998) In vitro antifungal activity of FK463, a novel water-soluble echinocandin-like lipopeptide. In: Program and abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington DC, Abstract no. F141

  110. Kurtz MB, Heath IB, Marrinan J, Dreikorn S, Onishi J, Douglas C (1994) Morphological effects of lipopeptides against Aspergillus fumigatus correlate with activities against (1,3)-beta-D-glucan synthase. Antimicrob Agents Chemother 38:1480–1489

    CAS  PubMed  Google Scholar 

  111. Oakley KL, Moore CB, Denning DW (1998) In vitro activity of the echinocandin antifungal agent LY303,366 in comparison with itraconazole and amphotericin B against Aspergillus species. Antimicrob Agents Chemother 42:2726–2730

    CAS  PubMed  Google Scholar 

  112. Rennie R, Sand C, Sherburne R (1997) Electron microscopic evidence of the effect of LY303366 on Aspergillus fumigatus. In: Abstracts of the 13th Meeting of the International Society for Human and Animal Mycology, Abstract no. P451

  113. Bowman JC, Hicks PS, Kurtz MB, Rosen H, Schmatz DM, Liberator PA, Douglas CM (2002) The antifungal echinocandin caspofungin acetate kills growing cells of Aspergillus fumigatus in vitro. Antimicrob Agents Chemother 46:3001–3012

    Article  CAS  PubMed  Google Scholar 

  114. Petraitiene R, Petraitis V, Groll AH, Candelario M, Sein T, Bell A, Lyman CA, McMillian CL, Bacher J, Walsh TJ (1999) Antifungal activity of LY303366, a novel echinocandin B, in experimental disseminated candidiasis in rabbits. Antimicrob Agents Chemother 43:2148–2155

    CAS  PubMed  Google Scholar 

  115. Petraitis V, Petraitiene R, Groll AH, Roussillon K, Hemmings M, Lyman CA, Sein T, Bacher J, Bekersky I, Walsh TJ (2002) Comparative antifungal activities and plasma pharmacokinetics of micafungin (FK463) against disseminated candidiasis and invasive pulmonary aspergillosis in persistently neutropenic rabbits. Antimicrob Agents Chemother 46:1857–1869

    Article  CAS  PubMed  Google Scholar 

  116. Petraitis V, Petraitiene R, Groll AH, Bell A, Callender DP, Sein T, Schaufele RL, McMillian CL, Bacher J, Walsh TJ (1998) Antifungal efficacy, safety, and single-dose pharmacokinetics of LY303366, a novel echinocandin B, in experimental pulmonary aspergillosis in persistently neutropenic rabbits. Antimicrob Agents Chemother 42:2898–2905

    Google Scholar 

  117. Petraitiene R, Petraitis V, Groll AH, Sein T, Schaufele RL, Francesconi A, Bacher J, Avila NA, Walsh TJ (2002) Antifungal efficacy of caspofungin (MK-0991) in experimental pulmonary aspergillosis in persistently neutropenic rabbits: pharmacokinetics, drug disposition, and relationship to galactomannan antigenemia. Antimicrob Agents Chemother 46:12–23

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  119. Klepser ME, Ernst EJ, Ernst ME, Pfaller MA (1997) Growth medium effect on the antifungal activity of LY303366. Diagn Microbiol Infect Dis 29:227–231

    Article  CAS  PubMed  Google Scholar 

  120. Green LJ, Marder P, Mann LL, Chio LC, Current WL (1999) LY303366 exhibits rapid and potent fungicidal activity in flow cytometric assays of yeast viability. Antimicrob Agents Chemother 43:830–835

    CAS  PubMed  Google Scholar 

  121. Zhanel G, Zelenitsky S, Laing N, Balko T, Karlowsky J, Hoban D (1998) Correlation between LY303366 area under the concentration curve (AUC) and regrowth of fluconazole sensitive (flu-s) and fluconazole-resistant (flu-r) Candida albicans, using an in vitro pharmacodynamic model. In: Program and abstracts of the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington DC, Abstract no. J-14

  122. Groll AH, Mickiene D, Petraitiene R, Petraitis V, Lyman CA, Bacher JS, Piscitelli SC, Walsh TJ (2001) Pharmacokinetic and pharmacodynamic modeling of anidulafungin (LY303366): reappraisal of its efficacy in neutropenic animal models of opportunistic mycoses using optimal plasma sampling. Antimicrob Agents Chemother 45:2845–2855

    Article  CAS  PubMed  Google Scholar 

  123. Matsumoto S, Warabe E, Wakai Y, Koide Y, Ushitani T, Teratani N, Ohtomo K, Hatano K, Ikeda F, Goto T, Matsumoto F, Kuwahara S (2000) Pharmacodynamics of FK463 in a thigh infection model with Candida albicans. In: Program and abstracts of the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington DC, Abstract no. 1687

  124. Louie A, Deziel M, Liu W, Drusano M, Gumbo T, Drusano GL (2003) AUC/MIC is the pharmacodynamic variable for caspofungin as determined in a non-neutropenic mouse model of candidiasis. In: Program and abstracts of the 43rd International Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington DC, Abstract no. A-1572

  125. Andes D, Marchillo K, Lowther J, Bryskier A, Stamstad T, Conklin R (2003) In vivo pharmacodynamics of HMR 3270, a glucan synthase inhibitor, in a murine candidiasis model. Antimicrob Agents Chemother 47:1187–1192

    Article  CAS  PubMed  Google Scholar 

  126. Lewis RE, Kontoyiannis DP (2001) Rationale for combination antifungal therapy. Pharmacotherapy 21 (Suppl):149–164

    PubMed  Google Scholar 

  127. Sugar AM (2001) Antifungal combination therapy. Curr Opin Invest Drugs 2:1364–1365

    CAS  Google Scholar 

  128. Medoff G, Comfort M, Kobayashi GS (1971) Synergistic action of amphotericin B and 5-fluorocytosine against yeast-like organisms. Proc Soc Exp Biol Med 138:571–574

    CAS  PubMed  Google Scholar 

  129. Bennett JE, Dismukes WE, Haywood M, Duma R, Medoff G (1979) A comparison of amphotericin B alone and in combination with flucytosine in the treatment of cryptococcal meningitis. N Engl J Med 301:126-131

    CAS  PubMed  Google Scholar 

  130. van der Horst CM, Saag MS, Cloud GA, et al (1997) Treatment of cryptococcal meningitis associated with the acquired immunodeficiency syndrome. N Engl J Med 337:15–21

    Article  Google Scholar 

  131. Schaffner A, Bohler A (1993) Amphotericin B refractory aspergillosis after itraconazole: evidence for significant antagonism. Mycoses 36:421–424

    CAS  PubMed  Google Scholar 

  132. Sugar AM, Hitchcock CA, Troke PF, Picard M (1995) Combination therapy of murine invasive candidiasis with fluconazole and amphotericin B. Antimicrob Agents Chemother 39:598–601

    CAS  PubMed  Google Scholar 

  133. Sugar AM, Liu XP (1998) Interactions of itraconazole with amphotericin B in the treatment of murine invasive candidiasis. J Infect Dis 177:1660–1663

    CAS  PubMed  Google Scholar 

  134. Rex JH, Pappas PG, Karchmer AW, Sobel J, Edwards JE, Hadley S, Brass C, Vazquez JA, et al, the National Institute of Allergy and Infectious Diseases Mycoses Study Group (2003) A randomized and blinded multicenter trial of high-dose fluconazole plus placebo versus fluconazole plus amphotericin B as therapy for candidemia and its consequences in nonneutropenic subjects. Clin Infect Dis 36:1221–1228

    Article  CAS  PubMed  Google Scholar 

  135. Groll AH, Walsh TJ (2001) Caspofungin: pharmacology, safety and therapeutic potential in superficial and invasive fungal infections. Expert Opin Invest Drugs 10:1545–1558

    CAS  Google Scholar 

  136. Groll AH, Walsh TJ (2000) FK-463. Curr Opin Anti-Infect Invest Drugs 2:405–412

  137. Kirkpatrick WR, Perea S, Coco BJ, Patterson TF (2002) Efficacy of caspofungin alone and in combination with voriconazole in a guinea pig model of invasive aspergillosis. Antimicrob Agents Chemother 46:2564–2568

    Article  CAS  PubMed  Google Scholar 

  138. Petraitis V, Petraitiene R, Sarafandi AA, Kelaher AM, Lyman CA, Casler HE, Sein T, Groll AH, Bacher J, Avila NA, Walsh TJ (2003) Combination therapy in treatment of experimental pulmonary aspergillosis: synergistic interaction between an antifungal triazole and an echinocandin. J Infect Dis 187:1834–1843

    Google Scholar 

  139. Rubin MA, Carroll KC, Cahill BC (2002) Caspofungin in combination with itraconazole for the treatment of invasive aspergillosis in humans. Clin Infect Dis 34:1160–1161

    Google Scholar 

  140. Aliff TB, Maslak PG, Jurcic JG, Heaney ML, Cathcart KN, Sepkowitz KA, Weiss MA (2003) Refractory Aspergillus pneumonia in patients with acute leukemia: successful therapy with combination caspofungin and liposomal amphotericin. Cancer 97:1025–1032

    Article  CAS  PubMed  Google Scholar 

  141. Wheat LJ (2003) Combination therapy for aspergillosis: is it needed, and which combination? J Infect Dis 187:1831–1833

    Article  PubMed  Google Scholar 

  142. Groll AH, De Lucca AJ, Walsh TJ (1998) Emerging targets for the development of novel antifungal therapeutics. Trends Microbiol 6:117–124

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to A. H. Groll.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Groll, A.H., Kolve, H. Antifungal Agents: In Vitro Susceptibility Testing, Pharmacodynamics, and Prospects for Combination Therapy. Eur J Clin Microbiol Infect Dis 23, 256–270 (2004). https://doi.org/10.1007/s10096-004-1108-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10096-004-1108-6

Keywords

Navigation