Amphotericin B/pharmacology; Antifungal Agents/pharmacology; Aspergillus/drug effects; Drug Antagonism; Drug Combinations; Drug Synergism; Echinocandins; Microbial Sensitivity Tests/methods; Peptides, Cyclic/pharmacology; Pyrimidines/pharmacology; Triazoles/pharmacology
Abstract :
[en] OBJECTIVES: The in vitro effects of caspofungin combined with voriconazole and amphotericin B were tested in triplicate experiments against nine clinical isolates of Aspergillus fumigatus, Aspergillus flavus and Aspergillus terreus. METHODS: The isolates were tested against a range of concentrations of voriconazole (0.015-1.0 mg/L), caspofungin (0.125-256 mg/L) and five concentrations of amphotericin B (0.1-0.5 mg/L) with a microdilution chequerboard method based on the CLSI M38-A reference method and the results were analysed with the fractional inhibitory concentration (FIC) index. The effect of individual drugs on the FIC index of each of the double combinations was also evaluated. RESULTS: The triple combination of voriconazole, caspofungin and amphotericin B against all Aspergillus spp. was synergistic (FIC index 0.49-0.57) at low median concentrations of amphotericin B (0.10-0.22 mg/L) and voriconazole (0.07-0.15 mg/L) over a wide range of caspofungin concentrations (4.32-17.28 mg/L). Antagonistic interactions (FIC index 1.65-2.15) were found at higher median concentrations of amphotericin B (0.3-0.5 mg/L) and voriconazole (0.23-0.68 mg/L) over a similarly wide range of caspofungin concentrations (1.47-32 mg/L). CONCLUSIONS: These concentration-dependent interactions may have important clinical implications, which require further evaluation in animal models of invasive aspergillosis.
Groll AH, Walsh TJ. Antifungal chemotherapy: Advances and perspectives. Swiss Med Wkly 2002; 132: 303-11.
Arikan S, Lozano-Chiu M, Paetznick V et al. In vitro synergy of caspofungin and amphotericin B against Aspergillus and Fusarium spp. Antimicrob Agents Chemother 2002; 46: 245-7.
Manavathu EK, Alangaden GJ, Chandrasekar PH. Differential activity of triazoles in two-drug combinations with the echinocandin caspofungin against Aspergillus fumigatus. J Antimicrob Chemother 2003; 51: 1423-5.
Perea S, Gonzalez G, Fothergill AW et al. In vitro interaction of caspofungin acetate with voriconazole against clinical isolates of Aspergillus spp. Antimicrob Agents Chemother 2002; 46: 3039-41.
Luque JC, Clemons KV, Stevens DA. Efficacy of micafungin alone or in combination against systemic murine aspergillosis. Antimicrob Agents Chemother 2003; 47: 1452-5.
Petraitis V, Petraitiene R, Sarafandi AA et al. Combination therapy in treatment of experimental pulmonary aspergillosis: Synergistic interaction between an antifungal triazole and an echinocandin. J Infect Dis 2003; 187: 1834-43.
Elanjikal Z, Sorensen J, Schmidt H et al. Combination therapy with caspofungin and liposomal amphotericin B for invasive aspergillosis. Pediatr Infect Dis J 2003; 22: 653-6.
Steinbach WJ, Stevens DA, Denning DW. Combination and sequential antifungal therapy for invasive aspergillosis: Review of published in vitro and in vivo interactions and 6281 clinical cases from 1966 to 2001. Clin Infect Dis 2003; 37 Suppl 3: S188-224.
Tascini C, Tagliaferri E, Iapoce R et al. Caspofungin in combination with itraconazole and amphotericin B for the treatment of invasive aspergillosis in humans, with a method to test ex vivo synergism. Clin Microbiol Infect 2003; 9: 901-2.
Sims-McCallum RP. Triple antifungal therapy for the treatment of invasive aspergillosis in a neutropenic pediatric patient. Am J Health Syst Pharm 2003; 60: 2352-6.
National Commmittee for Clinical Laboratory Standards. Reference Method for Broth Dilution Antifungal Susceptibility Testing of Filamentous Fungi: Approved Standard M38-A. NCCLS, Wayne, PA, USA, 2002.
Bekersky I, Fielding RM, Dressler DE et al. Pharmacokinetics, excretion, and mass balance of liposomal amphotericin B (AmBisome) and amphotericin B deoxycholate in humans. Antimicrob Agents Chemother 2002; 46: 828-33.
Walsh TJ, Karlsson MO, Driscoll T et al. Pharmacokinetics and safety of intravenous voriconazole in children after single- or multiple-dose administration. Antimicrob Agents Chemother 2004; 48: 2166-72.
Walsh TJ, Adamson PC, Seibel NL et al. Pharmacokinetics, safety, and tolerability of caspofungin in children and adolescents. Antimicrob Agents Chemother 2005; 49: 4536-45.
Berenbaum MC. A method for testing for synergy with any number of agents. J Infect Dis 1978; 137: 122-30.
Eliopoulos G, Moellering RC Jr. Antimicrobial combinations. In: Lorian V, ed. Antibiotics in Laboratory Medicine. Baltimore, MD: The Williams & Wilkins Co., 1996; 330-96.
Hidler J. Antimicrobial susceptibility testing. In: Isenberg HD, ed. Clinical Microbiology Procedures Handbook. Washington, DC: ASM Press, 1995; pp. 15.18.11-15.18.20.
Meletiadis J, Mouton JW, Meis JF et al. Methodological issues of drug interaction modelling in moulds. Rev Med Microbiol 2003; 47: 106-17.
Vitale RG, Afeltra J, Dannaoui E. Antifungal combinations. Methods Mol Med 2005; 118: 143-52.
Meletiadis J, Verweij PE, te Dorsthorst DTA et al. Assessing in vitro combinations of antifungal drugs against yeasts and filamentous fungi: comparison of different drug interaction models. Med Mycol 2005; 34: 133-52.
Odds FC. Synergy, antagonism, and what the chequerboard puts between them. J Antimicrob Chemother 2003; 52: 1.
Johnson MD, MacDougall C, Ostrosky-Zeichner L et al. Combination antifungal therapy. Antimicrob Agents Chemother 2004; 48: 693-715.
Berenbaum MC. What is synergy? Pharmacol Rev 1989; 41: 93-141.
Yoon J, Urban C, Terzian C et al. In vitro double and triple synergistic activities of polymyxin B, imipenem, and rifampin against multidrug-resistant Acinetobacter baumannii. Antimicrob Agents Chemother 2004; 48: 753-7.
Odds FC. Interactions among amphotericin B, 5-fluorocytosine, ketoconazole, and miconazole against pathogenic fungi in vitro. Antimicrob Agents Chemother 1982; 22: 763-70.
Yu VL, Zuravleff JJ, Bornholm J et al. In-vitro synergy testing of triple antibiotic combinations against Staphylococcus epidermidis isolates from patients with endocarditis. J Antimicrob Chemother 1984; 14: 359-66.
Dannaoui E, Lortholary O, Dromer F. In vitro evaluation of double and triple combinations of antifungal drugs against Aspergillus fumigatus and Aspergillus terreus. Antimicrob Agents Chemother 2004; 48: 970-8.
Kirkpatrick WR, Perea S, Coco BJ et al. Efficacy of caspofungin alone and in combination with voriconazole in a guinea pig model of invasive aspergillosis. Antimicrob Agents Chemother 2002; 46: 2564-8.
Cuenca-Estrella M, Gomez-Lopez A, Garcia-Effron G et al. Combined activity in vitro of caspofungin, amphotericin B, and azole agents against itraconazole-resistant clinical isolates of Aspergillus fumigatus. Antimicrob Agents Chemother 2005; 49: 1232-5.
Clemons KV, Espiritu M, Parmar R et al. Comparative efficacies of conventional amphotericin B, liposomal amphotericin B (AmBisome), caspofungin, micafungin, and voriconazole alone and in combination against experimental murine central nervous system aspergillosis. Antimicrob Agents Chemother 2005; 49: 4867-75.
Sionov E, Mendlovic S, Segal E. Efficacy of amphotericin B or amphotericin B-intralipid in combination with caspofungin against experimental aspergillosis. J Infect 2006; 53: 131-9.
Meletiadis J, Petraitis V, Petraitiene R et al. Triazole-polyene antagonism in experimental invasive pulmonary aspergillosis: In vitro and in vivo correlation. J Infect Dis 2006; 194: 1008-18.
Meletiadis J, te Dortshorst DTA, Verweij PE. The concentration-dependent nature of amphotericin B-itraconazole interaction in vitro against Aspergillus fumigatus: Isobolographic and response surface analysis of complex pharmacodynamic interactions. Int J Antimicrob Agents 2006; 28: 439-449.
Lamb D, Kelly D, Kelly S. Molecular aspects of azole antifungal action and resistance. Drug Resist Updat 1999; 2: 390-402.
Schaffner A, Bohler A. Amphotericin B refractory aspergillosis after itraconazole: Evidence for significant antagonism. Mycoses 1993; 36: 421-4.
Scheven M, Schwegler F. Antagonistic interactions between azoles and amphotericin B with yeasts depend on azole lipophilia for special test conditions in vitro. Antimicrob Agents Chemother 1995; 39: 1779-83.
Sugar AM, Liu XP. Interactions of itraconazole with amphotericin B in the treatment of murine invasive candidiasis. J Infect Dis 1998; 177: 1660-3.
Moore CB, Sayers N, Mosquera J et al. Antifungal drug resistance in Aspergillus. J Infect 2000; 41: 203-20.
Manavathu EK, Vazquez JA, Chandrasekar PH. Reduced susceptibility in laboratory-selected mutants of Aspergillus fumigatus to itraconazole due to decreased intracellular accumulation of the antifungal agent. Int J Antimicrob Agents 1999; 12: 213-19.
Cohen BE. Concentration- and time-dependence of amphotericin-B induced permeability changes across ergosterol-containing liposomes. Biochim Biophys Acta 1986; 857: 117-22.
