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Antimicrobial Agents and Chemotherapy, April 2002, p. 1032-1037, Vol. 46, No. 4
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.4.1032-1037.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Antifungal Activities of Posaconazole, Ravuconazole, and Voriconazole Compared to Those of Itraconazole and Amphotericin B against 239 Clinical Isolates of Aspergillus spp. and Other Filamentous Fungi: Report from SENTRY Antimicrobial Surveillance Program, 2000

M. A. Pfaller,1* S. A. Messer,1 R. J. Hollis,1 R. N. Jones,2 and and the Sentry Participants Group

Department of Pathology, University of Iowa College of Medicine, Iowa City,1 The JONES Group/JMI Laboratories, North Liberty, Iowa2

Received 19 October 2001/ Returned for modification 10 December 2001/ Accepted 8 January 2002


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ABSTRACT
 
Posaconazole, ravuconazole, and voriconazole are new triazole derivatives that possess potent, broad-spectrum antifungal activity. We evaluated the in vitro activity of these investigational triazoles compared with that of itraconazole and amphotericin B against 239 clinical isolates of filamentous fungi from the SENTRY Program, including Aspergillus spp. (198 isolates), Fusarium spp. (7 isolates), Penicillium spp. (19 isolates), Rhizopus spp. (4 isolates), Mucor spp. (2 isolates), and miscellaneous species (9 isolates). The isolates were obtained from 16 different medical centers in the United States and Canada between January and December 2000. In vitro susceptibility testing was performed using the microdilution broth method outlined in the National Committee for Clinical Laboratory Standards M38-P document. Overall, posaconazole was the most active compound, inhibiting 94% of isolates at a MIC of <=1 µg/ml, followed by voriconazole (91%), amphotericin B (89%), ravuconazole (88%), and itraconazole (70%). All three new triazoles demonstrated excellent activity (MIC, <=1 µg/ml) against Aspergillus spp. (114 Aspergillus fumigatus, 22 Aspergillus niger, 13 Aspergillus flavus, 9 Aspergillus versicolor, 8 Aspergillus terreus, and 32 Aspergillus spp.): posaconazole (98%), voriconazole (98%), ravuconazole (92%), amphotericin B (89%), and itraconazole (72%). None of the triazoles were active against Fusarium spp. (MIC at which 50% of the isolates tested were inhibited [MIC50], >8 µg/ml) or Mucor spp. (MIC50, >8 µg/ml). Posaconazole and ravuconazole were more active than voriconazole against Rhizopus spp. (MIC50, 1 to 2 µg/ml versus >8 µg/ml, respectively). Based on these results, all three new triazoles exhibited promising activity against Aspergillus spp. and other less commonly encountered isolates of filamentous fungi. The clinical value of these in vitro data remains to be seen, and in vitro-in vivo correlation is needed for both new and established antifungal agents. Surveillance efforts should be expanded in order to monitor the spectrum of filamentous fungal pathogens and their in vitro susceptibility as these new antifungal agents are introduced into clinical use.


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INTRODUCTION
 
Although Candida spp. and Cryptococcus neoformans remain the most common causes of invasive opportunistic mycotic infection (14, 15, 35), serious infections due to Aspergillus spp. and other filamentous fungi are emerging as prominent causes of infectious morbidity and mortality worldwide (5, 11, 13, 27). Invasive aspergillosis occurs at a rate of 12.4 cases per million people per year in the United States (35). Dasbach et al. (4) estimated that invasive aspergillosis increased by approximately eightfold between 1976 and 1996, with over 10,000 cases and a cost of $548 million annually in the United States. Likewise, an expanding number of hyaline filamentous fungi (e.g. Fusarium, Acremonium, Penicillium, and Scedosporium species), Zygomycetes, and dematiaceous filamentous fungi (e.g., Bipolaris, Alternaria, and Exophiala species) pose additional threats to the ever-increasing population of immunocompromised hosts in hospitals and the community (13, 27, 29, 35).

Current diagnostic and therapeutic approaches fall short in addressing the problem of filamentous fungal infections (5, 13, 16). Although amphotericin B remains the standard therapy for these infections, therapeutic outcomes are suboptimal (3, 13, 37, 39). Clearly, there is a need for alternative antifungal agents to address these serious infections (7, 12, 13, 17, 38).

Although ongoing antimicrobial surveillance systems have provided useful information regarding the spectrum of pathogens and the antifungal susceptibility of yeasts causing invasive fungal infections (1, 15, 30, 31, 33), there is little, if any, such information for the filamentous fungi (29, 35). Expansion of existing surveillance programs to include filamentous fungi will provide information regarding the frequency of various species causing invasive disease and in vitro susceptibility testing of these opportunistic pathogens against both new and established antifungal agents will provide data that may have important implications for antifungal drug treatment regimens in the appropriate clinical setting.

The SENTRY Antimicrobial Surveillance Program has documented the spectrum and activity of various antifungal agents against Candida spp. on a global scale since 1997 (6, 30-33). In January 2000, the SENTRY Surveillance Program was expanded to include monitoring of Aspergillus spp. and other filamentous fungi causing invasive mycoses in hospitalized patients. Clinical isolates from 16 different medical centers were sent to the University of Iowa for characterization, including antifungal susceptibility testing. In this study, we report the results of the first 12 months of filamentous fungal pathogen surveillance in the SENTRY Program (United States and Canada) and compare the in vitro activity of three new triazole antifungal agents, posaconazole, ravuconazole, and voriconazole, with that of itraconazole and amphotericin B using the National Committee for Clinical Laboratory Standards (NCCLS) M38-P microdilution method (23).


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MATERIALS AND METHODS
 
Organisms. A total of 239 clinical isolates of filamentous fungi were obtained from 16 different medical centers in the United States (14 centers) and Canada (2 centers) between January and December 2000. The isolates were obtained from a variety of sources, including sputum, bronchoscopy, and tissue biopsy specimens. The collection included the following isolates: Aspergillus fumigatus, (114 isolates), Aspergillus niger (22 isolates), Aspergillus flavus (13 isolates), Aspergillus versicolor (9 isolates), Aspergillus terreus (8 isolates), Aspergillus spp. (32 isolates), Penicillium spp. (19 isolates), Fusarium spp. (7 isolates), Rhizopus spp. (4 isolates), Mucor spp. (2 isolates), Paecilomyces spp. (2 isolates), Trichosporon spp. (2 isolates), and one isolate each of Acremonium sp., Biopolaris sp., Chrysosporium sp., Geotrichum sp., and Wangiella dermatitidis. All isolates were stored as spore suspensions in sterile distilled water at room temperature until they were used in the study. Before testing, each isolate was subcultured at least twice on potato dextrose agar (Remel, Lenexa, Kans.) to ensure its viability and purity.

Antifungal drugs. Posaconazole (Schering-Plough Research Institute, Kenilworth, N.J.), ravuconazole (Bristol-Myers Squibb, Wallingford, Conn.), voriconazole (Pfizer Pharmaceutical Group, New York, N.Y.), itraconazole (Janssen, Beerse, Belgium) and amphotericin B (Sigma Chemical Co., St. Louis, Mo.) were all obtained as reagent-grade powders from their respective manufacturers. Stock solutions were prepared in polyethylene glycol (posaconazole and itraconazole) and dimethyl sulfoxide (ravuconazole, voriconazole, and amphotericin B). All drugs were diluted in RPMI 1640 medium (Sigma Chemical Co.) buffered to pH 7.0 with 0.165 M morpholinepropanesulfonic acid (MOPS) buffer (Sigma) and dispensed into 96-well microdilution trays. The recommendations stated in NCCLS document M38-P were followed for the dilution of each antifungal agent (23). Trays containing an aliquot of 0.1 ml in each well of appropriate drug solution (2x final concentration) were sealed and stored at -70°C until they were used. The final ranges of drug concentrations tested were 0.008 to 8 µg/ml for all five antifungal agents.

Susceptibility testing. MICs were determined by the NCCLS M38-P broth microdilution methodology (23). Briefly, each isolate was grown on potato dextrose agar slants at 35°C for a period of 7 days. The fungal colonies were then covered with 1 ml of sterile 0.85% saline and gently scraped with a sterile pipette. The resulting suspensions were transferred to sterile tubes, and heavy particles were allowed to settle. The turbidity of the conidial spore suspensions was measured at 530 nm and was adjusted to obtain a final inoculum of 0.4 x 104 CFU/ml. To determine the final inoculum, an appropriate dilution was performed and an aliquot (0.01 ml) was plated on potato dextrose agar (Remel). Plates were incubated at 30°C and were examined daily for the presence of fungal colonies. The microdilution trays were incubated at 35°C, and MICs were read at 48 h. Drug-free controls were included in each tray. Following incubation, MIC endpoints were interpreted with the aid of a reading mirror. Only wells that showed no growth (optically clear) or approximately 75% reduction in growth compared to that of drug-free controls were recorded as the MIC.

Quality control. Quality control was ensured by testing the following strains recommended in the NCCLS M38-P document (23): A. flavus ATCC 204304, Candida parapsilosis ATCC 22019, and Candida krusei ATCC 6258. All results were within the recommended limits.


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RESULTS AND DISCUSSION
 
The antifungal activities of posaconazole, ravuconazole, voriconazole, itraconazole, and amphotericin B against 198 isolates of Aspergillus spp. are shown in Table 1. Posaconazole, ravuconazole, and voriconazole were all highly active against A. fumigatus (98 to 100% susceptible at a MIC of <=1 µg/ml), A. flavus (100%), A. terreus (100%), and Aspergillus spp. (91 to 94%). Among the 198 isolates of Aspergillus species tested, 98% were inhibited by <=1 µg/ml of posaconazole and voriconazole, followed by ravuconazole (92%), amphotericin B (89%), and itraconazole (72%). Notably, only 25% of A. terreus isolates were inhibited by <=1 µg/ml of amphotericin B compared to 92% of all other Aspergillus species.


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  		TABLE 1. In vitro susceptibilities of 198 isolates of Aspergillus species to amphotericin B, itraconazole, and three investigational triazole antifungal agents

The new triazoles were less active against the miscellaneous filamentous fungi (Table 2). None of the triazoles, including itraconazole, were active against Fusarium spp. (MIC at which 50% of the isolates tested were inhibited [MIC50], >8 µg/ml) or Mucor spp. (MIC50, >8 µg/ml). Although the number of isolates was small, posaconazole, ravuconazole, and voriconazole were more active against isolates of Pencillium spp. (MIC90, 1 µg/ml), Paecilomyces spp. (MIC50, 0.12 to 2 µg/ml), Trichosporon spp. (MIC50, 0.12 to 1 µg/ml), Acremonium sp. (MIC, 0.5 to 1 µg/ml), Bipolaris sp. (MIC, 0.5 to 1 µg/ml), Geotrichum sp. (MIC, 0.06 to 0.5 µg/ml) and W. dermatitidis (MIC, 0.06 to 1 µg/ml). Posaconzole and ravuconazole were more active than voriconazole against Rhizopus spp. (MIC50, 1 to 2 µg/ml versus >8 µg/ml, respectively).


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  		TABLE 2. In vitro susceptibilities of 41 isolates of miscellaneous filamentous fungi to amphotericin B, itraconazole, and three investigational triazole antifungal agents

Overall, 94% of the 239 filamentous fungi tested were inhibited by <=1 µg/ml of posaconazole, followed by voriconazole (91%), amphotericin B (89%), ravuconazole (88%), and itraconazole (70%) (data not shown).

These findings agree with those published earlier with smaller numbers of filamentous fungal isolates (8-10, 18, 19, 21, 25, 34). We found that all three investigational triazoles were more active than itraconazole against all of the Aspergillus species tested. In almost every instance, the in vitro potencies of posaconazole, ravuconazole, and voriconazole were comparable to one another and slightly greater than that of amphotericin B. Our findings for voriconazole against Rhizopus spp. and for all three new triazoles against Fusarium spp. and Mucor spp. are in agreement with previously published in vitro data (8-10, 18, 19, 21, 25, 34, 36). However, clinical studies of refractory mycoses treated with voriconazole or posaconazole documented success rates of 38 and 50%, respectively, in treatment of invasive fusariosis (R. Y. Hachem, I. I. Raad, C. M. Afif, R. Negroni, J. Graybill, S. Hadley, H. Kantarjian, S. Adams, and G. Mukwaya, 40th Intersci. Conf. Antimicrob. Agents Chemother., abstr. 1009, 2000; J. R. Perfect, I. Lutsar, A. Gonzalez-Ruiz, 38th Ann. Meeting Infect. Dis. Soc. Am., abstr. 303, 2000).

These promising in vitro data do seem to be corroborated by encouraging in vivo results from experimental models and early clinical studies although additional data correlating in vitro activity with clinical outcome are clearly needed (2, 20, 22, 26, 28, 36; B. Dupont, D. E. Denning, H. Lode, S. Yanren, P. F. Troke, and N. Sarantis, 36th ICAAC, abstr. F81, 1995; Hachem et al. 40th ICAAC). Pharmacokinetic studies with all three new triazoles have demonstrated peak concentrations of >5 µg/ml in plasma, with sustained levels exceeding 1 µg/ml (24, 28; D. M. Grasela, S. J. Olsen, V. Mummaneni, P. Rolan, L. Christopher, J. Norton, O. H. Hadjilambris, and M. R. Marino, 40th ICAAC, abstr. 839, 2000; B. E. Patterson and P. E. Coates, 35th ICAAC, abstr. F78, 1995). Thus, the dosing regimens for these agents result in concentrations in plasma that exceed the MICs for 92 to 98% of Aspergillus species and 88 to 94% of all of the tested filamentous fungi (Tables 1 and 2).

We have also provided further evidence for the feasibility of the NCCLS M38-P broth microdilution method for comparing the activity of both new and established antifungal agents and for testing larger numbers of filamentous fungal isolates in the context of an antifungal surveillance program. Continued longitudinal surveillance efforts of this type using standardized susceptibility testing methods will provide the means with which to track the emergence of antifungal resistance over time among Aspergillus species and other filamentous fungal pathogens. The role of such testing in clinical decision-making, however, must await further studies establishing a correlation between in vitro MIC data and clinical outcome. Until such information is available, routine in vitro susceptibility testing of filamentous fungi as a prelude to clinical decision-making is not warranted (23).

Recently, Espinel-Ingroff et al. (10) reported that the NCCLS M38-P microdilution method was able to reliably differentiate between susceptible and potentially resistant strains of Aspergillus species for itraconazole and possibly for the new triazoles as well. Espinel-Ingroff et al. (10) noted that cross-resistance between itraconazole and the newer triazoles was not universal and may vary according to the strain of Aspergillus and the specific triazole being tested. Our results support these findings and are most notable for A. fumigatus, of which >=95% of 114 isolates were inhibited by <=0.5 µg/ml of posaconazole, ravuconazole, and voriconazole compared to only 24% with itraconazole (Table 1).

In summary, we found that posaconazole, ravuconazole, and voriconazole all exhibit excellent in vitro activity against Aspergillus spp. and several less common filamentous fungi. These agents are more active than amphotericin B against Aspergillus spp. and offer important advantages over itraconazole in terms of spectrum and potency. Continued surveillance for emerging resistance and continued development of these exciting new agents is encouraged.


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ACKNOWLEDGMENTS
 
We thank Linda Elliott for secretarial assistance in the preparation of the manuscript. We appreciate the contributions of all SENTRY site participants. The following participants contributed data or isolates to the study: Christiana Care Health Services, Wilmington, Del. (L. Steele-Moore); Summa Health System, Akron, Ohio (J. R. Dipersio), University of New Mexico Health Sciences Center, Albuquerque, N.M. (G. D. Overturf), University of Iowa Health Care, Iowa City, Iowa (M. A. Pfaller), Froedtert Memorial Lutheran Hospital, Milwaukee, Wis. (S. Kehl), Strong Memorial Hospital, Rochester, N.Y. (D. Hardy), University of Washington Medical Center, Seattle, Wash. (S. Swanzy and T. Fritsche), University of Texas Medical Branch at Galveston, Galveston, Tex. (B. Reisner), University of Louisville Hospital, Louisville, Ky. (J. Snyder), University of Virginia Health System, Charlottesville, Va. (K. Hazen), University of Utah Hospitals and Clinics, Salt Lake City, Utah (K. Carroll), Lahey Clinic, Burlington, Mass. (K. Chapin), Mount Sinai Medical Center, Miami Beach, Fla. (S. Sharp), Mount Sinai Medical Center, New York, N.Y. (S. Jenkins), University of Alberta Hospital, Edmonton, Canada (R. Rennie), and Ottawa Hospital, Ottawa, Ontario, Canada (B. Toye).

This study was supported in part by research and educational grants from Bristol-Myers Squibb Company (SENTRY), Pfizer Pharmaceuticals, and Schering-Plough Research Institute.


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FOOTNOTES
 
* Corresponding author. Mailing address: Medical Microbiology Division, C606 GH, Department of Pathology, University of Iowa College of Medicine, Iowa City, IA 52242. Phone: (319) 384-9566. Fax: (319) 356-4916. E-mail: michael-pfaller{at}uiowa.edu. Back


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Antimicrobial Agents and Chemotherapy, April 2002, p. 1032-1037, Vol. 46, No. 4
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.4.1032-1037.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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