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Antimicrobial Agents and Chemotherapy, March 2006, p. 917-921, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.917-921.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Head-to-Head Comparison of the Activities of Currently Available Antifungal Agents against 3,378 Spanish Clinical Isolates of Yeasts and Filamentous Fungi

Manuel Cuenca-Estrella,* Alicia Gomez-Lopez, Emilia Mellado, Maria J. Buitrago, Araceli Monzon, and Juan Luis Rodriguez-Tudela

Servicio de Micología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Madrid, Spain

Received 16 November 2005/ Returned for modification 10 December 2005/ Accepted 3 January 2006


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ABSTRACT
 
We have compared the activities of posaconazole and other currently available antifungal agents against a collection of 3,378 clinical isolates of yeasts and filamentous fungi. A total of 1,997 clinical isolates of Candida spp., 359 of other yeast species, 697 strains of Aspergillus spp., and 325 nondermatophyte non-Aspergillus spp. were included. The average geometric means of the MICs of agents that were tested against Candida spp. were 0.23 µg/ml for amphotericin B, 0.29 µg/ml for flucytosine, 0.97 µg/ml for fluconazole, 0.07 µg/ml for itraconazole, 0.04 µg/ml for voriconazole, 0.15 µg/ml for caspofungin, and 0.03 µg/ml for posaconazole. Voriconazole and posaconazole were active in vitro against the majority of isolates, with resistance to fluconazole and itraconazole, and against Cryptococcus neoformans and other Basidiomycota yeasts. Posaconazole was the most active of antifungal agents tested against Aspergillus spp., with an average geometric mean of 0.10 µg/ml. It was active against Paecilomyces spp., Penicillium spp., Scedosporium apiospermum, and some black fungi, such as Alternaria spp. Multiresistant filamentous fungi, such as Scedosporium prolificans, Scopulariopsis brevicaulis, and Fusarium solani, were also resistant to voriconazole, caspofungin, and posaconazole. Amphotericin B and posaconazole were found to be active against most of the Mucorales strains tested. Posaconazole and currently available antifungal agents exhibit a potent activity in vitro against the majority of pathogenic fungal species.


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INTRODUCTION
 
Posaconazole is a new triazole agent with an extended spectrum of in vitro activity. It is active against opportunistic, endemic, and dermatophytic fungi (10, 13, 14, 15) as well as Candida, Cryptococcus, and other yeast species (1, 3, 17, 22, 23), including isolates that exhibit resistance to fluconazole and itraconazole (3, 10, 23). It also has a potent activity in vitro against Aspergillus species; posaconazole appears to be more active in vitro against Aspergillus than are amphotericin B, itraconazole, voriconazole, and ravuconazole, inhibiting 95% of isolates at a MIC of ≤1 µg/ml (2, 9, 24). In addition, the new triazoles have been shown to have antifungal activity against other species of filamentous fungi, such as Penicillium spp., Paecilomyces spp., and Acremonium spp., and Sporothrix schenckii as well as some isolates of Fusarium spp., Scedosporium apiospermum, and black fungi (9, 10, 13, 18, 24, 30). Most notably, posaconazole is more active than the other triazole compounds against zygomycetes, with MICs around or below 1 µg/ml. Within the class of Zygomycetes, posaconazole appears to be more active against Rhizopus spp. and Absidia corymbifera than against Mucor spp., which is consistent with the prior observation that the zygomycetes appear to be a heterogeneous group with regard to their susceptibilities to antifungal agents (7, 9, 16, 24, 29).

We have analyzed the in vitro activity of posaconazole and other currently available antifungal agents against a collection of 3,378 clinical isolates of yeasts and filamentous fungi. A total of 1,997 clinical isolates of Candida spp., 359 of other yeast species, 697 strains of Aspergillus spp., and 325 nondermatophyte non-Aspergillus spp. were included, representing one of the largest and most diverse panels of fungal species that have been tested to date against posaconazole. Comparisons between susceptibility results per species were done in order to better understand the activity profile of this novel antifungal agent.


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MATERIALS AND METHODS
 
The strains were recovered from 102 Spanish hospitals through a period of five years, from 2001 to 2006. The isolates were obtained from blood (1,327/3,378, 39.3%), respiratory tract specimens (804/3,378, 23.8%), biopsies and other deep sites, (365/3,378, 10.8%), skin samples (247/3,378, 7.3%), and other locations (635/3,378, 18.8%). Candida parapsilosis ATCC 22019, Candida krusei ATCC 6258, Cryptococcus neoformans ATCC 90112, Aspergillus fumigatus ATCC 204306, and Aspergillus flavus ATCC 204304 were included as control isolates.

The antifungal agents used in the study were posaconazole (Schering-Plough, Kenilworth, NJ), amphotericin B (Sigma-Aldrich Química, SA, Madrid, Spain), flucytosine (Sigma-Aldrich), fluconazole (Pfizer, SA, Madrid, Spain), itraconazole (Janssen Pharmaceutica, Madrid, Spain), voriconazole (Pfizer, Ltd., Sandwich, United Kingdom), and caspofungin (Merck & Co., Inc., Rahway, NJ).

Susceptibility testing was performed by broth microdilution. For Candida species, MICs were determined by using the reference procedure of the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antibiotic Susceptibility Testing for testing fermentative yeasts (AFST-EUCAST, document 7.1) (25). Briefly, testing was performed in flat-bottomed microdilution plates by using RPMI 1640 medium supplemented with 2% glucose and an inoculum size of 106 CFU/ml. MIC end points were determined spectrophotometrically at 24 and 48 h. For amphotericin B, the MIC end points were defined as the lowest drug concentration that resulted in a reduction in growth of 90% or more compared with that of a drug-free-growth control well. For flucytosine and azoles, the MIC end point was defined as a 50% reduction in optical density. Caspofungin susceptibility testing was done following the recommendations of Odds et al. (21).

For C. neoformans and other species of nonfermentative yeasts, susceptibility testing strictly followed the recommendations proposed by the EUCAST, with the following minor modification: microdilution plates were sealed to limit evaporation, attached to an electrically driven wheel inside the incubator, and agitated at 350 rpm at 30°C for 48 h (26).

For filamentous fungi broth, microdilution testing was performed following the Clinical Laboratory Standards Institute (CLSI) reference method (19), with the following minor modifications: RPMI 1640 with L-glutamine (buffered to pH 7 with 0.165 M morpholinepropanesulfonic acid [MOPS] and 10 M NaOH) supplemented with 2% glucose (RPMI-2% glucose; OXOID, Madrid, Spain) and an inoculum size of 1 x 106 to 5 x 106 CFU/ml (8, 12, 27). Denning et al. (8) demonstrated that inoculum sizes higher than those proposed by CLSI document M38-A (1 x 104 to 5 x 104 CFU/ml) also generate reproducible in vitro susceptibility data for Aspergillus spp. that can predict clinical outcome. Gomez-Lopez et al. (12) did not find significant differences in MICs using RPMI 1640 or RPMI 1640 supplemented with glucose, and MICs were not falsely elevated even if an inoculum size of 106 CFU/ml was used. Inoculum suspensions were prepared from plates that were 3 to 5 days old. The plates were incubated at 35°C for 48 h in a humid atmosphere, and visual readings were performed with the help of a mirror. The MIC was defined as the lowest concentration of drug that completely inhibited growth. Caspofungin was not tested since a reference method for filamentous fungi has not been defined.

Statistical analysis was done with the Statistical Package for the Social Sciences (SPSS, version 13.0.) (SPSS, SL, Madrid, Spain).


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RESULTS
 
The MICs for all antifungal agents are summarized in Tables 1 and 2. The average geometric mean (GM) for posaconazole against Candida spp. was 0.03 µg/ml, and the GMs for the other drugs were as follows: amphotericin B, 0.23 µg/ml; flucytosine, 0.29 µg/ml; fluconazole, 0.97 µg/ml; itraconazole, 0.07 µg/ml; voriconazole, 0.04 µg/ml; and caspofungin, 0.15 µg/ml. Posaconazole and voriconazole were active against the majority of isolates belonging to species which can frequently exhibit decreased susceptibility or resistance to fluconazole, such as Candida glabrata, Candida krusei, Candida guilliermondii, Candida famata, and Candida pelliculosa. In addition, the panel that was tested included a number of fluconazole-resistant strains of species that are normally susceptible to fluconazole. For this subset of isolates, posaconazole and voriconazole were active in vitro against 12 out of 15 (80%) strains of Candida albicans, 2 out of 5 (40%) strains of Candida tropicalis, and all 3 (100%) of the C. parapsilosis isolates.


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  		TABLE 1. Susceptibility in vitro to posaconazole and other antifungal agents of yeast species


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  		TABLE 2. Susceptibility in vitro to posaconazole and other antifungal agents of filamentous fungi included in the study

In reference to other species of yeasts, posaconazole was highly active against Dipodascus capitatus, Saccharomyces cerevisiae, Yarrowia lipolytica, and Galactomyces geotrichum. Posaconazole was also active against species of Basidiomycota. The GM of posaconazole for C. neoformans var. neoformans was 0.16 µg/ml, and only one strain had a MIC of >1 µg/ml. The GM for tested isolates of C. neoformans var. gattii was 0.25, and all strains were inhibited at a MIC of ≤0.5 µg/ml. Posaconazole was less active against Trichosporon spp., with a GM that was significantly higher than those of other species. A total of 11 out of 45 (24.4%) Trichosporon strains tested had posaconazole MICs of ≥2 µg/ml; 6 of these strains were Trichosporon asahii. Notably, 12 of 24 Rhodotorula mucilaginosa organisms had posaconazole MICs of ≤1 µg/ml; the GM for all 24 strains was 1.68 µg/ml. The majority of R. mucilaginosa isolates were resistant to fluconazole, itraconazole, and voriconazole.

For the filamentous fungi, posaconazole was the most active of the antifungal agents tested against Aspergillus spp. Its average GM was 0.10 µg/ml, and the GMs of amphotericin B, itraconazole, and voriconazole were 0.41, 0.33, and 0.48, respectively. Posaconazole was active in vitro particularly against A. fumigatus and Aspergillus terreus. The collection that was tested included nine Aspergillus isolates with itraconazole resistance in vitro (MIC > 8 µg/ml). Posaconazole exhibited activity against five of these nine isolates (55.5%). More precisely, posaconazole was active against one of the three A. fumigatus strains, the A. terreus isolate, and all three Aspergillus niger isolates; however, it lacked activity against the itraconazole-resistant Aspergillus nidulans strains.

Other species of hyaline filamentous fungi were also susceptible in vitro to posaconazole, and almost all of the isolates from the following genera were inhibited by the triazole: Penicillium spp., Paecilomyces spp., Acremonium spp., and Arthrographis spp. The GM of posaconazole against S. apiospermum was 1.3 µg/ml, and 40 out of 65 (61.5%) isolates analyzed were inhibited by the agent. However, the most active compound against S. apiospermum was voriconazole, with a GM of 0.89 µg/ml and a MIC of ≤1 µg/ml for 58 of 65 (89.2%) organisms tested. Posaconazole was inactive in vitro against most of Scopulariopsis spp., Fusarium spp., and Trichoderma spp., with an average GM of >4 µg/ml. In the case of Fusarium spp., posaconazole exhibited activity in vitro for only 1 of 15 Fusarium oxysporum isolates and for 3 of 11 Fusarium verticilloides isolates studied.

None of the antifungal agents that were tested appeared to be active against the black fungus Scedosporium prolificans. With regard to other black fungi, posaconazole was active against the majority of Alternaria isolates (9/11, 82%) and the three Rhinocladiella strains. The limited number of isolates analyzed for the other species prevents significant conclusions from being drawn.

Finally, posaconazole was shown to have an inhibitory effect for some Mucorales isolates. The majority of these isolates were susceptible in vitro to amphotericin B and resistant to itraconazole and voriconazole. The average GM of posaconazole for 31 isolates tested was 1.1 µg/ml. Nine of 31 (29%) strains were resistant in vitro to posaconazole, with MICs as high as >8 µg/ml. The compound was more active against Rhizopus oryzae, Absidia corymbifera, and Rhizomucor pusillus, with MICs of ≤1 µg/ml for 12 of 15 (80%) R. oryzae isolates and for all A. corymbifera organisms tested. However, the majority of isolates of Mucor spp. and of Rhizopus microsporus were resistant in vitro to the triazole.

Table 3 displays the susceptibility results for reference strains per antifungal agent tested. Table 3 includes MIC data after 30 repetitions on different days. In addition, Table 3 shows MICs that were obtained for reference strains by the reference procedures of CLSI documents M27-A2 and M38-A (19, 20).


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  		TABLE 3. MIC ranges (µg/ml) for control strains by reference procedures and by the modified methodsa


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DISCUSSION
 
We present the results of one of the largest and the most diversified surveys on the profile of activity in vitro of posaconazole and other currently available antifungal agents. The triazole showed a good activity against the majority of species studied. The GM of MICs of posaconazole for the 3,378 isolates was 0.11 µg/ml. Breakpoints for posaconazole have not been established, but pharmacokinetic studies have shown that after the administration of posaconazole oral suspension (800 mg), the resulting maximum serum concentrations ranged between 1 and 2 µg/ml (4, 11, 16).

Posaconazole exhibited potent activity against Candida spp., extending to species and isolates with decreased susceptibility or resistance to fluconazole. Of the 186 isolates with a fluconazole MIC of ≥16 µg/ml, only 27 had a posaconazole MIC of >1 µg/ml; put another way, 85.5% of strains that exhibited decreased susceptibility in vitro to fluconazole were susceptible to posaconazole. In addition, 32 of the 59 (54.3%) itraconazole-resistant isolates (MIC ≥ 1 µg/ml), and 10 of the 37 (27%) strains with decreased susceptibility to voriconazole (MIC ≥ 2 µg/ml), exhibited posaconazole MICs of ≤1 µg/ml.

Posaconazole was particularly active against Cryptococcus neoformans isolates; its activity was similar to that of amphotericin B and superior to that of either itraconazole or voriconazole. In addition, posaconazole was active against many of the strains belonging to species which cause infections that are difficult to treat, such as Dipodascus, Saccharomyces, Trichosporon, and Rhodotorula spp. These results indicate that the new triazole exhibits a more extended spectrum than currently licensed antifungal agents and that it could be a useful alternative for the treatment of these mycoses.

Consistent with previous data, we found that posaconazole was the most active agent against Aspergillus spp. (9, 24). The compound was also active against these species in animal models of infection (31) and demonstrated clinically relevant activity in patients with invasive aspergillosis who were refractory to or intolerant of other antifungal therapy in an open-label, multicenter, phase III study (16). These data suggest that this new azole could play a significant role in the treatment of aspergillosis.

Regarding other hyphomycetes species, posaconazole and voriconazole appeared to be equally active. Posaconazole was active in vitro against the majority of strains of some species, such as Paecilomyces spp., Penicillium spp., and S. apiospermum. Notably, it exhibited a potent effect (GM, 0.16 µg/ml) against Paecilomyces lilacinus, a rare emerging hyphomycete that can cause disseminated and invasive infections in immunocompromised patients (28). However, multidrug-resistant filamentous fungi, such as S. prolificans, Scopulariopsis brevicaulis, and Fusarium solani, exhibited reduced susceptibility (MICs > 8 µg/ml) to posaconazole (5, 6).

Many of the Mucorales isolates studied were susceptible to posaconazole and resistant to other azole agents. Posaconazole was active against the 71% of the strains tested. R. oryzae and A. corymbifera were the most susceptible organisms, a result that is consistent with the results published by Dannaoui et al. (7). These data suggest that posaconazole may be a useful alternative to amphotericin B for treating these mycoses. In this regard, it should be noted that posaconazole had an overall success rate of 54% in preliminary studies on the treatment of mucormycosis (16).

In conclusion, this study demonstrated that posaconazole is an extended-spectrum triazole. This triazole and other currently available antifungal agents, such as voriconazole and caspofungin, exhibit potent in vitro activity against the majority of the isolates that were tested. Posaconazole has the potential to be a useful therapeutic option for treating infections due to rare emerging species or for those mycoses caused by resistant isolates.


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ACKNOWLEDGMENTS
 
A. Gomez-Lopez holds a contract from the RESITRA (Spanish Research Network of Infection in Transplantation) fund of the Fondo de Investigaciones Sanitarias, G03/75. E. Mellado holds the contract Ramón y Cajal from the Ministry of Science and Technology.

We thank Pfizer, Janssen Pharmaceutical, Schering-Plough, and Merck & Co., Inc. for supplying antifungal powders.


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FOOTNOTES
 
* Corresponding author. Mailing address: Servicio de Micología, Centro Nacional de Microbiología, Instituto de Salud Carlos III, Ctra Majadahonda-Pozuelo Km 2, 28220 Majadahonda (Madrid), Spain. Phone: 34-91-5097961. Fax: 34-91-5097966. E-mail: mcuenca-estrella{at}isciii.es. Back


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Antimicrobial Agents and Chemotherapy, March 2006, p. 917-921, Vol. 50, No. 3
0066-4804/06/$08.00+0     doi:10.1128/AAC.50.3.917-921.2006
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