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Antimicrobial Agents and Chemotherapy, September 2007, p. 3378-3380, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00496-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

In Vitro Susceptibility to Posaconazole of 1,903 Yeast Isolates Recovered in France from 2003 to 2006 and Tested by the Method of the European Committee on Antimicrobial Susceptibility Testing{triangledown}

Olivier Lortholary,1,2* Eric Dannaoui,1,7 Dorothée Raoux,1 Damien Hoinard,1 Annick Datry,3 André Paugam,4 Jean-Louis Poirot,5 Claire Lacroix,6 Françoise Dromer,1 the YEASTS Group

Centre National de Référence Mycologie et Antifongiques, Unité de Mycologie Moléculaire, CNRS URA3012, Institut Pasteur,1 Université René Descartes, Hôpital Necker-Enfants Malades, Service des Maladies Infectieuses et Tropicales, Centre d'Infectiologie Necker-Pasteur,2 Hôpital Pitié-Salpétrière,3 Université René Descartes, Hôpital Cochin,4 Hôpital Saint Antoine,5 Hôpital Saint Louis,6 Université René Descartes, Hôpital Européen Georges Pompidou, Unité de Parasitologie-Mycologie Paris, France7

Received 13 April 2007/ Returned for modification 12 May 2007/ Accepted 11 June 2007


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ABSTRACT
 
The posaconazole MIC90 for 1,903 yeast isolates from France was 1 µg/ml (range, ≤0.015 to 8 µg/ml). Ninety percent of isolates with fluconazole MICs of ≥8 µg/ml (n = 509) and 90% of those with voriconazole MICs of ≥2 µg/ml (n = 80) were inhibited by 2 and 8 µg/ml of posaconazole, respectively.


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TEXT
 
Yeasts, especially Candida spp., are among the most frequent causes of nosocomial bloodstream infections. Several non-albicans Candida spp. and rare species are often less susceptible to fluconazole (5). Among the new antifungals available, posaconazole has emerged as the one with the broadest spectrum of in vitro activity against yeasts and filamentous and dimorphic fungi (8, 13). Using the method standardized by the Antifungal Susceptibility Testing Subcommittee of the European Committee on Antimicrobial Susceptibility Testing (AFST-EUCAST), we report here the in vitro susceptibility profiles to posaconazole of 1,903 yeast isolates.

(This work was presented in part at the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, 27 to 30 September 2006, San Francisco, CA [2b].)

A total of 1,903 yeast isolates from 79 medical centers were collected at the French National Reference Center for Mycoses and Antifungals (Institut Pasteur, Paris, France) between 1 January 2003 and 31 July 2006. Isolates were recovered from 1,443 blood cultures, including 1,241 consecutive fungemia cultures obtained through the active prospective surveillance program in the Paris area (2a), from other sterile sites (n = 187), and from superficial infections (n = 273).

Active powders of known potency of posaconazole (Schering-Plough Research Institute, Kenilworth, NJ), fluconazole, and voriconazole (both from Pfizer Central Research, Sandwich, United Kingdom) were used. The final concentrations tested were 0.015 to 8 µg/ml for posaconazole and voriconazole and 0.125 to 64 µg/ml for fluconazole.

The MICs of posaconazole, fluconazole, and voriconazole were determined according to AFST-EUCAST discussion document 7.1 (12). Quality control strains were included in each set. Since breakpoints have not yet been published, we used thresholds that defined 95% of the C. albicans isolates as susceptible and 98% of the C. krusei isolates as resistant to fluconazole. Thus, isolates were considered fluconazole resistant or susceptible when MICs were ≥8 µg/ml or ≤4 µg/ml, respectively. Likewise, an arbitrary threshold of ≥2 µg/ml defined isolates with decreased susceptibility to voriconazole and posaconazole.

The overall susceptibilities to posaconazole, divided into those for yeast isolates from blood (n = 1,383) and those for isolates from other sites (n = 428), are reported in Table 1 for the 10 most frequently isolated species of our collection. The MIC50 (range) value for the 1,535 Candida sp. isolates was 0.06 µg/ml (≤0.015 to ≥8 µg/ml). Twenty-nine percent (74/254 isolates) of C. glabrata isolates exhibited posaconazole MICs of ≥2 µg/ml. Considering the C. glabrata isolates with fluconazole MICs of ≥8 µg/ml (n = 230), 68% were inhibited by 1 µg/ml of posaconazole and 83% were inhibited by 1 µg/ml of voriconazole. Considering the C. glabrata isolates with voriconazole MICs of ≥2 µg/ml (n = 41), the posaconazole MIC50 was ≥8 µg/ml. For C. krusei, the activity of posaconazole was similar to that of voriconazole, although 3/50 isolates presented voriconazole MICs of ≥2 µg/ml and remained inhibited by ≤1 µg/ml of posaconazole. Table 2 summarizes the in vitro susceptibilities to posaconazole, in comparison to those to fluconazole and voriconazole, of 79 uncommon yeasts (i.e., at least 2 but less than 12 isolates per species). Posaconazole MICs were lower than the corresponding fluconazole MICs, and overall, voriconazole had equal or lower MICs than those of posaconazole. MICs for posaconazole against Rhodotorula spp. were lower than those of voriconazole. Yeast species with reduced intrinsic activity of fluconazole had higher posaconazole and voriconazole MICs, with the highest MICs of the three azoles tested being observed for C. haemulonii isolates.


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  		TABLE 1. Susceptibility to posaconazole of yeast clinical isolates corresponding to the 10 most frequently isolated species in the collection of the French National Reference Center for Mycoses and Antifungals


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  		TABLE 2. Susceptibility to posaconazole of 79 uncommon yeast clinical isolates recovered from various sites of infection (blood cultures or deep or superficial sites) in France

Overall, considering the 1,903 isolates, comparative MIC50s (range) were 0.5 µg/ml (≤0.125 to ≥64 µg/ml), ≤0.015 (≤0.015 to ≥8 µg/ml), and 0.125 (≤0.015 to 8 µg/ml) for fluconazole, voriconazole, and posaconazole, respectively, showing that posaconazole was more active than fluconazole, but slightly less active than voriconazole, against these clinical isolates.

Table 3 shows the distribution of posaconazole MICs according to those of fluconazole or voriconazole for all isolates. There was a clear correlation (P < 0.0001) between posaconazole MICs and either fluconazole (R2 = 0.63) or voriconazole (R2 = 0.69) MICs. Considering isolates with fluconazole MICs of ≤4 µg/ml (n = 1,394), the posaconazole MIC50 and MIC90 were 0.06 and 0.25 µg/ml, respectively, and for those with fluconazole MICs of ≥8 µg/ml (n = 509), the posaconazole MIC50 and MIC90 were 0.5 and 2 µg/ml, respectively. Considering yeast isolates with voriconazole MICs of ≤1 µg/ml (n = 1,823), the posaconazole MIC50 and MIC90 were 0.06 and 1 µg/ml, respectively, and for those with voriconazole MICs of ≥2 µg/ml (n = 80), the posaconazole MIC50 and MIC90 were 4 and 8 µg/ml, respectively.


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  		TABLE 3. Distribution of posaconazole MICs according to fluconazole or voriconazole MICs for 1,903 yeast isolates collected in France

We report here the in vitro susceptibilities to posaconazole of 1,903 yeast isolates recently collected in France, mostly from blood, with a MIC50 of 0.125 µg/ml. In previous studies and here, clinical isolates of C. albicans and C. dubliniensis were the most susceptible species to posaconazole (1, 3, 5, 11, 14). In considering C. glabrata isolates, the posaconazole MIC90 values determined here were slightly higher than those reported elsewhere (1, 11). Posaconazole was slightly less active than voriconazole against C. glabrata, as shown in at least two other studies (10, 11). Cryptococcus neoformans isolates were highly susceptible to posaconazole, and slightly higher posaconazole MIC50 values than those of voriconazole were found, in accordance with previous data for a smaller sample (1, 6, 11). Interestingly, posaconazole was also active against several rare but potentially emerging yeast species known to be less susceptible to antifungals, including fluconazole. Few reports have emphasized that the activity of voriconazole is reduced against Candida sp. isolates with decreased susceptibility to fluconazole (2, 4, 9). Cross-resistance between extended-spectrum azoles has been mentioned previously, especially for C. glabrata isolates. Indeed, Pfaller et al. reported that among fluconazole-resistant C. glabrata isolates, only 4% remained susceptible to posaconazole and 13% remained susceptible to voriconazole with a cutoff MIC of ≤1 µg/ml for posaconazole and voriconazole (7). In this study, we also evidenced such reduced posaconazole activity against yeast isolates with reduced susceptibility to fluconazole and voriconazole.


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ACKNOWLEDGMENTS
 
We thank the following principal investigators of the YEASTS Group (in alphabetical order by city, except for those in Paris), who contributed to the current database: Claire Bouges-Michel (Hôpital Avicenne, Bobigny), Isabelle Poilane (Hôpital Jean Verdier, Bondy), Marie-Elisabeth Bougnoux and Jean Dunand (Hôpital Ambroise Paré, Boulogne), Guy Galeazzi (Hôpital Louis Mourier, Colombes), Stéphane Bretagne (Hôpital Henri Mondor, Créteil), Nathalie Fauchet (Centre Hospitalier Intercommunal de Créteil, Créteil), Elisabeth Forget (Hôpital Beaujon, Clichy), Christine Lawrence (Hôpital Raymond Poincaré, Garches), Françoise Botterel and Christine Bonnal (Hôpital du Kremlin-Bicêtre), Odile Eloy (Hôpital Mignot, Le Chesnay), Marie-Françoise David and Lilianan Mihaila (Hôpital Paul Brousse, Villejuif), Elisabeth Chachaty and Olivier Adam (Institut Gustave Roussy, Villejuif), and (in Paris) Christian Chochillon (Hôpital Bichat), André Paugam and Marie-Thérèse Baixench (Hôpital Cochin), Muriel Cornet (Hôpital de l'Hôtel Dieu), Marie-Christine Escande (Curie), Svetlana Challier and Marie-Elisabeth Bougnoux (Necker Enfants Malades), Véronique Lavarde and Eric Dannaoui (Hôpital Européen Georges Pompidou), Annick Datry, Houria Laklache, Bader Lminmouni, and Sophie Brun (Hôpital de la Pitié-Salpétrière), Jean-Louis Poirot (Hôpital Saint Antoine), Claire Lacroix (Hôpital Saint Louis), Didier Moissenet (Hôpital Trousseau), Michel Develoux (Hôpital Tenon), and Stéphane Bonacorsi (Hôpital Robert Debré).

We thank Schering-Plough and Pfizer for supplying antifungal powders.


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FOOTNOTES
 
* Corresponding author. Mailing address: Centre National de Référence Mycologie et Antifongiques, Unité de Mycologie Moléculaire, CNRS URA3012, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France. Phone: 33 1 45 68 83 55. Fax: 33 1 45 68 84 20. E-mail: olortho{at}pasteur.fr Back

{triangledown} Published ahead of print on 18 June 2007. Back


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Antimicrobial Agents and Chemotherapy, September 2007, p. 3378-3380, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00496-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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  • Pfaller, M. A., Messer, S. A., Boyken, L., Tendolkar, S., Hollis, R. J., Diekema, D. J. (2008). Selection of a Surrogate Agent (Fluconazole or Voriconazole) for Initial Susceptibility Testing of Posaconazole against Candida spp.: Results from a Global Antifungal Surveillance Program. J. Clin. Microbiol. 46: 551-559 [Abstract] [Full Text]  

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