This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cuenca-Estrella, M.
Right arrow Articles by Rodriguez-Tudela, J. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cuenca-Estrella, M.
Right arrow Articles by Rodriguez-Tudela, J. L.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, December 2005, p. 5136-5138, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.5136-5138.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

In Vitro Activity of Ravuconazole against 923 Clinical Isolates of Nondermatophyte Filamentous Fungi

Manuel Cuenca-Estrella,* Alicia Gomez-Lopez, Emilia Mellado, Guillermo Garcia-Effron, Araceli Monzon, and Juan Luis Rodriguez-Tudela

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

Received 13 July 2005/ Returned for modification 22 August 2005/ Accepted 12 September 2005


arrow
ABSTRACT
 
The in vitro activities of ravuconazole against 575 clinical strains of Aspergillus spp. and 348 nondermatophyte non-Aspergillus spp. were analyzed. Ravuconazole was active against Aspergillus spp., other hyaline filamentous fungi, black molds, and some Mucorales. Species such as Scedosporium prolificans, Fusarium spp., and Scopulariopsis spp. were resistant to the triazole.


arrow
TEXT
 
Ravuconazole is an extended-spectrum investigational triazole agent that is highly active in vitro against Candida spp., Cryptococcus neoformans, and other yeast species (9, 12, 20, 24, 28), even against the majority of fluconazole-resistant isolates of yeasts (4, 10, 22). Ravuconazole also has shown the capability of inhibiting in vitro growth of Aspergillus spp. (7, 8, 18, 23, 27). In addition, reports from studies including a limited number of clinical strains have indicated that ravuconazole has an inhibitory effect against most of the isolates belonging to species such as Penicillium spp., Paecilomyces spp., Scedosporium apiospermum, and dermatophytes (2, 7, 13, 17, 26). However, strains of other species are largely resistant to ravuconazole in vitro, as has been reported for Fusarium, Scedosporium prolificans, and several species of Mucorales (2, 7, 26).

We have analyzed the activities of ravuconazole against a collection of 923 clinical isolates of filamentous fungi. A total of 575 strains of Aspergillus spp. and 348 nondermatophyte non-Aspergillus spp. were included, representing the largest panel of non-Aspergillus molds against which ravuconazole has been tested up to now.

The strains were recovered from 83 Spanish hospitals through a period of 5 years, from 2000 to 2004. The isolates were obtained from respiratory tract specimens (571/923; 61.9%), skin samples (114/923; 12.4%), and other locations (238/923; 25.7%). Aspergillus fumigatus ATCC 204305 and Aspergillus flavus ATCC 204304 were included as control isolates in each set of experiments.

The following antifungal agents were used in the study: Ravuconazole (Bristol-Myers Squibb, Princeton, N.J.), amphotericin B (Sigma Aldrich Quimica S.A., Madrid, Spain), itraconazole (Janssen S.A., Madrid, Spain), and voriconazole (Pfizer S.A., Madrid, Spain).

A broth microdilution test was performed by following the Clinical Laboratory Standards Institute (CLSI [formerly NCCLS]) reference method (19), with minor modifications. The modifications included the use of RPMI 1640 with L-glutamine buffered to pH 7 with 0.165 M morpholinepropanesulfonic acid and 10 M NaOH, supplemented with 18 g of glucose per liter (RPMI-2% glucose; OXOID, Madrid, Spain) and an inoculum size of (1 to 5) x 105 CFU/ml (6, 11, 14). Table 1 displays the susceptibility results for reference strains per antifungal agent tested. The table includes MIC data after 30 repetitions on different days. In addition, the table shows MICs obtained by the CLSI M38-A reference procedure.


View this table:
[in this window]
[in a new window]
  		TABLE 1. MIC ranges for control strains by M38-A reference procedure and by the modified method

Inoculum suspensions were prepared from fresh, mature (3- to 5-day-old) cultures following a methodology reported previously (25). The plates were incubated at 35°C for 48 h in a humid atmosphere. Visual readings were performed with the help of a mirror. MICs were defined as the lowest concentrations of the antifungal agent that completely inhibited fungal growth.

Strains were classified as 64 distinct species (Table 2). Ravuconazole exhibited a potent activity in vitro against the majority of filamentous fungi tested, with an average geometric mean (GM) of MICs of 1.1 µg/ml. The magnitude of the inhibitory effect of ravuconazole was comparable to those of amphotericin B, itraconazole, and voriconazole, whose GM were 0.68, 0.71, and 1.1 µg/ml, respectively. Interpretative breakpoints of ravuconazole still are not defined. Pharmacokinetics from murine models of infection have shown that after oral administration of 4 to 10 mg/kg of the triazole, the maximum drug concentration in plasma was around 1.8 to 2.5 µg/ml, and concentrations in tissues were two times higher than the corresponding blood concentrations (1, 15, 16, 21). Taking these data into account, ravuconazole was active (GM of MIC, <4 µg/ml) against 47 of 64 (73.4%) species included in the study. A total of 307/923 (24.1%) isolates exhibited a ravuconazole MIC of ≥4 µg/ml.


View this table:
[in this window]
[in a new window]
  		TABLE 2. In vitro susceptibility to ravuconazole and other antifungal agents of species included in the study

Per species, 6/314 (1.9%) strains of A. fumigatus had a ravuconazole MIC equal to or more than 4 µg/ml, being four isolates with MICs of 4 µg/ml and two with MICs of ≥8 µg/ml. With regard to other Aspergillus spp., 8/261 (3%) isolates were resistant in vitro to ravuconazole. In reference to other species of hyaline, non-Aspergillus spp., ravuconazole was active in vitro against the majority of isolates of Penicillium spp., Paecilomyces spp., and Acremonium spp. However, a total of 13/49 (26.5%) strains of Penicillium spp., 6/26 (23.1%) of Paecilomyces spp., and 4/11 (36.4%) of Acremonium spp. exhibited ravuconazole MICs of ≥4 µg/ml. In addition, the triazole showed inhibitory effects against a number of Scedosporium apiospermum organisms, with MICs of <4 µg/ml for 18/54 (33.3%) strains. It should be noted that voriconazole was the most potent antifungal agent against this pathogen, with a MIC at which 50% of isolates were inhibited (MIC50) of 1.0 µg/ml and activity in vitro (MIC ≤ 2 µg/ml) against 47/54 (87%) of isolates.

However, ravuconazole was inactive in vitro against almost the whole panel of isolates belonging to some hyaline species, such as Fusarium spp. and Scopulariopsis spp. For example, ravuconazole was active in vitro against 5/54 (9.3%) isolates of Fusarium spp. and 2/31 (6.5%) strains of Scopulariopsis spp.

Turning to phaeoid hyphomycetes, the triazole was invariably inactive against the isolates of Scedosporium prolificans included in the study. Other species of black fungi were largely susceptible in vitro, particularly Alternaria spp., since 10/11 (90.9%) organisms tested were inhibited by ravuconazole concentrations under 2 µg/ml. Ravuconazole revealed an inhibitory effect for some Mucorales. It was active against 18/32 (56.2%) strains tested. In reviewing susceptibility results per species, ravuconazole was particularly potent against Rhizopus oryzae, the species of Mucorales most commonly isolated in clinical samples, with a MIC50 of 1.0 µg/ml.

The results of this study indicate that ravuconazole is a broad-spectrum antifungal agent, highly active against Aspergillus spp. and with inhibitory effects for other species of hyaline filamentous fungi, black molds, and Mucorales. Its activity profile is very similar to those of itraconazole and voriconazole, and multiresistant species, such as S. prolificans and Scopulariopsis brevicaulis, are also resistant in vitro to this triazole (3, 5). But some differences in spectrum should be noted, since ravuconazole was active against 56.2% of Mucorales tested, while itraconazole was active against a third of the isolates and voriconazole was inactive for almost the whole collection of Mucorales. The number of Mucorales strains susceptible to ravuconazole is comparable to that from data reported by Minassian et al. (17) but somewhat higher than those published by Diekema et al., who found rates of susceptibility to ravuconazole of 30% among Mucorales species (7). Differences in percentages of resistance could be explained by the limited number of isolates tested and by differences in species distribution. For example, our study included 12 strains of R. oryzae, a species particularly susceptible to this triazole.


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

We thank Pfizer, Janssen Pharmaceutical, and Bristol-Myers Squibb for supplying antifungal powders.


arrow
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


arrow
REFERENCES
 
    1
  1. Andes, D., K. Marchillo, T. Stamstad, and R. Conklin. 2003. In vivo pharmacodynamics of a new triazole, ravuconazole, in a murine candidiasis model. Antimicrob. Agents Chemother. 47:1193-1199.[Abstract/Free Full Text]
    2. 2
  2. Carrillo, A. J., and J. Guarro. 2001. In vitro activities of four novel triazoles against Scedosporium spp. Antimicrob. Agents Chemother. 45:2151-2153.[Abstract/Free Full Text]
    3. 3
  3. Cuenca-Estrella, M., A. Gomez-Lopez, E. Mellado, M. J. Buitrago, A. Monzon, and J. L. Rodriguez-Tudela. 2003. Scopulariopsis brevicaulis, a fungal pathogen resistant to broad-spectrum antifungal agents. Antimicrob. Agents Chemother. 47:2339-2341.[Abstract/Free Full Text]
    4. 4
  4. Cuenca-Estrella, M., A. Gomez-Lopez, E. Mellado, G. Garcia-Effron, and J. L. Rodriguez-Tudela. 2004. In vitro activities of ravuconazole and four other antifungal agents against fluconazole-resistant or -susceptible clinical yeast isolates. Antimicrob. Agents Chemother. 48:3107-3111.[Abstract/Free Full Text]
    5. 5
  5. Cuenca-Estrella, M., B. Ruiz-Diez, J. V. Martinez-Suarez, A. Monzon, and J. L. Rodriguez-Tudela. 1999. Comparative in-vitro activity of voriconazole (UK-109,496) and six other antifungal agents against clinical isolates of Scedosporium prolificans and Scedosporium apiospermum. J. Antimicrob. Chemother. 43:149-151.[Abstract/Free Full Text]
    6. 6
  6. Denning, D. W., S. A. Radford, K. L. Oakley, L. Hall, E. M. Johnson, and D. W. Warnock. 1997. Correlation between in-vitro susceptibility testing to itraconazole and in-vivo outcome of Aspergillus fumigatus infection. J. Antimicrob. Chemother. 40:401-414.[Abstract/Free Full Text]
    7. 7
  7. Diekema, D. J., S. A. Messer, R. J. Hollis, R. N. Jones, and M. A. Pfaller. 2003. Activities of caspofungin, itraconazole, posaconazole, ravuconazole, voriconazole, and amphotericin B against 448 recent clinical isolates of filamentous fungi. J. Clin. Microbiol. 41:3623-3626.[Abstract/Free Full Text]
    8. 8
  8. Espinel-Ingroff, A., A. Fothergill, J. Peter, M. G. Rinaldi, and T. J. Walsh. 2002. Testing conditions for determination of minimum fungicidal concentrations of new and established antifungal agents for Aspergillus spp.: NCCLS collaborative study. J. Clin. Microbiol. 40:3204-3208.[Abstract/Free Full Text]
    9. 9
  9. Fung-Tomc, J. C., E. Huczko, B. Minassian, and D. P. Bonner. 1998. In vitro activity of a new oral triazole, BMS-207147 (ER-30346). Antimicrob. Agents Chemother. 42:313-318.[Abstract/Free Full Text]
    10. 10
  10. Fung-Tomc, J. C., T. C. White, B. Minassian, E. Huczko, and D. P. Bonner. 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.[CrossRef][Medline]
    11. 11
  11. Gomez-Lopez, A., A. Aberkane, E. Petrikkou, E. Mellado, J. L. Rodriguez-Tudela, and M. Cuenca-Estrella. 2005. Analysis of the influence of Tween concentration, inoculum size, assay medium, and reading time on susceptibility testing of Aspergillus spp. J. Clin. Microbiol. 43:1251-1255.[Abstract/Free Full Text]
    12. 12
  12. Gomez-Lopez, A., E. Mellado, J. L. Rodriguez-Tudela, and M. Cuenca-Estrella. 2005. Susceptibility profile of 29 clinical isolates of Rhodotorula spp. and literature review. J. Antimicrob. Chemother. 55:312-316.[Abstract/Free Full Text]
    13. 13
  13. Gupta, A. K., Y. Kohli, and R. Batra. 2005. In vitro activities of posaconazole, ravuconazole, terbinafine, itraconazole and fluconazole against dermatophyte, yeast and non-dermatophyte species. Med. Mycol. 43:179-185.[Medline]
    14. 14
  14. Meletiadis, J., J. F. Meis, J. W. Mouton, and P. E. Verweij. 2001. Analysis of growth characteristics of filamentous fungi in different nutrient media. J. Clin. Microbiol. 39:478-484.[Abstract/Free Full Text]
    15. 15
  15. Mikamo, H., X. H. Yin, Y. Hayasaki, M. Satoh, and T. Tamaya. 2001. Effect of ravuconazole, a new triazole antifungal, in a rat intraabdominal abscess model. Chemotherapy 47:377-380.[Medline]
    16. 16
  16. Mikamo, H., X. H. Yin, Y. Hayasaki, Y. Shimamura, K. Uesugi, N. Fukayama, M. Satoh, and T. Tamaya. 2002. Penetration of ravuconazole, a new triazole antifungal, into rat tissues. Chemotherapy 48:7-9.[Medline]
    17. 17
  17. Minassian, B., E. Huczko, T. Washo, D. Bonner, and J. Fung-Tomc. 2003. In vitro activity of ravuconazole against Zygomycetes, Scedosporium and Fusarium isolates. Clin. Microbiol. Infect. 9:1250-1252.[CrossRef][Medline]
    18. 18
  18. Moore, C. B., C. M. Walls, and D. W. Denning. 2000. In vitro activity of the new triazole BMS-207147 against Aspergillus species in comparison with itraconazole and amphotericin B. Antimicrob. Agents Chemother. 44:441-443.[Abstract/Free Full Text]
    19. 19
  19. National Committee for Clinical Laboratory Standards. 2002. Reference method for broth dilution antifungal susceptibility testing of filamentous fungi. Approved standard. NCCLS document M38-A. National Committee for Clinical Laboratory Standards, Wayne, Pa.
    20. 20
  20. Paphitou, N. I., L. Ostrosky-Zeichner, V. L. Paetznick, J. R. Rodriguez, E. Chen, and J. H. Rex. 2002. In vitro antifungal susceptibilities of Trichosporon species. Antimicrob. Agents Chemother. 46:1144-1146.[Abstract/Free Full Text]
    21. 21
  21. Petraitiene, R., V. Petraitis, C. A. Lyman, A. H. Groll, D. Mickiene, J. Peter, J. Bacher, K. Roussillon, M. Hemmings, D. Armstrong, N. A. Avila, and T. J. Walsh. 2004. Efficacy, safety, and plasma pharmacokinetics of escalating dosages of intravenously administered ravuconazole lysine phosphoester for treatment of experimental pulmonary aspergillosis in persistently neutropenic rabbits. Antimicrob. Agents Chemother. 48:1188-1196.[Abstract/Free Full Text]
    22. 22
  22. Pfaller, M. A., D. J. Diekema, S. A. Messer, L. Boyken, R. J. Hollis, and R. N. Jones. 2004. In vitro susceptibilities of rare Candida bloodstream isolates to ravuconazole and three comparative antifungal agents. Diagn. Microbiol. Infect. Dis. 48:101-105.[CrossRef][Medline]
    23. 23
  23. Pfaller, M. A., S. A. Messer, R. J. Hollis, and R. N. Jones. 2002. 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. Antimicrob. Agents Chemother. 46:1032-1037.[Abstract/Free Full Text]
    24. 24
  24. Pfaller, M. A., S. A. Messer, R. J. Hollis, R. N. Jones, and D. J. Diekema. 2002. In vitro activities of ravuconazole and voriconazole compared with those of four approved systemic antifungal agents against 6,970 clinical isolates of Candida spp. Antimicrob. Agents Chemother. 46:1723-1727.[Abstract/Free Full Text]
    25. 25
  25. Rodriguez-Tudela, J. L., E. Chryssanthou, E. Petrikkou, J. Mosquera, D. W. Denning, and M. Cuenca-Estrella. 2003. Interlaboratory evaluation of hematocytometer method of inoculum preparation for testing antifungal susceptibilities of filamentous fungi. J. Clin. Microbiol. 41:5236-5237.[Abstract/Free Full Text]
    26. 26
  26. Serena, C., M. Ortoneda, J. Capilla, F. J. Pastor, D. A. Sutton, M. G. Rinaldi, and J. Guarro. 2003. In vitro activities of new antifungal agents against Chaetomium spp. and inoculum standardization. Antimicrob. Agents Chemother. 47:3161-3164.[Abstract/Free Full Text]
    27. 27
  27. Varanasi, N. L., I. Baskaran, G. J. Alangaden, P. H. Chandrasekar, and E. K. Manavathu. 2004. Novel effect of voriconazole on conidiation of Aspergillus species. Int. J. Antimicrob. Agents 23:72-79.[CrossRef][Medline]
    28. 28
  28. Yamazumi, T., M. A. Pfaller, S. A. Messer, A. Houston, R. J. Hollis, and R. N. Jones. 2000. In vitro activities of ravuconazole (BMS-207147) against 541 clinical isolates of Cryptococcus neoformans. Antimicrob. Agents Chemother. 44:2883-2886.[Abstract/Free Full Text]

Antimicrobial Agents and Chemotherapy, December 2005, p. 5136-5138, Vol. 49, No. 12
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.12.5136-5138.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Hariprasad, S M, Mieler, W F, Lin, T K, Sponsel, W E, Graybill, J R (2008). Voriconazole in the treatment of fungal eye infections: a review of current literature. Br. J. Ophthalmol. 92: 871-878 [Abstract] [Full Text]  
  • Cuenca-Estrella, M., Alastruey-Izquierdo, A., Alcazar-Fuoli, L., Bernal-Martinez, L., Gomez-Lopez, A., Buitrago, M. J., Mellado, E., Rodriguez-Tudela, J. L. (2008). In Vitro Activities of 35 Double Combinations of Antifungal Agents against Scedosporium apiospermum and Scedosporium prolificans. Antimicrob. Agents Chemother. 52: 1136-1139 [Abstract] [Full Text]  
  • Cortez, K. J., Roilides, E., Quiroz-Telles, F., Meletiadis, J., Antachopoulos, C., Knudsen, T., Buchanan, W., Milanovich, J., Sutton, D. A., Fothergill, A., Rinaldi, M. G., Shea, Y. R., Zaoutis, T., Kottilil, S., Walsh, T. J. (2008). Infections Caused by Scedosporium spp.. Clin. Microbiol. Rev. 21: 157-197 [Abstract] [Full Text]  
  • Pasqualotto, A. C., Denning, D. W. (2008). New and emerging treatments for fungal infections. J Antimicrob Chemother 61: i19-i30 [Abstract] [Full Text]  
  • Nucci, M., Anaissie, E. (2007). Fusarium Infections in Immunocompromised Patients. Clin. Microbiol. Rev. 20: 695-704 [Abstract] [Full Text]  
  • Cuenca-Estrella, M., Gomez-Lopez, A., Buitrago, M. J., Mellado, E., Garcia-Effron, G., Rodriguez-Tudela, J. L. (2006). In Vitro Activities of 10 Combinations of Antifungal Agents against the Multiresistant Pathogen Scopulariopsis brevicaulis.. Antimicrob. Agents Chemother. 50: 2248-2250 [Abstract] [Full Text]  

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Cuenca-Estrella, M.
Right arrow Articles by Rodriguez-Tudela, J. L.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Cuenca-Estrella, M.
Right arrow Articles by Rodriguez-Tudela, J. L.

Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»