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 Sun, Q. N.
Right arrow Articles by Graybill, J. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sun, Q. N.
Right arrow Articles by Graybill, J. R.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, May 2002, p. 1581-1582, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1581-1582.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

In Vitro Activities of Posaconazole, Itraconazole, Voriconazole, Amphotericin B, and Fluconazole against 37 Clinical Isolates of Zygomycetes

Qiu N. Sun,1,2 Annette W. Fothergill,3* Dora I. McCarthy,3 Michael G. Rinaldi,3,4 and John R. Graybill1,4

Division of Infectious Diseases (7811), Department of Medicine,1 The Fungus Testing Laboratory, Department of Pathology, The University of Texas Health Science Center at San Antonio,3 Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, Texas 78229,4 Department of Dermatology, Beijing Union Medical University Hospital, Beijing, 100730, People's Republic of China2

Received 28 February 2001/ Returned for modification 24 August 2001/ Accepted 2 February 2002


arrow
ABSTRACT
 
In vitro antifungal susceptibility testing results of a new antifungal triazole, posaconazole (POS), were compared to results with amphotericin B (AMB), itraconazole (ITC), voriconazole (VRC), and fluconazole (FLC) against clinical agents of zygomycosis. The MICs of POS at which 50% and 90% of the isolates were inhibited were 0.25 and 4 µg/ml, respectively. POS was significantly more active than VRC and FLC and slightly more active than ITC. The results suggest that POS has significant potential for clinical development against the zygomycetes.


arrow
TEXT
 
Invasive mycoses have increased dramatically over the past several years, largely as a result of increasing numbers of immunosuppressed patients. The zygomycetes are less common causes of invasive human infection compared to Aspergillus spp. and Candida spp. In several large studies of the occurrence of fungal infection in high-risk populations, infections with zygomycetes represented 5 to 12% of all fungal infections (1, 14), while in another study, zygomycosis represented up to 25 to 44% of all invasive fungal diseases (6, 9). The manifestations of zygomycosis include primary rhinocerebral, pulmonary, gastrointestinal, cutaneous or subcutaneous, or allergic disease and disseminated disease (11). Amphotericin B (AMB) is the first-line therapy of choice for most cases of zygomycosis, but its use is limited by its potentially severe side effects.

In the study described here, we compared the in vitro activities of four triazoles and AMB against 37 clinical isolates of zygomycetes. The isolates included 7 isolates of Mucor spp., 10 isolates of Rhizopus spp., 5 isolates of Absidia coryambifera, 5 isolates of Cunninghamella spp., 4 isolates of Apophysomyces elegans, 2 isolates of Cokeromyces recurvatus, and 4 isolates of Saksenaea vasiformis. All isolates came from the Fungus Testing Laboratory at The University of Texas Health Science Center (UTHSC) at San Antonio. Isolates were retrieved from storage at -70°C or from water stocks and were subcultured onto slants of potato flake agar with incubation at room temperature until adequate growth was obtained. Paecilomyces variotii strain UTHSC 90-459 was used as a control. MIC endpoints were read visually after 24 and 48 h of incubation. Standard antifungal powders of posaconazole (POS; Schering-Plough), voriconazole (VRC; Pfizer), fluconazole (FLC; Pfizer), itraconazole (ITC; Janssen), and AMB (Bristol-Myers Squibb) were obtained from their respective manufacturers. Stock solutions of POS, VRC, and ITC were prepared in polyethylene glycol 400, while AMB and FLC were dissolved in water. Final dilutions of POS, VRC, FLC, and ITC were made in RPMI 1640 medium with L-glutamine and morpholinepropanesulfonic acid buffer (Angus Chemical Co., Niagara Falls, N.Y.). AMB was made with Antibiotic Medium 3 (Difco). Serial twofold dilutions of each antifungal agent were prepared to the following final drug concentrations: AMB, 0.03 to 16 µg/ml; POS and ITC, 0.015 to 8 µg/ml; FLC and VRC, 0.125 to 64 µg/ml. Stock solutions of these drugs were stored at -70°C until use. Fungal strains were cultured on potato flake agar slants at room temperature for 1 week. Tested strains were overlaid with sterile distilled water and suspensions were obtained by gently scraping the surface of colonies with the tip of a sterile wooden applicator stick. Large fragments were allowed to settle, and homogeneous suspensions of conidia were removed and adjusted to a concentration of 105 conidia/ml by adding sterile distilled water and counting with a hemacytometer. Fungal suspensions were diluted 1:10 with RPMI medium or Antibiotic Medium 3 to obtain final suspensions. A drug-free growth control was included for each isolate.

MICs were determined by a broth microdilution method by following NCCLS recommendations for filamentous fungi (standard M38-P [7]). Previously prepared aliquots containing 0.1 ml of the various drug concentrations were allowed to thaw at room temperature and inoculated with 0.9 ml of each suspension. Tubes were incubated at 35°C for 24 and 48 h. MICs were read visually and were defined at 48 h of incubation as the lowest concentration resulting in 80% inhibition of growth compared with that of the growth control for POS, ITC, VRC, and FLC and as the first tube that was optically clear for AMB. The control strain P. variotii UTHSC 90-459 was used in all tests. Testing of these isolates was performed in duplicate.

The MIC results are summarized in Table 1. The mean of the MIC of POS was 1.22 µg/ml, which was slightly more active than ITC (MIC mean, 1.95 µg/ml) and considerably more active than VRC (MIC mean, 41.14 µg/ml) and FLC (MIC mean, 57.82 µg/ml). POS had a MIC of <8 µg/ml for 91.9% of isolates tested, and ITC had a MIC of <8 µg/ml for 81.1% of the isolates. Overall, the isolates were generally susceptible to POS, ITC, and AMB. Most isolates were resistant to FLC, while only one isolate was susceptible to VCR. Both POS and ITC were more active than VRC and FLC against this group of fungi, and POS was slightly more active than ITC.


View this table:
[in this window]
[in a new window]
  		TABLE 1. In vitro activities of five antifungal agents against 37 strains of zygomycetes

Organisms within the class Zygomycetes are found in two orders: Mucorales and Entomophthorales. For the most part, the Mucorales organisms are considered to be opportunistic pathogens, with members of the genera Rhizopus, Mucor, Rhizomucor, Abisdea, Apophysomyces, Saksenaea, Cunninghamella, and Cokeromyces all having been implicated as causing human disease (4, 13). Because zygomycosis is less common than aspergillosis and the course is progressively rapid, the effectiveness of antifungal chemotherapy in small case studies is difficult to evaluate. AMB is the first-line drug of choice for most cases of zygomycosis caused by the Mucorales, but it is not an effective treatment in many cases, particularly if the patient presents late in the disease course or has disseminated disease (11). Also, there is no clinical support available for the use of FLC or VRC in zygomycosis, and experience with ITC is limited to scattered case reports (2, 10). POS has been shown to have potent in vitro and in vivo activities against Candida spp., Cryptococcus neoformans, Aspergillus spp., Blastomyces dermatitidis, and Coccidioides immitis (3, 5, 8, 12). In our study, POS also had good activity against zygomycetes. In that the MICs (means) of POS were about 1.6-fold lower than those of ITC, 33-fold lower than those of VRC, and 47-fold lower than those of FLC, this suggests that POS may be useful in the treatment of zygomycosis. However, further in vivo studies with experimental animal models are needed to confirm this activity.


arrow
FOOTNOTES
 
* Corresponding author. Mailing address: The Fungus Testing Laboratory, Department of Pathology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900. Phone: (210) 567-4131. Fax: (210) 567-4076. E-mail: fothergill{at}uthscsa.edu. Back


arrow
REFERENCES
 
    1
  1. Atkinson, J. B., D. H. Connor, M. Robinowitz, H. A. McAllister, and R. Virmani. 1984. Cardiac fungal infection: review of autopsy findings in 60 patients. Hum. Pathol. 15:935-942.[CrossRef][Medline]
    2. 2
  2. Barnert, J., W. Behr, and H. Reich. 1985. An amphotericin B-resistant case of rhinocerebral mucormycosis. Infection 13:134-136.[CrossRef][Medline]
    3. 3
  3. Galgiani, J. N., and M. L. Lewis. 1997. In vitro studies of activities of the antifungal triazole SCH56592 and itraconazole against Candida albicans, Cryptococcus neoformans, and other pathogenic yeast. Antimicrob. Agents Chemother. 41:180-183.[Abstract]
    4. 4
  4. Kwon-Chung, K. J., and J. E. Bennett. 1992. Medical mycology, p. 3-34. Lea & Febiger, Philadelphia, Pa.
    5. 5
  5. Lutz, J. E., K. V. Clemons, B. H. Aristizabal, and D. A. Steven. 1997. Activity of the triazole SCH 56592 against disseminated murine coccidoidomycosis. Antimicrob. Agents Chemother. 41:1558-1561.[Abstract]
    6. 6
  6. Nash, G., F. D. Foley, M. N. Goodwin, H. M. Bruck, K. A. Greenwald, and B. A. Pruitt. 1971. Fungal burn wound infection. JAMA 215:1664-1666.[Abstract/Free Full Text]
    7. 7
  7. National Committee for Clinical Laboratory Standards. 1997. Reference method for broth dilution antifungal susceptibility testing of conidium-forming filamentous fungi. Approved standard M38-P. National Committee for Clinical Laboratory Standards, Wayne, Pa.
    8. 8
  8. Oakley, K. L., G. Morrissey, and D. W. Denning. 1997. In vitro activity of SCH56592 and comparison with activity of amphotericin B and itraconazole against Aspergillus spp. Antimicrob. Agents Chemother. 41:1124-1126.[Abstract]
    9. 9
  9. Parkhurst, G. F., and G. D. Vlahide. 1967. Fatal opportunistic fungus disease. JAMA 202:131-133.[CrossRef][Medline]
    10. 10
  10. Parthiban, K., S. Gnanaguruvelan, C. Janaki, G. Sentamilselvi, and J. M. Boopalraj. 1998. Rhinocerebral zygomycosis. Mycoses 41:51-53.
    11. 11
  11. Ribes, J. A., C. L. Vanover-Sams, and D. J. Baker. 2000. Zygomycetes in human disease. Clin. Microbiol. Rev. 13:236-301.[Abstract/Free Full Text]
    12. 12
  12. Sugar, A. M., and X. P. Liu. 1996. In vitro and in vivo activity of SCH 56592 against Blastomyces dermatitidis. Antimicrob. Agents Chemother. 40:1314-1316.[Abstract]
    13. 13
  13. Vartivarian, S. E., E. J. Anaissie, and G. P. Bodey. 1993. Emerging fungal pathogens in immunocompromised patients: classification, diagnosis, and management. Clin. Infect. Dis. 17(Suppl. 2):S487-S491.
    14. 14
  14. Wajszczuk, C. P., J. S. Dummer, M. Ho, D. H. V. Thiel, T. E. Starzl, S. Iwatsuki, and B. Show. 1985. Fungal infections in liver transplant recipients. Transplantation 40:347-353.[Medline]

Antimicrobial Agents and Chemotherapy, May 2002, p. 1581-1582, Vol. 46, No. 5
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.5.1581-1582.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • CHUA, A.-P., BILLINGS, S. D., BUDEV, M. M., MEHTA, A. C. (2009). Ulcerative leg nodules in a transplant recipient. Cleveland Clinic Journal of Medicine 76: 575-576 [Full Text]  
  • Khan, Z. U., Ahmad, S., Brazda, A., Chandy, R. (2009). Mucor circinelloides as a Cause of Invasive Maxillofacial Zygomycosis: an Emerging Dimorphic Pathogen with Reduced Susceptibility to Posaconazole. J. Clin. Microbiol. 47: 1244-1248 [Abstract] [Full Text]  
  • Morris, M. I. (2009). Posaconazole: A new oral antifungal agent with an expanded spectrum of activity. Am J Health Syst Pharm 66: 225-236 [Abstract] [Full Text]  
  • Rodriguez, M. M., Serena, C., Marine, M., Pastor, F. J., Guarro, J. (2008). Posaconazole Combined with Amphotericin B, an Effective Therapy for a Murine Disseminated Infection Caused by Rhizopus oryzae. Antimicrob. Agents Chemother. 52: 3786-3788 [Abstract] [Full Text]  
  • Espinel-Ingroff, A., Canton, E. (2008). Comparison of Neo-Sensitabs Tablet Diffusion Assay with CLSI Broth Microdilution M38-A and Disk Diffusion Methods for Testing Susceptibility of Filamentous Fungi with Amphotericin B, Caspofungin, Itraconazole, Posaconazole, and Voriconazole. J. Clin. Microbiol. 46: 1793-1803 [Abstract] [Full Text]  
  • Espinel-Ingroff, A., Johnson, E., Hockey, H., Troke, P. (2008). Activities of voriconazole, itraconazole and amphotericin B in vitro against 590 moulds from 323 patients in the voriconazole Phase III clinical studies. J Antimicrob Chemother 61: 616-620 [Abstract] [Full Text]  
  • Mikesch, J.-H., Rudat, A., Zuhlsdorf, M., Berdel, W. E., Mesters, R., Conrad, B., Becker, K., Fegeler, W., Anthoni, C. (2007). Subcutaneous Zygomycosis in Neutropenia. JCO 25: 4844-4845 [Full Text]  
  • Almyroudis, N. G., Sutton, D. A., Fothergill, A. W., Rinaldi, M. G., Kusne, S. (2007). In Vitro Susceptibilities of 217 Clinical Isolates of Zygomycetes to Conventional and New Antifungal Agents. Antimicrob. Agents Chemother. 51: 2587-2590 [Abstract] [Full Text]  
  • Schwarz, P., Lortholary, O., Dromer, F., Dannaoui, E. (2007). Carbon Assimilation Profiles as a Tool for Identification of Zygomycetes. J. Clin. Microbiol. 45: 1433-1439 [Abstract] [Full Text]  
  • Krishna, G., Sansone-Parsons, A., Martinho, M., Kantesaria, B., Pedicone, L. (2007). Posaconazole Plasma Concentrations in Juvenile Patients with Invasive Fungal Infection. Antimicrob. Agents Chemother. 51: 812-818 [Abstract] [Full Text]  
  • Torres-Narbona, M., Guinea, J., Martinez-Alarcon, J., Pelaez, T., Bouza, E. (2007). In Vitro Activities of Amphotericin B, Caspofungin, Itraconazole, Posaconazole, and Voriconazole against 45 Clinical Isolates of Zygomycetes: Comparison of CLSI M38-A, Sensititre YeastOne, and the Etest. Antimicrob. Agents Chemother. 51: 1126-1129 [Abstract] [Full Text]  
  • Iwen, P. C., Sigler, L., Noel, R. K., Freifeld, A. G. (2007). Mucor circinelloides Was Identified by Molecular Methods as a Cause of Primary Cutaneous Zygomycosis. J. Clin. Microbiol. 45: 636-640 [Abstract] [Full Text]  
  • Espinel-Ingroff, A. (2006). Comparison of Three Commercial Assays and a Modified Disk Diffusion Assay with Two Broth Microdilution Reference Assays for Testing Zygomycetes, Aspergillus spp., Candida spp., and Cryptococcus neoformans with Posaconazole and Amphotericin B. J. Clin. Microbiol. 44: 3616-3622 [Abstract] [Full Text]  
  • Enoch, D. A., Ludlam, H. A., Brown, N. M. (2006). Invasive fungal infections: a review of epidemiology and management options.. J Med Microbiol 55: 809-818 [Abstract] [Full Text]  
  • Sabatelli, F., Patel, R., Mann, P. A., Mendrick, C. A., Norris, C. C., Hare, R., Loebenberg, D., Black, T. A., McNicholas, P. M. (2006). In Vitro Activities of Posaconazole, Fluconazole, Itraconazole, Voriconazole, and Amphotericin B against a Large Collection of Clinically Important Molds and Yeasts.. Antimicrob. Agents Chemother. 50: 2009-2015 [Abstract] [Full Text]  
  • Sansone-Parsons, A., Krishna, G., Calzetta, A., Wexler, D., Kantesaria, B., Rosenberg, M. A., Saltzman, M. A. (2006). Effect of a Nutritional Supplement on Posaconazole Pharmacokinetics following Oral Administration to Healthy Volunteers.. Antimicrob. Agents Chemother. 50: 1881-1883 [Abstract] [Full Text]  
  • Schwarz, P., Bretagne, S., Gantier, J.-C., Garcia-Hermoso, D., Lortholary, O., Dromer, F., Dannaoui, E. (2006). Molecular Identification of Zygomycetes from Culture and Experimentally Infected Tissues. J. Clin. Microbiol. 44: 340-349 [Abstract] [Full Text]  
  • Antachopoulos, C., Meletiadis, J., Roilides, E., Sein, T., Walsh, T. J. (2006). Rapid Susceptibility Testing of Medically Important Zygomycetes by XTT Assay. J. Clin. Microbiol. 44: 553-560 [Abstract] [Full Text]  
  • Chamilos, G., Lewis, R. E., Kontoyiannis, D. P. (2006). Lovastatin Has Significant Activity against Zygomycetes and Interacts Synergistically with Voriconazole. Antimicrob. Agents Chemother. 50: 96-103 [Abstract] [Full Text]  
  • Greenberg, R. N., Mullane, K., van Burik, J.-A. H., Raad, I., Abzug, M. J., Anstead, G., Herbrecht, R., Langston, A., Marr, K. A., Schiller, G., Schuster, M., Wingard, J. R., Gonzalez, C. E., Revankar, S. G., Corcoran, G., Kryscio, R. J., Hare, R. (2006). Posaconazole as Salvage Therapy for Zygomycosis. Antimicrob. Agents Chemother. 50: 126-133 [Abstract] [Full Text]  
  • Pimentel, J. D., Dreyer, G., Lum, G. D. (2006). Peritonitis due to Cunninghamella bertholletiae in a patient undergoing continuous ambulatory peritoneal dialysis. J Med Microbiol 55: 115-118 [Abstract] [Full Text]  
  • Brown, J. (2005). Zygomycosis: An emerging fungal infection. Am J Health Syst Pharm 62: 2593-2596 [Abstract] [Full Text]  
  • Bialek, R, Konrad, F, Kern, J, Aepinus, C, Cecenas, L, Gonzalez, G M, Just-Nubling, G, Willinger, B, Presterl, E, Lass-Florl, C, Rickerts, V (2005). PCR based identification and discrimination of agents of mucormycosis and aspergillosis in paraffin wax embedded tissue. J. Clin. Pathol. 58: 1180-1184 [Abstract] [Full Text]  
  • Karanth, M, Taniere, P, Barraclough, J, Murray, J A (2005). A rare presentation of zygomycosis (mucormycosis) and review of the literature. J. Clin. Pathol. 58: 879-881 [Abstract] [Full Text]  
  • Spellberg, B., Edwards, J. Jr., Ibrahim, A. (2005). Novel Perspectives on Mucormycosis: Pathophysiology, Presentation, and Management. Clin. Microbiol. Rev. 18: 556-569 [Abstract] [Full Text]  
  • Gil-Lamaignere, C., Hess, R., Salvenmoser, S., Heyn, K., Kappe, R., Muller, F.-M. C. (2005). Effect of media composition and in vitro activity of posaconazole, caspofungin and voriconazole against zygomycetes. J Antimicrob Chemother 55: 1016-1019 [Abstract] [Full Text]  
  • Barron, M. A., Lay, M., Madinger, N. E. (2005). Surgery and Treatment with High-Dose Liposomal Amphotericin B for Eradication of Craniofacial Zygomycosis in a Patient with Hodgkin's Disease Who Had Undergone Allogeneic Hematopoietic Stem Cell Transplantation. J. Clin. Microbiol. 43: 2012-2014 [Abstract] [Full Text]  
  • Courtney, R., Sansone, A., Smith, W., Marbury, T., Statkevich, P., Martinho, M., Laughlin, M., Swan, S. (2005). Posaconazole Pharmacokinetics, Safety, and Tolerability in Subjects With Varying Degrees of Chronic Renal Disease. J Clin Pharmacol 45: 185-192 [Abstract] [Full Text]  
  • Pfaller, M. A., Diekema, D. J. (2004). Rare and Emerging Opportunistic Fungal Pathogens: Concern for Resistance beyond Candida albicans and Aspergillus fumigatus. J. Clin. Microbiol. 42: 4419-4431 [Full Text]  
  • Courtney, R., Radwanski, E., Lim, J., Laughlin, M. (2004). Pharmacokinetics of Posaconazole Coadministered with Antacid in Fasting or Nonfasting Healthy Men. Antimicrob. Agents Chemother. 48: 804-808 [Abstract] [Full Text]  
  • Marty, F. M., Cosimi, L. A., Baden, L. R. (2004). Breakthrough Zygomycosis after Voriconazole Treatment in Recipients of Hematopoietic Stem-Cell Transplants. NEJM 350: 950-952 [Full Text]  
  • Dannaoui, E., Meis, J. F. G. M., Loebenberg, D., Verweij, P. E. (2003). Activity of Posaconazole in Treatment of Experimental Disseminated Zygomycosis. Antimicrob. Agents Chemother. 47: 3647-3650 [Abstract] [Full Text]  
  • Courtney, R., Pai, S., Laughlin, M., Lim, J., Batra, V. (2003). Pharmacokinetics, Safety, and Tolerability of Oral Posaconazole Administered in Single and Multiple Doses in Healthy Adults. Antimicrob. Agents Chemother. 47: 2788-2795 [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 Sun, Q. N.
Right arrow Articles by Graybill, J. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sun, Q. N.
Right arrow Articles by Graybill, J. R.

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