This Article
Right arrow Full Text
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 Marchetti, O.
Right arrow Articles by Sanglard, D.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Marchetti, O.
Right arrow Articles by Sanglard, D.

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, May 2003, p. 1565-1570, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1565-1570.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Fungicidal Synergism of Fluconazole and Cyclosporine in Candida albicans Is Not Dependent on Multidrug Efflux Transporters Encoded by the CDR1, CDR2, CaMDR1, and FLU1 Genes

Oscar Marchetti,1 Philippe Moreillon,1 Josè M. Entenza,1 Jacques Vouillamoz,1 Michel P. Glauser,1 Jacques Bille,2 and Dominique Sanglard2*

Division of Infectious Diseases, Department of Internal Medicine,1 Institute of Microbiology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland2

Received 26 September 2002/ Returned for modification 6 December 2002/ Accepted 6 February 2003

The combination of fluconazole (FLC) and cyclosporine (CY) is fungicidal in FLC-susceptible C. albicans (O. Marchetti, P. Moreillon, M. P. Glauser, J. Bille, and D. Sanglard, Antimicrob. Agents Chemother. 44:2373-2381, 2000). The mechanism of this synergism is unknown. CY has several cellular targets including multidrug efflux transporters. The hypothesis that CY might inhibit FLC efflux was investigated by comparing the effect of FLC-CY in FLC-susceptible parent CAF2-1 (FLC MIC, 0.25 mg/liter) and in FLC-hypersusceptible mutant DSY1024 (FLC MIC, 0.03 mg/liter), in which the CDR1, CDR2, CaMDR1, and FLU1 transporter genes have been selectively deleted. We postulated that a loss of the fungicidal effect of FLC-CY in DSY1024 would confirm the roles of these efflux pumps. Time-kill curve studies showed a more potent fungistatic effect of FLC (P = 0.05 at 48 h with an inoculum of 103 CFU/ml) and a more rapid fungicidal effect of FLC-CY (P = 0.05 at 24 h with an inoculum of 103 CFU/ml) in the FLC-hypersusceptible mutant compared to those in the parent. Rats with experimental endocarditis were treated for 2 or 5 days with high-dose FLC, high-dose CY, or both drugs combined. FLC monotherapy for 5 days was more effective against the hypersusceptible mutant than against the parent. However, the addition of CY to FLC still conferred a therapeutic advantage in animals infected with mutant DSY1024, as indicated by better survival (P = 0.04 versus the results obtained with FLC) and sterilization of valves and kidneys after a very short (2-day) treatment (P = 0.009 and 0.002, respectively, versus the results obtained with FLC). Both in vitro and in vivo experiments consistently showed that the deletion of the four membrane transporters in DSY1024 did not result in loss of the fungicidal effect of FLC-CY. Yet, the accelerated killing in the mutant suggested a "dual-hit" mechanism involving FLC hypersusceptibility due to the efflux pump elimination and fungicidal activity conferred by CY. Thus, inhibition of multidrug efflux transporters encoded by CDR1, CDR2, CaMDR1, and FLU1 genes is not responsible for the fungicidal synergism of FLC-CY. Other cellular targets must be considered.

* Corresponding author. Mailing address: Institut de Microbiologie, Rue du Bugnon 44, CH-1011 Lausanne, Switzerland. Phone: 41 21 3144083. Fax: 41 21 3144060. E-mail: Dominique.Sanglard{at}chuv.hospvd.ch.

Antimicrobial Agents and Chemotherapy, May 2003, p. 1565-1570, Vol. 47, No. 5
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.5.1565-1570.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Dannaoui, E., Schwarz, P., Lortholary, O. (2009). In Vitro Interactions between Antifungals and Immunosuppressive Drugs against Zygomycetes. Antimicrob. Agents Chemother. 53: 3549-3551 [Abstract] [Full Text]  
  • Guo, N., Liu, J., Wu, X., Bi, X., Meng, R., Wang, X., Xiang, H., Deng, X., Yu, L. (2009). Antifungal activity of thymol against clinical isolates of fluconazole-sensitive and -resistant Candida albicans. J Med Microbiol 58: 1074-1079 [Abstract] [Full Text]  
  • Cowen, L. E., Steinbach, W. J. (2008). Stress, Drugs, and Evolution: the Role of Cellular Signaling in Fungal Drug Resistance. Eukaryot Cell 7: 747-764 [Full Text]  
  • Li, Y., Sun, S., Guo, Q., Ma, L., Shi, C., Su, L., Li, H. (2008). In vitro interaction between azoles and cyclosporin A against clinical isolates of Candida albicans determined by the chequerboard method and time-kill curves. J Antimicrob Chemother 61: 577-585 [Abstract] [Full Text]  
  • Perumal, P., Mekala, S., Chaffin, W. L. (2007). Role for Cell Density in Antifungal Drug Resistance in Candida albicans Biofilms. Antimicrob. Agents Chemother. 51: 2454-2463 [Abstract] [Full Text]  
  • LaFleur, M. D., Kumamoto, C. A., Lewis, K. (2006). Candida albicans Biofilms Produce Antifungal-Tolerant Persister Cells. Antimicrob. Agents Chemother. 50: 3839-3846 [Abstract] [Full Text]  
  • Prasad, T., Chandra, A., Mukhopadhyay, C. K., Prasad, R. (2006). Unexpected Link between Iron and Drug Resistance of Candida spp.: Iron Depletion Enhances Membrane Fluidity and Drug Diffusion, Leading to Drug-Susceptible Cells. Antimicrob. Agents Chemother. 50: 3597-3606 [Abstract] [Full Text]  
  • Sanguinetti, M., Posteraro, B., La Sorda, M., Torelli, R., Fiori, B., Santangelo, R., Delogu, G., Fadda, G. (2006). Role of AFR1, an ABC Transporter-Encoding Gene, in the In Vivo Response to Fluconazole and Virulence of Cryptococcus neoformans. Infect. Immun. 74: 1352-1359 [Abstract] [Full Text]  
  • Saini, P., Prasad, T., Gaur, N. A., Shukla, S., Jha, S., Komath, S. S., Khan, L. A., Haq, Q. Mohd. R., Prasad, R. (2005). Alanine scanning of transmembrane helix 11 of Cdr1p ABC antifungal efflux pump of Candida albicans: identification of amino acid residues critical for drug efflux. J Antimicrob Chemother 56: 77-86 [Abstract] [Full Text]  
  • Mukherjee, P. K., Sheehan, D. J., Hitchcock, C. A., Ghannoum, M. A. (2005). Combination Treatment of Invasive Fungal Infections. Clin. Microbiol. Rev. 18: 163-194 [Abstract] [Full Text]  
  • Steinbach, W. J., Singh, N., Miller, J. L., Benjamin, D. K. Jr., Schell, W. A., Heitman, J., Perfect, J. R. (2004). In Vitro Interactions between Antifungals and Immunosuppressants against Aspergillus fumigatus Isolates from Transplant and Nontransplant Patients. Antimicrob. Agents Chemother. 48: 4922-4925 [Abstract] [Full Text]  
  • Pascon, R. C., Ganous, T. M., Kingsbury, J. M., Cox, G. M., McCusker, J. H. (2004). Cryptococcus neoformans methionine synthase: expression analysis and requirement for virulence. Microbiology 150: 3013-3023 [Abstract] [Full Text]  
  • Shukla, S., Ambudkar, S. V., Prasad, R. (2004). Substitution of threonine-1351 in the multidrug transporter Cdr1p of Candida albicans results in hypersusceptibility to antifungal agents and threonine-1351 is essential for synergic effects of calcineurin inhibitor FK520. J Antimicrob Chemother 54: 38-45 [Abstract] [Full Text]  


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