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, September 2000, p. 2373-2381, Vol. 44, No. 9
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Potent Synergism of the Combination of Fluconazole and Cyclosporine in Candida albicans

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

Division of Infectious Diseases1 and Institute of Microbiology,2 University Hospital, Lausanne, Switzerland

Received 18 January 2000/Returned for modification 16 March 2000/Accepted 24 May 2000

Several types of drugs currently used in clinical practice were screened in vitro for their potentiation of the antifungal effect of the fungistatic agent fluconazole (FLC) on Candida albicans. These drugs included inhibitors of multidrug efflux transporters, antimicrobial agents, antifungal agents, and membrane-active compounds with no antimicrobial activity, such as antiarrhythmic agents, proton pump inhibitors, and platelet aggregation inhibitors. Among the drugs tested in an agar disk diffusion assay, cyclosporine (Cy), which had no intrinsic antifungal activity, showed a potent antifungal effect in combination with FLC. In a checkerboard microtiter plate format, however, it was observed that the MIC of FLC, as classically defined by the NCCLS recommendations, was unchanged when FLC and Cy were combined. Nevertheless, if a different reading endpoint corresponding to the minimal fungicidal concentration needed to decrease viable counts by at least 3 logs in comparison to the growth control was chosen, the combination was synergistic (fractional inhibitory concentration index of <1). This endpoint fitted to the definition of MIC-0 (optically clear wells) and reflected the absence of the trailing effect, which is the result of a residual growth at FLC concentrations greater than the MIC. The MIC-0 values of FLC and Cy tested alone in C. albicans were >32 and >10 µg/ml, respectively, and decreased to 0.5 and 0.625 µg/ml when the two drugs were combined. The combination of 0.625 µg of Cy per ml with supra-MICs of FLC resulted in a potent antifungal effect in time-kill curve experiments. This effect was fungicidal or fungistatic, depending on the C. albicans strain used. Since the Cy concentration effective in vitro is achievable in vivo, the combination of this agent with FLC represents an attractive perspective for the development of new management strategies for candidiasis.

* 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, September 2000, p. 2373-2381, Vol. 44, No. 9
0066-4804/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


This article has been cited by other articles:

  • Kolaczkowski, M., Kolaczkowska, A., Motohashi, N., Michalak, K. (2009). New High-Throughput Screening Assay To Reveal Similarities and Differences in Inhibitory Sensitivities of Multidrug ATP-Binding Cassette Transporters. Antimicrob. Agents Chemother. 53: 1516-1527 [Abstract] [Full Text]  
  • Holmes, A. R., Lin, Y.-H., Niimi, K., Lamping, E., Keniya, M., Niimi, M., Tanabe, K., Monk, B. C., Cannon, R. D. (2008). ABC Transporter Cdr1p Contributes More than Cdr2p Does to Fluconazole Efflux in Fluconazole-Resistant Candida albicans Clinical Isolates. Antimicrob. Agents Chemother. 52: 3851-3862 [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]  
  • Uppuluri, P., Nett, J., Heitman, J., Andes, D. (2008). Synergistic Effect of Calcineurin Inhibitors and Fluconazole against Candida albicans Biofilms. Antimicrob. Agents Chemother. 52: 1127-1132 [Abstract] [Full Text]  
  • Sun, S., Li, Y., Guo, Q., Shi, C., Yu, J., Ma, L. (2008). In Vitro Interactions between Tacrolimus and Azoles against Candida albicans Determined by Different Methods. Antimicrob. Agents Chemother. 52: 409-417 [Abstract] [Full Text]  
  • Kontoyiannis, D. P., Lewis, R. E., Alexander, B. D., Lortholary, O., Dromer, F., Gupta, K. L., John, G. T., del Busto, R., Klintmalm, G. B., Somani, J., Lyon, G. M., Pursell, K., Stosor, V., Munoz, P., Limaye, A. P., Kalil, A. C., Pruett, T. L., Garcia-Diaz, J., Humar, A., Houston, S., House, A. A., Wray, D., Orloff, S., Dowdy, L. A., Fisher, R. A., Heitman, J., Albert, N. D., Wagener, M. M., Singh, N. (2008). Calcineurin Inhibitor Agents Interact Synergistically with Antifungal Agents In Vitro against Cryptococcus neoformans Isolates: Correlation with Outcome in Solid Organ Transplant Recipients with Cryptococcosis. Antimicrob. Agents Chemother. 52: 735-738 [Abstract] [Full Text]  
  • Onyewu, C., Eads, E., Schell, W. A., Perfect, J. R., Ullmann, Y., Kaufman, G., Horwitz, B. A., Berdicevsky, I., Heitman, J. (2007). Targeting the Calcineurin Pathway Enhances Ergosterol Biosynthesis Inhibitors against Trichophyton mentagrophytes In Vitro and in a Human Skin Infection Model. Antimicrob. Agents Chemother. 51: 3743-3746 [Abstract] [Full Text]  
  • Stavri, M., Piddock, L. J. V., Gibbons, S. (2007). Bacterial efflux pump inhibitors from natural sources. J Antimicrob Chemother 59: 1247-1260 [Abstract] [Full Text]  
  • Zhang, N.-N., Dudgeon, D. D., Paliwal, S., Levchenko, A., Grote, E., Cunningham, K. W. (2006). Multiple Signaling Pathways Regulate Yeast Cell Death during the Response to Mating Pheromones. Mol. Biol. Cell 17: 3409-3422 [Abstract] [Full Text]  
  • Quan, H., Cao, Y.-Y., Xu, Z., Zhao, J.-X., Gao, P.-H., Qin, X.-F., Jiang, Y.-Y. (2006). Potent In Vitro Synergism of Fluconazole and Berberine Chloride against Clinical Isolates of Candida albicans Resistant to Fluconazole. Antimicrob. Agents Chemother. 50: 1096-1099 [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]  
  • Onyewu, C., Wormley, F. L. Jr., Perfect, J. R., Heitman, J. (2004). The Calcineurin Target, Crz1, Functions in Azole Tolerance but Is Not Required for Virulence of Candida albicans. Infect. Immun. 72: 7330-7333 [Abstract] [Full Text]  
  • Niimi, M., Niimi, K., Takano, Y., Holmes, A. R., Fischer, F. J., Uehara, Y., Cannon, R. D. (2004). Regulated overexpression of CDR1 in Candida albicans confers multidrug resistance. J Antimicrob Chemother 54: 999-1006 [Abstract] [Full Text]  
  • Cuenca-Estrella, M. (2004). Combinations of antifungal agents in therapy-what value are they?. J Antimicrob Chemother 54: 854-869 [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]  
  • Sussman, A., Huss, K., Chio, L.-C., Heidler, S., Shaw, M., Ma, D., Zhu, G., Campbell, R. M., Park, T.-S., Kulanthaivel, P., Scott, J. E., Carpenter, J. W., Strege, M. A., Belvo, M. D., Swartling, J. R., Fischl, A., Yeh, W.-K., Shih, C., Ye, X. S. (2004). Discovery of Cercosporamide, a Known Antifungal Natural Product, as a Selective Pkc1 Kinase Inhibitor through High-Throughput Screening. Eukaryot Cell 3: 932-943 [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]  
  • Kaur, R., Castano, I., Cormack, B. P. (2004). Functional Genomic Analysis of Fluconazole Susceptibility in the Pathogenic Yeast Candida glabrata: Roles of Calcium Signaling and Mitochondria. Antimicrob. Agents Chemother. 48: 1600-1613 [Abstract] [Full Text]  
  • Steinbach, W. J., Schell, W. A., Blankenship, J. R., Onyewu, C., Heitman, J., Perfect, J. R. (2004). In Vitro Interactions between Antifungals and Immunosuppressants against Aspergillus fumigatus. Antimicrob. Agents Chemother. 48: 1664-1669 [Abstract] [Full Text]  
  • Niimi, K., Harding, D. R. K., Parshot, R., King, A., Lun, D. J., Decottignies, A., Niimi, M., Lin, S., Cannon, R. D., Goffeau, A., Monk, B. C. (2004). Chemosensitization of Fluconazole Resistance in Saccharomyces cerevisiae and Pathogenic Fungi by a D-Octapeptide Derivative. Antimicrob. Agents Chemother. 48: 1256-1271 [Abstract] [Full Text]  
  • Afeltra, J., Vitale, R. G., Mouton, J. W., Verweij, P. E. (2004). Potent Synergistic In Vitro Interaction between Nonantimicrobial Membrane-Active Compounds and Itraconazole against Clinical Isolates of Aspergillus fumigatus Resistant to Itraconazole. Antimicrob. Agents Chemother. 48: 1335-1343 [Abstract] [Full Text]  
  • Johnson, M. D., MacDougall, C., Ostrosky-Zeichner, L., Perfect, J. R., Rex, J. H. (2004). Combination Antifungal Therapy. Antimicrob. Agents Chemother. 48: 693-715 [Full Text]  
  • Hirasawa, M., Takada, K. (2004). Multiple effects of green tea catechin on the antifungal activity of antimycotics against Candida albicans. J Antimicrob Chemother 53: 225-229 [Abstract] [Full Text]  
  • Bonilla, M., Cunningham, K. W. (2003). Mitogen-activated Protein Kinase Stimulation of Ca2+ Signaling Is Required for Survival of Endoplasmic Reticulum Stress in Yeast. Mol. Biol. Cell 14: 4296-4305 [Abstract] [Full Text]  
  • Bader, T., Bodendorfer, B., Schroppel, K., Morschhauser, J. (2003). Calcineurin Is Essential for Virulence in Candida albicans. Infect. Immun. 71: 5344-5354 [Abstract] [Full Text]  
  • Blankenship, J. R., Wormley, F. L., Boyce, M. K., Schell, W. A., Filler, S. G., Perfect, J. R., Heitman, J. (2003). Calcineurin Is Essential for Candida albicans Survival in Serum and Virulence. Eukaryot Cell 2: 422-430 [Abstract] [Full Text]  
  • Marchetti, O., Moreillon, P., Entenza, J. M., Vouillamoz, J., Glauser, M. P., Bille, J., Sanglard, D. (2003). 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. Antimicrob. Agents Chemother. 47: 1565-1570 [Abstract] [Full Text]  
  • Onyewu, C., Blankenship, J. R., Del Poeta, M., Heitman, J. (2003). Ergosterol Biosynthesis Inhibitors Become Fungicidal when Combined with Calcineurin Inhibitors against Candida albicans, Candida glabrata, and Candida krusei. Antimicrob. Agents Chemother. 47: 956-964 [Abstract] [Full Text]  
  • Cronin, S. R. (2002). I'll Simply Die Without My Calcium: Ca2+ Signaling and Surviving Cellular Stress. Mol. Interv. 2: 284-285 [Abstract] [Full Text]  
  • Bonilla, M., Cunningham, K. W. (2002). Calcium Release and Influx in Yeast: TRPC and VGCC Rule Another Kingdom. Sci Signal 2002: pe17-pe17 [Abstract] [Full Text]  
  • Nakamura, K., Niimi, M., Niimi, K., Holmes, A. R., Yates, J. E., Decottignies, A., Monk, B. C., Goffeau, A., Cannon, R. D. (2001). Functional Expression of Candida albicans Drug Efflux Pump Cdr1p in a Saccharomyces cerevisiae Strain Deficient in Membrane Transporters. Antimicrob. Agents Chemother. 45: 3366-3374 [Abstract] [Full Text]  
  • Marchetti, O., Entenza, J. M., Sanglard, D., Bille, J., Glauser, M. P., Moreillon, P. (2000). Fluconazole plus Cyclosporine: a Fungicidal Combination Effective against Experimental Endocarditis Due to Candida albicans. Antimicrob. Agents Chemother. 44: 2932-2938 [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»