Fluconazole plus Cyclosporine: a Fungicidal Combination Effective against Experimental Endocarditis Due to Candida albicans

ABSTRACT Recent observations demonstrated that fluconazole plus cyclosporine (Cy) synergistically killed Candida albicans in vitro. This combination was tested in rats with C. albicansexperimental endocarditis. The MICs of fluconazole and Cy for the test organism were 0.25 and >10 mg/liter, respectively. Rats were treated for 5 days with either Cy, amphotericin B, fluconazole, or fluconazole-Cy. Although used at high doses, the peak concentrations of fluconazole in the serum of rats (up to 4.5 mg/liter) were compatible with high-dose fluconazole therapy in humans. On the other hand, Cy concentrations in serum (up to 4.5 mg/liter) were greater than recommended therapeutic levels. Untreated rats demonstrated massive pseudohyphal growth in both the vegetations and the kidneys. However, only the kidneys displayed concomitant polymorphonuclear infiltration. The therapeutic results reflected this dissociation. In the vegetations, only the fungicidal fluconazole-Cy combination significantly decreased fungal densities compared to all groups, including amphotericin B (P < 0.0001). In the kidneys, all regimens except the Cy regimen were effective, but fluconazole-Cy remained superior to amphotericin B and fluconazole alone in sterilizing the organs (P < 0.0001). While the mechanism responsible for the fluconazole-Cy interaction is hypothetical, this observation opens new perspectives for fungicidal combinations between azoles and other drugs.

[1]  D. Sanglard,et al.  Potent Synergism of the Combination of Fluconazole and Cyclosporine in Candida albicans , 2000, Antimicrobial Agents and Chemotherapy.

[2]  Joseph Heitman,et al.  Synergistic Antifungal Activities of Bafilomycin A1, Fluconazole, and the Pneumocandin MK-0991/Caspofungin Acetate (L-743,873) with Calcineurin Inhibitors FK506 and L-685,818 against Cryptococcus neoformans , 2000, Antimicrobial Agents and Chemotherapy.

[3]  Michael H. Miller,et al.  Pharmacokinetic Studies of Fluconazole in Rabbits Characterizing Doses Which Achieve Peak Levels in Serum and Area under the Concentration-Time Curve Values Which Mimic Those of High-Dose Fluconazole in Humans , 1998, Antimicrobial Agents and Chemotherapy.

[4]  K. Kuchler,et al.  Genetic separation of FK506 susceptibility and drug transport in the yeast Pdr5 ATP-binding cassette multidrug resistance transporter. , 1998, Molecular biology of the cell.

[5]  R. Chen,et al.  Effectiveness of quinolone antibiotics in modulating the effects of antifungal drugs , 1997, Antimicrobial agents and chemotherapy.

[6]  K. Joiner,et al.  Characterization of anti-Toxoplasma activity of SDZ 215-918, a cyclosporin derivative lacking immunosuppressive and peptidyl-prolyl-isomerase-inhibiting activity: possible role of a P glycoprotein in Toxoplasma physiology , 1997, Antimicrobial agents and chemotherapy.

[7]  M. Ghannoum,et al.  Combination therapy with amphotericin B and fluconazole against invasive candidiasis in neutropenic-mouse and infective-endocarditis rabbit models , 1997, Antimicrobial agents and chemotherapy.

[8]  D. Sanglard,et al.  Cloning of Candida albicans genes conferring resistance to azole antifungal agents: characterization of CDR2, a new multidrug ABC transporter gene. , 1997, Microbiology.

[9]  E. Anaissie,et al.  Controversies in management of candidiasis in neutropenic patients treated for malignant diseases: new versus old or better versus worse , 1997 .

[10]  D. Sanglard,et al.  Susceptibilities of Candida albicans multidrug transporter mutants to various antifungal agents and other metabolic inhibitors , 1996, Antimicrobial agents and chemotherapy.

[11]  L Timmermann,et al.  The mechanism of action of cyclosporin A and FK506. , 1996, Clinical immunology and immunopathology.

[12]  D. Snydman,et al.  The changing face of candidemia: emergence of non-Candida albicans species and antifungal resistance. , 1996, The American journal of medicine.

[13]  A. List,et al.  Role of multidrug resistance and its pharmacological modulation in acute myeloid leukemia. , 1996, Leukemia.

[14]  R. Farinotti,et al.  Comparison of fluconazole and amphotericin B for treatment of experimental Candida albicans endocarditis in rabbits , 1996, Antimicrobial agents and chemotherapy.

[15]  E. Brummer,et al.  Synergy of fluconazole with human monocytes or monocyte-derived macrophages for killing of Candida species. , 1995, The Journal of infectious diseases.

[16]  K. Kuchler,et al.  Mechanisms of resistance to azole antifungal agents in Candida albicans isolates from AIDS patients involve specific multidrug transporters , 1995, Antimicrobial agents and chemotherapy.

[17]  E. Anaissie,et al.  Safety, plasma concentrations, and efficacy of high-dose fluconazole in invasive mold infections. , 1995, The Journal of infectious diseases.

[18]  M. Levenstein,et al.  A Randomized Trial Comparing Fluconazole with Amphotericin B for the Treatment of Candidemia in Patients without Neutropenia , 1994 .

[19]  A. Bayer,et al.  Comparison of fluconazole and amphotericin B for treatment of experimental Candida endocarditis caused by non-C. albicans strains , 1993, Antimicrobial Agents and Chemotherapy.

[20]  D. Irwin,et al.  Isogenic strain construction and gene mapping in Candida albicans. , 1993, Genetics.

[21]  C. Beck-Sague,et al.  Secular trends in the epidemiology of nosocomial fungal infections in the United States, 1980-1990. National Nosocomial Infections Surveillance System. , 1993, The Journal of infectious diseases.

[22]  C. Higgins,et al.  ABC transporters: from microorganisms to man. , 1992, Annual review of cell biology.

[23]  C. Klee,et al.  Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[24]  K. A. Porter,et al.  The Kidneys: The Urinary Tract , 1992 .

[25]  S. Schreiber,et al.  The mechanism of action of cyclosporin A and FK506. , 1992, Immunology today.

[26]  M. Witt,et al.  Comparison of fluconazole and amphotericin B for prevention and treatment of experimental Candida endocarditis , 1991, Antimicrobial Agents and Chemotherapy.

[27]  Stuart L. Schreiber,et al.  Calcineurin is a common target of cyclophilin-cyclosporin A and FKBP-FK506 complexes , 1991, Cell.

[28]  P. Sonneveld,et al.  Reversal of drug‐resistance by cyclosporin‐A in a patient with acute myelocytic leukaemia , 1990, British journal of haematology.

[29]  J. K. Faulkner,et al.  Pharmacokinetics and tissue penetration of fluconazole in humans. , 1990, Reviews of infectious diseases.

[30]  H. Gallis,et al.  Amphotericin B: 30 years of clinical experience. , 1990, Reviews of infectious diseases.

[31]  A. Schaffner,et al.  Comparison of immunosuppressive effects of cyclosporine A in a murine model of systemic candidiasis and of localized thrushlike lesions , 1989, Infection and immunity.

[32]  T. Walsh,et al.  Pharmacokinetics and tissue penetration of fluconazole in rabbits , 1989, Antimicrobial Agents and Chemotherapy.

[33]  C. Mody,et al.  Treatment of murine cryptococcosis with cyclosporin-A in normal and athymic mice. , 1989, The American review of respiratory disease.

[34]  I. Pastan,et al.  Multiple-drug resistance in human cancer. , 1987, The New England journal of medicine.

[35]  S. Thiru,et al.  BLOOD LEVELS AND NEPHROTOXICITY OF CYCLOSPORIN A AND G IN RATS , 1986, The Lancet.

[36]  J. Perfect,et al.  Comparison of amphotericin B and N-D-ornithyl amphotericin B methyl ester in experimental cryptococcal meningitis and Candida albicans endocarditis with pyelonephritis , 1985, Antimicrobial Agents and Chemotherapy.

[37]  M. Haynes,et al.  Cyclosporin partitions into phospholipid vesicles and disrupts membrane architecture. , 1985, Immunology letters.

[38]  J. Fierer,et al.  Cyclosporin A inhibits Coccidioides immitis in vitro and in vivo , 1983, Antimicrobial Agents and Chemotherapy.

[39]  M. Glauser,et al.  Natural history of aortic valve endocarditis in rats , 1982, Infection and immunity.

[40]  M. Rotondo,et al.  Candida albicans Endocarditis: Ultrastructural Studies of Vegetation Formation , 1978, Infection and immunity.

[41]  J. Rahal,et al.  Tissue penetration of amphotericin B in Candida endocarditis. , 1974, Chest.

[42]  B. T. Fields,et al.  Amphotericin B serum concentrations during therapy. , 1970, Applied microbiology.