The interactions of the azole antifungal agents fluconazole, itraconazole, ketoconazole, or miconazole with amphotericin B (AmB) in their effect on Candida albicans were investigated. These four azoles antagonized the fungistatic activity of AmB at sub-MICs if both substances acted simultaneously. This coincubation test was primarily developed to observe the azole-mediated demethylase inhibition quantitatively by bioassay. Interestingly, the occurrence of azole-AmB antagonism depended on azole lipophilia if specially selected test conditions were applied. By a consecutive incubation regimen, preincubation at high azole concentrations (1 to 50 g/ml) and then subsequent incubation with AmB (1 g/ml), only preincubation with the three lipophilic azoles decreased the fungicidal activity of AmB but not that of FCZ. It was shown that yeasts absorb only lipophilic azoles to a remarkable extent. This fact might be responsible for the absence of antagonism of FCZ to AmB when yeasts were incubated consecutively. It can be concluded with caution that consecutive treatment of candidiasis with FCZ and AmB does not necessarily result in a clinically relevant antagonism.Alterations of the effects of amphotericin B (AmB) on pathogenic fungi by azoles were observed repeatedly in vivo as well as in vitro. The majority of reports mention antagonisms (2-4, 6, 7, 11, 12, 16, 17), but indifference (1, 10, 18) and synergism (10, 14, 18) have also been described. The results were influenced by a variety of factors, especially experimental conditions as well as the particular fungal strains or species. The fact that the results depend on the properties of antifungal agents has been described sporadically (12). At first, a postexposure antagonism of azoles to AmB was assumed. In experiments dealing with this question, it was found that lipophilic azoles are able to influence the fungicidal activity of subsequently applied AmB on yeasts but not that of fluconazole (FCZ). To detect this behavior of lipophilic azoles, special test conditions (unusually high drug concentrations as well as a high density of organisms) had to be selected. Decreasing both inoculum size and antifungal concentration resulted in a failure to detect an influence of azoles on the fungicidal activity of AmB. For this aim of the investigation, the test conditions had to be very different from those that work with drug concentrations similar to those found in vivo, that is, sub-MICs, to observe postantifungal effects (9) with possible clinical significance.Additional tests that were performed in order to explain the dependence of the long-lasting effects of azoles on their lipophilicities also required large quantities of test organisms.The results presented in this report focus on a further aspect of the azole-AmB antagonism. The antagonism between azoles and AmB has been explained by the inhibition of ergosterol synthesis and then a disappearance of ergosterol from the cell membrane (12,13,17,19). The affinity of AmB for ergosterol precursors is not as high as that fo...

The lipophilic azoles itraconazole (ICZ), ketoconazole (KCZ) and miconazole (MCZ) have two things in common regarding their effect on Candida albicans. First, these azoles cause a growth inhibition that persists for at least 24 h after exposure (post-antibiotic effect), although this is only occasionally observed for ICZ. Secondly, these substances cause a decrease in the fungicidal activity of amphotericin B (AMB, 1 mg l-1) upon subsequent exposure to this drug. In contrast, fluconazole (FCZ) exhibits neither of these two effects. Further tests suggest that both of these phenomena observed may be related to the non-covalent binding of the three lipophilic azoles to lipophilic cytoplasmic components of yeast cells. With fluconazole, such bonds seem to be much weaker. The amount of relatively hydrophilic fluconazole that is bound non-specifically to the fungal cell is evidently too low to produce long-lasting post-exposure effects like those caused by lipophilic azoles.

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Fluconazole is a bis-triazole antifungal which partly antagonizes the activity of amphotericin B against Candida albicans (and other Candida species). This antagonism can easily be demonstrated by radial agar diffusion. Amphotericin B at reservoir concentrations of up to 1.2 mg l-1 showed a diffusion behaviour which was described by means of a simple mathematical analysis. Therefore quantitative determination of the antagonism was possible. Using a reference strain of Candida albicans, the critical concentration of amphotericin B was increased by fluconazole up to 2.4-fold.

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Antagonism between fluconazole (FCZ) and amphotericin B (AMB) was determined with an agar diffusion technique using series of agar plates containing no or 10 mgl-1 FCZ (comparative diffusion assay). Serial dilutions of AMB produced concentration-dependent inhibition zones that varied between the two agar plate series. This technique served as screening method to determine FCZ-AMB interactions in 18 Candida albicans strains. The critical concentrations of AMB were enhanced 1.33- to 7.0-fold by FCZ. The critical time, T0, was reduced by half by FCZ.

Zusammenfassung. Es wird eine schwere Verlaufsform einer Candida‐albicans‐Sepsis vorgestellt, die erfolgreich mit der Kombinationstherapie Flucytosin plus Fluconazol behandelt wurde. Nach einem großen bauchchirurgischen Eingriff entwickelte ein 70‐jähriger Patient eine fulminante Candida‐albicans‐Sepsis mit beginnendem Nierenversagen. Letzteres zwang uns, eine therapeutische Alternative zum “Gold‐Standard” Amphotericin B plus Flucytosin zu suchen. Summary. A case of a severe Candida sepsis is reported, which was treated successfully by a combination therapy of flucytosine with fluconazole. After an extensive abdominal operation, a 70‐year‐old man developed a syndrome of fulminant sepsis due to Candida albicans with the beginnings of renal failure. The latter fact forced us to search for a therapeutic alternative to the classical amphotericin B plus flucytosine combination therapy.