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A comparative study of the amphotericin B contents in the skin and subcutaneous fatty tissue was performed on guinea pigs after local application of amphotericin ointment by phonophoresis and with preliminary treatment of the skin by dimethyl sulfoxide (DMSO). When the amphotericin ointment was used in combination with ultrasound the content of amphotericin B in the skin and subcutaneous fatty tissue 1, 3, 24, 48 and 72 hours after the application was much higher than that after the ointment local application without the ultrasonic treatment. When the amphotericin ointment was applied locally after the preliminary treatment with DMSO the maximum content of the antibiotic in the skin and subcutaneous fatty tissue was observed 3 hours after the application which was significantly higher than the content observed after the ointment application by phonophoresis and especially locally without the ultrasonic treatment. In 24, 48 and 72 hours the amphotericin B concentration in the skin and subcutaneous fatty tissue under any conditions lowered and in 24 hours had a tendency to level in the areas treated with ultrasound and DMSO. In 48 and 72 hours the highest concentrations of the antibiotic were in the skin and subcutaneous fatty tissue after the ointment application by phonophoresis.

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The cell population of Penicillin solitum was studied during maximum accumulation of lipase in the medium with electron microscopic and immunofluorescence methods. The data provided a conclusion that 2 types of lypolytic enzymes with various substrate and antigenic characteristics formed in the cells of P. solitum. It is likely that there is a specific inductor for exolipase synthesis as well as relationship endoenzymatic systems.

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It was shown that combined use of the polyene antibiotic amphoglucamine (AMG) and 5-fluorocytosine (5-FC), rifampicin, or methacycline was much more efficient in therapy of experimental generalized candidiasis. Combination of AMG with 5-FC or rifampicin proved to be the most favourable. The use of these combinations resulted in a 7-8-fold increase in the average lifespan of experimental animals, markedly increased their survival and lowered contamination of the internal organs with the fungus. Combination of AMG with 5-FC resulted in complete healing of experimental mice by the end of the treatment. Summation of the antifungal action of the drugs provided the required effect with the polyene dose 2 times lower than the therapeutic one.

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It was shown that polyenic antibiotics and their combinations with some other antifungal and antibacterial agents prevented transformation of the C. albicans yeast phase into the tissue one. Moreover, the fungus tissue form proved to be more sensitive than the yeast form to the drugs and especially to their combinations. The in vitro findings were confirmed by the in vivo studies. Combinations of amphotericin B with methacycline, rifampicin, 5-fluorocytosine or polymyxin B were more efficient than the polyene alone. Summation of the drug antifungal effects provided a 4-fold decrease in the polyene quantity required for administration to experimental animals.

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The combined effect of various polyenic antibiotics and other antifungal and antibacterial drugs on Candida was studied. The efficacy of the combinations was estimated with the method of square titration followed by quantitative plating out of the samples. By the interaction type the combinations were divided into 3 groups. The character of the drug interaction in these groups might be considered as indifferent, additive or synergistic. No antagonistic effect was observed in any of the combinations. The findings may be useful in more successful treatment of candidiasis when monotherapy is not sufficiently efficient, as well as in optimization of schemes for treating mixed infections.

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The combined effect of amphotericin B, a polyene antibiotic, and metacycline, a tetracycline antibiotic, on the cells of C. albicans was studied. The method of square titration followed by quantitative plating of the samples was used for estimation of the combination efficiency. An attempt was also made to investigate the characteristic features of metacycline penetration into the yeast cells under the effect of various doses of the polyene antibiotic. The capacity of metacycline for fluorescence in the yellow-green pectral region was employed for this purpose. It was shown that the drugs had a synergistic effect on C. albicans. The fluorescence research methods allowed one to demonstrate that even low subinhibitory doses of amphotericin B increased the permeability level of the cytoplasmic membrane and provided penetration of metacycline into the cytoplasm almost during the first hours of the contact. The time course of metacycline cumulation in the cells was followed up and the characteristic features of the antibiotic localization were analysed.

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Fungi C. albicans killed by various methods were injected intravenously to mice resulting in the granuloma formation in the liver and spleen. These granulomas were similar to those developing in newborns affected with candidiasis. The components of the fungus cellular wall are responsible for the granuloma development and act as the antigenic material. Polynuclears which are capable of dealing with the antigenic material more actively than mononuclear liver phagocytes, play an essential role as the trigger mechanism in the granuloma formation produced by the killer C. albicans. At the same time long persistence of C. albicans antigenic material in the granulomas proves the deficiency of the phagocytic response directed to the utilization of this material. It is assumed that similar mechanisms are responsible for the morphogenesis of both human candidiasis granulomas and those produced by the killed C. albicans.

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Changes in the volume, mass and concentration of the dry matter in the cells of Candida albicans during 48-hour incubation with various doses of amphotericin B were studied with the use of a polarization interference microscope (BIOLAR, Poland). The changes of the parameters studied had a wave-like pattern under the effect of fungicidal, fungistatic and subfungistatic doses. It was shown that within the first minutes of the contact any dose increased the volume and lowered the concentration of the dry matter of C. albicans cells due to impairment of the cytoplasmic membrane permeability. Later the fungicidal and fungistatic doses of amphotericin B induced irreversible pathological changes in the cells accompanied by an increase in the volume and a decrease in the mass and concentration of the dry matter in the cytoplasm. The subinhibitory concentrations of the drug promoted the fungus growth instead of its inhibition.

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The role of mononuclear phagocytes as universal carriers of biologically active substances in a focus of inflammation is clearly seen in mediated effect of polyenic antibiotic in experimental candidiasis. This function of macrophages is very important in the mechanism of action of polyenic antibiotics and is a component of pathomorphosis in antibiotic therapy, since it affects the relationship of cells in a forming inflammatory focus.

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The mechanism of amphotericin B action was studied with the aid of cytochemical methods providing determination of the activity of the 4 main enzymes characterizing the cell energetics, i. e. succinate dehydrogenase, lactate dehydrogenase, alcohol dehydrogenase and glucose-6-phosphate dehydrogenase inside the cell. With an increase in the concentration of amphotericin B in the medium the activity of all the 4 enzymes decreased, the percentage of the inactive cells being regularly increased. Changes in the fermentative activity of C. albicans as dependent on the incubation time with the antibiotic were studied. Only the respiration activity decreased in 2 hours. As a result of a 4-hour exposure to the polyen in the cells of C. albicans the activity of the lactic acid fermentation, respiration through succinate dehydrogenase and activity of the pentose shunt decreased 1.5--2 times. In 24 hours of incubation the activity of the above decreased 80--90 per cent as compared to the activity of the initial culture.

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Studies of phagocytic cells of the abdominal cavity in rats in experimental candidosis were carried out. The processes of interaction between phagocytic cells and the pathogene in intact animals and after the vaccination, were analysed. It was established that in parallel with an increase in the functional activity, phagocytes changed morphologically and cytochemically: their nucleo-cytoplasmatic ratio drastically dropped, motility increased, as well as the activity of hydrolytic enzymes. In the sensitized macrophages there appeared activity of alkaline phophotase (in intact macrophages in rats this enzyme was not revealed). Particular attention was paid to the activation of the hexose-monophosphate cycle regulating phagocytosis, and to accumulation in neutrophiles of bactericidal free aldehydes. Enzymatic characteristics and differences between peritoneal macrophages and neutrophilic leucocytes were shown.

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