Treatment of Experimental Murine Cryptococcosis: a Comparison of Miconazole and Amphotericin B

Abstract

Miconazole was compared with amphotericin B in the treatment of murine cryptococcosis. Both subcutaneous and intraperitoneal administration of miconazole produced serum levels higher than the minimum inhibitory concentration for the challenge strain. However, maximal tolerable doses of miconazole gave no increase in survival. When combined with amphotericin B, miconazole demonstrated neither additive nor antagonistic effects on survival. Spleen and brain counts of cryptococci were not lowered by miconazole; also, miconazole did not alter the effect of amphotericin B on reducing tissue counts. In vitro studies confirmed that the strain of Cryptococcus neoformans was quite susceptible to both miconazole and amphotericin B. However, miconazole had a delayed onset of antifungal activity. This was apparent even at miconazole levels 20 times greater than the minimum inhibitory concentration. Also, the antifungal activity of miconazole was markedly inhibited by serum. Delayed antifungal activity and serum inhibition may limit the in vivo effectiveness of miconazole in murine cryptococcosis.

Interaction of Chemotherapy and Immune Defenses in Experimental Murine Cryptococcosis

“…Figure 3 This course of a total of 30 mg of amphotericin B per kg was highly effective in that it caused all mice to survive for more than 3 months after challenge, when they were sacrificed. Prior studies with normal BALB/c mice similarly treated had produced similar results and also had shown markedly reduced, sometimes undetectable, spleen and brain cryptococcal counts immediately after completion of their treatment (14). Thus, we considered that these amphotericin Btreated nu/X, thymus-containing mice were probably "cured" of their cryptococcosis.…”

“…This is consistent with the serum levels in both VOL. 14,1978 on May 7, 2018 by guest http://aac.asm.org/ Downloaded from nu/nu and nu/X mouse sera being close to the minimum inhibitory concentration for amphotericin B at 24 h after the dose. A second study, in which serum was obtained 6 h after the dose, showed similar growth rates in control sera inoculated with 104 C. neoformans.…”

“…Mouse serum is markedly inhibitory to growth of C. neoformans at pH 7.4, but not at pH 5.6. This is probably due to transferrin, which binds iron at physiological pH but not at low pH (14). Therefore, sera were adjusted to pH 5.6.…”

Efficacy of Oral Encochleated Amphotericin B in a Mouse Model of Cryptococcal Meningoencephalitis

“…In contrast, in a discovery study of multiple formulations, a 3-day delay in therapy ( Fig. 1B) resulted in reduced efficacy of all drugs tested, allowing discrimination of median survivals between the fungistatic drug fluconazole (53 days, P Ͻ 0.002 versus untreated), monotherapy with 5FC (47 days, P Ͻ 0.002 versus untreated), and a high-dose amphotericin B regimen previously described to be effective in a mouse model (10) in combination with 5FC (11). Using this model, CAmB at 5 mg/kg/day i.p.…”

“…In these studies, multiple formulations of CAmB were evaluated to test which compound and route of administration were most efficient against C. neoformans in mice. A delayed-treatment model that results in more rapid failure of fungistatic drugs such as fluconazole than of fungicidal amphotericin B was also utilized (10).…”