Effect of Amphotericin B and Rifampin Against Coccidioides immitis In Vitro and In Vivo

Abstract

Amphotericin B, the principal drug used for treating systemic mycoses, possesses undesirable toxic properties. The ability of this antibiotic to potentiate antifungal activity of other compounds suggests that lower doses of amphotericin B could be used in combination with a second drug without loss of therapeutic efficacy. In vitro tests demonstrated that amphotericin B potentiated rifampin against the mycelial growth phase of Coccidioides immitis but not against the spherule-endospore phase. Therapy for murine coccidioidomycosis with a combined amphotericin B-rifampin regimen was not better than treatment with amphotericin B alone; in fact, combined drugs may have been even less effective. This would have clinical significance for therapy of concurrent infections.

Rifampin Combination Therapy for Nonmycobacterial Infections

“…The early in vitro data for treatment with rifampin and amphotericin B showed killing, despite the lack of laboratory testing standards, of Histoplasma, Candida species, Cryptococcus, Rhizopus sp., and Aspergillus sp. (27,50,75,95,126,148,172). The combination had no effect on a Coccidioides immitis murine model (126).…”

“…(27,50,75,95,126,148,172). The combination had no effect on a Coccidioides immitis murine model (126). There are two case reports of amphotericin B-rifampin therapy successfully treating a leukemic patient with pulmonary aspergillosis and another patient with endocarditis caused by Wangiella dermatitidis (212,255).…”

“…The rationale for using this combination 30 years ago was to diminish the toxicity of conventional amphotericin B, as there were no other treatment options (126). The early in vitro data for treatment with rifampin and amphotericin B showed killing, despite the lack of laboratory testing standards, of Histoplasma, Candida species, Cryptococcus, Rhizopus sp., and Aspergillus sp.…”

Uniform Susceptibility of Various Strains of Coccidioides immitis to Amphotericin B

“…immitis strain Silveira (ATCC 28868), that has been used in many previous studies (2,14,17). However, it is reasonable to monitor periodically the serum levels of amB in patients with coccidioidomycosis so that the intravenous dosage can be adjusted to provide serum levels of 1.0 to 2.0 ug/ml, which appears to suffice for inhibition of C. immitis.…”

“…The spherule-endospore phase of C. immitis strain Silv cultured in synthetic medium was inhibited by an even lower concentration, 0.03 to 0.15 gg/ml (2,3,14).…”