The combination of tamoxifen with amphotericin B, but not with fluconazole, has synergistic activity against the majority of clinical isolates of Cryptococcus neoformans

Abstract

Summary Background Cryptococcal meningitis has fatality rates of 40%‐70%, resulting in 200 000 deaths each year. The best outcomes are achieved with amphotericin combined with flucytosine but flucytosine is expensive and unavailable where most disease occurs. More effective and affordable treatments are needed. Tamoxifen, a selective oestrogen receptor modulator frequently indicated for breast cancer, has been found to have synergistic activity against the Cryptococcus neoformans type strain when combined with amphotericin or fluconazole. It is cheap, off‐licence, widely available and well‐tolerated, and thus a pragmatic potential treatment for cryptococcal disease. Objectives We wanted to determine the susceptibility of clinical isolates of C. neoformans to tamoxifen alone and in combination with other antifungals, to determine whether there is sufficient evidence of activity to justify a clinical trial. Methods We used the CLSI broth microdilution protocol to test the susceptibility of 30 randomly selected clinical isolates of C. neoformans to tamoxifen, in dual combination with amphotericin, fluconazole or flucytosine, and in triple combination with amphotericin and fluconazole. Evidence of drug interactions was assessed using the fractional inhibitory concentration index. Results The MIC50 and MIC90 of tamoxifen were 4 and 16 mg/L, respectively. The combination of tamoxifen and amphotericin suggested a synergistic interaction in 20 of 30 (67%) isolates. There was no interaction between tamoxifen and either fluconazole or flucytosine. Synergy was maintained in 3‐Dimensional chequerboard testing. There was no evidence of antagonism. Conclusions Tamoxifen may be a useful addition to treatment with amphotericin and fluconazole for cryptococcal meningitis; a trial is justified.

Drug repurposing strategies in the development of potential antifungal agents

“…In this review, we summarized the antifungal effects of a number of non-antifungal agents. In addition, some antitumor agents such as miltefosine (Wu et al 2020 ), tamoxifen (Hai et al 2019 ), methotrexate (Yang et al 2019 ), and antiepileptic drugs (Kathwate et al 2015 ) have been reported to have antifungal effects. The use of drug repurposing strategies in the discovery of novel antifungal agents is a revelation in the identification of new antifungal drugs through structural readjustment.…”

New Approaches for Cryptococcosis Treatment

“…Tamoxifen has in vitro antifungal activity against Cryptococcus spp. clinical isolates, with MIC ranging from 2 to 16 µg/mL, acting synergistically when combined with AMB and FLC [73,74]. In the murine disseminated cryptococcosis model, treatment with tamoxifen at 200 mg/kg/day combined with FLC at 5 mg/kg/day decreased the burden fungal by~1 log in the brain tissue [74].…”

Screening Repurposing Libraries for Identification of Drugs with Novel Antifungal Activity

“…Sertraline (see also below) reached phase III clinical trials for treatment of cryptococcal meningitis; however, the drug did not demonstrate superiority compared to current treatment options in preventing morbidity and mortality (35,36). Other notable reports on repurposing drugs as antifungals include AR-12, a derivative of celecoxib which demonstrated broad-spectrum antifungal activity (37,38); tamoxifen, an estrogen receptor antagonist used primarily to treat breast cancer (39,40); and derivatives of the antimalarial drug mefloquine (41).…”