Abstract
Cryptococcal meningitis has high mortality. Flucytosine is a key treatment but is expensive and rarely available. The anticancer agent tamoxifen has synergistic anti-cryptococcal activity with amphotericin in vitro. It is off-patent, cheap, and widely available. We performed a trial to determine its therapeutic potential. Open label randomized controlled trial. Participants received standard care - amphotericin combined with fluconazole for the first 2 weeks - or standard care plus tamoxifen 300 mg/day. The primary end point was Early Fungicidal Activity (EFA) - the rate of yeast clearance from cerebrospinal fluid (CSF). Trial registration https://clinicaltrials.gov/ct2/show/NCT03112031. Fifty patients were enrolled (median age 34 years, 35 male). Tamoxifen had no effect on EFA (-0.48log10 colony-forming units/mL/CSF control arm versus -0.49 tamoxifen arm, difference -0.005log10CFU/ml/day, 95% CI: -0.16, 0.15, p=0.95). Tamoxifen caused QTc prolongation. High-dose tamoxifen does not increase the clearance rate of Cryptococcus from CSF. Novel, affordable therapies are needed. The trial was funded through the Wellcome Trust Asia Programme Vietnam Core Grant 106680 and a Wellcome Trust Intermediate Fellowship to JND grant number WT097147MA.
Highlights
Cryptococcal meningitis is a leading cause of death in HIV-infected patients, with an estimated 223,000 cases in 20141
Tamoxifen had no effect on Early Fungicidal Activity (EFA) (36 0.48log10 colony-forming units/mL/cerebrospinal fluid (CSF) control arm versus -0.49 tamoxifen arm, difference 37 0.005log10CFU/ml/day, 95%CI: -0.16, 0.15, P=0.95)
A selective estrogen receptor modulator used to treat breast cancer, has anti-cryptococcal activity, appearing to act synergistically when combined with other antifungals against the type strain in vitro, and to be fungicidal when combined with fluconazole in the mouse infection model11,12. We found it to act synergistically with amphotericin against two-thirds of clinical isolates of Cryptococcus neoformans and C. gattii from our archive and to have an additive interaction when combined with fluconazole in vitro14
Summary
Cryptococcal meningitis is a leading cause of death in HIV-infected patients, with an estimated 223,000 cases in 20141. Current international guidelines recommend initial induction treatment with amphotericin combined with flucytosine, followed by consolidation therapy with fluconazole. Current international guidelines recommend initial induction treatment with amphotericin combined with flucytosine, followed by consolidation therapy with fluconazole2 This combination delivers the fastest rates of clearance of yeast from cerebrospinal fluid (CSF) and the best survival rates. This combination delivers the fastest rates of clearance of yeast from cerebrospinal fluid (CSF) and the best survival rates3,4 Even on this gold standard therapy, 30% of patients will die within 10 weeks of diagnosis. The anti-cancer agent tamoxifen has synergistic anti-cryptococcal activity with amphotericin in vitro. It is off-patent, cheap, and widely available.
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