Abstract
SummaryBackgroundCryptococcal 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.ObjectivesWe 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.MethodsWe 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.ResultsThe 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. ConclusionsTamoxifen may be a useful addition to treatment with amphotericin and fluconazole for cryptococcal meningitis; a trial is justified.
Highlights
Every year, more than 200 000 people die from cryptococcal menin‐ gitis.[1]
Cryptococcal meningitis occurs in immunocompetent patients, where Cryptococcus gattii sensu lato is an important cause, in the tropics, Western Canada and the Pacific Northwest of the USA.[2]
There was no evidence of antagonism between any of the tamoxifen‐antifungal combinations, suggesting that the effects of fluconazole or flucytosine and tamoxifen are additive for most strains
Summary
More than 200 000 people die from cryptococcal menin‐ gitis.[1] The vast majority of cases are due to Cryptococcus neoformans and occur in patients who have underlying immunosuppression. The most frequent cause of immunosuppression is HIV infection, but iatrogenic causes, including therapy for connective tissue disorders, cancers and solid organ transplantation, are increas‐ ingly important as healthcare advances.[2] Cryptococcal meningitis occurs in immunocompetent patients, where Cryptococcus gattii sensu lato is an important cause, in the tropics, Western Canada and the Pacific Northwest of the USA.[2] In Southeast and East Asia, both C. neoformans and C. gattii sensu lato cause disease in apparently immunocompetent patients.[3]. Treatment guidelines for cryptococcal meningitis are based upon the results of a number of randomised controlled trials, largely completed in patients with HIV infection.[4,5,6,7,8] The best clini‐ cal outcomes are achieved using induction treatment consisting of amphotericin combined with flucytosine.[6,9] This combination was first shown to deliver improved rates of sterilisation of cerebrospi‐ nal fluid (CSF) compared with amphotericin monotherapy in 1997; subsequently, a trial from Vietnam demonstrated that as well as delivering faster rates of clearance of yeast from CSF, it re‐ sulted in better survival, with a 40% reduction in the risk of death by 10 weeks.[4,6] even on gold standard therapy, death rates 3 months after diagnosis remain high, at between 15 (USA) and 40% (Asia and Africa).[1]
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