Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal

Loyse, Angela; Dromer, Françoise; Day, Jeremy; Lortholary, Olivier; Harrison, Thomas S.

doi:10.1093/jac/dkt221

Cited by 132 publications

(110 citation statements)

References 78 publications

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“…Efforts by international agencies to make flucytosine available are gaining momentum. 7,15,28,29 In conclusion, in our trial, 1 week of amphotericin B plus flucytosine was the most effective option for induction therapy for patients with HIVassociated cryptococcal meningitis in resourcelimited settings. Our results also suggest that in the absence of availability of amphotericin B or in conditions in which amphotericin B cannot be administered safely, the oral combination of fluconazole plus flucytosine provides an effective and sustainable alternative.…”

Section: Discussionmentioning

confidence: 79%

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa

et al. 2018

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BACKGROUNDCryptococcal meningitis accounts for more than 100,000 human immunodeficiency virus (HIV)-related deaths per year. We tested two treatment strategies that could be more sustainable in Africa than the standard of 2 weeks of amphotericin B plus flucytosine and more effective than the widely used fluconazole monotherapy. METHODSWe randomly assigned HIV-infected adults with cryptococcal meningitis to receive an oral regimen (fluconazole [1200 mg per day] plus flucytosine [100 mg per kilogram of body weight per day] for 2 weeks), 1 week of amphotericin B (1 mg per kilogram per day), or 2 weeks of amphotericin B (1 mg per kilogram per day). Each patient assigned to receive amphotericin B was also randomly assigned to receive fluconazole or flucytosine as a partner drug. After induction treatment, all the patients received fluconazole consolidation therapy and were followed to 10 weeks. RESULTSA total of 721 patients underwent randomization. Mortality in the oral-regimen, 1-week amphotericin B, and 2-week amphotericin B groups was 18.2% (41 of 225), 21.9% (49 of 224), and 21.4% (49 of 229), respectively, at 2 weeks and was 35.1% (79 of 225), 36.2% (81 of 224), and 39.7% (91 of 229), respectively, at 10 weeks. The upper limit of the one-sided 97.5% confidence interval for the difference in 2-week mortality was 4.2 percentage points for the oral-regimen group versus the 2-week amphotericin B groups and 8.1 percentage points for the 1-week amphotericin B groups versus the 2-week amphotericin B groups, both of which were below the predefined 10-percentage-point noninferiority margin. As a partner drug with amphotericin B, flucytosine was superior to fluconazole (71 deaths [31.1%] vs. 101 deaths [45.0%]; hazard ratio for death at 10 weeks, 0.62; 95% confidence interval [CI], 0.45 to 0.84; P = 0.002). One week of amphotericin B plus flucytosine was associated with the lowest 10-week mortality (24.2%; 95% CI, 16.2 to 32.1). Side effects, such as severe anemia, were more frequent with 2 weeks than with 1 week of amphotericin B or with the oral regimen.

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Section: Discussionmentioning

confidence: 79%

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa

et al. 2018

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“…The combination of flucytosine with amphotericin B for 2 weeks is the induction step of the gold standard treatment for AIDS-related cryptococcal meningitis [6,26]. However, flucytosine is not available and unregistered in most of Africa and Asia, where the burden of c ryptococcal meningitis is greatest (reviewed in [27]). …”

Section: Current Classes Of Antifungalsmentioning

confidence: 99%

Sphingolipids as Targets for Treatment of Fungal Infections

et al. 2016

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Invasive fungal infections have significantly increased in the last few decades. Three classes of drugs are commonly used to treat these infections: polyenes, azoles and echinocandins. Unfortunately each of these drugs has drawbacks; polyenes are toxic, resistance against azoles is emerging and echinocandins have narrow spectrum of activity. Thus, the development of new antifungals is urgently needed. In this context, fungal sphingolipids have emerged as a potential target for new antifungals, because their biosynthesis in fungi is structurally different than in mammals. Besides, some fungal sphingolipids play an important role in the regulation of virulence in a variety of fungi. This review aims to highlight the diverse strategies that could be used to block the synthesis or/and function of fungal sphingolipids.

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“…Even though flucytosine is a simple, off-patent agent that has been in clinical use for over five decades, [7] there are two major barriers to access in SA. First, while flucytosine is still registered with the Medicines Control Council (MCC), this registration has not been maintained.…”

Section: Access To Flucytosine For Hiv-infected Patients With Cryptocmentioning

confidence: 99%