Short course amphotericin B with high dose fluconazole for HIV-associated cryptococcal meningitis

Muzoora, Conrad; Taseera, Kabanda; Ortu, Giuseppina; Ssentamu, John; Hearn, Pasco; Mu, James; Longley, Nicky; Jarvis, Joseph N; Jaffar, Shabbar; Harrison, Thomas

doi:10.1016/j.jinf.2011.10.014

Cited by 67 publications

(58 citation statements)

References 17 publications

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“…Also supportive of the generalizability of the results was the finding that mortality in the 2-week amphotericin B-fluconazole group (41.3% at 10 weeks) was the same as that seen in the placebo group of the recent multicenter trial of adjunctive glucocorticoids in which the same antifungal regimen was used. 20 The results were consistent with those in animal models and in our phase 2 studies [10][11][12][13] and may reflect, at least in part, a balance between the rate of clearance of infection and the drug-related side effects. Flucytosine as the partner drug with amphotericin B was associated with more rapid clearance of infection than fluconazole and had a similar side-effect profile, as was previously shown in a study in Vietnam.…”

Section: Discussionsupporting

confidence: 80%

“…10 Shorter-course amphotericin B had a more favorable side-effect profile than standard 2-week courses, with no diminution in the rate of clearance of infection in the second week, perhaps because of the long half-life of amphotericin B in brain tissue. 11,12 The efficacy of shorter-course amphotericin B treatment has also been shown in animal models. 13 In addition, the drug of choice to combine with amphotericin B remains unclear.…”

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confidence: 99%

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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: Discussionsupporting

confidence: 80%

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confidence: 99%

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa

et al. 2018

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“…On the basis of evidence from clinical trials, 23,25-31 treatment guidelines for crypto coccal meningitis recommend 2 weeks of amphotericin B-based treatment as fi rst-line treatment, where possible. [16][17][18] A strategy of short-course (5-7 days) ampho tericin B was associated with rapid cryptococcal clearance in two African studies, 28,31 enabling substantial reductions in both cost and toxic eff ects of induction treatment. Although prohibitively expensive for patients in low-income and middleincome countries, liposomal formulations of amphotericin B allow the delivery of high doses of amphotericin B and seem to be at least as eff ective and less nephrotoxic than conventional amphotericin B.…”

Section: Amphotericin Bmentioning

confidence: 99%

Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries

Loyse

Thangaraj

Easterbrook

et al. 2013

The Lancet Infectious Diseases

157

144

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“…As such, combining fluconazole with AmB is often employed to address this lack of access to 5-FC, and although less effective immediately, CAF therapy with AmB and fluconazole appears at higher doses to be useful in these resource-limited settings [29][30][31][32]. With LAmB formulations rarely available outside Western countries and the high toxicity of conventional AmB especially with renal dysfunction, short courses of AmB with high doses of fluconazole (1,200 mg/day) have been employed and demonstrated rapid EFA in the CSF, and little toxicity but no clinical outcomes data has been included [32].…”

Section: Cryptococcusmentioning

confidence: 99%

Combination Antifungal Therapy: When, Where, and Why

Belanger

Yang

Forrest

2015

Curr Clin Micro Rpt

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Combination antifungal therapy in the treatment of invasive fungal infections remains a controversial topic despite its increasing use based off case reports and series. There remains a paucity of well-controlled clinical studies to address which combination, the timing, and the benefits to the underlying host without causing toxicity. The evidence for using amphotericin B with 5 flucytosine for cryptococcal infections to reduce mortality has been effectively proven but the inaccessibility to 5 flucytosine requires the utilization of less effective combinations in many countries. For invasive aspergillosis, a large controlled clinical study in hematologic malignancy patients showed a trend for combination of voriconazole and anidulafungin to reduce mortality, especially in a subgroup of patients with positive galactomannan results. Outside of these two indications, the use of combination antifungal therapy in other patients and those with rare mold infections has not been proven and outcomes are heavily influenced by host factors rather than the combinations of antifungal treatment selected.

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Short course amphotericin B with high dose fluconazole for HIV-associated cryptococcal meningitis

Cited by 67 publications

References 17 publications

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa

Antifungal Combinations for Treatment of Cryptococcal Meningitis in Africa

Cryptococcal meningitis: improving access to essential antifungal medicines in resource-poor countries

Combination Antifungal Therapy: When, Where, and Why

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