Comparison of the Early Fungicidal Activity of High-Dose Fluconazole, Voriconazole, and Flucytosine as Second-Line Drugs Given in Combination With Amphotericin B for the Treatment of HIV-Associated Cryptococcal Meningitis

2011 ◽  
Vol 54 (1) ◽  
pp. 121-128 ◽  
Author(s):  
A. Loyse ◽  
D. Wilson ◽  
G. Meintjes ◽  
J. N. Jarvis ◽  
T. Bicanic ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Cryptococcal Meningitis ◽  
Fungicidal Activity ◽  
High Dose ◽  
Second Line ◽  
Early Fungicidal Activity

scholarly journals A randomized open label trial of tamoxifen combined with amphotericin B and fluconazole for cryptococcal meningitis.

2019 ◽  
Vol 4 ◽  
pp. 8 ◽  
Author(s):  
Nguyen Thi Thuy Ngan ◽  
Nguyen Thi Hoang Mai ◽  
Nguyen Le Nhu Tung ◽  
Nguyen Phu Huong Lan ◽  
Luong Thi Hue Tai ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Cryptococcal Meningitis ◽  
Treatment Guidelines ◽  
Controlled Trial ◽  
Safety Data ◽  
Open Label ◽  
Receptor Modulator ◽  
Open Label Trial ◽  
Early Fungicidal Activity

Background: Cryptococcal meningitis is a leading cause of death in HIV-infected patients. International treatment guidelines recommend induction therapy with amphotericin B and flucytosine. This antifungal combination is most effective, but unfortunately flucytosine is expensive and unavailable where the burden of disease is greatest. Where unavailable, guidelines recommend treatment with amphotericin and fluconazole, but this is less effective, with mortality rates of 40-50%. Faster rates of clearance of yeast from cerebrospinal fluid (CSF) are associated with better outcomes - improving the potency of antifungal therapy is likely to be an effective strategy to improve survival. Tamoxifen, a selective estrogen receptor modulator used to treat breast cancer, has anti-cryptococcal activity, appearing synergistic when combined in vitro with amphotericin, and fungicidal when combined with fluconazole. It is concentrated in the brain and macrophages, off-patent, cheap and widely available. We designed a randomized trial to deliver initial efficacy and safety data for tamoxifen combined with amphotericin and fluconazole. Method: A phase II, open-label, randomized (1:1) controlled trial of tamoxifen (300mg/day) combined with amphotericin (1mg/kg/day) and fluconazole (800mg/day) for the first 2 weeks therapy for HIV infected or uninfected adults with cryptococcal meningitis. The study recruits at Cho Ray Hospital and the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. The primary end point is Early Fungicidal Activity (EFA-the rate of yeast clearance from CSF), over the first two weeks of treatment. 50 patients will be recruited providing ≈80% and 90% power to detect a difference in the EFA of -0.11 or -0.13 log10CFU/ml/day, respectively. Discussion: The results of the study will inform the decision to proceed to a larger trial powered to mortality. The size of effect detectable has previously been associated with reduced mortality from this devastating disease. Particular side effects of interest include QT prolongation. Trial registration: Clinicaltrials.gov NCT03112031 (11/04/2017)

scholarly journals Amphotericin B for cryptococcal meningitis in HIV positive patients: Low dose versus high dose

2007 ◽  
Vol 11 (3) ◽  
pp. 112-116 ◽  
Author(s):  
S. Rajeshwari ◽  
Prabha M.R. Adhikari* ◽  
John T. Ramapuram* ◽  
Satish Rao* ◽  
M.R.S.M. Pai ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Cryptococcal Meningitis ◽  
Low Dose ◽  
Hiv Positive ◽  
High Dose

scholarly journals HIV-associated Cryptococcal Meningitis: a Review of Novel Short-Course and Oral Therapies

2020 ◽  
Vol 12 (4) ◽  
pp. 422-437
Author(s):  
Letumile R. Moeng ◽  
James Milburn ◽  
Joseph N. Jarvis ◽  
David S. Lawrence
Keyword(s):  
Amphotericin B ◽  
Cryptococcal Meningitis ◽  
Liposomal Amphotericin ◽  
Phase Iii ◽  
Induction Treatment ◽  
High Dose ◽  
Ongoing Research ◽  
Short Course ◽  
Incidence And Mortality ◽  
The Impact

Abstract Purpose of review HIV-associated cryptococcal meningitis remains a significant public health problem in parts of Africa and Asia and a major cause of AIDS-related mortality, accounting for 15% of all AIDS-related deaths worldwide. Cryptococcal meningitis is uniformly fatal if untreated, and access to antifungal therapy in regions with the highest burden is often limited. Outcomes with fluconazole monotherapy are poor, and induction treatment with amphotericin B and high-dose fluconazole for 2 weeks is associated with significant drug-related toxicities and prolonged hospital admissions. This review focuses on the potential of novel short-course and oral combination therapies for cryptococcal meningitis. Recent findings Recent clinical trials have shown that shorter courses of amphotericin, if paired with oral flucytosine, rather than fluconazole, can achieve non-inferior mortality outcomes. In addition, an oral combination of fluconazole and flucytosine is a potential alternative. Liposomal amphotericin B may further simplify treatment; it is associated with fewer drug-related toxicities, and a recent phase II randomised controlled trial demonstrated that a single, high dose of liposomal amphotericin is non-inferior to 14 standard daily doses at clearing Cryptococcus from cerebrospinal fluid. This has been taken forward to an ongoing phase III, clinical endpoint study. Summary The incidence and mortality associated with cryptococcal meningitis is still unacceptably high. There is evidence supporting the use of short-course amphotericin B and oral combination antifungal treatment regimens for cryptococcal meningitis (CM). Ongoing research into short-course, high-dose treatment with liposomal amphotericin may also help reduce the impact of this devastating disease.

scholarly journals High Mortality in HIV-Associated Cryptococcal Meningitis Patients Treated With Amphotericin B–Based Therapy Under Routine Care Conditions in Africa

2018 ◽  
Vol 5 (11) ◽  
Author(s):  
Raju K K Patel ◽  
Tshepo Leeme ◽  
Caitlin Azzo ◽  
Nametso Tlhako ◽  
Katlego Tsholo ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Cryptococcal Meningitis ◽  
Treatment Guidelines ◽  
Routine Care ◽  
Outcome Data ◽  
High Dose ◽  
Recommended Treatment ◽  
Amphotericin B Deoxycholate ◽  
Intravenous Amphotericin

Abstract Background Cryptococcal meningitis (CM) causes 10%–20% of HIV-related deaths in Africa. Due to limited access to liposomal amphotericin and flucytosine, most African treatment guidelines recommend amphotericin B deoxycholate (AmB-d) plus high-dose fluconazole; outcomes with this treatment regimen in routine care settings have not been well described. Methods Electronic national death registry data and computerized medical records were used to retrospectively collect demographic, laboratory, and 1-year outcome data from all patients with CM between 2012 and 2014 at Botswana’s main referral hospital, when recommended treatment for CM was AmB-d 1 mg/kg/d plus fluconazole 800 mg/d for 14 days. Cumulative survival was estimated at 2 weeks, 10 weeks, and 1 year. Results There were 283 episodes of CM among 236 individuals; 69% (163/236) were male, and the median age was 36 years. All patients were HIV-infected, with a median CD4 count of 39 cells/mm3. Two hundred fifteen person-years of follow-up data were captured for the 236 CM patients. Complete outcome data were available for 233 patients (99%) at 2 weeks, 224 patients (95%) at 10 weeks, and 219 patients (93%) at 1 year. Cumulative mortality was 26% (95% confidence interval [CI], 20%–32%) at 2 weeks, 50% (95% CI, 43%–57%) at 10 weeks, and 65% (95% CI, 58%–71%) at 1 year. Conclusions Mortality rates following HIV-associated CM treated with AmB-d and fluconazole in a routine health care setting in Botswana were very high. The findings highlight the inadequacies of current antifungal treatments for HIV-associated CM and underscore the difficulties of administering and monitoring intravenous amphotericin B deoxycholate therapy in resource-poor settings.

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