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

ABSTRACT In vitro and in vivo efficacies of NS-718, a lipid nanosphere-encapsulated amphotericin B (AMPH-B), have been studied. Of the tested AMPH-B formulations, NS-718 had the lowest MIC forCryptococcus neoformans. In a murine model, low-dose therapy (0.8 mg/kg of body weight) with NS-718 showed higher efficacy than that with AmBisome. High-dose therapy (2.0 mg/kg) with NS-718 was much more effective than those with Fungizone and AmBisome. In mice treated with a high dose of NS-718, only a few yeast cells had grown in lung by 7 days after inoculation. A pharmacokinetic study showed higher concentrations of AMPH-B in lung following administration of NS-718 than after administration of AmBisome. Our results indicated that NS-718, a new AMPH-B formulation, is a promising antifungal agent for treatment of pulmonary cryptococcosis and could be the most effective antifungal agent against C. neoformans infections.

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High-dose ascorbate with low-dose amphotericin B attenuates severity of disease in a model of the reappearance of candidemia during sepsis in the mouse

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00238.2014 ◽

2015 ◽

Vol 309 (3) ◽

pp. R223-R234 ◽

Cited By ~ 15

Author(s):

Asada Leelahavanichkul ◽

Poorichaya Somparn ◽

Tanabodee Bootprapan ◽

Hongbin Tu ◽

Pattarin Tangtanatakul ◽

...

Keyword(s):

Cell Wall ◽

Candida Albicans ◽

Mouse Model ◽

Amphotericin B ◽

Low Dose ◽

Cecal Ligation ◽

Kidney Injury ◽

Sodium Deoxycholate ◽

High Dose ◽

Phagocytic Cells

Amphotericin B (Ampho B) is a fungicidal drug that causes cell wall injury. Pharmacological ascorbate induces the extracellular prooxidants, which might enter the Ampho B-induced cell wall porosity and act synergistically. We tested low-dose Ampho B with a short course of pharmacological ascorbate using a mouse model of sepsis preconditioned with an injection of Candida albicans 6 h prior to cecal ligation and puncture (CLP). In this model, candidemia reappeared as early as 6 h after CLP with a predictably high mortality rate. This characteristic mimics sepsis in the phase of immunosuppression in patients. Using the model, at 12- and 18-h post-CLP, we administered isotonic (pH neutralized) pharmacological ascorbate intravenously with low-dose Ampho B or sodium deoxycholate, vehicle-controlled, administered IP. The survival rate of low-dose Ampho B plus ascorbate was 53%, compared with <11% for low-dose Ampho B or high-dose Ampho B alone. In addition, a beneficial effect was demonstrated in terms of kidney damage, liver injury, spleen histopathology, and serum markers at 24 h after CLP. Kidney injury was less severe in low-dose Ampho B plus ascorbate combination therapy due to less severe sepsis. Moreover, ascorbate enhanced the effectiveness of phagocytosis against C. albicans in human phagocytic cells. Taken together, the data indicate that the new mouse model simulates sepsis-induced immunosuppression and that the combination of pharmacological ascorbate with an antifungal drug is a potentially effective treatment that may reduce nephrotoxicity, and perhaps also increase fungicidal activity in patients with systemic candidiasis caused by Candida albicans.

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

Current Treatment Options in Infectious Diseases ◽

10.1007/s40506-020-00239-0 ◽

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.

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High dose amphotericin B with flucytosine, and amphotericin B plus high dose fluconazole for treatment of cryptococcal meningitis in human immunodeficiency (HIV)-infected patients

http://isrctn.org/> ◽

10.1186/isrctn68133435 ◽

2012 ◽

Author(s):

Thomas Harrison

Keyword(s):

Amphotericin B ◽

Cryptococcal Meningitis ◽

High Dose

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O169 High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV: a randomised study

International Journal of Antimicrobial Agents ◽

10.1016/s0924-8579(07)70109-7 ◽

2007 ◽

Vol 29 ◽

pp. S34

Author(s):

T. Bicanic ◽

G. Meintjes ◽

R. Wood ◽

K. Rebe ◽

A. Brouwer ◽

...

Keyword(s):

Amphotericin B ◽

Cryptococcal Meningitis ◽

High Dose ◽

Randomised Study

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

Open Forum Infectious Diseases ◽

10.1093/ofid/ofy267 ◽

2018 ◽

Vol 5 (11) ◽

Cited By ~ 10

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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Comparative Effectiveness of Induction Therapy for Human Immunodeficiency Virus-Associated Cryptococcal Meningitis: A Network Meta-Analysis

Open Forum Infectious Diseases ◽

10.1093/ofid/ofv010 ◽

2015 ◽

Vol 2 (1) ◽

Cited By ~ 4

Author(s):

Jeffrey I. Campbell ◽

Steve Kanters ◽

John E. Bennett ◽

Kristian Thorlund ◽

Alexander C. Tsai ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Amphotericin B ◽

Induction Therapy ◽

Cryptococcal Meningitis ◽

Comparative Effectiveness ◽

Treatment Guidelines ◽

Meta Analysis ◽

High Dose ◽

Mortality Benefit ◽

Immunodeficiency Virus

Abstract Background. Multiple international treatment guidelines recommend amphotericin-based combination regimens for induction therapy of cryptococcal meningitis. Yet, only 1 trial has reported a mortality benefit for combination amphotericin-flucytosine, and none have reported a mortality benefit for combination amphotericin-fluconazole. Methods. We conducted a Bayesian network meta-analysis to estimate the comparative effectiveness of recommended induction therapies for HIV-associated cryptococcal meningitis. We searched PubMed and Cochrane CENTRAL for clinical reports of induction therapy for HIV-associated cryptococcal meningitis. We extracted or calculated early (two-week) and late (six to 12-week) mortality by treatment arm for the following induction regimens: amphotericin B alone, amphotericin B + flucytosine, amphotericin B + triazoles, amphotericin B + flucytosine +triazoles, triazoles alone, triazoles + flucytosine, liposomal amphotericin B, and amphotericin B + other medicines. Results. In the overall sample (35 studies, n = 2483), we found no evidence of decreased mortality from addition of flucytosine or triazoles to amphotericin B, compared with amphotericin B alone. Although we did find a nonsignificant benefit for addition of flucytosine to amphotericin B in studies including participants with altered levels of consciousness, we did not ide.jpegy a benefit for combination therapy in restricted analyses in either resource-rich or resource-limited settings, studies conducted before or after 2004, and studies restricted to a high dose of amphotericin B and fluconazole. Conclusions. Given considerations of drug availability and toxicity, there is an important need for additional data to clarify which populations are most likely to benefit from combination therapies for human immunodeficiency virus-associated cryptococcal meningitis.

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