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

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.

Download Full-text

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.

Download Full-text

HIV-Associated Cryptococcal Meningitis Patients Treated with Amphotericin B Deoxycholate Plus Flucytosine under Routine Care Conditions in a Referral Center in São Paulo, Brazil

Mycopathologia ◽

10.1007/s11046-020-00512-2 ◽

2020 ◽

Vol 186 (1) ◽

pp. 93-102

Author(s):

José E. Vidal ◽

Camila de Albuquerque Moraes ◽

Renata Elisie Barbalho de Siqueira ◽

Nathalya Fernanda Brito Miranda ◽

Rosa Marcusso ◽

...

Keyword(s):

Amphotericin B ◽

Cryptococcal Meningitis ◽

Routine Care ◽

Sao Paulo ◽

São Paulo ◽

Referral Center ◽

Amphotericin B Deoxycholate

Download Full-text

A review of the management and outcome of patients admitted with cryptococcal meningitis at a regional hospital in KwaZulu-Natal province

South African Family Practice ◽

10.4102/safp.v61i4.4962 ◽

2019 ◽

Vol 61 (4) ◽

pp. 27

Author(s):

Andrew J. Ross ◽

Egide Ndayishimiye

Keyword(s):

Hospital Mortality ◽

Amphotericin B ◽

Cryptococcal Meningitis ◽

Regional Hospital ◽

Cd4 Count ◽

High Dose ◽

Department Of Health ◽

Significant Difference ◽

Dose Oral ◽

Intravenous Amphotericin

Background: South Africa has 7.06 million people who are HIV-positive, with those having a low CD4 count being susceptible to cryptococcal meningitis (CCM), which has an estimated mortality of 30–50%. This study aimed to establish the outcome of patients admitted with CCM to a regional hospital in Durban between June 2015 and May 2016, and the extent to which the National Department of Health (NDoH) protocol was adhered to in managing their condition.Method: This retrospective observational descriptive study reviewed the records of patients ≥ 12 years old admitted with CCM between June 2015 and May 2016, from which their demographic and medical data were extracted.Results: Seventy-six complete records were found of which 49 were men and 27 were women. The average CD4 count was 55.9 cells/mm3, 85.5% were treated with intravenous amphotericin B and high-dose oral fluconazole, 6.7% received only amphotericin B and 5.2% received only fluconazole. There was an in-hospital mortality of 31.6%, and the NDoH protocol was adhered to in 72.4% (55/76) of patients. There was, however, no significant difference in outcome between those who were and were not managed as per the protocol (p = 0.177).Discussion and conclusion: In-hospital mortality for CCM continues to be significant despite high rates of adherence to the NDoH protocol in the majority of patients. For this to be addressed, early diagnosis of HIV and initiation of ART to prevent the profound immunosuppression is essential.

Download Full-text

Faculty Opinions recommendation of High-dose amphotericin B with flucytosine for the treatment of cryptococcal meningitis in HIV-infected patients: a randomized trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1112097.572042 ◽

2008 ◽

Author(s):

Tania Sorrell ◽

Sharon Chen

Keyword(s):

Randomized Trial ◽

Amphotericin B ◽

Cryptococcal Meningitis ◽

High Dose

Download Full-text

Cryptococcosis in pregnancy and the postpartum period: Case series and systematic review with recommendations for management

Medical Mycology ◽

10.1093/mmy/myz084 ◽

2019 ◽

Vol 58 (3) ◽

pp. 282-292

Author(s):

Katelyn A Pastick ◽

Elizabeth Nalintya ◽

Lillian Tugume ◽

Kenneth Ssebambulidde ◽

Nicole Stephens ◽

...

Keyword(s):

Survival Rate ◽

Pregnant Women ◽

Amphotericin B ◽

Cryptococcal Meningitis ◽

Treatment Guidelines ◽

Case Reports ◽

Case Series ◽

First Trimester ◽

Secondary Prophylaxis ◽

Fetal Survival

Abstract Cryptococcal meningitis causes 15% of AIDS-related deaths. Optimal management and clinical outcomes of pregnant women with cryptococcosis are limited to case reports, as pregnant women are often excluded from research. Amongst pregnant women with asymptomatic cryptococcosis, no treatment guidelines exist. We prospectively identified HIV-infected women who were pregnant or recently pregnant with cryptococcosis, screened during a series of meningitis research studies in Uganda from 2012 to 2018. Among 571 women screened for cryptococcosis, 13 were pregnant, one was breastfeeding, three were within 14 days postpartum, and two had recently miscarried. Of these 19 women (3.3%), 12 had cryptococcal meningitis, six had cryptococcal antigenemia, and one had a history of cryptococcal meningitis and was receiving secondary prophylaxis. All women with meningitis received amphotericin B deoxycholate (0.7–1.0 mg/kg). Five were exposed to 200–800 mg fluconazole during pregnancy. Of these five, three delivered healthy babies with no gross physical abnormalities at birth, one succumbed to meningitis, and one outcome was unknown. Maternal meningitis survival rate at hospital discharge was 75% (9/12), and neonatal/fetal survival rate was 44% (4/9) for those mothers who survived. Miscarriages and stillbirths were common (n = 4). Of six women with cryptococcal antigenemia, two received fluconazole, one received weekly amphotericin B, and three had unknown treatment courses. All women with antigenemia survived, and none developed clinical meningitis. We report good maternal outcomes but poor fetal outcomes for cryptococcal meningitis using amphotericin B, without fluconazole in the first trimester, and weekly amphotericin B in place of fluconazole for cryptococcal antigenemia.

Download Full-text

Population Pharmacokinetic Model and Meta-analysis of Outcomes of Amphotericin B Deoxycholate Use in Adults with Cryptococcal Meningitis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02526-17 ◽

2018 ◽

Vol 62 (7) ◽

Cited By ~ 4

Author(s):

Katharine E. Stott ◽

Justin Beardsley ◽

Sarah Whalley ◽

Freddie Mukasa Kibengo ◽

Nguyen Thi Hoang Mai ◽

...

Keyword(s):

Amphotericin B ◽

Rate Constant ◽

Cryptococcal Meningitis ◽

Drug Exposure ◽

Meta Analysis ◽

Central Compartment ◽

Order Rate Constant ◽

Peripheral Compartment ◽

First Order ◽

Amphotericin B Deoxycholate

ABSTRACT There is a limited understanding of the population pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAmB) for cryptococcal meningitis. A PK study was conducted in n = 42 patients receiving DAmB (1 mg/kg of body weight every 24 h [q24h]). A 2-compartment PK model was developed. Patient weight influenced clearance and volume in the final structural model. Monte Carlo simulations estimated drug exposure associated with various DAmB dosages. A search was conducted for trials reporting outcomes of treatment of cryptococcal meningitis patients with DAmB monotherapy, and a meta-analysis was performed. The PK parameter means (standard deviations) were as follows: clearance, 0.03 (0.01) × weight + 0.67 (0.01) liters/h; volume, 0.82 (0.80) × weight + 1.76 (1.29) liters; first-order rate constant from central compartment to peripheral compartment, 5.36 (6.67) h−1; first-order rate constant from peripheral compartment to central compartment, 9.92 (12.27) h−1. The meta-analysis suggested that the DAmB dosage explained most of the heterogeneity in cerebrospinal fluid (CSF) sterility outcomes but not in mortality outcomes. Simulations of values corresponding to the area under concentration-time curve from h 144 to h 168 (AUC144–168) resulted in median (interquartile range) values of 5.83 mg · h/liter (4.66 to 8.55), 10.16 mg · h/liter (8.07 to 14.55), and 14.51 mg · h/liter (11.48 to 20.42) with dosages of 0.4, 0.7, and 1.0 mg/kg q24h, respectively. DAmB PK is described adequately by a linear model that incorporates weight with clearance and volume. Interpatient PK variability is modest and unlikely to be responsible for variability in clinical outcomes. There is discordance between the impact that drug exposure has on CSF sterility and its impact on mortality outcomes, which may be due to cerebral pathology not reflected in CSF fungal burden, in addition to clinical variables.

Download Full-text

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

Wellcome Open Research ◽

10.12688/wellcomeopenres.15010.1 ◽

2019 ◽

Vol 4 ◽

pp. 8 ◽

Cited By ~ 7

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)

Download Full-text

Liposomal Amphotericin B, and Not Amphotericin B Deoxycholate, Improves Survival of Diabetic Mice Infected with Rhizopus oryzae

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.47.10.3343-3344.2003 ◽

2003 ◽

Vol 47 (10) ◽

pp. 3343-3344 ◽

Cited By ~ 65

Author(s):

Ashraf S. Ibrahim ◽

Valentina Avanessian ◽

Brad Spellberg ◽

John E. Edwards

Keyword(s):

Overall Survival ◽

Body Weight ◽

Amphotericin B ◽

Murine Model ◽

Liposomal Amphotericin ◽

Rhizopus Oryzae ◽

Liposomal Amphotericin B ◽

High Dose ◽

Diabetic Mice ◽

Amphotericin B Deoxycholate

ABSTRACT The efficacies of liposomal amphotericin B (LAmB) and amphotericin B deoxycholate (AmB) were compared in a diabetic murine model of hematogenously disseminated Rhizopus oryzae infection. At 7.5 mg/kg of body weight twice a day (b.i.d.), LAmB significantly improved overall survival compared to the rates of survival in both untreated control mice (P = 0.001) and mice treated with 0.5 mg of AmB per kg b.i.d. (P = 0.047). These data indicate that high-dose LAmB is more effective than AmB in treating murine disseminated zygomycosis.

Download Full-text