Short-Course Induction Treatment with Intrathecal Amphotericin B Lipid Emulsion for HIV Infected Patients with Cryptococcal Meningitis

Cryptococcal meningitis (CM) is a common cause of death among HIV infected patients in developing countries, especially in sub-Saharan Africa. In this observational HIV cohort study in a resource-limited setting in India, we compared the standard two-week intravenous amphotericin B deoxycholate (AmBd) (Regimen I) with one week of intravenous AmBd along with daily therapeutic lumbar punctures and intrathecal AmB lipid emulsion (Regimen II) during the intensive phase of CM treatment. 78 patients received Regimen I and 45 patients received Regimen II. After adjustment for baseline characteristics (gender, age, altered mental status or seizures at presentation, CD4 cell count, white blood cells, cerebrospinal fluid white cells, and haemoglobin), the use of Regimen II was associated with a significant relative risk reduction in mortality (adjusted hazard ratio 0.4, 95% confidence interval, 0.22–0.76) and 26.7% absolute risk reduction (95% confidence interval, 9.9–43.5) at 12 weeks. The use of Regimen II resulted in lower costs of drugs and hospital admission days. Since the study is observational in nature, we should be cautious about our results. However, the good tolerability of intrathecal administration of AmB lipid emulsion and the clinically important mortality reduction observed with the short-course induction treatment warrant further research, ideally through a randomized clinical trial.

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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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Standardized Electrolyte Supplementation and Fluid Management Improves Survival During Amphotericin Therapy for Cryptococcal Meningitis in Resource-Limited Settings

Open Forum Infectious Diseases ◽

10.1093/ofid/ofu070 ◽

2014 ◽

Vol 1 (2) ◽

Cited By ~ 18

Author(s):

Nathan C. Bahr ◽

Melissa A. Rolfes ◽

Abdu Musubire ◽

Henry Nabeta ◽

Darlisha A. Williams ◽

...

Keyword(s):

Amphotericin B ◽

Cryptococcal Meningitis ◽

Fluid Management ◽

Sub Saharan Africa ◽

Induction Treatment ◽

Mulago Hospital ◽

Intravenous Fluids ◽

Resource Limited Settings ◽

Resource Limited ◽

Fluid And Electrolyte Management

Abstract Background. Amphotericin B is the preferred treatment for cryptococcal meningitis, but it has cumulative severe side effects, including nephrotoxicity, hypokalemia, and hypomagnesemia. Amphotericin-induced severe hypokalemia may predispose the patient to cardiac arrhythmias and death, and there is very little data available regarding these toxicities in resource-limited settings. We hypothesized that standardized electrolyte management during amphotericin therapy is essential to minimize toxicity and optimize survival in sub-Saharan Africa. Methods. Human immunodeficiency virus-infected, antiretroviral therapy naive adults with cryptococcal meningitis were prospectively enrolled at Mulago Hospital in Kampala, Uganda in 3 sequential cohorts with amphotericin B deoxycholate induction treatment. Intravenous fluid use was intermittent in 2001–2002, and universal in 2006–2012. In 2001–2009, serum potassium (K+) was monitored on days 1, 7, and 14 of treatment with replacement (K+, Mg2+) per clinician discretion. In 2011–2012, K+ was measured on days 1, 5, and approximately every 48 hours thereafter with universal electrolyte (K+, Mg2+) supplementation and standardized replacement. Clinical outcomes were retrospectively compared between fluid and electrolyte management strategies. Results. With limited intravenous fluids, the 14-day survival was 49% in 2001–2002. With universal intravenous fluids, the 30-day survival improved to 62% in 2006–2010 (P = .003). In 2011–2012, with universal supplementation of fluids and electrolytes, 30-day cumulative survival improved to 78% (P = .021 vs 2006–2010 cohort). The cumulative incidence of severe hypokalemia (<2.5 mEq/L) decreased from 38% in 2010 to 8.5% in 2011–2012 with universal supplementation (P < .001). Conclusions. Improved survival was seen in a resource-limited setting with proactive fluid and electrolyte management (K+, Mg2+), as part of comprehensive amphotericin-based cryptococcal therapy.

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Toxicity of Amphotericin B Deoxycholate-Based Induction Therapy in Patients with HIV-Associated Cryptococcal Meningitis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01698-15 ◽

2015 ◽

Vol 59 (12) ◽

pp. 7224-7231 ◽

Cited By ~ 49

Author(s):

Tihana Bicanic ◽

Christian Bottomley ◽

Angela Loyse ◽

Annemarie E. Brouwer ◽

Conrad Muzoora ◽

...

Keyword(s):

Amphotericin B ◽

Cryptococcal Meningitis ◽

Induction Treatment ◽

Standardized Protocol ◽

Short Course ◽

Amphotericin B Deoxycholate ◽

Intravenous Saline ◽

Electrolyte Replacement ◽

Grade Iii ◽

Electrolyte Abnormalities

ABSTRACTAmphotericin B deoxycholate (AmBd) is the recommended induction treatment for HIV-associated cryptococcal meningitis (CM). Its use is hampered by toxicities that include electrolyte abnormalities, nephrotoxicity, and anemia. Protocols to minimize toxicity are applied inconsistently. In a clinical trial cohort of AmBd-based CM induction treatment, a standardized protocol of preemptive hydration and electrolyte supplementation was applied. Changes in blood counts, electrolyte levels, and creatinine levels over 14 days were analyzed in relation to the AmBd dose, treatment duration (short course of 5 to 7 days or standard course of 14 days), addition of flucytosine (5FC), and outcome. In the 368 patients studied, the hemoglobin levels dropped by a mean of 1.5 g/dl (95% confidence interval [CI], 1.0 to 1.9 g/dl) following 7 days of AmBd and by a mean of 2.3 g/dl (95% CI, 1.1 to 3.6 g/dl) after 14 days. Serum creatinine levels increased by 37 μmol/liter (95% CI, 30 to 45 μmol/liter) by day 7 and by 49 μmol/liter (95% CI, 35 to 64μmol/liter) by day 14 of AmBd treatment. Overall, 33% of patients developed grade III/IV anemia, 5.6% developed grade III hypokalemia, 9.5% had creatinine levels that exceeded 220 μmol, and 6% discontinued AmBd prematurely. The addition of 5FC was associated with a slight increase in anemia but not neutropenia. Laboratory abnormalities stabilized or reversed during the second week in patients on short-course induction. Grade III/IV anemia (adjusted odds ratio [aOR], 2.2; 95% CI, 1.1 to 4.3;P= 0.028) and nephrotoxicity (aOR, 4.5; 95% CI, 1.8 to 11;P= 0.001) were risk factors for 10-week mortality. In summary, routine intravenous saline hydration and preemptive electrolyte replacement during AmBd-based induction regimens for HIV-associated CM minimized the incidence of hypokalemia and nephrotoxicity. Anemia remained a concerning adverse effect. The addition of flucytosine was not associated with increased neutropenia. Shorter AmBd courses were less toxic, with rapid reversibility.

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Cost-effectiveness and budget impact of flucytosine as induction therapy in the treatment of cryptococcal meningitis in HIV-infected adults in South Africa

10.21203/rs.2.22856/v1 ◽

2020 ◽

Author(s):

Jacqui Miot ◽

Trudy Leong ◽

Simbarashe Takuva ◽

Andrew Parrish ◽

Halima Dawood

Keyword(s):

South Africa ◽

Cost Effectiveness ◽

Amphotericin B ◽

Induction Therapy ◽

Cryptococcal Meningitis ◽

Budget Impact ◽

Cost Effective ◽

Standard Of Care ◽

Sub Saharan Africa ◽

Oral Regimen

Abstract Background Cryptococcal meningitis in HIV-infected patients in sub-Saharan Africa accounts for three-quarters of the global cases and 135 000 deaths per annum. Current treatment includes the use of fluconazole and amphotericin B. Recent evidence has shown that the synergistic use of flucytosine improves efficacy and reduces toxicity, however affordability and availability has hampered access to flucytosine in many countries. This study investigated the evidence and cost implications of introducing flucytosine as induction therapy for cryptococcal meningitis in HIV-infected adults in South Africa. Methods A decision analytic cost-effectiveness and budget impact model was developed based on survival estimates from the ACTA trial and local costs for flucytosine as induction therapy in HIV-infected adults with cryptococcal meningitis in a public sector setting in South Africa. The model considered four treatment arms: (a) standard of care; 2-week course of amphotericin B/fluconazole (2wk AmBd/Flu), (b) 2-week course of amphotericin B/flucytosine (2wk AmBd/5FC), (c) short course; 1-week course amphotericin B/flucytosine (1wk AmBd/5FC) and (d) oral course; 2-week oral fluconazole/flucytosine (oral). A sensitivity analysis was conducted on key variables. Results The highest total treatment costs were in the 2-week AmBd/5FC arm followed by the 2-week oral regimen, then the 1-week AmBd/5FC with the lowest cost in the standard of care arm. Compared to standard of care the 1-week flucytosine course is most cost-effective at USD31/QALY, followed by the oral 2-week course at USD155/QALY and the 2-week flucytosine course at USD568/QALY. The budget impact analysis shows that the 1-week course has the lowest incremental cost, followed by the oral course and then the 2-week flucytosine course compared to what is currently spent on standard of care. Sensitivity analyses suggest that the model is most sensitive to the price of flucytosine and hospital costs, particularly length of stay. Conclusions The addition of flucytosine as induction therapy for the treatment of cryptococcal meningitis in patients infected with HIV is cost-effective regardless of whether it is used as a 1-week, 2-week or oral regimen. Savings could be achieved with early discharge of patients as well as a reduction in the price of flucytosine.

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Unique clinical features of cryptococcal meningitis among Chinese patients without predisposing diseases against patients with predisposing diseases

Medical Mycology ◽

10.1093/mmy/myy154 ◽

2019 ◽

Vol 57 (8) ◽

pp. 944-953 ◽

Cited By ~ 5

Author(s):

Lijun Xu ◽

Xinyue Zhang ◽

Yongzheng Guo ◽

Ran Tao ◽

Xiahong Dai ◽

...

Keyword(s):

Risk Factors ◽

Serum Albumin ◽

Amphotericin B ◽

Clinical Features ◽

Cryptococcal Meningitis ◽

White Blood Cells ◽

Chinese Patients ◽

Fungal Burden ◽

Risk Of Death ◽

Culture Positivity

Abstract The clinical features of cryptococcal meningitis (CM) in patients without predisposing diseases (PD) remain unclear. In sum, 162 of the 167 patients without PD and 162 of the 309 patients with PD were enrolled after propensity score matching. Demographic characteristics, symptoms, blood, and cerebrospinal fluid (CSF) characteristics were compared between the two groups. Kaplan-Meier curves and a Cox proportional hazards model were used to assess the factors associated with 10-week mortality. In total, approximately 35.1% of CM patients were without PD. CM patients without PD had blood profiles of higher white blood cells (WBC) [8.9(6.7–11.0) × 109/l], hemoglobin (128.4 ± 20.9 g/l), platelets [(226.2 ± 64.1) × 109/l], and serum albumin (41.2 ± 5.8 g/l) (all P ≤ .001) and CSF profiles of lower glucose (2.0 ± 1.2 mmol/l), pleocytosis [65.0 (18.0–160.0) × 106/l] and higher total protein [0.9 (0.7–1.4)g/l] (all P < .05). CM patients without PD had lower Cryptococcus culture positivity in CSF (62.5% vs. 74.1%, P = .039) but higher 2-week of CSF culture sterilization rates (69.4% vs. 51.3%, P = .031). The overall 10-week survival rate was 84.7% in patients without PD and 81.1% in patients with PD (Log-rank P = .439). CSF glucose <1.5 mmol/l, CSF fungal burden >20 cells/high power field and treatment lacking amphotericin B had a 3–4 times higher risk of death in patients without PD, whereas serum albumin <35 g/l, CSF glucose < 1.5 mmol/l, and CSF WBC <55 × 106 cell/l were risk factors for patients with PD. CM patients without PD had unique blood and CSF profiles, especially, had lower Cryptococcus culture positivity in CSF, and higher 2-week CSF culture sterilization. Low CSF glucose levels, higher fungal burden, and treatment without amphotericin B were risk factors for 10-week mortality.

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Amphotericin B in a lipid emulsion for the treatment of cryptococcal meningitis in AIDS patients

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/38.1.117 ◽

1996 ◽

Vol 38 (1) ◽

pp. 117-126 ◽

Cited By ~ 17

Author(s):

V. Joly ◽

C. Geoffary ◽

J. Reynes ◽

C. Goujard ◽

D. Méchali ◽

...

Keyword(s):

Amphotericin B ◽

Cryptococcal Meningitis ◽

Lipid Emulsion ◽

Aids Patients

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Towards malaria microscopy at the point-of-contact: an assessment of the diagnostic performance of the Newton Nm1 microscope in Uganda

Parasitology ◽

10.1017/s0031182014000833 ◽

2014 ◽

Vol 141 (14) ◽

pp. 1819-1825 ◽

Cited By ~ 10

Author(s):

J. RUSSELL STOTHARD ◽

BETTY NABATTE ◽

JOSE C. SOUSA-FIGUEIREDO ◽

NARCIS B. KABATEREINE

Keyword(s):

Confidence Interval ◽

Positive Predictive Value ◽

Predictive Value ◽

Blood Cells ◽

Diagnostic Performance ◽

White Blood Cells ◽

Sub Saharan Africa ◽

Resource Poor ◽

Sub Saharan ◽

Malaria Microscopy

SUMMARYMalaria microscopy in sub-Saharan Africa is often restricted by access to light microscopes. To address this gap, a novel portable inverted monocular microscope, the Newton Nm1, was designed and is now commercially available. Its diagnostic performance was assessed in a blinded-slide trial at ×1000 (oil) of Giemsa-stained thick blood films against a conventional microscope as undertaken by four Ugandan Ministry of Health technicians. With the Newton Nm1, diagnostic performance was: sensitivity 93·5% (95% confidence interval (CI) 78·6–99·2%), specificity 100·0% (95% CI 82·4–100·0%), positive predictive value 100·0% (95% CI 88·1–100·0%) and negative predictive value 90·5% (95% CI 69·6–98·8%). Discordance was due to a systematic error underestimating parasitaemia by ~45%; when counting Plasmodium parasites against 200 white blood cells, blood films with low parasitaemia (i.e. <100 μL−1 of blood) could be overlooked and misclassified. By contrast, specificity was excellent with no false positives encountered. Whilst proven useful, especially in resource-poor environments, it is still unclear how we can ensure the uptake of the Newton Nm1 within sub-Saharan Africa.

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High burden of cryptococcal antigenemia and meningitis among patients presenting at an emergency department in Maputo, Mozambique

PLoS ONE ◽

10.1371/journal.pone.0250195 ◽

2021 ◽

Vol 16 (4) ◽

pp. e0250195

Author(s):

Robert Deiss ◽

Carolina V. Loreti ◽

Ana G. Gutierrez ◽

Eudoxia Filipe ◽

Milton Tatia ◽

...

Keyword(s):

Emergency Department ◽

Cryptococcal Meningitis ◽

Screening Program ◽

Point Of Care ◽

Rapid Assessment ◽

Vital Signs ◽

Cd4 Count ◽

Sub Saharan Africa ◽

Induction Treatment ◽

Cryptococcal Antigen

Background Cryptococcal meningitis is a leading cause of HIV-related mortality in sub-Saharan Africa, however, screening for cryptococcal antigenemia has not been universally implemented. As a result, data concerning cryptococcal meningitis and antigenemia are sparse, and in Mozambique, the prevalence of both are unknown. Methods We performed a retrospective analysis of routinely collected data from a point-of-care cryptococcal antigen screening program at a public hospital in Maputo, Mozambique. HIV-positive patients admitted to the emergency department underwent CD4 count testing; those with pre-defined abnormal vital signs or CD4 count ≤ 200 cells/μL received cryptococcal antigen testing and lumbar punctures if indicated. Patients with CM were admitted to the hospital and treated with liposomal amphotericin B and flucytosine; their 12-week outcomes were ascertained through review of medical records or telephone contact by program staff made in the routine course of service delivery. Results Among 1,795 patients screened for cryptococcal antigenemia between March 2018—March 2019, 134 (7.5%) were positive. Of patients with cryptococcal antigenemia, 96 (71.6%) were diagnosed with CM, representing 5.4% of all screened patients. Treatment outcomes were available for 87 CM patients: 24 patients (27.6%) died during induction treatment and 63 (72.4%) survived until discharge; of these, 38 (60.3%) remained in care, 9 (14.3%) died, and 16 (25.3%) were lost-to follow-up at 12 weeks. Conclusions We found a high prevalence of cryptococcal antigenemia and meningitis among patients screened at an emergency department in Maputo, Mozambique. High mortality during and after induction therapy demonstrate missed opportunities for earlier detection of cryptococcal antigenemia, even as point-of-care screening and rapid assessment in an emergency room offer potential to improve outcomes.

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