A cost-effectiveness analysis of the use of oral ibrexafungerp versus fluconazole for acute vulvovaginal candidiasis in the UK NHS primary care service.

BACKGROUND: Vulvovaginal Candidiasis (VVC) is a fungal infection causing inflammation of the vagina and/or the vulva. Symptoms include itching, irritation, and discharge. VVC presents commonly across primary care and, despite its mild symptoms, carries psychological burden and has a significant impact on women's quality of life. UK guidelines support treatment via oral or topical azole antifungal agents. Recent evidence attests to the superiority of novel non-azole antifungals. Thus, rigorous financial assessment of both antifungals is necessary for optimal VVC treatment allocation in UK primary care. AIM: To evaluate the cost-effectiveness of ibrexafungerp against the gold standard fluconazole as first-line treatment of VVC within the NHS. METHOD: A systematic review on the efficacy of ibrexafungerp and fluconazole in acute VVC was conducted. Cost-effectiveness analysis was initiated using health outcome data from the DOVE trial, a Phase 2 RCT. Costs in pound sterling were ascertained in monetary units, and effectiveness determined as reduced need for follow-up medication. RESULTS: An incremental cost-effectiveness ratio of £2185.74 was determined. This suggests oral ibrexafungerp being largely more costly yet slightly more effective than fluconazole, and thus has unfavourable net benefit. Two sensitivity analyses were conducted considering follow-up medication combination and market price, which provided confidence in the calculated cost-effectiveness ratio. CONCLUSION: This analysis highlights fluconazole's cost-effectiveness in current UK guidelines and favourability.

Comparison of the safety and cost-effectiveness of nebulized liposomal amphotericin B and amphotericin B deoxycholate for antifungal prophylaxis after lung transplantation.

INTRODUCTION: Fungal infection after lung transplantation can lead to poor clinical outcome, for which lung transplant recipients require prophylaxis. One of the antifungal agents used after lung transplantation is nebulized amphotericin B (AMB). Nebulized AMB causes adverse events such as dyspnea and airway irritation, and long-term use leads to high economic costs. So far, prophylactic regimens employing AMB deoxycholate (AMB-d) and liposomal AMB (L-AMB) have been developed. This study compared the efficacy, safety, and cost of AMB-d and L-AMB. PATIENTS AND METHODS: Patients who underwent lung transplantation at Kyoto University Hospital from January 2021 to May 2023 were included in this study. Thirty-three patients received nebulized AMB-d, whereas 29 received nebulized L-AMB. RESULTS: Both regimens maintained comparable prophylactic efficacy regarding the development of fungal infection in the AMB-d and L-AMB groups (3.0% vs. 3.4%, P = 0.877). Patients treated with nebulized L-AMB experienced fewer respiratory-related adverse reactions than those treated with nebulized AMB-d (6.9% vs. 30.3%, P < 0.05), leading to a longer treatment duration with L-AMB than with AMB-d. Additionally, the daily cost of administering L-AMB was lower than that of administering AMB-d (3609 Japanese yen vs. 1792.3 Japanese yen, P < 0.05). DISCUSSION: These results suggest that nebulized L-AMB is safer and more cost-effective than nebulized AMB-d, with comparable efficacy.

Ampliação de uso da anfotericina B lipossomal para pessoas diagnosticadas com mucormicose rino-órbitocerebral / Expanded use of liposomal amphotericin B for people diagnosed with rhino-orbitocerebral mucormycosis

INTRODUÇÃO: A mucormicose é uma infecção fúngica que, em geral, causa doença grave em indivíduos imunossuprimidos, especialmente aqueles com significativas desordens metabólicas tal como o diabete descontrolado. Sua incidência tem sido crescente pelo aumento da população suscetível, tal como diabéticos, portadores de neoplasias submetidos a quimioterapia, transplantados de medula óssea e de órgãos sólidos e terapia com corticosteróides. Nos dois últimos anos, a mucormicose teve marcada relação com a Covid-19, em vista do grande número de diabéticos que desenvolveram a forma grave da infecção pelo SARS-Cov-2 e necessitaram de uso de corticoterapia para melhor manejo clínico. Assim, durante a pandemia da Covid-19, observou-se elevação da incidência da mucormicose. Apresenta elevada mortalidade, que varia entre 40% e 80% a depender do local de comprometimento e das condições clínicas do paciente. O tratamento de escolha para a mucormicose é a anfotericina B, que pode ser usada tanto na terapia de indução como na de consolidação. Existe também a possibilidade do descalonamento na fase de consolição para posaconazol ou isavuconazol. As recomendações internacionais trazem o uso das formulações lipídicas como fármacos de primeira linha, especialmente a anfotericina B lipossomal, pela maior evidência do uso deste antifúngico nesta fase, em especial nos pacientes com a forma rino-óbrito-cerebral, pelo seu efeito em sistema nervoso central. TECNOLOGIA: Anfotericina B lipossomal. PERGUNTA: O uso da anfotericina B lipossomal é eficaz, seguro e custo-efetivo em pacientes diagnosticadas com mucormicose rino-órbito-cerebral, quando comparado à anfotericina B complexo lipídico ou à anfotericina B convencional? EVIDÊNCIAS CLÍNICAS: Foi realizada uma busca nas plataformas de busca Medline (PUBMED), EMBASE e Cochrane Library, não sendo identificadas revisões sistemáticas (RS), ensaios clínicos randomizados (ECR) ou estudos observacionais que comparassem tratamentos. Desta forma, optou-se por realizar uma RS de relatos de casos e relatos de série de casos. A partir da busca das evidências disponíveis na literatura, 106 estudos foram selecionados, sendo 92 relatos de caso e 14 séries de casos. Do total de estudos incluídos foram considerados para extração de dados um total de 165 casos. O resultado da avaliação da qualidade metodológica dos estudos incluídos mostrou que todos preencheram mais de 80% dos critérios considerados necessários para a apresentação adequada dos desenhos de estudo e para 100% foi aplicada "yes" para as questões consideradas essenciais para a inclusão na revisão. Com relação aos estudos de relatos de caso e relato de séries de casos, a confiança na evidência analisada foi classificada como o ponto mais baixo de evidência, de acordo com a ferramenta Grading of Recommendations Assessment, Development and Evaluation (GRADE). Foi considerado como desfecho primário desejável o sucesso terapêutico do tratamento da mucormicose, utilizando-se monoterapia com anfotericina B lipossomal (intervenção) ou anfotericina B complexo lipídico ou anfotericina B desoxicolato (comparadores). Pacientes tratados com anfotericina B lipossomal tiveram maior taxa de sucesso terapêutico comparados àqueles tratados com anfotericina B desoxicolato (51,3% vs 31,5%; p=0,01). Como os grupos de pacientes que receberam cada uma dessas formulações de anfotericina B não foram homogêneos, foi realizada uma análise dos fatores associados ao sucesso terapêutico em etapas de análise uni e multivariadas. Ajustados para estas diferenças, a análise multivariada identificou que idade [OR=1,02 (1,01 - 1,04); p=0,03] e presença de lesão em órbita [OR=2,51 (1,11 - 5,66); p=0,03) foram fatores independentes para falha terapêutica, enquanto que o uso de monoterapia da anfotericina B lipossomal na terapia de indução [OR=0,42 (0,19 - 0,91); p=0,03] e realização de cirurgia para desbridamento das lesões [OR=0,18 (0,05 - 0,63); p=0,007] foram fatores independentes para se obter o sucesso terapêutico. AVALIAÇÃO ECONÔMICA: Considerou-se a perspectiva do Sistema Único de Saúde (SUS) e um horizonte temporal de um ano. Portanto, não se aplicou taxa de desconto. Como comparador da anfotericina B lipossomal, utilizou-se a anfotericina B complexo lipídico, fármaco já distribuído pelo Ministério da Saúde a pacientes com mucormicose. O desfecho considerado também foi o sucesso terapêutico do tratamento da mucormicose. O tratamento com monoterapia de anfotericina B lipossomal na dose de 5 mg/kg/dia mostrou um custo incremental de R$ 228.923,40 (70.604,29 - 450.744,22), enquanto que na dose de 10 mg/kg/dia o valor foi de R$ 453.794,48 (138.797,81 - 902.013,30). A razão de custo-efetividade incremental foi de R$ 1.156.178,78/sucesso terapêutico (401.160,74 - 2.177.508,31) para tratamento na dose de 5 mg/kg/dia e de R$ 2.291.891,31/sucesso terapêutico (788.623,92 - 4.357.552,17) para a dose de 10 mg/kg/dia. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: Estimou-se um impacto orçamentário incremental de R$ 11.446.170,00 para o cenário da dose de 5 mg/kg/dia e de R$ 22.689.724,00 para o cenário da dose de 10 mg/kg/dia para o ano de 2022. O impacto incremental acumulado dos próximos cinco anos seria de R$ 71.195.174,40 para o cenário da dose de 5 mg/kg/dia e de R$ 141.130.093,28 para o cenário da dose de 10 mg/kg/dia. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: No horizonte considerado, não foram detectadas tecnologias para compor o esquema terapêutico da mucormicose rino-órbito-cerebral. RECOMENDAÇÕES INTERNACIONAIS: Não foram encontradas recomendações de outras agências internacionais de ATS sobre o uso da anfotericina B lipossomal para tratamento da mucormicose rino-órbito-cerebral. CONSIDERAÇÕES FINAIS: As recomendações internacionais baseiam-se em série de casos e algumas revisões sistemáticas de série de casos para considerar a anfotericina B lipossomal como droga de primeira linha de tratamento. As evidências presentes apontam este medicamento como primeira linha no tratamento da forma rino-órbito-cerebral da mucormicose, especialmente em pacientes com comprometimento do sistema nervoso central, condição prevalente nesta forma clínica, devido a sua difusão em tecido nervoso e pela possibilidade de uso de doses elevadas para se alcançar penetração tecidual adequada. Atualmente, o programa de micoses sistêmicas do Ministério da Saúde oferece a anfotericina B complexo lipídico, outra formulação da anfotericina B, cuja evidência para tratamento desta forma clínica é muito escassa. Os resultados da revisão sistemática de casos e série de casos realizada, comparando a anfotericina B lipossomal com a anfotericina B desoxicolato, apontaram a superioridade de eficácia da lipossomal sobre a desoxicolato (51,3 vs 31,5%; p=0,01) e corroborados na análise multivariada que identificou o uso da lipossomal como preditor independente de melhor prognóstico [OR=0,42 (0,19 - 0,91); p=0,03]. Estes dados fortalecem sobremaneira as recomendações que já têm sido preconizadas por guidelines internacionais e endossadas pelo Ministério da Saúde. PERSPECTIVA DO PACIENTE: A chamada pública de número 59/202 para participar da Perspectiva do Paciente sobre o tema da anfotericina B lipossomal para tratamento de pessoas com diagnóstico de mucormicose na sua forma rino-órbitocerebral foi aberta de 10/11/2021 a 17/11/2022 e não houve inscritos. RECOMENDAÇÃO PRELIMINAR DA CONITEC: O Plenário da Conitec, em sua 107ª Reunião Ordinária, no dia 06 de abril de 2022, deliberou que a matéria fosse disponibilizada em Consulta Pública com recomendação preliminar favorável à ampliação de uso da anfotericina B lipossomal para pessoas diagnosticadas com mucormicose na forma rino-órbito-cerebral, no âmbito do Sistema Único de Saúde (SUS). Os membros da Conitec consideraram que o uso da anfotericina B lipossomal apresentou efetividade e segurança superiores ao comparador, potencialmente diminuindo o risco de mortalidade dos pacientes. CONSULTA PÚBLICA: Foram recebidas 12 contribuições, sendo oito técnico-científicas e quatro sobre experiência ou opinião. Todas as contribuições recebidas foram favoráveis à recomendação inicial da Conitec. Incluindo a Sociedade Brasileira de Infectologia, as pessoas reforçaram a utilização da anfotericina B lipossomal para o tratamento da mucormicose. Assim, os membros do Plenário concordaram em manter a recomendação deliberada na apreciação preliminar do tema. RECOMENDAÇÃO FINAL DA CONITEC: O Plenário da Conitec, em sua 109ª Reunião Ordinária, no dia 09 de junho de 2022, deliberou por unanimidade recomendar a ampliação de uso da anfotericina B lipossomal para pessoas diagnosticadas com mucormicose na forma rino-órbito-cerebral, no âmbito do Sistema Único de Saúde (SUS). Por fim, foi assinado o Registro de Deliberação nº 743/2022. DECISÃO: Ampliar o uso da anfotericina B lipossomal para pessoas diagnosticadas com mucormicose na forma rino-órbitocerebral, no âmbito do Sistema Único de Saúde - SUS conforme a Portaria nº 67, publicada no Diário Oficial da União nº 132, seção 1, página 135, em 14 de julho de 2022.

Cost-Benefit and Cost-Utility Analysis of Amphotericin B Supplementation of Corneal Storage Media With Endothelial Keratoplasty-Prepared Tissue.

PURPOSE: To determine the cost-effectiveness of amphotericin B supplementation, we analyzed both current costs to treat postendothelial keratoplasty (EK) fungal infections and potential costs associated with amphotericin B supplementation. METHODS: We collected 19 US cases of post-EK fungal eye infections from the published literature and assessed the associated costs from the literature. A survey of surgeons was also conducted with questions regarding their experiences in managing these infections. RESULTS: We estimated that the costs to diagnose, manage, and treat post-EK fungal keratitis and post-EK fungal endophthalmitis are USD $21,113 and $34,850, respectively. The largest portion of the costs can be attributed to the need for additional surgical management, which is required in 79% of the cases. We estimated the total cost of amphotericin B supplementation to be $44.39 per graft with use of conventional amphotericin B and conservative assumptions regarding supplementation processes. Cost-effectiveness analysis demonstrated that amphotericin B supplementation is cost-effective at $100,000 per quality-adjusted life-year level only if amphotericin B supplementation can prevent more than 69.62% of post-EK fungal infections, assuming the incidence of post-EK fungal infection remains at the level it was between 2012 and 2017. CONCLUSIONS: We found that amphotericin B supplementation can be cost-effective under conservative assumptions if it is moderately effective in preventing post-EK fungal infections.

Amphotericin B Loaded Nanostructured Lipid Carriers for Parenteral Delivery: Characterization, Antifungal and In vitro Toxicity Assessment.

BACKGROUND: Amphotericin B (AmB) is important for the treatment of systemic fungal infections. Nowadays, only intravenous administration (IV) of AmB has been available due to its low aqueous solubility. Two forms of AmB are available. The first is Fungizone®, a mixture of AmB and sodium deoxcycholate that produces severe nephrotoxicity. The second are lipid-based formulations that reduce nephrotoxicity, but they are costly and require higher dose than Fungizone®. Thus, a cheaper delivery system with reduced AmB toxicity is required. OBJECTIVE: To develop and characterize AmB loaded-nanostructured lipid carriers (AmB-loaded NLCs) for IV administration to reduce AmB toxicity. METHODS: AmB-loaded NLCs with different solid lipids were prepared by the high-pressure homogenization technique. Their physicochemical properties and the drug release profile were examined. The molecular structure of AmB, antifungal and hemolysis activities of developed AmB-loaded NLCs were also evaluated. RESULTS: AmB-loaded NLCs ~110 to ~140 nm in diameter were successfully produced with a zeta potential of ~-19 mV and entrapment efficiency of ~75%. In vitro release showed fast release characteristics. AmB-loaded NLCs could reduce the AmB molecular aggregation as evident from the absorbance ratio of the first to the fourth peak showing a partial aggregation of AmB. This result suggested that AmB-loaded NLCs could offer less nephrotoxicity compared to Fungizone®. In vitro antifungal activity of AmB-loaded NLCs showed a minimum inhibitory concentration of 0.25 µgmL-1. CONCLUSION: AmB-loaded NLCs present high potential carriers for effective IV treatment with prolonged circulation time and reduced toxicity.

Treatment for human visceral leishmaniasis: a cost-effectiveness analysis for Brazil.

OBJECTIVE: To estimate the cost-effectiveness of strategies for the treatment of VL in Brazil. METHODS: Cost-effectiveness study comparing three therapeutic options: meglumine antimoniate (MA), liposomal amphotericin B (LAMB) and a combination of LAMB plus MA (LAMB plus MA), from public health system and societal perspectives. An analytical decision-making model was used to compare strategies for the following outcomes: early therapeutic failure avoided at 30 days, days of hospitalisation avoided and VL cure at 180 days. The efficacy and safety parameters of the drugs came from a randomised, open-label trial and the cost data came from a cost-of-illness study, both carried out in Brazil. RESULTS: For all outcomes analysed, the LAMB strategy was more effective. The MA strategy was inferior to the LAMB plus MA strategy for the outcomes early therapeutic failure avoided and cure. When only LAMB and MA were compared from a societal perspective, a cost of US$ 278.56 was estimated for each additional early therapeutic failure avoided, a cost of US$ 26.88 for each additional day of hospitalisation avoided and a cost of US$ 89.88 for each additional case of cured VL, for the LAMB strategy vs. MA. CONCLUSION: In Brazil, the LAMB strategy proved to be cost-effective for treating VL, considering a GDP per capita as the willingness-to-pay threshold, for all of the outcomes analysed in comparison to MA.

OBJECTIF: Estimer la rentabilité des stratégies de traitement de la leishmaniose viscérale (LV) au Brésil. MÉTHODES: Etude coût-efficacité comparant trois options thérapeutiques: l'antimoniate de méglumine (AM), amphotéricine B liposomale (LAMB) et une combinaison de LAMB et MA (LAMB plus AM), du point de vue du système de santé publique et sociétal. Un modèle décisionnel analytique a été utilisé pour comparer les stratégies pour les résultats suivants: échec thérapeutique précoce évité à 30 jours, jours d'hospitalisation évités et guérison de la LV à 180 jours. Les paramètres d'efficacité et de sécurité des médicaments provenaient d'un essai randomisé ouvert et les données relatives aux coûts, d'une étude sur le coût de la maladie, toutes deux menées au Brésil. RÉSULTATS: Pour tous les résultats analysés, la stratégie LAMB était plus efficace. La stratégie AM était inférieure à la stratégie LAMB plus AM pour les résultats: échec thérapeutique précoce évité et guérison. Lorsque seules les stratégies LAMB et AM ont été comparées d'un point de vue sociétal, un coût de 278,56 USD a été estimé pour chaque échec thérapeutique précoce additionnel évité, un coût de 26,88 USD pour chaque jour d'hospitalisation additionnel évité et un coût de 89,88 USD pour chaque cas additionnel de LV guéri, pour la stratégie LAMB par rapport à AM. CONCLUSION: Au Brésil, la stratégie LAMB s'est avérée rentable pour traiter la LV, considérant un PIB par habitant comme seuil de volonté de payer, pour tous les résultats analysés par rapport à l'AM.

Management of amphotericin-induced phlebitis among HIV patients with cryptococcal meningitis in a resource-limited setting: a prospective cohort study.

BACKGROUND: Amphotericin-induced phlebitis is a common infusion-related reaction in patients managed for cryptococcal meningitis. High-quality nursing care is critical component to successful cryptococcosis treatment. We highlight the magnitude and main approaches in the management of amphotericin-induced phlebitis and the challenges faced in resource-limited settings. METHODS: We prospectively determined the incidence of amphotericin-induced phlebitis during clinical trials in Kampala, Uganda from 2013 to 2018. We relate practical strategies and challenges faced in clinical management of phlebitis. RESULTS: Overall, 696 participants were diagnosed with HIV-related cryptococcal meningitis. Participants received 7-14 doses of intravenous (IV) amphotericin B deoxycholate 0.7-1.0 mg/kg/day for induction therapy through peripheral IV lines at a concentration of 0.1 mg/mL in 5% dextrose. Overall, 18% (125/696) developed amphotericin-induced phlebitis. We used four strategies to minimize/prevent the occurrence of phlebitis. First, after every dose of amphotericin, we gave one liter of intravenous normal saline. Second, we rotated IV catheters every three days. Third, we infused IV amphotericin over 4 h. Finally, early ambulation was encouraged to minimize phlebitis. To alleviate phlebitis symptoms, warm compresses were used. In severe cases, treatment included topical diclofenac gel and oral anti-inflammatory medicines. Antibiotics were used only when definite signs of infection developed. Patient/caregivers' education was vital in implementing these management strategies. Major challenges included implementing these interventions in participants with altered mental status and limited access to topical and oral anti-inflammatory medicines in resource-limited settings. CONCLUSIONS: Amphotericin-induced phlebitis is common with amphotericin, yet phlebitis is a preventable complication even in resource-limited settings. TRIAL REGISTRATION: The ASTRO-CM trial was registered prospectively. ClincalTrials.gov : NCT01802385 ; Registration date: March 1, 2013; Last verified: February 14, 2018.

AMBIsome Therapy Induction OptimisatioN (AMBITION): High dose AmBisome for cryptococcal meningitis induction therapy in sub-Saharan Africa: economic evaluation protocol for a randomised controlled trial-based equivalence study.

INTRODUCTION: Cryptococcal meningitis is responsible for around 15% of all HIV-related deaths globally. Conventional treatment courses with amphotericin B require prolonged hospitalisation and are associated with multiple toxicities and poor outcomes. A phase II study has shown that a single high dose of liposomal amphotericin may be comparable to standard treatment. We propose a phase III clinical endpoint trial comparing single, high-dose liposomal amphotericin with the WHO recommended first-line treatment at six sites across five counties. An economic analysis is essential to support wide-scale implementation. METHODS AND ANALYSIS: Country-specific economic evaluation tools will be developed across the five country settings. Details of patient and household out-of-pocket expenses and any catastrophic healthcare expenditure incurred will be collected via interviews from trial patients. Health service patient costs and related household expenditure in both arms will be compared over the trial period in a probabilistic approach, using Monte Carlo bootstrapping methods. Costing information and number of life-years survived will be used as the input to a decision-analytic model to assess the cost-effectiveness of a single, high-dose liposomal amphotericin to the standard treatment. In addition, these results will be compared with a historical cohort from another clinical trial. ETHICS AND DISSEMINATION: The AMBIsome Therapy Induction OptimisatioN (AMBITION) trial has been evaluated and approved by the London School of Hygiene and Tropical Medicine, University of Botswana, Malawi National Health Sciences, University of Cape Town, Mulago Hospital and Zimbabwe Medical Research Council research ethics committees. All participants will provide written informed consent or if lacking capacity will have consent provided by a proxy. The findings of this economic analysis, part of the AMBITION trial, will be disseminated through peer-reviewed publications and at international and country-level policy meetings. TRIAL REGISTRATION: ISRCTN 7250 9687; Pre-results.

Cost-effectiveness analysis of diagnostic-therapeutic strategies for visceral leishmaniasis in Brazil.

INTRODUCTION: Visceral leishmaniasis (VL) is fatal if not diagnosed and treated. This study aimed to estimate the cost-effectiveness of diagnostic-therapeutic alternatives for VL in Brazil. METHODS: A decision model estimated the life expectancy and costs of six diagnostic-therapeutic strategies. RESULTS: IT LEISH + liposomal amphotericin B emerged the best option, presenting lower costs and higher effectiveness. DAT-LPC + liposomal amphotericin B showed an incremental cost-effectiveness ratio of US$ 326.31 per life year. CONCLUSIONS: These findings indicate the feasibility of incorporating DAT and designating liposomal amphotericin B as the first-line drug for VL in Brazil.

Cost-effectiveness analysis of diagnostic-therapeutic strategies for visceral leishmaniasis in Brazil

Abstract INTRODUCTION: Visceral leishmaniasis (VL) is fatal if not diagnosed and treated. This study aimed to estimate the cost-effectiveness of diagnostic-therapeutic alternatives for VL in Brazil. METHODS: A decision model estimated the life expectancy and costs of six diagnostic-therapeutic strategies. RESULTS: IT LEISH + liposomal amphotericin B emerged the best option, presenting lower costs and higher effectiveness. DAT-LPC + liposomal amphotericin B showed an incremental cost-effectiveness ratio of US$ 326.31 per life year. CONCLUSIONS: These findings indicate the feasibility of incorporating DAT and designating liposomal amphotericin B as the first-line drug for VL in Brazil.

AMBIsome Therapy Induction OptimisatioN (AMBITION): High Dose AmBisome for Cryptococcal Meningitis Induction Therapy in sub-Saharan Africa: Study Protocol for a Phase 3 Randomised Controlled Non-Inferiority Trial.

BACKGROUND: Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen). METHODS: An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10% and 90% power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance. DISCUSSION: A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment. TRIAL REGISTRATION: ISRCTN, ISRCTN72509687 . Registered on 13 July 2017.

Assessment of effectiveness and safety of repeat administration of proinflammatory primed allogeneic mesenchymal stem cells in an equine model of chemically induced osteoarthritis.

BACKGROUND: This study aimed at assessing the effectiveness and safety of repeated administrations of allogeneic bone marrow-derived mesenchymal stem cells (BM-MSCs) primed with tumor necrosis factor (TNF)-α and interferon-γ in an equine model of chemically-induced osteoarthritis. Arthritis was induced in both radio-carpal (RC)-joints by amphotericin-B in 18 ponies, divided into three groups depending on the treatment injected: MSC-naïve (n = 7), MSC-primed (n = 7) and control (n = 4). The study consisted of two phases and used one RC-joint of each animal in each phase, with four months time-lapse, in order to assess two end-points. Clinical, synovial, radiological and ultrasonographic follow-up was performed. At six months, animals were euthanized and both carpi were assessed by magnetic resonance imaging (MRI), gross anatomy, histopathology, histochemistry and gene expression. RESULTS: Clinical and synovial inflammatory signs were quicker reduced in MSC-treated groups and repeated allogeneic administration did not produce adverse reactions, but MSC-primed group showed slight and transient local inflammation after second injection. Radiology and MRI did not show significant differences between treated and control groups, whereas ultrasonography suggested reduced synovial effusion in MSC-treated groups. Both MSC-treated groups showed enhanced cartilage gross appearance at two compared to six months (MSC-naïve, p < 0.05). Cartilage histopathology did not reveal differences but histochemistry suggested delayed progression of proteoglycan loss in MSC-treated groups. Synovium histopathology indicated decreased inflammation (p < 0.01) in MSC-primed and MSC-naïve at two and six months, respectively. At two months, cartilage from MSC-primed group significantly (p < 0.05) upregulated collagen type II (COL2A1) and transforming growth factor (TGF)-ß1 and downregulated cyclooxygenase-2 and interleukin (IL)-1ß. At six months, MSC-treatments significantly downregulated TNFα (p < 0.05), plus MSC-primed upregulated (p < 0.05) COL2A1, aggrecan, cartilage oligomeric protein, tissue inhibitor of metalloproteinases-2 and TGF-ß1. In synovium, both MSC-treatments decreased (p < 0.01) matrix metalloproteinase-13 expression at two months and MSC-primed also downregulated TNFα (p < 0.05) and IL-1ß (p < 0.01). CONCLUSIONS: Both MSC-treatments provided beneficial effects, mostly observed at short-term. Despite no huge differences between MSC-treatments, the findings suggested enhanced anti-inflammatory and regulatory potential of MSC-primed. While further research is needed to better understand these effects and clarify immunogenicity implications, these findings contribute to enlarge the knowledge about MSC therapeutics and how they could be influenced.

Economic evaluation of micafungin versus liposomal amphotericin B (LAmB) for treating patients with candidaemia and invasive candidiasis (IC) in Turkey.

Micafungin was reported to be non-inferior to liposomal amphotericin B (LAmB) in treating patients with candidaemia and invasive candidiasis (IC). The current study aimed to evaluate the economic impact of using micafungin versus LAmB for treatment of candidaemia and IC in Turkey. A decision analytic model, which depicted economic consequences upon administration of micafungin or LAmB for treating patients with candidaemia and IC in the Turkish hospitals, was constructed. Patients were switched to an alternative antifungal agent if initial treatment failed due to mycological persistence. All patients were followed up until treatment success or death. Outcome probabilities were obtained from published literature and cost inputs were derived from the latest Turkish resources. Expert panels were used to estimate data that were not available in the literature. Cost per patient treated for each intervention was then calculated. Sensitivity analyses including Monte Carlo simulation were performed. For treatment of candidaemia and IC, micafungin (€4809) was associated with higher total cost than LAmB (€4467), with an additional cost of €341 per treated patient. Cost of initial antifungal treatment was the major cost driver for both comparators. The model outcome was robust over a wide variation in input variables except for drug acquisition cost and duration of initial antifungal treatment with micafungin or LAmB. LAmB is cost-saving relative to micafungin for the treatment of candidaemia and IC from the Turkish hospital perspective, with variation in drug acquisition cost of the critical factor affecting the model outcome.

Efficacy and safety of amphotericin B formulations: a network meta-analysis and a multicriteria decision analysis.

OBJECTIVES: Despite its broad spectrum, conventional amphotericin B (AB) is associated with serious adverse events. Lipid-based formulations may offer safer options. We aimed to synthesize the evidence of efficacy and safety of AB formulations. METHODS: We performed a systematic review and network meta-analysis (NMA) to compare all available formulations: conventional AB; lipid complex or ABLC; colloidal dispersion or ABCD; liposomal or LAB; AB in Intralipid. Randomized controlled trials were searched in four databases. Cure, fever, chills, nephrotoxicity, death and drug discontinuation were assessed. NMA was based on Bayesian methods accounting for direct and indirect comparisons. Probability ranks estimating the best formulation were built for each outcome. The relative benefit-risk of formulations was assessed with stochastic multicriteria acceptability analyses (SMAA). KEY FINDINGS: We identified 25 trials (n = 2996). No significant differences among drugs were observed for cure or death. All lipid-based formulations were safer than conventional AB for nephrotoxicity. AB-Intralipid was more tolerable than conventional AB and caused less chills than ABCD. AB-Intralipid was the best therapy (>60%) regarding nephrotoxicity, fever, chills and discontinuation. The scenario from SMAA favoured AB-Intralipid (81% acceptability). Conventional AB was secondary to all lipid-based formulations. CONCLUSIONS: Amphotericin B-Intralipid was identified as safer, cost-saving treatment in comparison with other formulations.

Assessment of high-priced systemic antifungal prescriptions.

OBJECTIVES: To assess compliance with international guidelines for costly antifungal prescriptions and to compare these results with a first study performed in 2007. METHODS: Retrospective study including all costly antifungal prescriptions made in surgical and medical intensive care units and in a hepatobiliary, pancreatic, and digestive surgery unit. Prescriptions were assessed in terms of indication, dosage, and antifungal de-escalation. RESULTS: Seventy-four treatments were analyzed. Treatments were prescribed for prophylactic (1%), empirical (22%), pre-emptive (16%), or targeted therapy (61%). Caspofungin accounted for 68% of prescriptions, followed by voriconazole (20%) and liposomal amphotericin B (12%). Indication was appropriate in 91%, debatable in 1%, and inappropriate in 8%. Dosage was appropriate in 69%, debatable in 8%, and inappropriate in 23%. Prescriptions were inappropriate for the following reasons: lack of dosage adjustment in light of the hepatic function (10 cases), underdosage or excessive dosage by>25% of the recommended dose in seven cases. De-escalation to fluconazole was implemented in 40% of patients presenting with a fluconazole-susceptible candidiasis. CONCLUSION: The overall incidence of appropriate use was higher in 2012 compared with 2007 (62% and 37% respectively, P=0.004). Nevertheless, costly antifungal prescriptions need to be optimized in particular for empirical therapy, dosage adjustment, and potential de-escalation to fluconazole.

Biopharmaceutical Assessment and Irritation Potential of Microemulsions and Conventional Systems Containing Oil from Syagrus cearensis for Topical Delivery of Amphotericin B Using Alternative Methods.

The aim of this study was to compare the biopharmaceutical characteristics and irritation potentials of microemulsions (MEs) and conventional systems (CSs) containing oil from Syagrus cearensis for topical delivery of Amphotericin B (AmB). Pseudo-ternary phase diagrams were constructed using a water titration method to develop the MEs, and the CSs were prepared according to the classical technique of phase inversion. In the skin permeation and retention study, dermatomed pig skin without stratum corneum was used as an alternative disturbed skin model. The irritation potential was evaluated using three different methods, chorioallantoic membrane assays (HET-CAM and CAM-TBS), and bovine corneal opacity and permeability (BCOP) test. The optimized formulation (ME1) consisting of 0.1% (w/w) Amphotericin B, 9.1% (w/w) catolé oil, 81% (w/w) Smix (1:1, Tween 20 and Kolliphor EL) possessed droplet size of 31.02 ± 0.9 nm, zeta potential of -23.4 mV, and viscosity 0.63 ± 0.1 Pa.s. ME1 exhibited greater retention of AmB in to skin layers (84.79 ± 2.08 µg cm-2) than all the others formulations. In general, MEs showed higher drug release and retention than CSs and all of the formulations showed greater retentivity than permeability. Only MEs developed using Labrasol/Plurol Oleique (L/PO) as the surfactant and co-surfactant exhibited a moderate irritation potential; all other MEs and CSs were classified as non-irritants or slight irritants. The results indicate that formulations containing oil from S. cearensis are promising alternatives for the delivery of AmB targeting the treatment of cutaneous leishmaniasis.

Eficacia y seguridad de posaconazol en pacientes pediátricos con mucormicosis y tratamiento previo con amfotericina B / Efficacy and safety of posaconazole in pediatric patients with mucormycosis and previous treatment with amphotericin B

INTRODUCCIÓN: Antecedentes: Se evaluó la eficacia y seguridad del uso de posaconazol en pacientes adultos con mucormicosis y respuesta inadecuada o eventos adversos al uso de amfotericina B. En el referido Dictamen, se apueba el uso de posaconazol en base a la opinión de expertos en consenso documentada en alguunas de práctica clínica y series de casos, así como base en base a la experiencia clínica observada por los especialistas de EsSalud. Aspectos Generales: La mucormicosis (también conocida como zygomicosis) es una infección oportunista poco frecuente, potencialmente mortal causada por hongos del orden Morales. Aunque es una infección por hongos relativamente poco común en la población general, en comparación con la candidiasis y aspergilosis; los casos de mucormicosis han sido en aumento durante la última década. El aumento global, puede deberse al aumento del uso de la quimioterapia y los esteroides, asociado a un estado inmunocomprometido prolongado. Tecnología Sanitaria de Interés: El posaconazol pertenece a la familia de los antifúngicos azoles, e inhibe la producción de ergosterol en el hongo mediante la unión y la inhibición de la lanosterol-14alpha-desmetilasa, que se encuentra presente en casi todos los hongos, excepto Pneumocystis y Pythium. Tiene una estructura química diferente de fluconazol y voriconazol, que le permite interactuar con un dominio adicional de la diana, de modo que puede inhibir incluso cepas mutadas resistentes a fluconazol y voriconazol. Además puede permanecer activo cuando otros azoles ya están inactivos. METODOLOGÍA: Estrategia de Búsqueda: Se utilizó el motor de búsqueda empleando el algoritmo mostrado en la sub-sección B y los filtros correspondientes a meta-análisis, revisiones sistemáticas y ensayos clínicos, en línea con los criterios de elegibilidad. Se llevó a cabo una búsqueda sistemática de la literatura con respecto a la eficcia y seguridad de posaconazol en pacientes pediáricos con mucormicosis que hayan recibido previamente tratamiento con Amfotericina B. La búsqueda se inicio revisando la información sobre el uso del medicamento de acuerdo con entidades reguladoras como la Food and Druga Administration de los Estados Unidos (FDA), la European Medicines Agency (EMA) y la Dirección General de Medicamentos y Drogas (DIGEMID). RESULTADOS: Sinopsis de la Evidencias: A la fecha aún no existe una indicación de etiqueta para el uso de posaconazol en niños con mucormicosis, por lo que su aplicación en casos pediátricos se basa únicamente en decisión y criterio clínico del caso. Debido a esto, la literatura científica disponible se refiere a la eficacia y seguridad de posaconazol en adultos con mucormicosis. En la presente sinopsis se describe toda la evidencia considerada para el presente dictamen (tanto la evidencia nueva encontrada como la evidencia utilizada en el Dictamen previo). y se explica cómo esta evidencia falla en responder de manera precisa la pregunta PICO de interés. CONCLUSIONES: El presente dictamen expone la evaluación de tecnologia sanitaria de la eficacia y seguridad de posaconazol en pacientes pediátricos con mucormicosis que hayan recibido Amfotericina B. Posaconazol ha sido propuesto como un medicamento de segunda línea de tratamiento en pacientes pediátricos con mucormicosis que presentan falla al tratamiento, son intolerantes por eventos adversos, o vienen recibiendo tratamiento por largos periodos de tiempo, dado que al momento no existe una segunda línea de tratamiento definida para este tipo de pacientes. El Instituto de Evaluación de Tecnologías en Salud e Investigación_IETSI aprueba el uso de posaconazol en pacientes pediátricos con mucormicosis que hayan recibido Amfotericina B. La vigencia del presente Dictamen Premilimiar es de un año. Asimismo, se establece que el efecto de posaconazol se evaluará con datos de los pacientes que usen medicamento para determinar su impacto en desenlaces clínicos. Esta información servirá para una re-evaluación del medicamento al terminar la vigencia del presente dictamen preliminar.

Fungal diseases: could nanostructured drug delivery systems be a novel paradigm for therapy?

Invasive mycoses are a major problem for immunocompromised individuals and patients in intensive care units. Morbidity and mortality rates of these infections are high because of late diagnosis and delayed treatment. Moreover, the number of available antifungal agents is low, and there are problems with toxicity and resistance. Alternatives for treating invasive fungal infections are necessary. Nanostructured systems could be excellent carriers for antifungal drugs, reducing toxicity and targeting their action. The use of nanostructured systems for antifungal therapy began in the 1990s, with the appearance of lipid formulations of amphotericin B. This review encompasses different antifungal drug delivery systems, such as liposomes, carriers based on solid lipids and nanostructure lipids, polymeric nanoparticles, dendrimers, and others. All these delivery systems have advantages and disadvantages. Main advantages are the improvement in the antifungal properties, such as bioavailability, reduction in toxicity, and target tissue, which facilitates innovative therapeutic techniques. Conversely, a major disadvantage is the high cost of production. In the near future, the use of nanosystems for drug delivery strategies can be used for delivering peptides, including mucoadhesive systems for the treatment of oral and vaginal candidiasis.

Prevalence and Hospital Management of Amphotericin B Deoxycholate-Related Toxicities during Treatment of HIV-Associated Cryptococcal Meningitis in South Africa.

BACKGROUND: We aimed to establish the prevalence of amphotericin B deoxycholate (AmBd)-related toxicities among South African patients with cryptococcosis and determine adherence to international recommendations to prevent, monitor and manage AmBd-related toxicities. METHODS: Clinical data were collected from cases of laboratory-confirmed cryptococcosis at 25 hospitals, October 2012 -February 2013. Anemia was defined as hemoglobin (Hb) concentration <10 g/dl, hypokalemia as serum potassium (K) <3.4 mEq/L and nephrotoxicity as an increase in serum creatinine (Cr) to >1.1 times the upper limit of normal. To determine adherence to toxicity prevention recommendations, we documented whether baseline Hb, K and Cr tests were performed, whether pre-emptive hydration and IV potassium chloride (KCl) was administered prior to 80% and 60% of AmBd doses and whether daily oral KCl supplementation was given ≥60% of the time. To determine adherence to monitoring recommendations, we ascertained whether a daily fluid chart was completed, Hb was monitored weekly and K or Cr were monitored bi-weekly. RESULTS: Of 846 patients, clinical data were available for 76% (642/846), 82% (524/642) of whom received AmBd. Sixty-four per cent (n = 333) had documented baseline laboratory tests, 40% (n = 211) were given pre-emptive hydration and 14% (n = 72) and 19% (n = 101) received intravenous and oral KCl. While on AmBd, 88% (n = 452) had fluid monitoring; 27% (n = 142), 45% (n = 235) and 44% (n = 232) had Hb, K and Cr levels monitored. Toxicities developed frequently during treatment: anemia, 16% (86/524); hypokalemia, 43% (226/524) and nephrotoxicity, 32% (169/524). CONCLUSION: AmBd-related toxicities occurred frequently but were potentially preventable with adequate monitoring, supplemental fluid and electrolyte therapies.

Solid lipid nanoparticles of amphotericin B (AmbiOnp): in vitro and in vivo assessment towards safe and effective oral treatment module.

Amphotericin B, a gold standard broad spectrum antibiotic used in treatment of systemic fungal infections and visceral leishmaniasis, though is effective parenterally offers severe nephrotoxicity whereas the oral delivery is reported to give very meager oral bioavailability. Thus, to alleviate the toxicity and to improve oral bioavailability, an effective oral delivery approach in the form of solid lipid nanoparticles of amphotericin B (AmbiOnp) was reported earlier by our group. In this investigation, we report the predominant formation of nontoxic superaggregated form of amphotericin B, resulting from the probe sonication-assisted nanoprecipitation technique. The developed formulation was further confirmed to retain this nontoxic form and was found to be stable over the varied gastrointestinal conditions. Further, in vitro antifungal activity of AmbiOnp against Candida albicans showed minimum inhibitory concentration value of 7.812 µg/mL attributed to controlled release of drug from nanoparticulate matrix. In vivo pharmacokinetic studies revealed a relative bioavailability of AmbiOnp to be 1.05-fold with a Cmax of 1109.31 ± 104.79 ng/mL at the end of 24 h which was comparable to Cmax of 1417.49 ± 85.52 ng/mL achieved with that of marketed formulation (Fungizone®) given intravenously establishing efficacy of AmbiOnp. In vivo biodistribution studies indicated very low levels of Amphotericin B in kidneys when given as AmbiOnp as compared to that of marketed formulation proving its safety and was further corroborated by renal toxicity studies. Further, the formulations were found to be stable under refrigeration condition over a period of 3 months.