Economic and budgetary impact evaluation of isavuconazole (Cresemba®) versus voriconazole (Vfend®) for the treatment of patients with possible invasive aspergillosis from the perspective of the Brazilian supplementary health system.

OBJECTIVES: This study aims to evaluate the cost-utility and the budgetary impact of isavuconazole compared to voriconazole in patients with suspected invasive aspergillosis (IA) from the perspective of the Brazilian supplementary health system (SHS). METHODS: In this model, a decision tree was developed and included patients with possible IA. Efficacy parameters were extracted from the clinical studies. Drug acquisition, hospitalization costs and adverse events were also collected. Alternative 3- and 10-year time horizon scenarios were used. In addition, deterministic and probabilistic sensitivity analyses were simulated. A budget impact analysis of isavuconazole versus voriconazole was performed, assuming a time horizon of 5 years. In addition, sensitivity analyses were conducted to assess the robustness of the model. Results are reported in Brazilian Real (BRL), year values 2022. RESULTS: The economic analysis of the base case showed that isavuconazole is associated with a saving of 95,174.00 BRL per patient compared to voriconazole. All other simulated scenarios showed that isavuconazole is dominant versus comparators when considering a willingness to pay 40,688.00 BRL/Quality-Adjusted Life Years (QALY). The results were considered robust by the sensitivity analyses. The budget impact analysis showed that the incorporation of isavuconazole generates savings to the SHS, compared to voriconazole, of approximately 20.5 million BRL in the first year. This reaches about 54 million BRL in the fifth incorporation year, considering the market penetration of 20% in the first year, and 50% in the fifth year. CONCLUSION: Compared with voriconazole, isavuconazole is regarded as a dominant treatment strategy for patients with suspected IA and generates savings for the SHS.

The cost-utility analysis of antifungal prophylaxis for invasive fungal infections in acute myeloid leukaemia patients receiving chemotherapy: a study from a middle-income country.

BACKGROUND: Invasive fungal infections (IFIs) contribute to morbidity and mortality during acute myeloid leukaemia (AML) treatment. Without prophylaxis, IFI rate during AML treatment in Thailand is high and results in a high mortality rate and a prolonged hospital stay. AIM: To evaluate the cost-utility of antifungal therapy (AFT) prophylaxis during AML treatment. METHODS: We assessed the cost-utility of AFT available in Thailand, including posaconazole (solution), itraconazole (solution and capsule), and voriconazole. A hybrid model consisting of a decision tree and the Markov model was established. RESULTS: The costs to prevent overall IFI using any AFT were all lower than the treatment cost of a non-prophylaxis group, resulting in a saving of 808-1507 USD per patient. Prevention with voriconazole prophylaxis showed the highest quality-adjusted life years (QALYs = 3.51, incremental QALYs = 0.23), followed by posaconazole (QALYs = 3.46, incremental QALY = 0.18) and itraconazole solution (QALYs = 3.45, incremental QALYs = 0.17). Itraconazole capsule reduced QALY in the model. For invasive aspergillosis prevention, posaconazole and voriconazole both resulted in better QALYs and life year savings compared with no prophylaxis. However, posaconazole prophylaxis was the only cost-saving option (976 USD per patient). CONCLUSION: Posaconazole, itraconazole solution and voriconazole were all cost saving compared with no prophylaxis for overall IFI prophylaxis, with voriconazole being the most cost-effective option. Posaconazole and voriconazole were both cost effective for invasive aspergillosis prevention but only posaconazole was cost saving. A change in reimbursement policy for the use of AFT prophylaxis during intensive AML treatment could provide both clinical benefits to patients and substantial economic benefits to healthcare systems.

Health economic analysis of patients treated with isavuconazole in a German comprehensive cancer centre.

BACKGROUND: Invasive fungal diseases (IFD) are life-threatening and demand timely and appropriate treatment. Research showed that isavuconazole treatment positively affects clinical outcome and length of hospital stay (LOS). OBJECTIVES: The aim of this study was to assess the hospital costs of patients diagnosed with IFD and treated with isavuconazole using real-world data from a German cancer centre. PATIENTS/METHODS: Data and LOS collected from Jan-2016 to Jun-2021 at Department I of Internal Medicine, University Hospital Cologne were retrieved. Case-related resources consumed during the hospital stay across isavuconazole routes of administration (oral, parenteral, and mixed administration) were identified, quantified, valued and compared via a cost analysis that adopted the healthcare payer perspective. RESULTS: In total, 101 cases with isavuconazole treatment were identified (oral: n = 22, 21.8%; parenteral: n = 59, 58.4%; mixed: n = 20, 19.8%). Median total LOS was greater in the mixed group (46.5 days; p = .009). Median ICU LOS and ventilation duration were both longest in the parenteral-only group (16 days, p = .008; 224 h, p = .003). Invasive aspergillosis was the most frequent isavuconazole indication (n = 86, 85.2%). Average hospital costs were highest in the mixed group (€ 101,226). The median overall costs of cases treated with isavuconazole was € 52,050. CONCLUSIONS: Treating IFD is resource intensive, often requires intensive care and implies high rates of in-hospital mortality. Our study emphasises the high hospital treatment costs and thus the need for reimbursement systems to enable live-saving costly treatments.

A systematic review of epidemiology, risk factors, diagnosis, antifungal resistance, and management of invasive aspergillosis in Africa.

Invasive aspergillosis (IA) affects more than 300,000 people annually worldwide with a case fatality rate reaching 80%. However, in Africa despite the presence of risk factors for the development of IA, the burden of these fungal infections remained unknown. This systematic review aimed to update the available information on the epidemiology and the therapeutic management of IA in Africa. The published papers were systematically searched on major medical databases from September 20 to October 10, 2021. The list of references of eligible articles and the Google scholar database were also checked in order to search for possible eligible articles. Results were reported following the Preferred Reporting Items for Systematic and Meta-analyses (PRISMA) guidelines. The search yielded 1864 articles of which 29 met the inclusion criteria. This systematic review showed the existence of IA in Africa. The prevalence of IA can reach 27% with a fatality rate of more than 60%. The most common clinical form of IA found was invasive pulmonary aspergillosis. The main predisposing conditions identified were neutropenia, HIV/AIDS, renal transplant recipients, and renal failure. Aspergillus section Flavi and Nigri were the main Aspergillus species identified and Aspergillus section Fumigati was uncommon. The main management strategy for IA cases was to start antifungal therapy only after a failure of broad-spectrum antibiotic therapy. This review provided evidence of the existence of invasive aspergillosis in Africa and especially a high rate of undiagnosed invasive aspergillosis cases.

Aspergillosis in a colony of Humboldt penguins (Spheniscus humboldti) under managed care: a clinical and environmental investigation in a French zoological park.

Aspergillosis is pervasive in bird populations, especially those under human care. Its management can be critically impacted by exposure to high levels of conidia and by resistance to azole drugs. The fungal contamination in the environment of a Humboldt penguin (Spheniscus humboldti) group, housed in a French zoological park next to numerous large crop fields, was assessed through three serial sessions of surface sampling in nests, in 2018-20: all isolates were counted and characterized by sequencing. When identified as Aspergillus fumigatus, they were systematically screened for resistance mutations in the cyp51A gene and tested for minimal inhibitory concentrations (MICs) determination. At the same time, the clinical incidence of aspergillosis was evaluated in the penguin population by the means of systematic necropsy and mycological investigations. A microsatellite-based analysis tracked the circulation of A. fumigatus strains. Environmental investigations highlighted the substantial increase of the fungal load during the summer season (>12-fold vs. the other timepoints) and a large overrepresentation of species belonging to the Aspergillus section Fumigati, ranging from 22.7 to 94.6% relative prevalence. Only one cryptic species was detected (A. nishimurae), and one isolate exhibited G138S resistance mutation with elevated MICs. The overall incidence of aspergillosis was measured at ∼3.4% case-years, and mostly in juveniles. The analysis of microsatellite polymorphism revealed a high level of genetic diversity among A. fumigatus clinical isolates. In contrast, one environmental strain appeared largely overrepresented during the summer sampling session. In all, the rural location of the zoo did not influence the emergence of resistant strains.

Disease burden and demographic characteristics of mucormycosis: A nationwide population-based study in Taiwan, 2006-2017.

BACKGROUND: Epidemiological knowledge of mucormycosis obtained from national population-based databases is scarce. OBJECTIVES: This study aimed to depict the disease burden and demographics of mucormycosis in Taiwan by using the Taiwan National Health Insurance Research Database (NHIRD) and those of aspergillosis as a comparator. METHODS: Data from patients with either mucormycosis or aspergillosis from 2006 to 2017 identified with the International Classification of Diseases (ICD) codes were extracted from the NHIRD. The incidence, demographics and clinical data of both diseases were analysed. RESULTS: A total of 204 patients with mucormycosis and 2270 patients with aspergillosis who were hospitalised and treated with mould-active antifungals between 2006 and 2017 were identified. The average annual incidence of aspergillosis (0.81 cases per 100,000 population [0.81/100,000]) was 11-fold higher than that of mucormycosis (0.07/100,000). A significant increase in incidence was observed for aspergillosis (from 0.48/100,000 in 2006 to 1.19/100,000 in 2017, p < .0001) but not for mucormycosis (from 0.04/100,000 in 2006 to 0.11/100,000 in 2017, p = .07). The major underlying disease identified was diabetes mellitus (60.8%) for mucormycosis and malignant neoplasms (45.9%) for aspergillosis. The all-cause 90-day mortality rate was similar between mucormycosis and aspergillosis patients (39% vs. 37%, p = .60). For mucormycosis patients, multivariate analysis revealed that posaconazole use was associated with lower in-hospital mortality (aOR 0.38; 95% CI 0.15-0.97; p = .04). CONCLUSIONS: Mucormycosis is an uncommon fungal disease in Taiwan, occurring mostly in diabetic patients. However, the incidence might be underestimated due to limited diagnostics. Continuous surveillance might aid in delineating the evolving features of mucormycosis.

Voriconazol para tratamento de pacientes com aspergilose invasiva / Voriconazole for treatment of patients with invasive aspergillosis

CONTEXTO: A aspergilose é uma doença cujas manifestações clínicas são determinadas pela resposta imune do indivíduo, podendo apresentar-se de forma alérgica, saprofítica ou invasiva. A aspergilose invasiva é considerada uma infecção fúngica oportunista, progressiva, aguda e severa, de mau prognóstico, com o maior risco de vida em doentes imunodeprimidos ou que são sujeitos a terapias agressivas pelo uso de corticoides, antibióticos e drogas imunossupressoras. Os sintomas incluem febre, calafrios, choque, delírio e coágulos sanguíneos. Insuficiência renal e hepática (causando icterícia), além de dificuldade respiratória podem surgir. A morte pode ocorrer rapidamente. A taxa de incidência anual de infeção invasiva por Aspergillus spp. é de 12 casos por 1.000.000 hab. O Aspergillus fumigatus é responsável por mais de 90% das infeções humanas. Se iniciado precocemente, o tratamento gera um melhor prognóstico. TECNOLOGIA: Voriconazol versus anfotericina B (desoxicolato ou formulações lipídicas). PERGUNTA DE PESQUISA: O voriconazol é eficaz e seguro, quando comparado a anfotericina B (desoxicolato ou formulações lipídicas) para o tratamento de pessoas com aspergilose invasiva? EVIDÊNCIAS CLÍNICAS: A busca de evidências foi realizada nas bases de dados científicas: Medline (PUBMED), EMBASE, The Cochrane Library, Literatura Latino-americana e do Caribe em Ciências da Saúde (LILACS), Scopus e Web of Science. Foram 986 registros e ao final do processo de seleção de estudos, foram escolhidos três artigos científicos, sendo um estudo clínico randomizado multicêntrico e duas análises post-hoc da amostra original do estudo clínico randomizado multicêntrico citado anteriormente. De acordo com análise dos estudos incluídos, há evidência "baixa" favorável ao uso da tecnologia para o sucesso do tratamento em 12 semanas (RR: 1,67; IC95%: 1,25-2,24; p = 0,0006), sobrevida em 12 semanas (RR: 1,22; IC95%: 1,02-1,46; p = 0,03) e redução de efeitos adversos diretamente relacionados a droga (RR: 0,55; IC95%: 0,36-0,85; p = 0,008) quando comparada a Anfotericina B desoxicolato. Não houve diferença significativa em relação ao tempo de internação hospitalar e internação na UTI. Porém, deve ser salientado que não foram encontrados estudos comparando diretamente o voriconazol e formulações lipídicas da anfotericina B (anfotericina B lipossomal ou complexo lipídico de anfotericina B). Em uma revisão sistemática com metanálise, a eficácia do desoxicolato de anfotericina B e das formulações à base de lipídios foi semelhante. Não há estudo clínico randomizado com amostra grande do complexo lipídico de anfotericina B. EVIDÊNCIAS ECONÔMICAS: Foi conduzida avaliação econômica do tipo árvore de decisão, com horizonte temporal de doze semanas. Considerou-se como desfechos primários de efetividade: sobrevivência ao final do tratamento e sucesso terapêutico como medidas de efetividade. A análise de custo-efetividade mostrou que voriconazol é custo-efetivo, dominando todas alternativas. A análise de sensibilidade determinística não produziu alterações nas conclusões. ANÁLISE DE IMPACTO ORÇAMENTÁRIO: A análise de impacto orçamentário (AIO) foi realizada para um horizonte temporal de cinco anos. Para a pergunta 1 de pesquisa, a incorporação de voriconazol teria um custo adicional de aproximadamente 198 milhões de reais. Estimou-se também o impacto orçamentário de 100% de voriconazol no tratamento farmacológico de pacientes com aspergilose invasiva. Nesse contexto, ocorreria uma economia da ordem de 83 milhões para a substituição do CLAB pelo voriconazol e de 144 milhões para substituição o ABD pelo voriconazol, em cinco anos. RECOMENDAÇÕES INTERNACIONAIS: Foi realizada busca por recomendações de uso do voriconazol em instituições e agências de ATS. Não foi identificada recomendação do NICE para a tecnologia. CADTH emitiu uma recomendação de reembolso em 2004. SMC e TGA recomendam o uso da tecnologia para o tratamento de pacientes com aspergilose invasiva. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: Foi detectada uma tecnologia para compor o esquema terapêutico da candidíase invasiva. CONSIDERAÇÕES FINAIS: Foi identificada evidência baixa ou muito baixa de benefício no uso da tecnologia para o sucesso do tratamento, sobrevida em 12 semanas e redução de efeitos adversos diretamente relacionados a droga. Porém, deve ser salientado que não foram encontrados estudos comparando diretamente o voriconazol e formulações lipídicas da anfotericina B (anfotericina B lipossomal ou complexo lipídico de anfotericina B). Dadas as evidências apresentadas, o uso de voriconazol tem potencial custo-efetivo para o tratamento da aspergilose invasiva. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do Plenário presentes na 107ª Reunião Ordinária da Conitec, no dia 06 de abril de 2022, deliberaram por unanimidade que a matéria fosse disponibilizada em consulta pública com recomendação preliminar favorável à incorporação de voriconazol para tratamento de pacientes com aspergilose invasiva. Dentre as justificativas para a recomendação, considerou-se a tecnologia custo-efetiva e que, de acordo com uma certeza de evidência baixa, resulta em maior no sucesso do tratamento, sobrevida em 12 semanas e redução de efeitos adversos diretamente relacionados a droga. A matéria foi disponibilizada em consulta pública. CONSULTA PÚBLICA: A Consulta Pública no 29/2022 foi realizada entre os dias 29/04/2022 a 18/05/2022. Foram recebidas 11 contribuições, sendo quatro pelo formulário para contribuições técnico-científicas e sete pelo formulário para contribuições sobre experiência ou opinião de pacientes, familiares, amigos ou cuidadores de pacientes, profissionais de saúde ou pessoas interessadas no tema. As contribuições foram recebidas na consulta pública foram todas a favor da recomendação preliminar da Conitec que recomendava a recomendar a incorporação da anidulafungina. As argumentações destacaram os benefícios clínicos que o medicamento oferece com base em evidências já apresentadas na discussão inicial do tema e reitera que o medicamento se trata de opção terapêutica com melhor eficácia do que as opções de tratamento atualmente disponíveis no SUS, levando a maior sobrevida e menor incidência de efeitos colaterais. Não foram adicionadas na CP referências que alterassem a análise das evidências científicas e econômicas apresentadas no relatório preliminar de recomendação. RECOMENDAÇÃO FINAL DA CONITEC: Os membros do plenário presentes na 109ª reunião ordinária da Conitec, no dia 09 de junho de 2022, deliberaram, por unanimidade, recomendar a incorporação, no SUS, do voriconazol para tratamento de pacientes com aspergilose invasiva. Não foram adicionadas na consulta pública referências que alterassem a recomendação preliminar. Foi assinado o Registro de Deliberação nº741/2022. DECISÃO: Incorporar, no âmbito do Sistema Único de Saúde - SUS, o voriconazol para tratamento de pacientes com aspergilose invasiva conforme a Portaria nº 59, publicada no Diário Oficial da União nº 142, seção 1, página 130, em 28 de julho de 2022.

Assessment of the Safety and Efficacy of an Oral Probiotic-Based Vaccine Against Aspergillus Infection in Captive-Bred Humboldt Penguins (Spheniscus humboldti).

Aspergillosis is a fungal infection caused mainly by Aspergillus fumigatus that often results in respiratory disease in birds. Aspergillosis is a major cause of morbidity and mortality in captive-bred penguin species. Currently, there is no registered vaccine to prevent aspergillosis. Recent research demonstrated that oral administration of gram-negative bacteria expressing high levels of galactose-α-1,3-galactose (α-Gal) modulates anti-α-Gal immunity and protects turkeys from clinical aspergillosis caused by experimental A. fumigatus infection. The role of anti-α-Gal immunity in penguins has not been studied. Here, we tested the distribution of α-1,3-galactosyltransferase (α1,3GT) genes in the fecal microbiome of Humboldt penguins (Spheniscus humboldti). The occurrence of natural anti-α-Gal antibodies (Abs) in sera and eggs of healthy Humboldt penguins was also assessed. A trial was then conducted to test whether oral administration of Escherichia coli Nissle, expressing high α-Gal levels, modulates anti-α-Gal immunity in a colony of Humboldt penguins. Animals in the vaccination and placebo groups were evaluated before the trial and followed for one year for aspergillosis detection using a diagnostic panel including computed tomography scans, capillary zone electrophoresis, 3-hydroxybutyrate levels, and anti-A. fumigatus Abs. Anti-α-Gal Abs were detected in sera (IgM and IgY) and eggs (IgY) of healthy penguins. Microbiota analysis and functional predictions revealed the presence of α1,3GT genes in the microbiota of Humboldt penguins and other penguin species. A strong decrease in anti-α-Gal IgM levels was observed in all animals in the placebo group three months after vaccination protocol. This decrease was not observed in E. coli Nissle-treated penguins. After the vaccination protocol, we found a positive correlation between anti-E. coli IgY and anti-α-Gal IgY in the E. coli Nissle group, suggesting a correlation between the presence of the bacteria and these Abs. During the study period, three penguins exhibited respiratory signs consistent with aspergillosis. Two were from the placebo group whose symptoms resolved with specific treatments, while a single vaccinated individual developed fatal respiratory aspergillosis eight months after the trial. We conclude that E. coli Nissle represents a safe potential probiotic with a protective effect against aspergillosis in Humboldt penguins that deserves to be further explored for therapeutic uses in these animals.

Real-World Financial and Clinical Impact of Diagnostic-Driven and Empirical-Treatment Strategies in High-Risk Immunocompromised Patients with Suspected Aspergillus Infection in the United Kingdom.

A diagnostic-driven (DD) treatment strategy has proven successful for treating invasive fungal infections (IFIs) caused by Aspergillus. However, uptake of this treatment strategy is not fully embraced. This study compares the economic and clinical impact of DD and empirical-treatment (ET) strategies used within hospitals. Methods: a decision-analytic model was developed to compare costs and clinical outcomes associated with ET or a DD strategy of identifying infections caused by Aspergillus via galactomannan-antigen testing or Aspergillus polymerase chain reaction (PCR) in neutropenic patients with unexplained fever. Patients were treated prophylactically with antifungal treatments as seen in United Kingdom (UK) hospitals. The IFI incidence, response, mortality, resource use, and adverse events were obtained from meta-analyses and other clinical studies. Analyses were performed from the U.K. hospital perspective, and costs were obtained from standard costing sources. Although diagnostic-testing costs increased, total cost and length of stay were reduced by £1,121 and 1.54 days when treating via a DD strategy. Intensive care and general ward days accounted for > 40% of total costs and > 58% of the cost reduction came from reduced antifungal costs. Treating with a DD strategy reduced the number of patients being treated with antifungal agents while survival was increased. Thus, a DD strategy was cost savings (-£136,787 cost per death avoided) compared with an ET strategy. Conclusion: this study suggests that incorporating a DD strategy as the preferred treatment protocol may be a cost-saving and clinically improved treatment strategy for managing neutropenic patients with unexplained fever. IMPORTANCE Patients at risk of invasive fungal infections (IFIs), such as Aspergillus spp., tend to be immunocompromised and usually take several medications which may generate many side effects. Prescribing is further complicated by comorbidities, drug interactions and challenges accessing diagnostics. Therefore, adding another agent may be neither straightforward nor the best option for these types of patients. A diagnostic-driven (DD) treatment strategy has proven successful for treating IFIs. However, uptake of this treatment strategy is not fully embraced in clinical practice perhaps because this strategy is thought to be more costly and/or to result in higher mortality relative to treating empirically. We developed a decision-analytic model to examine the impact of these 2 strategies on costs and health outcomes. This study indicates that incorporating a DD strategy as the preferred treatment protocol may be a cost-saving and clinically improved treatment strategy for managing neutropenic patients with unexplained fever.

Economic evaluation of isavuconazole for suspected invasive pulmonary aspergillosis in Canada.

BACKGROUND: Invasive mold infections (IMI) directly impact life expectancy, especially with delayed therapy. Among IMI, aspergillosis (IA) is more common than mucormycosis (IM), resulting in IA-targeted empirical treatment with voriconazole for suspected invasive pulmonary aspergillosis (IPA), despite IM ineffectiveness. Recently, isavuconazole was approved in Canada for IA and IM. The primary objective was to assess the cost-effectiveness of isavuconazole compared to voriconazole for suspected IPA in Canada. A secondary objective was to assess the impact of varying time horizons to address the wide spectrum of life expectancies, according to patients underlying diseases. RESEARCH DESIGN AND METHODS: A 5-year decision-tree was developed from the Canadian Ministry of Health (MoH) and societal perspectives. Efficacy parameters were extracted from SECURE/VITAL trials. Costs included treatment acquisition, hospitalization, adverse events and productivity loss. 3- and 10-year time horizon alternative scenarios and extensive sensitivity analyses were also conducted. RESULTS: From a MoH perspective, isavuconazole compared to voriconazole resulted in an incremental cost-utility ratio (ICUR) of $C30,160/QALY. 3- and10-year ICURs were also cost-effective, relative to a willingness-to-pay threshold of $C50,000/QALY. CONCLUSIONS: This study demonstrates that, in comparison to voriconazole, isavuconazole is a cost-effective strategy for the treatment of patients with suspected IPA, regardless of their life expectancy.

Serious fungal diseases in Democratic Republic of Congo - Incidence and prevalence estimates.

A literature review was conducted to assess the burden of serious fungal infections in the Democratic Republic of the Congo (DRC) (population 95,326,000). English and French publications were listed and analysed using PubMed/Medline, Google Scholar and the African Journals database. Publication dates spanning 1943-2020 were included in the scope of the review. From the analysis of published articles, we estimate a total of about 5,177,000 people (5.4%) suffer from serious fungal infections in the DRC annually. The incidence of cryptococcal meningitis, Pneumocystis jirovecii pneumonia in adults and invasive aspergillosis in AIDS patients was estimated at 6168, 2800 and 380 cases per year. Oral and oesophageal candidiasis represent 50,470 and 28,800 HIV-infected patients respectively. Chronic pulmonary aspergillosis post-tuberculosis incidence and prevalence was estimated to be 54,700. Fungal asthma (allergic bronchopulmonary aspergillosis and severe asthma with fungal sensitization) probably has a prevalence of 88,800 and 117,200. The estimated prevalence of recurrent vulvovaginal candidiasis and tinea capitis is 1,202,640 and 3,551,900 respectively.Further work is required to provide additional studies on opportunistic infections for improving diagnosis and the implementation of a national surveillance programme of fungal disease in the DRC.

Invasive aspergillosis in solid organ transplant patients: diagnosis, prophylaxis, treatment, and assessment of response.

BACKGROUND: Invasive aspergillosis (IA) is a rare complication in solid organ transplant (SOT) recipients. Although IA has significant implications on graft and patient survival, data on diagnosis and management of this infection in SOT recipients are still limited. METHODS: Discussion of current practices and limitations in the diagnosis, prophylaxis, and treatment of IA and proposal of means of assessing treatment response in SOT recipients. RESULTS: Liver, lung, heart or kidney transplant recipients have common as well as different risk factors to the development of IA, thus each category needs a separate evaluation. Diagnosis of IA in SOT recipients requires a high degree of awareness, because established diagnostic tools may not provide the same sensitivity and specificity observed in the neutropenic population. IA treatment relies primarily on mold-active triazoles, but potential interactions with immunosuppressants and other concomitant therapies need special attention. CONCLUSIONS: Criteria to assess response have not been sufficiently evaluated in the SOT population and CT lesion dynamics, and serologic markers may be influenced by the underlying disease and type and severity of immunosuppression. There is a need for well-orchestrated efforts to study IA diagnosis and management in SOT recipients and to develop comprehensive guidelines for this population.

Post-Tuberculosis Lung Disease: Clinical Review of an Under-Recognised Global Challenge.

An estimated 58 million people have survived tuberculosis since 2000, yet many of them will suffer from post-tuberculosis lung disease (PTLD). PTLD results from a complex interplay between organism, host, and environmental factors and affects long-term respiratory health. PTLD is an overlapping spectrum of disorders that affects large and small airways (bronchiectasis and obstructive lung disease), lung parenchyma, pulmonary vasculature, and pleura and may be complicated by co-infection and haemoptysis. People affected by PTLD have shortened life expectancy and increased risk of recurrent tuberculosis, but predictors of long-term outcomes are not known. No data are available on PTLD in children and on impact throughout the life course. Risk-factors for PTLD include multiple episodes of tuberculosis, drug-resistant tuberculosis, delays in diagnosis, and possibly smoking. Due to a lack of controlled trials in this population, no evidence-based recommendations for the investigation and management of PTLD are currently available. Empirical expert opinion advocates pulmonary rehabilitation, smoking cessation, and vaccinations (pneumococcal and influenza). Exacerbations in PTLD remain both poorly understood and under-recognised. Among people with PTLD, the probability of tuberculosis recurrence must be balanced against other causes of symptom worsening. Unnecessary courses of repeated empiric anti-tuberculosis chemotherapy should be avoided. PTLD is an important contributor to the global burden of chronic lung disease. Advocacy is needed to increase recognition for PTLD and its associated economic, social, and psychological consequences and to better understand how PTLD sequelae could be mitigated. Research is urgently needed to inform policy to guide clinical decision-making and preventative strategies for PTLD.

The cost-effectiveness of isavuconazole compared to voriconazole, the standard of care in the treatment of patients with invasive mould diseases, prior to differential pathogen diagnosis in Spain.

BACKGROUND: Invasive mould diseases are associated with high morbidity, mortality and economic impact. Its treatment is often started prior to differential pathogen diagnosis. Isavuconazole is approved for treatment of invasive aspergillosis (IA) and invasive mucormycosis (IM) when amphotericin-B is not indicated. OBJECTIVES: To estimate the cost-effectiveness of isavuconazole vs voriconazole for the treatment of adult patients with possible IA prior to differential pathogen diagnosis, in Spain. METHODS: A decision tree analysis was performed using the Spanish Healthcare System perspective. Among all patients with possible IA, it was considered that 7.81% actually had IM. Costs for laboratory analysis, management of adverse events, hospitalisation and drugs per patient, deaths and long-term effects in life years (LYs) and quality-adjusted LYs (QALYs) were considered. Efficacy data were obtained from clinical trials and utilities from the literature. Deterministic and probabilistic sensitivity analyses (PSA) were conducted. RESULTS: In patients with possible IA and when compared to voricanozole, isavuconazole showed an incremental cost of 4758.53€, besides an incremental effectiveness of +0.49 LYs and +0.41 QALYs per patient. The Incremental Cost Effectiveness Ratio was 9622.52€ per LY gained and 11,734.79€ per QALY gained. The higher cost of isavuconazole was due to drug acquisition. Main parameters influencing results were mortality, treatment duration and hospitalisation days. The PSA results showed that isavuconazole has a probability of being cost-effective of 67.34%, being dominant in 24.00% of cases. CONCLUSIONS: Isavuconazole is a cost-effective treatment compared to voriconazole for patients with possible IA for a willingness to pay threshold of 25,000€ per additional QALY.

Eficacia y seguridad de las terapias antifúngicas intravenosas para la aspergilosis invasiva, en pacientes adultos con nefrotoxicidad o intolerancia a la anfotericina B deoxicolato y enfermedad aguda o progresiva (segunda línea de tratamiento) / Efficacy and safety of intravenous antifungal therapies for invasive aspergillosis in adult patients with nephrotoxicity or intolerance to amphotericin B deoxycholate and acute or progressive disease (second-line treatment)

INTRODUCCIÓN: El presente dictamen preliminar expone la evaluación de la eficacia y seguridad de las terapias antifúngicas intravenosas para la aspergilosis invasiva, en pacientes adultos con nefrotoxicidad o intolerancia a la anfotericina B deoxicolato y enfermedad aguda o progresiva. La aspergilosis invasiva (AI) es una infección fúngica altamente letal en hospedadores inmunodeprimidos. Se estima que la tasa de mortalidad es de aproximadamente 30 a 80 %. La anfotericina B deoxicolato es el agente antifúngico (intravenoso) con mayor experiencia de uso para tratar la AI; sin embargo, se asocia con importantes toxicidades que limitan su uso, principalmente la nefrotoxicidad. En EsSalud, los pacientes con AI, nefrotoxicidad o intolerancia a anfotericina B deoxicolato y enfermedad aguda, disponen de caspofungina. Sin embargo, el IETSI recibió una solicitud de uso de isavuconazol intravenoso bajo la argumentación de que este fármaco representa la mejor opción terapéutica para este tipo de pacientes, basado en un mejor perfil de eficacia y seguridad. Considerando que, además del isavuconazol, existen otras alternativas antifúngicas intravenosas indicadas para este tipo de pacientes, algunas de las cuales tienen experiencia de uso en EsSalud, el equipo evaluador del IETSI optó por re-evaluar el problema de decisión y realizar una evaluación de múltiples tecnologías sanitarias con el fin de identificar la opción de tratamiento más efectiva, segura y costo-efectiva para la población de interés. METODOLOGÍA: Se realizó una búsqueda sistemática de literatura con el objetivo de identificar evidencia sobre la eficacia y seguridad de las terapias antifúngicas intravenosas para la aspergilosis invasiva, en pacientes adultos con nefrotoxicidad o intolerancia a la anfotericina B deoxicolato y enfermedad aguda o progresiva. Se utilizaron las bases de datos PubMed, Cochrane Library y LILACS, priorizándose la evidencia proveniente de ensayos clínicos controlados aleatorizados. Asimismo, se realizó una búsqueda dentro de bases de datos pertenecientes a grupos que realizan evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), incluyendo el Healthcare Improvement Scotland, el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), la Haute Autorité de Santé (HAS), el Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), además de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA) y páginas web de sociedades especializadas en aspergilosis como American Thoracic Society (ATS), Infectious Diseases Society of America (IDSA), European Society for Clinical Microbiology and Infectious Diseases (ESCMID) y European Conference on Infections in Leukaemia (ECIL). Se hizo una búsqueda adicional en la página web del Registro administrado por la Biblioteca Nacional de Medicina de los Estados Unidos (https://clinicaltrials.gov/) e International Clinical Trial Registry Platform (ICTRP) (https://apps.who.int/trialsearch/), para poder identificar ensayos clínicos en curso o que no hayan sido publicados para, de este modo, disminuir el riesgo de sesgo de publicación. Para que la búsqueda de información pueda ser empleada para responder a la pregunta PICO se utilizaron estrategias de búsqueda que incluyeron términos relacionados a la población de interés, la intervención, y el comparador. Se emplearon términos MeSH1 y términos libre junto con operadores booleanos acordes a cada una de las bases de datos elegidas para la búsqueda. Con la estrategia de búsqueda diseñada para PubMed, se generaron alertas diarias vía correo electrónico con el objetivo de identificar estudios publicados luego del 09 de octubre de 2020. La búsqueda bibliográfica se limitó a GPC, ETS, revisiones sistemáticas con meta-análisis, y ECA que hayan evaluado la pregunta PICO de interés del presente dictamen. Ante la ausencia de ECA, también se buscaron estudios observacionales comparativos. La búsqueda se limitó a estudios en inglés y español. Se excluyeron las series de casos, los reportes de casos, las cartas al editor, los comentarios, las editoriales, los resúmenes de congresos y los estudios in vitro. La selección de los estudios fue llevada a cabo en dos fases. La primera fase consistió en la revisión de los títulos o los resúmenes a través del aplicativo web Rayyan (https://rayyan.qcri.org), que permitió pre-seleccionar los estudios a incluir y/o los que requerían más información para decidir. En la segunda fase se aplicaron de nuevo los criterios de elegibilidad empleando el texto completo de los estudios que fueron pre-seleccionados. RESULTADOS: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de las terapias antifúngicas intravenosas para la aspergilosis invasiva, en pacientes adultos con nefrotoxicidad o intolerancia a la anfotericina B deoxicolato y enfermedad aguda o progresiva. A continuación, se describe la evidencia disponible según el orden jerárquico del nivel de evidencia o pirámide de Haynes 6S. CONCLUSIONES: El presente dictamen preliminar tuvo como objetivo evaluar la mejor evidencia sobre la eficacia y seguridad de las terapias antifúngicas intravenosas para la aspergilosis invasiva, en pacientes adultos con nefrotoxicidad o intolerancia a la anfotericina B deoxicolato y enfermedad aguda o progresiva (segunda línea de tratamiento). Las intervenciones de interés fueron el isavuconazol intravenoso, el voriconazol intravenoso y la L-AmB (intravenosa), y el comparador de interés fue la caspofungina. Los desenlaces de interés fueron la respuesta clínica, microbiológica y radiológica, la sobrevida global, la mortalidad, la calidad de vida y los eventos adversos. La evidencia disponible sobre la mejor alternativa antifúngica para pacientes con AI y nefrotoxicidad o intolerancia a anfotericina B deoxicolato (o tratamientos antifúngicos convencionales en general) es de baja calidad metodológica. La evidencia disponible sugiere, aunque con una gran incertidumbre, que los antifúngicos de interés para la presente evaluación (isavuconazol, voriconazol, L-AmB y caspofungina) tendrían similar eficacia, en términos de respuesta antifúngica, pero con diferentes perfiles de seguridad. De estos, caspofungina es el que tiene más evidencia en un contexto de intolerancia y sus estudios incluyen a la población de interés del presente dictamen preliminar. Caspofungina es mejor tolerado que otras clases de antifúngicos sistémicos, no habiéndose reportado eventos de nefrotoxicidad. En ese sentido, caspofungina sería el fármaco más adecuado para tratar a la población de interés del presente dictamen. De manera adicional, es importante resaltar que optar por el uso de caspofungina, en lugar de los otros antifúngicos evaluados, es una decisión con mejor perfil de costo-oportunidad; ya que este fármaco tiene los costos más asequibles a nivel institucional. Por lo expuesto, el IETSI no aprueba el uso de isavuconazol intravenoso, voriconazol intravenoso y L-AmB (intravenosa) en pacientes adultos con AI, nefrotoxicidad o intolerancia a la anfotericina B deoxicolato y enfermedad aguda o progresiva.

Evaluating posaconazole dosing regimens of the different formulations against Aspergillus spp. in adults: a pharmacokinetic/pharmacodynamic analysis using Monte Carlo simulation.

The objective of this study was to evaluate the efficacy of various posaconazole dosing regimens of the different formulations against Aspergillus spp. in adults. Monte Carlo simulations were conducted using pharmacokinetic (PK) parameters and pharmacodynamic (PD) data to determine the probability of target attainment (PTA) and cumulative fraction of response (CFR) in terms of area under the concentration-time curve/minimum inhibition concentration (AUC/MIC) targets of posaconazole. According to the results of the PTA analysis, currently recommended clinical dosing regimens of the delayed-release tablet and intravenous (i.v.) solution were appropriate in prophylaxis against Aspergillus spp. with MICs ≤ 0.125 µg/mL. However, only high-dose regimens of the delayed-release tablet could achieve the target PTA in the treatment against Aspergillus spp. at an MIC of 0.125 µg/mL. Furthermore, the CFR was calculated for each dosing regimen. For the oral suspension, none of the simulated dosing regimens was effective against Aspergillus spp. For the delayed-release tablet and i.v. solution, the recommended dosing regimens were effective for prophylaxis of invasive fungal infections by four Aspergillus spp. (Aspergillus flavus, Aspergillus fumigatus, Aspergillus nidulans and Aspergillus terreus). However, these recommended dosing regimens were only effective for the treatment of A. terreus infection. Therefore, the high-dose regimen (200 mg oral every 12 h) of the delayed-release tablet should be recommended to achieve optimal therapeutic efficacy against four Aspergillus spp. (A. flavus, A. fumigatus, A. nidulans and A. terreus). These PK/PD-based simulations rationalise and optimise the dosing regimens of the different posaconazole formulations against Aspergillus spp. in adults.

Influenza-Associated Aspergillosis: Nationwide Trends, Predictors and Outcomes From 2005 to 2014.

BACKGROUND: Influenza-associated aspergillosis (IAA) has been increasingly reported in the literature in recent years, but contemporary large-scale data on the morbidity and mortality burden of IAA are lacking. RESEARCH QUESTION: The goal of this study was to estimate the predictors, associations, and outcomes of IAA in the United States. STUDY DESIGN AND METHODS: This retrospective cohort study was performed by using the National (Nationwide) Inpatient Sample database from 2005 to 2014 to identify influenza and IAA hospitalizations. Baseline variables and outcomes were compared between influenza hospitalizations without IAA and those with IAA. These variables were then used to perform an adjusted analysis for obtaining predictors and associations of the diagnosis and in-hospital mortality of IAA. RESULTS: Of the 477,556 hospitalizations identified with the principal diagnosis of influenza, IAA was identified in 823 (0.17%) hospitalizations. The IAA cohort consisted more commonly of 45- to 65-year-olds in urban teaching hospitals with substance abuse. Yearly trends revealed that both influenza and IAA hospitalizations have increased over time, with a peak observed in 2009, the year of the influenza A(H1N1) pandemic. Mortality was higher (20.58% vs 1.36%), average length of stay was longer (17.94 vs 4.05 days), and mean cost per hospitalization was higher ($194,932 vs $24,286) in the IAA cohort compared with the influenza cohort without IAA (P < .005). Solid-organ transplantation, hematologic malignancies, and use of invasive mechanical ventilation were associated with higher odds of IAA, among other factors. Use of invasive mechanical ventilation (adjusted OR, 13.43; P < .005), longer length of stay (adjusted OR, 5.47; P < .005), utilization of extracorporeal membrane oxygenation (adjusted OR, 4.99; P = .014), and the group aged 45 to 64 years (adjusted OR, 3.03; P = .012) were associated with higher in-hospital mortality in the IAA cohort. INTERPRETATION: Although IAA is a rare complication of influenza hospitalizations, it is associated with increased all-cause mortality, more extended hospital stays, and higher hospital charges compared with influenza without IAA.

Development and Assessment of a Simulator for in Vivo Confocal Microscopy in Fungal and Acanthamoeba Keratitis.

BACKGROUND AND PURPOSE: In vivo confocal microscopy (IVCM) is a non-invasive imaging technique that allows morphological analysis as a diagnostic approach of the cornea in real time, thus providing a suspected diagnosis of fungal or amoebic keratitis immediately, whereas culture or PCR require several days or even weeks. Since these infections are rare, it is difficult for ophthalmologists to gain the experience necessary to differentiate infection from normal findings or artefacts. The purpose of this project was to establish a simulator, on which physicians could practice as well as acquiring a database of IVCM images of fungal or amoebic keratitis and respective analyses. PATIENTS AND METHODS: An IVCM simulator was set up with cadaver human corneas, infected with either acanthamoeba, candida or aspergillus. Twenty-one ophthalmologists were trained in IVC microscopy first in a Dry Lab, then practically on the simulator. For evaluation, the participants were asked to fill out a standardized questionnaire, with a pre- and post-course self-assessment. RESULTS: The self-assessed theoretical and practical skills in differentiating infectious from non-infectious keratitis in IVCM significantly increased (p = 0.0001, p = 0.0002, respectively). The barrier to use this technique decreased (p = 0.0474). CONCLUSION: A very simple protocol based on a model of ex vivo corneal mycotic and amoebic infections can be used to train novices in the structured approach and diagnostic use of IVCM for corneal infections.

US database study: burden and healthcare resource utilization in adults with systemic endemic mycoses and aspergillosis.

Aim: This study evaluated burden of illness in immunocompromised patients with systemic mycoses (SM) eligible for itraconazole treatment, specifically, histoplasmosis, blastomycosis and aspergillosis. Methods: A cross-sectional study used an electronic medical record network integrating information from 30 US hospitals, including >34 million patients, to evaluate burden and healthcare resource utilization over 6 months following initiation of antifungal therapy. Results: Symptomatic burden experienced by each of the otherwise healthy or age >65 or immunosuppressed cohorts receiving antifungal therapy for SM was comparable but significantly greater in cancer or HIV patients and transplant recipients. Across groups, there was substantially higher healthcare resource utilization in patients with SM versus matched controls without SM. Conclusion: The total impact of SM is particularly severe in high-risk or vulnerable populations.

Autopsy imaging for aspergillosis in King Penguin, an economically valuable zoo animal.

Autopsy imaging (Ai) was performed for a King Penguin. Ai-computed tomography (CT) revealed air sac membrane thickening, multiple nodules in the cranial air sac, suspected abscess, lung infiltration, and air sac contraction. Based on these findings, respiratory disorder was concerned. Aspergillosis, which is the highly observed in penguins, was considered as the primary differential diagnosis. The cultured sample showed characteristic conidial head of Aspergillus spp., the DNA of which was 100% identical to that of A. fumigatus. The cause of death was determined to respiratory failure due to aspergillosis. Ai-CT findings facilitated the dissection workflow and alerted the pathologist to potential hazards during the autopsy. Ai is useful to determine the cause of death and for readiness and safe pathological dissection.