Dosing of IV posaconazole to treat critically ill patients with invasive pulmonary aspergillosis: a population pharmacokinetics modelling and simulation study.

BACKGROUND: Posaconazole is used for the prophylaxis and treatment of invasive fungal infections in critically ill patients. Standard dosing was shown to result in adequate attainment of the prophylaxis Cmin target (0.7 mg/L) but not of the treatment Cmin target (1.0 mg/L). OBJECTIVES: To provide an optimized posaconazole dosing regimen for IV treatment of patients with invasive pulmonary aspergillosis in the ICU. METHODS: A population pharmacokinetics (popPK) model was developed using data from the POSA-FLU PK substudy (NCT03378479). Monte Carlo simulations were performed to assess treatment Cmin and AUC0-24 PTA. PTA ≥90% was deemed clinically acceptable. PopPK modelling and simulation were performed using NONMEM 7.5. RESULTS: Thirty-one patients with intensive PK sampling were included in the PK substudy, contributing 532 posaconazole plasma concentrations. The popPK of IV posaconazole was best described by a two-compartment model with linear elimination. Interindividual variability was estimated on clearance and volume of distribution in central and peripheral compartments. Posaconazole peripheral volume of distribution increased with bodyweight. An optimized loading regimen of 300 mg q12h and 300 mg q8h in the first two treatment days achieved acceptable PTA by Day 3 in patients <100 kg and ≥100 kg, respectively. A maintenance regimen of 400 mg q24h ensured ≥90% Cmin PTA, whereas the standard 300 mg q24h was sufficient to achieve the AUC0-24 target throughout 14 days, irrespective of bodyweight. CONCLUSIONS: We have defined a convenient, optimized IV posaconazole dosing regimen that was predicted to attain the treatment target in critically ill patients with invasive aspergillosis.

Targeted DPPC/DMPG surface-modified voriconazole lipid nanoparticles control invasive pulmonary aspergillosis in immunocompromised population: in-vitro and in-vivo assessment.

Invasive pulmonary aspergillosis (IPA) is the most devastating Aspergillus-related lung disease. Voriconazole (VRZ) is the first-line treatment against IPA. Despite availability in oral and parenteral dosage forms, risks of systemic toxicity dictate alternative pulmonary administration. Inspired by natural lung surfactants, dipalmitoylphosphatidylcholine/dimyristoylphosphatidylglycerol (DPPC/DMPG) surface-modified lipid nanoparticles (LNPs) were scrutinized for pulmonary administration. DPPC/DMPG-VRZ-LNPs prepared using ultrasonication/thin film hydration were investigated for colloidal properties over 3-month shelf storage. They were stable with a slight change in entrapment efficiency. They provided a sustained VRZ release over 24 h, with a rapid initial release. In vitro aerosolization indicated higher percentages of VRZ deposited on stages corresponding to secondary bronchi and alveolar ducts. Moreover, intrapulmonary administration maintained high lung VRZ concentration (27 ± 1.14 µg/g) after 6 h. A preclinical study using a cyclophosphamide-induced neutropenic rat model demonstrated a 3-fold reduction in BALF-Galactomannan down to 0.515 ± 0.22 µg/L confirming DPPC/DMPG-VRZ-LNPs potential in hyphal growth inhibition. Histopathological examination of infected/nontreated lung sections exhibited dense fungal load inside alveoli and blood vessels indicating massive tissue and angio-invasiveness. Nevertheless, DPPC/DMPG-VRZ-LNPs-treated animals displayed minimal hyphae with no signs of invasiveness. The developed bioinspired nanoparticles serve as prospective bioactive nanocarrier candidates for pulmonary administration of VRZ in the management of IPA.

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.

Serum Aspergillus-specific IgE, IgG and IgG4 immunoglobulins assessment in the work-up of invasive pulmonary aspergillosis: a prospective cohort study.

BACKGROUND: Positive microbiological fungal culture from bronchoalveolar-lavage-fluid (BAL) for Aspergillus or tissue biopsy and the detection of high levels of Aspergillus Galactomannan (GM) are commonly considered standard for diagnosing Invasive Pulmonary Aspergillosis (IPA). However, Aspergillus infection induces both cellular and humoral immune responses, characterized by the production of specific immunoglobulins, which can be easily detected in serum and accurately measured. This study hypothesized that Aspergillus-specific IgE, IgG, including IgG4, assays could be adopted as a rapid preliminary screening tool in patients with suspected Aspergillus-related lung disease in order to help in the identification of patients who require more invasive procedures (bronchoscopy, biopsy). METHODS: We prospectively stored 447 serum specimens of patients admitted for suspected IPA from 1 January 2010 to 31 July 2021. Serum total IgE and serum IgE, IgG and IgG4 specific for Aspergillus fumigatus and Aspergillus niger were determined for each sample. In addition, bronchoscopy with BAL for microbiologic culture and Aspergillus Galactomannan (GM) antigen were performed in all patients. RESULTS: Patients with IPA, diagnosed by detection of a positive BAL culture for Aspergillus and/or a positive GM, showed higher serum levels of specific Aspergillus fumigatus and Aspergillus niger immunoglobulins. Serum-specific Aspergillus fumigatus IgG at a cut-off of 22.6 mgA/L showed the highest sensitivity in predicting IPA, though quite moderate (AUC 0.62). Nonetheless, the simultaneous presence of values below the cut-off of Aspergillus IgE, IgG and IgG4 showed a negative predictive value greater than 90% both towards positive BAL culture and positive GM. CONCLUSIONS: In patients with suspected IPA, Aspergillus-specific immunoglobulins assay could be tested as a preliminary screening tool to support more invasive procedures, i.e. BAL.

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.

Eficacia y seguridad de isavuconazol oral, como terapia de mantenimiento, en pacientes adultos con aspergilosis invasiva y con falla o intolerancia a voriconazol oral y posaconazol oral / Efficacy and safety of oral isavuconazole, as maintenance therapy, in adult patients with invasive aspergillosis and with failure or intolerance to oral voriconazole and oral posaconazole

INTRODUCCIÓN: El presente dictamen preliminar expone la evaluación de la eficacia y seguridad de isavuconazol oral, en comparación con itraconazol oral, en pacientes adultos con aspergilosis invasiva con falla o intolerancia a voriconazol oral y posaconazol oral, que requieren terapia de mantenimiento posterior a la terapia de inducción con anfotericina B deoxicolato. La aspergilosis invasiva (AI) es la infección por hongos más común en huéspedes inmunodeprimidos. A pesar de los avances en el diagnóstico y el tratamiento de la AI, las tasas de mortalidad siguen siendo altas. A nivel mundial, se estima una incidencia acumulada anual de 250,000 casos de AI, con una tasa de mortalidad de aproximadamente 30 a 80 %. En el Perú, en el 2014 se estimó una prevalencia de 1,621 casos de AI. El tratamiento antimicótico de la AI suele ser prolongado, con una duración de varios meses a más de un año. En EsSalud, los pacientes con AI son tratados inicialmente con anfotericina B deoxicolato (terapia de inducción intravenosa) y luego, una vez estables, con azoles orales (voriconazol posaconazol o itraconazol) (terapia de mantenimiento). Sin embargo, basado en la opinión de expertos, es común que los pacientes con tratamiento prolongando presenten falla o intolerancia a la terapia de mantenimiento. Así, en un contexto clínico, en el que un paciente presenta falla o intolerancia a la terapia de mantenimiento con voriconazol oral y posaconazol oral, la única opción disponible a nivel institucional es el itraconazol oral. Sin embargo, la Red Prestacional Sabogal ha propuesto el uso de isavuconazol oral como alternativa al tratamiento con itraconazol oral, basándose en una mayor biodisponibilidad1 y menor tasa de efectos adversos serios asociados a interacciones farmacológicas, lo que podría llevar a una mejor eficacia y seguridad comparativa. Cabe mencionar que para este grupo específico de pacientes con AI, no se disponen de datos epidemiológicos a nivel institucional. METODOLOGÍA: Se realizó una búsqueda sistemática de literatura con el objetivo de identificar evidencia sobre la eficacia y seguridad de isavuconazol oral, en comparación con itraconazol oral, en pacientes adultos con aspergilosis invasiva con falla o intolerancia a voriconazol oral y posaconazol oral, que requieren terapia de mantenimiento posterior a la terapia de inducción con anfotericina B deoxicolato. 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. La búsqueda sistemática se basó en una metodología escalonada, la cual consistió en la búsqueda inicial de estudios secundarios (tipo revisiones sistemáticas de ensayos clínicos) que respondan a la pregunta PICO, seguido de la búsqueda de estudios primarios (tipo ensayos clínicos aleatorizados). RESULTADOS: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de isavuconazol oral, en comparación con itraconazol oral, en pacientes adultos con aspergilosis invasiva con falla o intolerancia a voriconazol oral y posaconazol oral, que requieren terapia de mantenimiento posterior a la terapia de inducción con anfotericina B deoxicolato. A continuación, se describe la evidencia disponible según el orden jerárquico del nivel de evidencia o pirámide de Haynes 6S9, siguiendo lo indicado en los criterios de elegibilidad. CONCLUSIONES: El presente dictamen preliminar tuvo como objetivo evaluar la mejor evidencia sobre la eficacia y seguridad de isavuconazol oral, en comparación con itraconazol oral, en pacientes adultos con aspergilosis invasiva con falla o intolerancia a voriconazol oral y posaconazol oral, que requieren terapia de mantenimiento posterior a la terapia de inducción con anfotericina B deoxicolato. En la presente evaluación no se encontró evidencia que sustentara un mayor beneficio con isavuconazol oral en lugar de itraconazol oral en pacientes adultos con aspergilosis invasiva con falla o intolerancia a voriconazol oral y posaconazol oral, que requieren terapia de mantenimiento posterior a la terapia de inducción con anfotericina B deoxicolato. Sin embargo, se identificaron recomendaciones vigentes basadas en la opinión de expertos y la experiencia clínica que abordaron el tema en cuestión. Así, tanto en la GPC de la ATS como en DynaMed se realizaron recomendaciones a favor del uso de itraconazol oral como terapia de mantenimiento luego de la inducción con anfotericina B intravenosa (deoxicolato o liposomal). Además, en el contexto específico de falla o intolerancia a azoles orales, se identificaron recomendaciones de GPC a favor del cambio de un azol a otro en pacientes con aspergilosis tratados a largo plazo con azoles orales. Por otro lado, no se encontraron recomendaciones sobre el uso de isavuconazol oral en el contexto clínico de interés. Así, considerando la ausencia de evidencia que apoye la superioridad de isavuconazol oral sobre itraconazol oral en la población de interés, las recomendaciones de GPC a favor del uso de itraconazol oral en el contexto clínico de interés y la disponibilidad de itraconazol oral en la institución, cuyo costo es 150 veces menor que el costo de isavuconazol oral, no es posible hacer una recomendación a favor del uso de isavuconazol oral. Por lo expuesto, el IETSI no aprueba el uso de isavuconazol oral en pacientes adultos con aspergilosis invasiva con falla o intolerancia a voriconazol oral y posaconazol oral, que requieren terapia de mantenimiento posterior a la terapia de inducción con anfotericina B deoxicolato.

Burden of serious fungal infections in the Netherlands.

BACKGROUND: Fungal diseases have an ever-increasing global disease burden, although regional estimates for specific fungal diseases are often unavailable or dispersed. OBJECTIVES: Here, we report the current annual burden of life-threatening and debilitating fungal diseases in the Netherlands. METHODS: The most recent available epidemiological data, reported incidence and prevalence of fungal diseases were used for calculations. RESULTS: Overall, we estimate that the annual burden of serious invasive fungal infections in the Netherlands totals 3 185 patients, including extrapulmonary or disseminated cryptococcosis (n = 9), pneumocystis pneumonia (n = 740), invasive aspergillosis (n = 1 283), chronic pulmonary aspergillosis (n = 257), invasive Candida infections (n = 684), mucormycosis (n = 15) and Fusarium keratitis (n = 8). Adding the prevalence of recurrent vulvo-vaginal candidiasis (n = 220 043), allergic bronchopulmonary aspergillosis (n = 13 568) and severe asthma with fungal sensitisation (n = 17 695), the total debilitating burden of fungal disease in the Netherlands is 254 491 patients yearly, approximately 1.5% of the country's population. CONCLUSION: We estimated the annual burden of serious fungal infections in the Netherlands at 1.5% of the population based on previously reported modelling of fungal rates for specific populations at risk. With emerging new risk groups and increasing reports on antifungal resistance, surveillance programmes are warranted to obtain more accurate estimates of fungal disease epidemiology and associated morbidity and mortality.

Utility of CT assessment in hematology patients with invasive aspergillosis: a post-hoc analysis of phase 3 data.

BACKGROUND: Pulmonary computed tomography (CT) scans are commonly used as part of the clinical criteria in diagnostic workup of invasive fungal diseases like invasive aspergillosis, and may identify radiographic abnormalities, such as halo signs or air-crescent signs. We assessed the diagnostic utility of CT assessment in patients with hematologic malignancies or those who had undergone allogeneic hematopoietic stem cell transplantation in whom invasive aspergillosis was suspected. METHODS: This post-hoc analysis assessed data from a prospective, multicenter, international trial of voriconazole (with and without anidulafungin) in patients with suspected invasive aspergillosis (IA; proven, probable, or possible, using 2008 European Organisation for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group criteria) [NCT00531479]. Eligible patients received at least one baseline lung CT scan. RESULTS: Of 395 patients included in this post-hoc analysis, 240 patients (60.8%) had 'confirmed' proven (9/240, 3.8%) or probable (231/240, 96.3%) invasive aspergillosis (cIA) and 155 patients (39.2%) had 'non-confirmed' invasive aspergillosis (all nIA; all possible IA (de Pauw et al., Clin Infect Dis 46:1813-21, 2008)). Mean age was 52.3 and 50.5 years, 56.3 and 60.0% of patients were male, and most patients were white (71.7 and 71.0%) in the cIA and nIA populations, respectively. Median baseline galactomannan was 1.4 (cIA) and 0.2 (nIA), mean Karnofsky score was 65.3 (cIA) and 66.8 (nIA), and mean baseline platelet count was 48.0 (cIA) and 314.1 (nIA). Pulmonary nodules (46.8% of all patients), bilateral lung lesions (37.5%), unilateral lung lesions (28.4%), and consolidation (24.8%) were the most common radiographic abnormalities. Ground-glass attenuation (cIA: 24.2%; nIA: 11.6%; P < 0.01) and pulmonary nodules (cIA: 52.5%; nIA: 38.1%; P < 0.01) were associated with cIA. Other chest CT scan abnormalities (including halo signs and air-crescent signs) at baseline in patients with hematologic malignancy or hematopoietic stem cell transplantation, and suspected IA, were not associated with cIA. CONCLUSIONS: These findings highlight the limitations in the sensitivity of chest CT scans for the diagnosis of IA, and reinforce the importance of incorporating other available clinical data to guide management decisions on individual patients, including whether empirical treatment is reasonable, pending full evaluation. TRIAL REGISTRATION: NCT00531479 (First posted on ClinicalTrials.gov on September 18, 2007).

Epidemiology and treatment approaches in management of invasive fungal infections in hematological malignancies: Results from a single-centre study.

Invasive fungal infections (IFIs) are a leading cause of morbidity and attributable mortality in oncohematologic patients. Timely diagnosis is essential but challenging. Herein we retrospectively describe 221 cases of antifungal treatments (AFT) administered in a monocentric real-life cohort of hematological malignancies. Between January 2010 and July 2017, 196 oncohematologic patients were treated with AFT at our Hematology Department. Diagnosis of IFIs was carried out according to EORTC/MSG-2008 guidelines.The most represented disease was acute myeloid leukemia (104 patients). Median age was 61 years; at fever onset 177 (80%) patients had a neutrophil count<0.5x109/L. Twenty-nine (13%) patients were receiving antifungal prophylaxis (26 posaconazole, 2 fluconazole, 1 itraconazole). The incidence of AFT was 13%. Serum galactomannan antigen (GM) was positive in 20% of the tested cases, while 85% of the patients had a CT scan suggestive for IFI. Twenty-one percent of these cases had a GM positive. Sixty-five out of 196 patients (33%) showed positive culture results, in particular Candida spp. were identified in 45 isolates, while Aspergillus spp. in 16 cases. Fourteen patients presented multiple positivity. Twenty-two (10%) cases were classified as proven IFIs, 61 (28%) as probable and 81 (37%) as possible, but 57 (26%) cases could not be classified. Fifty-nine percent of the patients received single agent AFT, 37% sequential AFT, 8% a combination regimen. Liposomal-amphotericin-B was the most used AFT. IFIs attributable mortality was 20%. This epidemiologic survey underlined a persistent significant use of AFT and a high mortality rate of IFIs. We suggest that further powerful diagnostic approaches should be investigated to improve the diagnostic accuracy and potential therapeutic implication.

A strategy for designing voriconazole dosage regimens to prevent invasive pulmonary aspergillosis based on a cellular pharmacokinetics/pharmacodynamics model.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a life-threatening disease in immunosuppressed patients. Voriconazole is commonly used to prevent and treat IPA in the clinic, but the optimal prophylactic antifungal regimen is unknown. The objective of this study was to clarify the mechanism underlying how voriconazole prevents IPA based on a target cellular pharmacokinetics/pharmacodynamics model, with the aim of identifying a way to design an optimal prophylactic antifungal regimen. METHODS: A nystatin assay was used to establish a target-cells model for A. fumigatus infection. An inhibitory effect sigmoid Emax model was developed to explore the cellular PK/PD breakpoint, and Monte Carlo simulation was used to design the prophylactic antifungal regimen. RESULTS: The intracellular activity of voriconazole in the target cells varied with its concentration, with the minimum inhibitory concentration (MIC) being an important determinant. For A. fumigatus strains AF293 and AF26, voriconazole decreased the intracellular inoculum by 0.79 and 0.84 lg cfu, respectively. The inhibitory effect sigmoid Emax model showed that 84.01% of the intracellular inoculum was suppressed by voriconazole within 24 h, and that a PK/PD value of 35.53 for the extracellular voriconazole concentration divided by MIC was associated with a 50% suppression of intracellular A. fumigatus. The Monte Carlo simulation results showed that the oral administration of at least 200 mg of voriconazole twice daily was yielded estimated the cumulative fraction of response value of 91.48%. Concentration of voriconazole in the pulmonary epithelial lining fluid and the plasma of > 17.77 and > 1.55 mg/L, respectively, would ensure the PK/PD > 35.53 for voriconazole against most isolates of A. fumigatus and may will be benefit to prevent IPA in clinical applications. CONCLUSIONS: This study used a target cellular pharmacokinetics/pharmacodynamics model to reveal a potential mechanism underlying how voriconazole prevents IPA and has provided a method for designing voriconazole prophylactic antifungal regimen in immunosuppressed patients.

A Multimodal Imaging Approach Enables In Vivo Assessment of Antifungal Treatment in a Mouse Model of Invasive Pulmonary Aspergillosis.

Aspergillus fumigatus causes life-threatening lung infections in immunocompromised patients. Mouse models are extensively used in research to assess the in vivo efficacies of antifungals. In recent years, there has been an increasing interest in the use of noninvasive imaging techniques to evaluate experimental infections. However, single imaging modalities have limitations concerning the type of information they can provide. In this study, magnetic resonance imaging and bioluminescence imaging were combined to obtain longitudinal information on the extent of developing lesions and fungal load in a leukopenic mouse model of invasive pulmonary aspergillosis (IPA). This multimodal imaging approach was used to assess changes occurring within lungs of infected mice receiving voriconazole treatment starting at different time points after infection. The results showed that IPA development depends on the inoculum size used to infect animals and that disease can be successfully prevented or treated by initiating intervention during early stages of infection. Furthermore, we demonstrated that a reduction in fungal load is not necessarily associated with the disappearance of lesions on anatomical lung images, especially when antifungal treatment coincides with immune recovery. In conclusion, multimodal imaging allows an investigation of different aspects of disease progression or recovery by providing complementary information on dynamic processes, which are highly useful for assessing the efficacy of (novel) therapeutic compounds in a time- and labor-efficient manner.

Endpoint Assessment in Rabbit Models of Invasive Pulmonary Aspergillosis and Mucormycosis.

Multiple animal models have been developed to study the pathogenesis of invasive pulmonary aspergillosis, as well as to evaluate the efficacy, pharmacokinetics, and pharmacodynamics of various antifungal agents and vaccines. Each model is beneficial depending on the questions that are asked. In this chapter, we will discuss the endpoints assessment of the persistently neutropenic rabbit models of invasive pulmonary aspergillosis and invasive pulmonary mucormycosis.

A new time-dependent approach for assessment of the impact of invasive aspergillosis shows effect on short- but not on long-term survival of patients with AML or high-risk MDS.

Invasive aspergillosis (IA) has been reported to yield high mortality rates. Patients with an unfavourable prognostic haematological disease not only have a higher probability of developing IA but are also more likely to die due to causes directly related to the underlying disease. This complexity of risk mechanisms confounds the causal interpretation of IA occurrence and mortality. Full consideration of the changing patient characteristics over time is necessary to obtain reliable estimates of the correlation of IA with mortality. We studied the effect of IA on mortality in 167 consecutive patients starting with remission-induction therapy for AML or of whom most patients continued to haematopoietic stem cell transplantation (HSCT). No standard antifungal prophylaxis was administered in the period before HSCT. Survival analyses were performed to determine risk estimates of IA for different phases of treatment before and after HSCT. Time-dependent adjustment for confounding variables was performed using Cox proportional hazards models. In 55 of 167 enroled patients, IA was diagnosed. Before HSCT, adjusted hazard ratios and 95% confidence intervals on mortality after the diagnosis of IA were 3.5 (1.7-7.5), 2.0 (0.69-5.9), 2.3 (0.79-6.8) and 0.80 (0.49-1.4) within 30 days, between 30 and 60 days, between 60 and 90 days or more than 90 days, respectively. A similar pattern was observed after HSCT. The occurrence of IA did not significantly influence the decision to follow through with HSCT. The results provide new insights in short- and long-term survival of patients diagnosed with IA. A significantly increased mortality risk was only observed in the first month after diagnosis of IA. No unfavourable association with mortality was observed in the later course of treatment. The occurrence of IA did not affect the probability of attaining HSCT in our population.

Serial assessment of pulmonary lesion volume by computed tomography allows survival prediction in invasive pulmonary aspergillosis.

BACKGROUND: Serial chest CT is the standard of care to establish treatment success in invasive pulmonary aspergillosis (IPA). Data are lacking how response should be defined. METHODS: Digital CT images from a clinical trial on treatment of IPA were re-evaluated and compared with available biomarkers. Total volume of pneumonia was added up after manual measurement of each lesion, followed by statistical analysis. RESULTS: One-hundred and ninety CT scans and 309 follow-up datasets from 40 patients were available for analysis. Thirty-one were neutropenic. Baseline galactomannan (OR 4.06, 95%CI: 1.08-15.31) and lesion volume (OR 3.14, 95%CI: 0.73-13.52) were predictive of death. Lesion volume at d7 and trend between d7 and d14 were strong predictors of death (OR 20.01, 95%CI: 1.42-282.00 and OR 15.97, 95%CI: 1.62-157.32) and treatment being rated as unsuccessful (OR 4.75, 95%CI: 0.94-24.05 and OR 40.69, 95%CI: 2.55-649.03), which was confirmed by a Cox proportional hazards model using time-dependent covariates. CONCLUSION: Any increase in CT lesion volume between day 7 and day 14 was a sensitive marker of a lethal outcome (>50%), supporting a CT rescan each one and 2 weeks after initial detection of IPA. The predictive value exceeded all other biomarkers. Further CT follow-up after response at day 14 was of low additional value. KEY POINTS: • CT evaluation offers good prediction of outcome for invasive pulmonary aspergillosis. • Predictive capability exceeds galactomannan, blood counts, and lesion count. • Any progression between day 7 and day 14 constitutes a high-risk scenario.

Is a biomarker-based diagnostic strategy for invasive aspergillosis cost effective in high-risk haematology patients?

Empirical antifungal therapy is frequently used in hematology patients at high risk of invasive aspergillosis (IA), with substantial cost and toxicity. Biomarkers for IA aim for earlier and more accurate diagnosis and targeted treatment. However, data on the cost-effectiveness of a biomarker-based diagnostic strategy (BDS) are limited. We evaluated the cost effectiveness of BDS using results from a randomized controlled trial (RCT) and individual patient costing data. Data inputs derived from a published RCT were used to construct a decision-analytic model to compare BDS (Aspergillus galactomannan and PCR on blood) with standard diagnostic strategy (SDS) of culture and histology in terms of total costs, length of stay, IA incidence, mortality, and years of life saved. Costs were estimated for each patient using hospital costing data to day 180 and follow-up for survival was modeled to five years using a Gompertz survival model. Treatment costs were determined for 137 adults undergoing allogeneic hematopoietic stem cell transplant or receiving chemotherapy for acute leukemia in four Australian centers (2005-2009). Median total costs at 180 days were similar between groups (US$78,774 for SDS [IQR US$50,808-123,476] and US$81,279 for BDS [IQR US$59,221-123,242], P = .49). All-cause mortality was 14.7% (10/68) for SDS and 10.1% (7/69) for BDS, (P = .573). The costs per life-year saved were US$325,448, US$81,966, and US$3,670 at 180 days, one year and five years, respectively. BDS is not cost-sparing but is cost-effective if a survival benefit is maintained over several years. An individualized institutional approach to diagnostic strategies may maximize utility and cost-effectiveness.

Pharmacodynamics of isavuconazole in experimental invasive pulmonary aspergillosis: implications for clinical breakpoints.

OBJECTIVES: Isavuconazole, a novel triazole antifungal agent, has broad-spectrum activity against Aspergillus spp. and other pathogenic fungi. The isavuconazole exposure-response relationship in experimental invasive pulmonary aspergillosis using galactomannan index (GMI) suppression as a marker of disease clearance was explored. METHODS: The impact of exposure on GMI suppression in persistently neutropenic rabbits treated with isavuconazonium sulphate (isavuconazole-equivalent dosages of 20, 40 or 60 mg/kg every 24 h, after a 90 mg/kg loading dose) for 12 days was linked using mathematical modelling. Bridging to humans using population pharmacokinetic (PK) data from a clinical trial in invasive aspergillosis was performed using Monte Carlo simulations. RESULTS: Mean plasma isavuconazole AUC/MIC (EC50) of 79.65 (95% CI 32.2, 127.1) produced a half-maximal effect in GMI suppression. The inhibitory sigmoid Emax curve dropped sharply after an AUC/MIC of ≥30 and was near maximum (EC80) at ∼130. Bridging the experimental PK/pharmacodynamic (PD) target to human population PK data was then used to return to the rabbit model to determine a clinically relevant PD endpoint. The clinical dosing regimen used in the trial would result in a mean GMI of 4.3 ±â€Š1.8, which is a 50% reduction from the starting GMI in the experiment. CONCLUSIONS: The clinical trial results showing the non-inferiority of isavuconazole to voriconazole for all-cause mortality further support the PK-PD endpoint, thereby demonstrating the usefulness of the rabbit model and endpoint for isavuconazole and implications on interpretive breakpoints. Importantly, the analysis supports this model as an important tool for development of antifungal agents.

Longitudinal, in vivo assessment of invasive pulmonary aspergillosis in mice by computed tomography and magnetic resonance imaging.

Invasive aspergillosis is an emerging threat to public health due to the increasing use of immune suppressive drugs and the emergence of resistance against antifungal drugs. To deal with this threat, research on experimental disease models provides insight into the pathogenesis of infections caused by susceptible and resistant Aspergillus strains and by assessing their response to antifungal drugs. However, standard techniques used to evaluate infection in a preclinical setting are severely limited by their invasive character, thereby precluding evaluation of disease extent and therapy effects in the same animal. To enable non-invasive, longitudinal monitoring of invasive pulmonary aspergillosis in mice, we optimized computed tomography (CT) and magnetic resonance imaging (MRI) techniques for daily follow-up of neutropenic BALB/c mice intranasally infected with A. fumigatus spores. Based on the images, lung parameters (signal intensity, lung tissue volume and total lung volume) were quantified to obtain objective information on disease onset, progression and extent for each animal individually. Fungal lung lesions present in infected animals were successfully visualized and quantified by both CT and MRI. By using an advanced MR pulse sequence with ultrashort echo times, pathological changes within the infected lung became visually and quantitatively detectable at earlier disease stages, thereby providing valuable information on disease onset and progression with high sensitivity. In conclusion, these non-invasive imaging techniques prove to be valuable tools for the longitudinal evaluation of dynamic disease-related changes and differences in disease severity in individual animals that might be readily applied for rapid and cost-efficient drug screening in preclinical models in vivo.

Burden of serious fungal infections in Nepal.

There are few reports of serious fungal infections in Nepal though the pathogenic and allergenic fungi including Aspergillus species are common in the atmosphere. Herein, we estimate the burden of serious fungal infections in Nepal. All published papers reporting fungal infection rates from Nepal were identified. When few data existed, we used specific populations at risk and fungal infection frequencies in those populations to estimate national incidence or prevalence. Of the 27.3 M population, about 1.87% was estimated to suffer from serious fungal infections annually. We estimated the incidence of fungal keratitis at 73 per 100,000 annually. Chronic obstructive pulmonary disease is common with 215,765 cases, contributing to 1119 cases of invasive aspergillosis annually. Of 381,822 adult asthma cases, we estimated 9546 patients (range 2673-13,364) develop allergic bronchopulmonary aspergillosis and 12,600 have severe asthma with fungal sensitisation. Based on 26,219 cases of pulmonary tuberculosis, the annual incidence of new chronic pulmonary aspergillosis (CPA) cases was estimated at 1678 with a 5 year period prevalence of 5289, 80% of CPA cases. Of 22,994 HIV patients with CD4 counts <350 not on antiretrovirals, Pneumocystis pneumonia was estimated at 990 cases annually. Cases of oral and oesophageal candidiasis in HIV/AIDS patients were estimated at 10,347 and 2950, respectively. There is a significant burden of serious fungal infections in Nepal. Epidemiological studies are necessary to validate these estimates.

Pharmacodynamics of amphotericin B deoxycholate, amphotericin B lipid complex, and liposomal amphotericin B against Aspergillus fumigatus.

Amphotericin B is a first-line agent for the treatment of invasive aspergillosis. However, relatively little is known about the pharmacodynamics of amphotericin B for invasive pulmonary aspergillosis. We studied the pharmacokinetics (PK) and pharmacodynamics (PD) of amphotericin B deoxycholate (DAMB), amphotericin B lipid complex (ABLC), and liposomal amphotericin B (LAMB) by using a neutropenic-rabbit model of invasive pulmonary aspergillosis. The study endpoints were lung weight, infarct score, and levels of circulating galactomannan and (1 → 3)-ß-D-glucan. Mathematical models were used to describe PK-PD relationships. The experimental findings were bridged to humans by Monte Carlo simulation. Each amphotericin B formulation induced a dose-dependent decline in study endpoints. Near-maximal antifungal activity was evident with DAMB at 1 mg/kg/day and ABLC and LAMB at 5 mg/kg/day. The bridging study suggested that the "average" patient receiving LAMB at 3 mg/kg/day was predicted to have complete suppression of galactomannan and (1 → 3)-ß-D-glucan levels, but 20 to 30% of the patients still had a galactomannan index of >1 and (1 → 3)-ß-D-glucan levels of >60 pg/ml. All formulations of amphotericin B induce a dose-dependent reduction in markers of lung injury and circulating fungus-related biomarkers. A clinical dosage of liposomal amphotericin B of 3 mg/kg/day is predicted to cause complete suppression of galactomannan and (1 → 3)-ß-D-glucan levels in the majority of patients.

Impact and cost of the serum galactomannan assay at a tertiary care facility.

BACKGROUND: Invasive aspergillosis carries a high mortality with a rising prevalence in immunocompromised hosts. Diagnosis of invasive aspergillosis is challenging and delays in treatment are associated with poor outcomes. The galactomannan assay (GM), a non-culture-based surrogate marker of fungal infection, is widely used in diagnosis. It is unknown whether this assay impacts clinical decision making. We evaluated whether GM testing results in earlier initiation of antifungal therapy and is cost effective. METHODS: We carried out a retrospective review of the electronic medical records of all patients undergoing GM at a 907-bed tertiary-care general hospital from July 11, 2011, to June 12, 2012. Records of patients with a positive GM were individually reviewed to determine the timing of the assay result, presence and timing of relevant culture data, whether BAL GM was performed, radiology data consistent with invasive aspergillosis, and the timing of initiation of antifungal therapy. For each case, it was determined whether GM results impacted the decision to initiate antifungal therapy. RESULTS: Forty-six nonduplicate GM samples were positive (>0.5) of 1419 performed. Results were considered to be false positives in 18 cases by care teams. In 21 cases, antifungal therapy was initiated before the assay result based on clinical suspicion, culture data, and/or radiology. The serum GM was performed 164 times at a cost of $21,789 for a single positive result effecting modification of patient care. CONCLUSION: Serum GM testing at a tertiary-care institution is commonly used but infrequently impacts clinical decision making with major financial burden.