Management Of Invasive Aspergillosis Research Articles

Low specificity of Aspergillus spp. ELITe MGB assay, and potential risks in management of invasive aspergillosis

ObjectivesIn recent years, commercial molecular tools for diagnosis of invasive aspergillosis have emerged, requiring evaluation to ensure quality. Here we assessed the specificity of Aspergillus spp.-ELITe MGB Assay a commercial assay tergeting 18S gene of Aspergillus spp. Design and methodsAs part of a method validation, we evaluate the specificity of the Aspergillus spp.-ELITe MGB Assay by testing fourteen culture based samples of sequenced non-Aspergillus fungal species. The benefits of a pre-lysis treatment was evaluated in parallel on serial dilutions of an Aspergillus fumigatus strain. ResultsOur findings revealed cross-reactivity in five strains using the 50 copies/mL cut-off recommended by the manufacturer, suggesting potential diagnostic errors and inappropriate management of patients. Pre-lysis treatment does not affect the limit of detection at serial dilution. ConclusionsIn conclusion, the Aspergillus spp. ELITe MGB Assay exhibits limited specificity in culture-based samples, underscoring the importance of careful utilization in laboratories. Further studies are warranted to better comprehend of the impact of this cross-reactivity on clinical samples.

Voriconazole-syringic acid co-crystals reduced voriconazole-induced hepatotoxicity: In vitro and in vivo studies

Voriconazole (VOR) is recommended for the management of Invasive Aspergillosis. However, hepatotoxicity is one of the most common adverse-effects of VOR. Therefore, the current study explored solid-phase modification of VOR by co-crystallization with hepatoprotective co-former, namely, syringic acid (SYR) to address hepatotoxicity concerns. The co-former was selected based on Molecular complementarity and Hydrogen bond propensity via the Mercury 2.0 software and based on Δpka rule. Consequently, the anti-solvent crystallization method was used to generate the VOR-SYR (2:1) co-crystals. Various analytical and spectral techniques were used to characterize co-crystals. The change in endotherm of VOR-SYR (2:1) co-crystal to the lower value (112.08 °C) than VOR (131.1 °C) and SYR (209 °C) indicated the possibility of a new solid form co-crystal. The alterations in characteristic peaks in the powder x-ray diffraction pattern confirmed the synthesis of VOR-SYR (2:1) co-crystals. The FT-IR (Fourier-Transforms Infrared) spectroscopy results revealed the generation of a new peak at 3470 cm−1 and the reduced intensity of peak observed at 3197 cm−1 for VOR-SYR (2:1) co-crystals. This suggested the formation of inter molecular hydrogen bonds. The solubility of the VOR-SYR co-crystals was similar to that of the pure drug. Dissolution of the VOR-SYR (2:1) co-crystals demonstrated 99.41% ± 2.58% release in 1 h, whereas the VOR displayed 100.28 ± 1.26% release in 4 h. The in vivo study revealed a significant decrease in hepatotoxicity in the C57bL/6 mice treated with VOR-SYR (2:1) co-crystals (∼40 mg kg−1/day) as compared to VOR (40 mg kg−1/day) treated mice. The reduction in hepatoxicity post administration of VOR-SYR (2:1) co-crystals may be attributed to slow down of metabolism owing to critical role of pyrimidine ring of VOR in co-crystal synthesis in addition to hepatoprotective, antioxidant and anti-inflammatory mechanisms of SYR. Thus, the VOR-SYR (2:1) co-crystals may be a potential dosage form for further pharmacodynamic analysis in experimental Invasive Aspergillosis infection.

Diagnosis and Treatment of Invasive Aspergillosis Caused by Non-fumigatus Aspergillus spp.

With increasing frequency, clinical and laboratory-based mycologists are consulted on invasive fungal diseases caused by rare fungal species. This review aims to give an overview of the management of invasive aspergillosis (IA) caused by non-fumigatus Aspergillus spp.-namely A. flavus, A. terreus, A. niger and A. nidulans-including diagnostic and therapeutic differences and similarities to A. fumigatus. A. flavus is the second most common Aspergillus spp. isolated in patients with IA and the predominant species in subtropical regions. Treatment is complicated by its intrinsic resistance against amphotericin B (AmB) and high minimum inhibitory concentrations (MIC) for voriconazole. A. nidulans has been frequently isolated in patients with long-term immunosuppression, mostly in patients with primary immunodeficiencies such as chronic granulomatous disease. It has been reported to disseminate more often than other Aspergillus spp. Innate resistance against AmB has been suggested but not yet proven, while MICs seem to be elevated. A. niger is more frequently reported in less severe infections such as otomycosis. Triazoles exhibit varying MICs and are therefore not strictly recommended as first-line treatment for IA caused by A. niger, while patient outcome seems to be more favorable when compared to IA due to other Aspergillus species. A. terreus-related infections have been reported increasingly as the cause of acute and chronic aspergillosis. A recent prospective international multicenter surveillance study showed Spain, Austria, and Israel to be the countries with the highest density of A. terreus species complex isolates collected. This species complex seems to cause dissemination more often and is intrinsically resistant to AmB. Non-fumigatus aspergillosis is difficult to manage due to complex patient histories, varying infection sites and potential intrinsic resistances to antifungals. Future investigational efforts should aim at amplifying the knowledge on specific diagnostic measures and their on-site availability, as well as defining optimal treatment strategies and outcomes of non-fumigatus aspergillosis.

Voriconazole in the treatment of invasive aspergillosis of orbit

BackgroundThe aim of the study was to evaluate the outcomes of voriconazole in terms of functional recovery and response on imaging in the management of invasive aspergillosis of orbit. MethodsThis was a prospective non-comparative interventional study. Diagnosed cases of invasive orbital aspergillosis were studied in a tertiary care hospital. Intravenous voriconazole followed by oral treatment was given. Sinus debridement was done, where needed. The response to treatment was assessed clinically and on radiology. ResultsA total of 10 diagnosed cases of invasive orbital aspergillosis were studied. Nine cases (90%) occurred in immunocompetent patients. Predisposing sinus infection was seen in 8 patients (80%). The most common presenting complaint was the protrusion of eye. On voriconazole treatment, there was a statistically significant improvement in vision and extraocular movements from first week onwards (p = 0.01 and p = 0.02, respectively) and reduction in proptosis from second week onwards (p = 0.003). Imaging was done at three months follow-up which revealed a good response to treatment in 90% of patients. All patients tolerated the drug well except one who had transient hepatic dysfunction. The mean follow-up was 5.8 months (range: 3–12 months). There was no recurrence of disease till the last follow-up. ConclusionInvasive orbital aspergillosis commonly presents as sino-orbital disease, mostly in immunocompetent adult patients. Voriconazole is a safe and effective drug with good short-term clinical outcome.

New Perspectives on Antimicrobial Agents: Isavuconazole.

Isavuconazole is the newest of the clinically available advanced generation triazole antifungals and is active against a variety of yeasts, molds, and dimorphic fungi. Its current FDA-approved indications include the management of invasive aspergillosis as well as mucormycosis, though the latter indication is supported by limited clinical data. Isavuconazole did not achieve noninferiority to caspofungin for the treatment of invasive candidiasis and therefore lacks an FDA-approved indication for this invasive disease. Significant advantages of isavuconazole, primarily over voriconazole but in some circumstances posaconazole as well, make it an appealing option for the management of complex patients with invasive fungal infections. These potential advantages include lack of QTc interval prolongation, more predictable pharmacokinetics, a less complicated drug interaction profile, and improved tolerability, particularly when compared to voriconazole. This review discusses these topics in addition to addressing the in vitro activity of the compound against a variety of fungi and provides insight into other distinguishing factors among isavuconazole, voriconazole, and posaconazole. The review concludes with an opinion section in which the authors provide the reader with a framework for the current role of isavuconazole in the antifungal armamentarium and where further data are required.

Efficacy and safety of Isavuconazole for the treatment of invasive Aspergillus infection - an update of the literature

ABSTRACT Introduction Invasive aspergillosis is associated with high morbidity and mortality in immunocompromised patients. It is now increasingly reported in critically ill patients, including those with respiratory viral infections, such as influenza and COVID-19. Antifungal management is challenging due to diagnostic delay, adverse drug reactions, drug–drug interactions, narrow therapeutic window, and the emergence of resistance. Isavuconazole is the most recent FDA approved azole for the treatment of invasive aspergillosis, with data continuing to accumulate. Areas covered The authors review the safety and efficacy of isavuconazole in the management of invasive aspergillosis based on the currently available evidence. The authors also report on the structure, mechanism of action, pharmacokinetic properties, in vitro and in vivo studies as well as clinical safety and efficacy reports of isavuconazole since its FDA approval. Expert opinion Isavuconazole is non-inferior to voriconazole and is a safe, effective, and better tolerated option for the treatment of invasive aspergillosis. It offers several advantages over other antifungal agents, including having a better adverse event profile with respect to hepatotoxicity, neuro-visual toxicity, QTc prolongation, as well as a stable pharmacokinetic profile obviating the need for therapeutic drug monitoring. Further studies are needed to evaluate its performance in prophylaxis against invasive aspergillosis as well as in the treatment of aspergillosis in critically ill patients without underlying cancer or transplant.

Consensus guidelines for the diagnosis and management of invasive aspergillosis, 2021.

Invasive aspergillosis (IA) in haematology/oncology patients presents as primary infection or breakthrough infection, which can become refractory to antifungal treatment and has a high associated mortality. Other emerging patient risk groups include patients in the intensive care setting with severe respiratory viral infections, including COVID-19. These guidelines present key diagnostic and treatment recommendations in light of advances in knowledge since the previous guidelines in 2014. Culture and histological-based methods remain central to the diagnosis of IA. There is increasing evidence for the utility of non-culture methods employing fungal biomarkers in pre-emptive screening for infection, as well as for IA diagnosis when used in combination. Although azole resistance appears to be uncommon in Australia, susceptibility testing of clinical Aspergillus fumigatus complex isolates is recommended. Voriconazole remains the preferred first-line antifungal agent for treating primary IA, including for extrapulmonary disease. Recommendations for paediatric treatment broadly follow those for adults. For breakthrough and refractory IA, a change in class of antifungal agent is strongly recommended, and agents under clinical trial may need to be considered. Newer immunological-based imaging modalities warrant further study, while surveillance for IA and antifungal resistance remain essential to informing the relevance of current treatment recommendations.

Efficacy of Ebselen Against Invasive Aspergillosis in a Murine Model.

Invasive aspergillosis is one of the major causes of morbidity and mortality among invasive fungal infections. The search for new antifungal drugs becomes imperative when existing drugs are not able to efficiently treat these infections. Ebselen, is an organoselenium compound, already successfully approved in clinical trials as a repositioned drug for the treatment of bipolar disorder and prevention of noise-induced hearing loss. In this study, we aimed to reposition ebselen for the treatment of invasive aspergillosis by showing ebselen effectiveness in a murine model. For this, BALB/c mice were immunosuppressed and infected systemically with Aspergillus fumigatus. Animals were divided and treated with ebselen, voriconazole, or drug-free control, for four days. The kidneys were used for CFU count and, histopathological and cytokine analysis. Ebselen was able to significantly reduce the fungal burden in the kidneys of infected mice with efficacy comparable with voriconazole treatment as both had reductions to the same extent. The absence of hyphae and intact kidney tissue structure observed in the histopathological sections analyzed from treated groups corroborate with the downregulation of IL-6 and TNF. In summary, this study brings for the first time in vivo evidence of ebselen efficacy against invasive aspergillosis. Despite these promising results, more animal studies are warranted to evaluate the potential role of ebselen as an alternative option for the management of invasive aspergillosis in humans.

A case series of non-valvular cardiac aspergillosis in critically ill solid organ transplant and non-transplant patients and systematic review.

Non-valvular cardiac aspergillosis is a rare infection of the pericardium, myocardium or endocardium and is associated with a high mortality. There is a paucity of reports of non-valvular cardiac aspergillosis in critically ill and solid organ transplant (SOT) patients. The majority of cases have been reported in haemato-oncology patients, some of whom have undergone a bone marrow transplant. We describe four cases affected by non-valvular cardiac aspergillosis in the intensive care setting including a systematic review of this extremely rare infection which is associated with high mortality. All four-patients died but presented with varying clinical, radiological and microbiological evidence of the disease. Three patients presented following complications after solid organ transplantation, two in the context of acute liver failure and emergency liver transplant and one several years after a double lung transplant. The last patient presented with necrotising gall stone pancreatitis, multi-organ failure and subsequently a prolonged intensive care unit (ICU) stay. On review of the literature, January 1955 to July 2019, 45 cases were identified, with different risk factors, clinical and radiological manifestations, treatment regimen and outcome. Antemortem diagnosis of cardiac aspergillosis is difficult and rare, with no cases reporting positive blood culture results. Galactomannan serology has poor sensitivity in solid organ transplant patients, further reduced by prophylactic antimicrobial treatment, which is common in the ICU setting especially post-transplant patients. Due to the scarcity of cases, treatment is extrapolated from invasive aspergillosis management, with emphasis on early treatment with combination therapy.

Urinary Tract Aspergillosis in a Patient With Diabetes Who Underwent Total Abdominal Hysterectomy

Urinary tract aspergillosis is uncommon even in the era of increased frequency of invasivemycoses. Experience is largely from isolated case reports and few case series or reviews.The majority of cases involve transplant recipients predominantly following renaltransplantation but is also reported in other immunocompromised states such as AIDS anduncontrolled diabetes mellitus. Most cases represent haematogenous spread to renalparenchyma, often in the absence of recognized focus of infection, presenting as small orlarge abscesses, infarcts, renal insufficiency or urinary drainage system fungal balls withobstructive uropathy. Diagnosis is usually made on the basis of renal tissue aspiration, urinecultures or by histopathology of the suspicious mass passed through urinary tract. Theeffective management of invasive aspergillosis includes strategies to optimize preventionand early antifungal treatment, immunomodulation, and, in some cases, surgery. Neweranti-Aspergillus drugs notably voriconazole offer less toxic therapeutic options and are quitesuccessful in combination with drainage measures to relieve urinary stasis. This reportdescribes a case of primary urinary tract aspergillosis with fungal bezoars formation in a 37years old female, diabetic, hypertensive, who presented with intermittent urinary tractobstruction and was successfully managed by oral voriconazole for six weeks as itraconazolewas found refractory.
 Bangladesh J Obstet Gynaecol, 2018; Vol. 33(1) : 74-77

Evaluation of the Performance of the IMMY sona Aspergillus Galactomannan Lateral Flow Assay When Testing Serum To Aid in Diagnosis of Invasive Aspergillosis.

Management of invasive aspergillosis has been improved by biomarker assays, but limited accessibility and batch testing limit the impact. Lateral flow assays (LFA) are a simple method for use outside specialist centers, provided performance is acceptable. The objective of this study was to determine the performance of the recently released IMMY sona Aspergillus LFA when testing serum samples. The study took the form of a retrospective, anonymous case/control study comprising 179 serum samples from 136 patients with invasive fungal disease, previously documented using recently revised internationally accepted definitions. The LFA was performed following the manufacturer's instructions using a cube reader to generate a galactomannan index (GMI). Performance parameters were determined, and receiver operator characteristic (ROC) analysis was used to identify an optimal threshold. Concordance with the Bio-Rad Aspergillus Ag assay (GM-EIA) was performed. At the recommended positivity threshold (GMI ≥ 0.5), LFA sensitivity and specificity were 96.9% (31/32) and 98% (98/100), respectively. ROC analysis confirmed the optimal threshold and generated an area under the curve of 0.9919. Qualitative agreement between LFA and GM-EIA was 89.0%, generating a Kappa statistic of 0.698, representing good agreement, with most discordance arising due to false-negative GM-EIA samples that were positive by LFA. The median GMI generated by the LFA was significantly greater than that generated by the GM-EIA. The IMMY sona Aspergillus LFA, when used with a cube reader, provides a rapid alternative to the well-established GM-EIA, potentially detecting more GM epitopes and enhancing sensitivity.

Surgical Management of an Aspergillus Empyema in a 3-Year-Old Child

Aspergillus empyema in nonimmunocompromised children is rare. A case of surgical management of invasive aspergillosis in a previously healthy 3-year-old child is presented. The patient was initially admitted to a hospital with severe respiratory deterioration and clinical instability, originally attributed to sepsis. After surgical intervention and the diagnosis of invasive aspergillosis, intravenous therapy with voriconazole was initiated. During postoperative care, the patient's condition remained stable with mild functional respiratory deficits. The diagnosis and treatment of Aspergillus empyema remains challenging, especially in cases that the recognition of aspergillosis is delayed and urgent surgical management of the empyema is required due to rapid clinical deterioration of the patient. The early initiation, prolonged administration, and close monitoring of high-dose antifungal treatment are highly recommended.

First azole-resistant Aspergillus fumigatus isolates with the environmental TR46 /Y121F/T289A mutation in Iran.

SummaryBackgroundAzole resistance in Aspergillus fumigatus is an emerging problem and reported from all continents. As triazole antifungals are the mainstay of therapy in the management of invasive aspergillosis, azole‐resistant A fumigatus has become a major medical concern and with complicated clinical management.ObjectiveScreening of environmental presence of azole‐resistant A fumigatus in Iran.MethodsCompost from Northern Iran, collected between 2017 and 2018, was screened for the presence of azole‐resistant A fumigatus with azole‐containing agar. Phenotypic MICs were obtained from selected, molecularly confirmed isolates. cyp51A gene sequencing and genotyping of azole‐resistant isolates were done.ResultsAmong 300 compost samples, three A fumigatus isolates had high voriconazole MICs (≥16 mg/L) and harboured the TR46/Y121F/T289A mutation in the cyp51A gene. Microsatellite typing of these isolates showed that two strains had the same allele across all nine examined microsatellite loci and were genotypically related to Indian azole‐resistant strains. The other isolate had a different genotype.ConclusionThis is the first report of A fumigatus with TR46/Y121F/T289A mutation from the region. Monitoring and surveillance of antifungal susceptibility of clinical A fumigatus is warranted in Iran and elsewhere in the region.

Prophylaxis and Treatment of Invasive Aspergillosis: Who and How of Prophylaxis, Treatment, and New Therapies

To discuss the approach to antifungal prophylaxis and treatment for invasive aspergillosis in immunocompromised patients with hematologic malignancies, hematopoietic stem cell transplant, and solid organ transplant recipients. Primary prophylaxis against Aspergillus is recommended for patients with acute myelogenous leukemia receiving remission-induction chemotherapy. Posaconazole or voriconazole are appropriate antifungal agents. A new formulation of itraconazole (SUBA-itraconazole) is an alternative option. Breakthrough infections on isavuconazole prophylaxis have been recently reported. For liver transplant recipients, targeted prophylaxis is recommended in the presence of certain risk factors. Voriconazole and isavuconazole are the preferred agents for the treatment of invasive aspergillosis. Isavuconazole, a novel extended-spectrum triazole with activity against Aspergillus and Mucorales, was found to be non-inferior compared to voriconazole. Combination of voriconazole with an echinocandin is generally not recommended. Reduction in immunosuppression is recommended as part of the management of invasive aspergillosis. The adjunctive use of interferon-γ may be considered in patients with severe or refractory disease, although a benefit has not been clearly demonstrated. The approach to prevention and treatment of invasive aspergillosis has evolved along with changes in immunosuppressive treatment and introduction of novel antifungal agents.

Molecular Mechanisms of Conidial Germination in Aspergillus spp.

Aspergilli produce conidia for reproduction or to survive hostile conditions, and they are highly effective in the distribution of conidia through the environment. In immunocompromised individuals, inhaled conidia can germinate inside the respiratory tract, which may result in invasive pulmonary aspergillosis. The management of invasive aspergillosis has become more complex, with new risk groups being identified and the emergence of antifungal resistance. Patient survival is threatened by these developments, stressing the need for alternative therapeutic strategies. As germination is crucial for infection, prevention of this process might be a feasible approach. A broader understanding of conidial germination is important to identify novel antigermination targets. In this review, we describe conidial resistance against various stresses, transition from dormant conidia to hyphal growth, the underlying molecular mechanisms involved in germination of the most common Aspergillus species, and promising antigermination targets. Germination of Aspergillus is characterized by three morphotypes: dormancy, isotropic growth, and polarized growth. Intra- and extracellular proteins play an important role in the protection against unfavorable environmental conditions. Isotropically expanding conidia remodel the cell wall, and biosynthetic machineries are needed for cellular growth. These biosynthetic machineries are also important during polarized growth, together with tip formation and the cell cycle machinery. Genes involved in isotropic and polarized growth could be effective antigermination targets. Transcriptomic and proteomic studies on specific Aspergillus morphotypes will improve our understanding of the germination process and allow discovery of novel antigermination targets and biomarkers for early diagnosis and therapy.

A positive BAL galactomannan in non-haemato-oncology patients risks harmful overtreatment.

Introduction. Evidence for the clinical utility of bronchoalveolar lavage (BAL) galactomannan in the management of fungal disease outside of haemato-oncology patients is limited.Aim. To determine how the introduction of BAL galactomannan testing impacted on the diagnosis and management of invasive aspergillosis and other fungal diseases in non-haemato-oncology patients.Methodology. Retrospective review of all adult patients (age ≥16 years) without a diagnosis of haematological malignancy who had a positive BAL galactomannan from 1 November 2014 to 30 April 2018. Using electronic patient records we obtained demographic data, clinical details, laboratory investigations, relevant radiology and antimicrobial history for each case.Results. In total, 121 episodes with a galactomannan OD index of ≥0.500 were included in the study; 29 cases (24 %) were felt to reflect fungal disease. Antifungal therapy was commenced as a direct consequence of a positive BAL galactomannan result in 13 patients where the ultimate diagnosis was subsequently considered to be non-mycological: associated medication-related side-effects in this group included deranged liver function tests (n=3), rash (n=1) and fever (n=1), related to amphotericin B (n=1) and voriconazole (n=4).Conclusion. We show that vigilance is required when interpreting galactomannan results in non-haematology patients to avoid potentially harmful overtreatment.

PS1272 A SURVEY OF PRACTICE RELATING TO THE PREVENTION AND TREATMENT OF INVASIVE FUNGAL INFECTIONS IN UK HAEMATOLOGY CENTRES

Background:Invasive fungal infections (IFIs), particularly due to Aspergillus species, are an important cause of morbidity and mortality in patients with haematological malignancies. In 2017 and 2018 the European Conference on Infections in Leukaemia (ECIL) published guidelines for both prophylaxis and treatment of IFIs in haematology patients. A previous survey of UK practice undertaken in 2010 demonstrated marked variability in practice in relation to the prevention and treatment of IFIs in this patient group, similar to what had been reported in earlier Europe‐wide surveys.Aims:The aim of the current study was to investigate whether variability in practice still exists in the UK or whether recently published guidelines have helped to standardise practice.Methods:A questionnaire was sent electronically to all members of the UKBMT pharmacists’ group. The majority of questions focused on prophylaxis and treatment of fungal infection in four clinical areas – AML induction, ALL induction, autologous stem cell transplantation (SCT) and allogeneic SCT. Further questions related to uptake of the newer azole, isavuconazole, and the use of therapeutic drug monitoring (TDM) for azoles.Results:Responses were received from 29 centres. All centres treated autologous SCT and AML/ALL patients and 25 treated allogeneic SCT patients. Seventeen centres treated adult patients only, seven were paediatric centres and five treated both adults and children. The most commonly recommended prophylactic antifungals for the four indications were:Autograft – fluconazole (59% of centres); Allograft – posaconazole (44%); AML induction – posaconazole (45%); ALL induction – lipid amphotericin (69%). There was marked variability in dosing schedules for fluconazole (50mg‐400 mg/day) and lipid amphotericin (12 different schedules ranging from 50 mg thrice weekly (TTW) to 3 mg/kg TTW) and only 69% of centres gave prophylaxis routinely to all 4 patient groups. Compared with the previous survey, itraconazole use had fallen sharply and was only used prophylactically by 38% of centres (previously 76%). Empirical therapy was recommended by 79% of centres. The criteria for starting an antifungal empirically (i.e. duration of fever unresponsive to broad spectrum antibiotics) varied from 48–120 hours. As in the previous survey, Ambisome® (at doses ranging from 1–3 mg/kg/day) was the most common empirical antifungal agent, followed by caspofungin. However, voriconazole had replaced Ambisome® as the most widely recommended first line drug for the management of invasive aspergillosis. Caspofungin, micafungin, posaconazole and IV itraconazole were only recommended in a minority of policies. Ambisome® was the most popular second line agent, being recommended in 62% of policies, followed by caspofungin (24%) and isavuconazole (17%). Twenty one centres (72%) would consider giving dual therapy. In terms of uptake of new agents, Isavuconazole was included in the antifungal policy in 34% of centres, had been used on an adhoc basis in a further 28% but had not yet been used in 38% of centres. For those centres that included the following azoles in their antifungal policies, the use of TDM was inconsistent – 76% of centres undertook TDM for voriconazole, 71% for itraconazole and 55% for posaconazole.Summary/Conclusion:Similar to the previous 2010 survey, this study showed significant variations in practice between UK haematology centres with respect to both preventing and treating invasive fungal infections. Recent guidelines in this area do not appear to have resulted in a noticeable standardisation of practice.

ESCMID-ECMM guideline: diagnosis and management of invasive aspergillosis in neonates and children

ScopePresenting symptoms, distributions and patterns of diseases and vulnerability to invasive aspergillosis (IA) are similar between children and adults. However, differences exist in the epidemiology and underlying conditions, the usefulness of newer diagnostic tools, the pharmacology of antifungal agents and in the evidence from interventional phase 3 clinical trials. Therefore, the European Society for Clinical Microbiology and Infectious Diseases (ESCMID) and the European Confederation of Medical Mycology (ECMM) have developed a paediatric-specific guideline for the diagnosis and management of IA in neonates and children. MethodsReview and discussion of the scientific literature and grading of the available quality of evidence was performed by the paediatric subgroup of the ESCMID-ECMM-European Respiratory Society (ERS) Aspergillus disease guideline working group, which was assigned the mandate for the development of neonatal- and paediatric-specific recommendations. QuestionsQuestions addressed by the guideline included the epidemiology of IA in neonates and children; which paediatric patients may benefit from antifungal prophylaxis; how to diagnose IA in neonates and children; which antifungal agents are available for use in neonates and children; which antifungal agents are suitable for prophylaxis and treatment of IA in neonates and children; what is the role of therapeutic drug monitoring of azole antifungals; and which management strategies are suitable to be used in paediatric patients. This guideline provides recommendations for the diagnosis, prevention and treatment of IA in the paediatric population, including neonates. The aim of this guideline is to facilitate optimal management of neonates and children at risk for or diagnosed with IA.

Successful outcome of disseminated mucormycosis in a 3-year-old child suffering from acute leukaemia: the role of isavuconazole? A case report

BackgroundThe use of isavuconazole is approved for the management of invasive aspergillosis and mucormycosis, only in adults, as no paediatric pharmacology studies have been reported to date. Very few paediatric cases have been published concerning the use of isavuconazole. Amphotericin B is the only antifungal agent recommended in paediatric mucormycosis, but adverse effects and especially nephrotoxicity, even with the liposomal formulation, could be problematic. In this context, the use of other antifungal molecules active on Mucorales becomes needful.Case presentationWe describe a case of mucormycosis with rapid onset dissemination in a 3-year-old girl recently diagnosed with acute lymphocytic leukaemia. She was successfully treated with isavuconazole alone and then in combination with liposomal amphotericin B. Isavuconazole therapy was guided by therapeutic drug monitoring.ConclusionsThis case offers new perspectives on the potential use of isavuconazole in children with mucormycosis, as an alternative or adjunct to liposomal amphotericin B.

Applying host disease status biomarkers to therapeutic response monitoring in invasive aspergillosis patients.

One critical factor impeding successful management of invasive aspergillosis (IA) is the lack of reliable biomarkers to assess therapeutic response. We hypothesized that changes in certain host biomarkers reflect the nature of infection status and disease progression. Upon primary IA diagnosis, these disease status biomarkers can be monitored to track response to antifungal therapy and provide early markers that prognosticate likelihood of response. Herein, we analyzed serum levels of three prominent host disease status biomarkers C-reactive protein (CRP), haptoglobin (Hp), and annexin A1 (ANXA1) in IA patients during antifungal therapy. A total of 81 serial serum samples were collected at five or six different time points relative to IA diagnosis from 15 probable IA patients (10 acute leukemia [AL] and five hematopoietic stem cell transplantation [HSCT]). Of note, different biomarker profiles were observed in AL and HSCT patients, as not only levels of markers were significantly lower in HSCT patients but also more prominent interconnections among markers were observed in AL patients. Using a composite evaluation, patients were categorized as responders, nonresponders, and stable cases at last specimen. For AL responders, typical biomarker profiles were high initially but rapidly decreased for CRP and Hp post antifungal therapy, while low initial ANXA1 values were restored to normal levels after treatment. In contrast, CRP and Hp were persistently elevated whilst ANXA1 remained low throughout therapy in AL non-responders. As a pilot proof-of-concept study, our work demonstrates the great potential of using host biomarkers to monitor early therapeutic response in leukemia patients.