Invasive Mould Diseases Research Articles

Isavuconazole for Treating Invasive Mould Disease in Solid Organ Transplant Recipients.

Solid organ transplant (SOT) recipients have a higher risk of developing invasive mould diseases (IMD). Isavuconazole is a novel broad-spectrum azole active against Aspergillus spp. and Mucor, well tolerated, with an excellent bioavailability and predictable pharmacokinetics, that penetrates in most tissues rapidly, and has few serious adverse effects, including hepatic toxicity. Contrary to other broad-spectrum azoles, such as voriconazole and posaconazole, isavuconazole appears to show significant smaller drug-drug interactions with anticalcineurin drugs. We have performed an extensive literature review of the experience with the use of isavuconazole in SOT, which included the SOTIS and the ISASOT studies, and published case reports. More than 140 SOT recipients treated with isavuconazole for IMD were included. Most patients were lung and kidney recipients treated for an Aspergillus infection. Isavuconazole was well tolerated (less than 10% of patients required treatment discontinuation). The clinical responses appeared comparable to that found in other high-risk patient populations. Drug-drug interactions with immunosuppressive agents were manageable after the reduction of tacrolimus and the adjustment of mTOR inhibitors at the beginning of treatment. In conclusion, isavuconazole appears to be a reasonable option for the treatment of IMD in SOT. More clinical studies are warranted.

Atypical imaging patterns during lung invasive mould diseases: lessons for clinicians.

Imaging of pulmonary invasive mould diseases (IMDs), which represents a cornerstone in their work-up, is mainly based on computed tomography (CT). The purpose of this review is to discuss their CT features, mainly those related to aspergillosis and mucormycosis. We will especially focus on atypical radiological presentations that are increasingly observed among non-neutropenic emerging populations of patients at risk, such as those receiving novel anticancer therapies or those in the intensive care unit. We will also discuss the interest of other available imaging techniques, mainly positron emission tomography/CT, that may play a role in the diagnosis as well as evaluation of disease extent and follow-up. We will show that any new airway-centred abnormality or caveated lesion should evoke IMDs in mildly immunocompromised hosts. Limitations in their recognition may be due to potential underlying abnormalities that increase the complexity of interpretation of lung imaging, as well as the non-specificity of imaging features. In this way, the differentials of all morphological/metabolic aspects must be kept in mind for the optimal management of patients, as well as the benefit of evaluation of the vascular status.

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.

BackgroundInvasive 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.ObjectivesTo estimate the cost‐effectiveness of isavuconazole vs voriconazole for the treatment of adult patients with possible IA prior to differential pathogen diagnosis, in Spain.MethodsA 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.ResultsIn 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.ConclusionsIsavuconazole 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.

European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European Conference on Infections in Leukaemia.

The European Conference on Infections in Leukaemia (ECIL) updated its guidelines on antifungal prophylaxis for adults using the grading system of IDSA. The guidelines were extended to provide recommendations for other haematological diseases besides AML and recipients of an allogeneic haematopoietic stem cell transplantation (HSCT). Posaconazole remains the drug of choice when the incidence of invasive mould diseases exceeds 8%. For patients undergoing remission-induction chemotherapy for AML and myelodysplastic syndrome (MDS), fluconazole can still offer an alternative provided it forms part of an integrated care strategy that includes screening with biomarkers and imaging. Similarly, aerosolized liposomal amphotericin B combined with fluconazole can be considered for patients at high risk of invasive mould diseases but other formulations of the polyene are discouraged. Fluconazole is still recommended as primary prophylaxis for patients at low risk of invasive mould diseases during the pre-engraftment phase of allogeneic HSCT whereas only a moderate recommendation could be made for itraconazole, posaconazole and voriconazole for patients at high risk. Posaconazole is strongly recommended for preventing invasive mould disease post-engraftment but only when graft-versus-host disease (GvHD) was accompanied by other risk factors such as its severity, use of an alternative donor or when unresponsive to standard corticosteroid therapy. The need for primary prophylaxis for other patient groups was less clear and should be defined by the estimated risk of invasive fungal disease (IFD).

Changes in the epidemiological landscape of invasive mould infections and disease.

Although a wide variety of pathogens are associated with invasive mould diseases, Aspergillus spp. have historically been one of the most common causative organisms. Most invasive mould infections are caused by members of the Aspergillus fumigatus species complex and an emerging issue is the occurrence of azole resistance in A. fumigatus, with resistance to amphotericin B documented in other Aspergillus spp. The epidemiology of invasive fungal disease has shifted in recent years as non-A. fumigatus Aspergillus spp. and other moulds have become progressively more important, although there are no consolidated data on the prevalence of less common species of moulds. The incidence of mucormycosis may have been underestimated, which is a potential concern since species belonging to the order Mucorales are more resistant to antifungal agents than Aspergillus spp. All species of Mucorales are unaffected by voriconazole and most show moderate resistance in vitro to echinocandins. Fusarium spp. may be the second most common nosocomial fungal pathogen after Aspergillus in some tertiary hospitals, and show a susceptibility profile marked by a higher level of resistance than that of Aspergillus spp. Recently, Scedosporium aurantiacum has been reported as an emerging opportunistic pathogen, against which voriconazole is the most active antifungal agent. Other mould species can infect humans, although invasive fungal disease occurs less frequently. Since uncommon mould species exhibit individual susceptibility profiles and require tailored clinical management, accurate classification at species level of the aetiological agent in any invasive fungal disease should be regarded as the standard of care.

New pharmacological opportunities for the treatment of invasive mould diseases.

Recently, several randomized studies have been published that will shape treatment decisions in the prevention and management of invasive mould infections. Liposomal amphotericin B is an option for empirical or targeted treatment of invasive aspergillosis or mucormycosis, but for prophylaxis therapy, the triazole class now predominates. The triazole voriconazole is currently regarded as a drug of choice for the treatment of proven or probable invasive aspergillosis, and has shown significantly higher response rates than amphotericin B deoxycholate in this setting, with fewer severe drug-related adverse events. Isavuconazole, the newest triazole agent, offers the advantages of once-daily dosing, a wider spectrum of antifungal activity than voriconazole, predictable pharmacokinetics and fewer CYP enzyme-mediated drug interactions. A recent large randomized clinical trial showed mortality to be similar under isavuconazole or voriconazole in patients with invasive mould disease, with fewer drug-related adverse events in isavuconazole-treated patients. Another study has indicated that isavuconazole is also effective in mucormycosis infections but patient numbers were small and confirmation is awaited. Experimental studies combining different drug classes with antimould activity have been promising, but the clinical database is limited. A large randomized trial of combination therapy compared voriconazole plus the echinocandin anidulafungin versus voriconazole monotherapy in patients with invasive aspergillosis. Results showed the overall response rate to be similar, but combination therapy improved survival for the subpopulation of patients in whom the diagnosis was confirmed by serum and/or bronchoalveolar lavage fluid galactomannan positivity. This active field of research is likely to continue evolving rapidly in the coming years.

Isavuconazole: A Review in Invasive Aspergillosis and Mucormycosis.

Isavuconazole is a second-generation triazole with activity against a broad spectrum of clinically important fungi. Its water-soluble prodrug, isavuconazonium sulfate (Cresemba®), available in interchangeable intravenous and oral formulations, is approved in the USA and EU for the treatment of adults with invasive aspergillosis and mucormycosis. In international phaseIII clinical trials, isavuconazole was efficacious and generally well tolerated in the treatment of these life-threatening diseases. In the phaseIII SECURE trial, isavuconazole was non-inferior to voriconazole for the primary treatment of invasive mould disease (primarily aspergillosis) and was associated with fewer drug-related treatment-emergent adverse events (TEAEs) than voriconazole. In addition, the single-arm, phaseIII VITAL trial and a matched case-control analysis of isavuconazole- versus amphotericinB-treated patients provided evidence of the efficacy of isavuconazole in the treatment of mucormycosis. The most commonly reported TEAEs among isavuconazole recipients were gastrointestinal disorders such as nausea, vomiting and diarrhoea. Isavuconazole has several other attributes that make it a useful new treatment option for these invasive mould diseases, including predictable pharmacokinetics, excellent bioavailability, no food effect with the oral formulation, and its potential utility in renally impaired patients given the absence of cyclodextrin in the intravenous formulation.

Care pathways for managing invasive mould diseases

In the last decade, there have been some favourable developments in the management of invasive fungal diseases, including definitions, diagnosis and drugs for treatment. This has led to a gradual awareness that caring for patients at risk need not solely rely on an empirical therapy approach but that a degree of individualisation is possible, provided certain prerequisites are met.

Invasive mould disease involving the gastrointestinal tract caused by Neosartorya pseudofischeri in a haematological patient

Invasive mould diseases (IMD) are serious, life-threatening complications in immunocompromised hosts. Patients with acute myeloid leukaemia (AML) as well as those after allogeneic bone marrow transplantation represent the highest risk group, with an IMD incidence of approximately 10%. Invasive aspergillosis (IA) is the most frequent type and represents 96% of all IMD cases. The incidence of IA in this high-risk group of patients is 10% and the mortality is 30–40%.1 In more than 90% of IA cases, the lungs are affected or the disease is disseminated. Importantly, isolated gastrointestinal involvement is very uncommon.2 Molecular techniques have been used in the diagnosis and identification of mould diseases and new fungal species morphologically similar to Aspergillus fumigatus have been described. The Aspergillus section Fumigati now includes anamorphic Aspergillus species and teleomorphic Neosartorya species. Neosartorya spp. is a filamentous fungus that is commonly found in soil throughout the world. Invasive mould infections caused by Neosartorya spp. have very rarely been described in literature.

Breakthrough invasive mould infections in patients treated with caspofungin

To describe and estimate the rate of breakthrough invasive mould diseases (IMD) in patients receiving caspofungin. Retrospective, non-interventional study conducted in three University Hospitals. Nineteen breakthrough infections have been identified including 13 aspergillosis, 2 mucormycosis, a fusariosis, a Hormographiella aspergillata infection and 2 possible IMD. Cases were equally distributed between the centres. Fourteen patients had a haematologic malignancy, four were transplant recipients (allogeneic haematopoietic stem cells in three, liver in one) and one had hepatic cirrhosis. Caspofungin has been prescribed as prophylaxis (n=3), empirical therapy (n=9) or directed therapy for candidemia (n=5) or aspergillosis (n=2). Aspergillus galactomannan was positive in serum or in bronchoalveolar lavage fluid in 10 of the 13 aspergillosis. Median duration of caspofungin treatment before breakthrough IMD was 15 days. Nine patients died within twelve weeks. Rate of breakthrough IMD in onco-haematology patients has been estimated to 7.3% for all mould infections and to 4.2% when restricted to documented aspergillosis. Our data call for Aspergillus galactomannan monitoring and close clinical and radiological examination in case of persistence or recurrence of infection signs in high-risk patients receiving caspofungin.

Guidelines for the prevention of invasive mould diseases caused by filamentous fungi by the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC)

Invasive fungal infections (IFIs) caused by filamentous fungi still have high rates of mortality, associated with difficulties in early detection of the infection and therapeutic limitations. Consequently, a useful approach is to prevent patients at risk of fungal infection from coming into contact with conidia of Aspergillus and other mould species. This document describes the recommendations for preventing IFI caused by filamentous fungi worked out by Spanish experts from different medical and professional fields. The article reviews the incidence of IFI in different risk populations, and questions related to environmental measures for prevention, control of hospital infections, additional procedures for prevention, prevention of IFI outside of hospital facilities and antifungal prophylaxis are also analysed.

Systematic review and mixed treatment comparison of randomized evidence for empirical, pre-emptive and directed treatment strategies for invasive mould disease

Randomized controlled trials (RCTs) provide the most reliable estimates of the effects of treatments. However, not all treatments are compared in available RCTs, making comparison of treatments problematic. Mixed treatment comparisons (MTCs) can provide estimates of the comparative effects of treatments across a range of available therapeutic options. MTCs use networks of available direct comparisons to estimate differences in treatments that have not been estimated in trials via a common comparator. We conducted a systematic review and MTCs of comparative RCTs in haematological patients of anti-mould active agents used for the empirical treatment of febrile neutropenia (Analysis 1), and pre-emptive therapy (Analysis 2) of invasive mould diseases. In addition, we summarized the evidence available associated with the use of directed treatment strategies (Analysis 3). For empirical therapy, caspofungin proved superior to amphotericin B, liposomal amphotericin B, amphotericin B lipid complex and voriconazole in the outcome of survival, but no agents showed superiority for treatment response. There was no evidence of a difference between pre-emptive and empirical strategies on mortality outcomes. For directed therapy, voriconazole was superior to amphotericin B for overall survival, and both voriconazole and liposomal amphotericin B were superior to amphotericin B and amphotericin B colloidal dispersion on the outcome of response. While limited to some degree by the availability of RCTs, the MTCs reported here provide the best available evidence of relative therapeutic success for different available treatment strategies.

Optimizing management of invasive mould diseases

We describe an integrated care pathway (ICP) for the optimal management of invasive mould disease (IMD). The ICP is for use by health professionals involved in the care of patients with haematological malignancies and haematopoietic stem cell transplant recipients who are at increased risk of IMD. The ICP is not intended for use in other patient groups where the evidence base is more limited. The ICP involves the patient and their carers, as well as describing the roles and the complex interaction of healthcare professionals in different departments. Therefore, the management of IMD as described in the ICP must be appropriate for the overall organization, and will be dependent on the facilities [e.g. high-efficiency particulate air (HEPA) filtration] and services available. The ICP deals with risk stratification, diagnostic tests, prophylactic and treatment strategies and how to incorporate these into the ICP. Outpatient drug management after hospital discharge and cessation of therapy are outlined. Local implementation of this ICP will vary from centre to centre: the ICP is a generic template for guidance indicating the requirements for optimal IMD management and as such provides a standard against which local practice can be audited. For clinical governance, to minimize variation in practice and, ultimately, to improve patient outcomes, each centre should regularly monitor and document compliance with the local ICP, from provision of patient information, appropriate prescribing and diagnostic investigation to clinical outcomes.

Infection Control Measures to Prevent Invasive Mould Diseases in Hematopoietic Stem Cell Transplant Recipients

Invasive mould diseases, particularly aspergillosis, are important causes of morbidity and mortality in allogeneic stem cell transplant recipients. Mould spores are ubiquitous in the environment. Guidelines established by the Centers for Disease Control (CDC) and other authoritative organizations focus on approaches to reduce exposure to mould spores. These recommendations include avoidance of areas and activities expected to result in high levels of mould spores (e.g., construction, gardening) and use of specially designed units (protected environments) where additional standards (e.g., HEPA-filtered rooms) are in place to minimize mould exposure. These recommendations are based on consensus criteria and limited clinical data largely derived from single-center retrospective studies. In addition, highly immunocompromised stem cell transplant recipients are commonly managed as outpatients, where engineering standards of the inpatient protected environment are not feasible. In the absence of an outbreak with an identified environmental source (e.g., a contaminated air vent), it is not possible to reliably distinguish community-acquired from nosocomial aspergillosis. Adherence to infection control guidelines, acknowledging their limitations, combined with evidence-based targeted antifungal prophylaxis for the highest risk transplant recipients, is likely to be the most effective approach to prevent invasive mould diseases.