Aerosolized Antifungals for the Prevention and Treatment of Invasive Fungal Infections

Invasive fungal infections result in significant morbidity and mortality, most notably in immunosuppressed patients. Aerosolized antifungal agents have been utilized primarily as prophylaxis (either alone or in combination with systemic antifungals) in patients at highest risk of invasive infections in attempts to optimize drug delivery while minimizing the potential for systemic toxicity and/or drug interactions. Published clinical experience with aerosolized antifungals most frequently involves various formulations of the polyene amphotericin B in patients undergoing lung transplantation and/or select patients with hematologic malignancy. Adverse events are infrequent and generally limited to dyspnea, dysgeusia, and cough. Existing data suggests lipid-based amphotericin B formulations may be better tolerated than amphotericin B deoxycholate. Published clinical experience with aerosolized antifungals as adjunctive treatment of invasive fungal infections is limited to case reports. Currently, there is insufficient evidence to support use of aerosolized echinocandins and azoles in clinical practice. Outstanding questions regarding comparative efficacy, optimal dose, duration and drug delivery present a continuing challenge when utilizing these agents in clinical practice.     

Invasive Fungal Infection in Primary Immunodeficiencies Other Than Chronic Granulomatous Disease

Purpose of review

We aimed to review invasive fungal infections complicating primary immunodeficiencies (PID).

Recent findings

Several PID predisposing to fungal infections were recently deciphered. CARD9 deficiency selectively predisposes to fungal infections including candidiasis, aspergillosis, deep dermatophytosis, and phaeohyphomycosis, with frequent central nervous system location, especially after Candida infection. Patients with heterozygous STAT1 gain-of-function mutations are mostly predisposed to chronic mucocutaneous candidiasis but may also display, even though less frequently, invasive fungal infections. Aspergillosis complicating STAT3 deficiency is also a major concern in patients with lung cavities. Antifungal prophylaxis is recommended in this first group of patients. Previously well-reported PID are known to predispose to fungal infections, such as genetic defects impairing the IL-12/IFN-γ axis can predispose to cryptococcosis, and dimorphic fungal infections.

Summary

Patients developing invasive fungal infections including candidiasis, aspergillosis, cryptococcosis, phaeohyphomycosis, pneumocystosis, or disseminated infections caused by dimorphic fungi, without known underlying risk factors, should be explored immunogenetically in order to diagnose primary immunodeficiencies, even in the absence of previous other infectious episodes.

     

Combination Therapy for Invasive Fungal Infections

The purpose of this review is to summarize and evaluate relevant literature on combination antifungal therapy for invasive fungal infections (IFIs). Cryptococcal meningitis has the largest body and highest quality in support of combination therapy with amphotericin B and flucytosine. More recent data in treatment of invasive aspergillosis suggest combination therapy with voriconazole and echinocandins may be effective in select patients. Quality studies are needed to define combination therapy in rare mold infections. Multiple strategies have been employed to optimize treatment of the growing incidence of IFIs. With exceptions as noted above, justification for the use of combination antifungal therapy is most often based on uncontrolled and/or underpowered studies, in vitro data, and case reports.     

Successful Treatment of Invasive Fungal Infection Due to Highly Resistant Aspergillus calidoustus in an Allogeneic Hematopoietic Cell Transplant Recipient

Invasive aspergillosis (IA) is the most common invasive fungal infection following a hematopoietic cell transplant, with emerging cryptic species exhibiting resistance to commonly used antifungals such as azoles. These species have been increasingly found after the introduction of anti-mold prophylaxis. We report a case of a 56-year-old female with primary myelofibrosis whose allogeneic hematopoietic cell transplant was complicated by disseminated fungal infection (skin, lung) due to Aspergillus calidoustus, a cryptic specie. Treatment of Aspergillus species remains challenging as these cryptic species are usually resistant to azoles including voriconazole which is the first line of treatment of IA. Infection was successfully treated with surgical excision and combination antifungal therapy based on in vitro susceptibility and synergy testing. Therapy included isavuconazole, a drug that has been shown to be non-inferior to voriconazole in the treatment of invasive mold infections.

     

Nucleic Acid Tools for Invasive Fungal Disease Diagnosis

Current Fungal Infection Reports - This review has incorporated the knowledge and experience of the leads of each of the laboratory working parties of the fungal PCR initiative in order to provide...     

中枢神经系统真菌感染的诊断与治疗

分析中枢神经系统真菌感染患者的临床特征、预后及其影响因素。收集我院2001年1月至2009年12月收治的42例中枢神经系统真菌感染患者的临床资料,对患者的诊断与误诊、实验室和病原学检查、治疗与预后等进行回顾性统计分析。42例患者中合并其他疾病者29例,占69.0%;首诊误诊32例,占76.2%。两性霉素B(AmpB)治疗者25例,其中6例在疾病早期联合5-氟胞嘧啶治疗,15例单用氟康唑治疗。治愈20例,占47.6%;好转11例,占26.2%;死亡11例,占26.2%。中枢神经系统真菌感染误诊率高,各种原因所致的免疫缺陷是引发中枢神经系统真菌感染的主要危险因素,尽早明确诊断,联合AmpB与5-FC抗真菌治疗、积极控制颅内压是降低病死率及改善预后的关键。     

Clinical Features of Fatal Pandemic Influenza A/H1N1 Infection Complicated by Invasive Pulmonary Fungal Infection

Mycopathologia - Severe pneumonia caused by influenza virus infection can be secondary to invasive pulmonary fungal (IPF) infection. This study aimed to summarize the incidence of IPF infection...     

21例淋巴瘤合并肺部侵袭性真菌感染的回顾性临床分析

摘要 目的：探讨淋巴瘤合并肺部侵袭性真菌感染( IPFI ) 的高危因素、临床特征和诊疗方案。方法：回顾性分析2019-2020年血液科收治的淋巴瘤合并IPFI患者的临床资料。结果：化疗后出现IPFI的淋巴瘤患者共计21例,总发病率为2.7%,平均年龄60岁,男性占77.8%,其中确诊5例、临床诊断7例、拟诊8例,确诊患者的病原菌为白色念珠菌（80%）和曲霉菌（20%）。肺部CT影像特征不典型,大多表现为弥漫、散在的斑片状絮样密度增高影、结节影,双肺受累多见,在接受一线抗真菌治疗后有18例患者缓解,总有效率为90.4%,其中原发病终末期患者及合并细菌感染患者死亡率高,预后差。结论：老年、男性、原发病控制不佳、高强度或大剂量化疗以及糖皮质激素的使用可能是淋巴瘤IPFI的高危因素,早期临床症状和影像学检查缺乏特异性,常规病原学检出率仍较低,1-3-β-D-葡聚糖试验（G试验）、半乳甘露聚糖试验（GM试验）结合肺部CT检查有助于早期诊断,一线抗真菌药物的使用可显著改善患者预后。     

Lateral-Flow Device for Diagnosis of Fungal Infection

Invasive aspergillosis (IA) is a life-threatening complication of haematological malignancy and haematopoietic stem cell transplantation caused by the ubiquitous fungus Aspergillus. Current diagnosis of IA is multifaceted relying on data from clinical, radiological, and microbiological sources. The detection of Aspergillus biomarkers provides strategies both to pre-empt and to exclude disease, but the choice of biomarker assays is limited, requiring specialist equipment and training. This review examines recent advances in the accurate diagnosis of IA through the development of an Aspergillus lateral-flow device (LFD) incorporating a monoclonal antibody, JF5, which detects an antigenic marker of active infection. Recent trials using bronchoalveolar lavage fluids and serum samples from humans and from animal models of disease, have demonstrated the utility of the LFD as a rapid and user-friendly adjunct test for the quick and accurate diagnosis of pulmonary infections.     

Update on Therapeutic Drug Monitoring of Antifungals for the Prophylaxis and Treatment of Invasive Fungal Infections

Purpose of Review

Certain antifungals used as therapy for invasive fungal disease, including the extended-spectrum triazoles, may be limited by variable pharmacokinetics and drug interactions. This is especially important when drug exposure, as measured by trough concentrations, may be linked to either efficacy or toxicity. We review the rationale, indications, and controversies in TDM of antifungals.

Recent Findings

The monitoring of voriconazole drug levels is often practiced in patients that receive this triazole based on clinical data. Posaconazole delayed-release tablets achieve higher drug exposure more consistently, necessitating reconsideration of a role for therapeutic drug monitoring. Isavuconazole has predictable population kinetics, although exposure appears to be reduced in certain groups. However, the utility of isavuconazole therapeutic drug monitoring is unknown.

Summary

Therapeutic drug monitoring is warranted for certain antifungals, while its utility is being reconsidered for others.

     

糖尿病合并侵袭性肺真菌感染的危险因素及预后分析

目的:分析糖尿病合并侵袭性肺真菌感染(IPFI)的危险因素及预后。方法:选取我院收治的糖尿病合并IPFI患者51例作为观察组,选取同期收治的糖尿病未合并IPFI患者49例作为对照组,对两组资料进行回顾性分析,通过多因素Logistic回归分析侵袭性肺真菌感染的危险因素。结果:白蛋白、血红蛋白、住院时间、广谱抗生素使用时间、体内保留导管、有创机械通气、长期糖皮质激素使用均是侵袭肺真菌感染的危险因素,有统计学意义(P0.05)。对单因素相关分析结果进行筛选,选择P0.05者,进行多因素Logistic回归分析,根据向后剔除法筛选变量,结果显示,低蛋白血症、贫血、长期使用广谱抗生素、有创机械通气均是侵袭性肺部真菌感染的独立危险因素,有统计学意义(P0.05)。结论:糖尿病合并侵袭性肺真菌感染的危险因素较多,预后较差,因此需要有针对性的预防工作和适宜的处理方法。     

Invasive Geotrichum clavatum Fungal Infection in an Acute Myeloid Leukaemia Patient: A Case Report and Review

Invasive Geotrichum clavatum fungal infections are extremely rare and unusual, occurring nearly exclusively in patients experiencing prolonged neutropenia during the treatment for acute myeloid leukaemia. Several groups of cases of fatal G. clavatum infection were reported in France between 2011 and 2012, but the ecological niche has not yet been identified. We report a case of a 32-year-old patient with acute myeloid leukaemia who developed G. clavatum sepsis with primary peritonitis, hepatic nodular lesions, and multivisceral failure during aplasia after induction followed by salvage chemotherapy. He was treated with voriconazole and is still alive 1 year after with controlled disease. We then discuss the epidemiological, clinical, and therapeutic features of these serious fungal infections compared to the published data.     

Invasive Pulmonary Fungal Infections in Cystic Fibrosis

Invasive pulmonary mycosis is after allergic bronchopulmonary aspergillosis (ABPA) a frequent and severe complication of CF lung disease. Among CF caregivers, there is an insecurity when and how to treat infections of the lung parenchyma caused by different fungi in patients with CF. This case series provides a multicenter experience on diagnostic, manifestation, and treatment of non-ABPA cases of pulmonary. Non-ABPA cases of pulmonary mycoses in patients with CF have been collected from the CF Centers in Berlin, Essen, Worms, Frankfurt (Germany), Leeds (UK), and Barcelona (Spain). Non-ABPA was defined as total serum IgE level <500 kU/L. Scedosporium and Lomentospora species seem to be more virulent in patients with CF and have been successfully treated with triple antifungal drug regimens in several cases. Rare fungi including yeasts can have pathogenic potential in CF. In this series, antibiotic treatment failure was the main indicator for the initiation of antifungal treatment. For an early and effective treatment of pulmonary mycoses in CF, the identification of biomarkers and of risk factors beyond antibiotic treatment failure is crucial and urgently needed. Furthermore, treatment efficacy studies are necessary for the different causative agents of these infections.     

Fungal Pathogens: The Battle for Plant Infection

The attempted infection of a plant by a pathogen, such as a fungus or an Oomycete, may be regarded as a battle whose major weapons are proteins and smaller chemical compounds produced by both organisms. Indeed, plants produce an astonishing plethora of defense compounds that are still being discovered at a rapid pace. This pattern arose from a multi-million year, ping-pong?type co-evolution, in which plant and pathogen successively added new chemical weapons in this perpetual battle. As each defensive innovation was established in the host, new ways to circumvent it evolved in the pathogen. This complex co-evolution process probably explains not only the exquisite specificity observed between many pathogens and their hosts, but also the ineffectiveness or redundancy of some defensive genes which often encode enzymes with overlapping activities. Plants evolved a complex, multi-level series of structural and chemical barriers that are both constitutive or preformed and inducible. These defenses may involve strengthening of the cell wall, hypersensitive response (HR), oxidative burst, phytoalexins and pathogenesis-related (PR) proteins. The pathogen must successfully overcome these obstacles before it succeeds in causing disease. In some cases, it needs to modulate or modify plant cell metabolism to its own benefit and/or to abolish defense reactions. Central to the activation of plant responses is timely perception of the pathogen by the plant. A crucial role is played by elicitors which, depending on their mode of action, are broadly classified into nonspecific elicitors and highly specific elicitors or virulence effector/avirulence factors. A protein battle for penetration is then initiated, marking the pathogen attempted transition from extracellular to invasive growth before parasitism and disease can be established. Three major types of defense responses may be observed in plants: non-host resistance, host resistance, and host pathogenesis. Plant innate immunity may comprise a continuum from non-host resistance involving the detection of general elicitors to host-specific resistance involving detection of specific elicitors by R proteins. It was generally assumed that non-host resistance was based on passive mechanisms and that nonspecific rejection usually arose as a consequence of the non-host pathogen failure to breach the first lines of plant defense. However, recent evidence has blurred the clear-cut distinction among non-host resistance, host-specific resistance and disease. The same obstacles are also serious challenges for host pathogens, reducing their success rate significantly in causing disease. Indeed, even susceptible plants mount a (insufficient) defense response upon recognition of pathogen elicited molecular signals. Recent evidence suggests the occurrence of significant overlaps between the protein components and signalling pathways of these types of resistance, suggesting the existence of both shared and unique features for the three branches of plant innate immunity.     

Epidemiology of Invasive Fungal Infections in Latin America

The pathogenic role of invasive fungal infections (IFIs) has increased during the past two decades in Latin America and worldwide, and the number of patients at risk has risen dramatically. Working habits and leisure activities have also been a focus of attention by public health officials, as endemic mycoses have provoked a number of outbreaks. An extensive search of medical literature from Latin America suggests that the incidence of IFIs from both endemic and opportunistic fungi has increased. The increase in endemic mycoses is probably related to population changes (migration, tourism, and increased population growth), whereas the increase in opportunistic mycoses may be associated with the greater number of people at risk. In both cases, the early and appropriate use of diagnostic procedures has improved diagnosis and outcome.     

Fungal Cell Gigantism during Mammalian Infection

The interaction between fungal pathogens with the host frequently results in morphological changes, such as hyphae formation. The encapsulated pathogenic fungus Cryptococcus neoformans is not considered a dimorphic fungus, and is predominantly found in host tissues as round yeast cells. However, there is a specific morphological change associated with cryptococcal infection that involves an increase in capsule volume. We now report another morphological change whereby gigantic cells are formed in tissue. The paper reports the phenotypic characterization of giant cells isolated from infected mice and the cellular changes associated with giant cell formation. C. neoformans infection in mice resulted in the appearance of giant cells with cell bodies up to 30 µm in diameter and capsules resistant to stripping with γ-radiation and organic solvents. The proportion of giant cells ranged from 10 to 80% of the total lung fungal burden, depending on infection time, individual mice, and correlated with the type of immune response. When placed on agar, giant cells budded to produce small daughter cells that traversed the capsule of the mother cell at the speed of 20–50 m/h. Giant cells with dimensions that approximated those in vivo were observed in vitro after prolonged culture in minimal media, and were the oldest in the culture, suggesting that giant cell formation is an aging-dependent phenomenon. Giant cells recovered from mice displayed polyploidy, suggesting a mechanism by which gigantism results from cell cycle progression without cell fission. Giant cell formation was dependent on cAMP, but not on Ras1. Real-time imaging showed that giant cells were engaged, but not engulfed by phagocytic cells. We describe a remarkable new strategy for C. neoformans to evade the immune response by enlarging cell size, and suggest that gigantism results from replication without fission, a phenomenon that may also occur with other fungal pathogens.