Training should be the first step toward an antifungal stewardship program.

The frequency of use of systemic antifungal agents has increased significantly in most tertiary centers. However, antifungal stewardship has received very little attention. The objective of this article was to assess the knowledge of prescribing physicians in our institution as a first step in the development of an antifungal stewardship program. Attending physicians from the departments that prescribe most antifungals were invited to complete a questionnaire based on current guidelines on diagnosis and therapy of invasive candidiasis and invasive aspergillosis (IA). The survey was completed by 60.8% (200/329) of the physicians who were invited to participate. The physicians belonged to the following departments: medical (60%), pediatric (19%), intensive care (15.5%), and surgical (5.5%). The mean (±SD) score of correct responses was 5.16±1.73. In the case of candidiasis, only 55% of the physicians clearly distinguished between colonization and infection, and 17.5% knew the local rate of fluconazole resistance. Thirty-three percent knew the accepted indications for antifungal prophylaxis, and 23% the indications for empirical therapy. However, most physicians knew which antifungals to choose when starting empirical therapy (73.5%). As for aspergillosis, most physicians (67%) could differentiate between colonization and infection, and 34.5% knew the diagnostic value of galactomannan. The radiological features of IA were well recognized by 64%, but only 31.5% were aware of the first line of treatment for IA, and 36% of the recommended duration of therapy. The usefulness of antifungal levels was known by 67%. This simple, easily completed questionnaire enabled us to identify which areas of our training strategy could be improved.

Clinical usefulness of therapeutic drug monitoring of voriconazole in a university hospital.

INTRODUCTION: The aim of this study was to assess the clinical usefulness of therapeutic drug monitoring (TDM) of voriconazole (VOR) in a university hospital. METHODS: A retrospective review was conducted on the clinical records of 52 patients treated with VOR and on whom TDM was performed. Steady-state trough plasma VOR concentration was measured at least 5 days after starting treatment. The therapeutic range of plasma VOR concentration was defined as 1-5.5µg/mL. RESULTS: The most frequent underlying conditions in the study population were lung transplant (48.1%) and hematological malignancies (26.9%). At the first TDM in each patient, VOR levels were outside the therapeutic range in 16 (30.7%) cases: <1µg/mL in 10 (19.2%) and >5.5µg/mL in 6 (11.5%). Eleven patients (21.2%) experienced severe muscle weakness and had considerable difficulty walking. All these patients were receiving concomitant treatment with corticosteroids. Age younger than 30 years (p=.005) and cystic fibrosis as the underlying disease (p=.04) were factors associated with low VOR levels. Almost all patients who had VOR concentrations >1µg/mL at the first TDM had a successful outcome (96%). CONCLUSIONS: Plasma VOR concentrations were outside the therapeutic range at the first TDM in 30% (16/52) of patients. Age younger than 30 years and cystic fibrosis were factors associated with low VOR levels. The potential interactions between corticosteroids and VOR should be highlighted, as they could be responsible for a high rate of muscle weakness observed in our patients. Prospective trials are needed to investigate VOR TDM and corticosteroid pharmacokinetics.

[The different manifestations of pulmonary aspergillosis: multidetector computed tomography findings]. / Las diferentes manifestaciones de la aspergilosis pulmonar. Hallazgos en tomografía computarizada multidetector.

Pulmonary aspergillosis is a fungal infection usually caused by inhaling Aspergillus fumigatus spores. However, when we talk about aspergillosis, we normally refer to the spectrum of clinical and radiological findings that depend directly on the patient's immune status, on the prior existence of lung disease, and on the virulence of the infective organism. There are four types of pulmonary aspergillosis (aspergilloma, allergic bronchopulmonary aspergillosis, chronic necrotizing pulmonary aspergillosis, and invasive aspergillosis), and each type has its own distinct radiologic findings. We review the signs of pulmonary aspergillosis on multidetector computed tomography and we correlate them with patients' symptoms and immune responses. Likewise, we discuss the differential diagnoses.

Invasive aspergillosis: A comprehensive review.

Invasive aspergillosis (IA) is a severe fungal infection caused by Aspergillus species, particularly Aspergillus fumigatus, although new species, sometimes resistant to antifungals are becoming more common. IA predominantly affects immunocompromised patients, such as those with haematological malignancies, solid organ transplant recipients, and critically ill patients. However, new at-risk populations have emerged in recent years, such as IA associated with severe viral infections. Advanced diagnostic methods are crucial, especially considering the rising concern of antifungal resistance. Early detection is critical for successful treatment, typically involving antifungal medications like voriconazole or amphotericin B, but new antifungals are arriving to complete the therapeutic strategies. Despite advancements, mortality rates remain high, underscoring the importance of timely interventions and ongoing research. Healthcare providers should maintain a high index of suspicion, especially in immunocompromised patients and other new risk factors that are arising, to promptly diagnose and manage invasive aspergillosis.

Characterization and real-live results of nebulized voriconazole: A single-center observational study. / [Artículo traducido] Caracterización y resultados del uso de voriconazol nebulizado en un entorno real: un estudio observacional unicéntrico.

OBJECTIVE: Pulmonary administration of voriconazole involves advantages, including optimization of lung penetration and reduction of adverse effects and interactions. However, there is scarce evidence about its use and there are no commercial presentations for nebulization. We aim to characterize a compounded voriconazole solution for nebulization and describe its use in our center. METHOD: This is a retrospective observational study including patients who received nebulized voriconazole to treat fungal lung diseases (infection or colonization). Voriconazole solution was prepared from commercial vials for intravenous administration. RESULTS: The pH and osmolarity of voriconazole solutions were adequate for nebulization. Ten patients were included, nine adults and a child. The dosage was 40 mg in adults and 10 mg in the pediatric patient, diluted to a final concentration of 10 mg/ml, administered every 12-24 hours. The median duration of treatment was 139 (range: 26-911) days. There were no reported adverse effects and the drug was not detected in plasma when nebulized only. CONCLUSION: Voriconazole nebulization is well tolerated and it is not absorbed into the systemic circulation; further research is needed to assess its efficacy.

Necrotizing pneumonia due to Aspergillus and Salmonella after immune checkpoint inhibitor treatment: An unusual case and review of the literature.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are a promising new treatment for different types of cancer. The infectious complications in patients taking ICIs are rare. CASE REPORT: A 58-year-old male who received chemotherapy consisting of pembrolizumab (PD-1 inhibitor) for esophagus squamous cell carcinoma one month before was admitted to the emergency room with shortness of breath soon after fiberoptic bronchoscopy, which was done for the inspection of the lower airway. A computed tomography of the chest revealed a progressive consolidation on the right upper lobe. Salmonella group D was isolated from the bronchoalveolar lavage (BAL) fluid culture. The fungal culture of the same clinical sample yielded Aspergillus niger; furthermore, a high titer (above the cut-off values) of Aspergillus antigen was found both in the BAL fluid and serum of the patient. Despite the effective spectrum and appropriate dose of antimicrobial treatment, the patient died due to disseminated intravascular coagulopathy. CONCLUSIONS: Awareness of unusual pathogens in the etiology of pneumonia after ICI treatment may help to avoid underdiagnosis.

Lethal destructive sinusopathy due to amphotericin B-resistant Aspergillus flavus: A case report.

BACKGROUND: The prevalence of pulmonary aspergillosis and the importance of its early diagnosis are recognized. However, non-pulmonary involvement, including the sinuses region, is not frequently reported, and an infection in this area can affect all paranasal sinuses (pansinusopathy), being a rare pathology that affects immunocompromised hosts. Recent studies have highlighted the occurrence of Aspergillus flavus resistant to antifungal therapy. Therefore, a nasal sinus infection by resistant Aspergillus strains in immunocompromised patients may be linked to a high risk of lethality. CASE REPORT: We are reporting a resistant A. flavus infection in an allogeneic hematopoietic stem cell transplant recipient with episodes of febrile neutropenia, and prolonged use of various antibacterial drugs and antifungal prophylaxis. The patient underwent brain magnetic resonance, which showed the presence of pansinusopathy, and presented necrosis in the left nasal region. Direct microscopic examination of a sample taken from the nasal mucosa revealed the presence of septate hyphae and conidiophores resembling those of A. flavus, that species being the identification achieved with MALDI-TOF MS. Antifungigram was performed by microdilution in broth (EUCAST-E.DEF. 9.3.2) and E-test, and resistance to amphotericin B was shown in both tests. The patient died after septic shock and hemorrhage. CONCLUSIONS: Invasive fungal infections due to amphotericin-B resistant A. flavus may lead to the death of the patient due to an ineffective therapeutic management. Therefore, antifungal susceptibility testing are of utmost importance for administering the proper treatment.

Impact of Aspergillus spp. isolation in the first 24 hours of admission in critically ill patients with severe influenza virus pneumonia.

OBJECTIVE: To determine the incidence and impact of Aspergillus spp. isolation (AI) on ICU mortality in critically ill patients with severe influenza pneumonia during the first 24h of admission. DESIGN: Secondary analysis of an observational and prospective cohort study. SETTING: ICUs voluntary participating in the Spanish severe Influenza pneumonia registry, between June 2009 and June 2019. PATIENTS: Consecutive patients admitted to the ICU with diagnosis of severe influenza pneumonia, confirmed by real-time polymerase chain reaction. INTERVENTIONS: None. MAIN VARIABLES OF INTEREST: Incidence of AI in respiratory samples. Demographic variables, comorbidities, need for mechanical ventilation and the presence of shock according at admission. Acute Physiology and Chronic Health Evaluation II (APACHE II) scale calculated on ICU admission. RESULTS: 3702 patients were analyzed in this study. AI incidence was 1.13% (n=42). Hematological malignancies (OR 4.39, 95% CI 1.92-10.04); HIV (OR 3.83, 95% CI 1.08-13.63), and other immunosuppression situations (OR 4.87, 95% CI 1.99-11.87) were factors independently associated with the presence of Aspergillus spp. The automatic CHAID decision tree showed that hematologic disease with an incidence of 3.3% was the most closely AI related variable. Hematological disease (OR 2.62 95% CI 1.95-3.51), immunosuppression (OR 2.05 95% CI 1.46-2.88) and AI (OR 3.24, 95% CI 1.60-6.53) were variables independently associated with ICU mortality. CONCLUSIONS: Empirical antifungal treatment in our population may only be justified in immunocompromised patients. In moderate-high risk cases, active search for Aspergillus spp. should be implemented.

Spectrum of opportunistic fungal lung co-infections in COVID-19: What the radiologist needs to know.

Fungal lung co-infections associated with COVID-19 may occur in severely ill patients or those with underlying co-morbidities, and immunosuppression. The most common invasive fungal infections are caused by aspergillosis, mucormycosis, pneumocystis, cryptococcus, and candida. Radiologists integrate the clinical disease features with the CT pattern-based approach and play a crucial role in identifying these co-infections in COVID-19 to assist clinicians to make a confident diagnosis, initiate treatment and prevent complications.

Evaluation of the diagnostic accuracy of galactomannan from the bronchoalveolar lavage fluid of patients with suspected invasive pulmonary aspergillosis.

BACKGROUND: Several studies to evaluate the accuracy of galactomannan (GM) in bronchoalveolar lavage fluid (BALF) as a diagnostic tool have been carried out; however, there are still controversies about the optimal cut-off point of BALF GM. AIMS: The objective of this study was to determine the diagnostic accuracy and the optimal cut-off point on BALF GM from patients with suspected invasive pulmonary aspergillosis (IPA) in a tertiary care hospital. METHODS: A cross-sectional study with 188 patients (≥18 years) that had undergone a bronchoscopy with BAL due to suspected IPA was carried out. IPA was diagnosed according to the EORTC/MSG guidelines. RESULTS: The optimal optical density cut-off point for BALF GM was 0.67, with sensitivity, specificity, positive predictive value, and negative predictive value of 100%, 70%, 32.3%, and 100%, respectively. CONCLUSIONS: BALF GM detection proved to be a useful supplementary technique in the early diagnosis of IPA in both neutropenic and non-neutropenic patients.

Invasive pulmonary aspergillosis in patients with acute respiratory syndrome by COVID-19.

Patients with COVID-19 who are admitted to intensive care unit (ICU) are at high risk of developing secondary infections, including invasive fungal infections such as invasive pulmonary aspergillosis (IPA). The main purpose was to analyse the putative COVID-19 Associated Pulmonary Aspergillosis (CAPA) patients in our setting. In these patients, we performed mycological culture in bronchoalveolar lavage (BAL) for isolation of Aspergillus sp. We followed the AspICU algorithm to diagnose putative IPA. Moreover, we considered relevant the positivity of Galactomannan in BAL. We diagnosed putative IPA in 3 patients. The common features of these 3 patients were: more than 21 days of stay in ICU, severe acute respiratory distress syndrome (ARDS) and treatment with steroids (1 mg/kg per day). Therefore, CAPA has to be systematically considered although a new algorithm to diagnose it is needed to treat patients in early stages in order to avoid catastrophic outcomes.

[Invasive fungal infection over the last 30 years]. / Evolución de la infección fúngica invasora en los últimos 30 años.

Clinical mycology is in continuous development. The appearance of new clinical guidelines has made it possible to improve the approach to opportunistic fungal infections, especially in immunosuppressed patients (oncohematological and/or transplant recipients). At the same time, the development of new diagnostic tools and new antifungals with a greater spectrum of action and fewer side effects have led to faster diagnoses and treatments that are more effective. Along with these advances, there has been a change in the epidemiology of invasive fungal infection (IFI), with the appearance of new patients (e.g., COPD, liver cirrhosis, post-influenza) and new microorganisms (Candida auris, Lomentospora prolificans, mucorales), and resistant fungi (isolates of Aspergillus resistant to azoles) which the clinician must take into account when choosing the treatment of a patient with an IFI. In this paper we will briefly review the advances in recent decades and the emerging problems.

Prevalence of pulmonary mycoses in smear-negative patients with suspected tuberculosis in the Brazilian Amazon.

BACKGROUND: Pulmonary mycoses resemble clinically and radiologically chronic pulmonary tuberculosis. Studies describing the prevalence, etiology and clinical features of pulmonary mycosis are of crucial importance in the Brazilian Amazon. AIMS: To estimate the frequency of pulmonary mycoses in smear-negative tuberculosis patients; to describe their demographic, epidemiological, and clinical characteristics; and to evaluate diagnostic methods. METHODS: A cross-sectional study was conducted at two tuberculosis reference institutions in Amazonas, Brazil. We included 213 patients and collected clinical data, blood and induced sputum to perform serological, direct microscopy, microbiologic culture and PCR-based assays to identify infections caused by Aspergillus fumigatus, Paracoccidioides brasiliensis, Histoplasma capsulatum, Cryptococcus, and HIV. Chest computed tomography was also performed. RESULTS: Pulmonary mycoses were diagnosed in 7% (15/213) of the cases, comprising ten aspergillosis cases, three cases of paracoccidioidomycosis and one case each of histoplasmosis and cryptococcosis. Among the patients with pulmonary mycoses, 86.7% were former tuberculosis patients. The most significant clinical characteristics associated with pulmonary mycoses were cavity-shaped lung injuries, prolonged chronic cough and hemoptysis. CONCLUSIONS: Our study confirmed the high prevalence of pulmonary mycoses in smear-negative tuberculosis patients in the Brazilian Amazon.

[Individualized antifungal therapy in critically ill patients with invasive fungal infection]. / Tratamiento antifúngico individualizado en el paciente crítico con infección fúngica invasora.

Invasive candidiasis (IC) is the most common invasive fungal infection (IFI) affecting critically ill patients, followed by invasive pulmonary aspergillosis (IPA). International guidelines provide different recommendations for a first-line antifungal therapy and, in most of them, echinocandins are considered the first-line treatment for IC, and triazoles are so for the treatment of IPA. However, liposomal amphotericinB (L-AmB) is still considered a second-line therapy for both clinical entities. Although in the last decade the management of IFI has improved, several controversies persist. The antifungal drugs currently available may have a suboptimal activity, or be wrongly used in certain IFI involving critically ill patients. The aim of this review is to analyze when to provide individualized antifungal therapy to critically ill patients suffering from IFI, emphasizing the role of L-AmB. Drug-drug interactions, the clinical status, infectious foci (peritoneal candidiasis is discussed), the fungal species involved, and the need of monitoring the concentration of the antifungal drug in the patient are considered.

Invasive pulmonary aspergillosis in patients with acute respiratory syndrome by COVID-19. / Aspergilosis pulmonar invasiva en pacientes con síndrome de distrés respiratorio por COVID-19.

Patients with COVID-19 who are admitted to intensive care unit (ICU) are at high risk of developing secondary infections, including invasive fungal infections such as invasive pulmonary aspergillosis (IPA). The main purpose was to analyse the putative COVID-19 Associated Pulmonary Aspergillosis (CAPA) patients in our setting. In these patients, we performed mycological culture in bronchoalveolar lavage (BAL) for isolation of Aspergillus sp. We followed the AspICU algorithm to diagnose putative IPA. Moreover, we considered relevant the positivity of galactomannan in BAL. We diagnosed putative IPA in 3 patients. The common features of these 3 patients were: more than 21 days of stay in ICU, severe acute respiratory distress syndrome (ARDS) and treatment with steroids (1mg/kg per day). Therefore, CAPA has to be systematically considered although a new algorithm to diagnose it is needed to treat patients in early stages in order to avoid catastrophic outcomes.

Fungal co-infection in COVID-19 patients: Should we be concerned?

Critically ill COVID-19 patients have higher pro-inflammatory (IL-1, IL-2, IL-6, tumor necrosis alpha) and anti-inflammatory (IL-4, IL-10) cytokine levels, less CD4 interferon-gamma expression, and fewer CD4 and CD8 cells. This severe clinical situation increases the risk of serious fungal infections, such as invasive pulmonary aspergillosis, invasive candidiasis or Pneumocystis jirovecii pneumonia. However, few studies have investigated fungal coinfections in this population. We describe an update on published reports on fungal coinfections and our personal experience in three Spanish hospitals. We can conclude that despite the serious disease caused by SARS-CoV-2 in many patients, the scarcity of invasive mycoses is probably due to the few bronchoscopies and necropsies performed in these patients because of the high risk in aerosol generation. However, the presence of fungal markers in clinically relevant specimens, with the exception of bronchopulmonary colonization by Candida, should make it advisable to early implement antifungal therapy.

Clinical factors associated with pulmonary aspergillosis in patients with chronic obstructive pulmonary disease. / Factores clínicos asociados a enfermedad pulmonar por Aspergillus spp. en pacientes con enfermedad pulmonar obstructiva crónica.

OBJECTIVE: To explore the clinical and epidemiological characteristics of chronic obstructive pulmonary disease (COPD) patients with Aspergillus spp. isolation from respiratory samples, and to identify which factors may help us to distinguish between colonisation and infection. METHODS: A retrospective cohort study was performed. All patients with COPD and respiratory isolation of Aspergillus spp. over a 12-year period were included. Patients were assigned to 2 categories: colonisation and pulmonary aspergillosis (PA), which includes the different clinical forms of aspergillosis. A binary logistic regression model was performed to identify the predictive factors of PA. RESULTS: A total of 123 patients were included in the study: 48 (39.0%) with colonisation and 75 (61.0%) with PA: 68 with probable invasive pulmonary aspergillosis and 7 with chronic pulmonary aspergillosis. Spirometric stages of the GOLD classification were not correlated with a higher risk of PA. Four independent predictive factors of PA in COPD patients were identified: home oxygen therapy (OR: 4.39; 95% CI: 1.60-12.01; P=.004), bronchiectasis (OR: 3.61; 95% CI: 1.40-9.30; P=.008), hospital admission in the previous three months (OR: 3.12; 95% CI: 1.24-7.87; P=.016) and antifungal therapy against Candida spp. in the previous month (OR: 3.18; 95% CI: 1.16-8.73; P=.024). CONCLUSIONS: Continuous home oxygen therapy, bronchiectasis, hospital admission in the previous three months and administration of antifungal medication against Candida spp. in the previous month were associated with a higher risk of pulmonary aspergillosis in patients with COPD.

Antifungal Resistance in Clinical Isolates of Aspergillus spp.: When Local Epidemiology Breaks the Norm.

Aspergillosis is a set of very frequent and widely distributed opportunistic diseases. Azoles are the first choice for most clinical forms. However, the distribution of azole-resistant strains is not well known around the world, especially in developing countries. The aim of our study was to determine the proportion of non-wild type strains among the clinical isolates of Aspergillus spp. To this end, the minimum inhibitory concentration of three azoles and amphotericin B (used occasionally in severe forms) was studied by broth microdilution. Unexpectedly, it was found that 8.1% of the isolates studied have a diminished susceptibility to itraconazole. This value turned out to be similar to the highest azole resistance rate reported in different countries across the world.

[Obstructive tracheobronchitis due to Aspergillus fumigatus in an immunocompetent patient]. / Traqueobronquitis obstructiva por Aspergillus fumigatus en un paciente inmunocompetente.

BACKGROUND: Aspergillus tracheobronchitis (ATB) is an uncommon type of invasive pulmonary aspergillosis in which fungal involvement is limited to the tracheobronchial tree. While the more severe forms, such as pseudomembranous and ulcerative ATB, occur almost exclusively in immunocompromised patients, the milder obstructive form may occur in patients without immune deficiency. CASE REPORT: The case of a 32 year-old man with no previous history of illness, who was evaluated for recurrent right lower lobe pneumonia, is presented. Microbiological sputum studies revealed growth of Serratia marcescens, and a limited growth of Aspergillus fumigatus, the latter interpreted as a contaminant in the specimen. Bronchoscopy revealed a dense mucous plug at level B10 of the right lower lobe, which could not be removed; no other macroscopic findings of interest were observed. During his hospital admission, the patient expectorated the mucous plug and had a significant subsequent bronchorrhoea. A substantial number of colonies of A. fumigatus grown in the sputum cultures. The patient was given voriconazole, leading to a clinical resolution, with no recurrences. CONCLUSIONS: Obstructive ATB is characterised by the excessive production of thick, hyphae-laden mucus, which can obstruct the airway lumen and generate relapsing post-obstructive pneumonias. It is important to consider this diagnosis in immunocompetent patients with recurrent respiratory infections and who show repeated isolation of Aspergillus colonies in the sputum, even in small quantities.

Executive summary of clinical practice guideline for the management of invasive diseases caused by Aspergillus: 2018 Update by the GEMICOMED-SEIMC/REIPI.

Aspergillus infection is a significant cause of morbi-mortality in an at-risk population. The Study Group of Fungal Infections (GEMICOMED) from the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) has reviewed announcements made in invasive aspergillosis management. We have organized our recommendations in such a way as to provide a guide in resolving different clinical situations concerning the entire spectrum of invasive diseases caused by Aspergillus in various populations. Diagnostic approach, treatment and preventions strategies are outlined. It is not our aim that these guidelines supplant clinical judgment with respect to specific patients; however, it is our objective to perform a comprehensive summary of quality of care evidence for invasive aspergillosis management in different settings.