Performance of the clarus Aspergillus galactomannan enzyme immunoassay prototype for the diagnosis of invasive pulmonary aspergillosis in serum.

BACKGROUND: Serum galactomannan (GM) testing is essential for diagnosing invasive aspergillosis (IA), particularly in immunocompromised individuals. The global lack of on-site GM testing capacities necessitates cost-effective alternatives, such as .the clarus Aspergillus GM enzyme immunoassay prototype (clarus AGM prototype). METHODS: This single-centre, cross-sectional study compared the diagnostic performance of the clarus AGM prototype (IMMY, Norman, Oklahoma) with the serological gold standard (=Platelia AGM assay; Bio-Rad, Marnes-la-Cocquette, France). IA was classified according to modified 2020 EORTC/MSG consensus and 2024 FUNDICU criteria. In total, 300 prospectively (May-Dec 2023) and retrospectively (2012-2015) collected samples were included. RESULTS: Among 300 samples from 232 patients, 49 (16%) were classified as proven (n = 1) or probable IA (n = 48). In non-IA cases (n = 250), one patient was classified as possible IA. With the manufacturer recommended cut-off of ≥0.2, sensitivity and specificity of the clarus AGM prototype were 27% (13/49; 95% confidence interval [CI]: 15%-41%) and 99% (248/250; 95% CI: 97%-100%), respectively, while sensitivity and specificity were 78% and 79% when using the optimised Youden's cut-off of 0.0045 ODI. ROC curve analysis demonstrated an area under the curve (AUC) of 0.829 (95% CI: 0.760-0.898) for the clarus AGM prototype in distinguishing between proven/probable IA and non-IA. The AUC for the Platelia AGM was 0.951 (95% CI: 0.909-994). Spearman's correlation analysis showed a weak correlation between the two assays (0.382; p < .001). CONCLUSIONS: The weak correlation between the clarus AGM prototype and Platelia AGM highlights the need for further investigation into the clinical performance of the clarus AGM prototype, giving the different antigen epitopes addressed.

Antifungals in Patients With Extracorporeal Membrane Oxygenation: Clinical Implications.

Extracorporeal membrane oxygenation (ECMO) is a life-saving technique used in critical care medicine for patients with severe respiratory or cardiac failure. This review examines the treatment and prophylaxis of fungal infections in ECMO patients, proposing specific regimens based on available data for different antifungals (azoles, echinocandins, amphotericin B/liposomal amphotericin B) and invasive fungal infections. Currently, isavuconazole and posaconazole have the most supported data, while modified dosages of isavuconazole are recommended in ECMO. Echinocandins are preferred for invasive candidiasis. However, choosing echinocandins is challenging due to limited and varied data on concentration loss in the ECMO circuit. Caution is likewise advised when using liposomal amphotericin B due to uncertain concentrations and potential ECMO dysfunction based on scarce data. We further conclude with the importance of further research on the impact of ECMO on antifungal drug concentrations to optimize dosing regimens in critically ill patients.

New treatment options for critically important WHO fungal priority pathogens.

BACKGROUND: Yet often overlooked in public health discourse, fungal infections pose a crucial global disease burden associated with annual mortality rates approximately equal to tuberculosis and HIV. In response, the WHO published its first global priority list of fungal pathogens in 2022 assigning Aspergillus fumigatus, Candida albicans, Candida auris, and Cryptococcus neoformans to the critical group. OBJECTIVES: This review provides succinct insights into novel antifungals in development, aiming to contribute valuable information and perspectives with a focus on recent clinical findings and new treatment approaches for critical members of the WHO fungal pathogen priority list. SOURCES: PubMed literature search using 'Aspergillus fumigatus', 'Cryptococcus neoformans', 'Candida auris', and 'Candida albicans', along with the names of novel antifungal substances, including 'fosmanogepix', 'ibrexafungerp', 'opelconazole', 'oteseconazole', 'MAT2203', 'olorofim', and 'rezafungin' was conducted. CONTENT: For each critical pathogen, current issues and global clinical data from recent trials are covered. The remarkable development of three new antifungal therapeutics recently receiving Food and Drug Administration approval (ibrexafungerp-June 2021, oteseconazole -April 2022, and rezafungin-March 2023) is outlined, with two more exciting new antifungal substances, namely, olorofim and fosmanogepix expecting approval within the next years. Ibrexafungerp, fosmanogepix, and rezafungin have additionally been granted orphan drug status by the European Medicines Agency in Europe (ibrexafungerp-November 2021, fosmanogepix-July 2022, and rezafungin-January 2024). IMPLICATIONS: Although the limited number of targets and the emergence of resistance have posed challenges to antifungal treatment, new drugs such as ibrexafungerp, rezafungin, fosmanogepix, or olorofim have shown promising clinical efficacy. These drugs not only provide alternative options for invasive fungal infections but also alleviate treatment in outpatient settings. More clinical data, implementation of stewardship programmes, and surveillance, including utilization of drugs in agriculture, are necessary to prevent resistance development and to ensure the safety and efficacy of these new agents.

Therapeutic drug monitoring of antifungal therapies: do we really need it and what are the best practices?

INTRODUCTION: Despite advancements, invasive fungal infections (IFI) still carry high mortality rates, often exceeding 30%. The challenges in diagnosis, coupled with limited effective antifungal options, make managing IFIs complex. Antifungal drugs are essential for IFI management, but their efficacy can be diminished by drug-drug interactions and pharmacokinetic variability. Therapeutic Drug Monitoring (TDM), especially in the context of triazole use, has emerged as a valuable strategy to optimize antifungal therapy. AREAS COVERED: This review provides current evidence regarding the potential benefits of TDM in IFI management. It discusses how TDM can enhance treatment response, safety, and address altered pharmacokinetics in specific patient populations. EXPERT OPINION: TDM plays a crucial role in achieving optimal therapeutic outcomes in IFI management, particularly for certain antifungal agents. Preclinical studies consistently show a link between therapeutic drug levels and antifungal efficacy. However, clinical research in mycology faces challenges due to patient heterogeneity and the diversity of fungal infections. TDM's potential advantages in guiding Echinocandin therapy for critically ill patients warrant further investigation. Additionally, for drugs like Posaconazole, assessing whether serum levels or alternative markers like saliva offer the best measure of efficacy is an intriguing question.

Fungal Endocarditis: Pathophysiology, Epidemiology, Clinical Presentation, Diagnosis, and Management.

Fungal endocarditis accounts for 1% to 3% of all infective endocarditis cases, is associated with high morbidity and mortality (>70%), and presents numerous challenges during clinical care. Candida spp. are the most common causes of fungal endocarditis, implicated in over 50% of cases, followed by Aspergillus and Histoplasma spp. Important risk factors for fungal endocarditis include prosthetic valves, prior heart surgery, and injection drug use. The signs and symptoms of fungal endocarditis are nonspecific, and a high degree of clinical suspicion coupled with the judicious use of diagnostic tests is required for diagnosis. In addition to microbiological diagnostics (e.g., blood culture for Candida spp. or galactomannan testing and PCR for Aspergillus spp.), echocardiography remains critical for evaluation of potential infective endocarditis, although radionuclide imaging modalities such as 18F-fluorodeoxyglucose positron emission tomography/computed tomography are increasingly being used. A multimodal treatment approach is necessary: surgery is usually required and should be accompanied by long-term systemic antifungal therapy, such as echinocandin therapy for Candida endocarditis or voriconazole therapy for Aspergillus endocarditis.

Sustained Increase in Very Low Influenza Vaccination Coverage in Residents and Healthcare Workers of Long-Term Care Facilities in Austria after Educational Interventions.

Residents of long-term care facilities (LTCFs) are particularly at risk for influenza infections. We aimed to improve influenza vaccination coverage among residents and healthcare workers (HCWs) in four LTCFs by implementing educational programs and enhanced vaccination services. We compared vaccination coverage before and after the interventions (2017/18 and 2018/19 seasons). Data on vaccination adherence were recorded during a four-year observational period (2019/20 to 2022/23 seasons). Following the interventions, vaccination coverage increased significantly from 5.8% (22/377) to 19.1% (71/371) in residents and from 1.3% (3/234) to 19.7% (46/233) in HCWs (p < 0.001). During the observational period (2019/20 to 2022/23 seasons), vaccination coverage remained high in residents but decreased in HCWs. Vaccination adherence was significantly higher in residents and HCWs in LTCF 1 compared to the other three LTCFs. Our study suggests that a bundle of educational interventions and enhanced vaccination services can be an effective method for improving influenza vaccination coverage in LTCFs in both residents and HCWs. However, vaccination rates are still well below the recommended targets and further efforts are needed to increase vaccine coverage in our LTCFs.

Treatment of Invasive Aspergillosis: How It's Going, Where It's Heading.

Despite improvements in treatment and diagnostics over the last two decades, invasive aspergillosis (IA) remains a devastating fungal disease. The number of immunocompromised patients and hence vulnerable hosts increases, which is paralleled by the emergence of a rise in IA cases. Increased frequencies of azole-resistant strains are reported from six continents, presenting a new challenge for the therapeutic management. Treatment options for IA currently consist of three classes of antifungals (azoles, polyenes, echinocandins) with distinctive advantages and shortcomings. Especially in settings of difficult to treat IA, comprising drug tolerance/resistance, limiting drug-drug interactions, and/or severe underlying organ dysfunction, novel approaches are urgently needed. Promising new drugs for the treatment of IA are in late-stage clinical development, including olorofim (a dihydroorotate dehydrogenase inhibitor), fosmanogepix (a Gwt1 enzyme inhibitor), ibrexafungerp (a triterpenoid), opelconazole (an azole optimized for inhalation) and rezafungin (an echinocandin with long half-life time). Further, new insights in the pathophysiology of IA yielding immunotherapy as a potential add-on therapy. Current investigations show encouraging results, so far mostly in preclinical settings. In this review we discuss current treatment strategies, give an outlook on possible new pharmaceutical therapeutic options, and, lastly, provide an overview of the ongoing research in immunotherapy for IA.

Salvage Treatment for Invasive Aspergillosis and Mucormycosis: Challenges, Recommendations and Future Considerations.

Invasive mold diseases are devastating systemic infections which demand meticulous care in selection, dosing, and therapy monitoring of antifungal drugs. Various circumstances regarding PK/PD properties of the applied drug, resistance/tolerance of the causative pathogen or host intolerability can lead to failure of the initial antifungal therapy. This necessitates treatment adaption in the sense of switching antifungal drug class or potentially adding another drug for a combination therapy approach. In the current state of drastically limited options of antifungal drug classes adaption of therapy remains challenging. Current guidelines provide restricted recommendations only and emphasize individual approaches. However, novel antifungals, incorporating innovative mechanisms of action, show promising results in late stage clinical development. These will expand options for salvage therapy in the future potentially as monotherapy or in combination with conventional or other novel antifungals. We outline current recommendations for salvage therapy including PK/PD considerations as well as elucidate possible future treatment options for invasive aspergillosis and mucormycosis.

Antifungal stewardship in solid organ transplantation.

BACKGROUND: Antifungal stewardship (AFS) has emerged as an important component of quality in managing invasive fungal infections (IFIs), and cost-benefit calculations suggest regular training in AFS is well worth the effort. METHODS: This review will discuss the most common IFIs in solid organ transplantation (SOT)-recipients, how to diagnose them, and current recommendations for antifungal treatment and prophylaxis before demonstrating key takeaway points of AFS in this high-risk population. RESULTS: Effective AFS starts before a patient is admitted for SOT, through education and regular interactions of the interdisciplinary clinical team involved in patient management, considering local factors such as epidemiological data and knowledge of diagnostic options including local turnaround times. Understanding the spectrum of antifungal agents, their efficacy and safety profiles, and pharmacokinetics, as well as duration of therapy is hereby essential. The most frequent IFIs in SOT recipients are caused by Candida species, followed by Aspergillus species, both with increasing resistance rates. Diagnosis of IFI can be challenging due to unspecific clinical presentation and difficult interpretation of microbiological findings and biomarkers. Prophylactic strategies, such as those for invasive aspergillosis in lung transplantation or invasive candidiasis (IC) in certain liver transplant settings, as well as the selection of the appropriate therapeutic agents require detailed knowledge on the pharmacokinetics and drug-drug interactions of antifungals. CONCLUSIONS: Here in this review, we address what constitutes good AFS in this heterogeneous field of solid organ transplant recipients.

Investigation of Non-invasive Continuous Body Temperature Measurements in a Clinical Setting Using an Adhesive Axillary Thermometer (SteadyTemp®).

Since the human body reacts to a variety of different diseases with elevated body temperature, measurement of body temperature remains relevant in clinical practice. The absolute temperature value for fever definition is still arbitrary and depends on the measuring site, as well as underlying disease and individual factors. Hence, a simple threshold for fever definition is outdated and a definition which relies on the relative changes in the individual seems reasonable as it takes these individual factors into account. In this prospective multicentric study we validate an adhesive axillary thermometer (SteadyTemp®) which allows continuous non-invasive temperature measurements. It consists of a patch to measure temperature and a smartphone application to process and visualize gathered data. This article provides information of the new diagnostic possibilities when using this wearable device and where it could be beneficial. Furthermore, it discusses how to interpret the generated data and when it is not practical to use, based on its characteristics and physiological phenomena.

Serum Lateral Flow assay with digital reader for the diagnosis of invasive pulmonary aspergillosis: A two-centre mixed cohort study.

BACKGROUND: Detection of galactomannan (GM) from bronchoalveolar lavage fluid (BALF) or serum is broadly used for diagnosis of invasive aspergillosis (IA), although the sensitivity of GM from serum is lower in non-neutropenic patients. We evaluated the Aspergillus galactomannan Lateral Flow assay (LFA) with digital readout from serum in a mixed cohort of patients. METHODS: We performed a retrospective two-centre study evaluating the LFA from serum of patients with clinical suspicion of IA obtained between 2015 and 2021 at the University of California San Diego and the Medical University of Graz. The sensitivity and specificity was calculated for proven/probable aspergillosis versus no aspergillosis. Correlation with same-sample GM was calculated using Spearman correlation analysis and kappa statistics. RESULTS: In total, 122 serum samples from 122 patients were analysed, including proven IA (n = 1), probable IA or coronavirus-associated pulmonary aspergillosis (CAPA) (n = 27), and no IA/CAPA/non-classifiable (n = 94). At a 0.5 ODI cut-off, the sensitivity and specificity of the LFA was 78.6% and 80.5%. Spearman correlation analysis showed a strong correlation between serum LFA ODI and serum GM ODI (ρ 0.459, p < .0001). Kappa was 0.611 when both LFA and GM were used with a 0.5 ODI cut-off, showing substantial agreement (p < .001). DISCUSSION: The LFA with digital read out from serum showed good performance for the diagnosis of probable/proven aspergillosis, with substantial agreement to GM from serum. Like the LFA from BALF, the LFA from serum may serve as a more rapid test compared to conventional GM, particularly in settings where GM is not readily available.

Measurement of aortofemoral volume wave velocity during the routine 12-channel ECG: relation to age, physiological hemoglobin A 1C, triglycerides and SBP in healthy individuals.

OBJECTIVE: Measurements of pulse wave velocity are generally thought to be too impractical for clinical routine. This study aimed to develop a method that can be performed during routine 12-channel ECG. METHODS: A 12-channel ECG simultaneously supplies arterial impedance plethysmographic signals from the extremities beside segmental multifrequency impedance measurements for obtaining body composition. The origin of the plethysmographic signal (volume wave) at the arms and legs was determined at the level of the elbows and the knees. The volume wave velocity (VWV) at the aorta and femoral arteries was calculated from the time difference of the plethysmographic signals between arms and legs. RESULTS: Automated measurement of VWV was highly reproducible (r = 0.96). In 107 participants in perfect health, VWV in different models was positively related to age, physiological hemoglobin A 1C, triglycerides, normal standardized unattended blood pressure, but not to physiological low-density lipoprotein-cholesterol and high-density lipoprotein-cholesterol. Aortofemoral VWV was significantly higher in patients with established coronary artery disease than in healthy controls of the same age group (18.1 ±â€Š5.8 vs. 11.9 ±â€Š1.7 m/s, P < 0.001). VWV in study participants was higher than tonometrically determined pulse wave velocity as muscular arteries are included (13.2 ±â€Š5.81 vs. 8.8 ±â€Š2.98 m/s, n = 115, P < 0.001). CONCLUSION: These background arterial impedance plethysmographic measurements for the measurement of VWV made simultaneously during 12-channel ECG show promise for large-scale, routine clinical assessment of large artery function.