Invasive Pulmonary Aspergillosis

BackgroundSuperinfections, including invasive pulmonary aspergillosis (IPA), are well-known complications of critically ill patients with severe viral pneumonia. Aim of this study was to evaluate the incidence, risk factors and outcome of IPA in critically ill patients with severe COVID-19 pneumonia.MethodsWe prospectively screened 32 critically ill patients with severe COVID-19 pneumonia for a time period of 28 days using a standardized study protocol for oberservation of developement of COVID-19 associated invasive pulmonary aspergillosis (CAPA). We collected laboratory, microbiological, virological and clinical parameters at defined timepoints in combination with galactomannan-antigen-detection from nondirected bronchial lavage (NBL). We used logistic regression analyses to assess if COVID-19 was independently associated with IPA and compared it with matched controls.FindingsCAPA was diagnosed at a median of 4 days after ICU admission in 11/32 (34%) of critically ill patients with severe COVID-19 pneumonia as compared to 8% in the control cohort. In the COVID-19 cohort, mean age, APACHE II score and ICU mortality were higher in patients with CAPA than in patients without CAPA (36% versus 9.5%; pInterpretationCAPA is highly prevalent and associated with a high mortality rate. COVID-19 is independently associated with invasive pulmonary aspergillosis. A standardized screening and diagnostic approach as presented in our study can help to identify affected patients at an early stage.

F901318 is an antifungal agent with a novel mechanism of action and potent activity against Aspergillus spp. An understanding of the pharmacodynamics (PD) of F901318 is required for selection of effective regimens for study in phase II and III clinical trials. Neutropenic murine and rabbit models of invasive pulmonary aspergillosis were used. The primary PD endpoint was serum galactomannan. The relationships between drug exposure and the impacts of dose fractionation on galactomannan, survival, and histopathology were determined. The results were benchmarked against a clinically relevant exposure of posaconazole. In the murine model, administration of a total daily dose of 24 mg/kg of body weight produced consistently better responses with increasingly fractionated regimens. The ratio of the minimum total plasma concentration/MIC (Cmin/MIC) was the PD index that best linked drug exposure with observed effect. An average Cmin (mg/liter) and Cmin/MIC of 0.3 and 9.1, respectively, resulted in antifungal effects equivalent to the effect of posaconazole at the upper boundary of its expected human exposures. This pattern was confirmed in a rabbit model, where Cmin and Cmin/MIC targets of 0.1 and 3.3, respectively, produced effects previously reported for expected human exposures of isavuconazole. These targets were independent of triazole susceptibility. The pattern of maximal effect evident with these drug exposure targets was also apparent when survival and histopathological clearance were used as study endpoints. F901318 exhibits time-dependent antifungal activity. The PD targets can now be used to select regimens for phase II and III clinical trials.IMPORTANCE Invasive fungal infections are common and often lethal. There are relatively few antifungal agents licensed for clinical use. Antifungal drug toxicity and the emergence of drug resistance make the treatment of these infections very challenging. F901318 is the first in a new class of antifungal agents called the orotomides. This class has a novel mechanism of action that involves the inhibition of the fungal enzyme dihydroorotate dehydrogenase. F901318 is being developed for clinical use. A deep understanding of the relationship between dosages, drug concentrations in the body, and the antifungal effect is fundamental to the identification of the regimens to administer to patients with invasive fungal infections. This study provides the necessary information to ensure that the right dose of F901318 is used the first time. Such an approach considerably reduces the risks in drug development programs and ensures that patients with few therapeutic options can receive potentially life-saving antifungal therapy at the earliest opportunity.

BackgroundRecent multicenter studies identified COVID-19 as a risk factor for invasive pulmonary aspergillosis (IPA). However, no large multicenter study has compared the incidence of IPA between COVID-19 and influenza patients.ObjectivesTo determine the incidence of putative IPA in critically ill SARS-CoV-2 patients, compared with influenza patients.MethodsThis study was a planned ancillary analysis of the coVAPid multicenter retrospective European cohort. Consecutive adult patients requiring invasive mechanical ventilation for > 48 h for SARS-CoV-2 pneumonia or influenza pneumonia were included. The 28-day cumulative incidence of putative IPA, based on Blot definition, was the primary outcome. IPA incidence was estimated using the Kalbfleisch and Prentice method, considering extubation (dead or alive) within 28 days as competing event.ResultsA total of 1047 patients were included (566 in the SARS-CoV-2 group and 481 in the influenza group). The incidence of putative IPA was lower in SARS-CoV-2 pneumonia group (14, 2.5%) than in influenza pneumonia group (29, 6%), adjusted cause-specific hazard ratio (cHR) 3.29 (95% CI 1.53-7.02, p = 0.0006). When putative IPA and Aspergillus respiratory tract colonization were combined, the incidence was also significantly lower in the SARS-CoV-2 group, as compared to influenza group (4.1% vs. 10.2%), adjusted cHR 3.21 (95% CI 1.88-5.46, p ConclusionsOverall, the incidence of putative IPA was low. Its incidence was significantly lower in patients with SARS-CoV-2 pneumonia than in those with influenza pneumonia. Clinical trial registration The study was registered at ClinicalTrials.gov, number NCT04359693 .

ObjectiveTo evaluate the incidence, diagnostic performance, clinical characteristics, and prognostic determinants of invasive pulmonary aspergillosis (IPA) in critically ill patients, using updated EORTC/MSG and FUNDICU criteria.MethodsWe retrospectively analyzed a heterogenous ICU pneumonia cohort between Jan 2022 and Jun 2025. All included patients underwent at least one mycological assessment. IPA was diagnosed based on integrated EORTC/MSG and FUNDICU criteria. Diagnostic accuracy of mycological assays was evaluated, and clinical profiles were compared between IPA and non-IPA patients. Independent risk factors for mortality were identified via multivariate Cox regression.ResultsAmong 1835 patients, the IPA incidence was 7.1% (n=131). Of all mycological assays, bronchoalveolar lavage fluid galactomannan (BALF GM) demonstrated the highest sensitivity (85.5%) with robust specificity (82.9%). Molecular testing combined with BALF GM yielded a sensitivity of 64.4% and a specificity of 80.0%. Serum GM exhibited the lowest sensitivity (41.7%) but the highest specificity (89.2%); its combination with culture or molecular methods further enhanced specificity to >95%. Although patchy infiltrates were the most frequent radiological findings in both groups, consolidation (63.4% vs. 40.3%, P P = 0.014), cavities (17.6% vs 3.9%, P = 0.004), and tree-in-bud signs (9.9% vs. 1.3%, P = 0.019) were significantly more prevalent in IPA patients. IPA patients experienced longer ICU stays (median 20 vs. 16 days) and significantly higher ICU mortality (55.0% vs 26.0%). Multivariable analysis identified IPA (HR: 2.064, 95% CI = 1.211-3.518, P = 0.008) and a prolonged interval from admission to the first positive mycological test (HR: 1.017, 95% CI = 1.004-1.031, P = 0.011) as independent risk factors for death. Conversely, anti-Aspergillus therapy (HR: 0.489, 95% CI = 0.275-0.871, P = 0.015) and tracheostomy (HR: 0.351, 95% CI = 0.222-0.557, P ConclusionIPA is a common and lethal complication in ICU pneumonia patients, serving as an independent predictor of mortality. BALF GM, particularly when integrated with molecular testing, is the most effective mycological diagnostic method. Reducing the diagnostic window, initiating timely antifungal therapy, and proactive airway management (e.g., tracheostomy) may significantly improve clinical outcome for these critically ill patients.