Romuald Bellmann

Purpose This study aimed to compare a high (HBF) and low (LBF) bicarbonate (HCO₃⁻) replacement fluid over 96 h after continuous veno-venous hemofiltration (CVVH) initiation using regional citrate anticoagulation to determine which fluid achieved better acid–base balance. Methods In this prospective, randomized, controlled, open-label, cross-over, single-center trial, patients were randomized to initially receive either LBF (22 mmol/l HCO₃⁻) or HBF (30 mmol/l HCO₃⁻) for 48 h (first phase), followed by changing to the other fluid for a further 48 h (second phase). Intracorporeal pH and HCO₃⁻ changes were analyzed by calculating the rates of levels outside the standard values (excursion rates). Generalized estimating equations were performed to estimate the odds ratios for at least one pH/HCO₃⁻ excursion. Time to normalization within the first phase for pH and HCO₃⁻ was assessed using Kaplan–Meier curves and log-rank tests. Results A total of 88 patients were included. The rates for at least one pH and HCO₃⁻ excursion were higher in patients treated with HBF compared to LBF (pH: first phase 52% vs. 41%; second phase 48% vs. 34%; HCO₃⁻: first phase 68% vs. 43%; second phase 73% vs. 43%). Adjusted odds ratios were 1.78 (95% CI 1.12–2.82; p = 0.015) for pH and 3.60 (95% CI 2.16–5.99; p < 0.001) for HCO₃⁻. The time to normalization of pH in acidotic patients and of HCO₃⁻ in patients with low HCO₃⁻ did not differ significantly between HBF and LBF (p = 0.102, p = 0.468). Conclusion LBF showed significantly lower rates of pH and HCO₃⁻ excursions compared to HBF and no significant differences to the pH normalization in acidotic patients were observed. ClinicalTrials.gov-identifier NCT04071171.

Sepsis causes millions of deaths each year. Rapid, targeted therapy can reduce mortality rates. Both bacterial and viral pathogens can trigger sepsis, but the utility of commonly used inflammatory markers for differentiation remains controversial. Moreover, little is known about the time courses of alternative inflammatory parameters. The aim of this prospective, two-center observational study was to investigate the differences in the course of soluble Neuropilin-1 (sNRP-1) levels between bacterial and viral sepsis over a 7-day period. To be included, adult patients had to meet the SEPSIS-3 criteria and be diagnosed with either a bacterial or viral pathogen. Immunosuppressed patients were excluded. While IL-6, PCT, and CRP levels decreased consistently over time, sNRP-1 levels remained elevated in the bacterial group throughout the entire ICU stay. PCT (p < 0.001) and CRP (p = 0.016) levels were significantly associated with the course of sNRP-1. The AUC of sNRP-1 was 0.777 for discriminating between bacterial and viral infections on day 1. sNRP-1 remained stable and significantly higher in bacterial than in viral infections. Furthermore, the AUC values for discrimination ranged from acceptable to good, depending on the day of the ICU stay. sNRP-1 may serve as a potential tool to differentiate between bacterial and viral pathogens in sepsis.

Zusammenfassung: Bei kritisch Kranken besteht ein hohes Risko für unerwünschte Arzneimittelinteraktionen. Pharmakodynamische Interaktionen können Organtoxizität verstärken. Pharmakokinetische Interaktionen gründen meist auf einer Hemmung oder Induktion von Enzymen des Arzneimittelmetabolismus wie Cytochrom-P-450-Isoenzymen und Transporterproteinen wie P‑Glykoprotein. Inhibitoren dieser Moleküle können so toxische Wirkspiegel der entsprechenden Substrate herbeiführen, Induktoren hingegen subtherapeutische Konzentrationen. Amiodaron, Makrolide, Azol-Antimykotika, direkt wirksame Antikoagulanzien, Vitamin-K-Antagonisten, Immunsuppressiva, Rifampicin und einige ZNS-wirksame Substanzen sind besonders häufig an Interaktionen beteiligt. Eine Überprüfung der Medikation unter strenger Risiko-Nutzen-Abwägung, therapeutisches Drugmonitoring, Verwendung elektronischer Alert-Systeme und Datenbanken zusammen mit klinischer Bewertung können zur Vermeidung unerwünschter Arzneimittelinteraktionen beitragen.

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.

Common variable immunodeficiency (CVID) is the most prevalent primary immunodeficiency. We present a 22‐year‐old Caucasian woman with CVID and granulomatous lymphocytic interstitial lung disease who contracted COVID‐19 and was successfully treated with sotrovimab and molnupiravir. This treatment may have contributed to the relatively mild disease course of COVID‐19 in our patient.

(1) Background: Coronavirus disease 2019 (COVID-19)-associated pulmonary aspergillosis (CAPA) raises concerns to contribute to an increased mortality. The incidence of CAPA varies widely within hospitals and countries, partly because of difficulties in obtaining a reliable diagnosis. (2) Methods: Here, we assessed Aspergillus culture-positive and culture-negative respiratory tract specimens via direct fungal microscopy (gold standard) and compared the results with galactomannan enzyme immunoassay (GM-EIA) and Aspergillus PCR. (3) Results: 241 respiratory samples from patients suffering from SARS-CoV-2 pneumonia were evaluated. Results showed both diagnostic tools, Aspergillus PCR and GM-EIA, to be positive or negative displaying a sensitivity of 0.90, a specificity of 0.77, a negative predictive value (NPV) of 0.95, and a positive predictive value (PPV) of 0.58 in Aspergillus sp. culture and microscopic-positive specimens. Non-bronchoalveolar lavage (BAL) samples, obtained within a few days from the same patient, showed a high frequency of intermittent positive or negative GM-EIA or Aspergillus PCR results. Positivity of a single biomarker is insufficient for a proper diagnosis. A broad spectrum of Aspergillus species was detected. (4) Conclusions: Our study highlights the challenges of combined biomarker testing as part of diagnosing CAPA. From the results presented, we highly recommend the additional performance of direct microscopy in respiratory specimens to avoid overestimation of fungal infections by applying biomarkers.

The epidemiology of invasive Candida infections is evolving. Infections caused by non-albicans Candida spp. are increasing; however, the antifungal pipeline is more promising than ever and is enric...

Background: Concerns have been expressed about the interchangeability of innovator and generic antifungals in their activity and chemical stability. Materials/methods: The activity of two different antimycotics was tested, each with one originator and two generics. For voriconazole, the originator VFEND^® (Pfizer) and the generics (Ratiopharm and Stada) were used for susceptibility testing (21 clinical isolates of Candida albicans (C. albicans); ATCC-90028 C. albicans) in RPMI growth media in compliance with the EUCAST criteria. Likewise, for anidulafungin, the originator ECALTA^® (Pfizer) and the generics (Stada and Pharmore) were used for testing (20 clinical isolates of Candida glabrata (C. glabrata); ATCC-22019 Candida parapsilosis (C. parapsilosis)). Time Kill Curves (TKC) with concentrations above and below the respective MIC were performed for one strain for each antifungal. Stability testing of the antimycotics stored at 4 °C and at room temperature over 24 h was done, and samples were subsequently analyzed with HPLC. Results: MIC results showed no significant difference in activity of generic and innovator antimycotic in all settings, which was also confirmed by TKC. Stability testing revealed no differences between originator and generic drugs. Conclusions: The present study demonstrates the interchangeability of generic and originator antimycotic in-vitro, potentially leading to broader public acceptance for generic antimycotics.

Pharmacokinetics and antifungal activity of the echinocandins anidulafungin (AFG), micafungin (MFG) and caspofungin (CAS) were assessed in ascites fluid and plasma of critically ill adults treated for suspected or proven invasive candidiasis. Ascites fluid was obtained from ascites drains or during paracentesis. The antifungal activity of the echinocandins in ascites fluid was assessed by incubation of Candida (C.) albicans and C. glabrata at concentrations of 0.03 to 16.00 μg/ml. In addition, ascites fluid samples obtained from our study patients were inoculated with the same isolates and evaluated for fungal growth. These patient samples had to be spiked with echinocandins to restore the original concentrations, because echinocandins had been lost during sterile filtration. In ascites fluid specimens of 29 patients, echinocandin concentrations were below the simultaneous plasma levels. Serial sampling in 20 patients revealed a slower rise and decline of echinocandin concentrations in ascites fluid than in plasma. Proliferation of C. albicans in ascites fluid was slower than in culture medium and growth of C. glabrata was lacking, even in the absence of antifungals. In CAS-spiked ascites fluid samples, fungal CFU counts moderately declined, whereas spiking with AFG or MFG, had no relevant effect. In ascites fluid of our study patients, echinocandin concentrations achieved by therapeutic doses did not result in a consistent eradication of C. albicans or C. glabrata. Thus, therapeutic doses of AFG, MFG, or CAS may result in ascites fluid concentrations preventing relevant proliferation of C. albicans and C. glabrata, but do not warrant reliable eradication.