Clinical and demographic factors affecting trough levels of isavuconazole in critically ill patients with or without COVID-19.

BACKGROUND: The broad-spectrum antifungal isavuconazole is administered to treat invasive aspergillosis and mucormycosis. OBJECTIVES: Isavuconazole plasma concentrations in critically ill ICU patients with or without COVID-19 and invasive fungal infection were determined, and factors for sub-therapeutic drug levels (<1 µg/mL) were evaluated. PATIENTS AND METHODS: Isavuconazole plasma levels were measured as part of therapeutic drug monitoring (TDM) in ICUs of a tertiary hospital. Concentrations determined 20-28 h after previous dosing were defined as trough (Cmin ) levels. A total of 160 Cmin levels from 62 patients with invasive fungal infections were analysed, 30 of which suffering from COVID-19. Patient characteristics included into univariable and multivariable analyses were gender, age, COVID-19 status, body mass index (BMI), sepsis-related organ failure (SOFA) score, renal replacement therapy (RRT) and extracorporeal membrane oxygenation (ECMO) requirement. RESULTS: The mean Cmin of isavuconazole in all patients was 1.64 µg/mL (interquartile range 0.83-2.24 µg/mL, total range 0.24-5.67 µg/mL). In total, 34.4% of the Cmin values (corresponding to 46.8% of patients) were below a threshold concentration of 1 µg/mL. Drug concentrations between patients with or without COVID-19 did not differ (p = .43). In contrast, levels were significantly lower in patients with female sex (p = .0007), age ≤ 65 years (p = .002), BMI > 25 (p = .006), SOFA score > 12 (p = .026), RRT (p = .017) and ECMO requirement (p = .001). CONCLUSIONS: Isavuconazole plasma levels can be negatively affected by patients' risk factors, supportive renal replacement and ECMO therapy. Future prospective studies analysing the relevance of isavuconazole drug levels in ICU patient outcome are urgently needed.

[Acute Kidney Injury]. / Nierenversagen.

"Acute kidney injury" (AKI) describes any acute deterioration in kidney function but also only injury to the kidneys without a severe loss of function. It is a common and severe complication in patients on the intensive care unit with a significant impact on patient's mortality and morbidity. Since no specific pharmacological therapy exists, the early identification of patients at risk for AKI or with acute kidney damage is most important before renal function further deteriorates. A stage-based management of AKI comprises more general measures like discontinuation of nephrotoxic agent but most importantly early hemodynamic stabilization. Recent research has contradicted that AKI is renal ischemia caused by vasoconstriction with consecutive tubular necrosis. In septic AKI renal blood flow is even increased. Intrarenal vasodilation together with microcirculatory changes and redistribution of blood flow are leading to a drop in glomerular filtration by functional changes. Accordingly, it had to be learned that not vasodilators, but vasoconstrictors are beneficial in AKI. A mean arterial blood pressure target of > 65 mmHg is often recommended but exact targets are not known and patients with preexisting hypertension do even need a higher perfusion pressure. Also, the concept that fluid therapy is always beneficial for the kidney in shock states had to be revised. A volume restrictive therapy with balanced, chloride restricted crystalloids only, is important also in AKI. Exposure to contrast material is often associated with AKI but less common the direct cause of AKI, so if indicated, contrast material should not be withheld in patients at risk for AKI.

Low-flow CO2 removal in combination with renal replacement therapy effectively reduces ventilation requirements in hypercapnic patients: a pilot study.

BACKGROUND: Lung-protective strategies are the cornerstone of mechanical ventilation in critically ill patients with both ARDS and other disorders. Extracorporeal CO2 removal (ECCO2R) may enhance lung protection by allowing even further reductions in tidal volumes and is effective in low-flow settings commonly used for renal replacement therapy. In this study, we describe for the first time the effects of a labeled and certified system combining ECCO2R and renal replacement therapy on pulmonary stress and strain in hypercapnic patients with renal failure. METHODS: Twenty patients were treated with the combined system which incorporates a membrane lung (0.32 m2) in a conventional renal replacement circuit. After changes in blood gases under ECCO2R were recorded, baseline hypercapnia was reestablished and the impact on ventilation parameters such as tidal volume and driving pressure was recorded. RESULTS: The system delivered ECCO2R at rate of 43.4 ± 14.1 ml/min, PaCO2 decreased from 68.3 ± 11.8 to 61.8 ± 11.5 mmHg (p < 0.05) and pH increased from 7.18 ± 0.09 to 7.22 ± 0.08 (p < 0.05). There was a significant reduction in ventilation requirements with a decrease in tidal volume from 6.2 ± 0.9 to 5.4 ± 1.1 ml/kg PBW (p < 0.05) corresponding to a decrease in plateau pressure from 30.6 ± 4.6 to 27.7 ± 4.1 cmH2O (p < 0.05) and a decrease in driving pressure from 18.3 ± 4.3 to 15.6 ± 3.9 cmH2O (p < 0.05), indicating reduced pulmonary stress and strain. No complications related to the procedure were observed. CONCLUSIONS: The investigated low-flow ECCO2R and renal replacement system can ameliorate respiratory acidosis and decrease ventilation requirements in hypercapnic patients with concomitant renal failure. Trial registration NCT02590575, registered 10/23/2015.

Glycoprotein N of human cytomegalovirus protects the virus from neutralizing antibodies.

Herpes viruses persist in the infected host and are transmitted between hosts in the presence of a fully functional humoral immune response, suggesting that they can evade neutralization by antiviral antibodies. Human cytomegalovirus (HCMV) encodes a number of polymorphic highly glycosylated virion glycoproteins (g), including the essential envelope glycoprotein, gN. We have tested the hypothesis that glycosylation of gN contributes to resistance of the virus to neutralizing antibodies. Recombinant viruses carrying deletions in serine/threonine rich sequences within the glycosylated surface domain of gN were constructed in the genetic background of HCMV strain AD169. The deletions had no influence on the formation of the gM/gN complex and in vitro replication of the respective viruses compared to the parent virus. The gN-truncated viruses were significantly more susceptible to neutralization by a gN-specific monoclonal antibody and in addition by a number of gB- and gH-specific monoclonal antibodies. Sera from individuals previously infected with HCMV also more efficiently neutralized gN-truncated viruses. Immunization of mice with viruses that expressed the truncated forms of gN resulted in significantly higher serum neutralizing antibody titers against the homologous strain that was accompanied by increased antibody titers against known neutralizing epitopes on gB and gH. Importantly, neutralization activity of sera from animals immunized with gN-truncated virus did not exhibit enhanced neutralizing activity against the parental wild type virus carrying the fully glycosylated wild type gN. Our results indicate that the extensive glycosylation of gN could represent a potentially important mechanism by which HCMV neutralization by a number of different antibody reactivities can be inhibited.

Down-regulation of the homeodomain factor Cdx2 in colorectal cancer by collagen type I: an active role for the tumor environment in malignant tumor progression.

The homeobox transcription factor Cdx2 specifies intestinal development and homeostasis and is considered a tumor suppressor in colorectal carcinogenesis. However, Cdx2 mutations are rarely found. Invasion of colorectal cancer is characterized by a transient loss of differentiation and nuclear accumulation of the oncoprotein beta-catenin in budding tumor cells. Strikingly, this is reversed in growing metastases, indicating that tumor progression is a dynamic process that is not only driven by genetic alterations but also regulated by the tumor environment. Here we describe a transient loss of Cdx2 in budding tumor cells at the tumor host interface, and reexpression of Cdx2 in metastases. Cell culture experiments show that collagen type I, through beta(1) integrin signaling, triggers a transient transcriptional down-regulation of Cdx2 and its intestine-specific target gene sucrase isomaltase, associated with a loss of differentiation. These data indicate an active role for the tumor environment in malignant tumor progression.