Simple and accurate quantitative analysis of cefiderocol and ceftobiprole in human plasma using liquid chromatography-isotope dilution tandem mass spectrometry: interest for their therapeutic drug monitoring and pharmacokinetic studies

International audienceObjectives Cefiderocol and ceftobiprole are new generation cephalosporin antibiotics that exhibit high inter-individual plasma concentration variability that potentially impact their efficacy or toxicity. The aim of this study was to develop and validate a selective, simple, and fast UPLC-MS/MS method for simultaneous quantification of cefiderocol and ceftobiprole in human plasma to enable their therapeutic drug monitoring (TDM) and support PK and PK/PD studies, in particular in critically ill patients. Methods After a simple and fast single-step protein precipitation, cefiderocol and ceftobiprole were separated on a Waters Acquity UPLC BEH C18 column by linear gradient elution; with subsequent detection by Shimadzu MS 8060 triple quadrupole tandem mass spectrometer in a positive ionization mode. Results Analysis time was 5 min per run. The analytical performance of the method in terms of specificity, sensitivity, linearity, precision, accuracy, matrix effect (ME), extraction recovery (ER), limit of quantification, dilution integrity, and stability of analytes under different conditions met all criteria for a bioanalytical method for the quantification of drugs. The calibration curves were linear over the range of 1–200 mg/L for cefiderocol and 0.5–100 mg/L for ceftobiprole with a linear regression coefficient above 0.995 for both. Conclusions A simple, fast, and selective liquid chroma-tography-tandem mass spectrometry method was developed and validated for the simultaneous quantification of cefiderocol and ceftobiprole. This new method was successfully applied to the measurement of plasma concentration of cefiderocol and ceftobiprole in critically ill patients and showed good performance for their therapeutic monitoring and optimizing antibiotic therapy

A multicentric prospective observational study of diagnosis and prognosis features in ICU mesenteric ischemia: the DIAGOMI study

International audienceBackground: Non-occlusive mesenteric ischemia (NOMI) is a challenging diagnosis and is associated with extremely high mortality in critically ill patients, particularly due to delayed diagnosis and when complicated by intestinal necrosis. Plasma citrulline and intestinal-fatty acid binding protein (I-FABP) have been proposed as potential biomarkers, but have never been studied prospectively in this setting. We aimed to investigate diagnostic features, the accuracy of plasma citrulline and I-FABP to diagnose NOMI and intestinal necrosis as well as prognosis. Methods: We conducted a prospective observational study in 3 tertiary ICU centers in consecutive patients with NOMI suspicion defined by at least two inclusion criteria among: new-onset or worsening circulatory failure, gastrointestinal dysfunction, biological signs and CT-scan signs of mesenteric ischemia. Diagnosis features and outcomes were compared according to NOMI, intestinal necrosis or ruled out diagnosis using stringent classification criteria. Results: Diagnosis of NOMI was suspected in 61 patients and confirmed for 33 patients, with intestinal necrosis occurring in 27 patients. Clinical digestive signs, routine laboratory results and CT signs of mesenteric ischemia did not discriminate intestinal necrosis from ischemia without necrosis. Plasma I-FABP was significantly increased in presence of intestinal necrosis (AUC 0.83 [0.70–0.96]). A threshold of 3114 pg/mL showed a sensitivity of 70% [50–86], specificity of 85% [55–98], a negative predictive value of 58% [36–93] and a positive predictive value 90% [67–96] for intestinal necrosis diagnosis. When intestinal necrosis was present, surgical resection was significantly associated with ICU survival (38.5%), whereas no patient survived without necrosis resection (HR = 0.31 [0.12–0.75], p = 0.01). Conclusion: In critically ill patients with NOMI, intestinal necrosis was associated with extremely high mortality, and increased survival when necrosis resection was performed. Elevated plasma I-FABP was associated with the diagnosis of intestinal necrosis. Further studies are needed to investigate plasma I-FABP and citrulline performance in less severe forms of NOMI

FX06 to rescue SARS-CoV-2-induced acute respiratory distress syndrome: a randomized clinical trial

International audienceBackground: Vascular leakage is a major feature of acute respiratory distress syndrome (ARDS). We aimed to evaluate the efficacy of FX06, a drug under development that stabilizes interendothelial cell junctions, at reducing vascular leakage during SARS-CoV-2-induced ARDS. Methods: This multicenter, double-blinded, randomized trial included adults with COVID-19-associated ARDS who had received invasive mechanical ventilation for < 5 days and were randomized to receive either intravenous FX06 (400 mg/d, for 5 days) or its vehicle as placebo. The primary endpoint was the lowering—from day 1 to day 7—of the transpulmonary thermodilution-derived extravascular lung-water index (EVLWi). Results: Twenty-five patients were randomized to receive FX06 and 24 the placebo. Although EVLWi was elevated at baseline (median [IQR] 15.6 mL/kg [13.5; 18.5]), its declines from day 1 to day 7 were comparable for FX06 recipients and controls (respectively, − 1.9 [− 3.3; − 0.5] vs. − 0.8 [− 5.5; − 1.1] mL/kg; estimated effect − 0.8 [− 3.1; + 2.4], p = 0.51). Cardiac indexes, pulmonary vascular permeability indexes, and fluid balances were also comparable, as were PaO2/FiO2 ratios and durations of mechanical ventilation. Adverse event rates were similar for the 2 groups, although more FX06 recipients developed ventilator-associated pneumonia (16/25 (64%) vs. 6/24 (24%), p = 0.009). Conclusions: In this unique-dosing–regimen study, FX06 did not lower SARS-CoV-2-induced pulmonary vascular leakage. Future investigations will need to evaluate its efficacy at earlier times during the disease or using other regimens. Trial registration NCT04618042. Registered 5 November 2020

Awake venoarterial extracorporeal membrane oxygenation for refractory cardiogenic shock

International audienceAbstract Background Venoarterial-extracorporeal membrane oxygenation (VA-ECMO) is currently one of the first-line therapies for refractory cardiogenic shock (CS), but its applicability is undermined by the high morbidity associated with its complications, especially those related to mechanical ventilation (MV). We aimed to assess the prognostic impact of keeping patients in refractory CS awake at cannulation and during the VA-ECMO run. Methods A 7-year database of patients given peripheral VA-ECMO support was used to conduct a propensity-score (PS)-matched analysis to balance their clinical profiles. Patients were classified as ‘awake ECMO’ or ‘non-awake ECMO’, respectively, if invasive MV was used during ≤50% or &gt;50% of the VA-ECMO run. Primary outcomes included ventilator-associated pneumonia and ECMO-related complication rates, and secondary outcomes were 60-day and 1-year mortality. A multivariate logistic-regression analysis was used to identify whether MV at cannulation was independently associated with 60-day mortality. Results Among 231 patients included, 91 (39%) were ‘awake’ and 140 (61%) ‘non-awake’. After PS-matching adjustment, the ‘awake ECMO’ group had significantly lower rates of pneumonia (35% vs. 59%, P = 0.017), tracheostomy, renal replacement therapy, and less antibiotic and sedative consumption. This strategy was also associated with reduced 60-day (20% vs. 41%, P = 0.018) and 1-year mortality rates (31% vs. 54%, P = 0.021) compared to the ‘non-awake’ group, respectively. Lastly, MV at ECMO cannulation was independently associated with 60-day mortality. Conclusion An ‘awake ECMO’ management in VA-ECMO-supported CS patients is feasible, safe, and associated with improved short- and long-term outcomes

Early functional connectome integrity and 1-year recovery in comatose survivors of cardiac arrest

Purpose: To assess whether early brain functional connectivity is associated with functional recovery 1 year after cardiac arrest (CA). Materials and Methods: Enrolled in this prospective multicenter cohort were 46 patients who were comatose after CA. Principal outcome was cerebral performance category at 12 months, with favorable outcome (FO) defined as cerebral performance category 1 or 2. All participants underwent multiparametric structural and functional magnetic resonance (MR) imaging less than 4 weeks after CA. Within-and betweennetwork connectivity was measured in dorsal attention network (DAN), default-mode network (DMN), salience network (SN), and executive control network (ECN) by using seed-based analysis of resting-state functional MR imaging data. Structural changes identified with fluidattenuated inversion recovery and diffusion-weighted imaging sequences were analyzed by using validated morphologic scales. The association between connectivity measures, structural changes, and the principal outcome was explored with multivariable modeling. Results: Patients underwent MR imaging a mean 12.6 days ± 5.6 (standard deviation) after CA. At 12 months, 11 patients had an FO. Patients with FO had higher within-DMN connectivity and greater anticorrelation between SN and DMN and between SN and ECN compared with patients with unfavorable outcome, an effect that was maintained after multivariable adjustment. Anticorrelation of SNDMN predicted outcomes with higher accuracy than fluid-Attenuated inversion recovery or diffusion-weighted imaging scores (area under the receiver operating characteristic curves, respectively, 0.88, 0.74, and 0.71). Conclusion: MR imaging-based measures of cerebral functional network connectivity obtained in the acute phase of CA were independently associated with FO at 1 year, warranting validation as early markers of long-Term recovery potential in patients with anoxic-ischemic encephalopathy

SARS-CoV-2 variants and mutational patterns: relationship with risk of ventilator-associated pneumonia in critically ill COVID-19 patients in the era of dexamethasone

International audienceWe aimed to explore the relationships between specific viral mutations/mutational patterns and ventilator-associated pneumonia (VAP) occurrence in COVID-19 patients admitted in intensive care units between October 1, 2020, and May 30, 2021. Full-length SARS-CoV-2 genomes were sequenced by means of next-generation sequencing. In this prospective multicentre cohort study, 259 patients were included. 222 patients (47%) had been infected with pre-existing ancestral variants, 116 (45%) with variant α, and 21 (8%) with other variants. 153 patients (59%) developed at least one VAP. There was no significant relationship between VAP occurrence and a specific SARS CoV-2 lineage/sublineage or mutational pattern

Remdesivir for Patients Hospitalized with COVID-19 Severe Pneumonia: A National Cohort Study (Remdeco-19)

International audienceBackground. Given the rapidly evolving pandemic of COVID-19 in 2020, authorities focused on the repurposing of available drugs to develop timely and cost-effective therapeutic strategies. Evidence suggested the potential utility of remdesivir in the framework of an early access program. REMDECO-19 is a multicenter national cohort study assessing the ability of remdesivir to improve the outcome of patients hospitalized with COVID-19. Methods. We conducted a retrospective real-life study that included all patients from the early access program of remdesivir in France. The primary endpoint was the clinical course evolution of critically ill and hospitalized COVID-19 patients treated with remdesivir. Secondary endpoints were the SOFA score evolution within 29 days following the admission and mortality at 29 and 90 days. Results. Eighty-five patients were enrolled in 22 sites from January to April 2020. The median WHO and SOFA scores were respectively reduced by two and six points between days 1 and 29. Improvement in the WHO-CPS and the SOFA score were observed in 83.5% and 79.3% of patients, respectively, from day 10. However, there was no effect of remdesivir on the 90-day survival based on the control cohort for hospitalized COVID-19 patients with invasive ventilation. Conclusions. SOFA score appeared to be an attractive approach to assess remdesivir efficacy and stratify its utilization or not in critically ill patients with COVID-19. This study brings a new clinical benchmark for therapeutic decision making and supports the use of remdesivir for some hospitalized COVID-19 patients

SARS-CoV-2 Genomic Characteristics and Clinical Impact of SARS-CoV-2 Viral Diversity in Critically Ill COVID-19 Patients: A Prospective Multicenter Cohort Study

International audienceThe SARS-CoV-2 variant of concern, α, spread worldwide at the beginning of 2021. It was suggested that this variant was associated with a higher risk of mortality than other variants. We aimed to characterize the genetic diversity of SARS-CoV-2 variants isolated from patients with severe COVID-19 and unravel the relationships between specific viral mutations/mutational patterns and clinical outcomes. This is a prospective multicenter observational cohort study. Patients aged ≥18 years admitted to 11 intensive care units (ICUs) in hospitals in the Greater Paris area for SARS-CoV-2 infection and acute respiratory failure between 1 October 2020 and 30 May 2021 were included. The primary clinical endpoint was day-28 mortality. Full-length SARS-CoV-2 genomes were sequenced by means of next-generation sequencing (Illumina COVIDSeq). In total, 413 patients were included, 183 (44.3%) were infected with pre-existing variants, 197 (47.7%) were infected with variant α, and 33 (8.0%) were infected with other variants. The patients infected with pre-existing variants were significantly older (64.9 ± 11.9 vs. 60.5 ± 11.8 years; p = 0.0005) and had more frequent COPD (11.5% vs. 4.1%; p = 0.009) and higher SOFA scores (4 [3-8] vs. 3 [2-4]; 0.0002). The day-28 mortality was no different between the patients infected with pre-existing, α, or other variants (31.1% vs. 26.2% vs. 30.3%; p = 0.550). There was no association between day-28 mortality and specific variants or the presence of specific mutations. At ICU admission, the patients infected with pre-existing variants had a different clinical presentation from those infected with variant α, but mortality did not differ between these groups. There was no association between specific variants or SARS-CoV-2 genome mutational pattern and day-28 mortali

Clinical phenotypes and outcomes associated with SARS-CoV-2 Omicron variants BA.2, BA.5 and BQ.1.1 in critically ill patients with COVID-19: a prospective, multicenter cohort study

International audienceBackground: Despite current broad natural and vaccine-induced protection, a substantial number of patients infected with emerging SARS-CoV-2 variants (e.g., BF.7 and BQ.1.1) still experience severe COVID-19. Real-life studies investigating the impact of these variants on clinical outcomes of severe cases are currently not available. We performed a prospective multicenter observational cohort study. Adult patients with acute respiratory failure admitted between December 7, 2021 and December 15, 2022, in one of the 20 participating intensive care units (17 from the Greater Paris area and 3 from the North of France) were eligible for inclusion if they had SARS-CoV-2 infection confirmed by a positive reverse transcriptase-polymerase chain reaction (RT-PCR). Full-length SARS-CoV-2 genomes from all included patients were sequenced by means of next-generation sequencing. The primary endpoint of the study was day-28 mortality. Results: The study included 158 patients infected with three groups of Omicron sublineages, including (i) BA.2 variants and their early sublineages referred as “BA.2” (n = 50), (ii) early BA.4 and BA.5 sublineages (including BA.5.1 and BA.5.2, n = 61) referred as “BA.4/BA.5”, and (iii) recent emerging BA.5 sublineages (including BQ.1, BQ.1.1, BF.7, BE.1 and CE.1, n = 47) referred as “BQ.1.1”. The clinical phenotype of BQ1.1-infected patients compared to earlier BA.2 and BA.4/BA.5 sublineages, showed more frequent obesity and less frequent immunosuppression. There was no significant difference between Omicron sublineage groups regarding the severity of the disease at ICU admission, need for organ failure support during ICU stay, nor day 28 mortality (21.7%, n = 10/47 in BQ.1.1 group vs 26.7%, n = 16/61 in BA.4/BA.5 vs 22.0%, n = 11/50 in BA.2, p = 0.791). No significant relationship was found between any SARS-CoV-2 substitution and/or deletion on the one hand and survival on the other hand over hospital follow-up. Conclusions: Critically-ill patients with Omicron BQ.1.1 infection showed a different clinical phenotype than other patients infected with earlier Omicron sublineage but no day-28 mortality difference

Characteristics, management, and prognosis of elderly patients with COVID-19 admitted in the ICU during the first wave: insights from the COVID-ICU study

International audienceBackground: The COVID-19 pandemic is a heavy burden in terms of health care resources. Future decision-making policies require consistent data on the management and prognosis of the older patients (&gt; 70 years old) with COVID-19 admitted in the intensive care unit (ICU). Methods: Characteristics, management, and prognosis of critically ill old patients (&gt; 70 years) were extracted from the international prospective COVID-ICU database. A propensity score weighted-comparison evaluated the impact of intubation upon admission on Day-90 mortality. Results: The analysis included 1199 (28% of the COVID-ICU cohort) patients (median [interquartile] age 74 [72–78] years). Fifty-three percent, 31%, and 16% were 70–74, 75–79, and over 80 years old, respectively. The most frequent comorbidities were chronic hypertension (62%), diabetes (30%), and chronic respiratory disease (25%). Median Clinical Frailty Scale was 3 (2–3). Upon admission, the PaO2/FiO2 ratio was 154 (105–222). 740 (62%) patients were intubated on Day-1 and eventually 938 (78%) during their ICU stay. Overall Day-90 mortality was 46% and reached 67% among the 193 patients over 80 years old. Mortality was higher in older patients, diabetics, and those with a lower PaO2/FiO2 ratio upon admission, cardiovascular dysfunction, and a shorter time between first symptoms and ICU admission. In propensity analysis, early intubation at ICU admission was associated with a significantly higher Day-90 mortality (42% vs 28%; hazard ratio 1.68; 95% CI 1.24–2.27; p &lt; 0·001). Conclusion: Patients over 70 years old represented more than a quarter of the COVID-19 population admitted in the participating ICUs during the first wave. Day-90 mortality was 46%, with dismal outcomes reported for patients older than 80 years or those intubated upon ICU admission