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Given the increasing threat of antimicrobial resistance, scientists are urgently seeking adjunct antimicrobial strategies, such as phage therapy (PT). However, despite promising results for the treatment of musculoskeletal infections in our center, crucial knowledge gaps remain. Therefore, a prospective observational study (PHAGEFORCE) and a multidisciplinary approach was set up to achieve and optimize standardized treatment guidelines. At our center, PT is strictly controlled and monitored by a multidisciplinary taskforce. Each phage treatment follows the same pathway to ensure standardization and data quality. Within the PHAGEFORCE framework, we established a testing platform to gain insight in the safety and efficacy of PT, biodistribution, phage kinetics and the molecular interaction between phages and bacteria. The draining fluid is collected to determine the phage titer and bacterial load. In addition, all bacterial isolates are fully characterized by genome sequencing to monitor the emergence of phage resistance. We hereby present a standardized bench-to-bedside protocol to gain more insight in the kinetics and dynamics of PT for musculoskeletal infections. [ABSTRACT FROM AUTHOR]

Purpose To evaluate aerobic exercise capacity in 5-year intensive care unit (ICU) survivors and to assess the association between severity of organ failure in ICU and exercise capacity up to 5-year follow-up. Methods Secondary analysis of the EPaNIC follow-up cohort (NCT00512122) including 433 patients screened with cardiopulmonary exercise testing (CPET) between 1 and 5 years following ICU admission. Exercise capacity in 5-year ICU survivors (N = 361) was referenced to a historic sedentary population and further compared to demographically matched controls (N = 49). In 5-year ICU survivors performing a maximal CPET (respiratory exchange ratio > 1.05, N = 313), abnormal exercise capacity was defined as peak oxygen consumption (VO.sub.2peak) < 85% of predicted peak oxygen consumption (%predVO.sub.2peak), based on the historic sedentary population. Exercise liming factors were identified. To study the association between severity of organ failure, quantified as the maximal Sequential Organ Failure Assessment score during ICU-stay (SOFA-max), and exercise capacity as assessed with VO.sub.2peak, a linear mixed model was built, adjusting for predefined confounders and including all follow-up CPET studies. Results Exercise capacity was abnormal in 118/313 (37.7%) 5-year survivors versus 1/48 (2.1%) controls with a maximal CPET, p < 0.001. Aerobic exercise capacity was lower in 5-year survivors than in controls (VO.sub.2peak: 24.0 ± 9.7 ml/min/kg versus 31.7 ± 8.4 ml/min/kg, p < 0.001; %predVO.sub.2peak: 94% ± 31% versus 123% ± 25%, p < 0.001). Muscular limitation frequently contributed to impaired exercise capacity at 5-year [71/118 (60.2%)]. SOFA-max independently associated with VO.sub.2peak throughout follow-up. Conclusions Critical illness survivors often display abnormal aerobic exercise capacity, frequently involving muscular limitation. Severity of organ failure throughout the ICU stay independently associates with these impairments., Author(s): Nathalie Van Aerde [sup.1], Philippe Meersseman [sup.2], Yves Debaveye [sup.1] [sup.3], Alexander Wilmer [sup.2], Michael P. Casaer [sup.1] [sup.3], Jan Gunst [sup.1] [sup.3], Joost Wauters [sup.2], Pieter J. Wouters [...]

Purpose Influenza-associated pulmonary aspergillosis (IAPA) is a frequent complication in critically ill influenza patients, associated with significant mortality. We investigated whether antifungal prophylaxis reduces the incidence of IAPA. Methods We compared 7 days of intravenous posaconazole (POS) prophylaxis with no prophylaxis (standard-of-care only, SOC) in a randomised, open-label, proof-of-concept trial in patients admitted to an intensive care unit (ICU) with respiratory failure due to influenza (ClinicalTrials.gov, NCT03378479). Adult patients with PCR-confirmed influenza were block randomised (1:1) within 10 days of symptoms onset and 48 h of ICU admission. The primary endpoint was the incidence of IAPA during ICU stay in patients who did not have IAPA within 48 h of ICU admission (modified intention-to-treat (MITT) population). Results Eighty-eight critically ill influenza patients were randomly allocated to POS or SOC. IAPA occurred in 21 cases (24%), the majority of which (71%, 15/21) were diagnosed within 48 h of ICU admission, excluding them from the MITT population. The incidence of IAPA was not significantly reduced in the POS arm (5.4%, 2/37) compared with SOC (11.1%, 4/36; between-group difference 5.7%; 95% CI - 10.8 to 21.7; p = 0.32). ICU mortality of early IAPA was high (53%), despite rapid antifungal treatment. Conclusion The higher than expected incidence of early IAPA precludes any definite conclusion on POS prophylaxis. High mortality of early IAPA, despite timely antifungal therapy, indicates that alternative management strategies are required. After 48 h, still 11% of patients developed IAPA. As these could benefit from prophylaxis, differentiated strategies are likely needed to manage IAPA in the ICU., Author(s): Lore Vanderbeke [sup.1] [sup.2], Nico A. F. Janssen [sup.3] [sup.4], Dennis C. J. J. Bergmans [sup.5], Marc Bourgeois [sup.6], Jochem B. Buil [sup.4] [sup.7], Yves Debaveye [sup.8] [sup.9], Pieter [...]

Background Posaconazole is used for the prophylaxis and treatment of invasive fungal infections in critically ill patients. Standard dosing was shown to result in adequate attainment of the prophylaxis C min target (0.7 mg/L) but not of the treatment C min target (1.0 mg/L). Objectives To provide an optimized posaconazole dosing regimen for IV treatment of patients with invasive pulmonary aspergillosis in the ICU. Methods A population pharmacokinetics (popPK) model was developed using data from the POSA-FLU PK substudy (NCT03378479). Monte Carlo simulations were performed to assess treatment C min and AUC0–24 PTA. PTA ≥90% was deemed clinically acceptable. PopPK modelling and simulation were performed using NONMEM 7.5. Results Thirty-one patients with intensive PK sampling were included in the PK substudy, contributing 532 posaconazole plasma concentrations. The popPK of IV posaconazole was best described by a two-compartment model with linear elimination. Interindividual variability was estimated on clearance and volume of distribution in central and peripheral compartments. Posaconazole peripheral volume of distribution increased with bodyweight. An optimized loading regimen of 300 mg q12h and 300 mg q8h in the first two treatment days achieved acceptable PTA by Day 3 in patients <100 kg and ≥100 kg, respectively. A maintenance regimen of 400 mg q24h ensured ≥90% C min PTA, whereas the standard 300 mg q24h was sufficient to achieve the AUC0–24 target throughout 14 days, irrespective of bodyweight. Conclusions We have defined a convenient, optimized IV posaconazole dosing regimen that was predicted to attain the treatment target in critically ill patients with invasive aspergillosis. [ABSTRACT FROM AUTHOR]

This document is a letter published in the journal Intensive Care Medicine. The letter discusses the development and validation of prediction models for urinary creatinine clearance (CrCl) in critically ill adults. The models were compared to predictions made by intensive care unit (ICU) physicians. The study found that the CrCl predictors performed well and were comparable to the predictions made by physicians. The authors suggest that these predictors could potentially assist physicians at the bedside, but further research is needed to evaluate their impact on clinical outcomes. [Extracted from the article]

Purpose To assess the independent association between ICU-acquired neuromuscular complications and 5-year mortality and morbidity. To explore the optimal threshold of the Medical Research Council (MRC) sum score, assessing weakness, for the prediction of 5-year outcomes. Methods Sub-analyses of a prospective, 5-year follow-up study including 883 EPaNIC patients (Early versus Late Parenteral Nutrition in Intensive Care) (Clinicaltrials.gov:NCT00512122), systematically screened in ICU for neuromuscular complications with MRC sum score ('MRC-cohort', N = 600), electrophysiology on day 8 ± 1 to quantify compound muscle action potential ('CMAP-cohort', N = 689), or both ('MRC&CMAP-cohort', N = 415). Associations between ICU-acquired neuromuscular complications and 5-year mortality, hand-grip strength (HGF, %predicted), 6-min-walk distance (6-MWD, %predicted) and physical function of the SF-36 quality-of-life questionnaire (PF-SF-36) at 5-years were assessed with Cox regression and linear regression, adjusted for confounders. The optimal threshold for MRC at ICU discharge to predict 5-year outcomes was determined by martingale residual plots (survival) and scatterplots (morbidity). Results Both lower MRC sum score at ICU discharge, indicating less strength [HR, per-point-increase: 0.946 (95% CI 0.928-0.968), p = 0.001], and abnormal CMAP, indicating nerve/muscle dysfunction [HR: 1.568 (95% CI 1.165-2.186), p = 0.004], independently associated with increased 5-year mortality. In the MRC&CMAP-cohort, MRC [HR: 0.956 (95% CI 0.934-0.980), p = 0.001] but not CMAP [HR: 1.478 (95% CI 0.875-2.838), p = 0.088] independently associated with 5-year mortality. Among 205 survivors, low MRC independently associated with low HGF [0.866 (95% CI 0.237-1.527), p = 0.004], low 6-MWD [105.1 (95% CI 12.1-212.9), p = 0.043] and low PF-SF-36 [- 0.119 (95% CI - 0.186 to - 0.057), p = 0.002], whereas abnormal CMAP did not correlate with these morbidity endpoints. Exploratory analyses suggested that MRC [less than or equal to] 55 best predicted poor long-term morbidity and mortality. Both MRC [less than or equal to] 55 and abnormal CMAP independently associated with 5-year mortality. Conclusions ICU-acquired neuromuscular complications may impact 5-year morbidity and mortality. MRC sum score, even if slightly reduced, may affect long-term mortality, strength, functional capacity and physical function, whereas abnormal CMAP only related to long-term mortality., Author(s): Nathalie Van Aerde [sup.1], Philippe Meersseman [sup.2], Yves Debaveye [sup.1] [sup.3], Alexander Wilmer [sup.2], Jan Gunst [sup.1] [sup.3], Michael P. Casaer [sup.1] [sup.3], Frans Bruyninckx [sup.4], Pieter J. Wouters [...]

Purpose Low plasma ACTH in critically ill patients may be explained by shock/inflammation-induced hypothalamus-pituitary damage or by feedback inhibition exerted by elevated plasma free cortisol. One can expect augmented/prolonged ACTH-responses to CRH injection with hypothalamic damage, immediately suppressed responses with pituitary damage, and delayed decreased responses in prolonged critical illness with feedback inhibition. Methods This randomized, double-blind, placebo-controlled crossover cohort study, compared ACTH responses to 100 [micro]g IV CRH and placebo in 3 cohorts of 40 matched patients in the acute (ICU-day 3-6), subacute (ICU-day 7-16) or prolonged phase (ICU-day 17-28) of critical illness, with 20 demographically matched healthy subjects. CRH or placebo was injected in random order on two consecutive days. Blood was sampled repeatedly over 135 min and AUC responses to placebo were subtracted from those to CRH. Results Patients had normal mean ± SEM plasma ACTH concentrations (25.5 ± 1.6 versus 24.8 ± 3.6 pg/ml in healthy subjects, P = 0.54) but elevated free cortisol concentrations (3.11 ± 0.27 versus 0.58 ± 0.05 [micro]g/dl in healthy subjects, P < 0.0001). The order of the CRH/placebo injections did not affect the ACTH responses, hence results were pooled. Patients in the acute phase of illness had normal mean ± SEM ACTH responses (5149 ± 848 pg/mL min versus 4120 ± 688 pg/mL min in healthy subjects; P = 0.77), whereas those in the subacute (2333 ± 387 pg/mL min, P = 0.01) and prolonged phases (2441 ± 685 pg/mL min, P = 0.001) were low, irrespective of sepsis/septic shock or risk of death. Conclusions Suppressed ACTH responses to CRH in the more prolonged phases, but not acute phase, of critical illness are compatible with feedback inhibition exerted by elevated free cortisol, rather than by cellular damage to hypothalamus and/or pituitary., Author(s): Bram Peeters [sup.1], Philippe Meersseman [sup.1] [sup.2], Sarah Vander Perre [sup.1], Pieter J. Wouters [sup.1], Yves Debaveye [sup.1], Lies Langouche [sup.1], Greet Van den Berghe [sup.1] Author Affiliations: (1) [...]

Background Coronavirus disease 2019 (COVID-19)–associated pulmonary aspergillosis (CAPA) is a frequent superinfection in critically ill patients with COVID-19 and is associated with increased mortality rates. The increasing proportion of severely immunocompromised patients with COVID-19 who require mechanical ventilation warrants research into the incidence and impact of CAPA during the vaccination era. Methods We performed a retrospective, monocentric, observational study. We collected data from adult patients with severe COVID-19 requiring mechanical ventilation who were admitted to the intensive care unit (ICU) of University Hospitals Leuven, a tertiary referral center, between 1 March 2020 and 14 November 2022. Probable or proven CAPA was diagnosed according to the 2020 European Confederation for Medical Mycology/International Society for Human and Animal Mycology (ECMM/ISHAM) criteria. Results We included 335 patients. Bronchoalveolar lavage sampling was performed in 300 (90%), and CAPA was diagnosed in 112 (33%). The incidence of CAPA was 62% (50 of 81 patients) in European Organisation for Research and Treatment of Cancer (EORTC)/Mycosis Study Group Education and Research Consortium (MSGERC) host factor–positive patients, compared with 24% (62 of 254) in host factor–negative patients. The incidence of CAPA was significantly higher in the vaccination era, increasing from 24% (57 of 241) in patients admitted to the ICU before October 2021 to 59% (55 of 94) in those admitted since then. Both EORTC/MSGERC host factors and ICU admission in the vaccination era were independently associated with CAPA development. CAPA remained an independent risk factor associated with mortality risk during the vaccination era. Conclusions The presence of EORTC/MSGERC host factors for invasive mold disease is associated with increased CAPA incidence and worse outcome parameters, and it is the main driver for the significantly higher incidence of CAPA in the vaccination era. Our findings warrant investigation of antifungal prophylaxis in critically ill patients with COVID-19. [ABSTRACT FROM AUTHOR]

Purpose For patients suffering from prolonged critical illness, it is unknown whether and when the hypothalamus-pituitary-adrenal axis alterations recover, and to what extent adrenocortical function parameters relate to sepsis/septic shock, to clinical need for glucocorticoid treatment, and to survival. Methods Patients still in ICU on day 7 (N = 392) and 20 matched healthy subjects were included. Morning blood and 24-h urine were collected daily and cosyntropin tests (250 [micro]g) performed weekly, repeated 1 week after ICU discharge on the regular ward. Results In all patients free of glucocorticoid treatment up until ICU day 28 (N = 347), plasma ACTH always remained low/normal, whereas free cortisol remained high (P [less than or equal to] 0.002) explained by reduced binding proteins (P [less than or equal to] 0.02) and suppressed cortisol breakdown (P [less than or equal to] 0.001). Beyond ICU day 28 (N = 64 long-stayers), plasma (free)cortisol was no longer elevated. One week after ICU discharge, plasma ACTH and (free)cortisol always rose to supra-normal levels (P [less than or equal to] 0.006), most pronounced in long-stayers. Long-stayers always showed low incremental total (P [less than or equal to] 0.001), but normal incremental free cortisol responses to weekly cosyntropin tests, explained by low cortisol plasma binding proteins. Sepsis/septic shock patients were not different from others, patients subsequently receiving glucocorticoids (N = 45) were not different from those who did not, and non-survivors were distinguishable from survivors only by higher (free)cortisol. Conclusions Irrespective of sepsis/septic shock, need for glucocorticoids and survival, low cortisol plasma binding proteins and suppressed cortisol breakdown determine systemic (free)cortisol availability in prolonged critical illness, the latter no longer elevated beyond ICU day 28. The uniform rise in ACTH and cortisol to supra-normal levels 1 week after ICU discharge indicates recovery of a central adrenocortical suppression while in ICU. Low cortisol plasma binding invalidates the cosyntropin test., Author(s): Bram Peeters [sup.1], Philippe Meersseman [sup.1] [sup.2], Sarah Vander Perre [sup.1], Pieter J. Wouters [sup.1], Dimitri Vanmarcke [sup.1], Yves Debaveye [sup.1], Jaak Billen [sup.3], Pieter Vermeersch [sup.3], Lies Langouche [...]

Purpose Muscle weakness in long-stay ICU patients contributes to 1-year mortality. Whether electrophysiological screening is an alternative diagnostic tool in unconscious/uncooperative patients remains unknown. We aimed to determine the diagnostic properties of abnormal compound muscle action potential (CMAP), sensory nerve action potential (SNAP), and spontaneous electrical activity (SEA) for Medical Research Council (MRC)-defined weakness and their predictive value for 1-year mortality. Methods Data were prospectively collected during the EPaNIC trial (ClinicalTrials.gov: NCT00512122). First, sensitivity, specificity, positive (PPV) and negative predictive values (NPV) of abnormal CMAP, SNAP, and SEA for weakness were determined. Subsequently, association between 1-year mortality and abnormal findings on electrophysiological screening was assessed by univariate and multivariate analyses correcting for weakness and other risk factors and the prediction model involved only a development phase. Results A total of 730 patients were electrophysiologically screened of whom 432 were tested for weakness. On day 8, normal CMAP excluded weakness with a high NPV (80.5 %). By day 15, abnormal SNAP and the presence of SEA had a high PPV (91.7 and 80.0 %, respectively). Only a reduced CMAP on day 8 was associated with higher 1-year mortality [35.6 vs 15.2 % (p < 0.001)]. This association remained significant after correction for weakness and other risk factors [OR 2.463 (95 % CI 1.113-5.452), p = 0.026]. Also among conscious/cooperative patients without weakness, reduced CMAP was independently associated with a higher likelihood of death occurring during 1 year [HR 2.818 (95 % CI 1.074-7.391), p = 0.035]. Conclusions The diagnostic properties of electrophysiological screening vary over time. Abnormal CMAP documented early during critical illness carries information about longer-term outcome, which should be further investigated mechanistically., Author(s): Greet Hermans [sup.1] [sup.2], Helena Van Mechelen [sup.1], Frans Bruyninckx [sup.3], Tine Vanhullebusch [sup.1], Beatrix Clerckx [sup.4], Philippe Meersseman [sup.2], Yves Debaveye [sup.1] [sup.4], Michael P. Casaer [sup.1] [sup.4], [...]